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Acute lymphoblastic leukaemia (ALL)

1. GENERAL INFORMATION

1.1 Incidence

Acute lymphoblastic leukaemia (ALL) is uncommon in adults. About 10,000 new cases are diagnosed in adults in Europe each year. In adults, ALL represents about 15% of leukaemias: the chronic form is five times more common. ALL is more common in men than women, with a sex ratio of about 1.4. The annual incidence rates in Europe were 1.3 per 100,000 in men and 0.9 in women. In adults aged more 15 and over, half the cases is under age 50, and ALL is rare over the age of 70. ALL is the most common malignancies in children, accounting for 30% of all cancers and 80% of all leukaemias. About 300 new case are diagnosed each year. ALL is slightly more common in boys than girls. In Europe the year incidence rates were between 2 and 4 per 100,000, broadly similar to the rates in other developed continents. Peak incidence occurs in boys aged 4 and girls aged 2; almost two-thirds of the cases occur in children aged 2 to 6 years. The trend in overall incidence of leukaemia have generally been stable or slowly increasing. However, a substantial reduction in death rates from ALL, particularly in childhood, have been observed since the 1970s, thanks to advances in treatment and consequent improvement in survival (Ferlay 1999; Ferlay 2001; Stewart 2003; Parkin 2002).

1.2 Survival

1.2.1

In Europe, during the period 1990-94, relative survival rates at 5 years after diagnosis for adult patients with ALL was 24% (25% in men and 23% in women). Five-year relative survival decreased markedly with age from 37% to 3% from the youngest (15-45 years) to the oldest age group of patients (75 years and over). In Europe a good overall progress in prognosis was seen especially for men. Unlike adult cancer survival, childhood cancer survival rates are better. Survival for children diagnosed with ALL in Europe, between 1990-1994, was 93% at one year and 79% at five-years (Carli 1998; Berrino 2003).

1.3 Prevalence

Prevalence of ALL, that is the number of people living with a diagnosis of ALL, is known for all leukaemias. In Europe, the proportion of prevalent people was 38 per 100,000. The 5 years prevalence, that is the number of living people with a diagnosis of leukaemia made 5 or less years before the index date, was 20 per 100,000. The last figure provides indications regarding the need for clinical follow-up and treatment for recurrences (Micheli 2002).

1.4 Risk factors

Little is known about the causes of the risk factors for childhood ALL, except of prenatal exposure to x-rays and specific syndromes. Sex, age, race and socioeconomic status are a group of known risk factors. Overall, boys have a 30% higher incidence compared to girls. There is a peak in the incidence between the ages of about 2 and 5. In the US, there is an approximate 2-fold higher risk in white children compared to black children. Higher socioeconomic status (SES) increases the risk for ALL diagnosed at ages 2-5 years. It unknown what aspect of higher SES is relevant but higher age of exposure to infectious agents has been hypothesised. In past studies, there was consistent, increased risk of about 1.5 fold for diagnostic x-ray exposure in uteri. This should be not the case of nowadays due to the fewer x-ray, increased shielding, and lower radiation levels. Therapeutic radiation for tinea capitis and thymus enlargement has been associated with an increased risk. The risk of ALL after exposure to radiation in the Chernobyl accident was significantly increased in subjects who were exposed to >10 mSv. Genetic condition such as Down syndrome, neurofibromatosis, Shwachman syndrome, Bloom syndrome, ataxia telangiectasia, Langerans cell histiocytosis, Klinefelter syndrome and Down syndrome are associated with the increased occurrence of ALL. Particularly, Down syndrome for whom there is a reported 20-fold increased risk. Some studies have shown a risk with exposure to high level residential extremely low frequency electromagnetic fields (Noshchenko 2002;Smith 1999; Little 1999). Many occupations and some specific chemicals encountered at work are associated with increased risk of ALL. Between the 25 chemicals established as human carcinogen (IARC group 1), benzene and ethylene oxide are associated with leukaemia. Among the other group of chemicals classified as probably carcinogenic to humans (IARC Group 2A), there are 1,3 butadiene, polychlorinated biphenyls in association with leukaemia. Then some industries and occupation are classified as carcinogens to human: boot and shoe manufacture and repair and rubber industry (certain occupation) (IARC group1) and occupational exposure in petroleum refining (IARC Group 2A) (Stewart 2003).

1.5 Referral

Because of the difficulty and complexity of the initial diagnostic and prognostic assessment, the choice of risk- and age-adapted treatment protocols, management of disease and treatment of complications, and the need for an accurate and prolonged follow-up, it is strongly recommended on a type C basis that adult ALL patients are always referred to qualified Oncology/Hematology centers.

1.6 Selected reviews

on aetiology
Greaves MF. Aetiology of acute leukaemia. Lancet 1997; 349: 344-349.

on a general overview of current and innovative therapeutics

Appelbaum FR. Allogeneic hematopoietic stem cell transplantation for acute leukemia. Semin Oncol 1997; 24: 114-123.

Bassan R. Randomized clinical trials in adult acute lymphoblastic leukemia: which is the question? Haematologica 1998; 83: 193-196.

Berman E. Recent advances in the treatment of acute leukemia. Curr Opin Hematol 1997; 4: 256-260.

Buchner T. Treatment of adult acute leukemia. Curr Opin Oncol 1997; 9: 18-25.

Clarkson B, Ellis S, Little C, Gee T, Arlin Z, Mertelsmann R, et al. Acute lymphoblastic leukemia in adults. Semin Oncol 1985; 12: 160-179.

Cortes JE, Kantarjian H, Freireich EJ. Acute lymphocytic leukemia: a comprehensive review with emphasis on biology and therapy. Cancer Treat Res 1996; 84:291-323.: 291-323.

Cripe LD. Adult acute leukemia. Curr Probl Cancer 1997; 21: 1-64.

Hoelzer D, Gokbuget N. New approaches to acute lymphoblastic leukemia in adults: where do we go? Semin Oncol 2000 Oct; 27 (5 ):540 -59 2000; 27: 540-559.

Hoelzer D. Treatment of acute lymphoblastic leukemia. Semin Hematol 1994b; 31: 1-15.

Kantarjian HM. Adult acute lymphocytic leukemia. Future research directions. Hematol Oncol Clin North Am 2001; 15: 207-11, viii.

Laport GF, Larson RA. Treatment of adult acute lymphoblastic leukemia. Semin Oncol 1997; 24: 70-82.
O’Connor OA, Weiss M. Recent advances in the biology and management of acute lymphoblastic leukemia in adults. Cancer Treat Res 1999; 99:307-33.: 307-333.

Ottmann OG, Hoelzer D. The ABL tyrosine kinase inhibitor STI571 (Glivec) in Philadelphia positive acute lymphoblastic leukemia – promises, pitfalls and possibilities. Hematol J 2002; 3: 2-6.

Webb IJ, Anderson KC. Transfusion support in acute leukemias. Semin Oncol 1997; 24: 141-146.

on diagnosis, classification and biological aspects
Faderl S, Kantarjian HM, Talpaz M, Estrov Z. Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 1998; 91: 3995-4019.

Faderl S, Albitar M. Insights into the biologic and molecular abnormalities in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am 2000 Dec ;14 (6 ):1267 -88 2000; 14: 1267-1288.

Huh YO, Ibrahim S. Immunophenotypes in adult acute lymphocytic leukemia. Role of flow cytometry in diagnosis and monitoring of disease. Hematol Oncol Clin North Am 2000; 14: 1251-1265.

Lai R, C.F., Bueso-Ramos C. Pathologic diagnosis of acute lymphocytic leukemia. Hematol Oncol Clin North Am 2000; 14: 1209-1235.

Wetzler M. Cytogenetics in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am 2000; 14: 1237-1249.

on ALL in the elderly
Annino L, Goekbuget N, Delannoy A. Acute lymphoblastic leukemia in the elderly. Hematol J 2002; 3: 219-223.

Extermann M. Acute leukemia in the elderly. Clin Geriatr Med 1997; 13: 227-244.

on age as a prognostic factor
Perentesis JP. Why is age such an important independent prognostic factor in acute lymphoblastic leukemia? Leukemia 1997; 11 Suppl 4:S4-7.: S4-S7.

on high dose treatments with stem cell transplantation
Barrett AJ. Bone marrow transplantation for acute lymphoblastic leukaemia. Baillieres Clin Haematol 1994; 7: 377-401.

Carella AM, Marmont AM. Autologous bone marrow transplantation in acute lymphoblastic leukaemia. Baillieres Clin Haematol 1994; 7: 403-419.

Finiewicz KJ, Larson RA. Dose-intensive therapy for adult acute lymphoblastic leukemia. Semin Oncol 1999; 26: 6-20.

Forman SJ. The role of allogeneic bone marrow transplantation in the treatment of high-risk acute lymphocytic leukemia in adults. Leukemia 1997; 11 Suppl 4:S18-9.: S18-S19.

Martin TG, Gajewski JL. Allogeneic stem cell transplantation for acute lymphocytic leukemia in adults. Hematol Oncol Clin North Am 2001a; 15: 97-120.

Martin TG, Linker CA. Autologous stem cell transplantation for acute lymphocytic leukemia in adults. Hematol Oncol Clin North Am 2001b; 15: 121-143.

Weisdorf DJ. Bone marrow transplantation for acute lymphocytic leukemia (ALL). Leukemia 1997; 11 Suppl 4:S20-2.: S20-S22.

on prognostic factors and risk-adapted individualized strategic approach
Bassan R, Lerede T, Barbui T. Institutional performance and dose intensity as prognostic factors in adult ALL. Leukemia 1995a; 9: 933-934.

Bassan R. Randomized clinical trials in adult acute lymphoblastic leukemia: which is the question? Haematologica 1998; 83: 193-196.

Chessells JM. Risk analysis in acute lymphoblastic leukaemia: problems and pitfalls. Eur J Cancer 1995; 31A: 1656-1659.

Linker CA. Risk-adapted treatment of adult acute lymphoblastic leukemia (ALL). Leukemia 1997; 11 Suppl 4:S24-7.: S24-S27.

Verma A, Stock W. Management of adult acute lymphoblastic leukemia: moving toward a risk-adapted approach. Curr Opin Oncol 2001; 13: 14-20.

Westbrook CA. Molecular subsets and prognostic factors in acute lymphoblastic leukemia. Leukemia 1997; 11 Suppl 4:S8-10.: S8-10.

on minimal residual disease
Cole-Sinclair MF, Foroni L, Hoffbrand AV. Genetic changes: relevance for diagnosis and detection of minimal residual disease in acute lymphoblastic leukaemia. Baillieres Clin Haematol 1994; 7: 183-233.

Pui CH, Campana D. New definition of remission in childhood acute lymphoblastic leukemia. Leukemia 2000; 14: 783-785.

Radich J, Thomson B. Advances in the detection of minimal residual disease. Curr Opin Hematol 1997; 4: 242-247.
Stasi R, Taylor CG, Venditti A, Del Poeta G, Aronica G, Bastianelli C, et al. Contribution of immunophenotypic and genotypic analyses to the diagnosis of acute leukemia. Ann Hematol 1995; 71: 13-27.

Stock W, Tsai T, Golden C, Rankin C, Sher D, Slovak ML, et al. Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia. Blood 2000; 95: 2364-2371.

Thandla S, Aplan PD. Molecular biology of acute lymphocytic leukemia. Semin Oncol 1997; 24: 45-56.

on salvage treatment
Bassan R, Lerede T, Barbui T. Strategies for the treatment of recurrent acute lymphoblastic leukemia in adults. Haematologica 1996a; 81: 20-36.

Garcia-Manero G, Thomas DA. Salvage therapy for refractory or relapsed acute lymphocytic leukemia. Hematol Oncol Clin North Am 2001; 15: 163-205.

Weiss MA. Treatment of adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Leukemia 1997; 11 Suppl 4:S28-30.: S28-S30.

on CNS prophylaxis and treatment
Berg SL, Poplack DG. Advances in the treatment of meningeal cancers. Crit Rev Oncol Hematol 1995; 20: 87-98.

Chessells JM. Central nervous system directed therapy in acute lymphoblastic leukaemia. Baillieres Clin Haematol 1994; 7: 349-363.

Cortes J. Central nervous system involvement in adult acute lymphocytic leukemia. Hematol Oncol Clin North Am 2001; 15: 145-162.

Gokbuget N, Hoelzer D. Meningeosis leukaemica in adult acute lymphoblastic leukaemia. J Neurooncol 1998; 38: 167-180.

on immunotherapy and biologic response modifiers
Caron PC, Scheinberg DA. Immunotherapy for acute leukemias. Curr Opin Oncol 1994; 6: 14-22.

Gribben JG, Cardoso AA, Schultze JL, Nadler LM. Biologic response modifiers in acute lymphoblastic leukemia. Leukemia 1997; 11 Suppl 4:S31-3.: S31-S33.

Velders MP, ter Horst SA, Kast WM. Prospect for immunotherapy of acute lymphoblastic leukemia. Leukemia 2001; 15: 701-706.

2. PATHOLOGY AND BIOLOGY

2.1 Diagnosis study

2.1.1 Morhological classification

Morphology is the main criterion for primary diagnosis of ALL and differentiation from AML (Lai 2000). The diagnosis of acute leukaemia (ALL) can be established when the bone marrow examination reveals a lymphoid blast cell content in excess of 20% of total cellularity. Three major morphological subtypes, according to the French-American-British (FAB) committee criteria can be distinguished (Bennett 1976): Category / Morphology / Incidence

L1 / small lymphoid cells, homogeneous chromatin, no nucleoli, scanty cytoplasm, regular nuclei / 25-30%

L2 / large heterogeneous cells, lacy chromatin, irregular nuclear shape, nucleoli present, cytoplasm / 65-70%

L3 / large homogeneous cells with finely stippled nuclear chromatin, prominent nucleolus, strongly basophilic and vacuolated cytoplasm / 5-10%

Light microscope morphology and cytochemistry represent the minimum requirements for an adequate ALL diagnosis. The subclassification of groups L1 and L2 is of minor relevance since it has no prognostic implications. The new WHO classification scheme for both T- and B-lineage ALL no longer considers this distinction but does rather distinguish between precursor B or T lymphoblastic leukemia (Brunning 2001a; Brunning 2001b), with different immunophenotypes and cytogenetic characteristics. The subgroup L3 gives a hint of the presence of B-ALL, but again this distinction is not absolute, since occasional B-ALLs display L1/L2 morphology and, conversely, L3-like morphology can be seen in acute nonlymphocytic leukaemia. Rarer morphological variants are “hand-mirror” cell ALL, ALL associated with hypereosinophilia, granulated ALL and ALL with mature cells that are nearly indistinguishable from mature lymphoid neoplasms and require expert observers for accurate identification (Kim 1998). The role of cytochemistry is limited to differentiating ALL from myeloid leukaemias. Since morphological diagnostic subclassification is rather arbitrary, it is recommended on a type C basis that diagnosis is always supplemented by the objective results provided by the immunophenotypic study.

2.1.2 Immunophenotyping

The consensus considers a 20% minimum threshold to define a positive reaction of blast cells to a given monoclonal antibody. Roughly 75% of cases of adult ALL are of B-cell lineage. B-lineage markers are CD19, CD20, CD22, CD24, and CD79a (Hurwitz 1992, Huh 2000).
The earliest B-lineage markers are CD19, CD22 (membrane and cytoplasm) and CD79a (Campana 1988, Janossy 1989). A positive reaction for any two of these three markers, without further differentiation markers, identifies pro-B ALL. The presence of CD10 antigen (CALLA) defines the “common” ALL subgroup. Cases with additional identification of cytoplasmatic IgM (heavy chain of mu type only) constitute the pre-B group, whereas the presence of surface immunglobulin light chains defines mature B-ALL.
T-cell ALL constitutes approximately 25% of all adult cases of ALL. T-cell markers are CD1a, CD2, CD3 (membrane and cytoplasm), CD4, CD5, CD7 and CD8. CD2, CD5 and CD7 antigens are the most immature T-cell markers, but none of them is absolutely lineage-specific, so that the unequivocal diagnosis of T-ALL rests on the demonstration of surface/cytoplasmic CD3.
ALL of B or T lineage can additionally express myeloid antigens or stem-cell antigen CD34. The latter has little diagnostic relevance but can be prognostically important (Czuczman 1999, Khalidi 1999, De Waele 2001).
The scoring system recently proposed by the EGIL group addressed the characterization of the acute leukemia as B or T lineage ALL, or AML by including the most specific markers for the lymphoid and myeloid lineages among those of earlier stages of cell differentiation, plus some non-specific but stem-cell markers. The system introduced a modified terminology specific to each ‘maturation’ step within the B- or T-cell lineage (EGICL 1995) and was confirmed as adequate for both diagnosis and subclassification of ALL (Thalhammer-Scherrer 2002). The use of the immunophenotypic EGIL classification is thus.

B-cell lineage (CD19 and/or CD79a and/or CD22: at least 2 always expressed)
Category Immunological markers
B-I (pro-B) ALL no further B-cell differentiation marker (only HLA-DR, TdT, CD34)
B-II (common) ALL as above, plus CD10
B-III (pre-B) ALL as B-I/B-II, plus cytoplasmic IgM
B-IV (mature) ALL cytoplasmic/surface kappa or lambda

 

Among other markers, stages B-I and B-II are often CD24
positive and 4G7 (pro- and pre-B surrogate light chain specific MoAb) positive (Lenormand 1998;Lemmers 2000); surface CD20 and CD22 are variably positive beyond stage B-I; CD13 and CD33 myeloid/cross lineage antigen can be expressed, as well as the CD34 stem cell antigen, particularly in Ph+ALL (often B-II with CD34, CD38, CD25 and CD13/33) (Lim 1999; Pajor 2000), but myeloid-specific CD117 should not be present and can be used to differentiate further between ALL and rare myeloid leukemias with negative myeloperoxidase expression (Keyhani 2000). Pro-B ALL with t(4;11)/MLL rearrangements is most often myeloid antigen-positive disease (including expression of CD15). TdT expression is usually lost in B-IV subgroup. T-cell markers are usually not expressed in B-lineage ALL but a CD19+ subset is concurrently CD2+. Loss of surface adhesion molecules has been described (Geijtenbeek 1999).

T-cell lineage (cytoplasmic CD3 always positive):

 

Category Immunological markers
T-I (pro-T) ALL CD7 (usually with TdT, CD34, CD38)
T-II (pre-T) ALL as above, plus CD5 and/or CD2 and/or CD8
T-III (cortical) ALL any T-cell marker combination, plus CD1a
T-IV (mature) ALL any T-cell marker combination . plus membrane CD3 (without CD1a)

In T-ALL the expression of CD10 is quite common (25%) and not specific (Greaves 1981); CD34 and myeloid antigens can be expressed too.

 

2.1.3 Cytogenetics

Various chromosome probes carried out by fluorescent in situ hybridization (FISH) can enable the detection and direct visualization of virtually all chromosomal abnormalities in ALL, with a sensitivity around 99% (Rieder 1998). Cytogenetic evaluation is recommended in all cases on a type C basis. Changes found in ALL include both numerical and structural alterations (Bloomfield 1986, Pui 1990,Walters 1990, Secker-Walker 1997 , GFCH 1996 , Wetzler 1999, Wetzler 2000 , Harrison 2001,Kolomietz 2001; Pedersen 2001). The combined immunophenotypic-cytogenetic evaluation allows the identification of Philadelphia-positive t(9;22)/(Ph+)+ ALL, usually associated with L2 (lymphoblastic scarcely differentiated) morphology and CD10+ common or pre-B phenotype (Kasprzyk 1999,Cobaleda 2000, Tabernero 2001). Ph+ ALL may constitute 25%-50% of CD10+ common or pre-B ALL cases. Translocations involving chromosome 8 (c-myc gene), such as t(8;14) (90% of cases), t(8;22) (10% of cases), and t(2;8) (rarely observed), are virtually present in 100% of cases of mature B-ALL with L3 (Burkitt-like) morphology and clonal surface immunoglobulins. ALL with t(4;11) is rare in adults (3-4%). It is associated with striking hyperleukocytosis and the presence of the immature pro-B-ALL subtype (Hagemeijer 1987 , Schardt 1992). ALL with t(1;19) is being recognized as a specific entity among the pre-B ALL group ( Secker-Walker 1992, Borowitz 1993, Privitera 1992). Cytogenetic aberrations are less frequent in T-lineage ALL (Schneider 2000). The most frequent aberrations involve 14q11 breakpoints e.g. t(10;14), t(11;14), t(1;14) or other. The presence of t(8;14) with breakpoints at q24;q11 (q24;q32 in B-ALL) in T-ALL is associated with a lymphomatous, aggressive presentation (Lange 1992). Other recurring chromosomal abnormalities being currently identified, that may bear prognostic relevance, are deletions and losses in chromosomes 5 and 7 (6%), trisomy 8, trisomy 21, del(9p) or t(9p) (5-15%), del (6q) in T-ALL (2-6%, with unfavorable prognostic effect), abn(11q23), del(12p) or t(12;21) which in B-lineage ALL identifies a favourable prognostic subgroup (5%), t(10;14) which confers a good outlook in T-ALL, del(1p) and t(8;12) (Faderl 1998, Dabaja 1999; Mancini 2002, Ribera 2002). Hypodiploidy with less than 45 chromosomes, conferring an adverse outcome, and hyperdiploidy (>46 chromosomes) associated with an intermediate-good prognosis also need to be recognized (Trueworthy 1992, Heerema 1999).

2.1.4 Genomic changes

The rearrangement of immunoglobulin or T-cell receptor genes, virtually present in all cases of ALL, can be detected by hybridization techniques such as Southern blotting or polymerase chain reaction (PCR) as well as cytometric techniques in cases of T cell receptor rearrangements (Langerak 2001). These analyses are optional, but are useful for the detection of the genetic lesions underlying chromosomal translocations when monitoring minimal residual disease in bone marrow samples showing microscopic remission (Cole-Sinclair 1994; Faderl 2000; Ferrando 2000). Molecular biology techniques demonstrate with great accuracy rearrangements of BCR and ABL genes (Heisterkamp 1985), as it occurs in t(9;22), PBX1 and E2A genes as in t(1;19), tal-1 and TCR beta as in t(1;14); myc and immunoglobulin heavy or light chains as in B-ALL with translocations involving chromosomes 8, 14, 22, and 2 ; ALL-1 and AF4 as in t(4;11), ETV6(TEL) and AML1 as in t(12;21), and transolaction/activation of Hox11L2 in t(5;14)+ T-ALL (Biondi 1993, Breit 1993, Reichel 2001,Alessandri 2002, Bernard 2001; Gleissner 2001). Other frequently reported lesions are mutations, deletions or methylations in genes regulating the cell cycle and other aspects of cellular metabolism. These abnormalities can have prognostic relevance, as they modify the proliferative potential of leukaemic cells and/or interfere with the induction of apoptosis by anticancer drugs, such as an overexpression of antiapoptotic bcl-2 (Uckun 1997). The described genes are p53, retinoblastoma (Rb), p14, p15, p16 (constituting the INK4 family of cyclin-dependent kinase inhibitors), p21, caspase 2 and 3, Ikaros, Apaf-1 and procaspases 2, 3, 7, 8, 9, CTGF, metalloproteinases 2 and 9, fragile histidine triad, calcitonin, LFA-1 and VLA-4 integrins, and HOX11/11L2 in T-ALL (Faderl 1999a, Faderl 1999b, Nakase 2000, Wong 2000, Stock 2000, Svingen 2000, Albitar 2001, Chim 2001, Kuittinen 2001,Roman 2001, Soenen 2001 , Ballerini 2002 , Hoshino 2002, Roman-Gomez 2002). Further elucidation of the mechanisms of leukemogenesis, ALL subclassification, and susceptibility to anticancer drugs, is expected from the results of the new microarray gene profiling technique (Ferrando 2002).

2.2 Differential diagnosis

2.2.1

It is recommended on a type C basis that ALL is initially differentiated from acute myeloblastic leukaemia (AML) and from rare acute undifferentiated leukaemia and biphenotypic leukaemias (Chan 1985, Browman 1986). Eventually, the cell lineage of ALL cells and the specific immunobiological diagnostic subsets should be defined. Conventional morphological evaluation is of limited value since the majority of adult ALL cases display L2 morphology , which is often difficult to differentiate with certainty from acute undifferentiated leukemia and the less mature AML types. This information and then the assignment of ALL cases to either T or B cell lineage and level of differentiation require additional cytochemistry and immunophenotype studies as standard procedure. Differentiation between ALL and AML is initially obtained by excluding reactivity to Sudan black B or myeloperoxidase stains in ALL cells (< 3% positive). On cytochemical evaluation some rare ALL cases are Sudan black positive but myeloperoxidase and chloroacetate esterase negative. PAS positivity may be absent to strongly positive with a block disposition. This is more typical of B-lineage disease. In T-ALL, a focal paranuclear positivity for acid phosphatase or nonspecific esterases is rather common (Gassmann 1997). Electron microscopy with the use of myeloperoxidase-specific monoclonal antibodies is recommended for detecting myeloperoxidase positivity in acute undifferentiated leukaemia cases (Heil 1991, Buccheri 1992). Acute undifferentiated leukemia may mask ALL if not expressing myeloperoxidase activity or platelet peroxidase and lymphoid antigens. ALL cases with pure lymphoid or mixed lympho-myeloid phenotypes and some degree of myeloperoxidase positivity have been described (Arber 2001). These cases, usually diagnosed as ALL, can represent early stem-cell bilineage acute leukaemias. However, true ALL cases that are immunoreactive to myeloperoxidase or express detectable levels of myeloperoxidase mRNA have been identified (Vainchenker 1988). A minor population of myeloperoxidase-positive blast cells can often be found in Ph+ ALL, and is occasionally observed in T-lineage ALL (Serrano 1999, Kantarijan 1990). Evaluation of CD117 antigen expression should also be carried out ( Hans 2002 ). Most ALL cases positively express the nuclear enzyme TdT. TdT-negative ALL is extremely rare, except L3/B-ALL, so that all TdT-negative L1 and L2 cases must be thoroughly investigated to exclude other aggressive lymphoid neoplasms in the leukaemic presentation (blastic mantle cell lymphoma, atypical plasmoblastic myeloma, other high-grade lymphomas) (Faber 2000). CD56, a marker of NK cell differentiation, defines a rare subgroup of about 3% of adult ALL cases which display other early T-cell antigens; true NK ALL is very rare (TdT+, CD56+, other T markers negative, unrearranged TCR genes) (Paietta 2001). About 5% of cases can express mixed-lineage markers in the same cell population (biphenotypic leukaemia) or in different populations (hybrid leukaemia). According to the expression of different T- and B-cell or myeloid markers in the EGIL scoring system, it may be possible to obtain a classification of cases with mixed diagnostic characteristics.

Scoring system for biphenotypic acute leukaemia

 

Points B-lineage T-lineage Myeloid
2 CD79a CD3 (cyt/m) MPO
cyt IgM anti-TCR
cyt CD22
1 CD19 CD2 CD13
CD10 CD5 CD33
CD20 CD8 CDw65
CD10
0.5 TdT TdT CD14
CD24 CD7 CD15
CD1a CD64
CD117

Biphenotypic acute leukemia is defined when scores are >2 for the myeloid lineage and >1 for the lymphoid lineages. In some T-ALL cases, clonality of TCRalpha/beta rearrangements can now be assessed cytofluorometrically ( Langerak 2001).

3. DIAGNOSIS

3.1 Physical and instrumental diagnosis

3.1.1 Clinical presentation

Symptoms of ALL at onset are primarily produced by the detrimental effects of the expanding cell population on bone marrow, and secondarily by infiltration of other organs and by metabolic disturbances (Henderson 1990, Hoelzer 1991, Gur 1999). Bone marrow is usually infiltrated with >90% blast cells. Infiltration with less than 50% blasts represents only 4% of cases. Normal trilineage haematopoiesis is consequently decreased. The classical triad of symptoms related to bone marrow failure is the following: fatigue and increasing intolerance to physical exercise (caused by anaemia), easy bruising and bleeding from mucosal surfaces and skin (caused by thrombocytopenia especially when platelets are 100.000 blast cells rarely lead to the leukostasis syndrome and catastrophic early bleeding ( Porcu 2000).

3.1.2 Laboratory findings

At diagnosis, severe anaemia (Hb1.6 mg/dl, uric acid >8 mg/dl, and elevated serum potassium or phosphorous are at high risk for an acute tumour lysis syndrome during chemotherapy, thus requiring close monitoring and adequate supportive measures (Cohen 1980). Clotting tests and fibrinogen concentration may reveal pre-treatment abnormalities in about 5% of cases. LDH levels are usually elevated in most cases.

3.2 Pathological diagnosis

3.2.1 Appropriate diagnostic sampling

Bone marrow aspiration is the standard procedure for obtaining diagnostic material for the initial evaluation and for subsequent immunophenotypic study and cytogenetic analysis, but bone marrow biopsy is recommended on a type C basis. Biopsy is necessary in cases with “dry tap” due to fibrosis or to heavily packed ALL cells in the bone marrow, because it may contribute to the demonstration of leukemic cells in the fat spaces, of residual normal hematopoiesis, and may have some prognostic relevance (Bennett 1976, Bain 1990, Thomas 2002). Peripheral blood can be used to collect and store the very large amounts of ALL cells needed for investigational purposes and is only considered adequate for diagnostic purposes in patients with circulating blasts or in whom bone marrow biopsy is not feasible. It is notable that up to 10% of cases show no circulating blasts. An early examination of the cerebro-spinal fluid is recommended on a type C basis in order to detect asymptomatic central nervous system disease. This procedure should be performed only if the platelet number is >20 x109/l. In cases with high peripheral blast count, there is a theoretical danger of contamination of the CSF with blast cells so that this maneuver is best performed after or during the initiation of chemotherapy. In cases where standard morphological examination gives rise to suspicion of meningeal disease, the cerebro-spinal fluid should be analyzed by immunophenotypic characterization.

3.2.2 Appropriate handling of diagnostic specimens

Freshly obtained diagnostic marrow and peripheral blood smears must undergo the usual procedure of direct May-Grunwald Giemsa staining and cytochemical reactions, while heparinized samples of the same material are simultaneously evaluated for immunophenotype and cytogenetics or complementary molecular biology studies. Since cytogenetics and molecular biology studies require time to completion, the early diagnostic approach rests essentially on bone marrow morphological assessment and immunophenotypic evaluation.

4. STAGING

4.1 Staging procedures

Routine staging procedures in adult ALL should include (Hoelzer 1991 ):
Medical history: co-morbid diseases
occupational risk factors
allergic reactions
drugs
Physical examination: general, performance status
head, neck, oral cavity
thorax (lungs, heart, blood pressure)
abdomen (liver, spleen)
extremities and neurological
superficial lymph nodes
skin
body temperature
optical fundus
haemorrhages/infections
Laboratory: Full blood counts with differential,
liver and kidney functions, serum LDH,
electrolytes, serum albumin
immunoglobulin level determination
glucose, clotting test, blood group
HLA typing,
serology for viral hepatitis type B and C,
HIV
Instrumental: Electrocardiogram, chest X-ray
Invasive procedures: Bone marrow aspirate/biopsy
Lumbar puncture

Furthermore, patients can be be given additional investigations on an individual basis as indicated by their clinical status and presence of host- or disease-related complications (CT, ultrasound scans etc.).

4.2 Staging classification

ALL is a widely disseminated malignancy from the very outset. Thus, staging systems such as those adopted for other tumours are not helpful and accordingly have not been developed. Rather, any presentation pattern reflecting a higher clinical aggressiveness and an elevated tumour burden must be recognized and classification of patients into high-, intermediate- and low-risk groups is recommended.

5. PROGNOSIS

5.1 Natural history

Untreated ALL is fatal in a few days or weeks, depending on the degree of bone marrow failure, related blood cytopenias, and effects of circulating blast cells and their metabolites on vital organs. Untreated cases will succumb rapidly to infections, hemorrhages, or a combination of both. Spread to CNS is expected to occur soon or very soon in untreated or inadequately treated patients, especially those with B-ALL and T-ALL ( Fenaux 2001 ). CR can be achieved in 70-85% of patients or more. Around 10-20% (depending on age) of patients die early during induction treatment, and a further 10% is truly refractory to remission-induction programs. In addition to these early failures, more than half of the patients who achieve a complete remission are expected to relapse. Of these, only a minority can achieve a second, long lasting remission and possibly cure with currently available salvage strategies. Altogether modern therapeutic strategies allow an overall chance of cure in approximately 20% to 40% of adult patients with newly diagnosed ALL.

5.2 Clinical prognostic factors

The two most important clinical prognostic factors are patient age and total white cell or blast count, which exert independent cumulative prognostic effects both during the induction of response and the subsequent phase of remission consolidation (Chessells 1995 ).

5.2.1 Age

Age appears to influence survival as a continuous variable, without definite cut-off points; in general, the older the age the worse the prognosis (Baccarani 1982, Taylor 1992, Perentesis 1997, Chessells 1998, Stiller 1999, Levi 2000). Since the median patient age in most clinical series is about 30 years, there has been a tendancy to report cut-off levels in this range (+/-5 years). Such reporting shows significant differences in remission and survival duration in favour of younger age groups. Patients aged over 50-60 years are usually regarded as a prognostically unfavourable group with a probability of survival not exceeding 0.20 at 3 years, while adolescents and teenagers under 20 years of age do nearly as well as the closely related paediatric ALL population and are probably best treated on childhood rather than adult ALL programs ( Crist 1988, Santana 1990, Nachman 1993, van den Berg 2000). The worse prognosis of elderly patients may be due to a reduced tolerance to intensive treatment strategies, to co-morbidity and to an age-dependent increase in high risk features such as chromosomal abnormalities particularly t(9;22) within the B-lineage subgroup, which produces a concurrent reduction in the incidence of the improved-prognosis subgroup of T-ALL (Kantarijan 1994,Ferrari 1995, Pagano 2000).

5.2.2 Cell count

The negative prognostic influence of an elevated ALL cell count, reflecting a higher tumour mass, has been confirmed in almost all larger studies. As for patient age, cut-off points associated with significant prognostic differences were retrospectively set at varying levels without firm rules, depending on the type of study and whether absolute blast count (greater or less than 10-15×109/l) or total white blood cell count (greater or less than 5-50×109/l) was employed. Use of total WBC count instead of blast cell count is recommended on a type R basis, based on the fact that morphological discrimination of true blast cells from nonleukaemic reactive or atypical mononuclear cells may be difficult.

5.2.3 Time to response

Although all of the above listed clinical and laboratory features greatly influence treatment outcome, the primary determinant for survival remains the disease sensitivity to chemo-radiotherapy. Patients achieving complete remission in 4 to 5 weeks and/or showing a slow peripheral blood (day 7) or bone marrow (day 14) blast cell clearing or a poor prednisone response carry a significant better outcome than those requiring additional treatment (Cortes 1999). Time to platelet recovery >100×109/L within 60 days may be another favorable clinical prognostic marker (Faderl 2002).

5.3 Biological prognostic factors

It is now recommended on a type C basis to consider immunophenotype and cytogenetics jointly in order to identify discrete ALL immuno-biologic subsets . It is especially important to recognize ALL syndromes that confer an ominous prognosis and therefore require nonconventional therapeutic approaches.

5.3.1 Immunophenotype

Modern aggressive treatment programs have substantially improved the prognosis of B-ALL (EGIL B-IV) and of T-ALL, once associated with disease-free survival of less than 10% and now curable in up to 50% and 40-60% of cases, respectively (T-ALL: not all subsets and not all major studies reported an improvement). The prognosis of common ALL (EGIL B-II) has not changed significantly in the past 15 years and disease-free survival ranges between 30-40%, with marked heterogeneity among different prognostic subgroups. Better results may be obtainable in Ph-negative B-II and t(4;11)-negative B-I ALL subtypes presenting with a blast cell count < 10-25×109/l, using dose-intensive anthracycline- and antimetabolite-rich programs. Because of its relatively high incidence in adults (20 to 50% of cases), Ph+ ALL with CD10- or CD10+ common phenotype is the worst possibility, with only 0 to 15% of patients surviving at five years. Ph+ ALL may respond well to induction treatment but is invariably associated with relapse and death within approximately one year from diagnosis. A subgroup of better-prognosis patients with Ph+ ALL, who survive longer, has been identified as in childhood ALL. The therapeutic effect of imatinib mesylate (Glivec), a new BCR-ABL-specific tyrosine kinase inhibit, in Ph+ ALL is undergoing assessment in several ongoing clinical studies. Another poor risk situation within B-lineage is pro-B (EGIL B-I) ALL associated with t(4;11), for which more intensive treatment programs based on high-dose and/or fractionated cyclophosphamide, cytarabine and methotrexate appear to have improved outcome (Mirro 1986, Ludwig 1998). Among T-lineage ALL, whether or not it is expressing translocations involving TCR genes, the prognosis is worse for pro-T (EGIL T-I) and perhaps mature T (EGIL T-IV) ALL compared with other phenotypes (Thiel 1989, Garand 1993, Digel 1994), and in general in patients with a leukocyte count >100×109/L. The independent prognostic value of cytogenetics and immunophenotype has been shown in recent studies, and attempts are underway to categorize patients in different risk classes according to these variables. The expression of myeloid antigens by ALL cells, namely CD13 and CD33, as occurs in so-called My+ ALL (Drexler 1991), and of the stem-cell antigen CD34, seems to confer a worse prognosis, partly because of an association with other major adverse prognostic factors (CD34 in Ph+ ALL) (Sobol 1987, Ball 1991, Boldt 1994, Thomas 1995a). This issue is still controversial, and newer intensified treatment schedules would appear beneficial in My+ ALL.

5.3.2 Cytogenetics and molecular genetics

Karyotype is an extremely important prognostic factor (Bloomfield1986, Boucheix 1994). Two karyotypic changes have been found associated with a better prognosis in adult ALL: del(12p) or t(12p)/t(12;21) in B-lineage ALL and t(10;14) in T-ALL. These favourable abnormalities are relativerly rare in adults compared with childhood ALL. Most cases of ALL fall within an intermediate-risk group. The probabilities of disease-free survival were 0.35 or more at 4 years in a combined normal diploid/hyperdiploid/no metaphases group. The intermediate-low risk cytogenetic group could be made up of these cases. Those with isolated trisomy 21, trisomy 8, del (9p) or t(9p), and del(6q) may constitute an intermediate-high risk group. Finally, patients with t(9;22) or BCR-ABL rearrangements or a positive FISH test (Ph+ ALL), t(4;11) or MLL rearrangements, monosomy 7, hypodiploidy, and t(1;19) would fall into the poor-risk cytogenetic category, with an overall disease-free survival rate not exceeding 25%, or 10% in the case of Ph+ ALL ( Secker-Walker 1991, Westbrook 1992, Barrett 1992, Schardt 1992, Grigg 1993, Annino 1994, Preti 1994, Rieder 1996, Westbrook 1997, Secker-Walker 1997, Aricò 2000, Bassan 2000, Faderl 2000b, Radich 2001, Gleissner 2002). The poorest outcome is usually observed in Ph+/BCR-ABL+ ALL, where survival beyond 2 years is < 10%-25%, at least in patients who cannot undergo allogeneic stem cell transplantation (link 6.9).

Prognostic cytogenetic classification of adult ALL

Prognosis Chromosomal changes

Favourable del(12p), t(12p), highly hyperdiploid, t(10;14), t(14q11-q13)
Intermediate Normal, others not favourable/unfavourable
Intermediate-unfavourable t(1;19), abn(9p), del(6q)
Unfavourable t(9;22), t(4;11), -7, +8, abn(11q23), hypodiploid

 

5.4 Predictive factors

5.4.1 Drug resistance mechanism

The cellular mechanism of drug resistance that has been most widely investigated is due to a P-glycoprotein encoded by the multidrug resistance gene (MDR1). MDR1+ gene or phenotype was detected at diagnosis in up to 38% of ALL cases, more frequently in poor prognosis CD7+ pro-T ALL and B-ALL, and was found to confer a great risk for primary treatment resistance or relapse. Increased MDR1 expression has been noted at subsequent relapses (Gekeler 1992, Miwa 1993,Goasguen 1993, Russo 1994, Damiani 2002, Tafuri 2002). MDR-associated protein (MRP) and LRP (lung-related protein) give rise to other drug resistance mechanisms whose signifgicance at presentation is uncertain, but these proteins are overexpressed at relapse (Burger 1994, Beck 1995). The coexistence of these and other drug resistance mechanisms in individual ALL cases has been demonstrated. Furthermore, studies investigating the resistance to single chemotherapeutic agents may reveal associations between adult ALL failing treatment and an altered drug accumulation profile, as has already been demonstrated for methotrexate polyglutamylation and glucocorticoid resistance(Trippett 1992, Pieters 1992, Goker 1993, Joncourt 1993, Hall 1994, Goker 1995, Gorlick 1997,Schrappe 1998, Estlin 2000a, Estlin 2000b, Styczynski 2000, Rots 2000, Whitehead 2001,Schmiegelow 2001). Adult Ph+ ALL may be resistant to corticosteroids and be significantly associated with LRP (Maung 1995, Remakers-van Woerden 2002). It is likely that demonstration of drug resistance will become a pivotal prognostic issue in predicting treatment outcome in adult ALL, or even lead to the use of individualized treatment schedules, as has already shown partial success in childhood ALL (Evans 1998). Sometimes, these findings and the resistance or relapse phase correlated with mutations of the p53 gene or other genes ( Wattel 1994, Hsiao 1994, Lanza 1995,Debatin 1995, Hangashi 1996, Tsai 1996, Soenen 2001), indicating a strict relationship between drug resistance phenomena and alterations of the molecular mechanisms involved in apoptotic cell death and control of cell cycle. Thus far, gene alterations associated with a worse outcome in adult ALL concern p53, Rb, p14, p15, p16, p21, HOX11L2, but not HOX11 in T-ALL, caspase 3, and calcitonin.

5.4.2 Minimal residual disease

The term minimal residual disease (MRD) applies to submicroscopic ALL present in the bone marrow and/or peripheral blood of remission patients (Miller 1991, Potter 1993 , Pui 2000 ). Remission marrows (as wells as peripheral blood samples) may still harbour up to 1010 leukaemic cells (Uckun 1993a). In essence, consolidation and maintenance therapy should eliminate MRD to warrant cure, while safer autologous transplant procedures should rely on a lesser contamination of bone marrow or peripheral blood harvests (Schultz 1989, Nagafuji 1993, Seriou 1995, Mizuta 1999). Persistence of MRD throughout treatment reflects intrinsic drug resistance heralding clinical recurrence. The course of MRD during subsequent treatment steps and/or before and after stem cell transplantation can be taken as the most sensitive way to predict relapse in individual patients (Campana 1995, Knechtli 1998 , Chen 2001). This notion is important, because otherwise risk-oriented strategies would be used which rely on traditional risk models that are failrly inaccurate (where 40% of good-risk cases eventually relapse and, by contrast, about 20% of high-risk ones do not). The initial experience gathered in large paediatric studies and some adult groups validates these assumptions (Estrov 1986,Brisco 1996, Goulden 1998, Roberts 1997, van Dongen 1998, Cavè 1998, Coustan-Smith 2000,Panzer-Grumayer 2000, Stock 2000b, Brueggemann 2001, Malec 2001, Mortuza 2002, Nyvold 2002). In reported MRD studies in adult ALL, the predictive value of MRD data at 3-12 months from remission was 80-90% for continuous remission and 80% for relapse in MRD negative and positive patients, respectively. Apart from the FISH technique ( Anastasi 1991, Kasprzyk 1997), two major options are available for clinical-scale detection and monitoring of MRD, both with a sensitivity level between 90% (Kallakury 1999). First, ALL-associated immunophenotypes can be evaluated using multiple-channel flow cytometry. Aberrant phenotypes reflecting ALL contamination were identified on the basis of different combinations and/or asynchronous expression and/or variable intensity staining of several antigens (B-lineage: CD19/CD34/TdT/CD10/CD22/CD45/CD38/CD45; T-lineage: TdT, CD2/cyt CD3/CD5/CD7 etc.) (Coustan-Smith 1998, Ciudad 1998, Ciudad 1999, Griesinger 1999, Lucio-Parreira 1999, Van Wering 2000, Middleton 2000, Lucio- Parreira 2001, Coustan-Smith 2002,Dworzak 2002, Sanchez 2002). Second, the polymerase chain reaction (PCR) and the novel real-time quantitative (RQ) PCR can detect specific sequences of leukaemic DNA, amplified and recognized with a sensitivity level usually < 10-5 (Kwan 2000). PCR targets are molecular rearrangements associated with recurrent chromosomal abnormalities (B-lineage: BCR-ABL for t(9;22), MLL-AF4 for t(4;11), TEL-AML1 for t(12;21), E2A-PBX1 for t(1;19), MYC-IgH for t(8;14); T-lineage: RHOM2-TCRgamma for t(11;14), HOX11-TCRalpha for t(10;14), TAL1 deletion) or rearranged immunoglobulin or T-cell receptor sequences (TCRdelta and gamma, IgH, IgK-Kde) unique to each ALL case (Janssen 1994,Foroni 1997, Pongers-Willemse 1998, Szczepanski 1998, Foroni 1999, Neale 1999, Brumpt 2000,Cimino 2000, Nakao 2000, de Haas 2000 , Donovan 2000, Szcwepanski 2000, Nirmala 2002, van der Velden 2002a, van der Velden 2002b, Willemse 2002). It is mandatory to obtain two or more sequences for each case, in view of the high rate of further rearrangements or genetic losses that occur in the unstable leukaemic clone, leading to false negative results. These and other technical pitfalls must be carefully considered in MDR studies, as well as its predictive role in very high-risk conditions such as Ph+ ALL, where achievement of a negative MRD status is not tantamount to cure, except after allografting (van Rhee 1995, Radich 1997, Preud’homme 1997, Mitterbauer 1999,Dombret 2002, Yokota 2002). Quantitation of molecular MRD is of the utmost importance. Dot blot dilution analysis offers significant information, but only RQ-PCR allows exact quantitation. Timing and number of MRD tests (i.e. time points) to be carried out are uncertain and probably vary in relation to ALL subtype and the design of specific remission induction and postremission protocols ( Biondi 2000). The study of MRD could become the most sensitive and accurate instrument to predict relapse in remission patients, and to guide the choice of optimal postremission therapy. On this basis the evaluation of MRD is recommended on a type 3 level of evidence.

5.5 Risk groups

5.5.1

Diagnostic and clinical features at presentation can be combined to identify discrete risk groups. Since failure to achieve initial response, a consequence of both overt drug resistance and induction death, concerns only about 10%-15% of cases, these prognostic models are essentially useful in predicting the long-term durability of remission. Since outcome may differ greatly according to diagnostic characteristics, efforts should be devoted to differentiate patients likely to benefit most from conventional chemotherapy regimens from those in whom other options are indicated. Once CR is achieved by the induction therapy, patients should be divided into two or three (subdividing further the high-risk group) main prognostic groups according to the adopted prognostic system (Barnett 1986,Gaynor 1988, Hoelzer 1993a, Hoelzer 1988, Hussein 1989, Kantarijan 1990b, Linker 1991, Lluesma-Gonalons 1991, Larson 1995, Linker 1997, Gokbuget 2000, Gokbuget 2001, Bassan 2001), which are determinants for treatment decisions in the postremission phase:
-patients at low risk, e.g. with probability of long term remission > 0.50
-patients at intermediate risk, e.g. with probability of long term remission between 0.25 and 0.50
-patients at high risk, e.g. with probability of long term remission < 0.25
In Europe, the risk model tested in successive multicentre German trials gained wide acceptance and has become a reference system. Slightly different systems have been developed by other groups, with an increasing trend to include cytogenetic data other than usual clinical parameters and ALL cell immunophenotype. These systems are recommended as standard option on a type 3 level of evidence. Importantly, pre-defined risk groups are subject to changes owing to improvements in treatment protocols, to confirm the primary prognostic impact of chemotherapy.

Current prognostic systems

No./System (ref.) Adverse factors by no. positive factors Probability of CR at 5 years

1. German (Hoelzer 1988) WBC >30 x109/l 0.62 with 0
Age >35 0.33 with 1
Null-ALL 0.22 with 2
CR >4 weeks 0.11 with 3
0 with 4
2. Modified German (Boucheix 1994) CR >4 weeks 0.27-0.30
Age >35 cumulative
WBC >30 x109/l 0.47-0.53 with 0
Null or B-ALL
3. New German (Goekbuget 2000;Goekbuget 2001)
B-lineage: 0.27 with >=1
WBC >30 x109/l vs 0.47 with 0
CR >4 weeks (excluding age and Ph)
Pro-B ALL
t(9;22)/BCR-ABL 0.21 (3 years)
t(4;11)/ALL1-AF4
Age >50 0.16
T-lineage:
WBC >100 x109/l
CR >4 weeks
Early/mature T-ALL 0.25-0.28vs 0.63
4. Sloan-Kettering
Cancer Center
(Gaynor 1988)
WBC >20 x109/l 0.61 with 0/1
Null or B-ALL 0.43 with CR >5 weeks
Age >60 weeks
Ph+ 0.20 with at least
CR >5 weeks 2 risk factors (excluding CR >5 >5 weeks)
5.M.D. Anderson
Cancer Center
(Kantarjian 1994)
Ph+ ALL < 0.30
B-ALL vs 0.70 with 0
CNS disease
WBC >5 x109/l
Two courses to CR
6. CALGB (Larson 1995 ) Age >60 years 1 with 0
FAB L3 0.74-0.58 with 1
WBC >30 x109/l 0.25 with 2/3
Ph+ or (4;11)+ 0 with 4
No mediastinal mass

Almost all of the recently developed systems no longer consider T-cell immunophenotype as an adverse factor, due to the positive effects of intensified treatments on this disease subtype. The new German prognostic score however identifies an immunophenotypic subset of very high-risk T-ALL cases. In the near future, given the increasing evidence supporting the prognostic importance of biological features, the introduction and evaluation of these models of additional factors is likely.

6. TREATMENT

6.1 Principles of remission induction phase

6.1.1 Pre-treatment hydration

Prevention and treatment of metabolic complications are the first essential steps in approaching patients with acute leukemia.

6.1.2 Remission induction chemotherapy

The primary therapeutic step in eradicating ALL is the achievement of a complete eradication of all detectable leukemic cells from blood and bone marrow. Most current programs are centred on a vincristine and prednisone (V+P) combination plus an anthracycline (daunorubicin, DNR; adriamycin, ADR; rubidazone, RDZ; idarubicin, IDA), with an overall probability of achieving a complete remission of more than 80%. Use of anthracyclines during remission induction in addition to V+P is recommended as standard treatment on a type 2 level of evidence (Gottlieb 1984, Stryckmans 1992,Bassan 1992, Bassan 1995b). In the CALGB study DNR was administered on three consecutive days, but many other studies employed it on a weekly schedule. A randomized study (Candelaria 1993) and a review (Bassan 1995b) indicate a modest advantage of a three-day schedule over weekly anthracycline administration. The response rate is no better when anthacycline-type drugs (DNR, mitoxantrone) are given as continuous infusion rather than as a bolus (Koc 1998, Hunault-Berger 2001). There is uncertainty as to the best anthracycline compound. Daunorubicin and doxorubicin can be considered standard on a type C basis, while rubidazone, mitoxantrone and idarubucin can be considered suitable for individual clinical use on a type 2 or 3 (rubidazone) level of e (Fière 1993,Cuttner 1991 , Bassan 1993, Bassan 1999a, Ifrah 1999). Idarubicin, as compared to DNR and ADR, might exhibit the property of partially overcoming the MDR1 phenotype (Berman 1992), at least in vitro. However, in view of its high myelotoxicity and higher costs, the use of this drug requires further evaluation (Weiss 1993, Wernli 1994). High-dose anthracycline-based induction has been piloted with excellent results in a single-centre phase II study involving a limited patient number (Todeschini 1994,Todeschini 1998; Todeschini 2001). Data from larger studies are more controversial (Takeuchi 2002). An intensive early use of anthracyclines can affect outcome favourably in B-lineage low-risk ALL (Bassan 2000, Bassan 2001). The role of liposome-encapsulated daunorubicin must be assessed(Kantarjian 2001). Subsequent trials have addressed the role of a fourth, fifth or sixth drug in this phase, namely L-asparaginase, cyclophosphamide, cytarabine (high-dose), etoposide, topotecan (Linker 1991, Nagura 1994, Mandelli 1992, Larson 1995, Thomas 1995b, Durrant 1997, Gore 1998,Ueda 1998, Daenen 1998, Kobayashi 1999, Bassan 1999b, Larson 2000, Kantarjian 2000, Garcia-Manero 2000, Cataland 2001, Annino 2002b, Halbook 2002). Despite superimposable remission rates between study and control, cyclophosphamide and L-asparaginase are commonly included in remission schedules, since they are believed to increase the quality of remissions, if not their number, or at least affect outcome in some subgroups with a poorer prognosis. However an early withdrawal of L-asparaginase on account of toxic reactions has no impact on remission (Larson 1998b). Pegylated asparaginase, with superior activity demonstrated in refractory childhood and adult ALL (Abshire 2000, Aguayo 1999), due to longer periods of asparagine depletion, is currently under study in several clinical trials (Gokbuget 2000, Larson 2000). Indeed, four/five-drug regimens were associated with response rates >80% in several uncontrolled studies (Kantarjian 1993a, Larson 1995, Kantarjian 2000). Induction programs of this kind (German multicentre ALL/GMALL phase 1, CALGB, MDACC) (Larson 1995, Hoelzer 1993a, Kantarjian 2000) can currently be regarded as suitable for individual clinical use on a type 3 level of evidence for patients at low risk and standard treatment on a type R basis for patients at intermediate and high risk r (Linker 1991, Nagura 1994, Kantarjian 1993a, Larson 1995, Hoelzer 1993a, Rohatiner 1990, Todeschini 1998, Bassan 2000, Kantarjian 2000, Halbook 2002). With these regimens, remission should be achieved in at least 75% of patients at intermediate risk and in almost 90% of patients with low risk . There is no proof that high-dose regimens which differ from vincristine + prednisone + anthracycline +/- cyclophosphamide and/or L-asparaginase are in any way superior. Pushing treatment intensity in the remission induction phase beyond this point (e.g., introducing high dose cytosine arabinoside, high dose mitoxantrone or high dose methotrexate) may be detrimental because of drug-associated toxicities (Weiss 1996, Wernli 1994, Weiss 2001). Therefore, remission induction regimens more aggressive than the examples below remain investigational. Patients with Burkitt’s ALL (L3 morphology with confirmed B-mature/EGIL B-IV phenotype) should receive standard treatment with specifically designed short-term programs including fractionated/high-dose cyclophosphamide, cytarabine, methotrexate, epipodophyllotoxins (Magrath 1996, Hoelzer 1996, Fenaux 2001, Lee 2001 ), based on a type 3 level of evidence. The Hyper-CVAD regimen associate with antiviral therapy can be used in HIV+ patients who develop B-ALL (Cortes 2002).

Representative examples of induction regimens for adult ALL.

Protocol (ref.) Drugs Dosage (mg/m2) Days

GMALL:
Phase 1
V 1.5 i.v. 1,8,15,22
60 p.o. 1-28 (taper)
DNR 25 i.v. 1,8,15,22
L-ASP 5.000(U) i.v. 15-28
Phase 2** CY 650 i.v. 29,43,57
Ara-C 75 i.v.
31-34,38-41,45-57
MP 60 p.o. 29-57
MTX 10 i.t. 31,38,45,52
CNS radio-prophylaxis
CALGB: V 2 total i.v. 1,8,15,22
P 60 p.o./i.v. 1-21
DNR 45 i.v. 1-3
CY 1.200 i.v. 1
L-ASP 6000 (U) s.c 5,8,11,15,18,22
Hyper-CVAD (MDACC):
Course 1
CY 300 i.v.(3-h)
every
12-h
1-3
(mesna, same dose c.i. until 6-h after finishing CY)
V 2 i.v 4, 11
ADR 50 i.v. 4
Dex 40 i.v. 1-4, 4-11
Course 2**

**corresponding to early intensification in patients achieving response within 4 weeks Drugs: V, vincristine; P, prednisolone; mP, methylprednisolone; Dex, dexamethasone DNR, daunorubicin; ADR, adriamycin; ASP, L-asparaginase; CY, cyclophosphamide; Ara-C, cytosine arabinoside; MP, mercaptopurine; MTX, methotrexate. CNS denotes central nervous system

6.1.3 Side effects and complications of remission induction regimens

Bone marrow depression with prolonged neutropenia and thrombocytopenia are the main adverse side effects of induction programs. Myelotoxicity is exacerbated by anthracyclines and is more pronounced when other myelotoxic agents are used concomitantly, such as cyclophosphamide and cytosine arabinoside. Patients thus have a definite risk of dying of infectious complications and/or bleeding without having resistant ALL. These induction deaths occur approximately in 5-15% of cases. Nonlethal treatment complications are also frequent, particularly infections, favouring postremission treatment delays. For these reasons prevention of bleeding and infection is crucial. Infections are perhaps a more relevant problem affecting a greater proportion of patients. Thrombocytopenic bleeding is managed with a regular transfusional policy of single or multiple donor platelets to maintain a count >10 x109/l, or higher in patients with high fever and infection. L-asparaginase is toxic to the liver and may cause hyperglycaemia and disturbances of clotting factor synthesis, including fibrinogen, antithrombin and other inhibitors, that predispose to haemorrhagic as well as thrombotic events. When the fibrinogen level falls to 50×109/l, when the APTT ratio should be adjusted to between 1.5-2.

6.1.4 Growth factors during remission induction

Since the primary determinant of infectious complications is absolute granulocytopenia, recombinant myeloid cell growth factor (granulocyte-colony stimulating factor, G-CSF) was recently considered as an addition to the induction regimen. Three randomized studies demonstrated some advantages for G-CSF-treated patients in terms of CR rate, time to recovery of >1×109/l neutrophils, incidence of febrile neutropenia and infectious complications, and reduced chemotherapy delays. Since the safety of this regimen and the lack of untoward effects were confirmed, the use of G-CSF at 5 mg/kg/ as an adjunct to induction therapy is recommended on a type 1 level of evidence (Ottmann 1995, Larson 1998a, Geissler 1997), particularly with the more myelotoxic schedules employing anthracyclines on three consecutive days and in the elderly (Bassan 1997). Delay of G-CSF administration until day 10 did not increase risk of neutropenic complications using the Hyper-CVAD regimen ( Weiser 2002). G-CSF-primed growth of Ph+ ALL cells has been described in vitro, however no such correlation was as yet reported in vivo (Inukai 2000, Kobbe 1998).

6.2 Principles of post-remission therapy

6.2.1 Consolidation therapy

The general consensus is that postremission early consolidation/intensification therapy, administered before standard maintenance is employed will improve outcome, especially in high-risk groups. Therefore, inclusion of post-remission consolidation chemotherapy in the therapeutic program is standard treatment on a type C basis (Hoelzer 1994 Stryckmans 1992, Marcus 1986, Larson 1995 ,Hoelzer 1993b, Lluesma-Gonalons 1991, Linker 1991, Todeschini 1998 , Ribera 1998, Kantarjian 2000, Gokbuget 2000, Larson 2000, Bassan 2001, Petersdorf 2001). However, neither the optimal type nor duration of this phase for the various disease subsets are known. Several active programswere recently developed, some of which are derived from early GMALL studies or other schedules, however without a clear prognostic improvement over the early trials (Gokbuget 2000). Dose-intensive anthracycline was a key feature of effective regimens for standard risk B-lineage ALL (Bassan 2000, Bassan 2001) and, together with high dose cytarabine, for T-ALL (Todeschini 1998 ). A general feature of these programs is the alternate use of active drugs at variable dosage for some months.

Representative example of postremission chemotherapy. GMALL 84/02 Hoelzer 1993a)

Phase Drugs* Days

Consolidation I/II ara-C 75 mg/m2 i.v. 1-5
wk 12 and 16
VM-26 60 mg/m2 i.v.
Reinduction I DXM 10 mg/m2 p.o. 1-28
VCR 1.5 mg/m2 i.v. 1,8,15,22
ADR 25 mg/m2 i.v. 1,8,15,22
Reinduction II CY 650 mg/m2 i.v. 29
ara-C 75 mg/m2 i.v. 31-34,38-41
TG 60 mg/m2 p.o. 29-42
Consolidation III/IV ara-C 75 mg/m2 i.v. 1-5
wk 20 and 26
VM-26 60 mg/m2 i.v.
Maintenance MP 60 mg/m2 p.o. daily
wk 1-10 and 29-130
MTX 20 mg/m2 p.o./i.v.
weekly as above

*ara-C, cytosine arabinoside; VM-26, teniposide; DXM, dexamethasone; VCR, vincristine; ADR, adriamycin; TG, 6-thioguanine; MP, mercaptopurine; MTX, methotrexate. mode of administration: i.v., intravenously; p.o., orally.

Representative example of postremission chemotherapy. CALGB 8811 (Larson 1995)

Drugs* Days

Early intensification
(4 wk, repeat once)
MTX 15 mg i.t. 1
CY 1.000 mg/m2 i.v. 1
MP 60 mg/m2 p.o. 1-14
Ara-C 75 mg/m2 s.c. 1-4,8-11
VCR 2 mg i.v. 15,22
ASP 6.000 U/m2 s.c. 15,18,22,25
CNS prophylaxis
+interim maintenance
(12 wk)
Cranial irradiation
24 Gy on
days1-12
MTX 15 mg i.t. 1,8,15,22,29
MP 60 mg/m2 p.o. 1-70
MTX 20 mg/m2 p.o. 36,43,50,57,64
MTX 20 mg/m2 p.o. 36,43,50,57,64
Late intensification
(8 wk)
ADR 30 mg/m2 i.v. 1,8,15
VCR 2 mg i.v. 1,8,15
DXM10 mg/m 2 p.o. 1-14
CY 1000 mg/m2 i.v. 29
TG 60 mg/m2 p.o. 29-42
Ara-C 75 mg/m2 s.c. 29-32,36-39
Maintenance
(until 24 mo from
diagnosis)
VCR 2 mg i.v. every 4 wk
PDN 60 mg/m2 p.o. 1-5
MTX 20 mg/m2 p.o. 1,8,15,22
MP 60 mg/m2 p.o. 1-28

*MTX, methotrexate; CY, cyclophosphamide; MP, mercaptopurine; ara-C, cytosine arabinoside; VCR, vincristine; ASP, L-asparaginase; ADR, adriamycin; DXM, dexamethasone; TG, 6-thioguanine. Mode of administration: i.t., intrathecally; i.v., intravenously; p.o., orally; s.c., subcutaneously.

Representative example of postremission chemotherapy. MDACC Hyper-CVAD (Kantarjian 2000)

Phase Drugs* Days

Dose-intensive consolidation Courses 1**, 3, 5, 7 Courses 2, 4, 6, 8 MTX 200 i.v. (2-h) 1
800 i.v. (24-h)
(citrovorum factor 15 mg every 6-h x8 starting 24-h from finishing MTX)
1
Ara-C 3000 (2-h) i.v./b.d. 2,3
mP 50 i.v./b.d. 1-3
CNS prophylaxis
(low risk: x4
high risk: x16
unknown:8)
MTX 12 mg i.t. 2 (each course)
Ara-C 100 i.t. 8 (each course)
Maintenance (options 1-3)
1. Mature B-cell (B-IV) no maintenance
2. Ph+ ALL IFN 5 MU/m2 s.c. daily (2 years)
Ara-C 10 mg s.c. daily (2 years)
3. Others MP 150 mg p.o. daily (2 years)
MTX 20 mg/m 2 p.o. weekly (2 years)
VCR 2 mg i.v. monthly (2 years)
P 200 mg i.v. 1-5 (with VCR)

*MTX, methotrexate; MP, mercaptopurine; ara-C, cytosine arabinoside; VCR, vincristine; P, prednisone; mP, methylprednisolone; IFN, alpha-interferon
**Course 1 as induction course , courses 2-8 as consolidation courses
Mode of administration: i.t., intrathecally; i.v., intravenously; p.o., orally; s.c., subcutaneously.
Inclusion in these regimens of high dose cytosine arabinoside (4 to 12 doses at 1 to 3 g/m2), high dose methotrexate (usually up to 3 g/m2) or high dose etoposide is suitable for individual clinical use on a type 3 level of evidence (Hoelzer 1993b, Kantarjian 2000, Linker 2002, Ellison 1991 ) especially for intermediate and high risk patients. Additionally, patients with high-risk features are often considered for high-dose myeloblative procedures followed by transplantation of haematopoietic stem cells from histocompatible siblings or from an autologous source.

Innovative postremission chemotherapy trials for adult ALL

Study (ref.) Treatment program Probability of remission

GMALL 04/89* High-risk (Hoelzer 1993b) arm A 0.46 at 3 yr
arm B 0.64 at 3 yr
San Francisco
(Linker 1991)
Cyclical** 0.56 at 5 yr

*similar to basic GMALL regimen plus random assignement to either high-dose Ara-C + mitoxantrone (arm A) or high-dose methotrexate + L-asparaginase (arm B) **following sequence to be repeated once: 6 daunorubicin/vincristine/prednisone/L- asparaginase; 2. high-dose ara-C/VP-16; 3. high-dose methotrexate/mercaptopurine. Standard maintenance with mercaptopurine/methotrexate.

6.2.2 Central nervous system prophylaxis

For patients who do not present with overt CNS involvement at the time of diagnosis, prophylactic treatment for the CNS is standard treatment on a type C basis. Adults with ALL not undergoing early CNS-directed treatment may suffer from meningeal or neurologic involvement before the occurrence of overt bone marrow relapse. The cumulative risk of CNS leukaemia with no prophylactic regimen can be as high as 30% (7% during induction, 14% while in remission, and 5% simultaneously with marrow relapse). The risk is higher in cases with T-lineage ALL, mature B-ALL, high white blood cell count, elevated serum LDH, and rapidly proliferating cells (S+G2M >14%). Identification of risk factors for CNS disease is pivotal in order to avoid unnecessary and toxic prophylactic treatment in low-risk cases (Omura 1980, Kantarajian 1988). The type and intensity of CNS prophylaxis affect subsequent meningeal relapse rates, which vary from 13-15% with intrathecal therapy with/without cranial irradiation or with high-dose systemic chemotherapy (cytarabine, methotrexate) alone, to 8% with intrathecal therapy plus high-dose therapy, to 5% combining intrathecal, systemic high-dose and radiation therapies ( Cortes 1995, Goekbuget 1998, Cortes 2001, Surapeni 2002). The standard option on a type C basis for the prevention of CNS disease is based on intrathecal therapy with methotrexate or triple treatment (methotrexate plus ara-C plus corticosteroids) plus cranial irradiation (most schedules employ 24 total Gy delivered over 15-20 days, but 18 Gy are also effective) (Pinkel 1994). It is not yet clear whether consolidation regimens including high dose cytosine arabinoside or high dose methotrexate, that are increasingly used, could substitute for intrathecal therapy and could be considered suitable for individual clinical use (Cassileth 1992, Morra 1986, Wiernik 1993) or may represent a matter for further clinical studies, but only in patients at low risk of meningeal recurrence. The same conclusions may apply for systemic high-dose ara-C or methotrexate-treated patients, to the role of additional irradiation. Combined triple modality CNS prophylaxis is highly effective but is expected to increase the incidence of toxic side effects to the brain, although these effects are poorly known in adult compared to childhood ALL. The use of 18 Gy irradiation instead of 24 Gy irradiation may help to limit toxicity ( Cortes 2001). Intrathecal therapy should probably commence very early during the induction course and continue until completion of consolidation, or longer (up to 2 years) in patients not receiving cranial irradiation, particularly in the presence of high-risk features for the development of this complication. Delayed CNS prophylaxis is expected to increase the rate of meningeal relapse. Of note, imatinib mesylate does not appear active for the prevention of CNS disease in Ph+ ALL (Takayama 2002).

6.2.3 Maintenance therapy

Maintenance treatment consists of prolonged continuous administration of mercaptopurine and low dose methotrexate. The rationale for the use of maintainance therapy includes control of slowly growing leukemia cell subsets by killing or apoptosis and host immune response enhancement. The precise role of standard prolonged maintenance is undefined, but omitting this phase has been generally associated with worse results in large series ( Cuttner 1991, Cassileth 1992, Dekker 1997,Kobayashi 1999), except for B-ALL (Patte 1994, Hoelzer 1996, Fenaux 2001), where maintenance treatment is no longer considered necessary. Therefore, prolonged maintenance therapy phase after standard-intensity treatments is standard therapy on a type C basis. Repeated cycles of consolidation therapy during the maintainance phase remain investigational.

6.3 Principles of myeloablative therapy with haematopoietic stem cell rescue

6.3.1 Autologous and allogeneic haematopoietic stem cell rescue

The linear relationship between drug dosage and tumour response determined for some cancers, including leukaemias, has led to the development of very high-dose treatments which are able to induce permanent myeloablation and possibly eradicate the underlying malignancy ( Bensinger 1993,Barrett 1994, Fleming 1996, Labar 1996, Frassoni 1996, Appelbaum 1997a, Weisdorf 1997a, Rowe 1997, Abdallah 2001). This requires, for patient survival, an haematopoietic stem cell rescue with either bone marrow (BM) or peripheral blood-derived stem cells (BSC) obtained from fully or partially histocompatible siblings or unrelated volunteer donors, or directly harvested from the patient at a convenient time during remission. These procedures are known as allogeneic or autologous BM or blood-derived stem cells transplants, respectively (Molineux 1990, Makrynikola 1991, Henon 1992, To 1992, Roberts 1993, Langenmayer 1995, Muroi 2000). In the allogeneic setting, the antileukaemic effect is strictly associated with the occurrence of a graft-versus-host (GVH) disease ( Appelbaum 1997b, Zikos 1998, Passweg 1998, Cornelissen 2001, Uzunel 2001). Transplant with CD34 antigen-positive BSC offers, in comparison to BM cells, a significantly faster haematological and immunological recovery, especially during autologous transplantation, thereby decreasing therapy-related toxicity. CD34+ BSC can be obtained from normal donors with a brief exposure to myeloid growth factors, i.e. G-CSF or GM-CSF, and in remission patients after consolidation treatment plus growth factors.

6.3.2 Purging of autologous stem cells

In the autologous setting, harvest contamination by minimal residual disease is possible and is considered in part responsible for subsequent treatment failure. To reduce this risk, autologous BM and BSC can undergo in vitro manipulations prior to freezing and reinfusion, with cytotoxic monoclonal antibodies to ALL-related cell epitopes, drugs (mafosfamide), a combination or other ( Uckun 1987,Preijers 1989, Uckun 1990, Morishima 1993, Soiffer 1993, Laporte 1994, Rambaldi 1998). While these efforts are theoretically worthwhile, clinical evidence in favour of in vitro purging is still lacking (Gilmore 1991), and the procedure remains investigational or suitable for individual clinical use in selected patients (very high-risk patients, monitoring of minimal residual disease) on a type 3 level of evidence (Hagenbeek 1989, Ramsay 1985, Schultz 1989, Janossy 1988, Martin 1999, Granena 1999,Atta 2000, Martin 2001, Gorin 2002).

6.3.3 Role of conditioning regimen

Attempts to improve on the traditional cyclophosphamide plus total body irradiation (TBI) conditioning regimen were made in order to reduce the risks of both toxicity and recurrence of ALL. Use of high-dose cytosine arabinoside at 3 g/m2/dose (generally for 12 consecutive doses over six days) instead of cyclophosphamide was associated with lower relapse rate but greater incidence of toxic deaths in older age groups, so that overall leukaemia-free survival was unmodified. This program can be considered suitable for individual clinical use in selected patients of younger age at very high risk of relapse on a type 3 level of evidence ( Weyman 1993). The addition of melphalan 140 mg/m2 to the former regimen was highly effective in terms of reduced relapse rate but highly toxic (Deconinck 1997). With reference to radiation-free regimens in the allogeneic setting, a large retrospective European study showed no significant difference between results obtained with or without TBI-regimens, so that in the allogeneic setting radiation-free regimens are currently suitable for individual clinical use on a type 3 level of evidence (Labopin 1995). The busulphan-cyclophosphamide conditioning regimen seems however to be associated with a greater incidence of veno-occlusive disease (Hartman 1998). Another retrospective European analysis showed a survival advantage for patients undergoing autologous transplants that included TBI-regimens compared to radiation-free regimens (63% versus 41%). TBI conditioning is thus suitable for individual clinical use in the autografting procedures on a type 3 level of evidence ( Ringden 1996). A recent review focused on the feasibility and theoretical superiority of hyperfractionated regimens with high total doses (up to 15 Gy) over single-dose TBI or doses not exceeding 12 Gy (Shank 1994). Because radiation therapy is not cross-resistant with any other drug, increased-dose TBI may be suitable for individual clinical use on a type 3 level of evidence (Uckun 1991, Uckun 1993b) in allogeneic or autologous BM/BSC transplants of patients with high-risk, radioresistant CD3+ T-ALL and CD24- B-lineage ALL subsets. Intensified, TBI-based conditioning regimens were reported effective in Ph+ ALL and should be matter of further investigation (Kroeger 1998, Snyder 1999). A similar etoposide-TBI regimen (TBI 13.2 Gy) is currently being tested for both allogeneic and autologous transplantation of either Ph positive or negative adult ALL in a large joint European-North American clinical trial ( Durrant 2000,Rowe 2001). The role of non-myeloablative stem cell transplanation in adult ALL is presently unknown, and should be further investigated as an option for patients with contraindications to standard myeloablative therapy.

6.4 Supportive care

6.4.1 Prevention and treatment of metabolic complications

Renal function impairment, often correlating with hyperuricaemia is often observed at diagnosis in patients with ALL, and in particular in B-ALL and hyperleukocytic T-ALL. Hyperuricaemia and renal impairment can further worsen during therapy due to rapid cell destruction. Close monitoring and adequate supportive measures are recommended in all patients starting chemotherapeutic programs for ALL, and in particular in patients at risk with creatinine levels > 1.6 mg/dl, uric acid > 8 mg/dl and elevated serum potassium or phosphorous. Sufficient parenteral fluid administration to guarantee urine production of at least 100 ml/h and allopurinol 100 mg/8h reduce the danger of uric acid formation and of urate nephropathy. Recombinant urate oxidase (Rasburicase) is a new potent uricolytic agent, the use of which may be recommended on a type 2 level of evidence, instead of allopurinol, for the management of patients with extreme hyperuricaemia and/or at high risk of developing the tumour lysis syndrome ( Pui 2001).

6.4.2 Management of infections

The risk of infections is principally related to the occurrence of prolonged disease- or treatment-related severe neutropenia < 0.5 x109/l, other contributing factors being drug-induced mucositis, use of permanent intravenous devices, hospitalization and exposure to environmental pathogens such as fungi and Pseudomonas species. Because fever may be minimal or absent in severely neutropenic patients, or be masked by concomitant corticosteroid medications, it is recommended that the possibility of infection should be considered not only in the neutropenic febrile patient but also in afebrile patients complaining of malaise, hypotension, tenderness of high risk body sites, mucosal ulcers and changes in the skin surrounding intravenous catheters. Routine examination of patients at risk include evaluation of tender areas, oral cavity, perineum, a chest X-ray and culture of blood and urine. In ALL the incidence of infections varies widely according to patient age and treatment intensity. During induction, the incidence can vary between 30% and 100%, and during consolidation and maintenance therapy between 3% and 75%. Average infectious death rates during induction therapy are approx. 6%, during consolidation chemotherapy approx. 3%, during autologous bone marrow transplant approx. 5%, and during allogeneic bone marrow transplant approx 18%. The fatality rate for patients developing interstitial pneumonia during allotransplants is approx. 10%. In the past, most feared infections were caused by gram negative aerobes, such as E. coli, K. pneumoniae and P. aeruginosa. In recent years an increased incidence of infections by fungal species (mainly Candida and Aspergillus species) and Gram-positive rods has been noted. Pneumocystis carinii remains an important opportunistic pathogen to be considered in the immunosuppressed patient. Communal viral pathogens include herpes simplex, cytomegalovirus, varicella-zoster and Epstein-Barr viruses. Modern rules for optimal use of antimicrobial agents in neutropenic cancer patients ( Hughes 2002) and specifically in leukemia patients (Bassan 2002) have been reviewed and should therefore be adhered to on a type C basis. Prophylactic use of antibiotic therapy has shown to clearly reduce incidence of certain infection episodes, although it may be responsible for selection of resistant organisms. Therefore, the prophylactic use of oral fluoroquinolones to prevent Gram-negative infections can be considered suitable for individual clinical use on a type 3 level of evidence (Hughes 1990, Klastersky 1993, Pizzo 1993, Karp 1993, Chanock 1997, Hughes 2002) in patients expected to experience chemotherapy-induce severe neutropenia of long duration (>7-10 days), or when institutional review data suggest a high risk for Pseudomonas. Initial standard treatment on a type C basis for the febrile patient is monotherapy with a third generation cephalosporin or with a carbapenem ( Freifeld 1995, Sanders 1991) or, better, with dual antibiotic therapy. In this latter case, empirical treatment with a broad-spectrum antibiotic regimen including an antipseudomonal (extended-spectrum penicillin or new cephalosporin) plus an aminoglycoside can be recommended. The adjunct of a third drug against Gram-positive bacteria (vancomycin or teicoplanin) or fungi (amphotericin B, liposomal amphotericin B), modifications of the initial regimen (imipenem, aztreonam, metronidazole, clindamycin, co-trimoxazole), based on the microbiological test results and clinical reassessment, is suitable for individual clinical use. Routine association of vancomycin is not recommended on a type 1 level of evidence as initial treatment of febrile neutropenic patients unless a catheter related infection is suspected (Ramphal 1992, EORTC 1991). Persistent fever with negative microbiological results requires a search for hidden fungal infections, viruses, and noninfectious causes such as drug reactions and blood recovery syndromes. Prophylactic use of the new azoles (fluconazole and itraconazole) available to prevent fungal infections in patients treated with chemotherapy for ALL has not been shown to clearly decrease either overall morbidity or the therapeutic use of amphotericin B ( Winston 1993). Their prophylactic use should be regarded as suitable for individual clinical use on a type R basis. Empiric antimycotic treatment of the febrile neutropenic patient should be started when persistent undocumented fever lasts more than 5 days from beginning of empirical broad spectrum antibacterial treatment. Herpes virus infections resolve rapidly with acyclovir. Prophylactic administration of oral acyclovir is recommended on a type 2 level of evidence (Saral 1983) for patients with positive serology for HSV. Cytomegalovirus infection is treated with immunoglobulin, ganciclovir or foscarnet, and transfusion of cytomegalovirus-negative blood products to cytomegalovirus-negative patients. Varicella Zoster virus infection is treated with high dose intravenous acyclovir. Early use of VZV-immune globulin in the case of exposure of an immunedepressed patient (within 96 hours) is recommended to reduce intensity of the infection and spread of the infection to other patients.

6.4.3 Management of coagulation impairment

Thrombocytopenic bleeding is managed by a regular transfusion with single or multiple donor platelets to maintain a count >10 x109/l. Bleeding is infrequent in uncomplicated afebrile patients with a platelet count >10×109/l and normal fibrinogen (Gmur 1991, Schiffer 2001). L-asparaginase is toxic to the liver and may cause hyperglycaemia and disturbances of clotting factor synthesis, including fibrinogen, antithrombin and other inhibitors, that predispose to haemorrhagic as well as thrombotic events (Barbui 1993, Alberts 1999). When the fibrinogen level falls < 50 mg/dl or when any haemostatic accident not related to thrombocytopenia occurs, discontinuation of L-asparaginase is recommended. Administration of fresh frozen plasma is appropriate in the case of major bleeding and very low fibrinogen levels before clinically relevant disseminated intravascular coagulation (DIC) phenomena occur ( Sarris 1992). Heparin administration is not recommended in severely thrombocytopenic patients with or without DIC, but it may be appropriate in patients with cerebral thromboses with platelets >50×109/l, when the APTT ratio should be adjusted to between 1.5-2.

6.5 Upfront treatment strategy for all patients (low risk and high risk patients)

Optimal supportive care is the first therapeutic intervention required for all patients. Conventionalremission induction programs based on a vincristine and prednisone combination plus an anthracycline are standard treatment on a type 2 level of evidence (Gottlieb 1984, Stryckmans 1992 ). There is uncertainty as to the best anthracycline compound. Inclusion of a fourth or fifth drug, namely L-asparaginase and cyclophosphamide, in the remission induction program can be currently considered as suitable for clinical use on a type 3 level of evidence for patients at low risk and recommended as standard treatment on a type R basis for patients at intermediate and high risk(Kantarjian 1993a, Larson 1995, Hoelzer 1993a, Rohatiner 1990, Kantarjian 2000). Pushing treatment intensity in the remission induction phase beyond this point (e.g., introducing high dose cytosine arabinoside or high dose methotrexate) may be detrimental because of drug-associated toxicities (Weiss 1996, Wernli 1994, Bassan 1993 ). There is no proof that high-dose regimens differing from vincristine + prednisone + anthracycline +/-cyclophosphamide/L-asparaginase could be anything better. These regimens remain investigational. The early concomitant use of G-CSF at 5 mg/kg/d as an adjunct to induction therapy is recommended on a type 1 level of evidence (Ottmann 1995,Ottmann 1996, Larson 1998a, Geissler 1997, Ottmann 1998), particularly with the more myelotoxic schedules employing anthracyclines on three consecutive days and in the elderly. CNS prophylactic treatment early during induction phase is standard treatment on a type C basis.

6.6 Post-remission strategy: different approaches for different risk groups or uniform treatment

Three major post-remission approaches are possible, of which two address relevant prognostic and treatment-related issues in a prospective fashion. Thus far, none has proved superior. The first option is focused on clinical risk class, varying treatment type and intensity acording to risk. Patients at low-intermediate risk and/or with discrete diagnostic features (e.g. T-ALL, B-ALL etc.) are treated with chemotherapy programs that incorporate risk-/disease-specific elements of variable intensity, while high-dose procedures supported by autologous or allogeneic BM/BSC transplants are reserved for high risk subgroups. This strategy, mainly developed in the last decade by the GMALL group and others (Gokbuget 2000, Goekbuget 2001, Bassan 2001, Hunault 2001 , Linker 2001), is amenable to further refinement by considering the predictive role for relapse of minimal residual disease. The second way is to look directly at treatment-related issues, comparing chemotherapy versus autologous versus allogeneic transplantation in a randomized (or retrospective comparative) trial, trying in first instance to define the best overall treatment. Several such studies were published and updated (Horowitz 1991, Fière 1993, Sebban 1994, Attal 1995, Ueda 1998, Oh 1998, Thiebaut 2000,Thomas 2001b) and some are ongoing (Ribera 2000, Durrant 2000 , Rowe 2001). This option carries the risk of overtreating many low risk patients ( Gale 1998, Finiewicz 1999), considering a transplant-related mortality of 21% (Rowe 2001). The third option consists of the uniform application of a chemotherapy or an autograft-based regimen, seeking to allograft only patients at very high-risk such as those with Ph+ ALL and t(4;11)+ ALL (Larson 1995, Todeschini 1998, Daenen 1998, Bassan 1999a, Kantarjian 2000, Martin 2001a, Powles 1995 , Forman 1997, Powles 2002). The exact role of autologous transplantation and of postgraft maintenance in these studies is undefined.

6.7 Post-remission treatment strategy in good-risk patients

For patients with low-risk ALL, post-remission consolidation chemotherapy within the therapeutic program of conventional dose chemotherapy is standard treatment on a type C basis (Hoelzer 1994,Stryckmans 1992, Ellison 1991, Marcus 1986, Larson 1995, Hoelzer 1993a, Hoelzer 1993b, Lluesma-Gonalons 1991, Todeschini 1998, Kantarjian 2000 , Bassan 2001). Prolonged maintenance therapyafter the consolidation phase is standard therapy on a type C basis, except for B-ALL. Repeated cycles of consolidation therapy during the maintainance phase are investigational. Presently, patients with all low-risk features who receive allogeneic transplants in first remission are therefore regarded as overtreated, moreover, they do not experience a clearly superior outcome ( Gale 1998, Finiewicz 1999, Thiebaut 2000). For these patients high.dose treatment in first remission is investigational (Durrant 2000).

6.8 Post-remission treatment strategy in intermediate risk patients

6.8.1

For intermediate-risk patients , standard treatment on a type C basis (Hoelzer 1994 Stryckmans 1992,Ellison 1991, Marcus 1986, Larson 1995, Hoelzer 1993a, Hoelzer 1993b, Lluesma-Gonalons 1991,Todeschini 1998, Daenen 1998, Bassan 1999a, Kantarjian 2000 , Bassan 2001 ) is the use of innovative intensified consolidation programs. Inclusion in these regimens of high dose cytosine arabinoside (4 to 12 doses at 1 to 3 g/m2), high dose methotrexate (usually 6 to 8 gr/m2) or high dose etoposide is suitable for individual clinical use on a type 3 level of evidence (Hoelzer 1993b,Hoelzer 1994, Kantarjian 2000, Hoelzer 2000 , Linker 2002). Recent allogeneic BMT studies in unselected first remission ALL showed 3 to 5-year disease-free survival rates of 44%-68% but comparisons with similar chemotherapy-treated groups did not disclose any significant advantage. Therefore, intensification with high dose therapy and haematopoietic stem cell support is investigational or suitable for individual clinical use on a type 3 level of evidence ( Fière 1993, Vernant 1988 , Sutton 1993, Attal 1995, Sebban 1994, Vey 1994, Gale 1998, Ueda 1998, Oh 1998, Finiewicz 1999, Thiebaut 2000, Martin 2001a, Durrant 2000). It is also foreseeable that, through insights provided by the study of minimal residual disease and biological aspects of adult ALL, patients belonging to the intermediate-risk group will be eventually regrouped into the low or high-risk subsets, respectively.

6.9 Post-remission treatment strategy in high-risk patients

6.9.1

For high-risk cases , high-dose treatment with allogeneic or autologous haematopoietic stem cell support might be considered standard treatment on a type R basis, with a 5-year survival in remission following allogeneic BMT of 33-58% compared to less than 20% with chemotherapy (Chao 1991,Barrett 1992, Grigg 1993, Oh 1998, Ifrah 1999, Thiebaut 2000 , Durrant 2000, Bassan 2001, Lee 2002). The results are generally better in Ph- subsets than in Ph+ ALL. The impact of an improved conditioning regimen for Ph+ ALL, including high-dose etoposide and hyperfractionated TBI 13.2 Gy (Snyder 1999) is being evaluated in a larger study ( Durrant 2000). Where feasible, allogeneic rather than autologous BMT is suitable for individual clinical use on a type 2 level of evidence (Fière 1993,Vernant 1988, Attal 1995, Dombret 2002). Autologous haematopoietic stem cell support may be suitable for individual clinical use in patients with high-risk features lacking compatible donors (Horowitz 1991, Zhang 1995, Sierra 1993, Doney 1993, Tiley 1993, Carella 1994, Powles 1995, Martin 2001a, Hunault 2001), although its superiority over chemotherapy was never proven in comparative clinical trials ( Thiebaut 2000, Bassan 2001, Ribeira 2000, Durrant 2000, Linker 2001, Sotomayor 2002). Prolonged survival could be obtained in a small fraction of very high-risk patients with Ph+ ALL using a purged autograft with a double autotransplantation procedure (Martin 1999, Atta 2000). Partially matched related donor and matched unrelated donor allogeneic BMTs may be considered investigational in patients with high-risk features lacking compatible donors, and might be especially indicated in those with Ph+ ALL (Szydlo 1997, Marks 1998, Arnold 2002). The role, if any, of haploidentical mismatch transplantation in adult ALL is still totally unknown (Aversa 1996).

6.10 ALL in the elderly

Patients aged >60 years constitute a separate prognostic group where lower remission and survival rates are usually achieved. The incidence of elderly ALL within adult chemotherapy trial reports ranges between 15% and 31%, the higher value being from a population-based study ( Annino 2002a, Taylor 1992). Remission rates in this age group varied from 39% to 77% using unmodified four or five-drug protocols as used in younger adults (Ferrari 1995, Bassan 1996c). However median remission and overall survival durations were < 10% at 3 years in three studies, despite application of multi-drug, relatively intensive consolidation, and 5% at 5 years in a more recent single-centre update (Thomas 2001b). In a relatively younger patient group aged 50-65 years, the GMALL group reported an improved probability of CR of 0.31 at 3 years with the 04/89 protocol. In summary, standard treatment strategy on a type R basis for patients older than 60 years and for elderly patients should include conventional dose remission induction, consolidation and maintenance as for younger adults. However, dose reductions are often necessary and elderly patients can hardly achieve planned dose intensity (Ferrari 1995, Kantarjian 1994, Legrand 1997, Thomas 2001a). Use of hematopoietic growth factors in elderly patients is recommended on a type 2 level of evidence (Larson 1994).

6.11 ALL during pregnency

Because anticancer agents in use to treat adult ALL are teratogenic, particularly antifolates and alkylators, pregnancy is not recommended during drug treatment particularly in the first trimester, on a type C basis (Zuazu 1991). If pregnancy is however unquestionally desired, further management should not be postponed as this will significantly reduce chances of cure for the mother. Standard treatment in this case should consider, according to the risk class of the patient, avoidance of the most toxic drugs such as antifolics, alkylators, and radiotherapy. Transient oligohydramnios of the fetus during each chemotherapy course has been observed. The induction of labour or Caesarean section is desirable as soon as the fetus is viable and during the remission phase ( Zuazu 1991, Durie 1977, Fassas 1984 , Hansen 2001).

6.12 Restaging and response criteria

6.12.1 Definition of response

A complete response to induction chemotherapy on presentation is designated complete remission (CR). CR requires the patient to be in good health, with untransfused haemoglobin and platelet levels >10 g/dl and 100 x109/l respectively, neutrophils >1.5 x109/l, no circulating blast cells, no blast cells in the cerebro-spinal fluid and previously involved extramedullary sites, and the bone marrow to be normocellular or slightly hypocellular (regenerating with cellularity >25%) with normal trilineage haemopoiesis and blast cells 25% define primarily refractory disease. The second type of induction failure is death due to complications during treatment, before response could be evaluated. Recurrent ALL is diagnosed in CR patients when bone marrow blasts exceed 5%, or when ALL cells are detectable in the cerebro-spinal fluid or other extramedullary sites.

6.12.2 Restaging strategy and response evaluation problems

It is recommended that bone marrow morphology is checked following completion of the induction course, approximately on days 21-28 or later in patients with evidence of slow haematopoietic recovery. Use of standard criteria for response evaluation is important since time to CR (within 4 weeks or longer) may be prognostically relevant. Bone marrow biopsy is seldom necessary, but it is recommended in doubtful cases or when aspirates are hypocellular without clear evidence of persisting disease. Studies with monoclonals, cytogenetics, and molecular probes can be performed: these techniques are investigational but allow a more precise identification of residual disease than morphology. Overall survival is calculated in all patients from date of diagnosis to death by any cause. Durability of CR is calculated from date of CR to relapse in any site, death, or last follow-up. In chemotherapy studies, patients at risk, lost to follow-up or submitted to transplants are not included. Kaplan-Meier statistics, logrank analysis, Cox’s proportional hazards model, and Fisher’s test or chi-squared test with Yates’ correction are recommended to evaluate and compare results in different prognostic groups.

6.13 Salvage therapy

6.13.1 Chemotherapy of relapsed disease

The first therapeutic step in treating relapsed ALL is to confirm the original diagnosis (Chucrallah 1995) ruling out a secondary leukemia and to start a second remission induction program. Response to reinduction programs varies, but the best results have been obtained when anthracyclines, mitoxantrone, AMSA, spindle venoms/podophyllotoxins were combined with intermediate/high-dose Ara-C (Arlin 1982, Milpied 1990, Freund 1992, Welborn 1994, Henze 1995). Therefore, reinduction regimens including intermediate/high dose cytosine arabinoside are standard treatment on a type R basis ( Bassan 1996c , Weiss 1997, Weiss 1998, Giona 1994, Kantarjian 1992, Giona 1997,Hiddemann 1990, Koller 1997, Montillo 1997, Giona 1998, Thomas 1999, Martino 1999, Rosen 2000,Garcia-Manero 2001, Weiss 2002). These retreatment programs gave second or later CR rates between 37%-75%. Unfortunately long-term response rates with chemotherapy are below 10% and median duration of second CR is very short (about 3 months when relapse occurs after modern intensified first-line regimens), although it may vary from 2-11 months according to the cumulative incidence of risk factors (short first CR 40 years, circulating blasts) (Garcia-Manero 2001).

6.13.2 Stem cell transplantation as salvage therapy

Because the only way cure can be obtained in 25%-45% of relapsed patients is with allogeneic BMT (Chao 1994, Fleming 1994, Bassan 1996a, Giona 1998, Thomas 1999, Garcia-Manero 2001), the search for a donor is recommended on a type R basis for eligible patients in first relapse Partially matched related donor and matched unrelated donor allogeneic BMTs were also shown to offer survival possibilities, and are suitable for individual clinical use on a type 3 level of evidence for patients without a matched related donor (Busca 1994, Matthews 1995, Cavazzana-Calvo 1996). The crucial issues are that many patients do not have a suitable marrow related donor, that matched unrelated donor are found only in a few cases after a long search, and that prompt patient referral to a transplant centre may be delayed for medical complications or logistic problems. Autologous BM/BSC transplants may be suitable for individual clinical use in selected patients with high-risk features who lack compatible donors (Ager 1995), Carella 1995, Deane 1998). However, in recent trials directly comparing chemotherapy and allogeneic or unpurged autologous BMT, there were no major differences between chemotherapy and autologous BMT arms, while the data in favour of an allogeneic BMT was, with few exceptions, modest (Bassan 1996a, Giona 1998, Martino 1998, Thomas 1999, Mengarelli 2002). A large review of the European experience confirmed that disease-free survival of advanced-stage ALL patients undergoing transplants was significantly better with a TBI regimen than without TBI. Because lymphoid cell survival is abrogated at the 15 Gy level, hyperfractionation limits pulmonary and gastrointestinal toxicity, and relapse can follow a 12 Gy TBI dose in radiation resistant B and T cell ALL subsets. TBI dosages higher than 12 Gy are recommended at relapse on a type R level of evidence, particularly in the autologous transplant setting where the risk of interstitial pneumonitis is low. Increasing even further radiation dose to haematopoietic tissue by adopting a combined technique of external TBI plus intravenous 131I-labelled anti-CD45 antibody remains investigational. In cases with only low-risk features (age 12-18 months) retreatment strategy with intermediate intensity, high-dose cytosine arabinoside-containing regimens can be considered suitable for individual clinical use on a type R basis, to avoid the risks of partially matched related donor and matched unrelated donor (MUD) allogeneic BMTs (Weisdorf 1997b).

6.13.3 Salvage of refractory disease

The incidence of primarily refractory ALL with modern regimens can be as low as 5% and is generally within 10%. For eligible patients the search for a bone marrow donor or, alternatively, autologous BM/BSC transplants is suitable for non standard clinical use on a type R basis. Partially matched related donor and matched unrelated donor allogeneic BMTs may be suitable for individual clinical use in selected patients with high-risk features who lack compatible donors. For patients who are not candidates for myeloablative therapy, salvage regimens such including high-dose ara-C plus mitoxantrone and fludarabine (CR 50%) or alternative experimental therapies (link 6.14) might be considered suitable for individual clinical use on a type 3 level of evidence (Hiddemann 1990, Kern 2001, Garcia-Manero 2001 ).

6.14 Biotherapy

6.14.1 Biological therapies

Because of the tremendous advances in immunobiological and pharmacological knowledge, exploitation of biologically-oriented strategies is advisable (Hoelzer 2000, Kantarjian 2001). Use of myeloid cell growth factors, tracking of minimal residual disease, and BM/BSC in vitro purging procedures are aspects of this topic already covered in previous sections. Another point of interest was the demonstration that ALL cells may be susceptible to lysis by autologous LAK (lymphokine activated killer cells) or cytotoxic T lymphocytes (CTL) generated by using the CD40-stimulating strategy generated with interleukin-2, although not always and without clear correlation with clinical outcome. Interestingly, drug-resistant blasts are less sensitive to cell-mediated cytotoxicity too (Classen 1999 ). Adoptive LAK/T cell therapy can be considered investigational or suitable for individual clinical use in selected patients (LAK/CTL-susceptible ALL) on a type 3 level of evidence (Archimbaud 1991, Lauria 1994, Nemunaitis 1997, Cardoso 1999, Velders 2001, Gribben 1997,Lowdell 2002). Indeed, the results of a randomized trial did not support any role for IL-2 in this disease (Attal 1995). Treatment with alpha-interferon (IFN) was advocated for Ph+ ALL and can be considered investigational or suitable for individual clinical use in selected patients (Ph+ ALL) on a type R basis (Grigg 1993, Kantarjian 2000, Visani 2000).

6.14.2 Indications for biological therapies

The use of IL-2, and alpha-interferon (Ph+ ALL), reversants of drug-resistance and inducers of apoptosis (IL-4 can induce apoptosis in B-precursor ALL) could be potentially useful. IL-2 was used to generate killer cells in cultured bone marrow for autologous transplantation (Beaujean 1995). Resistance to apoptosis can be circumvented in T-ALL as well. However the short-term and long-term toxicities of these agents are poorly understood, so that these studies require a careful design and supervision and are regarded as investigational. Similarly, anti-sense oligonucleotides must undergo clinical testing (de Fabritiis 1995). The positive selection of nonleukaemic CD34+ BSC for autotransplants is a sound theoretical approach, based on the previously found correlation between residual ALL cells in harvests and subsequent recurrence. Preliminary evidence from pilot studies in Ph+ ALL indicated that both bone marrow immunomagnetic purging and BSC collection may sometimes result in a decreased BCR-ABL rearrangement signal compared to baseline and bone marrow, respectively. Experimental clinical trials were initiated accordingly. These therapies remain investigational.

6.15 Recent developments

New therapeutic possibilities are emerging from the fields of apoptosis and drug resistance research. Systems to overcome MDR phenotypes and other resistance mechanisms are within reach. In vitro reversal of the MDR phenotype was shown to be possible with cyclosporin A or the new non-immunosuppressive agent SDZ PSC 833 in ALL (Slater 1986, Gonzalez 1995, Jiang 1995). Decreased cellular uptake of methotrexate is more common in adult ALL compared to childhood disease. Recent studies in SCID mice hosting the CCRF-CEM methotrexate-resistant T-ALL cell line showed that a combination of trimetrexate plus folinic acid rescue followed again by methotrexate to eliminate trimetrexate-resistant cells can be highly effective (Lacerda 1995). Resistance mechanisms to cytosine arabinoside are poorly understood in adult ALL, probably because of the limited use of this drug thus far. Since high-dose ara-C is a component of some of the most promising new regimens and since higher doses have been suggested to be more effective than intermediate doses, an in-depth evaluation of this problem is warranted. Recent experience in poor-risk AML indicated a modulation of resistance to ara-C by the purine analogue fludarabine, through inhibition of deoxycytidine kinase and increased intracellular retention of ara-CTP (Gandhi 1995). Possible ways of overcoming drug resistance to thiopurines or caused by other mechanisms such as glutathione s-transferase and others have yet to be found . Both topotecan, a new topoisomerase I inhibitor, and interleukin-4 were found very effective in causing rapid apoptotic cell death of radio-resistant B-lineage ALL cells, including t(4;11) and t(8;14) ALL cell lines and very poor-prognosis Ph+ ALL (Kantaraijan 1993b,Manabe 1994, Uckun 1995). New drugs include also troxacitabine, a farnesyltransferase inhibitor, compound GW 506 for T-ALL, and antiangiogenesis agents (Giles 2001, Karp 2001). All these innovative forms of treatment must be regarded as investigational. Data regarding molecular engineering, from antisense oligonucleotides to gene therapy, are theoretically interesting but not yet sufficiently developed to be employed in the clinical setting.

6.15.1 Latest developments

Two new targeted therapeutic tools hold great promise and need to be discussed separately. These are the humanized cytotoxic monoclonal antibodies and the the BCR-ABL-specific tyrosine-kinase inhibitor STI571 for Ph+ leukaemias. Roughly 40% of B-lineage ALL express the surface antigen CD20 that can be targeted by Rituximab, a humanized cytotoxic anti-CD20 monoclonal antibody. Studies investigating other immunotoxins against CD19, CD22, and the pan-lymphoid antigen CD52 (Campath1-H) have been done or are underway (Uckun 1999, Herrera 2000, Jandula 2001). The possibility also exists for the therapeutic use of an anti-CD33 calicheamicin conjugate in My+ ALL (My+ Ph+ ALL) (De Vetten 2000). These studies are investigational. Ph+ ALL is the subset with the worst prognosis. STI571 is a specific and highly effective inhibitor of the BCR-ABL tyrosine kinase in Ph+ chronic myeloid leukemia (CML), and was also found active in the lymphoid blast crisis of CML and de novo Ph+ ALL ( Druker 1996, Druker 2001a, Druker 2001b, Ottmann 2002, Wassmann 2002). Mechanisms of activity of STI571 against Ph+ lymphoid blasts were investigated, as well as patterns of resistance and synergy with other drugs (especially Ara-C, alpha-interferon, anthracyclines, farnesyl-transferase inhibitors and others) (Thiesing 2000, Fang 2000, Tipping 2002, Topaly 2002,Visani 2002). Possible therapeutic synergies have been identified in in vitro studies that should be exploited in vivo, as response to imatinib alone in patients with advanced disease is rather poor. Mechanisms of resistance are being elucidated (Branford 2002, Hochhaus 2002, Hoffmann 2002). Studies have been initiated worldwide to exploit the therapeutic potential of STI571 in conjunction with chemotherapy and/or transplants in Ph+ ALL. The use of imatinib in Ph+ ALL is recommended within a clinical study on a type 3 level of evidence. Since it appears that reaching a negative molecular BCR-ABL status in vivo is a major prognostic advantage, it appears that imatinib-chemotherapy combinations should be evaluated according to the former clinical endpoint and that, additionally, an effort should be made towards the incorporation of imatinib therapy in the postgraft management of patients who remain BCR-ABL positive. A different, specific tyrosine kinase inhibitor was developed against CD19+ ALL. These trials are investigational.

7. LATE SEQUELAE

7.1 Late effects of treatment

7.1.1

Unlike the childhood setting, long-term survivors exposed to relatively high doses of anthracyclines (daunorubicin, adriamycin 300-405 mg/m2, idarubicin >100 mg/m2) have not been reported to develop cardiac problems at unusually high rates, but prospective comparisons are lacking (Bassan 1991, Todeschini 1994). With idarubicin, in the closely related setting of adult AML, cardiac toxicity was uncommon up to a dose level of 290 mg/m2. Additionally, endocrine, gonadal, and CNS functions may be damaged to some extent (due to the psychosocial distress caused by severe vascular disease and brain tumours) but neither the incidence nor severity of these treatment side-effects are known with certainty in adults with ALL exposed to current intensive regimens (Chan 2001, Kornblith 1998). Loss of active immunization caused by intensive chemo-radiotherapy is common, but late reimmunization with vaccines is usually not recommended and is not performed except in patients receiving transplants (Ridgway 1993). A recent review on transplant survivors (Socie 1999), regardless of initial diagnosis, age, and disease status, reported the following types and incidence of delayed complications: airway and pulmonary disease 10%-15%, occasional autoimmune dysfunction (blood cytopenia, myasthenia gravis, other autoantibodies), thyroid dysfunction 2%-56%, cataracts 30%-80% at 6 years with TBI regimens, occasional aseptic necrosis of the humerus or femur heads, occasional radiation nephritis, and secondary malignancies. As an overall effect, mortality rates are higher in these patients for many years following transplant (Deeg 1994).

7.2 Secondary tumours

Secondary cancers may be induced by curative chemo-radiotherapy previously administered for another neoplasm. Several active anti-ALL drugs including alkylators, etoposide, and radiation therapy bear the risk of second cancers (Pederson-Bjergaard 1991). The estimated incidence of secondary malignacies appear to rise over time from 0.59% and 3.63% (only secondary haematological cancers, 942/1170 patients in remission) at 5 and 10 years, respectively, as documented by a large retrospective analysis from the GIMEMA group (Pagano 1998), to 8% and 27% (all types of cancer) at 10 and 20 years, respectively, in a smaller series (34 patients) from Bart’s Hospital (Micallef 2001). Transplant survivors may have an overall incidence of secondary malignancies of 0.6/100 person years, corresponding to 6% (no TBI) and 10% (TBI) at 10 years. Postransplant malignancies in order of prevalence are lymphoproliferative disorders (which may or may not be associated with EBV infection), carcinoma, glioblastoma, acute leukaemia (ALL>AML), myelodysplastic syndrome, and melanoma. Most of these neoplasms are fatal. Etoposide, which is being increasingly used in ALL, induces chromosomal changes in the 11q region, leading rapidly (within 2 years) to a secondary acute myelomonocytic/monoblastic leukaemia with 11q23 rearrangements. The risk for this complication may be increased by the simultaneous use of other topoisomerase II inhibitors and L-asparaginase (Pui 1995), and was as high as 6% in recent pediatric series (Winick 1993). However, neither exact incidence of 11q23 AML nor additional risk factors are known for adult ALL survivors. The recently described occurrence of secondary ALL with chromosomal rearrangements at 11q23 raises the challenging question of therapy-related ALL in patients previously cured of ALL.

8. FOLLOW-UP

8.1 General principles and objectives

Detection of relapse and treatment complications are the two objectives of a regular follow-up. Uncomplicated patients in remission have a remarkably good performance status and are quickly back to work and a normal life-style, both of which should be encouraged. At completion of treatment, the patient or relatives can be told about the probability of cure, in his or her particular case. It should be emphasized that even at relapse curative-intent therapy would be possible. Because of this possibility, patient’s notes must include retreatment plans and family HLA and DR typing.

8.2 Suggested protocols

During the prolonged maintenance phase, it is recommended on a type C basis to monitor patients closely, every 2-3 weeks, in order to optimize the adherence to treatment protocol and an appropriate drug intake. Drug dosages are adjusted to maintain a total leukocyte count between 2.5-3 x109/l. Because there is no proof that detection of subclinical early relapse substantially alters the subsequent therapeutic conduct and overall prognosis, periodic bone marrow sampling in asymptomatic patients is not recommended. Similarly, surveillance lumbar punctures are not recommended in asymptomatic remission patients. The detection of an early molecular relapse during periodic monitoring of MRD may raise the issue of treatment for asymptomatic patients. This topic should be examined in well designed clinical trials. Cases developing unexplained blood cytopenia are first withdrawn from drug therapy and then re-evaluated at weekly intervals. Bone marrow is examined if cytopenia progresses or blast cells are disclosed in the blood smear. Routine biochemistry must be evaluated periodically, since maintenance drugs can impair liver function tests. Mild elevation of transaminases and other abnormalities do not require drug reductions, but since most patients at this stage will have been exposed to transfusion therapy, a serologic profile for hepatitis B and C virus infection is recommended. Following completion of all chemotherapy, patients are checked every 2-3 months for the first year and at greater intervals subsequently until once a year at 5 years and beyond. Outpatient checks include disease-oriented clinical examination (lymph nodes, spleen liver, testes, ocular fundi) and full blood counts with differentials. Other tests and bone marrow examination will depend on actual symptoms and problems.

INDEX

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Dr. Renato Bassan (Associate Editor)
Ospedali Riuniti – Bergamo, Italy
mail: rbassan@ospedaliriuniti.bergamo.it

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy
mail: carlo.tondini@ospedaliriuniti.bergamo.it

Dr. Roel Willemze (Reviewer)
Leiden University Medical Center – Leiden, The Netherlands
mail: R.Willemze@lumc.nl