OncoFacts Hematologic Malignancies - Annual Meeting 2010 Overview (tyrosine kinase inhibitors, DASISION trial, dasatinib, bosutinib, imatinib, ofatumumab, fludarabine, cyclophosphamide, lenalidomide, PRIMA trial, rituximab, panobinostat, rituximab, g - 100004

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OncoFacts Hematologic Malignancies - Annual Meeting 2010 Overview (tyrosine kinase inhibitors, DASISION trial, dasatinib, bosutinib, imatinib, ofatumumab, fludarabine, cyclophosphamide, lenalidomide, PRIMA trial, rituximab, panobinostat, rituximab, g

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Description: Abstracts LBA6500 and 6501
Two second-generation tyrosine kinase inhibitors (TKIs) for chronic myelogenous leukemia (CML) were highlighted at the Oncology Annual Meeting this year. The DASISION trial was presented by Hagop Kantarjian comparing front-line dasatinib with standard dose imatinib. The primary endpoint was 12-month confirmed complete cytogenetic response (CCyR), which favored dasatinib at 83% versus 72% for imatinib. In addition, 12 months major molecular response (MMR) also favored dasatinib at 46% versus 28% for imatinib. The ENESTnd trial, originally presented at the American Society of Hematology (ASH) 2009 Annual Meeting was updated at the Oncology Annual Meeting. This trial randomized newly diagnosed patients with chronic phase chronic myelogenous leukemia (CP-CML) to standard dose imatinib versus nilotinib at 300 mg BID or 400 mg BID. Skin Rash, alopecia, elevations of liver enzymes, lipase-amylase elevations, headache, and pruritus were more common with nilotinib. Gastrointestinal toxicities, fluid retention, and myelosuppression were more common with imatinib. Efficacy results demonstrated that at 18 months, MMR rates were 86% for nilotinib 300 mg, 88% for nilotinib 400 mg and 48% for imatinib. Overall CCyR rates for 85% for nilotinib 300 mg, 82% for nilotinib 400 mg, and 74% for imatinib. Progression to accelerated phase (AP)/blast crisis (BC) was seen in 0.7% of nilotinib 300 mg, 0.4% of nilotinib 400 mg, and 4.2% for imatinib.

Abstracts 6502 & 6509
Two abstracts reported on the efficacy of bosutinib, another second-generation TKI for CML in patients with imatinib resistant/intolerant CP-CML and in patients with AP or BC CML after resistance or intolerance to imatinib. In the CP-CML population, 78% achieved a complete hematologic response (CHR), 58% a major cytogenic response (MCyR), 46% a complete cytogenetic response (CCyR), and 49% achieved a MMR. In the patients with AP/BC, MCyR was seen among 48% of the patients with accelerated phase and 29% of the patients with blast crisis. The response rates were similar both in patients with new mutations and those without new mutations. Adverse events were primarily gastrointestinal and myelosuppression.

Abstract 6520
Bill Wierda from the M. D. Anderson Cancer Center reported the results of a randomized phase II study comparing 2 doses of ofatumumab in combination with fludarabine and cyclophosphamide (O-FC) in previously untreated patients with CLL. Ofatumumab 500 mg or 1000 mg were given on day 1 with fludarabine and cyclophosphamide given days 1-3. Complete response (CR) rate and overall response rate (ORR) for the 500 mg O-FC were 32% (CR) and 77% (ORR), and the 1000 mg O-FC were 50% (CR) and 73% (ORR), respectively. Response was significantly correlated with lower β2M, completion of 6 cycles and higher ofatumumab Cmin prior to the last infusion.

Abstract 6508
The leukemia group at the M. D. Anderson Cancer Center also reported a phase II study of single-agent lenalidomide as front-line therapy for elderly patients with CLL. Sixty patients were treated. The initial dose was 5 mg/day for 8 weeks with slow escalation up to a maximum daily dose of 25 mg. The ORR was 60% with 8% CRs and 8% nodular partial responses (nPRs). Best responses were observed after 9 cycles. There was a slow but progressive rise in serum IgG levels during treatment from a median of 724 mg/dL to 941 mg/dL over the course of 15 cycles of therapy.

Abstract 8004
The Groupe d'Etude des Lymphomes de l'Adulte (GELA) reported the results of their PRIMA trial evaluating the benefits of 2 years of maintenance rituximab in stage III-IV patients with high tumor burden follicular lymphoma treated with front-line chemoimmunotherapy. Seventy-five percent of the patients received R-CHOP as front-line therapy. The remainder received rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, fludarabine, cyclophosphamide, mitoxantrone (R-FCM). Over two thirds of the patients had intermediate or high Follicular Lymphoma International Prognostic Index (FLIPI) scores. In this trial, 1018 patients were then randomized to observation or rituximab every 8 weeks for 2 years. Seventy percent of the patients were in CR or unconfirmed complete response (CRu) at the time of randomization. With a median follow-up of 25 months, which is about when the patients on rituximab completed their maintenance rituximab, the PFS was 82% for rituximab maintenance versus 66% for observation. All sub-groups analyzed appeared to benefit from maintenance, though follow-up is still fairly short. Time to next treatment and event-free survival also significantly favored rituximab maintenance. There was an increased incidence of infections and grade 3-4 adverse events in the rituximab maintenance arm.

Abstract 8007
An international multicenter phase II study of panobinostat (LBH589) in heavily pre-treated patients with refractory Hodgkin lymphoma reported 17 out of 81 patients had objective responses, but 72% had definite tumor reductions from single-agent therapy with this oral pan–histone deacetylase (HDAC) inhibitor.

Abstract 8011
The GELA group also reported on the combination of rituximab plus gemcitabine and oxaliplatin in a phase II study of patients with relapsed/refractory diffuse large B-cell lymphoma. After 4 cycles of Q 2 week treatments, 44% achieved a CR/CRu and 17% achieved a partial response (PR) for an ORR of 61%. Three-year disease-free survival (DFS) and overall survival (OS) were 20% and 28%.

Abstract 8036
The M. D. Anderson Cancer Center Lymphoma Group reported a phase II study of lenalidomide plus rituximab in patients with untreated indolent lymphomas. The ORR was 86% with 79% CR/CRu and 7% PR. Ninety-four percent of patients with follicular lymphoma responded. This study is being expanded to 110 patients.

Abstract 8047
A multicenter international group reported on the efficacy of romidepsin in cutaneous T-cell lymphoma. Ninety-six patients with at least 1 prior therapy were treated in the phase II study. Overall response rates included 40% response in skin involvement, 77% in circulating Sezary cells and 35% in lymph node diameters. The ORR by composite endpoint was 34%, and all of those patients met criteria for a skin response.

Abstract 8000
Ravi Vij and the Multiple Myeloma Resource Consortium (MMRC) reported on their phase II trials with carfilzomib in relapsed/refractory multiple myeloma. Sixty-eight percent of patients had previously received lenalidomide. In this presentation, they reported a 21% response rate in 36 patients who were bortezomib treated in cohort 1 at a dose of 20mg/m2 days 1 & 2 each week for 3 out of 4 weeks. There was a 45% response rate in 59 patients who were bortezomib-naïve in cohort 1. In cohort 2, the expanded bortezomib-naïve group had a 55% response rate at a somewhat higher carfilzomib dose of 27 mg/m2. Time-to-progression was 8.1 months in cohort 1, 8.3 months in the cohort 1 patients who were bortezomib-naïve, and 11.5 months in the cohort 2 expanded bortezomib-naïve patients. Peripheral neuropathy at baseline was seen in 40% - 50% of patients, but treatment emergent peripheral neuropathy was rare. Myelosuppression was the most common grade 3-4 adverse events.

Abstract 8002
Martha Lacy reported the results of pomalidomide and dexamethasone in patients who were refractory to both bortezomib and lenalidomide. The median number of prior treatment regimens was 6. Fourteen out of 35 patients had high-risk molecular markers. There was non-progression in 66% and progression in 34%. Very good partial response rate (VGPR) was 14% and PR rate was 17% with 23% minor responses. Overall survival at 6 months was 86%. Grade 1-2 peripheral neuropathy was seen in 6%. There was no grade 3 peripheral neuropathy.

Abstract 8001
A phase Ib trial of oral panobinostat plus bortezomib in relapsed/refractory multiple myeloma was presented by Ken Anderson. There was a median of 2 prior therapies. Twenty-eight of 47 patients had previously received bortezomib and 15 were refractory to it. The maximum tolerated dose (MTD) was determined to be panobinostat 20 mg 3 times per week and bortezomib 1.3 mg/m2 twice a week. There was a high incidence of thrombocytopenia and neutropenia. Fatigue was common. Peripheral neuropathy was minimal. No QT prolongation was noted. The ORR was 70% with 10% CR, 6% VGPR, and 38% PR. Sixty percent of patients who were bortezomib-refractory achieved either a PR or a minor response (MR). Patients remained on therapy for a median of 3 months. A large international randomized phase III trial of panobinostat-bortezomib versus bortezomib is ongoing (PANORAMA trial).

Abstract 8021
Gareth Morgan reported the results of the MRC IX study randomizing newly diagnosed patients with multiple myeloma to zoledronic acid monthly versus oral clondronate along with their anti-myeloma therapy. Treatment continued until disease progression. zoledronic acid reduced the proportion of patients with an skeletal related events (SRE) from 35% to 27%. Zoledronic acid also significantly increased the time to first SRE. Progression-free survival and OS were both significantly longer for the patients receiving zoledronic acid. Osteonecrosis of the jaw was more common with zoledronic acid at 3.5% versus 0.3% with clodronate.

Abstract 8020
Sagar Lonial reported the results of a phase I-II study of elotuzumab-lenalidomide plus low-dose dexamethasone in relapsed-refractory myeloma. Elotuzumab is a humanized monoclonal antibody against a cell surface glycoprotein CS1, highly expressed in multiple myeloma. Twenty-nine patients with a median of 3 prior treatment regimens were treated. Forty-one percent were refractory to their most recent therapy. The ORR was 82% with 54% PR and 29% VGPR. The ORR in lenalidomide-naïve patients was 95%. Median time-to-progression had not been reached at the time of presentation. Adverse events were primarily grade 1-2. Minor infusion reactions were seen. The 60-patient randomized phase II trial in lenalidomide-naïve patients is ongoing.

References
1. Kantarjian H, Shah NP, Hocchaus A, et al. Dasatinib compared to imatinib (IM) in patients (pts) with newly diagnosed chronic-phase chronic myelogenous leukemia in chronic phase (CML-CP): Twelve-month efficacy and safety from the phase III DASISION study. J Clin Oncol. 2010;28(15s). Abstract LBA6500.

2. Larson RA, le courte PD, Reiffers J, et al. Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond one year. J Clin Oncol. 2010;28(15s). Abstract 6501.

3. Cortes JE, Kantarjian H, Brümmendorf T, et al. Safety and efficacy of bosutinib (SKI-606) in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (IM). J Clin Oncol. 2010;28(15s). Abstract 6502.

4. Gambacorti-Passerini C, Cortes JE, Khoury HJ, et al. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: Update from study SKI-200. J Clin Oncol. 2010;28(15s). Abstract 6509.

5. Wierda WG, Kipps TJ, Dürig, et al. Chemoimmunotherapy with ofatumumab, fludarabine, and cyclophosphamide (O-FC) in previously untreated patients with chronic lymphocytic leukemia (CLL). J Clin Oncol. 2010;28(15s). Abstract 6520.

6. Badoux X, Wierda WG, O'Brien SM, et al. A phase II study of lenalidomide as initial treatment of elderly patients with chronic lymphocytic leukemia. J Clin Oncol. 2010;28(15s). Abstract 6508.

7. Salles GA, Seymour JF, Feugier P, et al. Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy. J Clin Oncol. 2010;28(15s). Abstract 8004.

8. Sureda A, Engert A, Browett PJ, et al. Interim results for the phase II study of panobinostat (LBH589) in patients (Pts) with relapsed/refractory Hodgkin's lymphoma (HL) after autologous hematopoietic stem cell transplant (AHSCT). J Clin Oncol. 2010;28(15s). Abstract 8007.

9. El Gnaoui T, Tilly H Mounier N, et al. Rituximab plus gemcitabine and oxaliplatine (R-GemOx) in refractory/relapsed patients with diffuse large B-cell lymphoma (DLBCL) who are not candidates for high-dose therapy (HDT): A GELA study. J Clin Oncol. 2010;28(15s). Abstract 8011.

10. Fowler NH, McLaughlin P, Hagemeister FB, et al. Complete response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2010;28(15s). Abstract 8036.

11. Kim E, Rook A, Kim Y, et al. Romidepsin activity in all three disease compartments (skin, blood, lymph nodes) in patients with cutaneous T-cell lymphoma (CTCL). J Clin Oncol. 2010;28(15s). Abstract 8047.

12. Vij R, siegel DS, Kaufman JL, et al. Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). J Clin Oncol. 2010;28(15s). Abstract 8000.

13. Lacy M, Gertz MA, Hayman SR, et al. Activity of pomalidomide plus dexamethasone (Pom/dex) in dual lenalidomide/bortezomib refractory multiple myeloma (MM). J Clin Oncol. 2010;28(15s). Abstract 8002.

14. San-Miguel JF, Sezer O, Siegel DS, et al. Phase Ib study of oral panobinostat (LBH589) plus intravenous bortezomib in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM).J Clin Oncol. 2010;28(15s). Abstract 8001.

15. Morgan G, Davies F, Gregory W, et al. Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study. J Clin Oncol. 2010;28(15s). Abstract 8021.

16. Lonial S, Vij R, Harousseau J, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma: A phase I/II study. J Clin Oncol. 2010;28(15s). Abstract 8020.

To enhance the abstracts presented here from the 2010 Annual Oncology Meeting, there are 9 “Best of the Day” interviews with leading national and international oncologists and hematologists that are available in the Imedex E-Learning Center.
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