A Review of Selected Presentations From the 2016 American Society of Hematology Annual Meeting and Exposition
December 3-6, 2016 • San Diego, California

PLUS Meeting Abstract Summaries

With Expert Commentary by:

Ruben A. Mesa, MD
Consultant Hematologist
Chair, Division of Hematology & Medical Oncology
Deputy Director, Mayo Clinic Cancer Center
Chair, Arizona Cancer Coalition
Professor of Medicine
Scottsdale, Arizona

A Pooled Overall Survival (OS) Analysis of 5-Year Data From the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF)

Ruxolitinib is a selective Janus kinase (JAK) 1 and 2 inhibitor approved for the treatment of patients with intermediate-risk or high-risk mye-lofibrosis (MF).¹ Ruxolitinib was approved based on results from the phase 3 COMFORT studies (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment), which enrolled patients with intermediate-2 or high-risk primary MF, post–polycythemia vera MF (PPV-MF), or post–essential thrombocythemia MF (PET-MF), with risk determined by the International Prognostic Scoring System (IPSS).^2,3 The comparator arm was placebo in the double-blind COMFORT-I study and best available therapy in the COMFORT-II study. In both studies, the ruxolitinib starting dose was 15 mg twice daily for patients with platelet counts of 100 to 200 × 10⁹/L or 20 mg twice daily for patients with platelet counts greater than 200 × 10⁹/L. Dose modifications were permitted for safety and efficacy. Patients were allowed to cross over from the control arm to the ruxolitinib arm in the case of progressive splenomegaly (which was defined as a spleen volume increase of 25% or greater relative to baseline in COMFORT-I or relative to study nadir in COMFORT-II) or the occurrence of other protocol-defined pro-gression events. In COMFORT-I, crossover was man-datory for patients receiving placebo following unblinding of treat-ment. In both studies, overall survival (OS) was a sec-ondary endpoint and evaluated based on intent-to-treat analysis. The studies showed that ruxolitinib treatment reduced spleen size, improved disease-related symptoms and quality of life, and yielded a superior OS.

Five-year data from COMFORT-I and COMFORT-II were pooled for an exploratory evaluation of long-term OS in patients from the 2 studies.⁴ COMFORT-I randomly assigned 155 patients to ruxolitinib and 154 to placebo.² COMFORT-II randomly assigned 146 patients to ruxolitinib and 73 to best available therapy.³ At 3 years’ follow-up, all remaining patients had crossed over from the control arm and were receiving treatment with ruxolitinib.

In the pooled ruxolitinib group, 162 patients (53.8%) had high-risk MF and 139 (46.2%) had intermediate-2 risk. After 5 years of follow-up, 128 patients (42.5%) had died in the ruxolitinib group compared with 117 (51.5%) in the control group. Median OS was 63.5 months with ruxolitinib vs 45.9 months in the control group, and ruxolitinib was associated with a 30% reduction in the risk of death (0.70; 95% CI, 0.54-0.91; P=.0065). After using rank-preserving structural failure time analysis to correct for the effect of crossover, median OS was 63.5 months with ruxolitinib vs 27.0 months in the control group (HR, 0.35; 95% CI, 0.23-0.59; Figure 1). An analysis that censored patients at the time of crossover also demonstrated a prolonged OS in patients treated with ruxolitinib (median OS, 63.5 months vs 28.3 months; HR, 0.53; 95% CI, 0.36-0.78; P=.0013). Among all patients treated with ruxolitinib, those with lower-risk disease demonstrated an OS that was not reached and was estimated at 102 months, whereas patients with high-risk disease demonstrated an OS of 50 months (HR, 2.86; 95% CI, 1.95-4.20; P<.0001). In the subgroup of patients with primary MF who were originally randomly assigned to ruxolitinib, median OS was significantly prolonged in patients with intermediate-2 risk vs those with high risk (HR, 2.55; 95% CI, 1.52-4.28; P=.0003).

After 5 years of follow-up, the analysis also demonstrated improved survival with ruxolitinib compared with historic controls. In patients with intermediate-2 primary MF, the estimated median OS was 5.8 years, with a lower 95% CI limit of 5.0 years compared with 4.0 years for historic controls. Among patients with high-risk primary MF, the median OS of historic controls was 2.3 years, and was estimated to be 2.8 years in ruxolitinib-treated patients, with a 95% CI lower limit of 2.5 years. Subgroup analyses exhibited a benefit with ruxolitinib regardless of the patients’ age, sex, disease type, risk status, JAK2 V617F mutation status, baseline spleen volume, anemic status, white blood cell count, or platelet count.

References

1. Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2016.

2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

3. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.

4. Verstovsek S, Gupta V, Gotlib J, et al. A pooled overall survival (OS) analysis of 5-year data from the COMFORT-I and COMFORT-II trials of ruxolitinib for the treatment of myelofibrosis (MF) [ASH abstract 3110]. Blood. 2016;128(suppl 22).

Final Results From PROUD-PV, A Randomized Controlled Phase 3 Trial Comparing Ropeginterferon Alfa-2b to Hydroxyurea in Polycythemia Vera Patients

In a phase 2 trial of patients with polycythemia vera (PV) reported in 2008, pegylated interferon α-2a demonstrated nor-m-alization of
myeloproliferation, red-uc-tion of vascular events, and a large decrease in cells harboring the JAK2 V617F mutation.¹ However, interferon is associated with toxicities, including flu-like symptoms, depression, and autoimmune events, resulting in discontinuation rates of approximately 25%.² Ropeginterferon α-2b is a novel isoform with a single polyethylene glycol moiety bound to a specific site on the interferon molecule. The monopegylated molecule has a longer half-life than unmodified interferon α and is administered once every 14 days, followed by once-per-month admin-istration for maintenance. In a phase 2 study, ropeginterferon α-2b yielded an objective response rate (ORR) of 90%, including a complete response (CR) rate of 47% and a partial response (PR) rate of 43%.³ Most patients experienced a reduction in spleen size. Complete molecular remissions were observed in approximately 20% of patients, although they typically occurred after several months of treatment.

The multicenter parallel-group phase 3 PROUD-PV study (Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera) evaluated ropeginterferon α-2b vs hydroxyurea in patients with PV.⁴ The study’s primary objective was demonstration of noninferiority of ropeginterferon α-2b compared with hydroxyurea based on the hematologic CR rate at 12 months of therapy. The noninferiority endpoint was chosen based on the relatively slow development of complete molecular remissions with ropeginterferon α-2b. Hematologic CR was defined as normal hematocrit, leukocyte and platelet counts, no need for phlebotomy in the preceding 3 months, and normal spleen size by central magnetic resonance imaging. Secondary objectives included res-ponse rates, individual response variables over time, rates of partial and complete molecular response, disease-related symptoms, quality of life, and adverse events (AEs). Enrolled patients had a diagnosis of PV based on World Health Organization 2008 criteria.⁵ Patients were treatment-naive and in need of cytoreduction, or they had received prior hydroxyurea and were not intolerant to treatment and did not achieve a CR. Patients with prior exposure to interferon-α were excluded, as were those with clinically relevant auto-immune disease or depression.

The 254 patients were randomly assigned to the 2 treatment arms. Baseline characteristics were well-balanced between the 2 arms. Patients had a median age of 60 years (range, 21-85 years), and 53% were female. Thirty-seven percent of patients had previously received hydroxyurea treat-ment. The median spleen length was 13.1 cm (range, 7.0-25.0 cm). Spleen size was normal or slightly enlarged in 90% of patients. In the ropeginterferon α-2b arm, the median plateau dose was 450 µg, which was reached from week 28. Dose reduction owing to an AE occurred in 25.2% of patients, and the 12-month discontinuation rate was 16.5%. In the hydroxyurea arm, the median plateau dose was 1250 mg, which was reached from week 8. Dose reduction owing to an AE occurred in 51.2% of patients, and the 12-month discontinuation rate was 12.6%.

Based on intent-to-treat analysis, the trial demonstrated noninferiority of ropeginterferon α-2b compared with hydroxyurea (P=.0028). The hem-a-tologic CR rate after 12 months was 43.1% with ropeginterferon α-2b vs 45.6% with hydroxyurea (Figure 2). The per-protocol analysis yielded similar results, with 12-month hem-atologic CR rates of 44.3% for ropeginterferon α-2b vs 46.5% for hydroxyurea (P=.0036). Spleen length was normal or close to normal in most patients at baseline, so the proportion of patients demonstrating normal spleen size after 12 months of treatment was not clinically relevant. Preliminary data in patients with 21 months of treatment demonstrated a higher rate of hematologic CRs with ropeginterferon α-2b vs hydroxyurea, underscoring the slow-acting nature of ropeginterferon α-2b treatment.

Ropeginterferon α-2b showed a superior safety profile vs hydroxyurea (Table 1). AEs of any grade were reported in 81.9% of the ropeginterferon α-2b group vs 87.4% of the hydroxyurea group. A treatment-related AE occurred in 59.6% vs 75.6%, respectively. A grade 3 AE occurred in 16.5% vs 20.5% of patients, respectively. No grade 3 AEs were observed in more than 10% of patients in either arm.

References

1. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072.

2. Gisslinger H, Gilly B, Woloszczuk W, et al. Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinant interferon-alpha. Clin Exp Immunol. 1992;90(3):363-367.

3. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, et al. Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015;126(15):
1762-1769.

4. Gisslinger H, Klade C, Georgiev P, et al. Final results from PROUD-PV a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients [ASH abstract 475]. Blood. 2016;128(suppl 22).

5. Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Curr Hematol Malig Rep. 2009;4(1):33-40.

Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients With Myelofibrosis (MF) Enrolled in the COMFORT-I Study

The phase 3 COMFORT-I and COMFORT-II studies showed that ruxolitinib improves splenomegaly, constitutional symptoms, and OS in patients with MF.^1,2 Retrospective studies suggest that ruxolitinib may improve or stabilize bone marrow fibrosis by decreasing cellularity; reducing the population of plasma cells, macrophages, and megakaryocytes; and correcting megakaryocytic atypia.^3,4

A study of data from the COMFORT-I trial was conducted to assess changes in bone marrow fibrosis with long-term ruxolitinib use in patients with MF.⁵ COMFORT-I enrolled patients with intermediate-2 or high-risk primary MF, PPV-MF, or PET-MF. All patients had palpable splenomegaly. Crossover from the placebo arm to the ruxolitinib arm was permitted prior to study unblinding for patients with worsening of splenomegaly or splenic pain despite narcotic treatment. Bone marrow biopsies were obtained at baseline, at weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years during treatment with ruxolitinib. Biopsies were reviewed independently in a blinded manner by 3 hematopathologists, with final grading based on consensus. There were 3 patient subgroups: 36 patients randomly assigned to ruxolitinib; 15 patients randomly assigned to placebo, with bone marrow measurements available from baseline and week 48; and 21 patients who crossed over to ruxolitinib, with bone marrow measurements available at baseline plus at least 1 postbaseline measurement available after crossover. Change in bone marrow fibrosis grade from baseline was measured as improved (-3 to -1), stable (0), or worsened (1 to 3). Baseline characteristics were generally well-balanced among the 3 groups. Mean exposure to ruxolitinib was 136.0 ± 67.4 weeks in the ruxolitinib group and 129.1 ± 67.7 weeks in the crossover group.

All patients had baseline bone marrow biopsy data and corresponding sequential assessments. From baseline to week 48, bone marrow fibrosis grade improved for 7 of 30 patients randomly assigned to ruxolitinib (23%) and for 2 of 15 patients randomly assigned to placebo (13%; Figure 3). Among the 57 patients who received ruxolitinib, a significant shift toward improvement of bone marrow fibrosis grade was observed from baseline to the last evaluation of bone marrow fibrosis (P=.0119). Thirty-three percent of the patients with ruxolitinib exposure experienced an improvement in fibrosis, including 11 with improvement in -1 grade (19%), 7 with improvement in -2 grade (12%), and 1 with improvement in -3 grade (2%). Bone marrow fibrosis was stable in 28 patients (49%) and worsened (to grade 1) in 10 (18%). In the group of 57 patients who had received any ruxolitinib treatment, the median time to a confirmed improvement in bone marrow fibrosis grade was 216 weeks, and the median duration of confirmed improvement was 192 weeks (Figure 4). In the same group, the median time to a confirmed stabilization of bone marrow fibrosis grade was 72 weeks, and the median duration of confirmed stabilization was not reached.

References

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

2. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.

3. Caocci G, Maccioni A, Murgia F, et al. Modulation of bone marrow microenvironment following ruxolitinib therapy in myelofibrosis. Leuk Lymphoma. 2016;57(5):1215-1218.

4. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Changes in activated bone marrow macrophages and mast cells in patients with myelofibrosis following ruxolitinib therapy [ASH abstract 3184]. Blood. 2014;124 (suppl 21).

5. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Effects of long-term ruxolitinib (RUX) on bone marrow (BM) morphology in patients with myelofibrosis (MF) enrolled in the COMFORT-I study [ASH abstract 1949]. Blood. 2016;128(suppl 22).

Examining the Clinical Features and Underlying Cardiovascular Risk Among Patients With Polycythemia Vera in the REVEAL Study

REVEAL (Prospective Observational Study of Patients With Polycythemia Vera in US Clinical Practices) is a multicenter, noninterventional, nonrandomized, prospective, observational, phase 4 study that is collecting data on PV patient demographics, disease burden, clinical management, patient-reported outcomes, and healthcare resource use in the United States.¹ The study enrolled a total of 2544 adults with PV from 219 study sites, all of whom were under active management by a physician in a community or academic treatment center. Patient-reported outcomes and physician assessments are being collected for 36 months. Ten-year cardiovascular risk factors were adapted from the Framingham Heart Study for Cardiovascular Diseases.²

A preliminary analysis of the REVEAL study included data from 2307 patients.³ At the time of enrollment, 77.3% of patients were classified as having high-risk PV, based on older age (≥60 years) and/or a history of thrombotic events. At enrollment, 91.5% of patients were under active management for their PV, with the most common treatments consisting of phlebotomy (34.0%), hydroxyurea (27.0%), and phlebotomy plus hydr-oxyurea (23.2%), all with or without concomitant aspirin. At least 1 underlying cardiovascular risk factor was observed in 86.0% of patients at enrollment, including hypertension (66.5%), history of smoking (46.2%), obesity (34.2%), hyperlipidemia (27.4%), diabetes (14.8%), and current smoking (10.9%).

Venous thrombotic events and arterial thrombotic events were rec-orded in 11.1% and 8.6% of patients, respectively. Among the 431 patients (18.7%) with a history of thrombotic events, 181 (42.0%) experienced a thrombotic event between the time of diagnosis and the time of enrollment. The events varied according to patients’ underlying cardiovascular risk factors (Figure 5). The most common venous thrombotic events were deep vein thrombosis (5.9%) and pulmonary embolism (2.5%), and the most common arterial thrombotic events were cerebrovascular arterial thrombosis, including transient ischemia (5.1%) and acute myocardial infarction (1.7%). The rate of thrombotic events was 10.5% among patients without any underlying cardiovascular risk factors, 23.6% in patients with hyperlipidemia, and 21.0% in patients with hypertension. Overall, rates of thrombotic events increased with the number of cardiovascular risk factors, from a low of 10.5% in patients with no risk factors to 23.7% in patients with 4 or more risk factors.

References

1. Stein B, Moliterno A, Boccia RV, et al. Disease and clinical characteristics of patients with polycythemia vera: an early view of the REVEAL study [ASH abstract 2813]. Blood. 2015;126(suppl 3).

2. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743-753.

3. Stein B, Naim A, Grunwald MR, et al. Examining the clinical features and underlying cardiovascular risk among patients with polycythemia vera in the REVEAL study [ASH abstract 1934]. Blood. 2016;128(suppl 2).

Clinical Outcomes With Ruxolitinib (RUX) in Patients With Myelofibrosis (MF) Stratified By Transfusion Status: A Pooled Analysis of the COMFORT-I and -II Trials

Pooled data from the COMFORT-I and COMFORT-II studies were evaluated to deter-mine the relationship between trans-fusion requirements and clinical out-comes in MF patients treated with rux-olitinib.^1-3 The analysis was based on data from 301 patients randomly assigned to receive ruxolitinib and 227 in the control group. Baseline anemia was reported in 45.8% of the ruxolitinib arm and 49.8% of the control arm.

The need for transfusion was assessed at week 24 (Figure 6). Patients who did not require trans-fusion during weeks 13 to 24 were considered independent, and patients who required transfusion during weeks 17 to 24 were considered dependent. In the ruxolitinib group, a greater proportion of patients who were nonanemic at baseline (range, 73.4%-73.8%) achieved transfusion independence compared with those who had anemia at baseline (range, 15.5%-22.4%).

At week 24, transfusion independence vs nonindependence did not significantly impact OS among patients receiving treatment with ruxolitinib (P=.1322). In contrast, transfusion status did significantly affect OS in the control group (P=.0004). Similarly, transfusion dependence vs nondependence at week 24 did not significantly affect OS in the ruxolitinib group (P=.4547; Figure 7). Median OS was significantly longer in the ruxolitinib arm vs the control arm among patients who were transfusion dependent (anemic at baseline, 200 vs 137 weeks; nonanemic, 271 vs 166 weeks; overall, P=.002) or who became transfusion dependent (anemic at baseline, 210 vs 127 weeks; nonanemic, 292 vs 90 weeks; overall, P=.0323).

Median OS was significantly improved with ruxolitinib overall, as well as in the group of patients who were transfusion-dependent at week 24 (P=.0014).

The median time to transfusion independence was 16.6 weeks in the ruxolitinib arm vs 12.0 weeks in the control arm. Among patients treated with ruxolitinib, the risk of transfusion dependence decreased after week 24 (from 0.51 at week 24 to 0.54 at week 36).

In patients treated with ruxolitinib, changes in spleen volume, body weight, and symptom scores from baseline were not affected by transfusion status. The probability that a patient would become transfusion-independent after 1 year of treatment was similar in both treatment groups. Among patients in the control arm, symptom scores were worse in patients who failed to achieve transfusion independence compared with those who did.

The authors concluded that transfusion requirements had little impact on clinical outcomes or treatment
discontinuation within the ruxolitinib group. In contrast, among patients in the control arm, the need for transfusion was associated with reduced OS and worsened total symptom scores. After 24 weeks of treatment with ruxolitinib, rapid decreases were seen in the risk of becoming transfusion dependent, the number of units of red blood cells administered, and the monthly proportions of patients who req-uired transfusions.

References

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

2. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):
787-798.

3. Gupta V, Verstovsek S, Paquette R, et al. Clinical outcomes with ruxolitinib (RUX) in patients with myelofibrosis (MF) stratified by transfusion status: a pooled analysis of the COMFORT-I and -II trials [ASH abstract 3118]. Blood. 2016;128(suppl 2).

Interim Analysis of the Myeloproliferative Disorders Research Consortium (MPD-RC) 112 Global Phase III Trial of Front Line Pegylated Interferon Alpha-2a Vs. Hydroxyurea in High Risk Polycythemia Vera and Essential Thrombocythemia

The optimal management of high-risk ET and PV remains unknown.¹ Several studies have demonstrated a reduction of thrombotic risk with hydroxyurea therapy.^2,3 Despite concerns regarding the leukemogenic potential of hydroxyurea, a clear correlation bet-ween hydroxyurea treatment and the development of acute leukemia has not been established. In phase 2 studies, interferon-α was associated with hematologic ORRs of greater than 75% and molecular CR rates of between 10% and 20%.^4-6

MPD-RC 112 (Myeloproliferative Disorders Research Consortium 112) is a global, randomized, phase 3 study con–ducted by the Myeloproliferative Disorders Research Consortium to compare first-line hydroxyurea vs peg-ylated interferon α-2a in patients with high-risk PV or ET.⁷ Patients were enrolled at 43 institutions in the United States, Canada, Europe, and Israel. The primary objective was to compare the hematologic CR rates (by European LeukemiaNet criteria)after 12 months of therapy based on blinded central review.⁸ Secondary objectives were to compare outcomes in the 2 treatment arms based on toxicity and tolerability; CR and PR rates; specific predefined toxicity and tolerance of therapy determined through the MPN Safety Assessment Form; survival and incidence of development of a myelodysplastic disorder, MF, or leukemic transformation; and impact of therapy on key disease biomarkers, including driver mutations. Key eligibility criteria included PV or ET by World Health Organization criteria, and high-risk disease, based on older age (≥60 years); previous documented thrombosis, erythromelalgia, or migraine (or hemorrhage for ET); platelet counts of greater than 1000 × 10⁹/L for PV and greater than 1500 × 10⁹/L for ET; symptomatic or significant splenomegaly; and/or diabetes or hypertension requiring pharmacologic therapy. Eligible patients had been diagnosed within 5 years of study enrollment and were treatment-naive, with less than 3 months of hydroxyurea therapy. An interim analysis was preplanned to occur after the first 75 patients had received 12 months of study treatment.

For patients with ET, modified European LeukemiaNet criteria for a CR were platelet count of no more than 400 × 10⁹/L, no disease-related symptoms (including microvascular disturbances, pruritus, and headache), normal spleen size on imaging, and a white blood cell count of no more than 10 × 10⁹/L. Patients with a PR were those who did not meet the criteria for a CR, with a platelet count of no more than 600 × 10⁹/L or a 50% reduction in platelet count from baseline.⁸ For patients with PV, modified European LeukemiaNet criteria for a CR were a hematocrit of no more than 45% without phlebotomy, platelet count of no more than 400 × 10⁹/L, white blood cell count of no more than 10 × 10⁹/L, normal spleen size on imaging, and no disease-related symptoms. Patients with a PR were those who did not meet the criteria for a CR, with a hematocrit of no more than 45% or a response in line with any of the remaining 4 criteria.

The 168 patients were randomly assigned to receive treatment with hydroxyurea or pegylated interferon α-2a. Data were available for 39 patients treated with hydroxyurea and 36 patients treated with pegylated interferon α-2a. Patient baseline characteristics were generally well-balanced between the 2 treatment arms. The 75 patients had a median age of 61 years (range, 20-85 years), and 47% were female.

Dose escalations were commonly used to achieve a hematologic response, resulting in a mean pegylated interferon α-2a dose of 90 µg weekly and a mean hydroxyurea dose of 6 g weekly. At the time of the interim analysis, 29 patients in the hydroxyurea arm and 33 patients in the pegylated interferon α-2a arm remained on therapy. ORR was 69% in the hydroxyurea arm vs 81% in the pegylated interferon α-2a arm; P=.6). The primary endpoint of CR rate also did not differ significantly between the 2 arms (33% vs 28%, respectively; P=.6). Among the patients with PV, the proportion of those with hematocrit control at 12 months was 57% with hydroxyurea vs 76% with pegylated interferon α-2a (P=.19). Also among these patients, platelet control at 12 months was 73% in both treatment arms (P>.99). Seven patients in each arm demonstrated a spleen response based on palpable splenomegaly, and 1 patient in the hydroxyurea arm experienced an increase in splenomegaly.

Complete histopathologic bone marrow responses were observed in 36% of patients in the hydroxyurea arm vs 8% of patients in the pegylated interferon α-2a arm. These rates were 50% vs 20% in patients with ET, and 25% vs 0% in patients with PV. The JAK2 V617F burden decreased from 19.7% at baseline to 8.3% after 12 months of hydroxyurea treatment and decreased from 18.8% at baseline to 8.4% after 12 months of pegylated interferon α-2a treatment (Figure 8). Molecular responses among the 19 patients in the hydroxyurea arm included 22% CRs, 28% PRs, and 50% with no response. Similar outcomes were seen among the 22 patients receiving pegylated interferon α-2a (14%, 32%, and 54%, respectively).

Frequently reported AEs of any grade included depression (0% with hydroxyurea vs 28% with pegylated interferon α-2a; P<.001), dyspnea (3% vs 19%; P=.02), flu-like symptoms (3% vs 33%; P<.001), injection site reaction (0% vs 25%; P=.001), and pruritus (8% vs 28%; P=.03). The rate of grade 3 or higher AEs was 14% in the hydroxyurea arm vs 47% in the pegylated interferon α-2a arm (P=.002).

Comparative analyses of quality of life and symptom burden were presented separately by Dr Ruben Mesa.⁹ Within the first 6 months, the improvement in symptom burden was greater with pegylated interferon α-2a than hydroxyurea. However, the low-grade side effects of pegylated interferon α-2a, such as injection site reactions, flu-like symptoms, and myalgias, increased over time.

References

1. Mascarenhas J, Mesa R, Prchal J, Hoffman R. Optimal therapy for polycythemia vera and essential thrombocythemia can only be determined by the completion of randomized clinical trials. Haematologica. 2014;99(6):945-949.

2. Fruchtman SM, Mack K, Kaplan ME, Peterson P, Berk PD, Wasserman LR. From efficacy to safety: a Polycythemia Vera Study group report on hydroxyurea in patients with polycythemia vera. Semin Hematol. 1997;34(1):17-23.

3. Harrison CN, Campbell PJ, Buck G, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353(1):33-45.

4. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072.

5. Quintas-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon alpha-2a. Blood. 2013;122(6):893-901.

6. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27(32):5418-5424.

7. Mascarenhas JO, Prchal JT, Rambaldi A, et al. Interim analysis of the Myeloproliferative Disorders Research Consortium (MPD-RC) 112 global phase III trial of front line pegylated interferon alpha-2a vs. hydroxyurea in high risk polycythemia vera and essential thrombocythemia [ASH abstract 479]. Blood. 2016;128(suppl 22).

8. Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22(2):437-438.

9. Mesa RA, Hoffman R, Kosiorek HE, et al. Impact on MPN symptoms and quality of life of front line pegylated interferon alpha-2a vs. hydroxyurea in high risk polycythemia vera and essential thrombocythemia: interim analysis results of myeloproliferative disorders research consortium (MPD-RC) 112 global phase III trial [ASH abstract 4271]. Blood. 2016;128(suppl 2).

Myeloproliferative Neoplasms: Current Mutational Landscape of Myeloproliferative Neoplasms

At the 2016 ASH Education Program on MPNs, Dr Jamile Shammo reviewed the mutational landscape.¹ Dr Shammo focused on the common genetic alterations in MPNs, including driver and nondriver mutations; their prognostic implications; and the potential impact of these mutations on selection of therapy and outcome.

Hematopoiesis is dependent on numerous cytokine signaling pathways.^2-4 In MPNs, the driver mutations are primarily found in JAK2, the myeloproliferative leukemia (MPL) gene, and calreticulin (CALR). A key signaling pathway involves cytokine or growth factor binding to MPL protein, activation of JAK1/2 and the signal transducers and activators of transcription (STAT) pathway, and nuclear transcription of genes involved in proliferation, survival, and differentiation. Mutations that induce constitutive activation of the signal transduction pathway controlled by MPL are key drivers of MPN pathogenesis.

Common Mutations in MPNs

The JAK2 V617F mutation is present in greater than 90% of PV cases, and activating mutations in JAK2 and MPL are the drivers in approximately 50% to 60% of patients with ET and MF.^5-8 The importance of mutations in CALR, the gene that encodes calreticulin, was revealed in 2013 by whole-exome sequencing.⁹ CALR mutation was identified in the majority of ET and MF patients who lacked mutations in JAK2 and MPL, and it is the key mutation in 30% to 40% of ET and MF patients. The mutations identified in CALR result in a frameshift such that the charge on the C-terminal peptide of calreticulin changes from negative to positive. The frameshift also causes loss of the C-terminal KDEL sequence that mediates retention in the endoplasmic reticulum. CALR mutation induces pathogenesis by allowing calreticulin to escape from the endoplasmic reticulum, after which it binds directly to MPL, activating the thrombopoietin receptor and the downstream JAK/STAT pathway.^10-12

Genetic evaluation of JAK2, MPL, and CALR is not currently part of routine prognostic assessment in patients with primary MF. However, the prognostic impact of driver mutations in MF has been studied extensively. In a study of 617 patients with primary MF, 64.7% had a JAK2 V617F mutation, 22.7% had a CALR exon 9 insertion or deletion, 4.0% carried a MPL mutation, and 8.6% had triple-negative disease, characterized by wild-type JAK2, CALR, and MPL.¹³ Median OS was highest in patients with a CALR mutation (17.7 years), followed by patients with a JAK2 mutation (9.2 years) and an MPL mutation (9.1 years). Median OS was lowest in patients with triple-negative disease, at 3.2 years. The group of patients with triple-negative disease also demonstrated the highest 10-year cumulative incidence of blast transformation, at 34.4%. In patients with JAK2, MPL, or CALR mutation, the 10-year cumulative incidences of blast transformation were 19.4%, 16.9%, and 9.4%, respectively. The patients with CALR mutation also exhibited reduced rates of anemia, thrombocytopenia, and leukocytosis compared with patients harboring the JAK2 V617F mutation. Dozens of CALR mutations have been identified, and the majority of mutations are either a type 1 deletion or type 2 insertion.⁹ CALR type 1 mutations are more commonly associated with MF.¹⁴ In patients who have ET and the CALR type 1 mutation, the risk of myelofibrotic transformation is higher. CALR type 2 mutations are more common in patients with ET, and these patients tend to have an indolent clinical course and a reduced risk of thrombosis.

In contrast to ET and MF, PV is associated with JAK2 driver mutations in greater than 90% of cases.¹⁵ In a study of 133 PV patients, the prevalence of nondriver mutations was evaluated by next-generation sequencing of a 27-gene panel.¹⁶ A driver mutation in JAK2 was found in 98% of patients. Mutations in genes other than JAK2, MPL, or CALR were observed in 44% of patients, with 1 mutation observed in 29% and 2 mutations observed in 14%. Of the 3 patients with wild-type JAK2, none expressed nondriver mutations. OS was negatively affected by the presence of mutations in SRSF2 (P=.006) and RUNX1 (P=.04), and by the presence of nondriver mutations. After a median follow-up of 9.8 years, median OS was 13 years in patients with no nondriver mutations, 11.5 years (HR, 1.7; 95% CI, 0.97-3.1) in those with 1 nondriver mutation, and 10 years (HR, 2.6; 95% CI, 1.3-5.2) in patients with 2 or more nondriver mutations (P=.01). Similar findings have emerged in patients with ET, and therefore routine genetic profiling of patients with ET/PV is not currently recommended.

In patients with primary MF, mutations in ASXL1, EZH2, SRSF2, or IDH1/2 are associated with an increased risk of leukemic transformation.¹⁷ ASXL1 mutation was associated with reduced survival, independent of the Dynamic IPSS (DIPSS)-plus model, which includes clinical and cytogenetic variables. A molecular prognostic model incorporating CALR and ASXL1 mutations was investigated in 570 patients with primary MF.¹⁸ Initial derivation of the model was performed by stratification of 277 patients, with subsequent validation in 293 patients. Median OS was longest in patients with mutated CALR/wild-type ASXL1, at 10.4 years, and was shortest in patients with wild-type CALR/mutated ASXL1, at 2.3 years (HR, 5.9; 95% CI, 3.5-10.0 years). The prognostic significance of the CALR and ASXL1 mutations was maintained for patients within a single IPSS category.

Researchers have defined high–molecular risk patients as those having at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2.¹⁹ In a cohort of 537 European patients with primary MF, 31% were high–molecular risk, including 23.6% with 1 mutation and 7.4% with 2 or more mutated genes.¹⁹ Patients with no mutations in the 5 genes had a median OS of 12.3 years. Median OS was 7.0 years in patients with 1 mutation and 2.6 years in patients with 2 or more mutations (HR, 3.8; 95% CI, 2.6-5.7). The results were validated in a cohort of 260 patients at the Mayo Clinic, and the prognostic significance in both cohorts was independent of IPSS and DIPSS-plus. The presence of 2 or more detrimental mutations was also associated with reduced leukemia-free survival (HR, 6.2; 95% CI, 3.5-10.7).

Therapy Choice and Outcome: Do Mutations Matter?

Despite the advances in molecular analytical techniques, the major prognostic indicators in PV continue to be the patient’s age and history of thrombosis.^20,21 Low-risk patients are those younger than 60 years with no history of thrombosis, and high-risk patients are ages 60 years or older and/or have a history of thrombosis. The CYTO-PV study (Cytoreductive Therapy in Polycythemia Vera) investigated the value of maintaining a hematocrit level of less than 45% in patients with PV and the JAK2 mutation.²² The study randomly assigned 365 patients to receive intensive treatment with phlebotomy, hydroxyurea, or both to achieve a hematocrit level of less than 45% or to receive less intensive treatment while maintaining a hematocrit level of 45% to 50%. The primary composite endpoint was time until death from cardiovascular or major thrombotic events. After a median follow-up of 31 months, primary endpoint events had occurred in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%; HR, 3.91; 95% CI, 1.45-10.53; P=.007).

For patients with low-risk PV, phlebotomy is used to maintain a hematocrit level of less than 45%, and aspirin is recommended for primary antiplatelet prophylaxis in the absence of contraindications, along with aggressive control of cardiovascular risk factors, including obesity, smoking, hypertension, and diabetes.²³ For patients with high-risk PV, phlebotomy is also used to maintain hematocrit levels below 45%. Additionally, hydroxyurea or interferon is used as first-line treatment for cytoreduction; busulfan is an option for older patients who may be unable to tolerate more aggressive treatment. Ruxolitinib is approved by the US Food and Drug Administration for the treatment of PV patients who are intolerant of hydroxyurea or have had an inadequate response.²⁴

Pegylated interferon α has been a mainstay of PV therapy for many years.²⁵ In a phase 2 study of 40 patients with PV harboring JAK2 V617F, 37 patients experienced a hematologic response after 12 months of treatment with pegylated interferon α-2a, including 35 with hematologic CRs. Three patients were excluded from the analysis. The median proportion of granulocytes harboring the JAK2 V617F mutation decreased from 45% at baseline to 22% at 12 months, 5% at 24 months, and 3% at 36 months. At the time of the last analysis, molecular CRs were observed in 7 of 29 patients (24.1%). TET2 mutation has since emerged as a factor in PV and may influence the efficacy of treatment with interferon.²⁶

Risk factors in patients with ET include older age (>60 years), platelet level of greater than 1500 × 10⁹/L, and a history of bleeding or thrombotic events. Cardiovascular risk factors should be managed in all patients. Aspirin is appropriate for patients with microvascular disturbance, cardiovascular risk, or JAK2 V617F mutation. However, aspirin is not appropriate for low-risk patients with a CALR mutation, owing to a lack of reduction in venous thrombotic events and increased bleeding events.²⁷ In patients with high-risk disease, hydroxyurea or interferon-α is appropriate for first-line treatment. These 2 agents may also be considered for patients with extreme or symptomatic thrombocytosis. For second-line therapy, or in patients for whom hydroxyurea therapy is not an option, choices include interferon-α, anagrelide, and busulfan. Clinical trials may also be considered.

Identification of a transformed clone is essential to confirm a diagnosis of MF. Although numerous therapies are available for patients with MF, the only curative treatment is allogeneic stem cell transplant. Watchful waiting is appropriate for patients with early, low-risk MF, as clinical trials have yet to establish the value of early treatment in this setting. Ruxolitinib is an option in patients who have high-risk disease, constitutional symptoms, and symptomatic splenomegaly. Clinical trials evaluating novel agents are another option. To manage anemia, appropriate therapies include erythropoiesis-stimulating agents, dan-azol, and prednisone. Ruxolitinib was approved for MF based on the phase 3 COMFORT trials.^28,29 Both trials yielded a reduction in spleen size in patients with MF. In COMFORT-I, response to ruxolitinib was not associated with JAK2 mutation, age, type of MF, IPSS risk score, or baseline spleen length. Ruxolitinib was also shown to be effective in patients with high or low molecular risk.³⁰ However, in a separate analysis of data from a phase 1/2 trial, ruxolitinib efficacy was reduced in patients with a larger number of mutations in a panel of genes recurrently mutated in hematologic malignancies (Figure 9).³¹ Patients with 2 mutations or fewer had 9-fold increased odds of a spleen response compared with patients harboring 3 or more mutations (OR, 9.37; 95% CI, 1.86-47.2), and patients with at least 3 mutations had a shorter time to treatment discontinuation and shorter OS.

Newer agents of interest include momelotinib, a JAK2 kinase inhibitor, and imetelstat, a telomerase inhibitor. In a phase 2 trial of patients with MF who were treated with momelotinib monotherapy, CALR and ASXL1 mutation status was associated with survival.³² Among 84 patients stratified based on mutational status, median OS was not reached in patients with CALR mutation, was 3.5 years in patients with wild-type copies of both CALR and ASXL1, and was 1.6 years in patients with wild-type CALR and mutated ASXL1. Imetelstat was evaluated in 33 patients with intermediate-2 or high-risk MF, yielding an ORR of 21% and a median duration of response of 18 months.³³ The telomerase inhibitor yielded a CR of 38% in patients with a mutation in SF3B1 or U2AF1 vs 4% in patients without these mutations (P=.04), prompting evaluation of imetelstat in refractory anemia with ring sideroblasts.

Conclusion

Dr Shammo concluded that the identification of a driver mutation is now essential for the diagnosis of MPN. The driver mutation provides important prognostic information. More data are needed to understand the influence on treatment selection and outcome.

References

1. Shammo JM, Stein BL. Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions. ASH Education Book. 2016(1).

2. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178(5):2623-2629.

3. Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol. 2008;19(4):385-393.

4. Verstovsek S. Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clin Cancer Res. 2010;16(7):1988-1996.

5. Kilpivaara O, Levine RL. JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia. 2008;22(10):1813-1817.

6. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7(9):
673-683.

7. Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol. 2010;91(2):165-173.

8. Oh ST. When the brakes are lost: LNK dysfunction in mice, men, and myeloproliferative neoplasms. Ther Adv Hematol. 2011;2(1):11-19.

9. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390.

10. Marty C, Pecquet C, Nivarthi H, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016;127(10):1317-1324.

11. Araki M, Yang Y, Masubuchi N, et al. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. Blood. 2016;127(10):1307-1316.

12. Chachoua I, Pecquet C, El-Khoury M, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127(10):1325-1335.

13. Rumi E, Pietra D, Pascutto C, et al; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014;124(7):1062-1069.

14. Pietra D, Rumi E, Ferretti VV, et al. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016;30(2):431-438.

15. Vannucchi AM. From leeches to personalized medicine: evolving concepts in the management of polycythemia vera. Haematologica. 2017;102(1):18-29.

16. Tefferi A, Lasho TL, Finke C, et al. Targeted next-generation sequencing in polycythemia vera and essential thrombocythemia [ASH abstract 354]. Blood. 2015;126(suppl 23).

17. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia. 2013;27(9):1861-1869.

18. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494-1500.

19. Guglielmelli P, Lasho TL, Rotunno G, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia. 2014;28(9):1804-1810.

20. Passamonti F. How I treat polycythemia vera. Blood. 2012;120(2):275-284.

21. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10):2224-2232.

22. Marchioli R, Finazzi G, Specchia G, et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33.

23. Barbui T, Barosi G, Birgegard G, et al; European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761-770.

24. Jakafi [package insert]. Wilmington, DE: Incyte Corporation; 2016.

25. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065-3072.

26. Quintás-Cardama A, Abdel-Wahab O, Manshouri T, et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013;122(6):
893-901.

27. Alvarez-Larrán A, Pereira A, Guglielmelli P, et al. Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation. Haematologica. 2016;101(8):926-931.

28. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

29. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.

30. Guglielmelli P, Biamonte F, Rotunno G, et al; COMFORT-II Investigators; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (AGIMM) Investigators. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014;123(14):2157-2160.

31. Patel KP, Newberry KJ, Luthra R, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015;126(6):790-797.

32. Pardanani A, Abdelrahman RA, Finke C, et al. Genetic determinants of response and survival in momelotinib-treated patients with myelofibrosis. Leukemia. 2015;29(3):741-744.

33. Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373(10):908-919.

Highlights in Myeloproliferative Neoplasms From the 2016 American Society of Hematology Meeting: Commentary

The 2016 American Society of Hematology (ASH) meeting included many important abstracts in myeloproliferative neoplasms (MPNs). Analyses reinforced the long-term safety and benefits of ruxolitinib in myelofibrosis. Studies in polycythemia vera compared interferon with hydroxyurea to provide the first large-scale phase 3 data. Novel therapies, such as sotatercept and anagrelide, were also evaluated. Interesting data were provided for a less common MPN, systemic mastocytosis.

Ruxolitinib

In 2011, the US Food and Drug Administration approved ruxolitinib for the treatment of myelofibrosis. Sev–eral presentations at the ASH meet-ing provided long-term follow-up from studies of ruxolitinib, such as the COMFORT trials (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment)^1,2 and the compassionate use JUMP study (INC424 for Patients With Myelofibrosis, Post Polycythemia Myelofibrosis or Post-Essential Throm-bocythemia Myelofibrosis).³ Rux–o-lit-inib remains the only approved ther-apy widely available throughout the world for myelofibrosis.

I was coauthor of a study presented by Dr Srdan Verstovsek, which analyzed combined survival data from COMFORT-I and COMFORT-II.⁴ Without question, ruxolitinib continues to be associated with a significant survival advantage compared with each of the control arms, whether placebo (in COMFORT-1) or best alternative therapy (in COMFORT-II). This advantage has been maintained despite the impact of crossover. In both COMFORT studies, most patients in the control arms transitioned to ruxolitinib, and the comparisons were made between patients who received ruxolitinib earlier vs later. These long-term data therefore suggest not only that ruxolitinib has a survival advantage, but that earlier treatment may be better than later treatment.

Other long-term analyses from the COMFORT studies also provided important data. Dr Vikas Gupta evaluated the impact of anemia.⁵ The analysis showed that the development of anemia, or any amount of anemia associated with the use of ruxolitinib, did not appear to have a negative impact on outcome or survival. The negative prognostic implications of disease-associated anemia may not occur with anemia induced by medication. There was always a question of whether the development of anemia was detrimental in these patients, and the results of this study provide assurance that it is not.

Dr Hans Michael Kvasnicka pre-sented data from a long-term analysis of the COMFORT-1 trial to identify how ruxolitinib might affect bone marrow.⁶ The study identified a favorable impact, with improvement or stabilization in bone marrow fibrosis in many patients. This favorable impact took some time to recognize. Improvements were seen in patients treated for well over 48 weeks. It is not a surprise that the process is lengthy; stem cell transplant can take up to a year to resolve fibrosis.

Supporting these long-term analyses from the COMFORT trials are data from the single-arm JUMP study, which evaluated more than 2000 patients treated with ruxolitinib in an open-label, expanded-access protocol.⁷ Dr Lynda Foltz presented the results of the study.⁷ The key takeaways are that the safety and efficacy in this much broader population mirror the benefits seen in the COMFORT studies.^1,2 Resolution of splenomegaly and other difficulties were very pronounced. The JUMP study included patients with intermediate-1 disease, and benefits were similar in these patients and in those with more advanced disease. These favorable observations further reinforce the safety and efficacy of ruxolitinib.

Interferon

Several studies at ASH evaluated long-acting interferon formulations. Dr Heinz Gisslinger presented results from the PROUD-PV trial (Pegylated Interferon Alpha-2b Versus Hydroxyurea in Polycythemia Vera), which compared pegylated interferon α-2b vs hydroxyurea in patients with polycythemia vera.⁸ Dr John Mascarenhas presented interim data from the
MPD-RC 112 trial (Myeloproliferative Disorders Research Consortium 112), which compared pegylated interferon α-2a vs hydroxyurea in patients with high-risk polycythemia vera or essential thrombocythemia.⁹

In both studies, within the first year of therapy, interferon was rel-atively equivalent to hydroxyurea in controlling blood counts and preventing vascular events. These studies are important because they provide the first randomized data that confirm the efficacy of interferon in this setting. There have been many single-arm institutional studies that have demonstrated the activity of interferon in these patients,^10,11 but no randomized data showing equivalence.

I presented a parallel analysis of the MPD-RC study assessing quality of life and symptoms throughout the course of the therapy.¹² It found that interferon improved symptom burden as compared with hydroxyurea in the first 6 months. However, the low-grade side effects of interferon—injection site reactions, flu-like symptoms, and myalgias—increase over time and were probably a bigger burden at 1 year than the side effects of hydroxyurea.

Dr Gisslinger’s presentation of the PROUD-PV study included longer-term data from a continuation study.⁸ These data showed that when patients were treated for a longer time, interferon appeared to decrease the allele burden more so than hydroxyurea.

These studies clearly show that interferon was active. At least within the first year, it is not clear whether interferon was superior to hydroxyurea in controlling blood counts or decreasing the risk of blood clots or bleeding events. It is possible that interferon may have a longer-term benefit in terms of better disease control at a molecular level among patients treated with extended therapy, but further analysis is needed. Currently, it is necessary to consider a patient’s individual factors, such as tolerability of a medication, age, and childbearing status, when deciding which therapy to use in the frontline setting.

Other Therapies

Anemia remains a significant unmet need in patients with myelofibrosis. Sotatercept is a novel therapy that has been active in other anemic disorders and aims to improve erythropoiesis in these patients.¹³ Dr Prithviraj Bose presented early results from an ongoing analysis of patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myel-ofibrosis.¹⁴ Sotatercept was well-tolerated and improved anemia. The study authors are expanding their efforts to evaluate sotatercept in combination with ruxolitinib. If it is possible to preserve the benefits of Janus kinase (JAK) inhibition—in terms of splenomegaly symptoms and survival—while further improving anemia, then a combination regimen would be of interest. Other potential candidates for this approach might be patients who have anemia that overlaps with a phenotype resembling a myelodysplastic syndrome.

Dr Heinz Gisslinger presented results from a study comparing a long-acting anagrelide compound vs placebo in patients with intermediate-risk essential thrombocythemia.¹⁵ This is an important study because there is no consensus on treatment in this setting. These patients are intermediate-risk, so they typically would not receive cytoreductive therapy. The study found that the long-acting anagrelide was safe and reasonably well-tolerated. Long-acting anagrelide was better than pure observation. A question raised at the ASH presentation concerned the lack of aspirin use in both arms. Some might argue that it would have been prudent to use aspirin in intermediate-risk patients. It is not clear whether the difference in event rates would have been erased by the use of aspirin. However, the study provides important information and suggests that intermediate-risk patients should receive treatment with something, whether it be cytoreduction, aspirin, or both.

Aspects of Disease Burden

Several abstracts focused on additional aspects of disease burden. To date, the observational REVEAL study (Pro-s-pective Observational Study of Patients With Polycythemia Vera in US Clinical Practices) is the largest study in polycythemia vera, with app-roximately 2300 patients.^16,17 It is providing valuable information about these patients. At the ASH meeting, Dr Brady Stein presented an analysis of the underlying cardiovascular risk factors in these patients.¹⁷ The analysis showed that a high proportion of patients with polycythemia vera have cardiovascular risk factors. It is important to consider these risk factors when treating patients with a current or previous thromboembolic event. Other considerations include the patient’s smoking status, hypertension, obesity, hyperlipidemia, and diabetes.

The LANDMARK study was a survey of patients with MPNs. I helped lead the study in the United States, and data were published in 2016.^18,19 At the ASH meeting, Dr Claire Harrison provided data for approximately 700 patients from Canada, Europe, Japan, and Australia.²⁰ The results reinforced our understanding that these diseases are associated with significant symptom burden, and that they impact quality of life, as well as employment status and the ability to be fully employed. This analysis confirms that the burdens associated with MPNs in the United States occur worldwide. Another relevant finding is that patients with essential thrombocythemia or polycythemia vera can experience similar difficulties as patients with myelofibrosis.

Uncommon MPNs

Most studies in MPNs focus on essential thrombocythemia, polycythemia vera, and myelofibrosis, which are the most common of the BCR/ABL-negative MPNs. However, atypical MPNs can also cause significant difficulties. Patients with systemic mastocytosis can experience very severe disease burden. High amounts of mast cells can lead to increased rates of allergic reactions, organ damage, and other morbidities, as well as mortality. There are few treatment options.

These patients frequently have a genetic mutation in the kinase KIT D816V. BLU-285 is a highly targeted therapy designed to inhibit that mutation. Dr Mark Drummond presented results from a phase 1, dose-escalation study.²¹ The study showed that BLU-285 had significant disease activity and was safe and well-tolerated. BLU-285 decreased mast cell burden and improved the end organ effects of mastocytosis. This targeted therapy is now being evaluated in other diseases driven by KIT D816V, such as gastrointestinal stromal tumors.

Conclusion

Abstracts at the 2016 ASH meeting continue to highlight the number and sophistication of treatment options for patients with MPNs. There was further refinement of information regarding therapies in myelofibrosis. New data confirm the utility of ruxolitinib in this population. Interferon and long-acting anagrelide are new therapies that are relevant for polycythemia vera and essential thrombocythemia. Other analyses provided more information regarding the overall disease burden and the favorable impact of therapies. New targeted approaches, based on molecular mutations, have benefits in the less-common MPNs.

Disclosure

Dr Mesa is a consultant for Novartis, AOP, Shire, Ariad, and Galena. He has performed research for Incyte, Gilead, CTI, Promedior, and Celgene.

References

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.

2. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798.

3. Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial. Haematologica. 2016;101(9):1065-1073.

5. Gupta V, Verstovsek S, Paquette R, et al. Clinical outcomes with ruxolitinib (RUX) in patients with myelofibrosis (MF) stratified by transfusion status: a pooled analysis of the COMFORT-I and -II trials [ASH abstract 3118]. Blood. 2016;128(suppl 2).

6. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Effects of long-term ruxolitinib (RUX) on bone marrow (BM) morphology in patients with myelofibrosis (MF) enrolled in the COMFORT-I study [ASH abstract 1949]. Blood. 2016;128(suppl 22).

7. Foltz L, Palumbo GA, Martino B, et al. Safety and efficacy of ruxolitinib for the final enrollment of JUMP: an open-label, multicenter, single-arm, expanded-access study in patients with myelofibrosis (N = 2233) [ASH abstract 3107]. Blood. 2016;128(suppl 22).

8. Gisslinger H, Klade C, Georgiev P, et al. Final results from PROUD-PV, a randomized controlled phase 3 trial comparing ropeginterferon alfa-2b to hydroxyurea in polycythemia vera patients [ASH abstract 475]. Blood. 2016;128(suppl 22).

9. Mascarenhas JO, Prchal JT, Rambaldi A, et al. Interim analysis of the Myeloproliferative Disorders Research Consortium (MPD-RC) 112 global phase III trial of front line pegylated interferon alpha-2a vs. hydroxyurea in high risk polycythemia vera and essential thrombocythemia [ASH abstract 479]. Blood. 2016;128(suppl 22).

10. Quintas-Cardama A, Kantarjian H, Manshouri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27(32):5418–5424.

11. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065–3072.

12. Mesa RA, Hoffman R, Kosiorek HE, et al. Impact on MPN symptoms and quality of life of front line pegylated interferon alpha-2a vs. hydroxyurea in high risk polycythemia vera and essential thrombocythemia: interim analysis results of Myeloproliferative Disorders Research Consortium (MPD-RC) 112 global phase III trial [ASH abstract 4271]. Blood. 2016;128(suppl 22).

13. Raftopoulos H, Laadem A, Hesketh PJ, et al. Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies. Support Care Cancer. 2016;24(4):1517-1525.

14. Bose P, Daver N, Jabbour EJ, et al. Phase-2 study of sotatercept (ACE-011) in myeloproliferative neoplasm-associated myelofibrosis and anemia [ASH abstract 478]. Blood. 2016;128(suppl 22).

15. Gisslinger H, Klade C, Abdulkadyrov K, et al. Final results from the phase 3 trial ARETA comparing a novel, extended-release anagrelide formulation to placebo in essential thrombocythemia patients with defined risk status [ASH abstract 476]. Blood. 2016;128(suppl 22).

16. Stein B, Moliterno A, Boccia RV, et al. Disease and clinical characteristics of patients with polycythemia vera: an early view of the REVEAL study [ASH abstract 2813]. Blood. 2015;126(suppl 23).

17. Stein B, Naim A, Grunwald MR, et al. Examining the clinical features and underlying cardiovascular risk among patients with polycythemia vera in the REVEAL study [ASH abstract 1934]. Blood. 2016;128(suppl 2).

18. Mesa RA, Miller CB, Thyne M, et al. Differences in treatment goals and perception of symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists/oncologists in the United States: findings from the MPN Landmark survey [published online September 30, 2016]. Cancer. 2016. doi:10.1002/cncr.30325.

19. Mesa R, Miller CB, Thyne M, et al. Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN Landmark survey [published online February 27, 2016]. BMC Cancer. 2016;16:167. doi:10.1186/s12885-016-2208-2.

20. Harrison CN, Koschmieder S, Foltz L, et al. The impact of myeloproliferative neoplasms (MPNs) on patients’ quality of life and productivity: results from the international MPN LANDMARK survey [ASH abstract 4267]. Blood. 2016;128(suppl 2).

21. Drummond M, DeAngelo D, Deininger M, et al. Preliminary safety and clinical activity in a phase 1 study of BLU-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis (SM) [ASH abstract 477]. Blood. 2016;128(suppl 2).