Publications by authors named "Ayalew Tefferi"

674 Publications

Current Management of Chronic Neutrophilic Leukemia.

Curr Treat Options Oncol 2021 Jun 7;22(7):59. Epub 2021 Jun 7.

Department of Internal Medicine, Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.

Opinion Statement: Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) characterized by oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R). Due in large part to the rarity of the disease and dearth of clinical trials, there is currently no standard of care for CNL. Available therapies range from conventional oral chemotherapy to targeted JAK inhibitors to hematopoietic stem cell transplant (HSCT), the latter representing the only potentially curative modality. For this reason, coupled with CNL's typically aggressive clinical course, allogeneic HSCT remains the primary recommended therapy for eligible patients. For ineligible patients, a number of nontransplant therapies have been evaluated in limited trials. These agents may additionally be considered "bridging" therapies pre-transplant in order to control myeloproliferation and alleviate symptoms. Historically, the most commonly utilized first-line agent has been hydroxyurea, though most patients ultimately require second (or subsequent)-line therapy; still hydroxyurea remains the conventional frontline option. Dasatinib has demonstrated efficacy in vitro in cases of CSF3R terminal membrane truncation mutations and may cautiously be considered upfront in such instances, though no substantive studies have validated its efficacy in vivo. Numerous other chemotherapy agents, practically re-appropriated from the pharmaceutical arsenal of MPN, have been utilized in CNL and are typically reserved for second/subsequent-line settings; these include interferon-alpha (IFN-a), hypomethylating agents, thalidomide, cladribine, and imatinib, among others. Most recently, ruxolitinib, a JAK1/2 inhibitor targeting JAK-STAT signaling downstream from CSF3R, has emerged as a potentially promising new candidate for the treatment of CNL. Increasingly robust data support the clinical efficacy, with associated variable reductions in allele burden, and tolerability of ruxolitinib in patients with CNL, particularly those carrying the CSF3RT618I mutation. Similar to conventional nontransplant strategies, however, no disease-modifying or survival benefits have been demonstrated. While responses to JAK-STAT inhibition in CNL have not been uniform, data are sufficient to recommend consideration of ruxolitinib in the therapeutic repertory of CNL. There remains a major unmet need for prospective trials with investigational therapies in CNL.
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http://dx.doi.org/10.1007/s11864-021-00856-xDOI Listing
June 2021

JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views.

Leukemia 2021 May 21. Epub 2021 May 21.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit (Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). "Idiopathic erythrocytosis" loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.
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http://dx.doi.org/10.1038/s41375-021-01290-6DOI Listing
May 2021

New drugs for myeloid neoplasms with ring sideroblasts: Luspatercept vs imetelstat.

Authors:
Ayalew Tefferi

Am J Hematol 2021 07 3;96(7):761-763. Epub 2021 May 3.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1002/ajh.26197DOI Listing
July 2021

Venetoclax with azacitidine or decitabine in blast-phase myeloproliferative neoplasm: A multicenter series of 32 consecutive cases.

Am J Hematol 2021 07 6;96(7):781-789. Epub 2021 May 6.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) has now emerged as an effective treatment regimen for acute myeloid leukemia, in both de novo and relapsed/refractory setting. The current multicenter study retrospectively examined Ven + HMA treatment outcome among 32 patients (median age 69 years; 59% males) with blast-phase myeloproliferative neoplasm (MPN-BP). Pre-leukemic phenotype included essential thrombocythemia (ET)/post-ET myelofibrosis (34%), polycythemia vera (PV)/post-PV myelofibrosis (38%) and primary myelofibrosis (28%). Twenty-nine study patients were fully annotated cytogenetically and molecularly (NGS): 69% harbored complex karyotype and/or mutations, including TP53 (41%), IDH1/2 (21%), ASXL1 (21%), N/KRAS (14%), SRSF2 (10%), EZH2 (10%) and U2AF1 (7%). All patients received Ven combined with either azacitidine (n = 12) or decitabine (n = 20); either up front (n = 23) or after failing another induction therapy (n = 9). Complete remission with (CR) or without (CRi) count recovery was achieved in 14 (44%) patients and was more likely to occur in the absence of pre-leukemic PV/post-PV myelofibrosis phenotype (p < .01), complex karyotype (p < .01) or K/NRAS (p = .03) mutations; seven of eight patients (88%) without vs four of 21 (19%) with complex karyotype or K/NRAS mutation achieved CR/CRi (p < .01); all 11 informative patients with pre-leukemic PV/post-PV myelofibrosis phenotype displayed complex karyotype (p < .01). In contrast, neither TP53 (p = .45) nor IDH1/2 (p = .63) mutations affected response. Compared to historical controls treated with HMA alone (n = 26), the CR/CRi rate (44% vs 4%) and median survival (8 vs 5.5 months) were more favorable with Ven + HMA, but without significant difference in overall survival. Importantly, six patients with CR/CRi subsequently received allogeneic hematopoietic stem cell transplant (AHSCT). Note, Ven + HMA produces robust CR/CRi rates in MPN-BP, especially in the absence of RAS mutations and complex karyotype, thus enabling AHSCT, in some patients.
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http://dx.doi.org/10.1002/ajh.26186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251544PMC
July 2021

Development and application of novel immunoassays for eosinophil granule major basic proteins to evaluate eosinophilia and myeloproliferative disorders.

J Immunol Methods 2021 Jun 6;493:113015. Epub 2021 Mar 6.

Division of Allergic Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, United States of America; Departments of Dermatology and Medicine, University of Utah, Salt Lake City, UT, United States of America.

Background: During eosinophil differentiation, the granule eosinophil major basic protein 1 (eMBP1) is synthesized as a 32-kDa precursor form, referred to as proMBP1, which is processed into the 14-kDa mature form of eMBP1. The prevalence of these two forms of MBP1 in most pathological conditions remains unknown.

Objective: To develop the immunoassays that differentiate mature eMBP1 and proMBP1 and apply them to analyze their levels in biological fluids from patients with eosinophilia and hematologic disorders.

Methods: We produced a series of monoclonal antibodies and selected pairs capable of discriminating between the two molecular forms of eMBP1. Radioimmunoassay (RIA) was performed to simultaneously quantitate the levels of mature eMBP1 and proMBP1 in secretions from patients with chronic rhinosinusitis (CRS) and sera from patients with hypereosinophilic syndrome (HES) and other myeloproliferative disorders.

Results: The novel immunoassays possessed less than 1% crossreactivity between mature eMBP1 and proMBP1. Mature eMBP1, but not proMBP1, was found in nasal secretions of CRS patients. In contrast, elevated serum levels of mature eMBP1 and proMBP1 were observed in approximately 60% and 90% of HES patients, respectively, with proMBP1 present in greater quantities than mature eMBP1. Patients with several myeloproliferative disorders also showed high serum levels of proMBP1 while mature eMBP1 remained at basal levels.

Conclusion: The novel immunoassays successfully differentiated mature eMBP1 and proMBP1 in human biological fluids. Further studies addressing the clinical correlates of these assays will help to develop biomarkers to diagnose and monitor patients with eosinophilia and myeloproliferative disorders.
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http://dx.doi.org/10.1016/j.jim.2021.113015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107142PMC
June 2021

Mayo Clinic experience with 1123 adults with acute myeloid leukemia.

Blood Cancer J 2021 Mar 2;11(3):46. Epub 2021 Mar 2.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Between 2004 and 2017, a total of 1123 adult patients (median age 65 years; 61% males) with newly diagnosed acute myeloid leukemia (AML), not including acute promyelocytic leukemia, were seen at the Mayo Clinic. Treatment included intensive (n = 766) or lower intensity (n = 144) chemotherapy or supportive care (n = 213), with respective median survivals of 22, 9, and 2 months (p < 0.01). Intensive chemotherapy resulted in complete remission (CR) and CR with incomplete count recovery (CRi) rates of 44 and 33%, respectively, with no difference in survival outcome between the two (p = 0.4). Allogeneic hematopoietic stem cell transplant (AHSCT) was documented in 259 patients and provided the best survival rate (median 55 months; p < 0.01). After a median follow-up of 13 months, 841 (75%) deaths were recorded. Multivariate analysis identified age >60 years (HR 2.2, 1.9-2.6), adverse karyotype (HR 2.9, 1.9-4.9), intermediate-risk karyotype (HR 1.6, 1.02-2.6), post-myeloproliferative neoplasm AML (HR 1.9, 1.5-2.4), and other secondary AML (HR 1.3 (1.1-1.6) as risk factors for shortened survival. These risk factors retained their significance after inclusion of FLT3/NPM1 mutational status in 392 informative cases: FLT3+NPM1- (HR 2.8, 1.4-5.6), FLT3+/NPM+ (HR 2.6 (1.3-5.2), and FLT3-NPM1- (HR 1.8, 1.0-3.0).
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http://dx.doi.org/10.1038/s41408-021-00435-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925511PMC
March 2021

Extreme thrombocytosis in low-risk essential thrombocythemia: Retrospective review of vascular events and treatment strategies.

Am J Hematol 2021 06 11;96(6):E182-E184. Epub 2021 Mar 11.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1002/ajh.26137DOI Listing
June 2021

LKB1/ Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms.

Cancer Discov 2021 Jun 12;11(6):1398-1410. Epub 2021 Feb 12.

Northwestern University, Chicago, Illinois.

The myeloproliferative neoplasms (MPN) frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/ led to enhanced self-renewal of murine MPN cells. Deletion of in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis, and an accumulation of immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells . LKB1 loss was associated with increased mitochondrial reactive oxygen species and stabilization of HIF1α, and downregulation of LKB1 and increased levels of HIF1α were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that is a tumor suppressor in the MPNs. SIGNIFICANCE: Progression of the myeloproliferative neoplasms to acute myeloid leukemia occurs in a substantial number of cases, but the genetic basis has been unclear. We discovered that loss of LKB1/ leads to stabilization of HIF1a and promotes disease progression. This observation provides a potential therapeutic avenue for targeting progression..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178182PMC
June 2021

Young platelet millionaires with essential thrombocythemia.

Am J Hematol 2021 04 18;96(4):E93-E95. Epub 2021 Feb 18.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1002/ajh.26114DOI Listing
April 2021

The Impact of Obesity on the Outcomes of Adult Patients with Acute Lymphoblastic Leukemia - A Single Center Retrospective Study.

Blood Lymphat Cancer 2021 22;11:1-9. Epub 2021 Jan 22.

Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Introduction: Obesity is a worldwide problem that is related to cardiac disease, thrombosis and cancer. However, little is known about the impact of obesity on the outcomes of adult acute lymphoblastic leukemia (ALL) patients.

Methods: We retrospectively evaluated a cohort of 154 newly diagnosed adult ALL patients between 1994 and 2011 at Mayo Clinic (Rochester). According to the World Health Organization (WHO) international BMI classification, patients were stratified as underweight, normal weight, overweight, and obese. For some analyses, patients were also stratified according to a two-sided non-obese or obese classification.

Results: The median follow-up time was 8.37 years. Obese patients were more likely to be women (p=0.024) and ≥60 years old (p=0.003). Five-year mortality rates were higher in obese patients than non-obese [HR 95% CI: 1.60 (1.03-2.50) p=0.035]. This was also the case in subgroup analysis among T-cell patients although the number of patients was small [HR 95% CI: 5.42 (1.84-15.98) p<0.001]. There was no difference in mortality among the B-cell patients. After adjusting for baseline variables, the difference in mortality remained in several models. There was no difference in EFS or cumulative incidence of relapse rates between obese and non-obese patients among the overall population.

Discussion: In conclusion, our study suggests that adult ALL patients with obesity have lower survival rates, especially in T-cell ALL.
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http://dx.doi.org/10.2147/BLCTT.S269748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837742PMC
January 2021

Myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T) - "2021 update on diagnosis, risk-stratification, and management".

Am J Hematol 2021 03 28;96(3):379-394. Epub 2021 Jan 28.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Disease Overview: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).

Diagnosis: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (MDS-RS-SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10 /L and large atypical megakaryocytes.

Mutations And Karyotype: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both.

Risk Stratification: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation.

Treatment: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first-in-class erythroid maturation agent is now approved for the management of anemia in patients with MDS-RS and MDS/MPN-RS-T. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains to be defined.
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http://dx.doi.org/10.1002/ajh.26090DOI Listing
March 2021

Myeloproliferative neoplasms and pregnancy: Overview and practice recommendations.

Am J Hematol 2021 03 28;96(3):354-366. Epub 2020 Dec 28.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy-associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low-risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions.
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http://dx.doi.org/10.1002/ajh.26067DOI Listing
March 2021

Venetoclax-based chemotherapy in acute and chronic myeloid neoplasms: literature survey and practice points.

Blood Cancer J 2020 11 23;10(11):122. Epub 2020 Nov 23.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Venetoclax (VEN), a small-molecule inhibitor of B cell leukemia/lymphoma-2, is now FDA approved (November 2018) for use in acute myeloid leukemia (AML), specific to newly diagnosed elderly or unfit patients, in combination with a hypomethylating agent (HMA; including azacitidine or decitabine) or low-dose cytarabine. A recent phase-3 study compared VEN combined with either azacitidine or placebo, in the aforementioned study population; the complete remission (CR) and CR with incomplete count recovery (CRi) rates were 28.3% and 66.4%, respectively, and an improvement in overall survival was also demonstrated. VEN-based chemotherapy has also shown activity in relapsed/refractory AML (CR/CRi rates of 33-46%), high-risk myelodysplastic syndromes (CR 39% in treatment naïve, 5-14% in HMA failure), and blast-phase myeloproliferative neoplasm (CR 25%); in all instances, an additional fraction of patients met less stringent criteria for overall response. Regardless, venetoclax-induced remissions were often short-lived (less than a year) but long enough to allow some patients transition to allogeneic stem cell transplant. Herein, we review the current literature on the use of VEN-based combination therapy in both acute and chronic myeloid malignancies and also provide an outline of procedures we follow at our institution for drug administration, monitoring of adverse events and dose adjustments.
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http://dx.doi.org/10.1038/s41408-020-00388-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684277PMC
November 2020

Primary myelofibrosis: 2021 update on diagnosis, risk-stratification and management.

Authors:
Ayalew Tefferi

Am J Hematol 2021 01 2;96(1):145-162. Epub 2020 Dec 2.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Disease Overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations. Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.

Diagnosis: Bone marrow morphology is the primary basis for diagnosis. Presence of JAK2, CALR, or MPL mutation, expected in around 90% of the patients, is supportive but not essential for diagnosis; these mutations are also prevalent in the closely related MPNs, namely polycythemia vera (PV) and essential thrombocythemia (ET). The 2016 World Health Organization classification system distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic ET in its presentation. Furthermore, approximately 15% of patients with ET or PV might progress into a PMF-like phenotype (post-ET/PV MF) during their clinical course.

Adverse Mutations: SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors. RAS/CBL mutations predicted resistance to ruxolitinib therapy.

Adverse Karyotype: Very high risk abnormalities include -7, inv (3), i(17q), +21, +19, 12p-, and 11q-.

Risk Stratification: Two new prognostic systems for PMF have recently been introduced: GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation- and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype. MIPSSv2 includes, in addition, clinical risk factors. GIPSS features four and MIPSSv2 five risk categories.

Risk-adapted Therapy: Observation alone is advised for MIPSSv2 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment for "very high" and "high" risk disease (estimated 10-year survival 0%-13%); treatment-requiring patients with intermediate-risk disease (estimated 10-year survival 30%) are best served by participating in clinical trials. In non-transplant candidates, conventional treatment for anemia includes androgens, prednisone, thalidomide, and danazol; for symptomatic splenomegaly, hydroxyurea and ruxolitinib; and for constitutional symptoms, ruxolitinib. Fedratinib, another JAK2 inhibitor, has now been FDA-approved for use in ruxolitinib failures. Splenectomy is considered for drug-refractory splenomegaly and involved field radiotherapy for non-hepatosplenic EMH and extremity bone pain.

New Directions: A number of new agents, alone or in combination with ruxolitinib, are currently under investigation for MF treatment (ClinicalTrials.gov); preliminary results from some of these clinical trials were presented at the 2020 ASH annual meeting and highlighted in the current document.
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http://dx.doi.org/10.1002/ajh.26050DOI Listing
January 2021

A multistate model of survival prediction and event monitoring in prefibrotic myelofibrosis.

Blood Cancer J 2020 10 14;10(10):100. Epub 2020 Oct 14.

FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy.

Among 382 patients with WHO-defined prefibrotic myelofibrosis (pre-PMF) followed for a median of 6.9 years, fibrotic or leukemic transformation or death accounts for 15, 7, and 27% of cases, respectively. A multistate model was applied to analyze survival data taking into account intermediate states that are part of the clinical course of pre-PMF, including overt PMF and acute myeloid leukemia (AML). Within this multistate framework, multivariable models disclosed older age (>65 years) and leukocytosis (>15 × 10/L) as predictors of death and leukemic transformation. The risk factors for fibrotic progression included anemia and grade 1 bone marrow fibrosis. The outcome was further affected by high molecular risk (HMR) but not driver mutations. Direct transition to overt PMF, AML, or death occurred in 15.2, 4.7, and 17.3% of patients, respectively. The risk of AML was the highest in the first 5 years (7%), but leveled off thereafter. Conversely, the probability of death from overt PMF or AML increased more rapidly over time, especially when compared to death in the pre-PMF state without disease progression. The probability of being alive with pre-PMF status decreased to 70 and 30% at 10 and 20 years, respectively. This study highlights the aspects of the clinical course and estimates of disease progression in pre-PMF.
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http://dx.doi.org/10.1038/s41408-020-00368-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566465PMC
October 2020

Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management.

Am J Hematol 2020 12 23;95(12):1599-1613. Epub 2020 Oct 23.

Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy.

Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus and risk of leukemic or fibrotic transformation.

Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR or MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis.

Survival: Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV.

Thrombosis Risk: In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation).

Risk-adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily or twice-daily aspirin (81 mg), in the absence of contraindications. Very low risk ET might not require therapy while aspirin therapy is advised for low risk disease. Cytoreductive therapy is recommended for high-risk ET and PV, but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.

New Treatment Directions: Controlled studies are needed to confirm the clinical outcome value of twice-daily vs once-daily aspirin dosing and the therapeutic role of pegylated interferons and direct oral anticoagulants.
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http://dx.doi.org/10.1002/ajh.26008DOI Listing
December 2020