Induced resistance to ofatumumab-mediated cell clearance mechanisms, including complement-dependent cytotoxicity, in chronic lymphocytic leukemia.

Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.

Phase II Trial of Bevacizumab Monotherapy in Pancreatic Neuroendocrine Tumors.

OBJECTIVES: Systemic therapies for pancreatic neuroendocrine tumors (PNETs) are limited. The combination of bevacizumab and temsirolimus showed significant antitumor activity, but the single-agent activity of bevacizumab was unknown. We conducted a single-arm, phase II trial to evaluate the efficacy of bevacizumab in PNETs. METHODS: Patients with progressive disease by the Response Evaluation Criteria in Solid Tumors version 1.1 within 7 months of enrollment were eligible for bevacizumab 10 mg/kg every 2 weeks. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. The primary end point was response rate (RR). RESULTS: Twenty-four patients were enrolled and followed up for a median duration of 36.1 months. Confirmed RR was 12.5%; 75.0% of patients had stable disease at 6 months. Median progression-free survival was 18.0 months; median overall survival was not reached. Common grade 3 adverse events were hypertension (45.8%) and proteinuria (8.3%). No grade 4 adverse events were observed. CONCLUSIONS: Bevacizumab demonstrated promising antitumor activity in progressive PNETs comparable to standard targeted therapy. Although this study failed to reject the null hypothesis (RR, 10%), bevacizumab seems a reasonable monotherapy and a potential component of combination therapies given clinical activity and low rates of adverse events.

Cumulative experience and long term follow-up of pentostatin-based chemoimmunotherapy trials for patients with chronic lymphocytic leukemia.

BACKGROUND: 7 regimens of pentostatin based chemoimmunotherapy (CIT) for progressive previously untreated CLL primarily with long term follow-up to update both efficacy and toxicity. RESEARCH DESIGN AND METHODS: Prognostic markers including assessment of IGVH and FISH status were done on all. Response rates and 95% binomial confidence intervals were calculated for each regimen and in the combined cohort. Overall survival and treatment-free survival were evaluated using Kaplan-Meier methods. RESULTS: The initial CIT trial was pentostatin (2 mgs/m2), cyclophosphamide (600 mg/m2) and rituximab (PCR) but subsequent P based CIT trials with modifications in subsequent trials. The cohort (n = 288) included 52% with unmutated IGVH status and del17p (4.5%) and del11q (14.9%). Toxicity profiles were primarily hematologic and no patient has developed MDS or AML after a median follow-up of 6.4 years. The overall response rate across all trials was found to be over 90% with a 41% complete response rate. We validated that the CLL IPI model segregates progressive CLL patients into 4 risk groups associated with OS and TFS. CONCLUSIONS: The high overall and complete response levels in favorable genetic risk CLL along with favorable toxicity profiles provide rationale for consideration of a PC based strategy for previously untreated progressive CLL.

A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia.

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) with in vitro pro-apoptotic and antiangiogenic effects on chronic lymphocytic leukemia (CLL) cells. As monotherapy in patients with CLL, it has no clinical activity. Here we report the results of an open-label, randomized phase II trial comparing the combination of pentostatin, cyclophosphamide and rituximab (PCR) either without or with bevacizumab (PCR-B) in previously untreated CLL patients. A total of 65 evaluable patients were enrolled, 32 receiving PCR and 33 PCR-B. A higher rate of grade 3-4 cardiovascular toxicity was observed with PCR-B (33% vs. 3%, p < 0.003). Patients treated with PCR-B had a trend for a higher complete remission (CR) rate (54.5% vs 31.3%; p = 0.08), longer progression-free survival (PFS)(p = 0.06) and treatment-free survival (TFS)(p = 0.09). No differences in PFS and TFS by IGHV mutational status were observed with the addition of bevacizumab. A significant post-treatment increase in VEGF levels was observed in the PCR-B arm (29.77 to 57.05 pg/mL); in the PCR-B arm, lower baseline CCL-3 levels were significantly associated with achievement of CR (p = 0.01). In conclusion, the addition of bevacizumab to chemoimmunotherapy in CLL is generally well-tolerated and appears to prolong PFS and TFS.

Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial.

BACKGROUND: Although several consolidation strategies to prolong treatment-free survival (TFS) in chronic lymphocytic leukaemia have been investigated, most have proven either ineffective or toxic. Ofatumumab is a human type I anti-CD20 antibody approved by the US Food and Drug Administration as maintenance treatment of patients with recurrent or progressive chronic lymphocytic leukaemia who are in complete or partial response after at least two lines of treatment; higher efficacy might be observed if used as consolidation strategy than without consolidation in previously untreated patients. METHODS: We recruited patients with previously untreated progressive chronic lymphocytic leukaemia who had an Eastern Cooperative Oncology Group performance status of 0-2 and adequate renal and hepatic function from centres in the USA. Patients with recent myocardial infarction; class III or IV heart failure; uncontrolled, HIV, or active hepatitis B or C infection; or active haemolytic anaemia were excluded. In the first arm of this study, which has been previously reported, patients were treated with six cycles of induction with pentostatin (2 mg/m(2) on day 1), cyclophosphamide (600 mg/m(2) on day 1), and ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg/m(2) on day 2; cycles 2-6: 1000 mg/m(2) on day 1) given intravenously every 21 days. Here were report the second arm, where patients received the same regimen as the first arm, with the addition of six cycles of consolidation with ofatumumab (1000 mg once every 4 weeks), also given intravenously. The primary endpoint was TFS at 18 months, assessed in those who began consolidation. We estimated the distribution of TFS using the Kaplan-Meier method, assessing between-group differences with log-rank statistics. The phase 2 trial, which is completed, is registered at ClinicalTrials.gov, number NCT01024010. FINDINGS: Between Sept 21, 2011, and Nov 7, 2012, 34 patients were recruited to this second arm of the trial. Among the 31 (91%) patients who completed induction treatment and started consolidation, 26 (84%) completed the planned six cycles of ofatumumab consolidation. TFS at 18 months was 94·1% (95% CI 78·5-98·5). Grade 3 or worse adverse events deemed at least possibly related to treatment were neutropenia (14 [41%] patients), infection (2 [6%]), and one (3%) each with anaemia, haemolysis, fatigue, and a neurological, metabolic, respiratory, and vascular complication. INTERPRETATION: Ofatumumab-based consolidation appears to be a well tolerated and effective consolidation strategy in patients with chronic lymphocytic leukaemia, which could improve survival. FUNDING: GlaxoSmithKline.

Addition of granulocyte macrophage colony stimulating factor does not improve response to early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab.

Thirty-three previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) were treated before meeting standard criteria with alemtuzumab and rituximab. Granulocyte macrophage colony stimulating factor (GM-CSF) was added to the regimen to determine whether it would improve treatment efficacy without increasing toxicity. High risk was defined as at least one of the following: 17p13-; 11q22.3-; unmutated IGHV (or use of VH3-21) together with elevated expression of ZAP-70 and/or CD38. Treatment was subcutaneous GM-CSF 250 µg Monday-Wednesday-Friday for 6 weeks from day 1, subcutaneous alemtuzumab 3 mg-10 mg-30 mg from day 3 and then 30 mg Monday-Wednesday-Friday for 4 weeks, and intravenous rituximab (375 mg/m(2)/week) for 4 weeks from day 8. Patients received standard supportive care and were monitored weekly for cytomegalovirus (CMV) reactivation. Using standard criteria, 31 (94%) patients responded to treatment, with nine (27%) complete responses (one with persistent cytopenia) and nine (27%) nodular partial responses. Median progression-free survival was 13.0 months and time to next treatment was 33.5 months. No patient died during treatment, seven (21%) had grade 3-4 toxicities attributable to treatment, and 10 (30%) had CMV viremia. Addition of GM-CSF to therapy with alemtuzumab and rituximab decreased treatment efficacy and increased the rate of CMV reactivation compared to a historical control.