Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia.

Selinexor, an oral inhibitor of the nuclear transport protein Exportin-1, shows promising single-agent activity in clinical trials of relapsed/refractory (R/R) acute myeloid leukemia (AML) and preclinical synergy with topoisomerase (topo) IIα inhibitors. We conducted a phase 1, dose-escalation study of selinexor with mitoxantrone, etoposide, and cytarabine (MEC) in 23 patients aged < 60 years with R/R AML. Due to dose-limiting hyponatremia in 2 patients on dose level 2 (selinexor 40 mg/m2), the maximum tolerated dose was 30 mg/m2. The most common grade ≥ 3 treatment-related non-hematologic toxicities were febrile neutropenia, catheter-related infections, diarrhea, hyponatremia, and sepsis. The overall response rate was 43% with 6 patients (26%) achieving complete remission (CR), 2 (9%) with CR with incomplete count recovery, and 2 (9%) with a morphologic leukemia-free state. Seven of 10 responders proceeded to allogeneic stem cell transplantation. The combination of selinexor with MEC is a feasibile treatment option for patients with R/R AML.

SWOG 1318: A Phase II Trial of Blinatumomab Followed by POMP Maintenance in Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

PURPOSE: Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS: Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome-negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS: Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION: Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome-negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

A phase 2a, single-arm, open-label study of tafasitamab, a humanized, Fc-modified, anti-CD19 antibody, in patients with relapsed/refractory B-precursor cell acute lymphoblastic leukemia.

BACKGROUND: B-precursor cell acute lymphoblastic leukemia (B-ALL) in adults is an aggressive and challenging condition, and patients with relapsed/refractory (R/R) disease after allogeneic stem cell transplantation (SCT), or noncandidates for SCT, have a particularly poor prognosis. The authors investigated the activity of the Fc-modified anti-CD19 antibody tafasitamab in adults with R/R B-ALL (NCT01685021). METHODS: Adults with R/R B-ALL received single-agent tafasitamab 12 mg/kg weekly for up to four 28-day cycles. Patients with complete remission (with or without neutrophil/platelet recovery; complete remission [CR] or complete remission with incomplete count recovery [CRi]) after cycles 2, 3, or 4 could continue tafasitamab every 2 weeks for up to 3 further months. The primary end point was overall response rate (ORR). RESULTS: Twenty-two patients were treated (median, 2 prior lines of therapy; range, 1-8). Six patients completed 2 cycles, and 2 of these patients responded for an ORR of 9%; 16 patients (73%) progressed before their first response assessment. Responses lasted 8 and 4 weeks in the 2 patients with CR and minimal residual disease (MRD)-negative CRi, respectively. Tafasitamab produced rapid B-cell/blast depletion in 21 of 22 patients within 1 to 2 weeks of first administration. Tafasitamab was well tolerated, with the most frequent adverse events being infusion-related reactions (59.1%) and fatigue (40.9%). Grade 3 to 4 febrile neutropenia (22.7%) was the most common hematologic adverse event. CONCLUSIONS: Tafasitamab monotherapy was associated with clinical activity in a subset of patients with R/R B-ALL, including short-lasting CR and MRD-negative CRi. Given its favorable tolerability profile, further development of tafasitamab in chemoimmunotherapy combinations and MRD settings should be explored.

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

Adherence trajectories in oral therapy for chronic myeloid leukemia: Overview of a research protocol.

Over a quarter of chemotherapy regimens now include oral agents. Individuals living with cancer are now responsible for administering this lifesaving therapy at home by taking every dose as prescribed. One type of oral chemotherapy, tyrosine kinase inhibitors (TKIs), is the current recommended treatment for chronic myeloid leukemia. This targeted therapy has markedly improved survival but comes with significant side effects and financial costs. In the study described in this protocol, the investigators seek to understand the dynamic nature of TKI adherence experienced by individuals diagnosed with CML. Using a mixed-method approach in this prospective observational study, funded by the National Cancer Institute, we seek to describe subjects' adherence trajectories over 1 year. We aim to characterize adherence trajectories in individuals taking TKIs using model-based cluster analysis. Next, we will determine how side effects and financial toxicity influence adherence trajectories. Then we will examine the influence of TKI adherence trajectories on disease outcomes. Additionally, we will explore the experience of patients taking TKIs by interviewing a subset of participants in different adherence trajectories. The projected sample includes 120 individuals taking TKIs who we will assess monthly for 12 months, measuring adherence with an objective measure (Medication Event Monitoring System). Identifying differential trajectories of adherence for TKIs is important for detecting subgroups at the highest risk of nonadherence and will support designing targeted interventions. Results from this study can potentially translate to other oral agents to improve care across different types of cancer.

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level -1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m2 cytarabine D5-8, and 8 mg/m2 idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials.gov identifier: NCT01132586).

Phase I study of AR-42 and decitabine in acute myeloid leukemia.

This phase I trial sought to determine a biologically safe and effective dose of AR-42, a novel histone deacetylase inhibitor, which would lead to a doubling of miR-29b prior to decitabine administration. Thirteen patients with previously untreated or relapsed/refractory AML were treated at 3 dose levels (DL): AR-42 20 mg qd on d1,3,5 in DL1, 40 mg qd on d1,3,5 in DL2 and 40 mg qd on d1,3,4,5 in DL3. Patients received decitabine 20 mg/m2 on d6-15 of each induction cycle and 20 mg/m2 on d6-10 of each maintenance cycle. One DLT of polymicrobial sepsis and multi-organ failure occurred at DL3. Two patients achieved a CRi and one patient achieved a CR for an ORR of 23.1%. The higher risk features of this patient population and the dosing schedule of AR-42 may have led to the observed clinical response and failure to meet the biologic endpoint.

Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study.

Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m2, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m2) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.

Preclinical activity and a pilot phase I study of pacritinib, an oral JAK2/FLT3 inhibitor, and chemotherapy in FLT3-ITD-positive AML.

Activating FLT3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) associate with inferior outcomes. We determined that pacritinib, a JAK2/FLT3 inhibitor, has in vitro activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Therefore, we conducted a phase I study of pacritinib in combination with chemotherapy in AML patients with FLT3 mutations to determine the pharmacokinetics and preliminary toxicity and clinical activity. Pacritinib was administered at a dose of 100 mg or 200 mg twice daily following a 3 + 3 dose-escalation in combination with cytarabine and daunorubicin (cohort A) or with decitabine induction (cohort B). A total of thirteen patients were enrolled (five in cohort A; eight in cohort B). Dose limiting toxicities include hemolytic anemia and grade 3 QTc prolongation in two patients who received 100 mg. Complete remission was achieved in two patients in cohort A, one of whom had a minor D835Y clone at baseline. One patient in cohort B achieved morphologic leukemia free state. Seven patients (two in cohort A; five in cohort B) had stable disease. In conclusion, pacritinib, an inhibitor of FLT3-ITD and resistant-conferring TKD mutations, was well tolerated and demonstrated preliminary anti-leukemic activity in combination with chemotherapy in patients with FLT3 mutations.

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Ruxolitinib Therapy Followed by Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study.

We evaluated the feasibility of ruxolitinib therapy followed by a reduced-intensity conditioning (RIC) regimen for patients with myelofibrosis (MF) undergoing transplantation in a 2-stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and nonrelapse mortality (NRM) compared with data from the previous Myeloproliferative Disorders Research Consortium 101 Study. The plan was to enroll 11 patients each in related donor (RD) and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) occurred in the RD arm or ≥6 failures occurred in the URD. A total of 21 patients were enrolled, including 7 in the RD arm and 14 in the URD arm. The RD arm did not meet the predetermined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated owing to poor accrual and a significant number of failures. In all 19 transplant recipients, ruxolitinib was tapered successfully without significant side effects, and 9 patients (47%) had a significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute graft-versus-host disease (GVHD), and chronic GVHD at 24 months were 16%, 28%, 64%, and 76%, respectively. On an intention-to-treat basis, the 2-year overall survival was 61% for the RD arm and 70% for the URD arm. Ruxolitinib can be integrated as pretransplantation treatment for patients with MF, and a tapering strategy before transplantation is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant.

Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the second most common type of leukemia in adults. Incidence of AML increases with age with a peak incidence at 67 years. Patients older than 60 years have an unfavorable prognosis due to resistance to conventional chemotherapy. Volasertib (BI 6727) is a cell-cycle regulator targeting polo-like kinase which has been evaluated in clinical trials in AML. We evaluated effects of volasertib in primary patient samples and NK cells. At equivalent doses, volasertib is cytotoxic to AML blasts but largely spares healthy NK cells. We then evaluated the effect of volasertib treatment in combination with BI 836858 on primary AML blast samples using antibody-dependent cellular cytotoxicity (ADCC) assays. Volasertib treatment of NK cells did not impair NK function as evidenced by comparable levels of BI 836858 mediated ADCC in both volasertib-treated and control-treated NK cells. In summary, volasertib is cytotoxic to AML blasts while sparing NK cell viability and function. Higher BI 836858 mediated ADCC was observed in patient samples pretreated with volasertib. These findings provide a strong rationale to test combination of BI 836858 and volasertib in AML.

A novel regimen for relapsed/refractory adult acute myeloid leukemia using a KMT2A partial tandem duplication targeted therapy: results of phase 1 study NCI 8485.

KMT2A partial tandem duplication occurs in approximately 5-10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1-10 and vorinostat 400 milligrams daily on days 5-10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).

Psychosocial risk predicts high readmission rates for hematopoietic cell transplant recipients.

Hematopoietic cell transplantation (HCT) is an intensive treatment resulting in disease control however subsequent psychosocial distress is common. Screening for psychosocial risk factors that contribute to morbidity is underutilized; moreover, the value in screening is uncertain. We performed a retrospective study of 395 HCT patients who were screened for psychosocial risk using the Transplant Evaluation Rating Scale (TERS). Patients were classified by psychosocial risk as no-risk (TERS = 26.5, 52%) vs. at-risk (TERS > 26.5, 48%), with at-risk patients stratified by cumulative deficits into mild risk (TERS = 27-35.5, 39%) and moderate risk (TERS > 35.5, 9%). At-risk patients were more likely to be readmitted within 90 days (mild risk HR = 1.62, p = 0.02; moderate risk HR = 2.50, p = 0.002). Prior psychiatric history (HR = 1.81, p = 0.002) and poor coping skills (HR = 1.64, p = 0.04) also influenced readmission. At-risk patients were more likely to be readmitted for infection (no-risk = 12% vs. at-risk = 25%, p = 0.002). Pre-HCT screening with the TERS did not predict survival or length of stay although at-risk patients are at a heighted risk of readmission. Implementing strategies to reduce readmission in higher risk patients is warranted.

NCCN Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2017.

The prognosis for patients with newly diagnosed acute lymphoblastic leukemia (ALL) has improved with the use of more intensive chemotherapy regimens, tyrosine kinase inhibitors, targeted agents, and allogeneic hematopoietic cell transplantation. However, the management of relapsed or refractory (R/R) ALL remains challenging and prognosis is poor. The NCCN Guidelines for ALL provide recommendations on standard treatment approaches based on current evidence. These NCCN Guidelines Insights summarize treatment recommendations for R/R ALL and highlight important updates, and provide a summary of the panel's discussion and underlying data supporting the most recent recommendations for R/R ALL management.

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.

BACKGROUND: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).

The Effect of Aromatherapy on Insomnia and Other Common Symptoms Among Patients With Acute Leukemia

Purpose/Objectives: To determine if the use of aromatherapy improves insomnia and other common symptoms in hospitalized patients with newly diagnosed acute leukemia. Design: A randomized, crossover, washout trial. Setting: An inpatient acute leukemia unit at the Arthur G. James Cancer Hospital and Richard L. Solove Research Institute of the Wexner Medical Center at Ohio State University in Columbus. Sample: 50 patients who were newly diagnosed with acute leukemia and hospitalized to receive their initial four weeks of intensive induction chemotherapy. Methods: Patients were offered a choice of three scents to be used during the trial: lavender, peppermint, or chamomile. Each patient was randomized to receive either the chosen aromatherapy intervention or a placebo intervention during alternate weeks, with a washout period in between. Sleep quality and other common symptoms were measured. Main Research Variables: Aromatherapy, sleep, insomnia, pain, tiredness, drowsiness, nausea, lack of appetite, shortness of breath, depression, anxiety, and well-being. Findings: Most patients reported poor quality sleep at baseline, but aromatherapy had a statistically significant positive impact. Improvements were noted in tiredness, drowsiness, lack of appetite, depression, anxiety, and well-being because of aromatherapy. Conclusions: Aromatherapy is a viable intervention for improving insomnia and other symptoms commonly experienced by patients with acute leukemia. Implications for Nursing: Oncology nurses can employ aromatherapy safely and inexpensively, and with minimal training, as an effective tool in decreasing many symptoms that plague patients with leukemia. Patients can exercise a greater sense of control over their treatment environments through the use of aromatherapy.

Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.