| Adult acute lymphoblastic leukaemia (ALL) |
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1. GENERAL INFORMATION 2. PATHOLOGY AND BIOLOGY 3. DIAGNOSIS 4. STAGING 5. PROGNOSIS 6. TREATMENT 7. LATE SEQUELAE 8. FOLLOW-UP References Contributors
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 Survival1.2.1 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 factorsLittle 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 ReferralBecause 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 reviewson aetiology
2. PATHOLOGY AND BIOLOGY
2.1 Diagnosis study 2.1.1 Morhological classification 2.1.2 Immunophenotyping
2.1.3 Cytogenetics 2.1.4 Genomic changes 2.2.1
3.1 Physical and instrumental diagnosis 3.1.1 Clinical presentation 3.1.2 Laboratory findings 3.2.1 Appropriate diagnostic sampling 3.2.2 Appropriate handling of diagnostic specimens
4. STAGING
4.1 Staging procedures Routine staging procedures in adult ALL should include (Hoelzer 1991
):
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 factorsThe 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 5.2.2 Cell count 5.2.3 Time to response 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 5.3.2 Cytogenetics and molecular genetics
5.4 Predictive factors 5.4.1 Drug resistance mechanism
5.4.2 Minimal residual disease 5.5.1
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.
6.1 Principles of remission induction phase 6.1.1 Pre-treatment hydration 6.1.2 Remission induction chemotherapy
**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 6.1.4 Growth factors during remission induction
6.2.1 Consolidation therapy
*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.
*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.
*MTX, methotrexate; MP, mercaptopurine; ara-C, cytosine arabinoside; VCR, vincristine; P, prednisone; mP, methylprednisolone; IFN, alpha-interferon
*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 6.2.3 Maintenance therapy 6.3.1 Autologous and allogeneic haematopoietic stem cell rescue 6.3.2 Purging of autologous stem cells 6.3.3 Role of conditioning regimen 6.4.1 Prevention and treatment of metabolic complications 6.4.2 Management of infections 6.4.3 Management of coagulation impairment Optimal supportive care is the first therapeutic intervention required for all patients. Conventional remission 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 treatmentThree 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 patientsFor 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 therapy after 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 patients6.8.1 6.9.1 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 pregnencyBecause 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 criteria6.12.1 Definition of response 6.12.2 Restaging strategy and response evaluation problems 6.13.1 Chemotherapy of relapsed disease 6.13.2 Stem cell transplantation as salvage therapy
6.13.3 Salvage of refractory disease 6.14.1 Biological therapies 6.14.2 Indications for biological therapies 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
7. LATE SEQUELAE
7.1 Late effects of treatment 7.1.1 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 protocolsDuring 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.
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Dr. Renato Bassan (Associate Editor) Dr. Gemma Gatta (Consultant) Dr. Carlo Tondini (Editor) Dr. Roel Willemze (Reviewer)
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