Citations

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti‐CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8‐12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m2 weekly)(n = 16) or low dose (20 mg/m2 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression‐free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti‐CD20 mAb therapy as a potentially more effective use of anti‐CD20 mAb in the treatment of CLL. Am. J. Hematol. 91:308–312, 2016. © 2015 Wiley Periodicals, Inc.

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.

AbstractObjectivesIn the 2008 World Health Organization classification, cases of acute myeloid leukemia (AML) and myelodysplastic syndrome that arise after chemotherapy or radiation therapy for a primary neoplasm are considered together as therapy-related myeloid neoplasms (TR-MNs). This concept, however, is not universally accepted since there are confounding variables in attributing myeloid neoplasms to earlier therapies.MethodsCases in session 6 of the 2013 Workshop of the Society for Hematopathology/European Association for Haematopathology illustrated myeloid neoplasms thought likely to be TR-MNs, and discussed the differences and biologic similarities with de novo myeloid neoplasms.ResultsWe reviewed data showing that diagnosis of TR-MN alters patient outcome only in specific subsets. The session also included examples of therapy-related AML with recurrent genetic abnormalities, such as t(15;17), inv(16), and t(8;21), and reports were highlighted showing that patients with these neoplasms have clinical outcomes similar to patients with their de novo counterparts.ConclusionsThe study of TR-MNs will likely provide insight into the pathogenesis of de novo myeloid disease and may explain why some patients with cancer develop TR-MN and evidently have a higher genetic susceptibility, whereas most patients treated with the same agents do not. These studies will also result in critical reappraisal of current concepts related to TR-MNs.

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 .

Colony stimulating factor 3 receptor gene (CSF3R) mutations have recently been associated with chronic neutrophilic leukemia (CNL). Fourteen patients with CSF3R‐mutated CNL (median age 67 years; 57% males) were screened for additional mutations; 8 (57%) and 5 (38%) harbored an ASXL1 and/or SETBP1 mutation (two patients expressed both), respectively. Two patients developed blastic transformation, both SETBP1‐mutated and ASXL1‐unmutated, whereas two other cases evolved into chronic myelomonocytic leukemia (CMML), both ASXL1‐mutated and SETBP1‐unmutated. Median survival was 23.2 months (10 deaths documented). On multivariable analysis mutated ASXL1 (P = 0.009; HR 19.6, 95% CI 2.1–184.1) and thrombocytopenia (P = 0.005; HR 28.8, 95% CI 2.8–298.2) were independently predictive of shortened survival. This study provides information on the natural history of CSF3R‐mutated CNL and identifies mutant ASXL1 and thrombocytopenia as risk factors for survival. The study also suggests pathogenetic roles for SETBP1 and ASXL1 mutations in disease evolution into blast phase disease and CMML, respectively. Am. J. Hematol. 90:653–656, 2015. © 2015 Wiley Periodicals, Inc.