Aids related lymphoma

Since 1985,aggressive B-cell lymphoma has been classified as an AIDS defining illness (ADI) ARL is generally a late event in the course of HIV infection . Risk factors include low CD4 counts, high HIV viral load, increased age, and male gender.

In general, the clinical setting and response to treatment of patients with AIDS-related lymphoma is very different from that of the non-HIV patients with lymphoma. The HIV-infected individual with aggressive lymphoma usually presents with advanced-stage disease that is frequently extranodal.The clinical course is more aggressive, and the disease is both more extensive and less responsive to chemotherapy. Immunodeficiency and cytopenias, common in these patients at the time of initial presentation, are exacerbated by the administration of chemotherapy. Treatment of the malignancy therefore increases the risk of opportunistic infections that, in turn, further compromise the delivery of adequate treatment

In the pre-HAART era, the median survival of patients with ARL was only 6 to 8 months with treatment. Because of advances in chemotherapy in the setting of HIV infection, enhanced antiretroviral options, and supportive care, patients with ARL in the HAART era are experiencing improved response rates and increased survival.

Categories of HIV-associated Lymphomas : WHO Classification
Lymphomas also occurring in immunocompetent patients
       Burkitt lymphoma
              Classic
              With plasmacytoid differentiation
              Atypical
       Diffuse large B-cell lymphoma
       Centroblastic
       Immunoblastic
   Extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue lymphoma (rare)
   Peripheral T-cell lymphoma (rare)
  Classic Hodgkin lymphoma
Lymphomas occurring more specifically in patients who are HIV* positive
  Primary effusion lymphoma
  Plasmablastic lymphoma of the oral cavity
Lymphomas occurring in other immunodeficiency states
  Polymorphic B-cell lymphoma
  *HIV, human immunodeficiency virus.

Lymphomas Also Occurring in Immunocompetent Patients. This includes Burkitt lymphoma, diffuse large B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, peripheral T-cell lymphoma, and classic Hodgkin lymphoma. While classic Burkitt lymphoma develops in HIV-infected patients, the plasmacytoid variant is unique to AIDS patients. Peripheral blood, bone marrow, and the leptomeninges frequently exhibit involvement. EBV in this setting is found in approximately 30% of classic, 30% to 50% of atypical, and 50% to 70% of the plasmacytoid Burkitt lymphomas.

The diffuse large B-cell lymphomas include centroblastic variant, immunoblastic, and CD30+ anaplastic large cell lymphomas. Immunoblastic lymphomas often exhibit plasmacytoid features. EBV is found in 30% of centroblastic and 90% of immunoblastic ARLs. HIV-related primary CNS lymphomas (PCNSLs) are usually of the immunoblastic type.

Lymphomas Occurring More Specifically in HIV-Infected Patients. Included in this category are primary effusion lymphoma (PEL) and plasmablastic lymphoma. Of the 2 forms of PEL, classic and solid, the latter is reported in patients infected with HIV either with or without associated effusions.The identification of HHV8 in clonal tumor cells is often essential to making the diagnosis.

Morphologically, classic PEL resembles immunoblastic and anaplastic large-cell lymphomas. Solid PEL demonstrates morphology (immunoblastic/anaplastic), immunophenotype, HHV8 viral status, and immunoglobulin light chain gene rearrangements identical to those of classic PEL.

Plasmablastic lymphoma is a distinct ARL first documented in the jaws and oral cavity of HIV-infected persons. More recently, HIV-related plasmablastic lymphoma has been documented in other sites, such as the anorectum, nasal and paranasal regions, skin, testes, bones, and lymph nodes.Plasmablasts in these lymphomas morphologically resemble immunoblasts and, like PEL cells, acquire a plasma cell immunophenotype. These are rapidly growing, destructive tumors with a brisk (>80%) mitotic activity that may mimic Burkitt lymphoma.

Lymphomas Also Occurring in Other Immunodeficiency States. Polymorphic lymphoma, or post-transplant lymphoproliferative disorder (PTLD)-like B-cell lymphoma, is currently the only entity included in this group. This ARL is comparable morphologically and molecularly to that arising after solid organ transplantation (hence, PTLD-like). It is characterized by a diffuse growth of polymorphous lymphocytes and exhibits a variable degree of plasmacytic differentiation and cytologic atypia. In many cases, both EBV and HHV8 are present. Clonal rearrangement and cytogenetic abnormalities (eg, c-MYC, Bcl-6, and p53 gene mutations) may be present and usually signify transformation into a diffuse large-cell lymphoma.

ARL differs from NHL in general population in following ways:
Propensity for advanced disease,
Presence of B symptoms,
Extranodal disease including bone marrow involvement
Leptomeningeal disease
Disease in unusual sites like body cavities, jaw, rectum,soft tissues, liver,meninges, and gastrointestinal tract, while very unusual sites are also characteristic, including anus, heart, bile duct, gingiva, and muscles.
Frequent plasmacellular differentiation,
Prominent association with Epstein Barr virus (EBV) and HHV-8

Clinically NHL encompasses:
Systemic NHL
Primary central nervous system NHL (PCNSL)
Primary effusion lymphoma (PEL)

Systemic NHL:
Studies have demonstrated that the relative risk of developing lymphoma within 3 years of an AIDS diagnosis was increased by 165-fold when compared with people without AIDS

Pathogenesis:
The heterogeneity of ARL likely reflects the various pathologic mechanisms important in lymphomagenesis, including HIV-induced immunosuppression, chronic antigenic stimulation, genetic abnormalities, cytokine release and dysregulation, dendritic cell impairment, and the role of herpesviruses EBV and HHV8. The classic antigen-driven model of HIV-associated

and HHV8. The classic antigen-driven model of HIV-associated lymphomagenesis proposes that hyperstimulation of B lymphocytes induced by EBV, HIV, and other infectious agents elicits the continuous release of various growth factors and cytokines promoting B-cell proliferation.

Soluble cytokines found to be elevated in HIV-infected patients who develop ARL include IL-6, IL-10, sCD23, sCD27, sCD30, and sCD44. Many of these stimulatory cytokines are potent growth and antiapoptotic factors for B cells.
Common oncogenes involved include the classic c-MYC oncogene in Burkitt lymphoma, BCL-6 mutations in diffuse large B-cell lymphoma, as well as abnormalities of tumor suppressor genes. As an example, in AIDS-related Burkitt lymphoma, which accounts for approximately 30% of ARL, the transforming events occur in the germinal centers, resulting in the translocation of the myc gene on chromosome 8 with the promoter for the heavy chain locus on chromosome 14, or the kappa or lambda light chain genes on chromosomes 2 and 22, respectively. However, EBV infection occurs in only 30% to 50% of ARL cases, indicating that pathogenetic mechanisms other than EBV must also be operative.

In the World Health Organization classification, AIDS-related diffuse large B-cell lymphomas (DLBCL) are divided into the centroblastic and the immunoblastic subtypes. While the centroblastic subtype has features of large cell lymphoma similar to those seen in the general population without HIV, the immunoblastic subtype is more characteristic of HIV infection. Infection with EBV occurs more commonly with the immunoblastic subtype (90%) when compared with the centroblastic subtype (30%). EBV-encoded LMP-1 antigen is found in 90% of the immunoblastic cases but is usually not found in the centroblastic subtype.Amplification of bcl-6, a proto-oncogene product selectively expressed in B cells located within germinal centers, is associated with the centroblastic but usually not the immunoblastic subtype. CD138/syndecan-1, normally expressed by B cells in late stages of B-cell differentiation, is more commonly expressed in the immunoblastic subtype.

These phenotypic differences have led to the suggestion that AIDS-related DLBCL can be divided into two categories: the LMP-1–/CD138–/BCL-6+ phenotype, which corresponds to the centroblastic subtype, and the LMP-1+/CD138+/BCL-6– phenotype, which corresponds to the immunoblastic subtype. These differences in immunophenotypic expression reflect their different histogenesis, with the centroblastic subtype arising from germinal centers and the immunoblastic variant arising from postgerminal center lymphocytes.

Host factors and cytokine genes may also influence NHL development. HIV-infected individuals, heterozygous for a deletion of the chemokine receptor CCR5, have a three-fold lower risk for NHL compared with individuals without this mutation. In contrast, those with stromal cell-derived factor-1 mutations are two- to four-fold more likely to develop NHL.

Diagnosis :

Unexplained constitutional symptoms in an HIV patient lasting more than a fortnight, such as weight loss, fevers, and night sweats, should have imaging by CT scan of chest, abdomen and pelvis for non palpable, pathologic pathology.
Biopsy of newly developed lymph nodes, pathologically enlarged (typically> 2cm), or progressively enlarging nodes should be done.
In patients without lymphadenopathy, biopsy of the liver, nodules in various organs, or the bone marrow may also lead to a diagnosis of lymphoma.

Clinicians should be vigilant even if patient is on HAART.
Biopsy is preferred to fine needle aspiration as it is required to subclassify the lymphoma.
Tests to help stage ARL include bone marrow biopsy, lumbar puncture, CT scans (chest, abdomen, and pelvis), gallium scans, and/or positron emission tomography to assess for the presence and extent of malignant disease.

Staging:

Although stage is important in selecting the treatment of patients with non-Hodgkin’s lymphoma (NHL) who do not have acquired immunodeficiency syndrome (AIDS), the majority of patients with AIDS-related lymphomas have far-advanced disease. In general, the staging system used is the Ann Arbor system, which is identical to that used for non-AIDS-related NHLs.

Staging Subclassification System

Stages I, II, III, and IV NHL can be subclassified into A and B categories : B for those with well-defined generalized symptoms and A for those without. The B designation is given to patients with any of the following symptoms:
l  Unexplained loss of >10% of body weight in the 6 months before diagnosis.
l  Unexplained fever with temperatures higher than 38°C.
l  Drenching night sweats.

The designation “E” is used when extranodal lymphoid malignancies arise in tissues away from the major lymphatic aggregates. If pathologic proof of involvement of 1 or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Sites are identified by the following notation :

Stage I

Stage I NHL means involvement of a single lymph node region (I), or localized involvement of a single extralymphatic organ or site (IE).

Stage II

Stage II NHL means involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE).

Stage III

Stage III NHL means involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extralymphatic organ or site (IIIE), involvement of the spleen (IIIS), or both (IIIS+E).

Stage IV

Stage IV NHL means disseminated (multifocal) involvement of 1 or more extralymphatic organs with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.

Typically, AIDS-related lymphomas are widespread with extranodal disease at the time of presentation. The most common extranodal sites are the gastrointestinal (GI) tract, central nervous system, bone marrow, and liver.

At diagnosis, 66% of patients have stage IV disease. In addition, unusual presentations include involvement of the rectum, heart, pericardium, pulmonary parenchyma, bile ducts, mouth, and subcutaneous and soft tissues. The clinical features of AIDS-related lymphomas correlate with histopathology. The majority of patients with small noncleaved cell (Burkitt) lymphomas present with stage IV disease, mostly because of bone marrow involvement. This compares with an approximately 40% stage IV presentation by those with immunoblastic and large cell lymphomas. A particular prevalence for GI involvement has been noted in patients who have immunoblastic and large noncleaved cell lymphoma types. While high-risk behavior should be looked for in every patient, HIV testing should probably be done for any patient who has Burkitt lymphoma or the atypical presentation of extranodal lymphoma that involves rare sites, i.e., rectum, GI tract, bone, or orbit. Similarly, malignant lymphoma should be considered in any HIV-infected patient who has progressive lymphadenopathy, tumors at any site, central nervous system symptoms, or unexplained wasting, fever, or abdominal pain.

Prognosis
Prognosis in ARL is related to severity of HIV infection and extent of lymphomatous involvement. In a pre HAART analysis, factors which had independent value were :
Age > 35
Stage 3 or 4 disease
CD4 < 100/cumm
H/o IV drug use.
When 0 or 1 factors was present, overall survival was 46 weeks
When 3or 4 factors were present, survival was just 18 weeks.
Control of HIV viral replication by HAART appears to be a major prognostic factor. A number of factors that are important for determining prognosis are not included in the staging system for NHLs. All of these factors should be considered when selecting treatment. Prognosis is related to the severity of the underlying immune deficiency (CD4 lymphocyte count), the presence or history of opportunistic infections (prior AIDS-defining illness), bone marrow involvement, performance status, and presence of extranodal disease.

Treatment

The treatment of patients with acquired immunodeficiency syndrome (AIDS)-related lymphomas presents the challenge of integrating therapy appropriate for the stage and histologic subset of malignant lymphoma with the limitations imposed by HIV infection, which to date is an incurable illness. In addition to antitumor therapy, essential components of an optimal non-Hodgkin’s lymphoma treatment strategy include antiretroviral therapy, prophylaxis for opportunistic infections, and rapid recognition and treatment of intercurrent infections.

Whenever possible HIV infected patients should receive same full dose chemotherapy regimens that would be used in the absence of HIV. Because HAART continues to have a positive effect on the overall health of patients, low-dose chemotherapy regimens are now generally reserved for those with advanced AIDS and multidrug-resistant HIV infection or for whom HAART is not available.

1. Full dose CHOP : cyclophosphamide, doxorubicin, vincristine, prednisolone with HAART. CHOP-based chemotherapy and HAART have yielded median survival periods in the range of 2 years.

2. CHOP with Rituximab : The role of Rituximab in patients with HIV is controversial. In a randomized phase 3 trial conducted by AIDS malignancy Consortium (AMC) of NCI,standard dose CHOP was compared with rituximab with CHOP. Although CR was higher (57%) in R- CHOP group compared with the patients who received CHOP alone (47%), this difference did not reach statistical significance. Additional use of Rituximab was associated with a statistically increases risk of death from infection. In contrast, to the AMC trial other studies have documented high CR rates, with the addition of Rituximab without an increase in mortality due to infections.
Infusion regimens like:

3. CDE : (cyclophosphamide, 200mg/m2 per day, days 1-4;doxorubicin,12.5mg/m2 per day 1-4 ,etoposide 60mg/m2 /day1-4;cycles repeated every 28 days) Sparano et al presented their results of a large multi-institutional trial that used the above regimen in 107 patients with previously untreated HIV-NHL. Overall complete response rate was 44%, median overall survival was 8.2 months.

4. Dose adjusted EPOCH : Little and colleagues from the National Cancer Institute (NCI) investigated the feasibility of omitting HAART during the administration of full dose chemotherapy. In this study, 6 cycles of dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) were administered to 39 patients with newly diagnosed ARL . The dose of cyclophosphamide on cycle 1 was based on the patient’s CD4 cell count at study entry (<100 cells/mm3 versus >100 cells/mm3) and was thereafter adjusted in increments or decrements of 187 mg/m2 (maximum dose, 750 mg/m2) according to the absolute neutrophil nadir. Antiretroviral agents were not used during chemotherapy but were restarted immediately at the completion of chemotherapy. Three-quarters of the patients received all 6 planned cycles of chemotherapy, and the administered dose intensity was 100% for doxorubicin, 99% for etoposide, 99% for vincristine, and 65% for cyclophosphamide. This dose intensity was achieved with acceptable toxicity. The complete response rate was an unprecedented 74%. Among patients with CD4 cell counts >100 cells/mm3, the complete response rate was even higher, at 87%, while the overall survival was 87% at 56 months. However, patients with CD4 cell counts <100 cell had an overall survival of only 16% at 56 months. Although the median CD4 cell count fell by 189 cells/mm3 and the mean viral load increased by 0.5 to 1.0 log10 copies/mL by the time the last cycle of chemotherapy was given, these values returned to baseline within 6 to 12 months following the reinstitution of HAART at the completion of chemotherapy. While no new opportunistic infections occurred during chemotherapy, 3 patients developed opportunistic infection within the first 3 months after completion of chemotherapy.

The response rate and overall survival in this study were the best reported to date. Outside the context of a clinical trial, dose-adjusted EPOCH would be a very reasonable regimen to use in the EPOCH would be a very reasonable regimen to use in the management of patients with ARL. From the results of this study, it is apparent that withholding antiretroviral therapy does not result in progression of AIDS and allows the full delivery of chemotherapy. In addition, the results suggested that good viral control during chemotherapy was not essential for optimal tumor response. However, it is important to stress that this approach requires the immediate reinstitution of HAART on completion of chemotherapy.

5. Liposomal doxorubicin : Similar benefits may be attained by substitution of liposomal doxorubicin for standard doxorubicin used in CHOP chemotherapy.
To address the controversy regarding the safety as well as the efficacy of rituximab, a randomized trial comparing concurrent administration of rituximab with EPOCH to EPOCH followed sequentially by rituximab weekly for 6 weeks is being conducted by the AIDS Malignancy Consortium. Thus, the role of rituximab in the treatment of AIDS-related lymphoma remains controversial and final conclusions await further investigation.

CNS prophylaxis; with intrathecal cytarbine, and or methotrexate should be considered. in
1. Patients with B-DLCL who have Epstein–Barr virus expression in the tumour tissue or cerebrospinal fluid
2. Patients with tumour involvement of the bone marrow, paranasal sinuses, testes or two or more extranodal sites.

Concomitant HAART and chemotherapy.
With the availability of HAART, it has become possible to give standard doses of chemotherapy, as infectious complications were reduced.

Interactions between chemotherapeutic and anti-retroviral agents is an area of concern and should be watched for. Care should be taken that the chemotherapy regimen is not compromised due to interactions and where necessary the HAART regimen should be changed or withheld.

Use of azidothymidine with chemotherapy is contraindicated, because it is associated with potential marrow failure and may worsen chemotherapy induced hematologic toxicities.

As antiretrovirals like stavudine, didanosine, zalcitabine may potentiate vincristine–induced neuropathy, careful attention to side effects and switching to alternative ARV may be necessary.

Nevirapine presents fewer problems than other retrovirals.
Given the evolving but still incomplete knowledge base regarding drug-drug interactions among antiretroviral agents, chemotherapy, and the medications most commonly prescribed by oncologists (eg, antiemetics, anxiolytics, narcotics, glucocorticoids, and antimicrobials), special care must be employed when developing a treatment strategy for the patient with AIDS-related lymphoma.

Supportive measures :
Pneumocystis carinii pneumonia (PCP) prophylaxis should be administerd to all patients regardless of CD4 counts.

Mycobacteria avium complex prophylaxis should be given if the CD4 counts are less than 50 mm³

Growth factor support should be used in all patients.

Relapsed or refractory ARL

With availability of effective anti-retroviral therapy, there has been an improvement in immune function, and haematologic reserves in HIV infected patients. These facts and improved supportive care have made stem cell mobilization and high dose chemotherapy possible in this group.

Krishnan et al from city of Hope, have reported their experience in 20 relapsed/refractory ARL who underwet progenitor cell transplant with a median follow up period of 31.8 months, 17 of the 20 patients remained alive and in CR. The progression free survival was 85% and overall survival was 85% for the entire group. Similar results have been reported by other investigator groups. These studies suggest that suitable patients with refractory or relapsed ARL should be considered for high dose chemotherapy with peripheral progenitor cell transplant.

Burkitt lymphoma. Currently, patients with HIV-associated Burkitts lymphoma are not treated differently from HIV-positive patients with other aggressive histologic subtypes.

Primary B cell CNS lymphoma (PCNSL)

PCNSL is usually associated with CD4 counts< 50 cells/mm³

There has been a significant decrease in incidence of PCNSL with introduction of HAART and consequent increase in CD4 counts.
MRI demonstates single or multiple contrast enhancing masses similar to toxoplasmosis.spect imaging can distinguish between the two as PCNSL is metabolically active and toxoplasmosis is metabolically inactive. Diagnosis is established by brain biopsy, positive CSF cytology, EBV viral DNA in CSF

Treatment
HAART should be initiated in all patients.

If performance status permits, systemic methotrexate 3-8gm/m2IV every 14days with leukoverin rescue (25mg/m2 q 6hrs) should be used until complete remission is achieved, and then continue monthly methotrexate for a year.

Radiotherapy is reserved for progression of disease on treatment or relapse.

If poor performance status then advised treatment is HAART along with palliative radiotherapy.

Primary effusion lymphoma (PEL)
Primary Effusion lymphoma is a rare subset of large B-cell lymphoma that mainly occurs in AIDS patients. (PEL) is a peculiar clinicopathologic entity characterized by human herpesvirus 8 (HHV-8) infection of tumor clone and by a peculiar tropism of the serous body cavities.1 HHV-8 occurs in 100% of patients and is frequently, although not always, associated with Epstein-Barr virus infection. At the clinicopathologic level, PEL is characterized by growth in the liquid phase in the absence of detectable tumor masses spreading along serous membranes without infiltrative growth patterns. Extraserous involvement of PEL has been reported. Some cases of PEL extend into tissues underlying the serous cavities, including the omentum and the lymph nodes, mediastinum, and lung. Moreover, some cases of extracavitary nodal presentation with a subsequent development of effusion have been reported. PEL usually displays a non-B or non-T phenotype, but immunogenotypic studies have defined its B-cell origin.

Treatment
There is no standard treatment for PEL. Outcome of PEL after polychemotherapy such as CHOP has generally been poor, with median survival ranging from 2 to 6 months. Immune reconstitution may play an important role in the management of PEL, and there have been reports of CR with HAART alone.

ABSTRACTS
1. Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin lymphoma. Vaccher E, Spina M, di Gennaro G, Talamini R, Nasti G, Schioppa O, Vultaggio G, Tirelli U. Division of Medical Oncology A, National Cancer Institute, Aviano, Italy. Cancer. 2001 Jan 1;91(1):155-63.

BACKGROUND: The feasibility and efficacy of concomitant chemotherapy and highly active antiretroviral therapy (HAART) is still unknown in patients with human immunodeficiency virus (HIV)-related malignancies. To evaluate the impact of chemotherapy plus HAART on the clinical course of patients with HIV-related, systemic, non-Hodgkin lymphoma (HIV-NHL), the authors compared retrospectively a group of 24 patients with HIV-NHL who were treated with the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen plus HAART with a group of 80 patients who were treated with CHOP chemotherapy or a CHOP-like regimen (i.e., cyclophosphamide, doxorubicin, teniposide, and prednisone with vincristine plus bleomycin) without receiving antiretroviral therapy. METHODS: All patients were enrolled in two sequential trials performed at the Aviano Cancer Center, Italy, from April 1988 to December 1998. HAART was included with combination therapy from January 1997. Antiretroviral regimens consisted of two reverse transcriptase inhibitors and one protease inhibitor. RESULTS: The two treatment groups were well matched with regard to patient demographics, NHL characteristics, HIV status, and treatment, i.e., the number of cycles and chemotherapy dose. The response rates were similar between the two groups. Severe anemia (Grade 3-4 according to the World Health Organization criteria) was significantly greater in the patients who received CHOP-HAART compared with the patients who received CHOP alone (33% vs. 7%, respectively; P = 0.001). Leukopenia was similar between the two groups, but colony stimulating factor support was significantly greater in the CHOP-HAART group than in the control group (92% vs. 66%, respectively; P = 0.03). Seventeen percent of CHOP-HAART patients developed severe autonomic neurotoxicity, whereas none of the CHOP patients developed neurotoxicity (P = 0.002). At similar median follow-up, opportunistic infection (OI) rates and mortality were significantly lower in the CHOP-HAART patients than in the CHOP patients (18% vs. 52%, respectively; P = 0.05; and 38% vs. 85%, respectively; P = 0.001). The median survival for CHOP-HAART patients was not reached, whereas the medial survival of CHOP patients was 7 months (P = 0.03).

CONCLUSIONS: The combination of CHOP plus HAART is feasible and may reduce the morbidity from OIs in HIV-NHL patients. However, careful attention must be directed to cross toxicity and possible pharmacokinetic interactions between antiretroviral and antineoplastic drugs. The impact of the combined chemotherapy plus HAART treatment on patient survival needs urgently to be evaluated in prospective studies.

2. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. Division of Hematology/Oncology, University of California, 400 Parnassus Ave, Rm A-502, San Francisco, CA 94143. Blood. 2005 Sep 1;106(5):1538-43. Epub 2005 May 24.

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy results in significant improvement in clinical outcome for individuals with non-HIV-associated aggressive B-cell lymphoma. To assess the potential risks and benefits of the addition of rituximab to CHOP for HIV-associated non-Hodgkin lymphoma (HIV-NHL) 150 patients receiving CHOP for HIV-NHL were randomized (2:1) to receive 375 mg/m(2) rituximab with each chemotherapy cycle (n = 99) or no immunotherapy (n = 50) in a multicenter phase 3 trial. The complete response rate (CR + CRu) was 57.6% for R-CHOP and 47% for CHOP (P = .147). With a median follow-up of 137 weeks, time to progression, progression-free survival, and overall survival times were 125, 45, and 139 weeks, respectively, for R-CHOP and 85, 38, and 110 weeks, respectively, for CHOP (P = not significant, all comparisons). Treatment-related infectious deaths occurred in 14% of patients receiving R-CHOP compared with 2% in the chemotherapy-alone group (P = .035). Of these deaths, 60% occurred in patients with CD4 counts less than 50/mm(3). Progression-free survival was significantly influenced by CD4(+) count (P < .001) and International Prognostic Index score (P = .022), but not bcl-2 status. The addition of rituximab to CHOP in patients with HIV-NHL may be associated with improved tumor responses. However, these benefits may be offset by an increase in infectious deaths, particularly in those individuals with CD4(+) lymphocyte counts less than 50/mm(3).

3. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. Ratner L, Lee J, Tang S, Redden D, Hamzeh F, Herndier B, Scadden D, Kaplan L, Ambinder R, Levine A, Harrington W, Grochow L, Flexner C, Tan B, Straus D; AIDS Malignancy Consortium. AIDS Malignancy Consortium Operation Center, University of Alabama, Birmingham, USA. J Clin Oncol. 2001 Apr 15;19(8):2171-8.

PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin’s lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL.

CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.

4. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Little RF, Pittaluga S, Grant N, Steinberg SM, Kavlick MF, Mitsuya H, Franchini G, Gutierrez M, Raffeld M, Jaffe ES, Shearer G, Yarchoan R, Wilson WH. Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health, Bethesda, MD 20892, USA. Blood. 2003 Jun 15;101(12):4653-9. Epub 2003 Feb 27.

The outcome of acquired immunodeficiency syndrome-related lymphomas (ARLs) has improved since the era of highly active antiretroviral therapy, but median survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral therapy in 39 newly diagnosed ARLs and examined protein expression profiles associated with drug resistance and histogenesis, patient immunity, and HIV dynamics and mutations. The expression profiles from a subset of ARL cases were also compared with a matched group of similarly treated HIV-negative cases. Complete remission was achieved in 74% of patients, and at 53 months median follow-up, disease-free and overall survival are 92% and 60%, respectively. Following reinstitution of antiretroviral therapy after chemotherapy, the CD4+ cells recovered by 12 months and the viral loads decreased below baseline by 3 months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and higher CD10 expression, consistent with a germinal center origin and good prognosis, but were more likely to be highly proliferative and to express p53, adverse features with standard chemotherapy. Unlike HIV-negative cases, p53 overexpression was not associated with a poor outcome, suggesting different pathogenesis. High tumor proliferation did not correlate with poor outcome and may partially explain the high activity of dose-adjusted EPOCH. The results suggest that the improved immune function associated with highly active antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from lymphomas of post-germinal center origin, which have a poor prognosis. These results suggest that tumor pathogenesis is responsible for the improved outcome of ARLs in the era of HAART.

5. Infusional CDE with rituximab for the treatment of human immunodeficiency virus-associated non-Hodgkin’s lymphoma: preliminary results of a phase I/II study. Tirelli U, Spina M, Jaeger U, Nigra E, Blanc PL, Liberati AM, Benci A, Sparano JA. National Cancer Institute, Aviano, Italy. Recent Results Cancer Res. 2002;159:149-53.

Infusional CDE (cyclophosphamide, doxorubicin, etoposide; iCDE) is one of the most effective chemotherapeutic regimen for human immunodeficiency virus (HIV)-associated non-Hodgkin’s lymphoma (NHL), with a complete remission rate of 46% and a median overall survival of 8.2 months (Sparano JA, Blood 1993; 81:2810). Since the majority of HIV-associated NHL are CD20-positive we reasoned that the addition of rituximab to iCDE (R-iCDE) could also improve the poor outcome of these patients. As a first step we investigated the safety of R-iCDE in a phase I/II study. Thirty patients with aggressive HIV-associated NHL were enrolled between June 1998 and October 2000. Characteristics of 29 evaluable patients were: median age: 38 years (range 29-65 years); male sex 24/29; histology: DLCL 16 (55%), Burkitt 10 (35%), ALCL 2 (7%), unclassified 1 (3%); stage: I (35%), II (10%), III (10%), IV (45%); International Prognostic Index: 0, 1 (59%), 2 (24%), 3 (17%), 4, 5 (0); CD4 count: median 132/ mm3 (range 3-470/mm3). Patients received rituximab (375 mg/m2) in conjunction with iCDE (five or six cycles). All patients were treated with G-CSF and highly active antiretroviral therapy (HAART). Twenty-six of 29 patients received treatment as planned, while chemotherapy had to be discontinued in three patients (2 persistent thrombocytopenias, 1 cerebral hemorrhage). Grade 3 or 4 toxicity was observed as follows: neutropenia 79%, anemia 45%, thrombocytopenia 34%, bacterial infection 34%, opportunistic infection 7%, mucositis 17%. A dose reduction was necessary in 22%. Complete remission was achieved in 86% of the patients, partial remission in 4%. Ten percent had progressive disease. After a median follow-up of 9 months the median overall survival is not reached. The actuarial survival at 2 years is 80% and the actuarial progression-free survival is 79%. Four of 29 patients (14%) have died, three from NHL and one from cryptosporidiosis. These findings suggest that the combination of rituximab with iCDE in patients with HIV-associated NHL is safe and feasible and that the addition of the anti-CD20 antibody does not increase the risk for infections. The high complete remission rate also indicates a potential therapeutic benefit and warrants further randomized trials.

6. Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin’s lymphoma: results of therapy and correlates of response. Levine AM, Tulpule A, Espina B, Sherrod A, Boswell WD, Lieberman RD, Nathwani BN, Welles L. Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA,USA. J Clin Oncol. 2004 Jul 1;22(13):2662-70

PURPOSE: To evaluate the safety and efficacy of liposomal doxorubicin (Myocet; Medeus Pharma Ltd, Herts,UK) when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin’s lymphoma (AIDS-NHL). Secondary objectives were to assess the impact of HIV viral control on response and survival, and to correlate MDR-1 expression with outcome. PATIENTS AND METHODS: Liposomal doxorubicin at doses of 40, 50, 60, and 80 mg/m(2) was given with fixed doses of cyclophosphamide, vincristine, and prednisone every 21 days. All patients received concurrent highly active antiretroviral therapy. NHL tissues were evaluated for multidrug resistance (MDR-1) expression. RESULTS: Twenty-four patients were accrued. 67% had high or high-intermediate International Prognostic Index scores; the median CD4 lymphocyte count was 112/mm(3) (range, 19/mm(3) to 791/mm(3)). No dose-limiting toxicities were observed at any level, with myelosuppression being the most frequent toxicity. Overall response rate was 88%, with 75% complete responses (CRs), and 13% partial responses. The median duration of CR was 15.6+ months (range, 1.7 to 43.5+ months). Effective HIV viral control during chemotherapy was associated with significantly improved survival (P =.027), but CRs were attained independent of HIV viral control. MDR-1 expression did not correlate with response, suggesting that the liposomal doxorubicin may evade this resistance mechanism.

CONCLUSION: Liposomal doxorubicin in combination with cyclophosphamide, vincristine, and prednisone is active in AIDS-NHL, with complete remissions achieved in 75% independent of HIV viral control or tissue MDR-1 expression. HIV viral control is associated with a significant improvement in survival. Additional studies are warranted.

7. Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas. Krishnan A, Molina A, Zaia J, Smith D, Vasquez D, Kogut N, Falk PM, Rosenthal J, Alvarnas J, Forman SJ. City of Hope Hematologic Neoplasia Program, City of Hope Cancer Center, Duarte, CA 90101, USA. Blood. 2005 Jan 15;105(2):874-8. Epub 2004 Sep 23

The treatment of HIV-associated lymphoma has changed since the widespread use of highly active antiretroviral therapy. HIV-infected individuals can tolerate more intensive chemotherapy, as they have better hematologic reserves and fewer infections. This has led to higher response rates in patients with HIV-associated Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) treated with chemotherapy in conjunction with antiretroviral therapy. However, for patients with refractory or relapsed disease, salvage chemotherapy still offers little chance of long-term survival. In the non-HIV setting, patients with relapsed Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) have a better chance of long-term remission with high-dose chemotherapy with autologous stem cell rescue (ASCT) compared with conventional salvage chemotherapy. In a prior report we demonstrated that this approach is well tolerated in patients with underlying immunodeficiency from HIV infection. Furthermore, similar engraftment to the non-HIV setting and low infectious risks have been observed. Herein, we expand upon this early experience with the largest single institution series of 20 patients. With long-term follow-up we demonstrate that ASCT can lead to an 85% progression-free survival, which suggests that this approach may be potentially curative in select patients with relapsed HIV-associated HD or NHL.