Hanson, Curtis A.

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.

Monocyte‐derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell‐cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte‐derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk‐stratification of CLL patients for TTT. As an elevated AMC at diagnosis is associated with accelerated disease progression, and monocyte‐derived cells in the CLL microenvironment promote CLL cell survival and proliferation, these findings suggest that monocytes and monocyte‐derived cells are rational therapeutic targets in CLL. Am. J. Hematol. 91:687–691, 2016. © 2016 Wiley Periodicals, Inc.

Abstract BACKGROUND We assessed the impact of clinical decision support (CDS) rules within the electronic health record for ionized calcium (iCa), serum magnesium (Mg), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in intensive care unit (ICU) inpatients at a large academic center. METHODS A repeat order for measurement of iCa or Mg placed within 24 (iCa) or 48 (Mg) h of a previously nonactionable result, or additional orders for NT-proBNP beyond 1 within a single hospitalization, triggered a CDS pop-up alert showing the prior result and offering the opportunity to cancel the order or to place the order after entering an indication for repeat testing. The number of tests performed for each of these analytes and incidence of adverse clinical outcomes potentially associated with hypocalcemia or hypomagnesemia were compared between the 90-day period before CDS implementation and two 90-day periods immediately following. RESULTS iCa test volumes decreased by 48%, Mg by 39%, and NT-proBNP by 28% in the 90-day period immediately following implementation and remained decreased by 54%, 49%, and 22%, respectively, during the following 90-day period (all P values &lt;0.0002). Adverse clinical outcomes potentially associated with hypocalcemia or hypomagnesemia did not increase (all P-values &gt;0.17). CONCLUSIONS Implementation of CDS dramatically decreased repeat testing of iCa, Mg, and NT-proBNP without adversely impacting clinical outcomes in the ICU. Expansion of the rules from the ICU units to include the entire hospitalized patient population and expansion to additional analytes is expected to lead to further reductions in testing.

About 85% of patients with essential thrombocythemia (ET) harbor one of three driver mutations: JAK2, calreticulin (CALR), and MPL; the remaining ( ∼15%) are wild type for all three mutations and are referred to as being “triple negative.” Furthermore, CALR mutations in ET are structurally classified as type 1/type 1‐like or type 2/type 2‐like variants. The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis‐free (MFFS), thrombosis‐free, and leukemia‐free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple‐negative. Among the 109 CALR‐mutated cases, 52% were classified as type 1/type 1‐like and 48% as type 2/type 2‐like. In univariate analysis, triple‐negative patients displayed the best and MPL mutated the worst OS (P = 0.007); however, the difference in OS was no longer apparent on multivariable analysis that included age and sex as covariates (P = 0.5). LFS was also similar among the different mutational groups (P = 0.6) whereas MFFS was significantly shorter in MPL‐mutated patients on both univariate and multivariable analyses (age‐adjusted P = 0.02; HR 7.9, 95% CI 2.0–31.5). Also in multivariable analysis that included thrombosis history, age, and cardiovascular risk factors, the presence of JAK2 or MPL mutations was independently associated with higher risk of thrombosis (P = 0.02; HR 1.9, 95% CI 1.1–3.4). In conclusion, driver mutational status in ET does not appear to influence overall or LFS, even after CALR variant stratification. However, the presence of MPL mutations might be associated with a higher risk of fibrotic transformation and the presence of JAK2/MPL mutations with higher risk of thrombosis. Am. J. Hematol. 91:503–506, 2016. © 2016 Wiley Periodicals, Inc.

Refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS‐T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS‐T. We analyzed clinical and laboratory variables in 82 patients and applied a 27‐gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2 V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis ( n = 82), anemia ( P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2–4.6] and abnormal karyotype ( P =.01) [HR 6.1, 95% CI 2.7‐13.8] were independently prognostic for inferior survival. In patients with NGS information ( n = 48), univariate analysis showed association between poor survival and presence of SETBP1 ( P = 0.04) or ASXL1 ( P = 0.08) mutations whereas the absence of these mutations ( ASXL1 wt/ SETBP1 wt) was favorable ( P = 0.04); the number of concurrent mutations did not provide additional prognostication ( P = 0.3). We developed a HR‐weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively ( P = 0.01). In summary, we confirm the unique mutational landscape in RARS‐T and provide a novel mutation‐enhanced prognostic model. Am. J. Hematol. 91:492–498, 2016. © 2016 Wiley Periodicals, Inc.

The primary objective of treatment in essential thrombocythemia (ET) is to prevent thromboembolic complications. In this regard, advanced age and thrombosis history have long distinguished “low” from “high” risk patients. More recently, JAK2V617F and cardiovascular (CV) risk factors were identified as additional modifiers, leading to the development of a 3‐tiered International Prognostic Score of Thrombosis for ET (IPSET‐thrombosis): “low,” “intermediate,” and “high”. The international data set used to develop IPSET‐thrombosis was recently re‐analyzed in order to quantify the additional pro‐thrombotic effect of JAK2V617F and CV risk factors in specific risk subcategories. The revised IPSET‐thrombosis identified four risk categories based on three adverse variables (thrombosis history, age >60 years and JAK2V617F): very low (no adverse features), low (presence of JAK2V617F), intermediate (age >60 years) and high (presence of thrombosis history or presence of both advanced age and JAK2V617F). In this study of 585 patients with ET (median age 68 years; 61% female), we validated the revised IPSET‐thrombosis by confirming significant differences in thrombosis risk between “very low” and “low” (HR 2.4, 95% CI 1.1 − 5.3) and between “intermediate” and “high” (HR 2.3, 95% CI 1.1 − 5.2) risk patients. Furthermore, in multivariable analysis, only JAK2V617F (HR=1.8, CI= 1.07 − 2.94) and history of thrombosis (HR=2.1, CI= 1.20 − 3.58) were independently predictive of future thrombotic events. The revised IPSET‐thrombosis needs confirmation in prospective studies, especially in terms of risk‐adapted therapy that includes the need for aspirin therapy in very low risk, twice‐daily aspirin therapy for low risk and cytoreductive therapy for low or intermediate risk patients. Am. J. Hematol. 91:390–394, 2016. © 2016 Wiley Periodicals, Inc.

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.