Bowen, Deborah A.

Abstract Background: PI3K/Akt activation is downstream of the B cell receptor (BCR) signaling cascade and is critical to mediate the interactions between CLL B-cell and bone marrow stroma which support leukemic survival. MK-2206 is a potent oral allosteric Akt inhibitor and we have demonstrated in vitro synergism with bendamustine (B) to induce CLL apoptosis. MK-2206 selectively abolishes BCR-stimulated cytokines CCL3, CCL4, CCL2, and IL-2Ra and significantly inhibits the BCR signaling pathway (Ding, BJH, 2013). We sought to assess the safety, maximal tolerated dose (MTD) and efficacy of MK-2206 in combination with B-rituximab (BR) in relapsed and refractory CLL/SLL patients in a phase I/II trial (NCCTG N1087 Alliance). Methods: Previously treated symptomatic CLL/SLL patients with up to 3 prior lines of therapy and ECOG performance status of 0-2 were eligible. Patients with 17p deletion or prior treatment with B were excluded. A standard phase I design was used to determine the MTD of MK-2206 in combination with BR (B 70mg/m2 for 2 days per cycle; R cycle 1: 375 mg/m2, cycle 2-6: 500 mg/m2). Phase II employed the MTD to evaluate safety and efficacy of the combination. Response was evaluated 2 months after the last cycle of therapy per IWCLL 2008 criteria. Results: 13 patients with a median age of 68 years (range 44-75) and 1.2 prior lines of therapy were treated. CLL FISH showed: del(11q) in 4 (31%), trisomy 12 in 2 (15%), del(13q) in 3 (23%), del(6q) (8%), del(17cen) (8%) and normal results in 2 (15%). IGHV was unmutated in 10 (91%) and mutated in 1 patient (9%) and was missing in 2 cases. ZAP-70 was positive in 8 (73%) and negative in 3 patients (27%). CD38 was positive in 8 (62%) and negative in 5 patients (38%). 70% of patients had received prior chemoimmunotherapy. At 90 mg of MK-2206, 1/6 patients experienced a DLT of grade 3 febrile neutropenia and hemolysis. 2/6 patients on the 135 mg dose experienced a DLT. One patient had grade 3 febrile neutropenia and one patient had a grade 3 acneiform rash. MTD was determined to be MK-2206 90 mg. The most common grade 3/4 adverse events were neutropenia (46%) including febrile neutropenia (23%), diarrhea (15%) and thrombocytopenia (15%). The most common all-grade toxicities were neutropenia (69%), thrombocytopenia (62%), anemia (54%), nausea (54%), diarrhea (39%), rash (38%), and hyperglycemia (31%). 10 patients were treated at 90 mg and 3 patients were treated at the 135 mg dose. The ORR was 92% (n=12). Responses were: 3 CR (23%), 2 CR with incomplete marrow recovery (CRi) (15%), 1 clinical CR (CCR) (8%) without marrow confirmation, 1 nodular partial remission (nPR) (8%), 5 PR (38%), and 1 progressive disease (8%). Median follow-up was 20 months (6-31 months). Median PFS in the CR/CRi group was not reached (NR) with 100% of patients progression free versus 12 months (95% CI 2 months-NR) if CR/CRi was not achieved (p=0.027). Median overall survival was NR in either the CR/CRi or non-CR/CRi groups but 2 deaths occurred in the latter group (p=0.44). One patient developed Richter transformation and died at 15 months and a second patient who had achieved PR died from autoimmune hemolytic anemia and fungal infection at 27 months. Two out of five patients who achieved CR or CRi had bone marrow MRD negative status at the final response evaluation. Conclusions: The Akt inhibitor MK-2206 administered at 90 mg once weekly in combination with BR is tolerated in patients with relapsed or refractory CLL and compares favorably to BR alone (59% ORR and 9% CR, Fischer, JCO, 2011). An ORR of 92% was observed with a 38% of patients achieving CR or CRi. The trial was terminated prematurely due to withdrawal of sponsor support, however further testing of Akt inhibition is needed given the promising results. Citation Format: Jeremy T. Larsen, Tait D. Shanafelt, Jose F. Leis, Betsy R. LaPlant, Timothy G. Call, Clive S. Zent, Curtis A. Hanson, Charles Erlichman, Thomas M. Habermann, Craig B. Reeder, Deborah A. Bowen, Michael Conte, Justin C. Boysen, Charla R. Secreto, Connie E. Lesnick, Renee C. Tschumper, Diane F. Jelinek, Neil E. Kay, Wei Ding. The Akt inhibitor MK-2206 in combination with rituximab and bendamustine demonstrates efficacy in relapsed/refractory chronic lymphocytic leukemia: Updated results from the NCCTG N1087 Alliance study. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B02.

BACKGROUND Although hypogammaglobulinemia is a well recognized complication in patients with chronic lymphocytic leukemia (CLL), its prevalence at the time of CLL diagnosis, and association with novel prognostic markers and clinical outcome is not well understood. METHODS All patients at the Mayo Clinic between January 1999 and July 2013 who had newly diagnosed CLL and had a baseline assessment of serum immunoglobulin G (IgG) were included. The relation between hypogammaglobulinemia at diagnosis and the novel prognostic parameters time to first treatment (TFT) and overall survival (OS) were evaluated. RESULTS Of 1485 patients who met the eligibility criteria, 382 (26%) had hypogammaglobulinemia (median IgG, 624 mg/dL), whereas the remaining 1103 patients (74%) had normal serum IgG levels (median IgG, 1040 mg/dL). Patients who had hypogammaglobulinemia at diagnosis were more likely to have advanced Rai stage (III‐IV; P = .001) and higher expression of CD49d ( P < .001) compared with patients who had normal IgG levels. Although the median TFT for patients who had hypogammaglobulinemia was shorter compared with that for patients who had normal IgG levels (3.8 years vs 7.4 years; P < .001), on multivariable analysis, there was no difference in OS between these 2 groups (12.8 years vs 11.3 years, respectively; P = .73). Of 1103 patients who had CLL with normal IgG levels at diagnosis and who did not receive CLL therapy, the risk of acquired hypogammaglobulinemia was 11% at 5 years and 23% at 10 years. CONCLUSIONS Hypogammaglobulinemia is present in 25% of patients with newly diagnosed CLL. Approximately 25% of patients who have CLL with normal IgG levels at diagnosis will subsequently develop hypogammaglobulinemia on long‐term follow‐up. The presence of hypogammaglobulinemia does not appear to impact overall survival. Cancer 2015;121:2883–2891. © 2015 American Cancer Society .

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab‐containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short‐duration regimen combining pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab designed to decrease the risk of treatment‐associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13−) (n = 3). Thirteen (33%) patients had both 17p13− and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty‐six (67%) patients completed therapy, with only five (13%) patients having treatment‐limiting toxicity and no treatment‐related deaths. Twenty‐two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression‐free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B‐cell lymphoma (n = 6). Correlative studies showed that low‐dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab is a tolerable and effective therapy for CLL and that low‐dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. Am. J. Hematol. 89:757–765, 2014. © 2014 Wiley Periodicals, Inc.

BACKGROUNDAlthough rituximab‐based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40% to 50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti‐CD20 monoclonal antibody with greater apparent single‐agent activity than rituximab in CLL patients.METHODSPreviously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide, and ofatumumab (PCO) followed by response assessment.RESULTSOf the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ nonhematologic toxicity (23%). Median CD4 count after induction and 6 months later were 186 × 106/L and 272 × 106/L. The overall response rate was 96% (46 of 48 patients), and the CR rate was 46% (22 of 48 patients). Among the 38 patients who underwent minimal residual disease evaluation, 7 (18%) were negative for minimal residual disease. After median follow‐up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab‐based CIT compare favorably to our historical trials of rituximab‐based CIT using an identical chemotherapy backbone (n = 64). Time to retreatment also appeared longer for ofatumumab‐based CIT (free of retreatment at 24 months: 86% [95% confidence interval = 75‐99] versus 68% [95% confidence interval = 56‐81] for rituximab‐based CIT).CONCLUSIONSOfatumumab‐based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab‐based CIT compares favorably to historical trials of rituximab‐based CIT, suggesting randomized trials comparing ofatumumab‐based CIT and rituximab‐based CIT should be considered. Cancer 2013;119:3788–3796. © 2013 American Cancer Society.

Key Points Lenalidomide consolidation repairs T-cell immune synapses in CLL patients. Lenalidomide consolidation improved the quality of response in CLL patients treated with chemoimmunotherapy.

Purpose The diagnosis of monoclonal B-cell lymphocytosis (MBL) is used to characterize patients with a circulating population of clonal B cells, a total B-cell count of less than 5 × 109/L, and no other features of a B-cell lymphoproliferative disorder including lymphadenopathy/organomegaly. The natural history of clinically identified MBL is unclear. The goal of this study was to explore the outcome of patients with MBL relative to that of individuals with Rai stage 0 chronic lymphocytic leukemia (CLL). Patients and Methods We used hematopathology records to identify a cohort of 631 patients with newly diagnosed MBL or Rai stage 0 CLL. Within this cohort, 302 patients had MBL (B-cell counts of 0.02 to 4.99 × 109/L); 94 patients had Rai stage 0 CLL with an absolute lymphocyte count (ALC) ≤ 10 × 109/L; and 219 patients had Rai stage 0 CLL with an ALC more than 10 × 109/L. Data on clinical outcome were abstracted from medical records. Results The percentage of MBL patients free of treatment at 1, 2, and 5 years was 99%, 98%, and 93%, respectively. B-cell count as a continuous variable (hazard ratio [HR] = 2.9, P = .04) and CD38 status (HR = 10.8, P = .006) predicted time to treatment (TTT) among MBL patients. The likelihood of treatment for MBL patients was lower (HR = 0.32, P = .04) than that of both Rai stage 0 CLL patients with an ALC less than 10 × 109/L (n = 94) and Rai stage 0 CLL patients with an ALC more than 10 × 109/L (n = 219; P = .0003). Conclusion Individuals with MBL identified in clinical practice have a low risk for progression at 5 years. Because B-cell count seems to relate to TTT as a continuous variable, additional studies are needed to determine what B-cell count should be used to distinguish between MBL and CLL.

Purpose To define the optimal dose of Polyphenon E for chronic daily administration and tolerability in patients with chronic lymphocytic leukemia (CLL). Patients and Methods Previously untreated patients with asymptomatic Rai stage 0 to II CLL were eligible for participation. Polyphenon E with a standardized dose of epigallocatechin-3-gallate (EGCG) was administered using the standard phase I design with three to six patients per dose level (range, 400 to 2,000 mg by mouth twice a day). Trough plasma EGCG levels were measured 1 month after initiation of therapy. Response was classified using the National Cancer Institute (NCI) Working Group (WG) Criteria. Results Thirty-three eligible patients were accrued to dose levels 1 to 8. The maximum-tolerated dose was not reached. The most common adverse effects included transaminitis (33%, all grade 1), abdominal pain (30% grade 1, 0% grade 2, and 3% grade 3), and nausea (39% grade 1 and 9% grade 2). One patient experienced an NCI WG partial remission. Other signs of clinical activity were also observed, with 11 patients (33%) having a sustained ≥ 20% reduction in absolute lymphocyte count (ALC) and 11 (92%) of 12 patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas during treatment. Trough plasma EGCG levels after 1 month of treatment ranged from 2.9 to 3,974 ng/mL (median, 40.4 ng/mL). Conclusion Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase I trial. Declines in ALC and/or lymphadenopathy were observed in the majority of patients. A phase II trial to evaluate efficacy using 2,000 mg twice a day began in November 2007.