Publications by authors named "John Mascarenhas"

172 Publications

Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.

Haematologica 2021 Sep 23. Epub 2021 Sep 23.

Icahn School of Medicine at Mount Sinai, New York.

Thrombocytopenia is common in patients with myelofibrosis and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (.
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http://dx.doi.org/10.3324/haematol.2021.279415DOI Listing
September 2021

Paradigm shift: combination BET and JAK inhibition in myelofibrosis.

Leukemia 2021 Sep 3. Epub 2021 Sep 3.

University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

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http://dx.doi.org/10.1038/s41375-021-01405-zDOI Listing
September 2021

Clinical Utility of Fedratinib in Myelofibrosis.

Onco Targets Ther 2021 21;14:4509-4521. Epub 2021 Aug 21.

Department of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Myelofibrosis (MF) is a clonal hematologic malignancy characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and constitutional symptoms with a propensity towards leukemic transformation. Constitutive activation of the JAK/STAT pathway is a well-described pathogenic feature of MF. Allogeneic stem cell transplant is the only curative therapy, but due to high morbidity and mortality this option is not available for most patients. There are two approved targeted therapy options for MF, ruxolitinib and fedratinib. In this review, we discuss the clinical utility of fedratinib in the myelofibrosis treatment paradigm. Fedratinib has shown impressive pre-clinical and clinical efficacy in patients with untreated MF as well as in those with ruxolitinib intolerance and those with relapsed/refractory MF. Here, we review the pre-clinical and clinical trials that led to the approval of fedratinib, and the ongoing late-phase trials. We highlight several areas regarding the clinical utility of fedratinib that remain unanswered. We discuss the limitations of fedratinib and address areas that are understudied and require further clinical evaluation and research. The approval of fedratinib has provided a significant expansion to the very limited treatment armamentarium available to patients with MF.
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http://dx.doi.org/10.2147/OTT.S267001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387309PMC
August 2021

Alternatives to intensive treatment in patients with AML.

Clin Adv Hematol Oncol 2021 Aug;19(8):526-535

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

A significant proportion of patients with acute myeloid leukemia (AML) are unable to tolerate standard induction chemotherapy regimens. This is particularly true for patients who are of advanced age, have a poor performance status, and/or have significant medical comorbidities. Recent advances in understanding the genetic and molecular properties of AML have led to a spate of new treatment options for patients considered ineligible for standard chemotherapy. Here, we discuss these new treatment options, provide an overview of the completed and ongoing trials of the new agents, and highlight promising future directions in the treatment of AML in patients ineligible for intensive induction chemotherapy.
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August 2021

TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis.

JCI Insight 2021 Sep 22;6(18). Epub 2021 Sep 22.

Tisch Cancer Institute.

Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF-MKs elaborated significantly greater levels of TGF-β1 than TGF-β2 and TGF-β3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF-β1/TGF-β3 protein trap, to block the excessive TGF-β signaling. Treatment of human mesenchymal stromal cells with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGF-β1 to induce collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with WT JAK2 rather than mutated JAK2V617F. This effect of AVID200 on MF PCs was attributed to its ability to block TGF-β1-induced p57Kip2 expression and SMAD2 activation, thereby allowing normal rather than MF PCs to preferentially proliferate and form hematopoietic colonies. To assess the in vivo effects of AVID200, Gata1lo mice, a murine model of MF, were treated with AVID200, resulting in the reduction in BM fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short-term and long-term HSCs. Collectively, these data provide the rationale for TGF-β1 blockade, with AVID200 as a therapeutic strategy for patients with MF.
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http://dx.doi.org/10.1172/jci.insight.145651DOI Listing
September 2021

MICA/B antibody induces macrophage-mediated immunity against acute myeloid leukemia.

Blood 2021 Aug 6. Epub 2021 Aug 6.

Icahn School of Medicine at Mount Sinai, New York, New York, United States.

Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. MICA and MICB (MICA/B) are stress-proteins expressed by cancer cells, and antibody-mediated inhibition of MICA/B shedding represents a novel approach to stimulate immunity against cancers. We found that the MICA/B antibody 7C6 potently inhibits the outgrowth of AML in two models in immunocompetent mice. Macrophages were essential for therapeutic efficacy, and 7C6 triggered antibody-dependent phagocytosis of AML cells. Furthermore, we found that romidepsin, a selective histone deacetylase inhibitor, increased MICB mRNA in AML cells and enabled subsequent stabilization of the translated protein by 7C6. This drug combination substantially increased surface MICA/B expression in a human AML line, pluripotent stem cell-derived AML blasts and leukemia stem cells, as well as primary cells from three untreated AML patients. Human macrophages phagocytosed AML cells following treatment with 7C6 and romidepsin, and the combination therapy lowered leukemia burden in a humanized model of AML. Therefore, inhibition of MICA/B shedding promotes macrophage-driven immunity against AML via Fc receptor signaling and synergizes with an epigenetic regulator. These results provide the rationale for the clinical testing of this innovative immunotherapeutic approach for the treatment of AML.
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http://dx.doi.org/10.1182/blood.2021011619DOI Listing
August 2021

Improving the investigative approach to polycythaemia vera: a critical assessment of current evidence and vision for the future.

Lancet Haematol 2021 Aug;8(8):e605-e612

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Polycythaemia vera is a challenging disease to study given its low prevalence and prolonged time-to-event for important clinical endpoints such as thrombosis, progression, and mortality. Although researchers in this space often rise to meet these challenges, there is considerable room for improvement in the analysis of retrospective data, the development of risk-stratification tools, and the design of randomised controlled trials. In this Viewpoint, we review the evidence behind the contemporary approach to risk stratification and treatment of polycythaemia vera. Frameworks for using data more efficiently, constructing more nuanced prognostic models, and overcoming challenges in clinical trial design are discussed.
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http://dx.doi.org/10.1016/S2352-3026(21)00171-XDOI Listing
August 2021

Mild anemia as a single independent predictor of mortality in patients with COVID-19.

EJHaem 2021 May 6. Epub 2021 May 6.

Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York New York USA.

The coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to an unprecedented international health crisis. COVID-19 clinical presentations cover a wide range from asymptomatic to severe illness and death. Given the limited therapeutic resources and unexpected clinical features of the disease, readily accessible predictive biomarkers are urgently needed to improve patient care and management. We asked the degree to which anemia may influence the outcome of patients with COVID-19. To this end, we identified 3777 patients who were positively diagnosed with COVID-19 between March 1 and April 1 2020 in New York City. We evaluated 2,562 patients with available red blood cell, hemoglobin, and related laboratory values. Multivariable cox proportional hazards regression showed that anemia was a significant independent predictor of mortality (hazard ratio (HR): 1.26, 95% Confidence Interval [CI]: 1.06-1.51), independent of age, sex, and comorbidities. There was a direct correlation between the degree of anemia and the risk of mortality when hemoglobin was treated as a continuous variable (HR 1.05; [CI]: 1.01-1.09). The hemoglobin level that was maximally predictive of mortality, was 11.5 g/dL in males and 11.8 g/dL in females. These findings identify a routinely measured biomarker that is predictive of disease outcomes and will aid in refining clinical care algorithms and optimize resource allocation. Mechanisms of impacts of anemia on COVID-19 outcome are likely to be multiple in nature and require further investigation.
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http://dx.doi.org/10.1002/jha2.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242891PMC
May 2021

Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis.

J Clin Oncol 2021 Sep 17;39(26):2881-2892. Epub 2021 Jun 17.

Hôpital Saint-Louis, Université Paris, Paris, France.

Purpose: Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086).

Patients And Methods: Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety.

Results: Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias.

Conclusion: In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.
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http://dx.doi.org/10.1200/JCO.20.02864DOI Listing
September 2021

Ruxolitinib discontinuation in polycythemia vera: Patient characteristics, outcomes, and salvage strategies from a large multi-institutional database.

Leuk Res 2021 May 27;109:106629. Epub 2021 May 27.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, United States. Electronic address:

Ruxolitinib is approved for the treatment of patients with polycythemia vera (PV) who are intolerant or resistant to hydroxyurea. While ruxolitinib discontinuation in myelofibrosis is associated with dismal outcomes, the analogous experience in PV has not been reported. Using a large, multi-institutional database of PV patients, we identified 93 patients with PV who were treated with ruxolitinib, of whom 22 discontinued therapy. Adverse events were the primary reason for discontinuation. After a median follow-up of 18.2 months following ruxolitinib discontinuation, no patients experienced a thrombotic event. One patient died 20.8 months after discontinuation. As compared with the 71 patients who were still receiving treatment with ruxolitinib at last follow up, patients who discontinued ruxolitinib were older at time of treatment initiation (67.5 versus 64.8 years, p = 0.0058), but had similar patient and disease characteristics. After discontinuation, only 4 patients (18 %) received subsequent cytoreductive therapy, including hydroxyurea in one patient and pegylated interferon α-2a in three patients. In stark contrast to the experience in myelofibrosis, discontinuation of ruxolitinib in PV was associated with generally favorable outcomes. However, there is a lack of available salvage therapies, highlighting the need for further therapeutic development in PV.
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http://dx.doi.org/10.1016/j.leukres.2021.106629DOI Listing
May 2021

Next Generation Therapeutics for the Treatment of Myelofibrosis.

Cells 2021 04 27;10(5). Epub 2021 Apr 27.

Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA.

Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis.
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http://dx.doi.org/10.3390/cells10051034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146033PMC
April 2021

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

Clin Lymphoma Myeloma Leuk 2021 Jul 1;21(7):461-469. Epub 2021 Mar 1.

Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

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.
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http://dx.doi.org/10.1016/j.clml.2021.02.011DOI Listing
July 2021

Red cell distribution width is associated with mortality in non-anemic patients with COVID-19.

J Med Virol 2021 07 23;93(7):4130-4132. Epub 2021 Apr 23.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

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http://dx.doi.org/10.1002/jmv.27011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251232PMC
July 2021

The Efficacy of Etoposide-Based Therapy in Adult Secondary Hemophagocytic Lymphohistiocytosis.

Acta Haematol 2021 7;144(5):560-568. Epub 2021 Apr 7.

Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, New York, USA.

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank p = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633-1.799, p = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.
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http://dx.doi.org/10.1159/000514920DOI Listing
April 2021

Contemporary Risk Stratification and Treatment of Chronic Myelomonocytic Leukemia.

Oncologist 2021 05 21;26(5):406-421. Epub 2021 Apr 21.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy characterized by absolute monocytosis, one or more lineage dysplasia, and proliferative features including myeloid hyperplasia, splenomegaly, and constitutional symptoms. Because of vast clinical heterogeneity in presentation and course, risk stratification is used for a risk-adapted treatment strategy. Numerous prognostic scoring systems exist, some of which incorporate mutational information. Treatment ranges from observation to allogeneic hematopoietic stem cell transplantation. Therapies include hydroxyurea for cytoreduction, hypomethylating agents, and the JAK1/2 inhibitor ruxolitinib to address splenomegaly and constitutional symptoms. Recently, oral decitabine with cedazuridine was approved and represents a convenient treatment option for CMML patients. Although novel therapeutics are in development for CMML, further work is needed to elucidate possible targets unique to the CMML clone. In this review, we will detail the pathophysiology, risk stratification, available treatment modalities, and novel therapies for CMML, and propose a modern treatment algorithm. IMPLICATIONS FOR PRACTICE: Chronic myelomonocytic leukemia (CMML) is a clinically heterogenous disease, which poses significant management challenges. The diagnosis of CMML requires bone marrow biopsy and aspirate with thorough evaluation. Risk stratification and symptom assessment are essential to designing an effective treatment plan, which may include hypomethylating agents (HMAs) in intermediate or high-risk patients. The recently approved oral decitabine/cedazuridine provides a convenient alternative to parenteral HMAs. Ruxolitinib may be effective in ameliorating proliferative symptoms and splenomegaly. Allogeneic stem cell transplantation remains the only treatment with curative potential; however, novel therapies are in clinical development which may significantly alter the therapeutic landscape of CMML.
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http://dx.doi.org/10.1002/onco.13769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100553PMC
May 2021

A Drosophila platform identifies a novel, personalized therapy for a patient with adenoid cystic carcinoma.

iScience 2021 Mar 20;24(3):102212. Epub 2021 Feb 20.

Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Adenoid cystic carcinoma (ACC) is a rare cancer type that originates in the salivary glands. Tumors commonly invade along nerve tracks in the head and neck, making surgery challenging. Follow-up treatments for recurrence or metastasis including chemotherapy and targeted therapies have shown limited efficacy, emphasizing the need for new therapies. Here, we report a Drosophila-based therapeutic approach for a patient with advanced ACC disease. A patient-specific Drosophila transgenic line was developed to model the five major variants associated with the patient's disease. Robotics-based screening identified a three-drug cocktail-vorinostat, pindolol, tofacitinib-that rescued transgene-mediated lethality in the Drosophila patient-specific line. Patient treatment led to a sustained stabilization and a partial metabolic response of 12 months. Subsequent resistance was associated with new genomic amplifications and deletions. Given the lack of options for patients with ACC, our data suggest that this approach may prove useful for identifying novel therapeutic candidates.
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http://dx.doi.org/10.1016/j.isci.2021.102212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940980PMC
March 2021

Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies.

Hemasphere 2021 Apr 9;5(4):e549. Epub 2021 Mar 9.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for , , and mutations, while nonresponders were associated with and mutations. Adaptive resistance was observed through various mechanisms including acquired pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.
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http://dx.doi.org/10.1097/HS9.0000000000000549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951133PMC
April 2021

Prevalence of unexplained erythrocytosis and thrombocytosis - an NHANES analysis.

Leuk Lymphoma 2021 08 28;62(8):2030-2033. Epub 2021 Feb 28.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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http://dx.doi.org/10.1080/10428194.2021.1888377DOI Listing
August 2021

The New Science and Concepts That Underlie Current and Future Treatments for Myeloproliferative Neoplasms.

Hematol Oncol Clin North Am 2021 Apr 26;35(2):xvii-xix. Epub 2021 Jan 26.

Leukemia Service, Department of Medicine, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Service, 530 East 74th Street, New York, NY 10021, USA. Electronic address:

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http://dx.doi.org/10.1016/j.hoc.2021.01.004DOI Listing
April 2021

Current Clinical Investigations in Myelofibrosis.

Hematol Oncol Clin North Am 2021 Apr 27;35(2):353-373. Epub 2021 Jan 27.

Adult Leukemia Program, Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA; Myeloproliferative Disorders Clinical Research Program, Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA. Electronic address:

The US Food and Drug Administration (FDA) approval of Janus kinase 2 inhibitors, ruxolitinib and fedratinib for the treatment of intermediate-2 or high-risk primary or secondary myelofibrosis (MF) has revolutionized the management of MF. Nevertheless, these drugs do not reliably alter the natural history of disease. Burgeoning understanding of the molecular pathogenesis and the bone marrow microenvironment in MF has galvanized the development of targeted therapeutics. This review provides insight into the novel therapies under clinical evaluation.
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http://dx.doi.org/10.1016/j.hoc.2020.12.003DOI Listing
April 2021

Use of pegylated interferon in young patients with polycythemia vera and essential thrombocythemia.

Pediatr Blood Cancer 2021 03 31;68(3):e28888. Epub 2020 Dec 31.

Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Myeloproliferative neoplasms (MPN) are rare disorders in young patients, and because of this, standardized treatment recommendations are not available. Pediatric patients are more frequently treated with hydroxyurea than interferon, yet there are no data suggesting this is the best practice. Current treatment guidelines for adults suggest using interferon as upfront therapy in young patients. We reviewed the cases of 13 young patients with polycythemia vera or essential thrombocythemia, who were treated with interferon. Extreme thrombocytosis was well controlled and the medication was tolerated by many. Our work shows the need for prospective studies evaluating interferon in our youngest patients with MPN.
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http://dx.doi.org/10.1002/pbc.28888DOI Listing
March 2021

Characteristics, anticoagulation, and outcomes of portal vein thrombosis after intra-abdominal surgery.

Surgery 2021 05 24;169(5):1175-1181. Epub 2020 Dec 24.

Icahn School of Medicine at Mount Sinai, Recanati/Miller Transplantation Institute, New York, NY.

Background: Intra-abdominal surgery is a cause of portal vein thrombosis; however, postsurgical portal vein thrombosis has not been extensively described.

Methods: This is a retrospective study of 107 patients with postsurgical portal vein thrombosis followed for a median 25 months (interquartile range 11-51). Outcomes were complete radiographic resolution of portal vein thrombosis and development of clinical portal hypertension.

Results: Surgeries associated with portal vein thrombosis included colectomy (n = 42), bariatric surgery (n = 25), and splenectomy (n = 11). Presentations were nonspecific, typically characterized by abdominal pain. Sixty-three patients (59%) achieved complete radiographic resolution. On univariable analysis, provoking surgery, occlusivity of portal vein thrombosis, and anticoagulant used were associated with complete radiographic resolution. Colectomy was associated with a complete radiographic resolution rate of 30/42 (71%), bariatric 10/25 (40%), splenectomy 2/11 (18%), and other 21/29 (72%), (log rank P = .0033). Nonocclusive thrombus was associated with a complete radiographic resolution rate of 44/62 (71%), occlusive thrombus 19/45 (42%), (log rank P = .0101). Direct oral anticoagulants were associated with a complete radiographic resolution rate of 27/35 (77%), enoxaparin 20/29 (69%), warfarin 14/31 (45%), and no anticoagulant 2/12 (17%), (log rank P = .0002). On multivariable analysis, only anticoagulant choice was significantly associated with complete radiographic resolution. Using direct oral anticoagulants as reference, no anticoagulant yielded an adjusted hazard ratio of 0.10 for complete radiographic resolution (95% confidence interval 0.023-0.44), warfarin 0.40 (95% confidence interval 0.20-0.78), and enoxaparin 0.64 (95% confidence interval 0.49-1.60). Failure to achieve complete radiographic resolution was associated with greater risk of future clinical portal hypertension. Twenty-three patients (21%) went on to develop clinical portal hypertension; 20 who failed to achieve complete radiographic resolution (45%), and only 3 who achieved complete radiographic resolution (5%), (log rank P < .0001).

Conclusion: The natural history of postsurgical portal vein thrombosis is variable and influenced by type of surgery, degree of occlusion, and, most notably, type of anticoagulant used. Failure to recanalize the portal vein carries considerable risk of future clinical portal hypertension.
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http://dx.doi.org/10.1016/j.surg.2020.11.016DOI Listing
May 2021

Prevalence of Cytopenia in the General Population-A National Health and Nutrition Examination Survey Analysis.

Front Oncol 2020 20;10:579075. Epub 2020 Nov 20.

Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Background: Cytopenia, a reduced count of blood cells manifesting as anemia, neutropenia, and/or thrombocytopenia is frequently associated with other medical conditions. However, a cytopenia may not be accompanied by a known determinant and in some of these cases, may be a precursor to pre-malignancies or hematologic cancers. Little is known about the prevalence of these unexplained cytopenias and their distribution in the population.

Materials And Methods: The National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 was used to identify those with a cytopenia in the general population. Those without an identifiable determinant in the NHANES were classified as having unexplained cytopenia. Weighted frequencies were examined to assess the prevalence of unexplained cytopenia in the population. Distribution of blood counts comparing those with unexplained cytopenia to the general population was examined. Multivariable logistic regression was conducted to assess the association between unexplained cytopenia and demographic factors.

Results: Of the 7,962 people in the sample, 236 (2.0%) had any cytopenia and 86 (0.9%) had an unexplained cytopenia. Approximately 43% of all cytopenias were not accompanied by a clinical determinant. Unexplained cytopenia was more common in men (1.1%) than in women (0.7%) and in Non-Hispanic Black participants (3.4%). Among those with an unexplained cytopenia, the majority (74.8%) manifested as neutropenia. Compared to those with no cytopenia, those with unexplained cytopenia were significantly less likely to be female, have body mass index ≥30 kg/m, and work in the service industry, and were significantly more likely to be non-Hispanic Black.

Conclusions: This is the first study to examine the prevalence of unexplained cytopenia in a nationally representative sample and may serve as a baseline for comparison with other populations. Future research to identify risk factors for development of malignant hematological disorders among those with unexplained cytopenia is warranted.
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http://dx.doi.org/10.3389/fonc.2020.579075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714991PMC
November 2020

Pacritinib demonstrates spleen volume reduction in patients with myelofibrosis independent of JAK2V617F allele burden.

Blood Adv 2020 12;4(23):5929-5935

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Myelofibrosis (MF) has heterogeneous clinical manifestations, with some patients exhibiting a myelodepletive phenotype characterized by cytopenias and an absent or low JAK2V617F allele burden. Ruxolitinib may be less effective in these patients. We assessed the efficacy of pacritinib, a JAK2/IRAK1 inhibitor, in MF patients with low JAK2V617F allele burden. In this post hoc analysis of the PERSIST-1 and -2 trials, patients with MF randomized to pacritinib or best available therapy (BAT) were stratified by JAK2V617F allele burden quartile for spleen response of ≥35% and improvement in total symptom score of ≥50%. Five hundred thirty-six patients were included. Patients with lower JAK2V617F allele burden had smaller baseline spleens and lower hemoglobin and platelet counts as compared with higher allele burden patients. Among pacritinib-treated patients, spleen responses were observed across all JAK2V617F allele burden quartiles and in JAK2V617F- disease. No spleen responses were observed among BAT-treated patients with allele burden ≤50% or JAK2V617F- disease. The intention-to-treat response rate was significantly higher on the pacritinib arm for JAK2V617F- disease (23.0% vs 0%; P = .033), and for the lowest allele burden quartiles (0%-25%: 20.9% vs 0%, P < .001; 25%-50%: 15.4% vs 0%, P = .020). There were significantly more symptom responders with pacritinib vs BAT in the 0% to 25% and 25% to 50% cohorts. Pacritinib treatment led to superior spleen and symptom burden reduction compared with BAT in patients with absent or low JAK2V617F allele burden, suggesting that pacritinib may be uniquely suited for patients with myelodepletive MF.
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http://dx.doi.org/10.1182/bloodadvances.2020002970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724916PMC
December 2020

Novel therapeutics in myeloproliferative neoplasms.

J Hematol Oncol 2020 12 2;13(1):162. Epub 2020 Dec 2.

Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, 10029, USA.

Hyperactive signaling of the Janus-Associated Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway is central to the pathogenesis of Philadelphia-chromosome-negative myeloproliferative neoplasms (MPN), i.e., polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) which are characterized by inherent biological and clinical heterogeneity. Patients with MPNs suffer from substantial symptom burden and curtailed longevity due to thrombohemorrhagic complications or progression to myelofibrosis or acute myeloid leukemia. Therefore, the management strategies focus on thrombosis risk mitigation in PV/ET, alleviation of symptom burden and improvement in cytopenias and red blood cell transfusion requirements, and disease course alteration in PMF. The United States Food and Drug Administration's (USFDA) approval of two JAK inhibitors (ruxolitinib, fedratinib) has transformed the therapeutic landscape of MPNs in assuaging the need for frequent therapeutic phlebotomy (PV) and reduction in spleen and symptom burden (PV and PMF). Despite improving biological understanding of these complex clonal hematopoietic stem/progenitor cell neoplasms, none of the currently available therapies appear to modify the proclivity of the disease per se, thereby remaining an urgent unmet clinical need and an ongoing area of intense clinical investigation. This review will highlight the evolving targeted therapeutic agents that are in early- and late-stage MPN clinical development.
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http://dx.doi.org/10.1186/s13045-020-00995-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709419PMC
December 2020

Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis.

Blood Adv 2020 11;4(22):5825-5835

Ichan School of Medicine at Mount Sinai, New York, NY.

PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.
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http://dx.doi.org/10.1182/bloodadvances.2020003314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686901PMC
November 2020

Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin.

Blood Adv 2020 11;4(22):5735-5744

Division of Hematology/Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Activation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.
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http://dx.doi.org/10.1182/bloodadvances.2020002379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686898PMC
November 2020

Safety, Efficacy, and Long-Term Outcomes of Anticoagulation in Cirrhotic Portal Vein Thrombosis.

Dig Dis Sci 2021 Oct 5;66(10):3619-3629. Epub 2020 Nov 5.

Division of Liver Diseases, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: The role of anticoagulation (AC) in the management of cirrhotic patients with portal vein thrombosis (PVT) remains unclear.

Aims: We conducted a retrospective study of cirrhotic patients diagnosed with PVT from 1/1/2000 through 2/1/2019, comparing those who received AC to those who did not.

Methods: Outcomes included rate of complete radiographic resolution (CRR) of PVT, recanalization of occlusive PVT (RCO), PVT extension, major bleeding, and overall survival (OS). The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox-proportional-hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals.

Results: A total of 214 patients were followed for a median 27 months (IQR 12-48). Eighty-six patients (39%) received AC. AC was associated with significantly greater CRR (48% vs. 27%, p = 0.0007), (multivariable HR for CRR with AC; 2.49 (1.54-4.04, p = 0.0002)). AC was also associated with significantly greater RCO (69% vs. 28%, p = 0.0013), (multivariable HR for RCO with AC; 4.86 (1.91-12.37, p = 0.0009)). Rates of major bleeding were similar with and without AC (20% vs. 17%, p = 0.5207), multivariable HR for major bleeding with AC; 1.29 (0.68-2.46, p = 0.4423)). OS rates in the AC and no-AC groups were 83% and 70%, respectively (p = 0.1362), (HR for death with AC; 0.69 (0.38-1.28, p = 0.2441)). Among 75 patients who had CRR, 10 (13%) experienced recurrent PVT during follow-up (none were receiving AC at the time of recurrence).

Conclusions: AC appears safe and effective for the treatment of cirrhotic PVT; however, prospective studies to confirm these findings and evaluate additional outcomes are needed.
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http://dx.doi.org/10.1007/s10620-020-06695-4DOI Listing
October 2021
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