- Email: [email protected]
Small Lymphocytic Lymphoma: Preliminary Results of Project Q-lite, by the Czech CLL Study Group
Abstracts peutic option for the treatment of fludarabine-resistant disease, but clinical trials to date have been limited by high levels of toxicity. Data from our group suggest that a novel inhibitor of Hsp90, SNX7081, restores the sensitivity of resistant cell lines and patient samples to fludarabine (Best et al. Submitted), but the mechanisms underlying this synergy are currently unclear. To study the mechanisms of the synergy between SNX7081 and fludarabine, we used isobaric tag for relative and absolute quantitation and label-free mass spectrometry techniques to detect and quantify protein changes induced by SNX7081, fludarabine, or a combination of the 2 agents in the MEC1 (CLL, fludarabine-resistant) cell line. The results were validated by western blot and reverse transcriptase polymerase chain reaction, and results are currently being translated to a patient sample by using a selected reaction monitoring technique. Fludarabine treatment induced upregulation of several proteins involved in DNA repair, including RAD50 and USP47. In contrast, SNX7081, alone or in combination with fludarabine, downregulated 10 proteins with proven roles in DNA repair and in maintaining genomic integrity. Furthermore, fludarabine induced the upregulation of antiapoptotic ER chaperone proteins, whereas SNX7081 alone or in combination with fludarabine had the contrary effect of inhibiting the expression of 4 ER chaperone proteins. Finally, the combination of SNX7081 and fludarabine increased the expression of Hsp70 binding protein-1, suggesting that the combination treatment may block the upregulation of Hsp70 associated with inhibition of Hsp90. In conclusion, our data suggest that the combination of Hsp90 inhibitors with fludarabine may represent an effective treatment strategy in fludarabineresistant cells and may lower the effective dose of Hsp90 inhibitors below the toxic levels observed in clinical trials of this class of compound.
5.27 Low-Dose Fludarabine and Cyclophosphamide Combined with Rituximab Is a Safe and Effective Treatment Option for Elderly and Comorbid Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Preliminary Results of Project Q-lite, by the Czech CLL Study Group Lukáš Smolej,1,ⴱ Yvona Brychtová,2 Martin Špacˇek,3 Michael Doubek,2 David Belada,1 Monika Motycˇková,1 Eduard Cmunt,4 Vít Procházka,5 Peter Rohonˇ,5 Hynek Poul,6 Katerˇina Klásková,3 Tomáš Kozák3 for the Czech CLL Study Group 1
Second Department of Medicine, Department of Hematology,
Charles University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic; 2Department of Internal Medicine—Hematology/Oncology, University Hospital, Brno, Czech Republic; 3Department of Hematology, University Hospital 4
Královské Vinohrady, Prague, Czech Republic; First Department. of Medicine, Charles University General Hospital, Prague, Czech Republic; 5Department of Hematology-Oncology, University Hospital, Olomouc, Czech Republic; 6Hematology Department, Hospital Pelhøimov, Czech Republic
Background: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) is currently considered the treatment of choice in
physically fit patients with chronic lymphocytic leukemia (CLL). However, many patients cannot tolerate this aggressive approach because of advanced age or serious comorbid conditions leading to unacceptable toxicity. For these patients, chlorambucil remains the standard of treatment. However, regimens based on low-dose fludarabine have recently demonstrated promising results in small studies. Aims: We sought to assess the efficacy and safety of a low-dose FCR regimen in elderly/ comorbid patients with CLL/small lymphocytic lymphoma (SLL). Patients and Methods: Between March 2009 and June 2011, we treated 111 patients with active disease (105 with CLL and 6 with SLL; 58% men; median age, 70 years [range, 58-83 years]; median Cumulative Illness Rating Score 4 [range, 0-10]; median creatinine clearance, 67 mL/min) with low-dose FCR at 15 centers cooperating within Czech CLL Study Group. Dose reduction of chemotherapy compared with the regular FCR regimen was as follows: fludarabine to 50% (12 mg/m2 i.v. or 20 mg/m2 orally on days 1 through 3) and cyclophosphamide to 60% (150 mg/m2 i.v./p.o. on days 1 through 3). The dose of rituximab was standard (375 mg/m2 in the first cycle, 500 mg/m2 from the second cycle). Treatment was repeated every 4 weeks. Antimicrobial prophylaxis with trimethoprim–sulfamethoxazole and acyclovir or their equivalents was recommended. Fifty-two percent of patients were being treated first-line; the remaining 48% had relapsed/refractory disease. Advanced Rai stages (III/IV) were present in 63% patients; 37% had bulky disease. IgVH genes were unmutated in 73%; according to a hierarchical model, del11q was present in 30% and del17p in 4%. Results: On the basis of the intention-to-treat principle, the overall response/complete response (CR) rate (including clinical CR without bone marrow biopsy and CR with incomplete blood count recovery) was 79/41% in first line and 73/31% in relapse. Serious (CTC grade III/IV) neutropenia occurred in 52% of patients, thrombocytopenia in 11%, and anemia in 14% of patients. Serious infections developed in 10% of patients. Twenty-one patients have died; the most common causes of death were CLL progression (n ⫽ 7) and infection (n ⫽ 8). Longer follow-up is needed for data on progression-free survival, overall survival, and quality of life. Conclusions: Treatment of elderly/comorbid patients with CLL/SLL with low-dose FCR demonstrated promising results in the first-line and relapsed/refractory disease settings. Toxicity was acceptable and manageable. Recruitment in the study is ongoing, and updated results will be presented.
5.28 Combining Fludarabine and Rituximab with Escalating Doses of Lenalidomide in Untreated Chronic Lymphocytic Leukemia: The REVLIRIT CLL5 AGMT Phase 1/2 Study—Results from Clinical and Exploratory Analyses of Induction A. Egle,1 M. Steurer,2 F. Gassner,1 R. Geisberger,1 T. Melchardt,1 L. Weiss,1 M. Fridrik,3 J. Thaler,4 A. Lang,5 R. Greil1 1
Third Medical Department, University Hospital Salzburg, Salzburg, Austria; 2Fifth Medical Department, University Hospital Innsbruck, Innsbruck, Austria; 3Third Medical Department, General Hospital Linz, Linz, Austria; 4Fourth Medical Department, Klinikum WelsGrieskirchen, Wels, Austria,; 5Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
Clinical Lymphoma, Myeloma & Leukemia Supplement October 2011
S261
5.27 Low-Dose Fludarabine and Cyclophosphamide Combined with Rituximab Is a Safe and Effective Treatment Option for Elderly and Comorbid Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Preliminary Results of Project Q-lite, by the Czech CLL Study Group Lukáš Smolej,1,ⴱ Yvona Brychtová,2 Martin Špacˇek,3 Michael Doubek,2 David Belada,1 Monika Motycˇková,1 Eduard Cmunt,4 Vít Procházka,5 Peter Rohonˇ,5 Hynek Poul,6 Katerˇina Klásková,3 Tomáš Kozák3 for the Czech CLL Study Group 1
Second Department of Medicine, Department of Hematology,
Charles University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic; 2Department of Internal Medicine—Hematology/Oncology, University Hospital, Brno, Czech Republic; 3Department of Hematology, University Hospital 4
Královské Vinohrady, Prague, Czech Republic; First Department. of Medicine, Charles University General Hospital, Prague, Czech Republic; 5Department of Hematology-Oncology, University Hospital, Olomouc, Czech Republic; 6Hematology Department, Hospital Pelhøimov, Czech Republic
Background: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) is currently considered the treatment of choice in
physically fit patients with chronic lymphocytic leukemia (CLL). However, many patients cannot tolerate this aggressive approach because of advanced age or serious comorbid conditions leading to unacceptable toxicity. For these patients, chlorambucil remains the standard of treatment. However, regimens based on low-dose fludarabine have recently demonstrated promising results in small studies. Aims: We sought to assess the efficacy and safety of a low-dose FCR regimen in elderly/ comorbid patients with CLL/small lymphocytic lymphoma (SLL). Patients and Methods: Between March 2009 and June 2011, we treated 111 patients with active disease (105 with CLL and 6 with SLL; 58% men; median age, 70 years [range, 58-83 years]; median Cumulative Illness Rating Score 4 [range, 0-10]; median creatinine clearance, 67 mL/min) with low-dose FCR at 15 centers cooperating within Czech CLL Study Group. Dose reduction of chemotherapy compared with the regular FCR regimen was as follows: fludarabine to 50% (12 mg/m2 i.v. or 20 mg/m2 orally on days 1 through 3) and cyclophosphamide to 60% (150 mg/m2 i.v./p.o. on days 1 through 3). The dose of rituximab was standard (375 mg/m2 in the first cycle, 500 mg/m2 from the second cycle). Treatment was repeated every 4 weeks. Antimicrobial prophylaxis with trimethoprim–sulfamethoxazole and acyclovir or their equivalents was recommended. Fifty-two percent of patients were being treated first-line; the remaining 48% had relapsed/refractory disease. Advanced Rai stages (III/IV) were present in 63% patients; 37% had bulky disease. IgVH genes were unmutated in 73%; according to a hierarchical model, del11q was present in 30% and del17p in 4%. Results: On the basis of the intention-to-treat principle, the overall response/complete response (CR) rate (including clinical CR without bone marrow biopsy and CR with incomplete blood count recovery) was 79/41% in first line and 73/31% in relapse. Serious (CTC grade III/IV) neutropenia occurred in 52% of patients, thrombocytopenia in 11%, and anemia in 14% of patients. Serious infections developed in 10% of patients. Twenty-one patients have died; the most common causes of death were CLL progression (n ⫽ 7) and infection (n ⫽ 8). Longer follow-up is needed for data on progression-free survival, overall survival, and quality of life. Conclusions: Treatment of elderly/comorbid patients with CLL/SLL with low-dose FCR demonstrated promising results in the first-line and relapsed/refractory disease settings. Toxicity was acceptable and manageable. Recruitment in the study is ongoing, and updated results will be presented.
5.28 Combining Fludarabine and Rituximab with Escalating Doses of Lenalidomide in Untreated Chronic Lymphocytic Leukemia: The REVLIRIT CLL5 AGMT Phase 1/2 Study—Results from Clinical and Exploratory Analyses of Induction A. Egle,1 M. Steurer,2 F. Gassner,1 R. Geisberger,1 T. Melchardt,1 L. Weiss,1 M. Fridrik,3 J. Thaler,4 A. Lang,5 R. Greil1 1
Third Medical Department, University Hospital Salzburg, Salzburg, Austria; 2Fifth Medical Department, University Hospital Innsbruck, Innsbruck, Austria; 3Third Medical Department, General Hospital Linz, Linz, Austria; 4Fourth Medical Department, Klinikum WelsGrieskirchen, Wels, Austria,; 5Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
Clinical Lymphoma, Myeloma & Leukemia Supplement October 2011
S261