ASH 2010 meeting report‐top 10 clinically oriented abstracts in lymphoma
Authors: Thomas M. Habermann
Journal: American Journal of Hematology (2011)

The 2010 American Society of Hematology (ASH) annual meeting was held in Orlando, Florida, USA from December 4-7, 2010. There were 4,372 abstracts published in the Fifty-Second Annual Meeting Abstracts book. In addition there were multiple education sessions. The meeting had broad international representation. In lymphoma, there were approximately 1,148 abstracts including 660 in non-Hodgkin lymphoma and 488 in Hodgkin lymphoma. Summarized here are my top 10 lymphoma abstracts which contain clinical information which is relevant to clinical practice. All 10 abstracts are published in full in the November 19, 2010 issue of Blood (volume 116, Issue 21) and are identified here by their abstract numbers. Ardeshna and colleagues in a trial sponsored by University College of London Hospitals presented the results of a prospective randomized Phase III trial in follicular lymphoma [1]. Eligibility criteria included asymptomatic patients with nonbulky Stages II, III, and IV disease. Totally, 186 patients randomized in arm A watchful waiting and observed. 84 patients in arm B were treated with rituximab weekly for four weeks at a dose of 372 mg/M2. 192 patients in arm C were treated with induction rituximab at a weekly dose 375 mg/M for four weeks followed by rituximab 375 mg/M2 maintenance every two months (starting at month 3 and continuing until month 25) for two years. Arm B was discontinued in September of 2007 because of evidence of the efficacy of maintenance rituximab. The median age was 60 years. Grade 3 or higher toxicities included infection (4%), allergy (3%), neutropenia (3%), and neutropenic sepsis (1%). The complete remission (CR)/partial remission (PR) rates in arm A were 3%/6%, arm B 45%/33%, and arm C 49%/36%. The progression free survival was 30%, 60%, and 80% (P < 0.001) in arms A, B, and C respectively. The time to new treatment (TNT) at four years was 33 months in arm A, and not reached in arms B and C (P < 0.001). There was no difference in the overall survival (OS) (P > 0.50). The authors concluded that initial treatment with rituximab significantly delays the need for new therapy and that this finding may change management strategies in patients with a new diagnosis of asymptomatic follicular lymphoma. The management strategy of choice was watch and wait for follicular lymphoma [2]. This rituximab-based trial is the first randomized trial of watch and wait versus treatment with immunotherapy. This study addresses the question of whether or not rituximab can delay the need for chemotherapy compared to observation. Patients who relapsed were treated with investigator choice regimens. This study reported a delay in the time to treatment with chemotherapy or radiotherapy and decreased the risk of the disease progressing. To date, there is no improvement in overall survival. Patients were not retreated with rituximab with progression or relapse. There was no improvement in quality of life. This was a plenary session presentation. The Eastern Cooperative Oncology Group has completed accrual to the RESORT (Rituximab Extended Schedule or ReTreatment Trial) for asymptomatic patients with Stages III/IV low tumor burden low grade lymphoma. The RESORT trial does not have an observation arm, but this trial will directly address the time to rituximab resistance. Both arms are randomized to induction rituximab for four weeks. Arm A patients were retreated with rituximab at disease progression whereas arm B patients were treated with rituximab every three months until disease progression. This will provide further information regarding the early treatment of patients with low tumor burden. The PRIMA (Primary Rituximab and Maintenance) study is a prospective randomized study which evaluated 1,217 patients with high tumor burden follicular lymphoma [3]. Totally 223 centers in 23 countries enrolled patients. Forty-three percent of patients had a FLIPI score of 3–5. The median age was 56 years. Ninety percent of patients were Stage IV. Seventy-five percent of patients were treated with R-CHOP, 22% with R-CVP, and 3% R-FCM. Patients that were restaged and who had a CR/Cru/PR were then randomized to maintenance rituximab 375 mg/M2 every eight weeks for two years versus observation. The three-year progression free survival was 74.9% in the maintenance rituximab arm and 57.6% in the observation arm (P < 0.0001). The time to new treatment (TNT) was statistically significantly different (HR = 0.60, P < 0.01). There were 6% deaths in the rituximab arm and 5% in the observation arm. Fifty-two percent of patients that were in a PR at the time of randomization converted to a CR or Cru at the end of two-year maintenance in the rituximab maintenance arm compared with 30% of patients in the observation arm (P = 0.0001). Immunochemotherapy incorporating rituximab with chemotherapy in the initial treatment improves overall survival in follicular lymphoma [4, 5]. Hochster et al. reported improved progression free survival in patients initially treated with cyclophosphamide, vincristine, and prednisone who were then randomized to maintenance rituximab versus observation with a OS at three years of 92% versus 86% (HR = 0.6; log-rank one-sided P = 0.05) [6]. The PRIMA study is the largest prospective randomized study of immunochemotherapy followed by maintenance rituximab. This data has one more year of maturity from the initial presentation in 2010 at the American Society of Clinical Oncology. Another interesting abstract from this study at this meeting reported that FDG PET-CT imaging after immunochemotherapy is a powerful prognostic indicator of outcomes in follicular lymphoma [7]. The 3-year PFS was 32% in PET positive patients and 74% in PET negative patients. The median PFS was 19 months for PET positive patients and not reached in PET negative patients. The role of PET scans is under evaluation in other studies. Patients were randomized to R-CHOP for six cycles followed by ASCT versus CHOP for three cycles, DHAP for three cycles, rituximab, and ASCT [8]. The time to treatment failure (TTF) was 49 months in the R-CHOP arm and not reached in the DHAP arm (P = 0.0384). The remission duration was 48 months in the R-CHOP arm versus not reached in the DHAP arm (P = 0.047). There was no difference in the overall survival, 79% versus 80% (P = 0.47). The management of mantle cell lymphoma is controversial. There are many phase II studies that have been reported. In a randomized trial of CHOP versus R-CHOP there was no significant difference [9]. Significant improvements in progression free survival has been reported with different regimens. R-hyperCVAD has been reported to have an eight year time to TTF of 46% and 68% OS in all patients in long-term follow-up [10]. In patients age of 65 years or less, the TTF was 4.6 years and the OS was not reached. A retrospective analysis by the NCCN group reported that R-CHOP followed by ASCT have similar outcomes [11]. Hermine et al. now report in a randomized study that the induction regimen containing high doses of Ara-C followed by ASCT should become the new standard of care in MCL up to 65 years of age. The critical two issues in mantle cell lymphoma remain: treatment-related toxicities and to have regimens which will cure mantle cell lymphoma rather than only improve progression-free survival. 196 patients were prospectively randomized to R-ACVBP (rituximab 375 mg/M2 Day 1, doxorubicin 75 mg/M2 Day 1, cyclophosphamide 1,200 mg/M2 Day 1, vindesine 2 mg/M2 Days 1 and 5, bleomycin 10 mg Days 1 and 5, prednisone 60 mg/M2 Days 1 and 5, intrathecal methotrexate 15 mg on Day 2, G-CSF from Days 6 to 13) [12]. Patients were then treated with sequential consolidation therapy with two courses of methotrexate at a dose of 3 gm/M2 followed by leucovorin rescue, four courses of rituximab at a dose of 375 mg/M2, etoposide 300 mg/M2 and ifosphamide 1,500 mg/M2 on Days 1, 2 courses of cytosine-arabinoside 100 mg/M2 subcutaneously for four days at 14-day intervals. 183 patients were randomized to standard dose R-CHOP21 for three weeks for eight cycles with intrathecal methotrexate on Day 1 for the first four cycles. The overall response rate (ORR) was 90.3% versus 88.5% (P = 0.57). The three-year EFS was 80.9% versus 66.7% (P = 0.0035), 3-year PFS 86.8% versus 73.4% (P = 0.0015), and overall survival 92.2% versus 83.8% (P = 0.0071). There were more toxicities in the R-ACVBP arm. 51% versus 7% required red blood cell transfusions and febrile neutropenia was reported in 39% versus 9% of patients. R-CHOP 21 has been the standard of care [13-15]. The GELA group now presents randomized trial data on the randomized study of R-ACVBP and R-CHOP which reports an improved overall survival. Other trials are ongoing evaluating consolidation ASCT, enzastaurin, and other approaches which are currently under evaluation. Vindsine is not available in the USA. This is the first report of the North American Intergroup locally extensive and advanced stage Hodgkin lymphoma study [16]. Totally, 404 patients were randomized to ABVD and 408 patients to the Stanford V regimen. The ORR response rates were 72% and 69%, respectively. The five-year FFS was 73% with ABVD and 71% with Stanford V (P = 0.29). The OS rate was 88% with ABVD and 87% with Stanford V (P = 0.87). There was no difference in second cancers with 12 in the ABVD arm and 14 in the Stanford V arm. Patients treated on the Stanford V arm had more lymphopenia (78% and 42%) (P < 0.0001) and more peripheral neuropathy (10% versus 3%) (P < 0.0001). The management of advanced stage HL has been under continued study. Three regimens have been utilized internationally over the last decade including ABVD, Stanford V, and dose adjusted BEACOPP. This study reported that ABVD and Stanford V were equivalent. In an accompanying abstract, the patients with bulky mediastinal Stages I/II were evaluated in a subset analysis [17]. Totally, 136 patients were randomized to ABVD with 36 Gy (82%) and 136 to Stanford V with radiation therapy to pretreatment lesions greater than 5 cm in 86% of patients with 82% and 88% protocol compliance to radiation therapy. The five-year FFS was 85% in the ABVD arm and 77% in the Stanford V arm (P = 0.13). The five-year OS was 92% with ABVD and 92% with Stanford V (P = 0.31). The authors concluded that ABVD for six to eight cycles plus 36 Gy radiation therapy remains the North American standard of care, and that the Stanford V regimen is a reasonable option if shorter duration of therapy or lower doses of adriamycin or bleomycin are warranted. Longer follow-up is required to assess radiation therapy and chemotherapy related late effects. The authors recommended that the future focus should be on risk stratification to identify the 15–20% of patients destined to relapse after standard therapy, and for the 80–85% of patients who are cured with standard therapy to determine how to achieve the same excellent outcomes with a reduction in chemotherapy and radiation therapy. A major concern with dose escalated BEACOPP is the risk of secondary myelodysplasia and acute myelogenous leukemia. The German Hodgkin Study Group (GHSG) reported that the current risk is 1.4% overall in patients followed up at 70 months [18]. After initial treatment, 207 patients were randomized to 90Y-Ibritumomab tiuxetin consolidation in first remission in advanced follicular lymphoma and 202 patients were observed [19]. The CR/CRu induction was 57%/not reached versus 43%/31 months (HR = 0.61). The five-year progression free survival was 47% versus 29% (P < 0.0001). The median progression free survival was 49 months in the consolidation treatment group and 14 months in the observation group. There were six cases of myelodysplasia in the treatment group and 1 in the observation group (P = 0.063). 77% and 78% of patients were treated with rituximab at the time of relapse, and the ORR rates were 79% and 78%, respectively. Radioimmunoconjugates first received FDA approval for patients with relapsed low grade lymphoma from a series of six studies. Strategies to improve upon the results of immunochemotherapy as induction therapy that has resulted in improved OS have been ongoing. This report of a large international study with radioimmunoconjugates is one such strategy. The toxicities at this point in time do not preclude this approach overall. Long-term follow-up will be essential to assess the impact of the overall improved duration of survival in patients with follicular lymphoma. In the US Intergroup Study E4494/C9793, 632 patients were stratified by IPI and randomized to R-CHOP versus CHOP every three weeks for six to eight cycles [20]. Patients who achieved a CR/PR after induction were stratified by the IPI score and randomized to rituximab 375 mg/M2 weekly for four doses every six months for two years. The median follow-up is now 9.4 years from induction and 9.0 years from maintenance randomization. The proportion of failures was similar for R-CHOP and observation at 38% and R-CHOP and maintenance rutuximab at 36% (P = NS). There was no difference in the FFS or OS in patients treated with R-CHOP followed by maintenance rituximab versus observation. This was the first clinical trial in diffuse large B-cell lymphoma that randomized patients treated with immunochemotherapy to rituximab versus observation. R-CHOP21 has become the standard of care [13-15]. The interpretation of this study has been complicated by the two by two design. The long-term follow-up data continues to support that there is no role for maintenance rituximab in patients treated with induction R-CHOP outside of a clinical trial. There is currently an international trial evaluating the role of maintenance rituximab in DLBCL. Nowakowski et al. reported a retrospective study of 97 patients with primary pulmonary MALT lymphoma from the Mayo Clinic Lymphoma Database [21]. The median follow-up was 10.4 years. Thirty-seven patients were surgically resected, and the median progression free survival was 11.2 years in this group of patients. The median survival for the 17 patients who were observed was 3.2 years. 14 patients were treated with chemotherapy with a 50% CR/PR rate and median PFS of 5.3 years. Eight patients were treated with rituximab and chemotherapy (immunochemotherapy). The CR/PR rate was 43% and the median PFS was not yet reached. This retrospective analysis suggests that surgery is the treatment of choice for Stage I MALT of the lung. In contrast, only one of eight patients responded to rituximab. Eight patients were treated with immunochemotherapy with a CR/PR rate of 43% and the median progression free survival was not yet reached. The indications for surgical resection with no other treatment are quite limited in lymphoproliferative disorders. Primary pulmonary MALT lymphoma may be an exception. A retrospective international collaborative study is currently under way to further assess outcomes in this uncommon subset of non-Hodgkin lymphoma. The British Columbia Cancer Agency retrospectively evaluated 1,126 patients retrospectively [22]. Totally 166 (15%) had primary refractory or early relapse diffuse large B-cell lymphoma. Ninety-three patients were over the age of 70 or too frail for more than two cycles of chemotherapy. Seventy-three patients were the subject of this report. The median OS for this group of patients was 10 months. Totally 33 (45%) had primary refractory disease. A total of 40 (55%) relapsed within three months of a CR/PR. Of these patients five were long term survivors. About 37% (50) were without serious comorbidity. Ten patients qualified for an ASCT and three of the six long-term survivors were transplanted. Patients with refractory and early relapse are complex. The prognosis has not been well documented in large series. This report differentiates patients who are not candidates for further treatment. Age over 70 is not necessarily a contraindication to further treatment or experimental studies. The outcomes support clinical trials with new non-approved agents with different mechanisms of action and further studies into the biology of DLBCL. Multiple agents are under evaluation, and some were reported at this meeting [23-25]. This is a further analysis of the Biovest study [26]. Totally 117 of 234 patients achieved a CR/CRu and were randomized and received at lease one dose. Seventy-six patients were randomized to Id vaccine and 41 to placebo. The median DFS was 44.2 months in the Id vaccine group and 30.6 months in the placebo group (P = 0.048). In patients with an IgM tumor/IgM Id, the median time to relapse was 50.6 months in the Id vaccine group in contrast to 27.1 months in the control group (P = 0.002). In patients with an IgG tumor and IgG Id, the median time to relapse was 35.1 months in the Id vaccine group and 32.4 months in the placebo group (P = 0.807). This vaccination trial was first presented at the American Society of Clinical Oncology in 2010. This was the first positive trial of three ongoing vaccination studies. These trials did not incorporate rituximab in the induction regimen which will be critical in future studies. This study was different than the other two studies. The time to treatment was 12 months rather than six months. The chemotherapy regimen was not a standard follicular lymphoma regimen. The survival was statistically significantly different. This data may further move vaccination trials forward. In the 2010 ASH meeting abstracts, my top 3 clinically relevant abstarcts were (i) the study by Ardeshna et al. reporting that initial treatment with rituximab significantly delays the need for new treatment a finding which “may change” the management of patients with newly diagnosed asymptomatic follicular lymphoma but needs further confirmation, (ii) the PRIMA study which supports the use of maintenance rituximab in patients previously treated with immunochemotherapy, and (iii) the CHOP, DHAP, rituximab, and ARA-C followed by ASCT over R-CHOP followed by ASCT. Ongoing follow-up of these and other studies, new therapeutic interventions, and new biologic observations in lymphoid neoplasms will further improve outcomes.