Decoding Bone Marrow Fibrosis in Myelodysplastic Syndromes.

BACKGROUND: Bone marrow fibrosis (BMF), a poor prognostic factor in myelodysplastic syndromes (MDS), in the context of new risk stratifications of MDS has not been fully explored. We examined the relationship between BMF in MDS and survival outcomes, and explored the landscape of somatic gene mutations in the setting of BMF. PATIENTS AND METHODS: We retrospectively evaluated 2624 MDS patients for BMF who were divided into 2 groups: grade 0-2 BMF (96%) and severe/grade 3 BMF (4%) based on analysis presented. Commonly MDS tested acquired somatic mutations were also compared between those 2 groups of patients with available next-generation sequencing data. RESULTS: Only grade 3 BMF was associated with worse overall survival independent from the Revised International Prognostic Scoring System (IPSS-R) (hazard ratio = 1.6; 95% confidence interval, 1.2-1.9; P < .005). More patients with severe BMF were classified as MDS-EB1 and -EB2 by the World Health Organization 2016 classification, a higher-risk International Prognostic Scoring System score, and a high/very high IPSS-R risk category than patients with grade 0-2 BMF. A complex karyotype, higher bone marrow myeloblasts, lower platelets, and higher rate of elevated lactate dehydrogenase were observed more often in patients with severe BMF. No differences in response to hypomethylating agents or lenalidomide were observed. Among somatic gene mutations tested in MDS, TP53 mutation and SETBP1 were more frequent in patients with grade 3 BMF. CONCLUSION: The presence of grade 3 BMF is associated with reduced overall survival independent from IPSS-R; however, BMF grade did not affect response to hypomethylating agent or lenalidomide treatment. TP53 and SETBP1 mutations occurred with greater frequency among patients with severe fibrosis.

Myelodysplastic Syndromes in Adolescent Young Adults: One Institution's Experience.

INTRODUCTION: There has been little improvement in cancer survival of adolescent and young adult (AYA) patients, aged 18 to 39 years, possibly reflecting different disease biology. Myelodysplastic syndrome (MDS) is mainly a disease of the elderly. The characteristics, outcomes, and response to treatment are not well described in the AYA population. PATIENTS AND METHODS: This was a retrospective review of patients from the Moffitt Cancer Center MDS database. We compared baseline characteristics and outcomes of the AYA population to older patients. We identified 51 AYA and 1897 older MDS patients. More female subjects and Hispanics were noted in AYA group. RESULTS: The AYA patients had higher risk disease, more circulating myeloblasts, and more hypoplastic MDS. Autoimmune disorders were more prevalent in older patients. The median overall survival (OS) was 47 months in the AYA group versus 40 months in the older group (P = .26). The median OS was 47 versus 56 months in lower risk AYA group and older group, respectively (P = .46). In the higher risk group, median OS was 82 months in the AYA group compared to 17 months in the older group (P = .001). Thirty individuals (59%) underwent allogeneic stem-cell transplantation in the AYA group versus 241 (13%) in the older group. The median OS for transplanted patients was 55 months in the AYA group and 46 months in the older group (P = .4). In the nontransplanted patients, median survival was 31 months for the AYA group and 39 months for the older group (P = .9). The rate of acute myeloid leukemia transformation was 37% versus 28% in the AYA and older groups, respectively (P = .17). No differences in use or response to hypomethylating agents were observed. Lenalidomide therapy was seldom used in AYA, as none presented with del5q. In AYA, poor karyotype was the only variable strongly associated with worse outcome. Fifteen patients had poor risk karyotypes (29%). The median OS was 47 months, not reached, and 29 months among patients with good, intermediate, and poor risk cytogenetics, respectively (P = .035). CONCLUSION: MDS is rare and tends to be more aggressive in the AYA population. Karyotype was the most important prognostic factor. Allogeneic stem-cell transplantation offered younger patients the best outcomes.

Eltrombopag Use in Patients With Chronic Myelomonocytic Leukemia (CMML): A Cautionary Tale.

INTRODUCTION: Eltrombopag used for thrombocytopenia in myelodysplastic syndrome (MDS) patients is being explored in clinical trials including those with chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: We report our experience treating patients with CMML enrolled in a sequential 2-stage dose escalation study with eltrombopag in patients with MDS after hypomethylating agent failure. Patients with CMML were compared with patients with MDS in respect to response and adverse events. RESULTS: Among 33 patients in the study, we treated 7 patients with CMML. Hematological improvement or better (by International Working Group 2006 criteria) was observed in 6 (23%) of 26 MDS patients and 1 (14%) of 7 patients with CMML. The responding patient with CMML had bilineage response. Two patients with CMML became platelet transfusion-independent. Five (71%) patients with CMML developed leukocytosis compared with 3 (12%) patients with MDS. Four (57%) patients with CMML showed peripheral myeloblasts after treatment compared with 11 (42%) in the MDS group. One (14%) patient with CMML developed grade 3 fibrosis from grade 0 to 1 at baseline compared with 3 (12%) patients with MDS. The rate of acute myeloid leukemia transformation was 39% and 29%, respectively, in patients with MDS and CMML. CONCLUSION: Further clinical studies are needed to identify patients with CMML who will benefit from this treatment.

A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML).

PURPOSE: To conduct a phase I clinical trial exploring the safety and efficacy of ruxolitinib, a JAK1/2 inhibitor, for chronic myelomonocytic leukemia (CMML). EXPERIMENTAL DESIGN: Patients with CMML-1 were included without regard to previous therapy. Key exclusion criteria included an absolute neutrophil count (ANC) <0.25 × 10(3) cells/dL and a platelet count <35 × 10(3) cells/dL. Four cohorts were enrolled using a "rolling six" study design, with doses ranging from 5 to 20 mg twice daily of ruxolitinib in 5-mg dose escalations. RESULTS: Between March 2013 and January 2015, 20 patients were enrolled and treated with ruxolitinib. Seventy percent of patients had the proliferative subtype and 47% had higher risk disease by the Global MD Anderson Scoring System. Eight patients (42%) received a prior hypomethylating agent. No dose-limiting toxicities for ruxolitinib were identified. One subject had grade (G)3 thrombocytopenia with no other drug-associated G3 or G4 adverse events. The mean duration of therapy was 122 days (range, 28-409 days). Four had hematologic improvement and one patient had a partial response per 2006 International Working Group (IWG) criteria. Five of 9 patients with splenomegaly had a reduction in spleen size. Ten of 11 patients with reported disease-related symptoms had clinically meaningful or complete resolution. When combining IWG and spleen responses, a total response rate of 35% (n = 7) was identified. Correlative analysis demonstrated a reduction in inflammatory cytokines and GM-CSF-dependent STAT5 phosphorylation. CONCLUSIONS: The recommended phase II dose of ruxolitinib is 20 mg twice daily. We demonstrate that ruxolitinib has promising activity in CMML with particular benefit in those with disease-related B symptoms that warrants further study. Clin Cancer Res; 22(15); 3746-54. ©2016 AACRSee related commentary by Solary, p. 3707.

Validation of the Lower-Risk MD Anderson Prognostic Scoring System for Patients With Myelodysplastic Syndrome.

The International Prognostic Scoring System (IPSS) is the most widely used tool for risk assessment and treatment decisions for myelodysplastic syndrome (MDS). Several new models have been proposed to identify a subset of lower-risk patients with MDS who are experiencing inferior than expected outcomes. We validated the Lower-Risk MD Anderson Risk Model (LR-MDAS) in 1288 lower-risk patients with MDS by the IPSS. On the basis of the LR-MDAS, 228 patients (17%) were in category 1, 730 patients (57%) were in category 2, 315 patients (25%) were in category 3, and 15 patients (1%) were in an unknown category. The median overall survival for the corresponding LR-MDAS categories was (1) 109 months (95% confidence interval [CI], 82-137), (2) 56 months (95% CI, 58-73), and (3) 29 months (95% CI, 24-35) (P < .005). Overall, 25% of patients were upstaged to category 3. LR-MDAS refined prognostic value among very low-, low-, and intermediate-risk Revised IPSS. The rate of acute myeloid leukemia transformation according to LR-MDAS was 15%, 18%, and 29% for categories 1, 2, and 3, respectively (P < .005). Our data validate the prognostic value of the LR-MDAS model, but the utility of it as a treatment decision tool should be studied prospectively.