Begna, Kebede H.

Outcomes of acute myeloid leukemia (AML) in elderly patients unfit for intensive chemotherapy is challenging. Hypomethylating agents (HMAs) can be effective in these patients but responses are usually short‐lived. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs. The data on 56 AML patients at Mayo Clinic, Rochester were reviewed. Patients were considered for our study if they received HMA as frontline therapy for their AML. Out of 56 patients, 15 (27%) patients received azacitidine (AZA) and 41 (73%) received decitabine. Complete remission was found in 10 (18%), with overall response of 28% and median response duration of 10 months. Thirteen (81%) out of 16 responders relapsed. Therefore 53 patients were included in the primary or secondary failure analysis with a median overall survival (OS) of 2 months after the date of failure. Out of 53 patients, 12 (23%) received subsequent treatments. None of the 12 patients who got first salvage therapy achieved remission. Five out of the 12 patients received second salvage therapy, 2 (40%) of which achieved CR. Median OS for patients who received subsequent salvage therapies was better than those who did not receive any subsequent therapy after failing HMA (9.5 vs. 2 months, P = .0009). Outcome for patients who have primary or secondary failure is very poor. Our study provides important historical data for future novel therapies, which are sorely needed for these patients.

Key Clinical MessageTyrosine kinase inhibitor treated chronic myelogenous leukemia patients with monosomy 7 arising in Philadelphia chromosome negative (Ph−) cells tend to evolve into MDS/AML. However, monosomy 7 in Ph− cells can be a transient finding, and it is not an absolute indication of the emergence of a new myeloid malignancy.

SummaryMomelotinib (a JAK1 and JAK2 inhibitor) induces both anaemia and spleen responses in myelofibrosis (MF). Momelotinib treatment‐emergent peripheral neuropathy (TE‐PN) was documented in 44 (44%) of 100 MF patients treated at our institution; median time of TE‐PN onset was 32 weeks and duration 11 months. Improvement after drug dose reduction or discontinuation was documented in only two patients. TE‐PN was significantly associated with treatment response (P = 0·02) and longer survival (P = 0·048) but significance was lost during multivariate analysis that included treatment duration. TE‐PN did not correlate with initial or maximum momelotinib dose or previous treatment with JAK inhibitor or thalidomide.

SummaryMyelofibrosis (MF) is a Philadelphia chromosome–negative stem cell myeloproliferative neoplasm (MPN) associated with cytopenias, splenomegaly, constitutional symptoms, and poor prognosis. MF patients commonly express JAK2 V617F mutation and activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Agents targeting the JAK/STAT pathway have demonstrated efficacy in patients with MF. This study evaluated panobinostat, a pan‐deacetylase inhibitor that depletes JAK2 V617F levels and JAK/STAT signalling in MPN cells, in patients with primary MF, post–essential thrombocythaemia MF, and post–polycythaemia vera MF. Patients received panobinostat 40 mg administered three times per week. Dose reductions were permitted for toxicities. The primary endpoint was response rate at 6 months using International Working Group for Myelofibrosis Research and Treatment (IWG‐MRT) consensus criteria. Analyses of peripheral blood cells from treated patients revealed that panobinostat inhibited JAK/STAT signalling, decreased inflammatory cytokine levels, and decreased JAK2 V617F allelic burden. However, panobinostat was poorly tolerated at the dose and schedule evaluated, and only 16 of 35 patients completed ≥2 cycles of treatment. One patient (3%) achieved an IWG‐MRT response. Common adverse events were thrombocytopenia (71·4%) and diarrhoea (80·0%). Although molecular correlative analyses suggested that panobinostat inhibits key intracellular targets, limited clinical activity was observed because of poor tolerance.

Cytogenetic classification by the revised international prognostic scoring system (IPSS‐R) and the prognostic value of monosomal karyotype (MK) were assessed in 783 patients with primary myelodysplastic syndromes (MDS). At 22 months median follow‐up, 562 (72%) deaths were recorded. Percentages of patients with IPSS‐R “very good,” “good,” “intermediate,” “poor,” and “very poor” cytogenetic categories was 5, 63, 18, 4, and 10%, respectively. The corresponding median survivals were 21, 40, 24, 18, and 6.5 months and the inter‐group differences (good vs. very good/intermediate/poor vs. very poor; P < 0.01) or similarities (very good vs. intermediate vs. poor; P = 0.79) were not significantly modified in multivariable analysis. Results were similar when analysis was restricted to 602 patients managed by supportive care. MK adversely affected survival in both poor and very poor karyotype groups (P < 0.01). In conclusion, we were unable to confirm the prognostic superiority of IPSS‐R‐very good karyotype or prognostically distinguish between very good, intermediate and poor karyotypes. Furthermore, we show additional prognostic information from MK in poor/very poor karyotype. Am. J. Hematol. 88:690–693, 2013. © 2013 Wiley Periodicals, Inc.

Abstract DIPSS-plus (the Dynamic International Prognostic Scoring System-plus) includes 8 risk factors for survival in primary myelofibrosis. In the present study of 884 karyotypically annotated patients with primary myelofibrosis, we sought to identify 1 or 2 parameters that can reliably predict death in the first 2 years of disease. After a median of 8.2 years from time of referral to the Mayo Clinic, 564 deaths (64% of patients in the study) had been recorded. Risk factors associated with > 80% 2-year mortality included monosomal karyotype, inv(3)/i(17q) abnormalities, or any 2 of the following: circulating blasts > 9%, leukocytes ≥ 40 × 109/L, or other unfavorable karyotype. Patients with any 1 of these risk profiles (n = 52) displayed significantly shorter overall survival than those otherwise belonging to a high-risk category per DIPSS-plus (n = 298); respective median survivals were 9 and 23 months (hazard ratio 2.2, 95% confidence interval 1.6-3.1; P < .01). The present information complements DIPSS-plus in the selection of primary myelofibrosis patients for high-risk treatment approaches.

Abstract Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis. Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival.

Purpose The Dynamic International Prognostic Scoring System (DIPSS) for primary myelofibrosis (PMF) uses five risk factors to predict survival: age older than 65 years, hemoglobin lower than 10 g/dL, leukocytes higher than 25 × 10 9 /L, circulating blasts ≥ 1%, and constitutional symptoms. The main objective of this study was to refine DIPSS by incorporating prognostic information from karyotype, platelet count, and transfusion status. Patients and Methods Mayo Clinic databases for PMF were used to identify patients with available bone marrow histologic and cytogenetic information. Results Seven hundred ninety-three consecutive patients were selected and divided into two groups based on whether or not their referral occurred within (n = 428; training set) or after (n = 365; test set) 1 year of diagnosis. Multivariable analysis identified DIPSS, unfavorable karyotype, platelets lower than 100 × 10 9 /L, and transfusion need as independent predictors of inferior survival. Hazard ratio (HR) –weighted adverse points were assigned to these variables to develop a composite prognostic model using the training set. The model was subsequently validated in the test set, and its application to all 793 patients resulted in median survivals of 185, 78, 35, and 16 months for low, intermediate-1 (HR, 2.2; 95% CI, 1.4 to 3.6), intermediate-2 (HR, 4.9; 95% CI, 3.2 to 7.7), and high-risk groups (HR, 10.7; 95% CI, 6.8 to 16.9), respectively (P < .001). Leukemia-free survival was predicted by the presence of thrombocytopenia or unfavorable karyotype (10-year risk of 31% v 12%; HR, 3.3; 95% CI, 1.9 to 5.6). Conclusion DIPSS plus effectively combines prognostic information from DIPSS, karyotype, platelet count, and transfusion status to predict overall survival in PMF. In addition, unfavorable karyotype or thrombocytopenia predicts inferior leukemia-free survival.