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Non-Hodgkin’s lymphoma

1. GENERAL INFORMATION

1.1 Epidemiology

1.1.1 Incidence and mortality

About 74,000 new cases of NHK are diagnosed in Europe each year, 3% of all malignancies (Ferlay 2004).In 2002 in men, the annual incidence rates ranged from 5 (Eastern Europe) and 16/100,000 (Western Europe), whereas for women the corresponding rates were 4 (Eastern) and 14 (Northern). Incidence is higher in men than women with a M/F ratio of about 1.3 (Figure 1) (Ferlay 2004).
In the world and in men incidence is very low in Asia and some African and Central American regions and high in North America, Europe and Oceania (Figure 2).

Figure 1. Non Hodgkin lymphoma, incidence by age in Northern Europe

Non Hodgkin lymphoma_figure1

Figure 2. Non Hodgkin lymphoma, incidence in the world, age-standardised rates (ASR)

Non Hodgkin lymphoma_figure2

Incidence increases with age, however differently from the epithelial tumours, cases are already diagnosed in childhood and younger ages. For instance, in Northern European men, the annual incidence was 1.1 in children and 4.4/100.000 in young adults (15-44 years). Rates increased faster and they were 14.5, 29.7 and 64.2 in the age groups of 45-54, 55-64 and 65 and more, respectively (Figure 1).

In Europe 37,000 people died for NHL each year (Ferlay 2004).

Mortality and incidence rates increased for many years. Figure 3 shows the incidence trend in some Northern European countries and in the US. In Northern Europe the increase in incidence was apparent already in the 1950s, and in Connecticut, USA, even in the 1930s (Zheng 1992). Interestingly, this increase is not limited in Europe and North America, but has been observed also in Japan, Brazil, India, Singapore and Puerto Rico (Devesa 1992). In the beginning of the 1990s, the rise in incidence began to level off in Sweden and Denmark. In the USA, data from the Surveillance, Epidemiology, and End Results (SEER) Program showed stabilization in overall NHL incidence rates in the early 1990s However, in population groups at low risk of human immunodeficiency virus (HIV)-infection and acquired immunodeficiency syndrome (AIDS), such as men above the age of 55 years and women of all ages, rate increases were still evident through the 1990s (Clarke 2002).

Figure 3. Trend of incidence for Non Hodgkin lymphoma in the USA and Northern European countries in male

Non Hodgkin lymphoma_figure3

1.1.2 Survival

According to the EUROCARE project (Verdecchia 2007; Brenner 2009), 1-5- and 10-year survival for the European patients with NHL diagnosed between 2000 and 2002 was 73, 54 and 42%. Five-year survival of European patients with NHL ranged from 62% in Germany to 41% in Poland. Ten-year survival was mostly 10 or more percent units lower, indicating that the excess risk of death persists for many years after diagnosis. Survival for NHL increased from 49% to 56% during the period 1988-99.  Improvements in treatment are likely to be the main reason (Verdecchia 2009).

1.1.3 Risk factors

Well established risk factors for NHL are primary or genetic disorders of immune dysfunction and acquired states of severe immunosoppression: HIV/AIDS and organ transplantation. However, these conditions explain few new cases in the general population.
Inherited disorders include severe combined immunodeficiency,  Wiskott-Aldrich syndrome, ataxia-telangiectasia, common variable immunodeficiency, X-linked lymphoproliferative disorder hyper-IgM syndrome, Nijmegen breakage syndrome and autoimmune lymphoproliferative syndrome (Jaffe 2001). About 25% of patients with these disorders will develop, during their lifetime, B-cell lymphoma (Filipovich 1992).
On the whole NHL risk has been estimated to be increased about 60- to 200-fold in HIV positive individuals relative to the general population. Even if with the introduction of highly active antiretroviral therapy (HAART) (ICHIVC 2000), the decline of the
incidence of AIDS-related lymphomas has been noted, NHL still accounts for more than 20% of AIDS related deaths in developed countries (Aboulafia 2004),
Immunosoppressive therapy following transplantation (bone marrow, liver, heart or renal) increses the risk of NHL. The risk is about 200-fold in heart transplantation recipients and 10- to 20- fold in renal allograft recipients with respect to the general population (Baris 2000; Opelz 2004).
The risk of NHL is increased about 2- to3-fold in first-degree relatives of patients with haematopoietic cancer or lymphoma (Zhu 1998; Chang 2005). The role of genetic susceptibility in lymphoma development is firstly implicated, however one may  suppose that familial clustering is attributable to shared environmental exposures rather than genetic predisposition (Zhu 1998; Chang 2005).
Several infectious agents have been consistently associated with NHL. Epstein-Barr virus (EBV) is considered to be a group I carcinogen by IARC  (IARC 1997), with conclusive evidence with respect to carcinogenicity in Burkitt lymphoma, non-Hodgkin lymphoma in immunosuppressed subjects and other malignancies. In healthy individuals, equilibrium exists between latent EBV infection and the host’s immune system. However, with severe immunodeficiency, control mechanisms are impaired which may lead to EBV-driven B-cell proliferation and development of B-cell lymphoma (Oertel 2002).
Some studies have reported 2- to 14-fold increased relative risk of B-cell NHL in association with hepatitis C infection. The observations are from countries with high HCV seroprevalence (5% to 10%). This is the case of southern and eastern Europe, Japan and southern USA, whereas no associations have generally been noted in studies from central and northern Europe, northern USA or Canada (Negri 2004). Other infectious agents have been consistently associated with malignant
Lymphomas: they are herpes virus HHV-8 (Judde 2000) and the retrovirus human T-cell lymphotrophic virus 1 (HTLV-1) (Jeang 2004).  Associated bacteria include Helicobacter pylori (H. pylori ) (Wotherspoon 1991; Isaacson 2005) and perhaps also Borrelia burgdorferi (Goodlad 2000; Wood 2000).
Excess risks of malignant lymphomas have been reported in some autoimmune and chronic inflammatory disorders. A number of studies have demonstrated increased risks of NHL in patients with rheumatoid arthritis (RA) . On average, reported excess risks of NHL overall range between 1.5- and 4-fold increased  (Kauppi 1997; Hakulinen 1985; Mellemkjaer 1996; Thomas 2000). The question is whether the treatment with immunosuppresants or the inflammatory activity may be of major importance. Few studies suggested that degree of inflammation was more important then treatment. Patients with Sjögren’s syndrome have an increased relative risk range from 4.5-to 44-fold, with higher estimates for primary disease than when secondary to rheumatoid arthritis, systemic lupus erythematosus or myositis (Leandro 2001; Kauppi 1997; Pertovaara 2001).
A population-based case-control study in Germany identified several occupational groups associated with significant increased risk of lymphomas, including chemical processors and related workers; electrical fitters and related electrical and electronics workers;  machine assemblers, precision instrument makers, machinery fitters; cooks, waiters, bartenders; maids; metal processors;  architects, engineers and related technicians;  medical, dental, veterinary and related workers; sales workers; food and beverage processors; and printers (Mester 2006).
A  quite strong evidence of a causal link between solvent and dioxin and NHL is reported by the International Agency for Research on Cancer (IARC) (McMichael 1988; Steenland 2004).  For solvent, a population-based study in Australia reported a significant 30% increased risk of NHL with occupational exposure to non-specific solvents; the more frequent the exposure and the more years exposed, the higher the risk (Fritschi 2005a). Evidence regarding the links between exposure to various pesticides and non-Hodgkin’s lymphoma (NHL) continue to emerge. Substantial exposure to pesticides as a group in one population-based case-control study in Australia was associated with a 3-fold risk of NHL  (Fritschi 2005b).
Several cohort and case control studies investigated BMI or obesity and NHL. A meta-analysis showed  (Larsson 2007) a significant relative risk of 1.07 for overweight individuals and 1.20 for obese compared to individuals of normal weight. The association was stronger for the diffuse large B-cell lymphoma. Obesity results in pathological states of inflammation and altered immune responses, both of which are factors that can influence lymphoid cell function.
Several studies indicated a significant associations with increased vegetable and fruit intake and reduced incidence of lymphoid cancers. Vegetables and fruits contain many potentially protective substances, including several antioxidants, as well as phytochemicals with antiproliferative capabilities. They are also a rich source of folate, which plays an important role in the synthesis, repair, and methylation of DNA.  A recent cohort study (the Iowa Women’n Health Study) based on about 35,200 women found a protection for specific antioxidants (relative risk, RR= 0.8 for vitamin C; RR=0.7 for both beta-carotene and proanthocyanidins) and dietary manganese (RR=0.6). Grater intake of total fruits and vegetables were associated with lower NHL risk. There were no associations with multivitamin use or supplemental intake of vitamins C, E, selenium, zinc, copper or manganese (Thompson 2010).

2. PATHOLOGY AND BIOLOGY

2.1 Histologic types

According to the World Health Organization (WHO), HIV-NHLs are divided into three categories: first, lymphomas that also occur in immunocompetent patients – such as Burkitt’s lymphoma (BL) (40% of cases) and diffuse large B-cell lymphoma (DLBCL) (60% of cases) – these include centroblastic (25%), immunoblastic (25%) and anaplastic variants (10%); second, lymphomas occurring more specifically in HIV patients such as primary effusion lymphoma (PEL) and plasmablastic lymphoma; and third lymphomas also occurring in other immunodeficiency states such as polymorphic or post-transplant lymphoproliferative disorder B-cell lymphoma-like associated with HIV infection (Raphael 2001).
AIDS-related BL and DLBCL display histological features similar to those exhibited by NHL seen in the general population. However, AIDS-NHL generally appear to display a higher frequency of mitotic figures, increased cellular debris and enhanced tendency to undergo necrosis than conventional NHLs, suggesting a higher proliferation index and a more rapid growth rate, which is consistent with their natural history (Knowles 2001).
PEL is a rare  NHL (3%), associated with infection by HHV8 and frequent coinfection with Epstein-Barr Virus (EBV) and two variants have been described: the classic PEL or “body cavity-based lymphoma,” which presents most frequently in body cavities (pleura, pericardium, peritoneum) as lymphomatous effusions without an associated mass, and extracavitary or solid PEL, which is an extraserous lymphoma reported in HIV-positive patients with or without associated effusions (Cesarman 1995; Carbone 2008). PELs have a distinctive set of morphologic and immunophenotypic patterns. In cytospin preparations, the cells range from cells with anaplastic morphology to large immunoblastic or plasmablastic cells. Extracavitary PELs are frequently classified as diffuse large cells, immunoblastic or anaplastic large cells. Immunohistochemistry for latency-associated nuclear antigen (LANA) allows demonstration of the presence of HHV8 in all the lymphoma cells ( Knowles 2001; Cadburn 2004; Carbone 2005). PELs express indeterminate immunophenotype,B cell genotype and expression of plasma cell markers such as CD138/Syndecan-1, indicating a pre-plasma cell or “plasmablastic” profile (Klein 2003; Carbone 2005).
Plasmablastic lymphoma is a rare (2-3%) subtype of DLBCL with plasmacytoid differentiation that typically involves the jaw and oral cavity of HIV patients. Pathological findings comprised large plasmablast cells that retain the blastoid morphology of immunoblasts but have otherwise acquired immunophenotypic features of plasma cells (Delecluse 1997; Carbone 2003; Schichman 2004).

2.2 Biological data

The pathological heterogeneity of HIV-associated NHL reflects the heterogeneity of their associated molecular lesions. In BL, the genetic lesions involve activation of c-myc, inactivation of p53 and infection with EBV in approximately 30% of cases. Immunoblastic lymphoma, infected by EBV in 90% of cases, is characterized by frequent expression of latent membrane protein-1 (LMP-1), an EBV oncoprotein (Gaidano 2003; Carbone 2008).
PELs are consistently associated with HHV-8 infection. Recently, gene expression analysis of PELs showed features again indicating a plasma cell profile (Jenner 2003).
Plasmoblastic lymphomas is associated with EBV in 50-100% of cases, but usually lacks expression of LMP-1 and EBV nuclear antigen-2. Several studies have recently showed that NHLs derive from two distinct histogenetic pathways.
Lymphomas that derive from germinal center (GC) B-cells are unlikely to be EBV-associated, whereas those from post-GC B-cells are more likely to show immunoblastic histology and to be EBV-associated (Carbone 2005).

3. DIAGNOSIS

3.1 Signs and symptoms

At onset, HIV-NHLs fall within stages III and IV in over 70% of the cases, with extranodal involvement in 70-98%. The most common extranodal sites of involvement comprise the gastrointestinal tract, the bone marrow and the central nervous system (CNS). Leptomeningeal involvement by lymphoma occurs in approximately 20% of patients with newly diagnosed HIV-NHLs. The most common symptoms at diagnosis are fever, night sweats and weight loss (75%). Typically HIV-NHLs are often bulky (nodal masses >10 cm in diameter), have a rapid growth rate and are associated with serum lactate dehydrogenase (LDH) levels well above normal range.
BL typically occurs at relatively higher CD4 cell count (> 200 cells/µL) whereas immunoblastic lymphomas in a more severe immunodeficiency (CD4 < 50 cells/µL) (Beral 1991; Sparano 2001; Frisch 2001).
Primary CNS lymphoma (PCNSL) presents a distinct extranodal presentation of DLBCL in HIV infection, usually of the immunoblastic type, that is associated with severe immunosuppression (CD4 < 50/µL), EBV-positivity, and a poor prognosis (Goldstein 1991; Cingolani 2005). PCNSL is not specific and approximately 50% of patients present with lethargy, confusion and personality changes, whereas many others lack lateralizing neurological signs.
PELs grow exclusively or mainly within pleural, pericardial or peritoneal cavities as lymphomatous effusions, usually in the absence of contiguous tumour mass. It usually remains strictly localized to the body cavity of origin and only infrequently spreads to local lymph nodes or distant sites (Simonelli 2003).
Plasmablastic lymphoma arises in jaw and oral cavity and then spreads to other sites such as the anorectum, nasal and paranasal regions, skin, testes, bones, and lymph nodes (Schichman 2004).

3.2 Diagnostic strategy

In the setting of HIV disease, NHL can be difficult to diagnose because of its variable presentation. It can mask many conditions of both HIV disease itself and its associated opportunistic infections. For instance, systemic ‘B’ symptoms are frequently associated with both advanced HIV infection and opportunistic infections. These symptoms mandate a careful evaluation to exclude other causes, including the presence of Mycobacterium avium-intracellulare, cytomegalovirus or tuberculosis infection.

3.3 Pathological diagnosis

A diagnosis of NHL should be made by histological examination of the tissue obtained by incisional or excisional biopsy. It may be possible, however, to make an adequate diagnosis from needle aspiration cytology, and this may be required if the patient’s clinical condition is critical or deteriorating rapidly.
The PCNSL may be radiographically indistinguishable from cerebral toxoplasmosis or other CNS infections. It has been shown that detection of cerebrospinal fluid (CSF) EBV-DNA by polymerase chain reaction (PCR) in HIV-infected patients is reliably associated with PCNSL (Cinque 1993). By combining CSF EBV-DNA detection by PCR with 201Tl single photon emission computed tomography, the presence of increased uptake and positive EBV-DNA had 100% sensitivity and 100% negative predictive value (Castagna 1997; Antinori 1999; Cinque 2004). Thus in patients with hyperactive lesions and positive EBV-DNA, brain biopsy may be avoided and patients should promptly undergo definitive therapy on a type C basis.

4. STAGING

4.1 Staging classification

Staging should be made according to the Ann Arbor classification:
Stage 1: NHL is limited to one lymph node group (e.g., neck, underarm, groin, etc.) above or below the diaphragm, or NHL is in an organ or site other than the lymph nodes (extranodal) but has not spread to other organs or lymph nodes.
Stage 2: NHL is limited to two lymph node groups on the same side of the diaphragm, or NHL is limited to one extranodal organ and has spread to one or more lymph node groups on the same side of the diaphragm.
Stage 3: NHL is in two lymph node groups, with/without partial involvement of an extranodal organ or site above and below the diaphragm.
Stage 4: NHL is extensive (diffuse) in one organ or site, with/without NHL in distant lymph nodes.
Additional designations (applicable to any of the stages):
A – Absent: (no) symptoms.
B – Presence of any of the following B symptoms: fever (> 38°C), drenching night sweats, unexplained weight loss of 10% or more within the last 6 months, severe itching (see Signs & Symptoms of Lymphoma).
E – Involvement of a single extranodal (other than the lymph nodes) site that directly adjoins or is next to the known nodal group.
X – Presence of “bulky” disease, that is, a nodal mass whose greatest dimension is more than 10 centimetres in size, and/or a widening of the mediastinum (middle chest) by more than one-third.
CS – Clinical stage as obtained by doctor’s examinations and tests.
PS – Pathological stage as obtained by exploratory laparotomy (surgery performed through an abdominal incision) with splenectomy (surgical removal of the spleen).

4.2 Staging procedures

The initial disease evaluation consists of a complete physical examination including Waldeyer ring evaluation. Particular attention should be given to recording the site and size of all abnormal lymph nodes and the size of liver and spleen. Imaging is required for the correct staging of patients with lymphomas. Computed Tomography (CT) of thorax and abdomen are recommended procedures in both the initial evaluation and follow-up to assess precisely the extent of disease. Considering that the patients with NHL have a high risk of CNS involvement, cerebrospinal fluid and radiographic studies of the CNS are needed. Two studies demonstrated the superiority of flow cytometry in comparison with conventional cytology for the diagnosis of leptomeningeal involvement (Hegde 2005; Subirá 2005). However, further patients need to be studied before this staging procedure can be generalized. Magnetic resonance imaging may be the most valuable in evaluating the brain and spinal cord on  a type  3 level of evidence.
Positron Emission Tomography (PET) examination recently showed higher sensitivity than conventional workup in HIV-negative patients (Juweid 2005). Particular caution should be taken in patients with HIV infection, who may demonstrate false-positive fluorodeoxyglucose PET (FDG-PET) imaging due to persistent generalized adenopathy (Bhargava 2006).
Bone marrow biopsy is required for initial staging because a significant percentage of patients have bone marrow involvement.

4.2.2 Virological-immunological assessment

The following laboratory tests should be performed for a new patient during initial patient visits:

4.2.2.1

HIV antibody testing (if prior documentation not available) or if HIV RNA is undetectableon  a type 1level of evidence

4.2.2.2

CD4 cell count on  a type 1 level of evidence

4.2.2.3

Plasma HIV RNA on  a type 1 level of evidence

4.2.2.4

For patients who have pretreatment HIV RNA > 1000 cp/mL, genotypic resistance testingat the point of entry into care is required, regardless of whether antiretroviral therapy will be initiated immediately on  a type 3 level of evidence (Hammer 2008).

5. PROGNOSIS

5.1 Natural history

5.1.1 General data

Clinical features and natural history of HIV-NHLs differs significantly from those observed in the general population. In HIV-positive patients, NHLs present with more advanced disease, more extensive extranodal involvement (most commonly gastrointestinal tract), higher International Prognostic Index (IPI) and frequently higher LDH levels and poor prognosis.
A comparison between the clinical features of the disease in highly active antiretroviral therapy (HAART)-treated and  receiving HAART are that patients are  older and present with a minor degree of extranodal involvement, especially of bone marrow and meninges (Vaccher 2003). Interestingly, HAART has a positive impact on the outcome of antiretroviral-receiving patients with significantly improved survival and disease-free progression vs HAART-naive patients; and above all a significantly improved disease-free survival (DFS) rate (possibly a result of the improved immune deficit) has been reported (Navarro 2001; Antinori 2001; Besson 2001; Gerard 2002; Vaccher 2003; Hoffmann 2003; Sparano 2004; Lim 2005; Mounier 2006; Mounier 2007).

5.1.2 Survival

In the pre-HAART era the prognosis of HIV-associated NHL was dismal, with overall and disease-free survival times ranging from 4–6 months and 15–20 months, respectively. The main unfavorable prognostic factors were presence of a severe immune deficit (CD4+ < 100/µL), prior AIDS diagnosis, and poor general health (Gisselbrecht 1993; Vaccher 1996; Sparano 2001; Vaccher 2003). The advent of HAART into clinical practice has changed outcome significantly. Median survival in the HAART era is now ranging from 43 to 65 months, which is similar to the survival of HIV-negative aggressive lymphoma (Vaccher 2003; Hoffmann 2003; Sparano 2004; Spina 2004; Lim 2005; Mounier 2006; Mounier 2007). Actually conventional survival-influencing lymphoma-related factors have a stronger impact on survival than factors associated with the underlying HIV infection. Particularly in the most extensive surveys, the IPI score (age, disease stage, extranodal involvement, performance status, LDH levels) is the most discriminating negative prognostic factor in patients with HIV-NHLs, together with Burkitt subtype and failure to obtain complete remission (CR) after first-line chemotherapy (Spina 2005; Lim 2005; Mounier 2006; Miralles 2007). It is noteworthy that patients with HIV-BL still have a median survival of 6 months, i.e. unchanged from the pre-HAART era.

6. TREATMENT

6.1 First line therapy

There is still much controversy regarding treatment of HIV-NHLs. Based on pathology and clinical features, aggressive chemotherapy treatment would be required, which is often incompatible with the complications related to the underlying HIV infection.
The prospective studies on the treatment of HIV-NHLs that were performed in the pre-HAART era belong to three major research lines: the first, followed by American investigators, comprise low-dose chemotherapy regimens that are administered  indiscriminately to all patients; the second research approach, supported by European investigators, consists of risk-adapted chemotherapy regimens; the third research line is again an American approach and includes the administration of continuous infusion chemotherapy.

6.1.1 Low-dose and risk-adapted chemotherapy

Low-dose M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) was associated with  complete remission (CR) rates (46-56%) and median survival (6.5-8 months) that were comparable with those achieved with standard doses (CR > 50%; median survival 7-8 months), but severe toxicity (G3-G4 according to WHO) was significantly lower with the administration of lower doses (51% vs 70%, p < 0.008) (Kaplan 1997).
In May 1993, the European Intergroup NHL-HIV Study started the first randomized study on the effectiveness of different dose-intensity chemotherapy regimens in the treatment of NHL, with patients stratified by presence/absence of prognostic factors (CD4 < 100/µL, prior AIDS diagnosis and performance status > 2). A total of 485 patients was enrolled. In the low risk group (no unfavorable prognostic factors), patients were randomized between the intensive ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisolone) regimen and the less aggressive CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy with G-CSF support. In the intermediate risk group (only one unfavorable prognostic factor) randomization was between CHOP and low-dose CHOP (reduced by 50%). In the high risk group (two or three unfavorable prognostic factors) patients were randomized between low-dose CHOP reduced to 50% and palliative vincristine plus prednisolone. In the low risk group both ACVBP and CHOP arms reached similar CR (66% vs 60%) and 5-year survival rates (51% vs 47%). In the intermediate risk group, CR rate was significantly higher after standard CHOP arm than with low-dose CHOP (49% vs 32%, p < 0.05), but 5-year OS rates were similar (28% vs 24%). In the high risk group the CR rate was much higher in the low-dose CHOP arm than in the group that had received vincristine plus prednisolone (20% vs 5%), but again the 5-year OS rates were similar (11% for low-dose CHOP vs 3% for vincristine plus prednisolone). The only factors influencing survival rates were the administration of HAART, HIV score and the IPI score. Investigators concluded that the study, which was terminated before monoclonal antibodies became available, showed that CHOP was the standard chemotherapy regimen for HIV-NHLs, as for NHLs in the general population, and that increasing the treatment dose-intensity in patients with good prognosis had no effect on the outcome (Mounier 2006). This latter conclusion may be now value only for NHL patients, which HIV infection is resistant to HAART, as suitable for individual clinical use.

6.1.2 Continuous infusional chemotherapy

Continuous infusional CDE (cyclophosphamide, doxorubicin, etoposide) for 4 days is the first study protocol in third-line  treatment of HIV-NHLs. With the CDE regimen the following rates were achieved: CR 45%, 2-year OS 43% and 2-year failure-free survival 36%. The prevalence of severe opportunistic infections during chemotherapy and follow-up was 14% and once again HAART had a positive impact on the patients’ outcome with improved survival and lower toxicity rates (Sparano 2004). The new continuous infusional ‘dose-modified’ EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin) regimen has been used so far to treat good-prognosis patients (median CD4 > 200/µL). Results are very satisfactory both in terms of CR (74%), progression-free survival (PFS) (92%) and OS (60%) rates at 53 months (Little 2003).
Overall, infusional chemotherapy has proved an effective and potentially curative treatment for NHL patients. However, no comparative trials have been performed in the HAART era between conventional CHOP and infusional CDE/EPOCH regimens, on a type 3 level of evidence and hence there is no “gold-standard” therapy.

6.1.3 Chemotherapy combined with rituximab

In recent years, the introduction of rituximab has significantly improved the survival of people with NHL in the general population as compared with patients receiving CHOP alone (Coiffier 2002). Based on these data, several authors have explored the feasibility and effectiveness of rituximab in combination with chemotherapy in patients with HIV-NHL. The Italian Cooperative Group on AIDS and Tumors (GICAT) performed a study on the administration of rituximab and infusional CDE every 4 weeks for a total of 6 cycles with concomitant HAART. Totally 74 patients were enrolled and 75% of them responded to treatment, of which 70% reached CR and 5% partial remission (PR). Treatment-related toxicity was acceptable for this patient setting except for infectious events. Non-opportunistic infections developed in 23% of the patients during neutropenia; 14% of the patients were diagnosed with AIDS-defining opportunistic infections during chemotherapy or in the first three months after conclusion of the treatment plan. After a median follow-up of 16 months (range 1-57 months), median survival has not been reached yet, and 2-year OS rate is 62%, DFS is 89% and PFS is 86% (Spina 2005). Other studies have evaluated the effectiveness of rituximab in combination with chemotherapy in the treatment of HIV-NHL. The first trial took place in France and used rituximab+CHOP in combination to treat 61 patients. A 77% CR rate was reported. After a median follow-up of 33 months, 2-year OS was 75% and PFS was 69% (Boué 2003). A phase II study was performed in Spain using the same treatment regimen. Out of 60 patients the following rates were achieved: CR 69%, 3-year OS 56% (Ribera 2008). Another trial is being carried out in the United States and is currently the only  randomized study comparing CHOP to CHOP with rituximab. One hundred fifty patients were enrolled (of which 99 received rituximab+CHOP and 50 CHOP alone). No differences were observed in CR (58% in the group that received the combination regimen vs 47% in the CHOP group) and OS rates. In the authors’ opinion, the toxic death rate attributed to infection was significantly higher in the rituximab-CHOP group than in the group treated with CHOP alone (14% vs 2%),  all in patients with CD4 count lower than 50 cells/µL at the time of enrolment. Moreover, the CR rate reported in the combination treatment arm was much lower than that recorded by other post-HAART studies with or without rituximab (50-58% vs 74% for EPOCH vs 76% for R-CDE vs 77% for R-CHOP), which may suggest a negative patient selection (Kaplan 2005).
Severe (grade 3-4) neutropenia is a common complication of rituximab chemotherapy, occurring in 33-78% of patients (Kaplan 2005; Spina 2005; Boué 2006), whereas hypogammoglobulinemia has been rarely reported (Miles 2005). On the basis of type C, the use of G-CSF support and opportunistic infection prophylaxis are mandatory during rituximab-based chemotherapy. Antiviral therapy with lamivudine has been shown to reduce viral reactivation in patients with chronic hepatitis B infection receiving chemotherapy and is recommended,  on a type 3 level of evidence , for patients treated with rituximab (Li 2006).
Presently, caution in the use of rituximab, especially in patients with CD4 counts < 50/µL, is advocated. This area remains contentious, on a type 2 level of evidence, and results from further trials are awaited. However, the benefit of rituximab for tumor control should not be underestimated (Mounier 2007).

6.1.4 Chemotherapy for Burkitt lymphoma

HAART has improved the immune status of HIV-positive patients, thereby reducing the incidence of opportunistic infections and improving the course of  NHL , with the  exception of BL, which has turned out to be clinically more aggressive than DLCL (Lim 2005; Spina 2005). Since this lymphoma subtype affects survival, a question has arisen whether it should be treated more aggressively. A retrospective analysis has been conducted on the feasibility of intensive aggressive chemotherapy regimens (i.e. CODOX-M/IVAC or PETHEMA-LAL3/97), which are usually used in the treatment of BL in the general population, in HIV patients as well. The results have been recently published: American and Spanish investigators report a 63%-68% CR rate, a 46%-60% failure-free survival rate at 2 years and the same toxicity as in the general population, which confirms the feasibility of the above regimens also in HIV setting, on a type 3 level of evidence (Wang 2003; Oriol 2003).

6.2 Salvage chemotherapy

6.2.1 Standard therapy

Lymphoma progression is the leading cause of death in 35-55% of the patients with HIV-NHL receiving chemotherapy, of whom around half need second-line chemotherapy following progression or relapse of the disease. To date, the results achieved by salvage therapies that do not include a standard high-dose chemotherapy regimen with peripheral blood stem cell transplant have been very frustrating (median survival 2-4 months) (Spina 2001). The results of treatment regimens incorporating experimental drugs, such as mitoguazone, have been just as disappointing with a 11% CR rate and median survival below 3 months (Levine 1997).

6.2.2 High–dose chemotherapy with Autologous Stem–Cell Transplantation

With the introduction of HAART into clinical practice more aggressive treatment protocols whose effectiveness has already been documented in HIV-negative lymphoma patients can be taken into consideration. Preliminary studies support the feasibility of high-dose chemotherapy in combination with autologous stem cell transplant in patients with HIV-NHLs, who have chemosensitive recurrence or PR after first-line chemotherapy. Preliminary findings show that peripheral blood stem cell collections are adequate, anchoring rates are similar to those recorded in HIV-negative patients and high-dose chemotherapy is well tolerated with no increase in the incidence of opportunistic infections, at least in the  short term (Gabarre 2000; Molina 2000; Krishnan 2001; Re 2003 ; Molina 2003). Within the GICAT, a study has been performed on a group of patients with NHL or refractory or recurred Hodgkin’s disease: the results support the feasibility of an adequate peripheral blood stem cell collection, with no transplant-related mortality and a very good outcome – 60% of the patients being alive and disease-free (Re 2003).
Patients who are potential candidates for effective HAART treatment and who have a chemosensitive relapsed NHL should now be considered, on a type 3 level of evidence, for high-dose chemotherapy in combination with autologous stem cell transplantation.
Routinely increased medical surveillance and opportunistic infection prophylaxis (http://aidsinfo.nih.gov/) during treatment and follow-up is standard for all patients, irrespective of their CD4 cell counts, on a type C basis.

6.3 Chemotherapy combined with HAART

The issue of timing of the administration of antiretroviral therapy in combination with chemotherapy (concurrent with chemotherapy versus after treatment), arises since there is potentiallya pharmacokinetic or pharmacodynamic interaction between cytotoxic and antiretroviral drugs. Available data suggest that it is feasible to administer the two therapies concomitantly, but some data suggest that there is increased toxicity risk with this approach.
Combination therapy with CHOP plus first generation protease inhibitor (PI)-based HAART regimens has been reported safe and without toxic deaths (Vaccher 2001; Ratner 2001). However, the combined therapy was characterized by an increased myelotoxicity and neurological toxicity involving the parasympathetic system compared with historic controls treated with chemotherapy alone. The latter toxicity, typical of vinca alkaloids, presents with severe constipation associated with abdominal pain or dynamic ileus in approximately 20% of cases, and is reversible with discontinuation of antiretroviral therapy. Myelotoxicity, in particular severe anaemia, occurred more frequently in patients treated with zidovudine (Vaccher 2003). Thus this drug should never be given, on a type 3 level of evidence, in combination with chemotherapy. On the other hands, pharmacokinetic analysis showed that cyclophosphamide clearance was decreased in approximately half of the patients compared with historic controls who did not received antiretroviral therapy (Ratner 2001).
Patients treated with CDE plus HAART experienced severe metabolic abnormalities in 17% of cases, liver toxicity and neurological toxicity both in 14%, but overall tolerance to chemotherapy was better in patients treated with HAART compared with patients treated with chemotherapy alone (Sparano 2004). Protease inhibitor-based HAART appears to significantly potentiate the myelotoxicity of CDE, compared with PI-sparing regimens (Bower 2004), but these data need to be confirmed in larger series.
The clinical benefits of concomitant therapy have already been explained above. It is noteworthy that HAART may preserve CD4 cells during chemotherapy (Ratner 2001; Powles 2002) and in vitro antiretroviral drugs can inhibit chemotherapy-induced apoptosis in lymphocytes (Phenix 2001).
To avoid possible pharmacokinetic interactions between HAART and chemotherapy, Little and colleagues (Little 2003) omitted HAART during the administration of EPOCH regimen. The overall survival at 5 years was 87% and the immunological recovery occurred within 6-12 months from the end of chemotherapy, but the survival of patients with CD4 < 100 cells/µL was only 16%. The latter element suggests a particular caution in deferred HAART therapy in all cases where the patient has a severe immune deficiency and/or the chemotherapy regimen used is very immunosuppressive, on a type 3 level of evidence .

6.4 Leptomeningeal disease management

CNS involvement remains a poor prognostic factor for HIV-NHL patients of the HAART era (Mounier 2006). Data from immunocompetent patients suggest that BL, advanced stages, young age, elevated serum LDH and B symptoms, along with extranodal disease sites including testes, paranasal sinues, paraspinal disease and bone marrow, are risk factor for CNS relapse.
Prophylactic intrathecal chemotherapy should be offered to HIV-infected patients with BL or DLCL with high risk factors for CNS relapse, on a type C basis.
Both intrathecal methotrexate (12 mg) and intrathecal cytarabine (40-50 mg) are used to prevent or treat CNS disease, on a type 3 level of evidence . On the basis of investigational option, a formulation of intrathecal cytarabine (Depocyte) may be an effective alternative treatment, as in the general population (Spina, personal communication).

6.5 Supportive therapy

Emerging evidence suggests that patients with AIDS-associated lymphomas should be treated in a similar manner as immunocompetent patients with the same disease, on a type 3 level of evidence. However, clinicians must be vigilant, on a type C basis, about implementing infection prophylaxis and promptly recognizing, diagnosing and treating bacterial, parasitic, fungal and viral infections that may occur as consequence of therapy. Infection prophylaxis should be instituted in all NHL patients receiving chemotherapy, irrespective of their CD4 counts, on a type C basis.
Evidence-based guidelines for infections prophylaxis and treatment, as well as for antiretroviral therapy are regularly updated and are available at http://aidsinfo.nih.gov/. Preventive G-CSF support should be administered in all patients, on a type C basis. Lastly, it is crucial to evaluate patients for their ability to comply with their HAART , on a type C basis.

6A Chemotherapy schedules
•    CHOP
Cyclophosphamide 750 mg/m2 iv day 1
Adryamicin 50 mg/m2 iv day 1
Vincristine 1.4 mg/ m2(max 2mg) iv day 1
Prednisone 100 mg per os days 1, 2, 3, 4, 5
Repeated every 21 days, for maximum of 6 cycles.

•    CDE
continuous intravenous infusion of:
Cyclophosphamide 187•5–200 mg/m2/day for 4 days
Doxorubicin 12•5 mg/m2/day for 4 days
Etoposide 60 mg/m2/day for 4 days, over 96 h
Granulocyte colony-stimulating factor filgrastim (G-CSF) 5/kg/day, subcutaneous injection from day 6 until neutrophil recovery
Repeat every 28 days, for a maximum of six cycles

•    EPOCH
Etoposide 50 mg/m2/day for 4 days
Vincristine 0•4 mg/m2/day for 4 days
Doxorubicin 10 mg/m2/day for 4 days
Cyclophosphamide 187 mg/m2 IV on day 5 when CD4-cell count < 0•1 x 109/l
or 375 mg/m2 IV on day 5 when CD4-cell count > 0•1 x 109/l
Prednisone 60 mg/m2 orally from days 1 to 5
Granulocyte colony-stimulating factor: start on day 6
Repeat every 21 days, for a maximum six cycles

•    RITUXIMAB-based chemotherapy
Rituximab 375 mg/m2 iv. the day before chemotherapy.
Cycles repeated every 21 days, for a maximum six cycles.

•    CODOX/M-IVAC
Cyclophosphamide 800 mg/m2 iv. day 1
Cyclophosphamide 200 mg/m2 iv. day 2-5
Adryamicin 40 mg/m2 iv. day 1
Vincristine 1.5 mg/m2 (max 2mg) iv. Day 1 and 8
Cytarabine 70 mg it. day 1 and 3
Methotrexate 3000 mg/m2 continuous intravenous infusion /h24 day 10
Methotrexate 12mg it. day 15
Folinic acid rescue after methotrexate

7. LATE SEQUELAE

No data have been published on late sequelae of NHL treatment. However, it is known that as HIV-infected patients have lived longer, there has been increasing concern over HAART long-term toxicity, including metabolic syndrome (see KS section), cardiovascular and liver disease (D’Arminio Monforte 2008) .
Further studies are needed to evaluate the short as well as the long-term cross-toxicity of the combined treatment of chemotherapy/radiotherapy and HAART, especially cardiovascular toxicity.

8. FOLLOW-UP

8.1 General principles and objectives

(see KS section for general principles and objectives)

8.1.1 Patient evaluation

The staging after treatment should include whole CT scans and a bone marrow biopsy (if CT scan shows CR and bone marrow was involved at diagnosis). Patients with residual mass should have a PET scan, on a type C basis.
Evaluation during follow-up consists of careful physical examination; additional studies should only be performed as indicated by the patient symptoms, findings on physical examination or laboratory studies, on a type C basis.

8.1.2 Laboratory tests

To monitor HIV infection,see staging procedure section. Laboratory testing will aim at monitoring treatment-related side effects.

8.2 Suggested protocols

A first complete evaluation should be performed one month after the completion of treatment. The next evaluation for patients in CR should be scheduled every two months for the first three years, every three-four months thereafter.

 

INDEX

 

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

Prof. Christian Gisselbrecht (Reviewer)
Hôpital Saint-Louis – Paris, France
e-mail: christian.gisselbrecht@sls.ap-hop-paris.fr

Dr. Nicholas Mounier (Reviewer)
Hôpital de l’Archet – Nice, France
e-mail: mounier.n@chu-nice.fr

Dr. Michele Spina (Author)
National cancer Institute – Aviano, Italy
e-mail: mspina@cro.it

Prof. Umberto Tirelli (Editor)
National cancer Institute – Aviano, Italy
e-mail: utirelli@cro.it

Dr. Emanuela Vaccher (Author)
National cancer Institute – Aviano, Italy
e-mail: evaccher@cro.it