Citations

Abstract Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 × 109/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.

Abstract Among 200 patients with primary myelofibrosis, karyotype at diagnosis was abnormal in 83 (42%). To assess their individual prognostic impact, specific cytogenetic abnormalities with more than or equal to 5 informative cases were identified and the rest grouped separately as “other abnormalities.” Median survival in patients with sole +9 (n = 6), sole 20q− (n = 21), sole 13q− (n = 8), normal karyotype (n = 117), “other abnormalities” (n = 28), complex karyotype (n = 13), and sole +8 (n = 7) were “not reached,” 112, 105, 80, 46, 34, and 28 months, respectively (P = .01). Accordingly, 4 cytogenetic risk groups were considered: (1) favorable (sole +9, 20q−, or 13q−), (2) normal, (3) unfavorable (complex karyotype or sole +8), and (4) “other abnormalities.” Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)–independent prognostic value of both 4-way and 2-way (ie, favorable/normal vs unfavorable/other abnormalities; IPSS-adjusted hazard ratio = 0.37; 95% confidence interval, 0.24-0.58) cytogenetic risk categorization (P < .01). The ability to prognostically dissect a specific IPSS category has major therapeutic implications.

Abstract The prognostic heterogeneity of the World Health Organization category of “systemic mastocytosis with associated clonal hematologic nonmast cell lineage disease” (SM-AHNMD) has not been systematically validated by primary data. Among 138 consecutive cases with SM-AHNMD, 123 (89%) had associated myeloid neoplasm: 55 (45%) myeloproliferative neoplasm (SM-MPN), 36 (29%) chronic myelomonocytic leukemia, 28 (23%) myelodysplastic syndrome (SM-MDS), and 4 (3%) acute leukemia. Of the myeloid subgroups, SM-MPN displayed a 2- to 3-fold better life expectancy (P = .003), whereas leukemic transformation was more frequent in SM-MDS (29%; P = .02). The presence of eosinophilia, although prevalent (34%), was prognostically neutral, and the overall results were not affected by exclusion of FIP1L1-PDGFRA-positive cases. We conclude that it is clinically more useful to consider specific entities, such as SM-MPN, systemic mastocytosis with chronic myelomonocytic leukemia, SM-MDS, and systemic mastocytosis with-acute leukemia, rather than their broad reference as SM-AHNMD.

Purpose Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide. Methods In a phase II randomized, multicenter, double-blind, adaptive design study, four treatment arms were evaluated: pomalidomide (2 mg/d) plus placebo, pomalidomide (2 mg/d) plus prednisone, pomalidomide (0.5 mg/d) plus prednisone, and prednisone plus placebo. Pomalidomide was administered for up to 12 28-day treatment cycles. Prednisone (30 mg/d) was given in a tapering dose schedule during the first three cycles. Response was assessed by International Working Group criteria. Results Eighty-four patients with myelofibrosis-associated anemia were randomly assigned to the aforementioned treatment arms: 22, 19, 22, and 21, respectively. Response in anemia was documented in 20 patients, including 15 who became transfusion independent. Response rates in the four treatment arms were 23% (95% CI, 5% to 41%), 16% (95% CI, 0% to 33%), 36% (95% CI, 16% to 56%), and 19% (95% CI, 2% to 36%). The corresponding figures for patients receiving ≥ 3 cycles of treatment (n = 62) were 38%, 23%, 40%, and 25%. Response to pomalidomide with or without prednisone was durable (range, 3.2 to 16.9+ months) and significantly better in the absence of leukocytosis (37% v 8%; P = .01); JAK2V617F or cytogenetic status did not affect response. Grade ≥ 3 toxicities were infrequent and included (in each treatment arm) neutropenia (9%; 16%; 5%; 5%), thrombocytopenia (14%; 16%; 9%; 5%), and thrombosis (9%; 5%; 0%; 0%). Conclusion Pomalidomide therapy at 0.5 or 2 mg/d with or without an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia.

Abstract Clinical phenotype in systemic mastocytosis (SM) is markedly variable, which complicates prognostication and decision making regarding the choice and timing of therapy. In a retrospective study of 342 consecutive adult patients with SM seen at the Mayo Clinic between 1976 and 2007, disease subdesignation according to the World Health Organization (WHO) proposal was indolent (ISM) in 159 (46%), with associated clonal hematologic non–mast cell lineage disease (SM-AHNMD) in 138 (40%), aggressive (ASM) in 41 (12%), and mast cell leukemia in 4 (1%). KITD816V was detected in bone marrow–derived DNA by allele-specific polymerase chain reaction (PCR) in 68% of 165 patients evaluated (ISM, 78%; ASM, 82%; SM-AHNMD, 60%; P = .03); JAK2V617F was detected in 4%, all in SM-AHNMD. Compared with those with nonindolent SM, life expectancy in ISM was superior and not significantly different from that of the age- and sex-matched US population. In addition, multivariable analysis identified advanced age, weight loss, anemia, thrombocytopenia, hypoalbuminemia, and excess bone marrow blasts as independent adverse prognostic factors for survival. The current study validates the prognostic relevance of the WHO subclassification of SM and provides additional information of value in terms of both risk stratification and interpretation of clinical presentation and laboratory results.

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities—some defined principally by genetic features—that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.