Thomas E. Boyd

Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

PURPOSE Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL. PATIENTS AND METHODS Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR). RESULTS Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups. CONCLUSION The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.

5-Year Survival in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia in a Randomized, Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen

PURPOSE A randomized trial of oblimersen plus fludarabine/cyclophosphamide (OBL-FC; n = 120) versus FC (n = 121) was conducted in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The primary end point was met: the complete response (CR) rate, defined as complete or nodular partial response, was significantly greater with OBL-FC than with FC (17% v 7%; P = .025). Among patients with CR, response duration was significantly longer with OBL-FC than with FC (median not reached; > 36 months v 22 months; P = .03). Maximum benefit with OBL-FC, including a four-fold increase in CR rate and a survival benefit with 3 years of follow-up (hazard ratio, 0.53; P = .05), was observed in patients with fludarabine-sensitive disease. We evaluated long-term survival and poststudy CLL therapy among all randomly assigned patients. METHODS Poststudy CLL treatment information was collected. Patients were observed for survival for up to 5 years from the date of random assignment. RESULTS Poststudy CLL treatment was balanced between arms. Intent-to-treat analysis of 5-year survival showed no significant between-treatment difference (hazard ratio, 0.87; P = .34). Among the greater than 40% of patients with complete or partial remission, a significant 5-year survival benefit was observed with OBL-FC (hazard ratio, 0.60; P = .038). Among patients with fludarabine-sensitive disease who had previously demonstrated maximum benefit with OBL-FC, the previously observed survival benefit improved: a 50% reduction in the risk of death was observed (P = .004). CONCLUSION In relapsed/refractory CLL, OBL combined with FC offers patients who achieve complete or partial remission, as well as those who have fludarabine-sensitive disease, a significant survival benefit.

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid malignancies characterized by multilineage cytopenias, recurrent cytogenetic abnormalities, and risk of progression to acute myeloid leukemia (AML). AML, which can occur de novo as well as secondary to MDS, is characterized by malignant clones of myeloid lineage in the bone marrow and peripheral blood, with dissemination into tissues. The cytidine nucleoside analog and epigenetic modifier azacitidine is approved in the U.S. for the treatment of all French-American-British subtypes of MDS and in many countries for the treatment of AML with 20%-30% blasts and multilineage dysplasia according to the World Health Organization classification. Benefits of azacitidine treatment of patients with AML with >30% blasts have also been shown in a recent phase III trial. Oral administration of azacitidine may enhance patient convenience, eliminate injection-site reactions, allow for alternative dosing and scheduling, and enable long-term treatment. Phase I studies with oral azacitidine (CC-486) have shown biological activity, clinical responses, and tolerability in patients with MDS and AML. Extended dosing schedules of oral azacitidine (for 14 or 21 days of 28-day cycles) are currently under investigation as frontline therapy in patients with lower risk MDS, as maintenance therapy for patients with AML not eligible for stem cell transplant, and as maintenance therapy for patients with MDS or AML following stem cell transplant. This review presents clinical data supporting the use of injectable azacitidine in MDS and AML and examines the rationale for and results of the clinical development of oral azacitidine.

Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Idelalisib, a first-in-class oral inhibitor of phosphatidylinositol-3-kinase δ, has shown considerable antitumor activity as a monotherapy in recurrent indolent non-Hodgkin lymphoma (iNHL). To evaluate the safety and activity of idelalisib in combination with immunotherapy, chemotherapy, or both, 79 patients with relapsed/refractory iNHL were enrolled based on investigator preference in 3 treatment groups. Patients received continuous idelalisib in combination with (1) rituximab (IR; 375 mg/m2 weekly × 8 doses), (2) bendamustine (IB; 90 mg/m2 per day × 2, for 6 cycles), or (3) both bendamustine and rituximab at aforementioned doses (IBR; monthly × 6 cycles). Patients had a median age of 61 years, a median of 3 prior therapies, and 46% had refractory disease. The overall response rate was 75% (22% complete response) for IR, 88% (36%) for IB, and 79% (43%) for IBR. The median progression-free survival was 37.1 months overall: 29.7 months for IR, 32.8 for IB, and 37.1 months for IBR. The median duration of response was 28.6 months in the IR group and has not been reached in the IB and IBR groups. The most common grade ≥3 adverse events and laboratory abnormalities were neutropenia (41%), pneumonia (19%), transaminase elevations (16%), diarrhea/colitis (15%), and rash (9%). The safety and efficacy reflected in these early data, however, stand in contrast with later observations of significant toxicity in subsequent phase 3 trials in frontline chronic lymphocytic leukemia and less heavily pretreated iNHL patients. Our findings highlight the limitations of phase 1 trial data in the assessment of new regimens. This trial was registered at www.clinicaltrials.gov as #NCT01088048 (an extension study was registered at www.clinicaltrials.gov as #NCT01090414).