International Working Group For Myelofibrosis Research And Treatment Research Articles

A Phase 1b Trial of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Myelofibrosis and Anemia

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic elevations in hepcidin contribute to the onset and severity of anemia. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Preclinical studies have shown that DISC-0974 suppresses hepcidin and increases serum iron. A healthy volunteer study has demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously, and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count. In this Phase 1b/2a, open-label, multiple-ascending dose study (NCT05320198), we are assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with MF and anemia. Eligible participants include patients over 18 years of age with intermediate-2 or higher-risk MF and anemia. MF is required to be confirmed using the World Health Organization 2016 criteria. Anemia is defined per protocol as Hgb < 10 g/dL or transfusion dependence, as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). A stable dose of hydroxyurea and/or Janus kinase (JAK) inhibitor is allowed on trial. Major exclusion criteria include: liver iron concentration ≥ 7 mg/g dry weight; splenectomy; nutritional, genetic, infectious, or autoimmune causes of anemia. Dose escalation is based on a Bayesian optimal interval design with accelerated titration. Safety Review Committee assessments gate escalation decisions. Dosing occurs monthly for a total of 6 doses. Primary endpoints include safety and tolerability assessments of adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include anemia response as defined by the IWG-MRT, transfusion response as defined by a decrease of 50% in transfusion requirement over any 8-week period, standard PK parameters and PD metrics including serum hepcidin-25, iron, transferrin saturation, ferritin, and hematology biomarkers. All data are summarized using descriptive statistics. Initial data show a dose-related increase in pharmacokinetic parameters. DISC-0974 treatment led to dose-dependent reductions in serum hepcidin-25 and increases in serum iron levels. There have been no serious AEs or AEs leading to study withdrawal. Most AEs were mild, transient, and unrelated to DISC-0974. As of August 1, 2023, enrollment and dose escalation are ongoing. Safety, PK, and PD data from at least the first two cohorts will be presented.

International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT)

Myelofibrosis with myeloid metaplasia (MMM) is a clinicopathologic entity characterized by stem cell-derived clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis, and bone marrow fibrosis and osteosclerosis. Patients with MMM have shortened survival and their quality of life is compromised by progressive anemia, marked hepatosplenomegaly, and severe constitutional symptoms including cachexia. After decades of frustration with ineffective therapy, patients are now being served by promising treatment approaches that include allogeneic hematopoietic stem cell transplantation and immunomodulatory drugs. Recent information regarding disease pathogenesis, including a contribution to the myeloproliferative disorder phenotype by a gain-of-function JAK2 mutation (JAK2(V617F)), has revived the prospect of targeted therapeutics as well as molecular monitoring of treatment response. Such progress calls for standardization of response criteria to accurately assess the value of new treatment modalities, to allow accurate comparison between studies, and to ensure that the definition of response reflects meaningful health outcome. Accordingly, an international panel of experts recently convened and delineated 3 response categories: complete remission (CR), partial remission (PR), and clinical improvement (CI). Bone marrow histologic and hematologic remissions characterize CR and CR/PR, respectively. The panel agreed that the CI response category is applicable only to patients with moderate to severe cytopenia or splenomegaly.

Alisertib (MLN8237), an Oral Selective Inhibitor of Aurora Kinase a, Has Clinical Activity and Restores GATA1 Expression in Patients with Myelofibrosis

Alisertib (MLN8237), an Oral Selective Inhibitor of Aurora Kinase a, Has Clinical Activity and Restores GATA1 Expression in Patients with Myelofibrosis

A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis

AbstractRuxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.

Essential Thrombocythemia and Myelofibrosis

This review details two major clonal stem cell disorders: essential thrombocythemia (ET) and myelofibrosis (MF). ET is distinguished by a sustained proliferation of megakaryocytes that results in peripheral blood thrombocytosis. Primary myelofibrosis (PMF) is associated with extramedullary hematopoiesis, splenomegaly, a leukoerythroblastic blood picture, and varying degrees of marrow fibrosis with marked megakaryocyte hyperplasia and atypia. The epidemiology, etiology/genetics, pathogenesis, diagnosis (including clinical manifestations and laboratory tests), differentials, management, and prognosis of each disorder are examined. Also included is the evaluation of treatment options for MF, including interferon alfa, JAK inhibitors, and allogeneic stem cell transplantation, the latter of which is still the only curative treatment for MF. Figures show treatment algorithms for ET and MF. Tables list the current criteria for the diagnosis of ET and PMF via the World Health Organization (WHO), the guidelines for diagnosis of post-ET MF via the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT), prognostic factors in the International Prognostic Score for ET (IPSET) and IPSET-thrombosis, prognostic scoring systems for MF, and the clinical activity of JAK2 inhibitors. This review contains ­2 highly rendered figures, 6 tables, and 60 references.

Ruxolitinib and Lenalidomide As a Combination Therapy for Patients with Myelofibrosis

Background: Ruxolitinib (RUX) is a potent and selective inhibitor of the JAK/STAT pathway that significantly abrogates splenomegaly and constitutional symptoms in patients (pts) with myelofibrosis (MF). Lenalidomide (LEN) is a second-generation immunomodulatory agent that may improve MF-associated anemia and thrombocytopenia. RUX and LEN possess complimentary efficacy profiles.Aim:Our single-center phase II open-labeled study was conducted to determine the efficacy and safety of the combination of RUX with LEN in pts with MF. Objective improvements were defined using International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 2007 criteria. We were cognizant of an overlapping toxicity of the two medications, namely myelosuppression.Methods:Pts received 15 mg RUX orally twice daily in continuous 28-day cycles with 5 mg LEN orally once daily on days 1-21. Dosage was reduced, increased or delayed based on the assessment of efficacy and toxicity.Results: Thirty-one pts were enrolled between October 2011 and August 2013. Twenty-one (68%) had received prior treatment, including 2 with thalidomide. After a med follow-up of 21.6 mo (1.9-27.7), 28 pts remain alive. The median time on study was 14.7 mo (1.8-26.6) and the median number of cycles administered was 15 (1-29).Simultaneous administration of RUX and LEN was difficult. Only 2 (6%) pts have not required a dose interruption/dose adjustment. The median time to first dose interruption/dose adjustment was 56 days (4-360). Among the 29 pts who needed a dose interruption/adjustment, 23 (79%) needed it within 3 months of starting therapy. The first change in 23 (74%) pts was a dose interruption: median time to first dose interruption was 56 days (4-360), with 20 (87%) of the dose interruptions occurring within 3 months of therapy. LEN was held in all 23 pts and 14 (61%) never restarted LEN. RUX was concurrently held in 7 (30%), reduced in 9 (40%), and continued at same dose in 7 (30%). Reasons for the first dose interruption were low platelets (n=8), low absolute neutrophil count (n=3), anemia (n=3), diarrhea (n=3), financial constraints (n=2), deep vein thrombosis (n=1), skin rash (n=1), transaminitis (n=1), and arthralgia/fever (n=1). The first change in 6 (19%) pts was a dose increase (all in RUX): median time to dose increase was 83 days, with 3 (50%) of the increases occurring within 3 months of starting therapy. The reasons for dose increase were leukocytosis (n=2), suboptimal response (n=2), increased spleen size (n=1), and thrombocytosis (n=1). At the time of submission, 18 pts remain on study: 7 on RUX alone and 11 on both medications.IWG-MRT defined clinical improvement (CI) in splenomegaly was noted in 11 (36%) pts. Of note, CI in splenomegaly was seen in 6 of 11 (55%) pts who did not require a dose interruption in the first 3 months. Median time to response was 1.0 mo (0.4-9.1) and median response duration was 19.3 mo (9.4-25.6+). An additional 18 (58%) pts had IWG-MRT defined stable disease. Reasons for discontinuation in 13 pts were lack of response (n=2), infection (n=2), progression (n=1), neuropathy (n=1), renal failure (n=1), diarrhea (n=1), myelosuppression (n=2), concurrent lymphoma (n=1), and financial constraints (n=2). Grade 3/4 myelosuppression was noted in 13 pts. Five pts experienced grade 3/4 non-hematological toxicity (related and unrelated): G3 diarrhea (n=1), G3 edema (n=1), G4 acute kidney injury (n=1), and G3 liver enzyme (n=2).Conclusion: Concomitant administration of RUX with LEN resulted in early dose interruption in a majority of pts. Most pts were unable to restart LEN after dose interruption. Starting the two drugs simultaneously compromised the expected efficacy of RUX alone. A sequential approach with single-agent RUX for the first 3-6 months followed by the addition of the second agent once a steady dose of RUX has been achieved and optimal benefit reached may be a more viable approach for future RUX combination strategies.Table 1:Pt characteristics (N = 31)CharacteristicN (%) / [range]Median age, years66 [37-82]Male18 (58%)Diagnosis Post-essential thrombocytosis MF Post-polycythemia MF Primary MF4 (13%) 12 (39%) 15 (48%)Splenomegaly28 (90%)Median WBC x 109/L19.0 [4.3-124.9]Median hemoglobin g/dL11.0 [8.9-17.5]Median platelets x 109/L250 [27-1898]Peripheral blood blasts ³ 1%15.0 (48%)JAK2 +26 (84%)CytogeneticsDiploid18 (58%)Abnormal12 (39%)Insufficient metaphases1 (3%) DisclosuresNaval:Incyte: Advisory board membership Other, Research Funding. Pemmaraju:Incyte: Advisory board membership Other. Verstovsek:Incyte: Research Funding.

A Multinational, Open-Label Phase 2 Study Of Ruxolitinib In Asian Patients (Pts) With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF)

BackgroundRuxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life (QoL), and prolonged survival in 2 phase 3 studies comparing ruxolitinib with placebo (COMFORT-I) and best available therapy (COMFORT-II). However, no clinical trial in pts with MF had been conducted in Asian countries, and only a limited number of Asian pts or healthy volunteers had been enrolled in any ruxolitinib study. MethodsThis study was an open-label phase 2 study evaluating ruxolitinib in Asian pts with PMF, PPV-MF, or PET-MF who had palpable splenomegaly ≥ 5 cm below the costal margin and intermediate-2– or high-risk MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Pts received starting doses of ruxolitinib 15 or 20 mg twice daily (bid) based on baseline platelet count (100-200 or > 200 × 109/L, respectively); dose adjustments balancing safety and efficacy were allowed to titrate each pt to their most appropriate dose. The primary endpoint was met if the proportion of pts achieving ≥ 35% reduction in spleen volume from baseline at week 24 was ≥ 27.5% as measured by MRI/CT. Symptomatic response was assessed as a secondary endpoint using the 7-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score (TSS) and European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). The study was conducted in China (n = 63), Japan (n = 30), Korea (n = 17), and Taiwan (n = 10). The data cutoff date for this analysis was 7 June 2013. ResultsOverall, 120 pts were enrolled (PMF, n = 80; PPV-MF, n = 21; PET-MF, n = 19), and their baseline characteristics were as follows: median age, 61 years (range, 25-80 years); 51.7% female; 69.2% intermediate-2 and 30.8% high risk by IWG-MRT criteria; median palpable spleen size, 15 cm (range, 5-45 cm); median spleen volume, 2159 cm3; 55.8% of pts had prior exposure to hydroxyurea. The median follow-up was 8.44 months; 22.5% of pts discontinued treatment, primarily for adverse events (AEs; 9.2%) and disease progression (7.5%). The median duration of treatment was 8.44 months (range, 0.5-21.7 months), and the median daily dose was 20.64 mg/day in the 15 mg bid group (n = 46) and 36.11 mg/day in the 20 mg bid group (n = 74). All pts were evaluable for achievement of the primary endpoint, 101 pts remained on study and were evaluable at week 24, and 96 pts had nonzero scores on the MFSAF-TSS and were evaluable for a reduction from baseline.Most pts who had assessments at week 24 (91% [92/101]) had a reduction from baseline in spleen volume (Figure). The study met the primary endpoint, with 31.7% (38/120) of all pts achieving ≥ 35% reduction from baseline at week 24. Overall, 38.3% (46/120) of pts achieved ≥ 35% reduction from baseline in spleen volume at any time on study. As measured by the 7-day MFSAF, 49% (47/96) of pts achieved ≥ 50% reduction from baseline in TSS (median reduction, 47.2%). Pts experienced an improvement from baseline at week 24 in EORTC global health status/QoL (mean change, 5.2). [Display omitted] The most common nonhematologic AEs (≥ 10%) regardless of relationship to study medication included diarrhea (25.8%), upper respiratory tract infection (17.5%), ALT level increased (15.0%), pyrexia (15.0%), AST level increased (13.3%), cough (11.7%), herpes zoster infection (11.7%), nasopharyngitis (10.8%), constipation (10.0%), gamma-glutamyl transferase level increased (10.0%), and headache (10.0%), and most were grade 1/2. Serious AEs were reported for 24.2% of pts, and 65.8% of all pts had grade 3/4 AEs. The most common new or worsening laboratory abnormalities were low hemoglobin (all grade 3, 55.7%), low lymphocyte (grade 3/4, 19.5%), low platelet (grade 3/4, 15.3%), and low ANC (grade 3/4, 7.6%) levels. AEs observed in this study were consistent with those observed in the 2 large phase 3 COMFORT studies. Six pts (5%) died on treatment or within 30 days of discontinuation. Summary/conclusionsFindings from this study demonstrated that ruxolitinib was relatively well tolerated in Asian pts with MF and provided substantial reductions in splenomegaly and modest improvements in MF-associated symptoms. The AEs observed with ruxolitinib treatment in this study are consistent with those observed in the large phase 3 COMFORT studies, and there were no new AEs associated with ruxolitinib in Asian pts with MF. Disclosures:Okamoto:Novartis: Honoraria, Research Funding. Sirulnik:Novartis: Employment. Ruiz:Novartis: Employment. Amagasaki:Novartis: Employment. Ito:Novartis: Employment. Akashi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase II trial of panobinostat, an oral pan‐deacetylase inhibitor in patients with primary myelofibrosis, post–essential thrombocythaemia, and post–polycythaemia vera myelofibrosis

Myelofibrosis (MF) is a Philadelphia chromosome-negative stem cell myeloproliferative neoplasm (MPN) associated with cytopenias, splenomegaly, constitutional symptoms, and poor prognosis. MF patients commonly express JAK2 V617F mutation and activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling. Agents targeting the JAK/STAT pathway have demonstrated efficacy in patients with MF. This study evaluated panobinostat, a pan-deacetylase inhibitor that depletes JAK2 V617F levels and JAK/STAT signalling in MPN cells, in patients with primary MF, post-essential thrombocythaemia MF, and post-polycythaemia vera MF. Patients received panobinostat 40 mg administered three times per week. Dose reductions were permitted for toxicities. The primary endpoint was response rate at 6 months using International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) consensus criteria. Analyses of peripheral blood cells from treated patients revealed that panobinostat inhibited JAK/STAT signalling, decreased inflammatory cytokine levels, and decreased JAK2 V617F allelic burden. However, panobinostat was poorly tolerated at the dose and schedule evaluated, and only 16 of 35 patients completed ≥2 cycles of treatment. One patient (3%) achieved an IWG-MRT response. Common adverse events were thrombocytopenia (71.4%) and diarrhoea (80.0%). Although molecular correlative analyses suggested that panobinostat inhibits key intracellular targets, limited clinical activity was observed because of poor tolerance.

Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903

A multicenter Eastern Cooperative Group (ECOG) phase 2 trial assessed whether adding prednisone to lenalidomide would improve previously reported responses in persons with myelofibrosis (MF). Forty-eight subjects with anemia (42 evaluable) received lenalidomide, 10 mg/d, with a 3-month low-dose prednisone taper. Ten subjects received 3 months, and 25 received 6 months of therapy. Myelosuppression was the main toxicity with 88% with ≥ grade 3 hematologic toxicity and 45% ≥ grade 3 nonhematologic toxicity. There were responses in 10 subjects (23%) using the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)-defined clinical improvement of anemia in 8 (19%) and/or decreased spleen size in 4 (10%). Serial bone marrow analysis showed no resolution of disease-related fibrosis or angiogenesis. With a median follow-up of 2.3 years, 23 subjects are alive. Lenali-domide and prednisone for myelofibro-sis evaluated through a multicentered-cooperative group mechanism is only modestly active and myelosuppre-sive. This study was registered at http://clinicaltrials.gov as NCT00227591.

Immunomodulatory Therapy with Combination of Low Dose Thalidomide, Alpha Interferon (IFN-a) and Prednisone Produces Durable Response In Myelofibrosis

AbstractAbstract 4123There is no effective therapy for primary myelofibrosis (MF) and post- essential thrombocythemia/polycythemia vera MF (ET/PV-MF) and conventional therapies are only palliative. Allogeneic stem cell transplantation which is the only curative option carries high mortality and morbidity and is precluded by age, poor performance status and co-morbidities. IMiDs like thalidomide and lenalidomide have been used with prednisone with some degree of response but the high doses used cause significant side effects. Single agent interferon use has in myelofibrosis has been disappointing and limited by toxicity at higher doses while low dose interferon has not been combined with other drugs. We used a unique combination of low doses of thalidomide (50 mg/day) along and prednisone (20 mg every other day) and IFN-a (1.5 million units three times a week) for patients with myelofibrosis. Methods:Subjects: A single institution retrospective review was carried out in 8 patients with primary or post-ET/PV MF. All patients had a baseline hemoglobin <10g/dl or were RBC-transfusion dependent (1 transfusion in 8 weeks prior to treatment). Any prior therapy was discontinues for at least 2 weeks prior to treatment. Patients were required to have adequate hepatic, renal function, ANC >1000/l, and platelets >100,000/l prior to starting therapy. Patients were started on thalidomide, prednisone orally, and IFN-a subcutaneously three times a week. Therapy was continued until there was progressive disease. At any time during the treatment phase, in case of unacceptable toxicity from thalidomide, patients were switched to low dose lenalidomide, 5 mg a day by mouth. Response assessments were based on the International Working group for Myelofibrosis research and treatment (IWG-MRT) criteria. Applicable responses under clinical improvements category for anemia included an increase in hemoglobin >2g/dl above baseline or RBC transfusion independence and for splenomegaly included a 50% reduction in the palpable component of spleen for 2 or more months. Results:We report results with a follow-up of 5.25 years from start of treatment. 1 patient discontinued therapy after 4 months due to progressive disease. Out of remaining 7 patients, 6 patients (85.7%) showed clinical improvement. 1 patient is still continuing on thalidomide combination at 5.25 years with clinical improvement. 1 patient who achieved CR was switched from thalidomide to lenalidomide after 1 year of therapy due to neurotoxicity and shows clinical improvement at 5 years from start of treatment. No grade 3–4 toxicity was seen in any patients. Improvement in anemia was seen in 6 out of 7 patients (85.7%). Major reductions in spleen size were seen in 3 out of 7 patients (43%). Median time form start of treatment to response was 1 month. Serial bone marrow analyses are available in 2 patients showing substantial decrease in fibrosis. Conclusions:The novel combination of low dose thalidomide, prednisone, and IFN-a results in durable and prolonged clinical response and is extremely tolerable with low toxicity. This promising combination should be explored further to offer treatment options to patients with myelofibrosis where currently there is no effective therapy. Disclosures:No relevant conflicts of interest to declare.

Efficacy and Safety of Peg-Interferon-α2a In Myelofibrosis: a Study of the FIM and GEM French Cooperative Groups

AbstractAbstract 4103 Background:The moderate effect of most palliative treatments in primary and secondary myelofibrosis (MF), in addition to the limited possibilities of allogeneic stem cell transplantation, has incited physicians to look for alternative treatments. Since 1987, several studies have suggested that interferon may be beneficial in the treatment of MF. However, important hematological and general limiting toxicities frequently occur in MF patients (pts), leading to rapid treatment discontinuation in more than 50% of pts. Better results were recently reported in a small series of 13 MF pts treated with Peg-Interferon-α2a (Ianotto et al., Br J Haematol, 2009). The present study aimed to collect data of pts with primary and secondary MF treated with Peg-Interferon-α2a in French centers members of the FIM (French Intergroup of Myeloproliferative disorders) and GEM (Groupe d'Etudes des Myelofibroses) groups, to better assess tolerance and efficacy of this form of interferon in MF. Patients and Methods:Between Dec 2006 and Feb 2010, 39 MF pts treated with Peg-Interferon-α2a were registered from 10 different French centers affiliated to FIM and GEM groups. Age of pts ranged from 41 to 81 years, 21 were men and 18 women. Sixteen pts had primary MF, 13 had post-PV and 10 post-ET MF, respectively. Twenty-five patients (64%) were JAK2V617F positive. Twenty-eight patients had previously received other cytoreductive treatment. Clinical and biological parameters were collected at diagnosis and every 3 months. Responses were assessed according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Analyses were performed in July 2010, after a median follow-up of 18 months (range: 3 – 42 months). Results:Among the 28 patients with splenomegaly, we observed 10 responses (36%) including 7 complete and 3 partial responses. Fourteen patients had constitutional symptoms which resolved in 8 of them (57%). Seven of 15 patients (47%) with an initial hemoglobin level below 100 g/L achieved complete response (CR). Three of 8 (37%) transfused pts became transfusion-independent. Twenty-two patients had abnormal WBC count which normalized in 13 of them (59%). Platelet count was abnormal in 27 patients, and 14 (52%) achieved CR with Peg-Interferon-α2a treatment. The evolution of the JAK2V617F allele burden is currently under investigation and will be presented at the meeting. The initial median dose of Peg-Interferon-α2a effectively received was 103 μ g/wk, further decreased to a median of 85 μ g/wk after one year. At time of analysis, treatment was stopped in 11/39 (28%) pts due to side effects, inefficacy or hematologic evolution. Conclusion:In this observational study, we found higher efficacy and better tolerance of interferon than previously reported in patients with primary or secondary MF. Such results were possibly due to a better tolerance of the pegylated form used, and to the low-dose schedule applied by the physicians. Our results suggest at least that Peg-Interferon-α2a should be considered as a possible therapeutic option in selected MF patients. Future clinical trials in MF will hopefully involve combinations of low dose Peg-Interferon-α2a with JAK2-inhibitors or immunomodulatory agents in order to improve tolerability and increase efficacy. Disclosures:OffLabelUse: This is an observational study of the off-label use of peg-Interferon-alfa2a in myelofibrosis.

Pomalidomide: A new IMiD with remarkable activity in both multiple myeloma and myelofibrosis

Pomalidomide: A new IMiD with remarkable activity in both multiple myeloma and myelofibrosis

RAD001, An Inhibitor of mTOR, Shows Clinical Activity in a Phase I/II Study in Patients with Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (PPV/PET MF).

Abstract 307Constitutive and enhanced activation of JAK/STAT pathway is found in patients (pts) with myeloproliferative neoplasms (MPN), particularly but not exclusively in those with mutation in the Janus tyrosine kinase 2 gene (JAK2V617F) or the MPL gene (MPLW515L/K/A). Activation of the Erk and PI3K/Akt pathways have also been described in cells harboring the JAK2V617F mutation. In in-vitro studies performed in our laboratory (AM Vannucchi et al, ASH 2009, abstract submitted) we observed that RAD001, a specific inhibitor of the serine/threonine kinase mTOR (mammalian target of rapamycin) that is a downstream target of PI3K, remarkably inhibited proliferation of JAK2V617F mutant cell lines and reduced the clonogenic activity of CD34+ cells from MPN pts. The PI3K/Akt/mTOR pathway has become an important focus for cancer therapy, and mTOR inhibitors have demonstrated activity against solid tumors and lymphomas. A phase I/II trial of RAD001 is being conducted in pts with PMF and PPV/PET MF, including JAK2V617F or MPL mutated as well as wild-type pts with intermediate/high risk score according to Lille criteria. Diagnosis of PMF and of PPV/PET-MF was made following the WHO and International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria, respectively. Phase I is a dose escalation of RAD001 involving 3 sequential cohorts of 3 pts each at 5.0, 7.5, and 10 mg daily, orally, for 3 months, to define maximum tolerated dose (MTD). Phase II involves the use of MTD for 4 months, according to a two-stage Simon design, aimed at assessing efficacy of the drug. Responses are evaluated using the EUMNET criteria for treatment response in myelofibrosis (Barosi G et al, Blood 2005). At the time of writing, 8 of 9 pts included in the Phase I have completed the 3-month study period without dose-limiting toxicities or other significant adverse events; the ninth pt at 10 mg is completing the last month of treatment. There were seven pts with PMF and 2 with PPV-MF. Main toxicities were represented by grade 2 mouth ulcers in 3 pts and transient grade 1/2 hypertrigliceridemia in 5 pts, that occurred irrespective of the dose. One pt at 10 mg presented transient muscular weakness and arthralgia. The initial dose of 5.0 mg resulted in a reduction in spleen size consistent with a complete response (CR) in one pt (from 4 to 0 cm below the left costal margin) and partial responses (PR) in two pts (from 10 and 13 cm to 1 and 9 cm, respectively). In the 7.5 mg cohort, there were one CR (from 4 to 0 cm) and one PR (from 16 to 8 cm) in splenomegaly; none of the 2 pts at 10 mg had a response in splenomegaly. In 1 pt CR in splenomegaly was maintained at +4 mo after suspension of drug while in the other responding pts there was a progressive re-enlargment of the spleen to baseline level. A complete resolution of systemic symptoms was achieved in 2 of 3 pts while aquagenic pruritus disappeared in all the 5 pts who complained of it. Overall, there were 2 major and 3 moderate responses, while 3 pts did not show a measurable response. At the end of therapy, the absolute count of circulating CD34+ cells had decreased in all but one pt of a median value of 39% from baseline (range 16% to 72%). There was no significant decrease in the burden of granulocyte V617F allele at the end of treatment in the 8 mutated pts. Single-colony JAK2V617F genotyping was performed in 4 pts, 2 each from the 5.0 and 7.5 mg cohort. In one patient receiving 7.5 mg the percentage of homozygous BFU-E and CFU-GM decreased from 14% and 45%, respectively, at baseline to 0 and 18% at the end of therapy; in the other 3 pts changes were minimal. In conclusion, initial results showed rapid reduction of splenomegaly and symptomatic improvement, without relevant toxicity, in pts with myelofibrosis receiving RAD001. The drug also reduced the circulating CD34+ cell count and V617F-homozygous progenitor cells appeared to be decreasing at least in some patients, although the allelic burden measured in granulocytes did not modify. Updated results on current patients and future patients enrolled in Phase II will be presented at the meeting. Disclosures:No relevant conflicts of interest to declare.

Improved Outcomes Using Tacrolimus/Sirolimus for Graft-versus-Host Disease Prophylaxis with a Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/- methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)+/-MTX, and the current series of 14 patients who received tacrolimus/sirolimus+/-MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P=.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P=.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus+/-MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF+/-MTX.

Lenalidomide and Prednisone for Primary and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (MF): An Eastern Cooperative Oncology Group (ECOG) Phase II Trial.

Background: Immunomodulatory therapy has been shown to be of benefit for the improvement of anemia, thrombocytopenia and splenomegaly in patients with myelofibrosis (MF) initially with thalidomide (Blood 2000; 96:4007), and further enhanced by combination therapy with corticosteroids (Blood 2003; 101:2534). We sought to further enhance our previously reported efficacy of single agent lenalidomide for MF patients (Blood 2006; 108:1158) by combination therapy with prednisone.Methods: Symptomatic patients with MF (all with baseline anemia, hemoglobin <10g/dL or transfusion dependent) were enrolled in the single arm Phase II trial. Adequate neutrophils (>1 x 109/L) and platelets (>100 x 109/L) were required for trial entry. Lenalidomide was administered at 10 mg daily with a 3 month prednisone taper (30mg/daily, 15 mg daily, 15 mg every other day months 1,2, and 3, respectively). Patients with at least stable disease remained on single agent lenalidomide for an additional 3 months. Responses were assessed by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Response Criteria (Blood 2006; 108:1498).Results:Patients 28 patients were enrolled in the first step of the trial, and a total of 48 patients were enrolled (3 were ineligible because of proximity of prior therapy with 43 deemed evaluable). The enrolled eligible patients (56 % males) had a median age of 64 (range 18–83). At baseline, 52% were red cell transfusion dependent, and the median hemoglobin amongst those non transfusion dependent patients was 8.8 g/dL (range 5.9–12.4). By entry criteria neutrophils (median 5.1 x 109/L (range 1.0–79.4)) and platelets (median 234 x 109/L (range 40–1253)) were adequate.Therapy and Toxicity: A median of 6 cycles of therapy was administered, 10 patients received 3 months, and 25 patients the full 6 months of therapy. Premature discontinuation of therapy occurred in 19 patients; progressive disease (3), toxicity (7), patient withdrawal (5), death from disease (1), comorbidities (2), or seeking alternative therapy other (1). Myelosuppression was the main toxicity with 45% experiencing ≥ grade 3 hematologic toxicity (16%/2% and 23%/26%, grade 3/4 thrombocytopenia and/or neutropenia, respectively) and with 34% of patients having ≥ grade 3 non-hematologic toxicity. Less severe toxicities (< grade 3) were again mainly secondary to myelosuppression (34%) or gastrointestinal (i.e. diarrhea). No significant steroid induced toxicities were observed.Response: Among 43 patients eligible for response assessment the best confirmed response observed was a partial response in 11 (26%), stable disease (54%), and progression during trial in 8 (18%), 1 was not evaluable because no medication was taken. Among the latter responses improvement in anemia was seen in 9 (21%) (IWG-MRT clinical improvement (CI)-sustained normalization of hemoglobin, >2 g/dL increase, or transfusion independence for >2 months), and major reductions in spleen size in 4 (9%) (IWG-MRT CI - sustained >50% decrease). Serial marrow analysis was available in a subset which did not show any significant resolution of disease related fibrosis, hypercellularity or increased angiogenesis typical of MF.Conclusions: 1) Lenalidomide plus a corticosteroid taper was active in patients with MF primarily in those who suffer from anemia, but myelosuppression (particularly neutropenia is common) 2) Response rates observed with combination therapy are almost identical to our previously reported response rate seen with single agent lenalidomide (22% single agent, 21% in this trial), 3) Current results would suggest that given the myelosuppression observed, and rates of efficacy, thalidomide and prednisone would be first line for treating MF associated cytopenias with lenalidomide being considered second line (first line if a del(5q) present).

Loss of Heterozygosity of Chromosome 1p34 and High Mutant Allele Burden in Patients with Post-Essential Thrombocythemia Myelofibrosis Carrying Somatic Mutations of MPL

The JAK2 (V617F) mutation is found in 95% of patients with polycythemia vera (PV) and in about 60% of those with essential thrombocythemia (ET) or primary myelofibrosis (PMF). In a portion of PV patients, the occurrence of a mitotic recombination of chromosome 9p in a hematopoietic cell that is heterozygous for the mutation generates a subclone of cells that are homozygous for JAK2 (V617F) [N Engl J Med. 2005 Apr 28;352(17):1779–90]. We have previously shown that the vast majority of patients with post-PV myelofibrosis (MF) have high percentages of granulocyte JAK2 (V617F) mutant alleles [Blood. 2008 Apr 1;111(7):3383–7], suggesting that transition from heterozygosity to homozygosity for JAK2 (V617F) is associated with progression to myelofibrosis in PV. Activating mutations of MPL, mainly involving a W515 substitution, have been detected in JAK2 (V617F)-negative patients with ET and PMF. MPL maps on chromosome 1p34, and whether a mitotic recombination of this chromosome occurs and involves a transition from heterozygosity to homozygosity for MPL mutations is currently unclear. At variance with post-PV MF, post-ET MF occurs rarely, with an estimated risk of about 6% at 15 years. We studied 315 patients with myeloproliferative disorders followed at the Department of Hematology Oncology, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. This study was approved by the local Ethics Committee. The revised World Health Organization (WHO) criteria were employed for the diagnosis of PV, ET and PMF, whereas the criteria of the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) were employed for the diagnosis of post-PV MF and post- ET MF. We developed a high-resolution melting-curve (HRM) assay for detecting MPL mutations in granulocyte and T lymphocyte gDNA. The study population included 205 patients with ET [58% of whom carried JAK2 (V617F)], 91 patients with PMF [62% of whom carried JAK2 (V617F)], and 19 patients with post-ET MF [42% of whom carried JAK2 (V617F)]. By means of HRM analysis and direct sequencing, we detected the following MPL mutations in circulating granulocytes but not in T lymphocytes: W515L, W515K, W515A, S505C, and V501A – these latter two being novel mutations. Two patients carried two different MPL mutations concurrently in circulating granulocytes, while another patient carried both JAK2 (V617F) and a MPL mutation. Based on the detection of abnormal melting curve profiles in granulocytes, the prevalence of MPL mutations was found to be 5.4% in all patients with ET [12.6% in JAK2 (V617)-negative subjects], 5.5% in those with PMF [14.3% in JAK2 (V617)-negative subjects], and 21.1% in patients with post-ET MF [36.4% in JAK2 (V617)-negative subjects]. The prevalence of MPL mutations was therefore significantly higher in post-ET MF than in ET (P<.01) or in PMF (P<.05). Patients with post-ET MF carried high percentages of granulocyte MPL mutant alleles (median value 94%). In these subjects, SNP analysis of sequences mapping on chromosome 1p36.32, 1p34.3, 1p34 and 1p22.1, respectively, showed loss of heterozygosity (LOH) of chromosome 1p34 and its telomeric sequences in granulocytes but not in T-lymphocytes. This may suggest that a mitotic recombination of chromosome 1p was responsible for 1pLOH. Thus, similarly to what happens with JAK2 (V617F) on chromosome 9p in patients with PV, a mitotic recombination of chromosome 1p might represent a mechanism responsible for transition from heterozygosity to homozygosity for MPL mutations. Although 1pLOH is likely much less frequent than 9pLOH in myeloproliferative disorders, in patients with ET carrying MPL mutations it appears to be associated with the development of marrow fibrosis, abnormal stem cell trafficking and myeloid metaplasia.

Pomalidomide Therapy in Anemic Patients with Myelofibrosis: Results from a Phase-2 Randomized Multicenter Study

BACKGROUND: Both thalidomide (Br J Haematol 2002; 117:288) and lenalidomide (Blood 2006; 108:1158) are effective for alleviating anemia in approximately 20% of patients with myelofibrosis (MF). However, the value of these drugs is undermined by their respective potential for peripheral neuropathy and severe myelosuppression. In the current study, we evaluated the safety and efficacy of the new immunomodulatory drug, pomalidomide (POM) in MF.METHODS: This is a phase-2 randomized, multicenter, double-blind, active-control, parallel-group study to determine safety and select a “Best” dose of POM alone or combined with prednisone (PRED). Patients were equally randomized to 4 treatment groups:POM (2 mg/day) + placebo,PRED (30 mg/day) + placebo,POM (2 mg/day) + PRED (30 mg/day), andPOM (0.5 mg/day) + PRED (30 mg/day). POM therapy was given for up to twelve 28-day treatment cycles.PRED therapy was given in a tapering dose schedule during the first three of these 12 treatment cycles. Protocol eligibility criteria included absolute neutrophil count of ≥ 1 × 109/L, platelet count of ≥ 50 × 109/L and hemoglobin level of < 10 g/dL including red blood cell (RBC) transfusion requirement. Patients with prior thalidomide or lenalidomide therapy and/or venous thrombosis were excluded from study participation. Response was assessed by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria (Blood. 2006; 108:1497) and by independent analysis of the component variables.RESULTS: A total of 104 patients with MF were assessed for eligibility; 85 were randomized and 84 received the assigned therapy. Blinded data for the first 82 patients are presented here; median age was 67 years and MF subtype was PMF in 70% of the patients and post-PV/ET MF in 30%. All patients belonged to either intermediate or high risk disease category (Blood 1996; 88:1013); 42 (51%) were RBC transfusion-dependent. Median duration of disease before randomization was 3 years (range 2–14). The number of patients assigned to each arm was relatively balanced: 21, 20, 19 and 22, respectively. After a median treatment duration of 3 months, 42 (51%) patients have discontinued protocol therapy because of lack of therapeutic effect (n=19), withdrawal of consent (n=11), adverse event (n=11) or death (n=2). Grade 3/4 adverse events (regardless of attribution) included anemia (10%), thrombocytopenia (9%), leukopenia (9%), fatigue (7%), dyspnea (5%), thrombosis (4%), diarrhea (4%) and hyperglycemia (4%). Combined response rate using IWG-MRT criteria was 25% (95% CI, 16–34%) and ranged between 11% and 42% among the four treatment arms.CONCLUSION: Pomalidomide, with or without concomitant prednisone therapy, is well tolerated in patients with MF, especially from the standpoint of myelosuppression. Response rates are high. Additional, unblinded, information regarding response details, remission duration and laboratory correlative studies will be presented at the meeting.

303: Role of Extensive Splenomegaly in Patients with Myelofibrosis undergoing a Reduced Intensity Allogeneic Stem Cell Transplant

Allogeneic stem cell transplantation has been shown to restore normal hematopoiesis in patients with intermediate or high risk primary myelofibrosis (PMF) or myelofibrosis preceeded by polycythemia vera or essential thrombocythemia. However, in patients with PMF and extensive splenomegaly it is not clear whether transplant is associated with an unacceptable risk or if splenectomy should be performed prior to transplant. In this study, ten consecutive patients with myelofibrosis who were not splenectomized received an allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors and were periodically monitored by ultrasound or CT scan for 12 months after transplant to assess the kinetics of the reduction of splenomegaly. These findings were correlated with the time to resolution of marrow fibrosis, time to engraftment and clinical outcome. Over a 12 month period a progressive reduction in spleen size was observed in all the patients and paralleled the reduction in marrow fibrosis. Of 10 patients, 5 with a splenic longitudinal diameter >30 cm showed a more prolonged time to engraftment ANC > 0.5 × 109/L (d 19 ± 5 vs 13 ± 2, p = 0.05) and platelet > 20 × 109/L (d 75 ± 104 vs 11 ± 2, p = 0.06). However, of the 5 patients with more extensive splenomegaly only 2 experienced delayed engraftment of platelets (d 77 and 256, respectively). Full donor chimerism was observed in all patients within 60 days after transplantation regardless of the size of the spleen. At a median follow-up of 51 months (range: 2–81) all the patients are alive but 1 who died of a TTP like syndrome 2 months after transplant and had a small spleen at the time of transplant. A clinical CR has been documented in 7 patients and 2 have achieved clinical improvement according to to the criteria established by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). These findings suggest that allogeneic HSCT with RIC regimen can be safely performed in patients with extensive splenomegaly. Although in these patients the time to achieve a full hematopoietic engraftment may be prolonged, the significant risk of morbidity and mortality associated with splenectomy may be avoided. Allogeneic stem cell transplantation has been shown to restore normal hematopoiesis in patients with intermediate or high risk primary myelofibrosis (PMF) or myelofibrosis preceeded by polycythemia vera or essential thrombocythemia. However, in patients with PMF and extensive splenomegaly it is not clear whether transplant is associated with an unacceptable risk or if splenectomy should be performed prior to transplant. In this study, ten consecutive patients with myelofibrosis who were not splenectomized received an allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors and were periodically monitored by ultrasound or CT scan for 12 months after transplant to assess the kinetics of the reduction of splenomegaly. These findings were correlated with the time to resolution of marrow fibrosis, time to engraftment and clinical outcome. Over a 12 month period a progressive reduction in spleen size was observed in all the patients and paralleled the reduction in marrow fibrosis. Of 10 patients, 5 with a splenic longitudinal diameter >30 cm showed a more prolonged time to engraftment ANC > 0.5 × 109/L (d 19 ± 5 vs 13 ± 2, p = 0.05) and platelet > 20 × 109/L (d 75 ± 104 vs 11 ± 2, p = 0.06). However, of the 5 patients with more extensive splenomegaly only 2 experienced delayed engraftment of platelets (d 77 and 256, respectively). Full donor chimerism was observed in all patients within 60 days after transplantation regardless of the size of the spleen. At a median follow-up of 51 months (range: 2–81) all the patients are alive but 1 who died of a TTP like syndrome 2 months after transplant and had a small spleen at the time of transplant. A clinical CR has been documented in 7 patients and 2 have achieved clinical improvement according to to the criteria established by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). These findings suggest that allogeneic HSCT with RIC regimen can be safely performed in patients with extensive splenomegaly. Although in these patients the time to achieve a full hematopoietic engraftment may be prolonged, the significant risk of morbidity and mortality associated with splenectomy may be avoided.

INCB018424, an Oral, Selective JAK2 Inhibitor, Shows Significant Clinical Activity in a Phase I/II Study in Patients with Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF).

Background: A mutation in the Janus tyrosine kinase 2 gene (JAK2 V617F) has been recognized in Philadelphia chromosome-negative myeloproliferative disorders, including PV (∼95% of patients), ET (∼50%) and PMF (∼50%). INCB018424 is a potent and orally bioavailable selective JAK2 inhibitor with >80-fold selectivity against a broad panel of kinases, including JAK3. INCB018424 potently inhibits JAK2 V617F mediated signaling and malignant cell survival in vitro and in vivo in mice. Preclinical safety studies with INCB018424 demonstrated an excellent safety profile with no off-target toxicities.Methods: A phase I/II trial of INCB018424 given orally BID is being conducted in patients with PMF and Post-PV/ET MF. Both JAK2 V617F and JAK2 wild type patients are eligible. PK and PD data are being collected. Responses are being evaluated using the International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT) (Tefferi et al., Blood , 108, 1497–1503, 2006).Results: The initial dose of 25 mg PO BID resulted in a rapid and marked reduction in splenomegaly. All 3 patients in the first cohort of patients achieved a reduction in spleen size that is consistent with a clinical improvement response provided it is sustained for 8 weeks; spleen sizes of 25, 22, and 7 cm below the left costal margin have decreased to 8, 10, and 0 cm in the first month of therapy. At two months follow-up, the patient with a baseline spleen size of 22 cm is now down to 2 cm. All 3 patients also noted significant symptomatic improvement. The second cohort of 3 patients started therapy at an increased dose (50 mg PO BID) and at one week follow-up, the initial two patients (one JAK2 wild type, one JAK2 V617F) had decreases in spleen size from 22 cm to 17 cm and from 22 cm to 16 cm, respectively. No dose-limiting toxicities or other significant adverse events occurred in any patients to date. PK/PD analyses demonstrated that administration of INCB018424 resulted in plasma drug concentrations sufficient to markedly inhibit JAK2, as shown by suppression of phosphorylated STAT3 (a substrate of JAK2) in whole blood cells in all 3 patients in the first cohort. The 3 patients in the first cohort were all JAK2 V617F mutation positive: percentages of JAK2 V617F positive whole blood cells before therapy were 79%, 49% and 91%, and after one month of therapy, they were 59%, 48% and 78%, respectively.Conclusions: Initial results show marked reduction in splenomegaly and symptomatic improvement, without significant toxicity. The percentage of blood cells with JAK2 V617F mutation appears to be decreasing in patients on therapy. Updated results on current and future patients will be presented at the meeting.

Clinical Evolution to Primary Myelofibrosis - Blast Phase: An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) Collaborative Retrospective Analysis.

Background: We sought to retrospectively analyze the clinical differences, at diagnosis and throughout the disease course, between patients with primary myeloifbrosis whom undergo blastic transformation (PMF-BP) and those whom expire from PMF complications without undergoing transformation.Methods: An international collaborative database of patients with PMF which progressed to PMF BP, and a control group of individuals with PMF who expired secondary to PMF was created. Data regarding clinical course, bone marrow, karyotypic, quantitative JAK2V617F analysis (when able), laboratory values, and therapy at the diagnosis of PMF, PMF BP and up to 4 return visits (R1-4) in between these milestones was abstracted.Results: COMPARISON AT DIAGNOSIS OF PMF: 136 cases of PMF who eventually underwent PMF-BP were included, with a control group of 42 PMF patients, were analyzed. Both groups of patients had similar demographic (median age at diagnosis 59 years (range 23–83)/ 59.1 (15–93); and disease parameters (median hemoglobin 10 g/dL (range 2–15.7) /9.8 (4.9–14.6); median platelet count 181 x 109/L (range 7–1400)/168 (16–1916)), and Lille PMF prognostic scores (p = n.s.) for PMF-BP vs. PMF control group respectively. Additionally, blasts (peripheral blood /marrow) were a median of 0% (range 0–18%)/ 2% (range 0–16%) for the study group versus 0.25% (range 0–5%)/ 3% (range 0–4%) (p = n.s. for both) for the control group, respectively. Both groups had similar rates of requiring therapy (86%; 93%) and survival from diagnosis (median 34 months (range 2–441); 29 months (1–236)) (p = n.s.). However, lactate dehydrogenase (LDH) (although high in both groups) was higher at diagnosis (median 802 IU/L (range 83–10353) vs. 416 IU/L (124–2197)) (p=0.04), as well as an abnormal marrow karyotype (85% vs. 25%; p<0.001) amongst the PMF BP group.SUBSEQUENT CLINICAL COURSE: Analyzing the clinical evolution between groups demonstrated persistently higher LDH and worsening thrombocytopenia in the PMF-BP cohort (see figure). [Display omitted] Peripheral blood blasts increased in both groups, but values above 10% were unique to the PMF BP group. Additionally marrow karyotype displayed clonal evolution developed in 56% of the PMF-BP patients as opposed to 14% of controls (p<0.001). Initial and serial quantitative JAK2V617F mutation analysis (available from 20 /19 patients from the PMF-BP and control group at diagnosis, with 11 / 12 serial samples) showed no difference between the groups, nor a pattern of mutation burden elevation with transformation to leukemia in the study group.Conclusions: Increasing LDH, peripheral blood blast percentages >10%, and clonal evolution are features commonly seen in PMF patients whom evolve to blast phase and may be a harbinger of movement towards PMF BP.