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The American Society of Hematology (ASH) 2010 Annual Meeting Plenary Session included one clinically important presentation. Abstract 6 described the results of an intergroup randomized trial of rituximab versus a watch and wait strategy in patients with stage II, III, and IV asymptomatic, non-bulky follicular lymphoma grades 1, 2, and 3A.¹ This United Kingdom trial randomized 462 patients with follicular lymphoma to (A) watch and wait versus (B) 4 weekly doses of rituximab versus (C) 4 weekly doses of rituximab followed by rituximab maintenance every 2 months for 2 years. In September 2007, arm B was dropped after accrual of 84 patients due to emerging data regarding the value of maintenance rituximab.

The primary endpoint of the trial was time to initiation of new treatment. Overall response rate (ORR) and progression-free survival (PFS) were secondary endpoints.
At a median of 3 years of follow-up, the percentage of patients not requiring initiation of new treatment was 48% for arm A, 81% for arm B, and 91% for arm C. For arm A (watch and wait), the median time to new treatment was 34 months. Progression-free survival at 3 years was 33% for arm A, 60% for arm B, and 81% for arm C. Overall survival (OS) at 3 years was approximately 96% for all 3 arms. Serious adverse events were more common in arm C and included allergic reactions, neutropenia, and infections. The authors concluded that initial treatment with rituximab significantly delays the need for new therapy and that this finding may change the management of patients with newly diagnosed asymptomatic follicular lymphoma.

Abstract 430 discussed another antibody-drug conjugate, inotuzumab ozogamicin, which combined a humanized anti-CD22 monoclonal antibody with calicheamicin.² Forty-three patients with indolent B-cell lymphoma who had progressed after 2 or more systemic therapies were treated. Twenty-six percent of patients discontinued treatment primarily due to laboratory abnormalities. The ORR was 53%, and 66% of patients with follicular lymphoma responded. Nineteen percent achieved a complete response (CR). Progression-free survival at 6 months was 67% among patients with follicular lymphoma.

Bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), has been approved in combination with chemotherapy for a number of solid tumors. Abstract 591 reported the results of a Southwest Oncology Group (SWOG) phase II trial combining rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with bevacizumab as front-line therapy for 64 patients with diffuse large B-cell lymphoma (DLBCL).³ Based on prior studies of R-CHOP, the projected 1-year PFS rate would be expected to be 71%. In this study, 1-year PFS was 77%, and 2-year PFS was 69%. One-year and 2-year OS rates were 86% and 79%, respectively. These results failed to meet the predetermined expectations for the R-CHOP-bevacizumab combination. Serious adverse events were seen among 30 patients. An increased incidence of cardiac dysfunction and gastrointestinal perforations was also noted. The authors concluded that their results did not support additional studies of this R-CHOP-bevacizumab regimen.

The role of radioimmunotherapy (RIT) in follicular lymphoma has been somewhat controversial. Logistical problems and reimbursement concerns have hindered widespread use of this therapeutic option for follicular lymphoma. Many physicians have reserved RIT for patients with follicular lymphoma who have relapsed after 2 or more systemic therapies although studies have suggested that RIT is most effective when utilized early in the course of disease. An international group presented the results of a phase II study of previously untreated patients with grades 1-3A follicular lymphoma who received first-line yttrium⁹⁰-ibritumomab tiuxetan.⁴ Sixty patients were recruited. The CR rate was 45%, and the partial response (PR) rate was 40% for an ORR of 85%. After 1-year of follow-up, 52% of patients were in CR and 20% in PR. Longer follow-up will be needed to determine the long-term value of RIT as a front-line regimen for follicular lymphoma.

Three-year follow-up of the FIT trial was presented at ASH in 2007. At the 2010 ASH Annual Meeting, the 5.5-year follow-up on this trial was presented. The FIT trial randomized newly diagnosed patients with indolent lymphoma to chemotherapy alone versus chemotherapy followed by RIT consolidation with ⁹⁰Y-ibritumomab tiuxetan.

The 3-year results included the following:

• Post induction response rates: PR = 48%/CR = 52%
•  Follow-up of 3 years: PFS increased from 13.5 months (controls) to 37 months (⁹⁰Y-ibritumomab tiuxetan); P<.0001
• After RIT: 77% patients in PR following induction converted to CR producing a final CR/unconfirmed complete response (CRu) rate of 87%

Now after 5.5 years of follow-up, the 5-year PFS was 47% in the RIT arm and 29% in the control arm. Median PFS was 49 months versus 14 months. In patients achieving CR/CRu after induction, 5-year PFS was 57% with median PFS unreached at 92 months for the RIT group versus 43% with a median PFS of 31 months in the control arm. The vast majority of patients who progressed went on to receive rituximab containing regimens as second-line therapy. Response rates to second-line therapy were 79% in the RIT group and 78% in the control group demonstrating no impairment in second response from the use of consolidation RIT. It should be noted that in this FIT trial, induction chemotherapy for 86% of patients did not include rituximab. Whether similar results would have been seen in a study comparing RIT versus control following rituximab-chemotherapy induction is unknown.

Abstract 283 reported the results of a phase II study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma.⁵ This novel agent is an antibody-drug conjugate that delivers monomethyl auristatin E (MMAE) to CD30-positive malignant cells. Monomethyl auristatin E disrupts the microtubule network leading to cell cycle arrest and apoptosis. In this trial, 102 patients with Hodgkin lymphoma who had a median of 4 prior chemotherapy regimens and a previous auto-SCT were treated. More than 70% had primary refractory disease. The most common adverse events included peripheral neuropathy (43%), fatigue, nausea, neutropenia, diarrhea, and pyrexia. Grade 4 events were rare. Ninety-four percent of patients had a reduction in tumor size. The overall objective response rate was 75%. Thirty-four percent of patients achieved a CR. Mediation duration of response was 29 weeks. Twelve-month OS was estimated to be 88%. These are very impressive results in a heavily pretreated Hodgkin lymphoma population.

The Eastern Cooperative Oncology Group (ECOG) reported the results of their E2496 phase III trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with Stanford V +/- radiation therapy in locally extensive and advanced Hodgkin lymphoma.^6,7 This trial was designed to detect a 33% improvement in failure-free survival (FFS) with Stanford V compared to ABVD. Patients with locally extensive disease, stages I-IIA/B with bulky mediastinal disease (BMD), or advanced disease, stages III-IV, were randomized to 6-8 cycles of ABVD + 36 Gy for BMD versus 12 weeks of Stanford V + 36 Gy to sites >5 cm in diameter or for macroscopic splenic disease. In this trial, 812 patients were randomized.⁶ Forty percent of the patients with ABVD received radiation versus 73% of the Stanford V patients. There were no significant differences in ORR. Five-year OS was also not significantly different between the 2 treatment groups. Among the patients with advanced disease, FFS was similar for low-risk patients. But among the patients who were high risk with 3 or more risk factors, FFS was significantly better for the ABVD group with 5-year FFS was 68% versus 58% for the Stanford V group. The authors concluded that ABVD remains the standard of care, although Stanford V was considered acceptable therapy for certain lower risk patients. There were significant differences in the exposure to bleomycin and doxorubicin between the treatment regimens. Whether this will result in long term differences in adverse event profiles cannot be stated until further follow-up is achieved.

A separate presentation, abstract 416, examined the results of the study in patients with stage I-II plus bulky mediastinal disease.⁷ Overall response rate and CR rates were similar as were 5-year FFS and OS. The authors recommended that ABVD remain the standard of care but that Stanford V was an acceptable regimen for patients for whom lower doses of doxorubicin or bleomycin were desired. Finally concern was expressed regarding the 20% of patients who failed to respond in both treatment arms. How to identify these patients upfront and how to treat them once they are identified remain significant questions.

Abstract 418 discussed the feasibility and efficacy of ABVD in those patients with Hodgkin lymphoma who present later in life.⁸ Approximately 20% of patients with Hodgkin lymphoma are diagnosed at age 60 or older. The German Hodgkin Study Group examined the results of ABVD therapy among older patients participating in their HD10 early favorable Hodgkin lymphoma trial and HD11 early unfavorable HL trial. The relative dose intensity was significantly lower than in younger patients due to more toxicity related treatment delays and reductions. The 5-year PFS estimates for elderly patients were 79% in HD10 and 69% in HD11 trial compared to 96% and 86% among the younger patients. The authors concluded that ABVD is effective therapy for the elderly patients with Hodgkin lymphoma who have early disease, but that treatment related toxicity is high.

Finally, a phase II study of oral panobinostat in post-auto-SCT relapsed Hodgkin lymphoma was presented by an international group of investigators.⁹ One hundred twenty-nine patients had received a median of 4 prior systemic therapies in addition to auto-SCT and 69% had received radiation therapy. Seventy-seven percent of patients experienced a reduction in measurable tumor size. Overall response rate was 27% in this heavily pre-treated population. Median duration of response was 7 months and median PFS was 5.7 months. Adverse events were primarily grade 1-2.

References

1. Ardeshna KM, Qian W, Smith P, etc. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (Grades 1, 2 and 3a). A preliminary analysis. Blood. 2010;116(21). Abstract 6 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

2. Goy A, Leach J, Ehmann WC, et al. Inotuzumab ozogamicin (CMC-544) in patients with indolent B-cell NHL that is refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy: Preliminary safety and efficacy from a phase 2 trial. Blood. 2010;116(21). Abstract 430 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

3. Stopeck AT, Unger JM, Rimsza LM, et al. Phase II trial of standard dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab (R-CHOP) plus bevacizumab for advanced stage diffuse large B-cell (DLBCL) NHL: Southwest Oncology Group Study S0515. Blood. 2010;116(21). Abstract 591 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

4. Scholz CW, Pinto A, Linkesch W, et al. 90Yttrium ibritumomab tiuxetan as first line treatment for follicular lymphoma. First results from an international phase II clinical trial. Blood. 2010;116(21). Abstract 593 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

5. Chen R, Gopal AK, Smith SE, et al. Results of a pivotal phase 2 study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2010;116(21). Abstract 283 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

6. Gordon LI, Hong F, Fisher R, et al. A randomized phase III trial of ABVD vs. Stanford V +/- radiation therapy in locally extensive and advanced stage Hodgkin's lymphoma: Intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). Blood. 2010;116(21). Abstract 415 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

7. Advani R, Hong F, Fisher R, et al. Randomized phase III trial comparing ABVD + radiotherapy and the Sanford V regimen in patients with stage I/II bulky mediastinal Hodgkin lymphoma: A subset analysis of the US Intergroup Trial E2496. Blood. 2010;116(21). Abstract 416 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

8. Böll B, Görgen H, Fuchs M, et al. Feasibility and efficacy of ABVD in elderly Hodgkin lymphoma patients: Analysis of two randomized prospective multicenter trials of the German Hodgkin Study Group (HD10 and HD11). Blood. 2010;116(21). Abstract 418 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

9. Sured A, Younes A, Ben-Yehuda D, et al. Final analysis: Phase II study of oral panobinostat in relapsed/refractory Hodgkin lymphoma patients following autologous hematopoietic stem cell transplant. Blood. 2010;116(21). Abstract 419 and oral presentation at: American Society of Hematology Annual Meeting; December 4-7, 2010; Orlando, FL.

 

Tags: ABVD, anti-CD22, bevacizumab, CD30, follicular lymphoma, Hematology, Hodgkin lymphoma, inotuzumab ozogamicin, Lymphoma, MMAE, R-CHOP, radioimmunotherapy, RIT, rituximab, VEGF