Doxorubicin, vinblastine, and gemcitabine (CALGB 50203) for stage I/II nonbulky Hodgkin lymphoma: pretreatment prognostic factors and interim PET.

To reduce doxorubicin, bleomycin, vinblastine and dacarbazine toxicity, the Cancer and Leukemia Group B conducted a phase 2 trial of doxorubicin, vinblastine, and gemcitabine for newly diagnosed, nonbulky stages I and II Hodgkin lymphoma. Ninety-nine assessable patients received 6 cycles of doxorubicin 25 mg/m(2), vinblastine 6 mg/m(2), and gemcitabine 800 mg/m(2) (1000 mg/m(2) in first 6) on days 1 and 15 every 28 days. Computed tomography (CT) and positron emission tomography (PET) were performed before and after 2 and 6 cycles. Complete remission (CR)/CR unconfirmed was achieved in 72 of 99 patients (72.7%) and partial remission in 24 of 99 patients (24.2%). The CR rate was 81% when using PET criteria. Two patients have died of Hodgkin lymphoma progression. Median follow-up for nonprogressing patients is 3.3 years. The progression-free survival (PFS) at 3 years was 77% (95% confidence interval, 68%-84%). The relapse rate was less than 10% for patients with favorable prognostic factors. The 2-year PFS for cycle 2 PET-negative and -positive patients was 88% and 54%, respectively (P = .0009), compared with 89% and 27% for cycle 6 PET-negative and -positive patients (P = .0001). Although the CR rate and PFS were lower than anticipated, patients with favorable prognostic features had a low rate of relapse. Cycle 2 PET and cycle 6 PET were predictive of PFS.

A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype.

BACKGROUND: A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting. DESIGN AND METHODS: The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23-83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed. RESULTS: With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities. CONCLUSIONS: These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. The trial was registered at ClinicalTrials.Gov (NCT00032019).

Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome.

Allogeneic stem cell transplantation (SCT) with reduced-intensity conditioning (RIC) has the potential to lead to long-term remissions for patients with lymphoma. However, the role of RIC SCT in the treatment of lymphoma is still unclear. Specifically, the relative benefit of RIC SCT across lymphoma histologies and the prognostic factors in this population are incompletely defined. We retrospectively analyzed the outcomes of 87 patients with advanced lymphoma who underwent RIC SCT at the Dana-Farber Cancer Institute over a 6-year period with a homogeneous conditioning regimen consisting of fludarabine and low-dose busulfan. Thirty-six patients had Hodgkin disease (HD) and 51 had non-Hodgkin lymphoma (NHL). Sixty-eight percent had undergone prior autologous transplantation. The 1-year cumulative incidence of nonrelapse mortality was 13%, and the 3-year cumulative incidence of progression was 49%. The incidence of grade 3-4 acute GVHD was 11%. The 2-year cumulative incidence of chronic GVHD was 68%, and its development was associated with a decreased risk of progression and an improved progression-free survival (PFS). Three-year overall survival (OS) was 56% for patients with HD, 81% for indolent NHL, 42% for aggressive NHL, and 40% for mantle cell lymphoma. The corresponding figures for 3-year PFS were 22%, 59%, 22%, and 30%, respectively. Multivariate analysis identified elevated pretransplantation lactate dehydrogenase (LDH) as an adverse factor for PFS, while indolent NHL histology was favorable. For OS, advanced age and elevated pretransplantation LDH were adverse factors, whereas indolent NHL histology was favorable. Low early donor chimerism was not predictive of poor outcome in univariate or multivariate analyses. Moreover, progression was not associated with loss of chimerism. These results emphasize the importance of lymphoma histology for patients undergoing RIC SCT, as well as the lack of relevance of donor chimerism for outcome in this patient population.

Relapsed and refractory Hodgkin's lymphoma: new avenues?

Relapse or progression following therapy for Hodgkin's lymphoma occurs in 10% to 60% of patients depending on initial clinical stage. Patterns of failure in advanced disease determine prognosis of salvage therapy. Progression or early relapse after less than 12 months requires intensive salvage therapy. Only late, isolated, asymptomatic relapse, which occurs in less than 25% of those relapsing from systemic therapy, can be treated with conventional-dose chemotherapy with or without radiation. Overall about 40% to 50% of relapses from advanced disease can be salvaged with higher percentages for patients relapsing from early stage disease.

Single agent bortezomib in the treatment of relapsed and refractory Hodgkin lymphoma: cancer and leukemia Group B protocol 50206.

Constitutive activation of nuclear factor-kappaB (NF-kappaB) has been described in patient-derived Reed - Sternberg cells and Hodgkin lymphoma (HL) cell lines and contributes to the proliferation and survival of HL. Therapeutic inhibition of the proteasome with bortezomib may inhibit over-expression of nuclear NF-kappaB by preventing degradation of IkappaB, which sequesters NF-kappaB in the cytoplasm. To evaluate this hypothesis, the Cancer and Leukemia Group B (CALGB) conducted a multi-institutional phase II trial of single agent bortezomib in patients with relapsed or refractory classical HL. Thirty patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, 11 and every 21 days for a median of 2 cycles (range, 1 - 8). Patients were heavily pre-treated with a median of four prior therapies, and 83% were previously transplanted. No responses were observed, 9 patients had stable disease, and 21 progressed. The median progression-free and overall survivals were 1.4 months [95% CI, (1.28, 1.91)] and 14.8 months [95% CI (11.2, 22.3)], respectively. Grade 3 - 4 adverse events, primarily thrombocytopenia, occurred in 15 patients. Therefore, although well tolerated, 1.3 mg/m(2) bortezomib administered biweekly has no single agent activity in relapsed/refractory classical HL.

High dose CHOP: a phase II study of initial treatment in aggressive non-Hodgkin lymphoma. Cancer and Leukemia Group B 9351.

Cyclophosphamide and doxorubicin, two important drugs in the treatment of lymphoma, exhibit a relationship between dose and fractional cell kill, and because of their toxicity profiles, they are candidates for significant dose escalation. We performed a phase II trial to determine the response rate, toxicity, and feasibility of escalated doses of both drugs as part of high dose CHOP in diffuse aggressive lymphoma. Patients who had advanced, previously untreated diffuse aggressive lymphomas (IWF E-H) and an International Prognostic Index of intermediate to high risk were eligible. Treatment was cyclophosphamide 2 gm/m(2)/day intravenously on Days 1 and 2 (total cycle dose 4 gm/m(2)), doxorubicin 35 mg/m(2)/day as a continuous infusion on Days 1 and 2 (total 70 mg/m(2)), vincristine 1.4 mg/m(2) (maximum 2 mg) on Day 1 and prednisone 100 mg/day orally on Days 1 - 5 repeated every 3 weeks for a total of four cycles. G-CSF, prophylactic antibiotics, and mesna were provided. A total of 99 patients were enrolled; 98 received therapy. Major toxicities were Grade 4 neutropenia and thrombocytopenia occurring in 97% and 92%, respectively. Serious infections occurred in 53%. Treatment-related mortality was 2%. The overall response rate is 85%, and two-year failure free and overall survival are 39% and 64%, respectively. Persistent or relapsed lymphoma was the overwhelming cause of death. Six patients have developed AML or MDS. In view of the substantial toxicity accompanying high dose CHOP, the observed outcome suggests that its efficacy is not sufficient to make further study feasible.

Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma: CALGB 59901.

Nelarabine (compound 506U78), a novel purine nucleoside, is a soluble pro-drug of 9-beta-D-arabinofuranosylguanine (ara-G). Nelarabine is rapidly demethoxylated in blood by adenosine deaminase to ara-G. Pre-clinical and clinical studies have demonstrated the selective cytotoxicity of ara-G to T-lineage derived cells. CALGB Protocol 59901 was a Phase II study of nelarabine in patients with systemically untreated cutaneous T-cell lymphoma (CTCL) or refractory/relapsed systemic T-cell lymphoma (STCL). The objectives were to determine response rate, remission duration and safety profile associated with nelarabine given at 1.5 g m(-2) per day on days 1, 3 and 5 as an intravenous infusion every 21 days for a minimum of two cycles and to continue up to two cycles beyond CR up to a maximum of eight cycles. Nineteen patients were enrolled in the study: 11 CTCL and eight STCL patients. Grade 3 or 4 adverse events were documented in 50% and 28%, respectively. In particular, 33% of patients experienced Grade 3 or 4 neurologic toxicities. There were two partial remissions lasting 3 months and 5.5 months, respectively. Median event-free survival was 1.2 months and median overall survival was 3 months. Due to lack of efficacy and excessive toxicity, nelarabine is not recommended as monotherapy in adult patients with CTCL and STCL at this dose schedule.

The cancer and leukemia group B lymphoma committee.

The malignant lymphomas include at least 30 entities that are distinct with respect to histology, immunology, genetics, clinical features, and outcome following therapy. The clinical behavior of these diseases ranges from indolent but generally incurable to aggressive and frequently fatal yet potentially curable with appropriate chemotherapy or chemotherapy-antibody regimens. Over the past 50 years, the Cancer and Leukemia Group B (CALGB) Lymphoma Committee has conducted a series of clinical trials that have contributed to an improvement in outcome for patients with a number of the more common lymphoma subtypes. The World Health Organization has classified approximately 30 neoplastic diseases of the hematopoietic and lymphoid tissues (1). The Cancer and Leukemia Group B (CALGB) Lymphoma Committee highlight below clinical trials that have resulted in improved patient outcome for the more frequent lymphoma subtypes.

Sequential doxorubicin and topotecan in relapsed/refractory aggressive non-Hodgkin's lymphoma: results of CALGB 59906.

Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Sequential administration of a topoisomerase II inhibitor followed by a topoisomerase I inhibitor is potentially synergistic due to increased target enzyme levels. Patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL) were eligible for this phase II study of doxorubicin 25 mg/m2 intravenous (IV) on day 1 and topotecan 1.75 mg/m2/day IV on days 3 - 5, every 21 days. The trial objectives included the overall response rate, progression-free survival, and toxicity. Twenty-six patients were enrolled and 25 patients are assessable for toxicity and response. The median age was 58 (range 23 - 74) years. The patients had received a median of two (range one to five) prior regimens, including five patients with a prior stem cell transplant. Five patients (20%, 95% confidence interval 0.07, 0.42) responded with two (8%) complete remissions and three (12%) partial remissions; an additional four (16%) patients had stable disease. Both patients achieving a complete remission had Burkitt's lymphoma. There were no treatment-related deaths. In conclusion, the combination of doxorubicin and topotecan is well tolerated and has modest activity in relapsed/refractory NHL, with occasional patients having a prolonged remission. The activity in Burkitt's lymphoma should be investigated further.

Combination chemotherapy of solid tumors: an American-Italian collaboration: a celebration of the work of Gianni Bonadonna.

This article highlights the important collaboration between the U.S. NCI in Bethesda, Maryland and the Istituto Tumori in Milan, Italy that had a major impact on the development of curative regimens for breast cancer, Hodgkin's disease and diffuse large B cell lymphoma.In addition to his contribution to developing new therapies, Gianni Bonadonna played an important role in bringing highly focused, disciplined, ethical clinical trials to the European continent.

Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial.

PURPOSE: In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkin's disease. We compared these regimens as initial chemotherapy for Hodgkin's disease. PATIENTS AND METHODS: Adult patients (N = 856) with advanced Hodgkin's disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies. RESULTS: The rates of complete remission (76% v 80%, P =.16), failure-free survival at 5 years (63% v 66%, P =.42), and overall survival at 5 years (82% v 81%, P =.82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P =.060 and.001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P =.057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P =.13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P =.011). CONCLUSION: ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkin's disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkin's disease.

Long-term survival and competing causes of death in patients with early-stage Hodgkin's disease treated at age 50 or younger.

PURPOSE: To analyze the long-term survival and the pattern and timing of excess mortality in patients with early-stage Hodgkin's disease. PATIENTS AND METHODS: Between 1969 and 1997, 1,080 patients age 50 or younger were treated for clinical stage IA to IIB Hodgkin's disease. Overall survival was determined, and prognostic factors were assessed. Relative risk and absolute excess risk (AR) of mortality were calculated for the entire cohort and by prognostic groups (on the basis of B symptoms, mediastinal status, and number of sites, modified from the European Organization for Research and Treatment of Cancer). RESULTS: The median follow-up was 12 years. The 15- and 20-year Kaplan-Meier survival estimates were 84% and 78%, respectively. Cox proportional hazards models showed that number of involved sites (P =.006), mediastinal status (P =.02), and histology (P =.02) were independent predictors of death from all causes. The AR of mortality in patients with a favorable prognosis increased over time, whereas for those with an unfavorable prognosis, the AR peaked in the first 5 years, predominantly from Hodgkin's disease. The relative risk of mortality from all causes, causes other than Hodgkin's disease, second tumors, and cardiac disease remained significantly elevated more than 20 years after treatment. CONCLUSION: Patients treated for early-stage Hodgkin's disease have a sustained excess mortality risk despite good control of the disease. Treatment reduction efforts in patients with early-stage, favorable-prognosis disease should continue, but for patients with an unfavorable prognosis, modified treatment may not be advisable. The excess mortality noted beyond two decades underscores the importance of long-term follow-up care in patients treated for Hodgkin's disease.

Lymphoma: present and future challenges.

Greater understanding of the basic biology of the cancer cell has provided new avenues for research in malignant lymphomas. Despite these advances, however, several challenges remain. First, what is the standard of care for patients with low-grade non-Hodgkin's lymphoma? To date, no single treatment strategy has emerged as superior in these patients. With respect to aggressive lymphomas, is anything better than the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen? For patients with Hodgkin's disease, is there a regimen superior to ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)? Finally, what is the optimal role of radiation therapy in patients with Hodgkin's disease? Clearly, the management of lymphoma remains a challenge, and research efforts aimed at developing new therapeutic agents should ultimately improve patient outcomes.