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Introduction: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. Methods: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively. Results: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. Conclusion: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies. Trial Registration: ClinicalTrials.gov: NCT02101268. Plain Language Summary: Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia. [ABSTRACT FROM AUTHOR]

Ruxolitinib improves splenomegaly and other disease-related symptoms in patients with myelofibrosis, but over time, many patients lose this benefit. It is difficult to determine whether this is due to resistance or intolerance to the drug; thus, we have used the more inclusive term of ruxolitinib failure. The survival of patients with myelofibrosis after ruxolitinib failure is poor but varies significantly by the pattern of the failure, underlining the need for a clinically appropriate classification. In this review, we propose diagnostic guidance for early recognition of the pattern of ruxolitinib failure and we recommend treatment options. The most frequent patterns of ruxolitinib failure are loss or failure to obtain a significant reduction in splenomegaly or symptom response, and the development or persistence of clinically significant cytopenias. Ruxolitinib dose modification and other ancillary therapies are sometimes helpful, and splenectomy is a palliative option in selected cases. Stem-cell transplantation is the only curative option for these patterns of failure, but its restricted applicability due to toxicity highlights the importance of ongoing clinical trials in this area. Recent approval of fedratinib by the US Food and Drug Administration provides an alternative option for patients with suboptimal or loss of spleen response. The transformation of myelofibrosis to accelerated or blast phase is an infrequent form of failure with an extremely poor prognosis, whereby patients who are ineligible for transplantation have limited treatment options. [ABSTRACT FROM AUTHOR]

Objectives: To standardize diagnostic investigations for myeloproliferative neoplasms (MPNs) to increase homogeneity in patient care and to streamline diagnostic approaches in the most efficient and cost-effective manner.Methods: The development of Canadian expert consensus recommendations for the diagnosis of MPNs began with a review of the following: clinical evidence, daily practice, existing treatment guidelines, and availability of diagnostic tools. Each group member was assigned a specific topic, which they discussed with the entire group during several consensus meetings.Results: This document provides the Canadian MPN group's recommendations, proposed diagnostic algorithms, and background evidence upon which decisions were made.Conclusions: Standardization of diagnostic investigations will increase homogeneity in patient care and provide a foundation for future clinical research in this rapidly evolving therapeutic area. Streamlining diagnostic approaches in the most efficient and cost-effective manner will also result in significant cost saving for the health care system. [ABSTRACT FROM AUTHOR]

Polycythaemia vera (PV) is closely associated with both an acquired activating mutation of the JAK2 tyrosine kinase ( JAK2 V617 F) in granulocyte-derived DNA and increased granulocyte polycythaemia rubra vera-1 ( PRV-1) expression. In order to explore the correlation between these two biological markers and compare their diagnostic utility, mutation analysis for JAK2 V617 F and quantitative measurement of granulocyte PRV-1 expression were performed on the same study sample from 100 participants: 38 with PV, 22 with essential thrombocythaemia (ET), 10 with agnogenic myeloid metaplasia (AMM), 19 with secondary polycythaemia (SP) and 11 healthy volunteers. The respective overall (homozygous) JAK2 V617 F mutational frequencies were 95% (26%), 55% (0%), 30% (0%), 0% and 0%. The corresponding figures for increased PRV-1 expression were 89%, 18%, 20%, 21% and 9%. In patients with either ET or AMM, the likelihood of detecting JAK2 V617 F was significantly higher in the presence of an increased PRV-1 expression (83% vs. 38%; P = 0·05). Similarly, in patients with PV, homozygous as compared with heterozygous JAK2 V617 F correlated with higher levels of PRV-1 expression ( P = 0·11). The present study suggests an allele dose-dependent effect of JAK2 V617 F on granulocyte PRV-1 expression. However, compared with the PRV-1 assay, mutation screening for JAK2 V617 F displayed greater accuracy in distinguishing PV from SP. [ABSTRACT FROM AUTHOR]

Abstract: Comparative genomic hybridization (CGH), using oligo arrays with either 44,000 or 105,000 oligonucleotides, was performed on granulocyte-derived DNA from 71 patients with BCR-ABL-negative classic myeloproliferative neoplasms (MPNs): 32 primary myelofibrosis (PMF), 26 polycythemia vera (PV) and 13 essential thrombocythemia (ET). Copy number changes (CNCs) were detected in 44%, 35%, and 15% of the cases with PMF, PV and ET, respectively. In ET and PMF, CNCs were more frequently detected in the presence of JAK2V617F (50% vs. 19%; p =0.05). Conventional chromosome analysis was obtained in 57 patients either at diagnosis or within 1 year of the array CGH study; all 21 patients with PV and 11 with ET displayed normal cytogenetic findings despite the presence of CNCs in 29% and 18%, respectively. In PMF, the respective rates of CNCs and abnormal karyotype were 48% and 36%; karyotypic abnormalities, including unbalanced translocations, were often detected by array CGH as chromosomal gains or losses. This preliminary report suggests a potential value for array CGH in terms of both clinical diagnostics and genomic research in MPNs. [Copyright &y& Elsevier]

Objective: To examine applicability of the Carobbio algorithm in routine practice and its potential use in identifying among patients presenting with thrombocytosis and clinically suspected to have ET, those with early PMF or MPN-U. Methods: A retrospective Personal Practice Assessment Program was conducted at 8 Canadian institutions. Eight hematology/pathology pairs reviewed charts of about 20 consecutive examined patients who presented with thrombocytosis and suspected to have ET. The first 5 out of 20 cases who met the Carobbio algorithm were selected for BM evaluation. Results: A total of 122 patients with a clinical history indicative of ET were assessed. 48 met the criteria outlined in the Carobbio algorithm, Figure. The BM examination was performed on 33 patients. About one third of the 33 patients met the WHO classification for ET and one third for PMF. Conclusions: Despite its methodological limitations, this initiative confirms that in real world clinical practice the Carobbio algorithm can be used to identify possible cases of early PMF and MPN unclassifiable among patients clinically suspected to have ET. It suggests a need for educational initiatives on using diagnostic algorithms to separate ET from PMF and the importance of hematologist-pathologist collaboration in reaching a final integrated diagnosis. [ABSTRACT FROM AUTHOR]