Distinctive Attributes of Indian Patients With Classical BCR::ABL1 Negative Myeloproliferative Neoplasms: Unified Clinical and Laboratory Data

IntroductionWe report one of the largest single center data from a mixed referral setting in India describing baseline characteristics and outcomes of patients with classical BCR::ABL1 negative myeloproliferative neoplasms (MPNs).Materials and MethodsPatients diagnosed from June 2019 to 2022 were included. Workup and treatment was as per current guidelines.ResultsDiagnosis comprised polycythemia vera (PV) in 51(49%), ET in 33(31.7%) and prefibrotic primary myelofibrosis (MF) pre fibrotic myelofibrosis (prePMF) and myelofibrosis in 10(9.6%) patients each. Median age at diagnosis was 52 years for PV and ET, 65.5 for MF and 79 years for prePMF. Diagnosis was incidental in 63(56.7%) and after thrombosis in 8(7.2%) patients. Baseline next generation sequencing (NGS) was available for 63(60.5%) patients. Driver mutations in PV: JAK2 in 80.3%; in ET: JAK2 in 41%, CALR in 26%, MPL in 2.9%; in prePMF JAK2 in 70%, CALR in 20%, MPL in 10%, and in MF: JAK2 in 10%, MPL in 30% and CALR in 40%. Seven novel mutations were detected of which 5 were potentially pathogenic on computational analysis. After median follow up of 30 months, 2 patients had disease transformation and none had new episodes of thrombosis. Ten patients died, most commonly with cardiovascular events(n = 5,50%). Median overall survival was not reached. Mean OS time was 10.19 years(95%CI, 8.6 to 11.74) and mean time to transformation was 12.2 years(95% CI,11.8 to 12.6).ConclusionOur data indicates comparatively indolent presentation of MPNs in India with younger age and lower risk of thrombosis. Further follow up will enable correlation with molecular data and guide modification of age based risk stratification models.     

Spleen deflation and beyond: The pros and cons of Janus kinase 2 inhibitor therapy for patients with myeloproliferative neoplasms

The myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are malignancies that frequently harbor the recurrent somatic point mutation JAK2^V617F. The discovery of this mutation has fueled the development of Janus kinase 2 (JAK2) inhibitors. Available results have indicated that JAK2 inhibitors are particularly effective at reducing spleen size. However, the activity of these agents is multifaceted and also involves a marked improvement of systemic symptoms and, for those agents with dual JAK1 and JAK2 inhibitory activity, a marked reduction in the levels of circulating cytokines involved in the pathogenesis of the disease. Because JAK2 inhibitors are not specific for JAK2^V617F, responses have also been observed in JAK2^V617F‐negative MPNs because of the inhibition of wild‐type JAK2, which is also likely responsible for the induction of cytopenias in patients with MF and for the normalization of peripheral blood counts observed in patients with ET or PV. Given the distinct mortality and morbidity associated with ET, PV, and MF, the use of JAK2 inhibitors appears reasonable for patients with MF as well as for those with ET or PV who have become resistant or intolerant to hydroxyurea. Ongoing randomized, placebo‐controlled, phase 3 trials will further delineate the role of these agents in the management of patients with MPNs. The pros and cons of JAK2 kinase inhibitor therapy are herein discussed. Cancer 2012;. © 2011 American Cancer Society.     

Classical Philadelphia-negative myeloproliferative neoplasms: focus on mutations and JAK2 inhibitors

Classical Philadelphia- negative myeloproliferative neoplasms (MPNs) encompass three main myeloid malignancies: polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Phenotype-driver mutations in Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) genes are mutually exclusive and occur with a variable frequency. Driver mutations influence disease phenotype and prognosis. PV patients with JAK2 exon 14 mutation do not differ in number of thrombotic events, risk of leukemic and fibrotic transformation, and overall survival to those with JAK2 exon 12 mutation. Type 2-like CALR-mutated ET patients have lower risk of thrombosis if compared with those carrying JAK2 or type 1-like CALR mutation. For ET, overall survival is comparable between patients with JAK2 and either type 1-like and type 2-like CALR mutations. For MF, better OS is demonstrated for patients harboring a type 1-like CALR mutation than those with type 2-like CALR or JAK2. The discovery of driver mutations in MPNs has prompted the development of molecularly targeted therapy. Among JAK2 inhibitors, ruxolitinib (RUX) has been approved for (1) treatment of intermediate-2 and high-risk MF and (2) PV patients who are resistant to or intolerant to hydroxyurea. RUX reduces spleen size and alleviates disease symptoms in a proportion of MF patients. RUX in MF leads to prolonged survival and reduces risk of death. RUX controls hematocrit, reduces spleen size and alleviates symptoms in PV. Adverse events of RUX are moderate, however, its long-term use may be associated with opportunistic infections. Trials with other JAK2 inhibitors are ongoing.     

Treatment Patterns,Health Care Resource Utilization,and Cost in Patients with Myelofibrosis in the United States

BackgroundThis study analyses treatment patterns, health care resource utilization (HCRU), and costs in patients with myelofibrosis (MF) and a subgroup treated with ruxolitinib (RUX).Materials and MethodsTreatment patterns, all-cause and MF-related HCRU, and costs were analyzed in adults with MF with continuous enrollment in a commercial or the Medicare Advantage health plan in the pre-index period, defined as the 12 months immediately prior to the index date (date of primary or secondary MF diagnosis), and the post-index period, defined as ≥6 months following the index date. In a subgroup analysis, outcomes were analyzed in patients treated with optimal RUX (OPT RUX, ≥30 mg) and suboptimal RUX (SUB RUX, <30 mg) in the pre-index RUX period, defined as the 3 months immediately prior to the index RUX date (first date for an RUX claim), and the post-index RUX period, defined as ≥6 months following the index RUX date.ResultsOf 2830 patients with an MF diagnosis, 1191 met eligibility requirements. The median age of patients was 72 years, 54% were male, and comorbidities were frequent. Sixty percent of patients received ≥1 line of therapy (LOT), of which 46% (n = 331) had ≥2 LOTs during the post-index MF period. Costs increased considerably 6-month pre-index to 6-month post-index (all-cause: cause ($24,216 to $48,966) and MF-related ($16,502 to $39,383), driven by inpatient stays and pharmacy costs. In the subgroup analysis, patients treated with RUX (n = 495) experienced significant disease burden and high costs, regardless of dose. A shorter duration of therapy and a higher rate of discontinuation were observed in patients treated with SUB RUX (n = 191) versus OPT RUX (n = 304).ConclusionThese findings suggest a significant disease and economic impacts associated with MF patients that persists with RUX therapy, highlighting the need for additional therapeutic options for MF.     

Predictive Value of Kozak Gene Polymorphism for Thrombosis in Patients with Philadelphia-Negative MPNs

Background: Philadelphia-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis are clonal haematopoietic stem cell disorders characterized by dysregulated proliferation. The arterial and venous thromboses are the major causes of morbidity and mortality in MPNs. The platelet GP Ib-IX-V receptor complex plays an important role in thrombus formation as the Kozak sequence polymorphism of platelet GP Ibα is associated with increased receptor density. Materials and Methods: This study was conducted on 286 diagnosed patients with Ph-negative MPNs (94 patients of PV, 102 of ET and 90 of MF). In addition, 107 apparently healthy individuals served as a control group. Results: This study revealed that by taking rs2243093 TT as the reference genotype and T as the reference allele; TC, CC, TC+CC genotypes showed lower frequency in ET patients (p= 0.005, 0.007 and 0.001 respectively) and MF patients (p= 0.002, 0.047 and 0.001 respectively) when compared to control groups also, C allele in both groups compared to control (p ≤ 0.001 both). CC genotypes and C allele showed lower frequency in PV patients when compared to control groups (p= 0.032 and 0.026 respectively). Conclusion: From this study we could conclude that patients with Philadelphia-negative MPNs carried Kozak gene polymorphism significantly TT genotype in all patients PV, ET, MF patients and TC in ET and MF patients. The platelet glycoprotein Ibα (Kozak) gene could be incorporated into the routine workup to predict venous thrombosis in patients with Ph-negative MPNs specially ET patients.     

Disease and Clinical Characteristics of Patients With a Clinical Diagnosis of Myelofibrosis Enrolled in the MOST Study

BackgroundClinical characteristics and treatment patterns of patients with lower-risk myelofibrosis (MF) are not well described. This analysis from the MOST (NCT02953704) assessed the demographic and clinical characteristics and treatment patterns of patients with the clinical diagnosis of lower-risk MF at enrollment.Patients and MethodsMOST is an ongoing, prospective, observational study in patients with clinical diagnoses of MF or essential thrombocythemia enrolled at clinical practices throughout the United States. Patients included in the MF cohort (≥18 years of age) had low-risk MF by the Dynamic International Prognostic Scoring System or intermediate-1 (INT-1) risk MF (by age >65 years only) at enrollment. Patient data were entered into an electronic case report form during usual-care visits over a planned 36 month observation period.ResultsTwo hundred five patients were eligible for this analysis (low risk, n = 85; INT-1 risk, n = 120; median age, 68 years [range, 35–88]); 166 patients (81.0%) had mutation testing results available. The median time from MF diagnosis to enrollment was 1.8 years. Hemoglobin and hematocrit levels were below the normal range in 50.5% and 48.7% of patients, respectively. Nearly all (98.0%) patients had comorbid conditions, most commonly hypertension (49.8%). Fatigue was the most common physician-reported MF symptom (30.7%). At enrollment, 55.6% of patients were receiving MF-directed monotherapy, most frequently hydroxyurea (46.5%) or ruxolitinib (40.4%).ConclusionFuture longitudinal analyses of data from MOST will help identify unmet needs and characterize how patients with lower-risk MF are managed throughout the disease course.     

JAK2 inhibitors: are they the solution?

The discovery of the JAK2V617F mutation in patients with Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) started the era of targeted therapy for these diseases. Until now, patients had few treatment options available, which usually were restricted to hydroxyurea, interferon preparations, and chemotherapy in more aggressive cases. JAK2 inhibitors have been developed over the past 5 years, and the results of the first clinical trials with JAK2 inhibitors for patients with myelofibrosis were recently published. Current research results suggest that JAK2 inhibitors have a potential to decrease disease burden and its activity, as manifested by a decrease in splenomegaly and improvement in systemic disease-related symptoms, but they do not seem to be able to eradicate the malignant clone. However, JAK2 inhibitors help patients regardless of their mutation status, because patients without JAK2V617F mutation benefit to the same extent as patients with JAK2V617F mutation. A greater understanding of the pathophysiology of MPNs is needed before we can cure myelofibrosis with drug therapy. Currently, several new JAK2 inhibitors are in clinical trials for patients with myelofibrosis, and clinical trials for patients with polycythemia vera and essential thrombocythemia have also started. We review recent data on JAK2 inhibitors for the management of patients with Ph-negative MPNs.     

The platelet–cancer loop in myeloproliferative cancer. Is thrombocythemia an enhancer of cancer invasiveness and metastasis in essential thrombocythemia,polycythemia vera and myelofibrosis?

Recent studies have provided evidence that the Philadelphia-negative chronic myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera and myelofibrosis (MPNs), may be preceded or accompanied by chronic inflammation and are associated with an increased risk of second cancers, both hematological and non-hematological. Thrombocythemia is one of the hallmarks in the early stages of these neoplasms. Several non-hematological cancers are associated with reactive thrombocythemia, which has been shown to have a major negative impact upon survival. In regard to treatment of MPNs a “wait and watch” strategy is recommended in patients with low-risk disease. Another strategy implies early treatment with interferon-alpha2 (IFN) to prohibit clonal evolution. Based upon experimental and clinical studies of the important role of platelets for cancer invasiveness and metastasis it is herein argued, that these detrimental platelet effects further support the “Early Interferon Concept” in MPNs to normalize elevated leukocyte and platelet counts. In the context of the known increased risk of second cancer in MPNs the prevailing “wait and watch” strategy is seriously challenged, when taking into account that this strategy may actually worsen prognosis of second cancers in MPNs due to elevated platelet counts, enhancing cancer invasiveness and its metastatic potential.     

Analysis of Predictive Factors for Early Response to Ruxolitinib in 320 Patients with Myelofibrosis From the Polish Adult Leukemia Group (PALG) Registry

IntroductionRuxolitinib is widely used in myelofibrosis (MF). However, some patients do not optimally respond and require more efficacious treatment. Our analysis aimed to establish predictors of ruxolitinib response.Patients and MethodsWe designed a multicenter, retrospective analysis of the efficacy of ruxolitinib treatment in patients with MF in 15 Polish hematology centers. As responses to ruxolitinib occur within the first 6 months, we used this point to evaluate the efficacy of treatment. Symptoms response was defined as ≥50% reduction of the MF constitutional symptoms assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Spleen response was defined as ≥50% reduction of the difference between the spleen's baseline length and the upper limit norm measured by ultrasonography.Results320 MF patients were enrolled. At 6 months of therapy, the spleen response was detected in 140 (50%) patients, and symptoms response in 241 patients (76%). Multivariable analysis identified leukocytosis <25 G/L (OR 2.06, 95%CI: 1.12-3.88, P = .0200), and reticulin fibrosis MF 1 (OR 2.22, 95%CI: 1.11-4.46, P = .0249) contributed to better spleen response. The time interval between MF diagnosis and ruxolitinib administration shorter than 3 months, and platelets ≥150 G/L (OR 1.69, 95% CI 1.01-2.83, P = .0466) influenced symptoms response.ConclusionEstablishing predictive factors for ruxolitinib response is particularly important given the potential for new therapies in MF. In patients with a low likelihood of responding to ruxolitinib, using other JAK inhibitors or adding a drug with a different mechanism of action to ruxolitinib may be of clinical benefit.     

Experimental therapeutics for patients with myeloproliferative neoplasias

Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) are characterized by stem cell-derived, unrestrained clonal myeloproliferation. The World Health Organization classification system, proposed in 2008, identifies 7 distinct categories of Ph-negative MPNs including essential thrombocythemia (ET); polycythemia vera (PV); primary myelofibrosis (PMF); mastocytosis; chronic eosinophilic leukemia; chronic neutrophilic leukemia; and MPN, unclassifiable. For many years, the treatment of ET, PV, and PMF, the most frequently diagnosed Ph-negative MPNs, has been largely supportive. In recent years, that paradigm has been challenged because of the discovery of a recurrent point mutation in the Janus kinase 2 (JAK2) gene (JAK2(V617F)). This mutation can be detected in the vast majority of patients with PV and approximately half of patients with ET or PMF and serves as both a diagnostic marker as well as representing a putative molecular target for drug development. Several putative targeted agents with significant in vitro JAK2 inhibitory activity and various degrees of JAK2 specificity are currently undergoing clinical evaluation. Furthermore, other investigational non-tyrosine kinase inhibitor approaches such as immunomodulatory agents and pegylated interferon- have also shown promising results in MPNs.     

Increased prevalence of autoimmune phenomena in myelofibrosis: Relationship with clinical and morphological characteristics,and with immunoregulatory cytokine patterns

Autoimmune phenomena and cytokines were investigated in 100 patients with myelofibrosis (MF) and related to marrow fibrosis and clinical risk. Anti-erythrocyte antibodies by mitogen-stimulated direct antiglobulin test (MS-DAT) were positive in 45%, anti-platelets in 15% and organ/non organ-specific in 57% of cases, without clinically overt disease, and mostly in low-risk/intermediate-risk-1 and MF-0/MF-1. TGF-β and IL-8 were increased in MS-DAT positive cases, and IFN-γ in patients with serological autoantibodies. TGF-β and IL-17 were elevated in early clinical and morphological stages, while IL-8 increased in advanced stages. These data suggest that autoimmune phenomena and cytokine disregulation are particularly relevant in early MF.     

Prognostication in Philadelphia Chromosome Negative Myeloproliferative Neoplasms: a Review of the Recent Literature

Purpose of Review

The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased risk for thrombotic complications, bleeding, and leukemic transformation. Several clinical, biological, and molecular prognostic factors have been identified in recent years, which provide important information in guiding management of patients with Ph-negative MPNs. In this review, we critically evaluate the recent published literature and discuss important new developments in clinical and molecular factors that impact survival, disease transformation, and thrombosis in patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

Recent Findings

Recent studies have identified several clinical factors and non-driver mutations to have prognostic impact on Ph-negative MPNs independent of conventional risk stratification and prognostic models. In polycythemia vera (PV), leukocytosis, abnormal karyotype, phlebotomy requirement on hydroxyurea, increased bone marrow fibrosis, and mutations in ASXL1, SRSF2, and IDH2 were identified as additional adverse prognostic factors. In essential thrombocythemia (ET), JAK2 V617F mutation, splenomegaly, and mutations in SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 were found to be additional negative prognostic factors. Bone marrow fibrosis and mutations in ASXL1, SRSF2, EZH2, and IDH1/2 have been found to be additional prognostic factors in primary myelofibrosis (PMF). CALR mutations appear to be a favorable prognostic factor in PMF, which has not been clearly demonstrated in ET.

Summary

The prognosis for patients with PV, ET, and PMF is dependent upon the presence or absence of several clinical, biological, and molecular risk factors. The significance of additional risk factors identified in these recent studies will need further validation in prospective studies to determine how they may be best utilized in the management of these disorders.

     

Disease and Clinical Characteristics of Patients With a Clinical Diagnosis of Essential Thrombocythemia Enrolled in the MOST Study

Few data exist regarding the disease and clinical characteristics of patients with essential thrombocythemia (ET) in the United States. The ongoing, multicenter, noninterventional, prospective, Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) was designed to collect data pertaining to the demographics, clinical management, and patient-reported outcomes in patients with myelofibrosis or ET in the United States (NCT02953704). This analysis examines the clinical characteristics of patients with clinical diagnoses of high-risk or low-risk ET receiving ET-directed therapy at enrollment. At data cutoff (June 17, 2019), 1207 of 1234 enrolled patients were eligible for this analysis (median age, 70 years; 65% female; 88% white); 917 patients (76%) had mutation testing results available. The median time from ET diagnosis to study enrollment was 4.2 years. The majority of patients (87%) had high-risk ET. Of 333 patients with a history of thrombotic events, 247 had at least 1 event classified as arterial and/or venous. Platelet count was above normal range in 54% of patients. Hypertension (56%) was the most common comorbidity. At enrollment, the majority of patients (low-risk ET, 94%; high-risk ET, 79%) were receiving ET-directed monotherapy. Additional prospective analyses from MOST will help to identify areas of unmet need.     

Myelofibrosis—When Do We Select Transplantation or Non-transplantation Therapeutic Options?

Janus kinase 1/2 (JAK1/2) inhibitor therapy is effective in alleviating myelofibrosis (MF)-related symptoms. However, at present, the only curative therapy for MF patients is hematopoietic cell transplantation (HCT). The decision of whether to proceed with HCT, which carries significant risks, or continue with JAK inhibitor therapy is a complicated one. Nevertheless, careful assessment of patient, disease, and transplant-related factors can guide this decision on a case-by-case basis. Difficult questions arise in the decision-making process such as age limits, whether lower-risk patients are suitable candidates, and HCT in patients responding well to JAK inhibitor therapy. The optimal timing of transplant is a major dilemma in the management of MF patients who are responding to or are stable on JAK inhibitor therapy. In this paper, we provide our perspective on selection of transplant versus non-transplant therapies in the management of MF.     

Analysis of Common Driver Mutations in Philadelphia-Negative Myeloproliferative Neoplasms

BackgroundPhiladelphia-negative myeloproliferative neoplasms (MPNs) are a group of hematopoietic stem cell disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This study examines the driver mutations among patients with MPNs in Kuwait.Patients and MethodsThis study was a retrospective review of 942 MPN cases with a driver mutation from July 2007 to June 2019 to examine their demographic, clinical, and laboratory attributes.ResultsThe annual incidence of MPNs is 1.6 per 100,000 persons, and ET is the most common subtype. The median age of our cohort was 55 years, and the patients were predominantly male. We found that the most frequent gene mutation of MPNs in our cohort was the JAK2V617F mutation, which was present in 90% of cases, followed by the CALR exon 9, MPLW515L/K, and JAK2 exon 12 mutations. In our cohort, thrombotic events were observed in 18.7% of cases.ConclusionAlthough Philadelphia-negative MPNs are rare hematologic malignancies, thrombosis is a relatively common initial presentation. The JAK2V617F mutation was the driver mutation in the majority of patients with MPN.     

The JAK2V617F tyrosine kinase mutation has no impact on overall survival and the risk of leukemic transformation in myelofibrosis

The prevalence of JAK2V617F tyrosine kinase mutation differs between various variants of myelofibrosis with the higher detection rate for patients with post-polycythemia vera myelofibrosis (post-PV MF; 91%) if compared to primary myelofibrosis (PMF; 45%) and post-essential thrombocythemia myelofibrosis (post-ET MF; 39%). The impact of V617F point mutation and its allele burden on overall survival (OS) and the risk of leukemic transformation (LT) has been the subject of several studies, but the results were ambiguous. Our study included 77 patients with the following variants: 42 patients with PMF (55%), 16 with post-ET MF (21%) and 19 with post-PV MF (24%). Median age at diagnosis for the entire cohort was 61?years (range 19-81), with 53% of female. A total of 42 patients were JAK2V617F positive, giving an overall frequency of 55%; the median allele burden was 22% (range 2-96%). The JAK2V617F point mutation was detected in 21 patients with PMF (50%), 14 with post-PV MF (88%) and 7 with post-ET MF (37%). Lower JAK2V617F allele burden was more frequently detected in PMF patients, whereas higher allele burden was predominantly seen in post-PV/ET MF group. There was no significant difference between V617F-positive and V617F-negative patients in terms of studied parameters in PMF as well as in post-PV/ET MF subgroup. No significant difference was also demonstrated when the above-mentioned subpopulations were analyzed according to JAK2V617F allele burden, except higher leukocyte count in post-PV/ET MF patients with higher allele burden (14.3?×?10(9)/L vs. 6.2?×?10(9)/L; p?=?.03). Median follow-ups for V617F-positive and V617F-negative patients were 16.6?months (range 3.6-206.4) and 36.4?months (range 2.5-142.1), respectively. The presence of JAK2V617F mutation did not affect OS and the risk of LT development.     

Top advances of the year: Myeloproliferative neoplasms

The rapid pace of drug development in hematology has led to multiple approvals for myelofibrosis (MF) and polycythemia vera (PV) in recent years. Moreover, there are many innovative agents and combinations being explored for myeloproliferative neoplasms (MPNs). In the past year, there have been several advances in MF, PV, and essential thrombocythemia. In MF, investigational approaches are focusing on strategies to optimize inhibition of signal transduction (including JAK inhibition), modify epigenetics, enhance apoptosis, target DNA replication, transform host immunity, and/or alter the tumor microenvironment. In PV, ropeginterferon alfa-2b has been introduced to the market in the United States, and data continue to accumulate to support the safety and efficacy of this treatment. Hepcidin mimesis is also emerging as a novel way to treat erythrocytosis. In essential thrombocythemia, ropeginterferon alfa-2b is being evaluated, as are therapies to modify epigenetics and inhibit CALR. The enhanced focus on MPNs brings hope that our field can improve morbidity and mortality in this group of diseases.