Citations

DNMT3A mutations are seen in ∼5% of patients with chronic myelomonocytic leukemia (CMML) and thus far, have had an indeterminate prognostic impact on survival. We carried out this study to assess the prognostic impact of DNMT3A mutations on a larger informative cohort of CMML patients (n = 261). DNMT3A mutations were seen in 6% (n = 16); 56% (n = 9) male, with a median age of 64 years. Eighty‐one % of DNMT3A mutations were missense, with the Arg882 mutational hot spot accounting for 63% of all changes. Five (31%) patients had an abnormal karyotype whereas concurrent gene mutations (SF3B1/SRSF2/U2AF1−56%, TET2−50%, and ASXL1−25%) were seen in all patients. Apart from a higher frequency of SF3B1 (P = 0.0001) and PTPN11 (P = 0.005) mutations and a lower frequency of SRSF2 (P = 0.004) mutations, there were no significant differences between DNMT3A mutated patients and their wildtype counterparts. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wildtype (median 27 months) patients (P = 0.0007; HR 2.9, 95% CI 1.5–5.7); with other variables of significance including lower hemoglobin (P = 0.002), higher leukocyte count (P = 0.0009), higher monocyte count (P = 0.0012), circulating blast % (P = 0.001), circulating immature myeloid cells (P = 0.01), bone marrow blast % (P = 0.045), abnormal karyotype (P = 0.02), and ASXL1 (P = 0.01) mutations. In a multivariable model that included the aforementioned variables, when both DNMT3A and ASXL1 mutations were added, only DNMT3A (P < 0.0001) and ASXL1 (P = 0.004) mutations remained significant. DNMT3A mutations were also predictive of a shortened leukemia‐free survival. These findings warrant inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models. Am. J. Hematol. 92:56–61, 2017. © 2016 Wiley Periodicals, Inc.

Abstract Introduction. First-line chemoimmunotherapy (CIT) has significantly increased the complete remission (CR) rate for patients with CLL; however, relapse is a common event and strategies aimed at eradicating disease more effectively are needed. Vascular Epithelial Growth Factor (VEGF) plays a crucial role in the cross talk between CLL B cells and their microenvironment. In addition low baseline VEGF levels predict a better response to CIT. Testing the combination of an anti-VEGF agent with CIT was therefore assessed by us in upfront CLL patients. Methods. Here we report the results of a phase II open-label randomized trial comparing the combination of bevacizumab, an anti-VEGF monoclonal antibody, with pentostatin, cyclophosphamide and rituximab (PCR-B) to PCR alone as front-line therapy in previously untreated patients with CLL. VEGF, b-fibroblast growth factor (FGF), thrombospondin (TSP)-1, chemokine ligand (CCL)-3 and CCL-4 plasma levels were measured at baseline and at time of response assessment. Results. Between 01/2009 and 01/2013, 62 patients were accrued in the study, 32 in the arm A (PCR-B) and 30 in arm B (PCR alone). A higher rate of grade 3-4 cardiovascular toxicity was observed with the use of PCR-B (34% vs 0%, p&lt;0.001): this included 7 cases of hypertension, 2 cases of congestive heart failure, 1 myocarditis, and 1 case of torsade de point. A higher CR rate (50% vs 33%, p = 0.21) and a significantly longer median progression-free (p = 0.04) and treatment-free (p = 0.05) survival were achieved with the use of PCR-B. No difference in chemokine kinetics was observed between the 2 arms, except for VEGF, which significantly increased after PCR-B. In the PCR-B arm, chemokine kinetics for CCL-3 (median drop 5.0 vs. median drop 31.8, respectively; p = 0.02) and CCL-4 (median drop 23.8 vs. median drop 120.9, respectively; p = 0.01) were significantly associated with achievement of CR. No significant correlations were found between cytokine plasma levels and responses for patients treated in the PCR only arm. Conclusions. The addition of bevacizumab to CIT is safe and effective, although associated with higher cardiovascular toxicity, in particular hypertension. The addition of bevacizumab produces higher CR rates, translating into improved progression-free survival, and is associated with decreased plasma levels of CCL-3 and CCL-4. Citation Format: PAOLO STRATI, TAIT D. SHANAFELT, BETSY LAPLANT, ADAM PETTINGER, CONNIE LESNICK, DANIEL NIKCEVICH, TIMOTHY CALL, WEI DING, CURTIS HANSON, NEIL KAY. The addition of bevacizumab to chemoimmunotherapy prolongs progression-free survival in patients with chronic lymphocytic leukemia (CLL) through modulation of the microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1423.

In routine practice, the World Health Organization classification of systemic mastocytosis (SM) is also the de facto prognostic system; a core value is distinguishing indolent (ISM) from advanced SM (includes aggressive SM [ASM], SM with associated hematological neoplasm [SM‐AHN] and mast cell leukemia [MCL]). We sequenced 27 genes in 150 SM patients to identify mutations that could be integrated into a clinical‐molecular prognostic model for survival. Forty four patients (29%) had ISM, 25 (17%) ASM, 80 (53%) SM‐AHN and 1 (0.7%) MCL; overall KITD816V prevalence was 75%. In 87 patients, 148 non‐KIT mutations were detected; the most frequently mutated genes were TET2 (29%), ASXL1 (17%), and CBL (11%), with significantly higher mutation frequency in SM‐AHN > ASM > ISM (P < 0.0001). In advanced SM, ASXL1 and RUNX1 mutations were associated with inferior survival. In multivariate analysis, age > 60 years (HR = 2.4), hemoglobin < 10 g/dL or transfusion‐dependence (HR = 1.7), platelet count < 150 × 109/L (HR = 3.2), serum albumin < 3.5 g/dL (HR = 2.6), and ASXL1 mutation (HR = 2.3) were associated with inferior survival. A mutation‐augmented prognostic scoring system (MAPSS) based on these parameters stratified advanced SM patients into high‐, intermediate‐, and low‐risk groups with median survival of 5, 21 and 86 months, respectively (P < 0.0001). These data should optimize risk‐stratification and treatment selection for advanced SM patients. Am. J. Hematol. 91:888–893, 2016. © 2016 Wiley Periodicals, Inc.