Publications by authors named "Noa Lavi"

45 Publications

Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.

Nat Med 2021 03 22;27(3):491-503. Epub 2021 Feb 22.

Department of Immunology, Weizmann Institute, Rehovot, Israel.

Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR-Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.
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http://dx.doi.org/10.1038/s41591-021-01232-wDOI Listing
March 2021

Daratumumab With Cetrelimab, an Anti-PD-1 Monoclonal Antibody, in Relapsed/Refractory Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Jan 22;21(1):46-54.e4. Epub 2020 Aug 22.

Winship Cancer Institute, Emory University, Atlanta, GA.

Background: Daratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 inhibitor, in RRMM.

Patients And Methods: This open-label, multiphase study enrolled adults with RRMM with ≥ 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses.

Results: Nine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee's global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had ≥ 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had ≥ 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%.

Conclusions: No new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination.
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http://dx.doi.org/10.1016/j.clml.2020.08.008DOI Listing
January 2021

Characteristics and outcome of multiple myeloma patients presenting with anaemia only: A retrospective multi-centre study.

Leuk Res 2021 02 31;101:106498. Epub 2020 Dec 31.

Department of Hematology, Tel Aviv Sourasky Medical Center, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.

Background: Multiple myeloma (MM) patients presenting with anaemia as their sole clinical manifestation are rare and not fully defined.

Methods: Retrospective multi-site study comparing the characteristics and outcome of MM patients with anaemia only with matched patients, presenting with multi-organ disease.

Results: Anaemia-only patients had a higher percentage of bone marrow monoclonal plasma cells group (median 60% [IQR 42-80%] vs. 37% [IQR 17-65%], respectively; p < 0.001), and a lower responsiveness to treatment (≥VGPR rates were 54% vs 74%, p = 0.049). Median survival in anaemia only patients was 65.9 ± 6.9 vs 83.4 ± 8.8 months in matched control patients (P = n.s).

Conclusions: MM patients presenting with anaemia only represents a unique, potentially less favorable population.
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http://dx.doi.org/10.1016/j.leukres.2020.106498DOI Listing
February 2021

Management and Outcome of Venous Thrombosis in Patients with Myeloproliferative Neoplasms: Data from the Israeli MPN Working Group.

Acta Haematol 2020 Dec 14:1-8. Epub 2020 Dec 14.

Department of Hematology, Shamir Medical Center (Assaf Harofeh), Zerifin, Israel.

The BCR-ABL-negative myeloproliferative neoplasms (MPN) are associated with high incidence of venous thrombosis and a significant rate of recurrent events, but there is no consensus regarding their management. In this retrospective study, we analyzed 96 patients with MPN-related venous thrombosis. The index venous thrombosis occurred at a median age of 58 years (IQR 37-71), with 58% of the events involving unusual sites. Patients who were on antiplatelet agents at the time of index thrombosis tended to be older than patients who were not receiving antiplatelets at the time of index thrombosis. The majority of index thromboses occurring after the diagnosis of MPN had uncontrolled blood counts at the time of event and were not receiving antithrombotic agents. Following the thrombotic episode, 75% of patients received long-term anticoagulation. At a median follow-up of 3.4 years, the recurrence rate was 14%. Thrombophilia was significantly more prevalent among patients with recurrent thrombosis compared to patients without recurrence (p < 0.01). Patients who developed a recurrent event early were more likely to have thrombophilia (either inherited or antiphospholipid antibodies), and controlled blood counts, and were likely to receive anticoagulation at the time of recurrence compared to patients with later recurrences. Thrombophilia may contribute to venous thrombosis recurrence, especially early after the index venous thrombosis. Suboptimal anticoagulation and blood count control are factors associated with late venous thrombosis recurrence.
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http://dx.doi.org/10.1159/000511426DOI Listing
December 2020

Deletions and amplifications of the IGH variable and constant regions:a novel prognostic parameter in patients with multiple myeloma.

Leuk Res 2020 12 4;99:106476. Epub 2020 Nov 4.

Hematology Unit, Bnai Zion Medical Center, Haifa, and The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. Electronic address:

Cytogenetic abnormalities are a recognized factor in the pathogenesis of multiple myeloma (MM). While chromosomal translocations involving the IGH gene have been investigated and reported, the implications of deletions or amplifications in the IGH gene have been less frequently examined. We conducted a retrospective analysis of 260 patients with MM from Northern Israel. Fluorescent in situ hybridization (FISH) analysis of separated CD-138 positive cells was done on bone marrow samples collected between 2016 and 2018. We used IGH break apart probes to identify IGH abnormalities and performed statistical analysis of clinical and prognostic features, comparing the different cytogenetic groups. Deletions in the variable region of the IGH (IGHv) were found in 17.3 % (n = 45) of patients and correlated with significantly worse progression free survival (PFS) after two years of follow up (p = 0.008), as well as with a worse response to 1st line treatment (p = 0.037). The median PFS was 7.1 and 17.7 months in patients with and without IGHv deletion, respectively. PFS differences remained significant (p = 0.017) in subgroup analysis of patients with high-risk cytogenetics (n = 108, 19 with IGHv deletion). Overall survival was not significantly different in the two groups. Constant region (IGHc) amplifications, were less frequently found (6.15 %, n = 16), yet significantly correlated with worse PFS after two years of follow up (p = 0.023). This difference remained valid in the high-risk subgroup (p = 0.001). In Conclusion, we identified that deletion of the IGH variable region and amplification in the IGH constant region, are both associated with poor prognosis and inferior outcome in MM.
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http://dx.doi.org/10.1016/j.leukres.2020.106476DOI Listing
December 2020

Multicentric Castleman disease presenting as a chylous pleural effusion.

Pathol Res Pract 2020 Nov 10;216(11):153209. Epub 2020 Sep 10.

Medical Intensive Care Unit, Rambam Health Care Campus, Haifa, Israel.

Castleman disease is a rare lymphoproliferative disorder presenting frequently with constitutional symptoms. Although pleural effusion is common, there is only one case report of an adult patient with chylous pleural effusion. We present the first case report of a hypervascular variant of Castleman disease presenting as a chylous pleural effusion and successfully treated with a combination of anti-interleukin-6 agent and steroids.
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http://dx.doi.org/10.1016/j.prp.2020.153209DOI Listing
November 2020

The impact of anti-bacterial prophylaxis on the outcome of patients treated with venetoclax-based regimens for relapsed/refractory plasma cell dyscrasias: Real-life data.

Leuk Res 2020 10 30;97:106429. Epub 2020 Jul 30.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2020.106429DOI Listing
October 2020

Bortezomib Maintenance Therapy as a Standard of Care Provides Favorable Outcomes in Newly Diagnosed Myeloma Patients: A Multisite Real-Life Study.

Clin Lymphoma Myeloma Leuk 2020 Nov 11;20(11):e850-e857. Epub 2020 Jun 11.

Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Lenalidomide and ixazomib maintenance improve long-term outcomes in newly diagnosed multiple myeloma (NDMM) patients. However, there is less evidence to support bortezomib (BTZ) maintenance therapy, and real-life data on maintenance are scarce. We investigated the efficacy and safety of BTZ maintenance therapy in NDMM.

Patients And Methods: A retrospective multisite study was performed in 6 medical centers in Israel. All consecutive patients with NDMM diagnosed between January 1, 2010, and July 3, 2019, who received a BTZ-based induction, with or without an autologous transplantation, followed by BTZ maintenance therapy, were identified. Maintenance therapy was defined as BTZ (1.3 mg/m) once every 2 weeks, administered subcutaneously alone or with dexamethasone, or weekly BTZ monotherapy.

Results: A total of 105 patients were identified, 58 of whom had received a transplant (transplant eligible) and 47 who had not (not transplant eligible). During BTZ maintenance therapy, 96% had one or more adverse event, 11.5% had grade 3 or higher adverse events, and 11.5% discontinued treatment due to toxicity. Median progression-free survival (PFS) and overall survival were 45 and 91.5 months, respectively; 4-year survival was 88%. Adverse cytogenetics was associated with worse PFS (24 vs. 46 months, P = .001). In subgroup analysis, adverse cytogenetics were associated with worse PFS (P < .001) and OS (P < .001) among transplant-ineligible but not transplant-eligible patients.

Conclusion: Analysis of multisite real-life data showed that BTZ maintenance therapy is safe, well tolerated, and effective. Median PFS was similar to that reported with alternative maintenance strategies. Our findings further support its use among patients with adverse cytogenetics, it may also be relevant for patients with lenalidomide-intolerant disease.
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http://dx.doi.org/10.1016/j.clml.2020.06.002DOI Listing
November 2020

Ixazomib-based regimens for relapsed/refractory multiple myeloma: are real-world data compatible with clinical trial outcomes? A multi-site Israeli registry study.

Ann Hematol 2020 Jun 20;99(6):1273-1281. Epub 2020 Mar 20.

Department of Hematology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.

Ixazomib, the first oral proteasome inhibitor (PI), has been approved for the treatment of relapsed refractory multiple myeloma (RRMM) in combination with lenalidomide and dexamethasone, based on the TOURMALINE-MM1 phase 3 trial, which demonstrated the efficacy and safety of this all-oral triplet, compared with lenalidomide-dexamethasone. However, clinical trial outcomes do not always translate into real-world outcomes. The aim of this study was to assess the outcomes of ixazomib-based combination for treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least one cycle of ixazomib-based treatment combination between June 2013 and June 2018 were identified. Data was extracted from medical charts focusing on demographics, disease characteristics, prior treatment, and responses. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), safety, and tolerability. A total of 78 patients across 7 sites were retrospectively included. Median follow-up was 22 months. Median age was 68 (range 38-90). Sixty-four percent received ixazomib in 2nd line, 19% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 87%) prior to IRd, 41% to IMiDs. Twenty-nine (48%, of 60 available) had high (t(4:14), t(14:16), del17p) or intermediate (+1q21) risk aberrations. Most patients (82%) received ixazomib in combination with lenalidomide and dexamethasone. An exploratory assessment for disease aggressiveness at diagnosis was classified by a treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 37%, respectively. Treatment was well tolerated, with a low discontinuation rate (11%). Median PFS on ixazomib therapy was 24 months (95% CI 17-30). PFS was 77% and 47% at 12 and 24 months, respectively. Median OS was not reached; OS was 91% and 80% at 12 and 24 months, respectively. Higher LDH, older age, and worse clinical aggressiveness were associated with worse PFS, whereas a deeper response to ixazomib (≥ VGPR) and a longer response to first-line bortezomib (≥ 24 m) were associated with an improved PFS on ixazomib. No effect on PFS was found for cytogenetic risk by FISH, ISS/rISS, and prior anti-myeloma treatment. Ixazomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting, regardless to cytogenetic risk, with a PFS of 24 months comparable with clinical trial data. This regimen had most favorable outcomes among patients who remained progression-free more than 24 months after a bortezomib induction and for those who have a more indolent disease phenotype.
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http://dx.doi.org/10.1007/s00277-020-03985-9DOI Listing
June 2020

Real-world data on incidence, clinical characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) in the era of novel therapies: A study of the Greco-Israeli collaborative myeloma working group.

Am J Hematol 2020 05 2;95(5):465-471. Epub 2020 Mar 2.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

We investigated incidence, characteristics and outcome of patients with macrofocal multiple myeloma (MFMM) treated mainly with novel therapies. Based on definition (BMPCs <20% and lytic lesions/plasmacytomas, without anemia, renal insufficiency or hypercalcemia) we identified 140 patients with MFMM, among 4650 myeloma patients (3%). Twice the number of patients with typical myeloma were used as controls; 60% were <65 years and 70% had advanced bone disease. Plasmacytomas were more frequent in MFMM compared with standard myeloma (68% vs 15%, P < .05). Adverse prognostic parameters (high lactate dehydrogenase, advanced stage, high risk cytogenetics, immunoparesis) were less common in patients with MFMM compared with controls (P < .05); 90% received novel agents and 47% underwent autologous transplantation upfront; 90% achieved an objective response; 70% had at least very good partial response which was significantly higher compared with controls (P < .05). After a median follow-up of 52 months, 33 patients have died. Early death (<12 months) was infrequent in MFMM. Median progression-free survival and overall survival (OS) were 46 and 129 months respectively, both significantly longer compared with controls (P < .001). Proteasome inhibitor (PI)-based therapy was the only independent predictor for OS in the multivariate analysis (HR: 3.9; P < .001). In conclusion, MFMM is a distinct entity presented in young and elderly subjects, characterized by limited bone marrow infiltration, advanced bone disease and frequent presence of plasmacytomas; MFMM patients have less often adverse prognostic features and achieve excellent responses and prolonged OS especially when treated with PI-based therapies. Novel imaging will help in a more accurate classification of this entity.
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http://dx.doi.org/10.1002/ajh.25755DOI Listing
May 2020

BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study.

Blood Adv 2019 11;3(22):3740-3749

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m2 per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m2 per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.
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http://dx.doi.org/10.1182/bloodadvances.2019000468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880904PMC
November 2019

Splanchnic vein thromboses associated with myeloproliferative neoplasms: An international, retrospective study on 518 cases.

Am J Hematol 2020 02 29;95(2):156-166. Epub 2019 Nov 29.

CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.

Myeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG-MRT), and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN-SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN-SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient-years. Vitamin K-antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN-SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN-SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN-U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to-date largest, contemporary cohort of MPN-SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.
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http://dx.doi.org/10.1002/ajh.25677DOI Listing
February 2020

Newly diagnosed myeloma patients with low-burden disease may benefit from tandem autologous stem cell transplantation: results of long-term follow-up.

Bone Marrow Transplant 2020 06 16;55(6):1200-1202. Epub 2019 Sep 16.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.

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http://dx.doi.org/10.1038/s41409-019-0671-5DOI Listing
June 2020

Proinflammatory Macrophages Promote Multiple Myeloma Resistance to Bortezomib Therapy.

Mol Cancer Res 2019 11 13;17(11):2331-2340. Epub 2019 Aug 13.

Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Multiple myeloma (MM) is a plasma cell neoplasia commonly treated with proteasome inhibitors such as bortezomib. Although bortezomib has demonstrated enhanced survival benefit, some patients relapse and subsequently develop resistance to such therapy. Here, we investigate the mechanisms underlying relapse and refractory MM following bortezomib treatment. We show that bortezomib-exposed proinflammatory macrophages promote an enrichment of MM-tumor-initiating cells (MM-TIC) both and . These effects are regulated in part by IL1β, as blocking the IL1β axis by a pharmacologic or genetic approach abolishes bortezomib-induced MM-TIC enrichment. In MM patients treated with bortezomib, high proinflammatory macrophages in the bone marrow negatively correlate with survival rates (HR, 1.722; 95% CI, 1.138-2.608). Furthermore, a positive correlation between proinflammatory macrophages and TICs in the bone marrow was also found. Overall, our results uncover a protumorigenic cross-talk involving proinflammatory macrophages and MM cells in response to bortezomib therapy, a process that enriches the MM-TIC population. IMPLICATIONS: Our findings suggest that proinflammatory macrophages in bone marrow biopsies represent a potential prognostic biomarker for acquired MM resistance to bortezomib therapy.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0487DOI Listing
November 2019

Characteristics, management and outcome of DLBCL patients, presenting with simultaneous systemic and CNS disease at diagnosis: A retrospective multicenter study.

Am J Hematol 2019 09 18;94(9):992-1001. Epub 2019 Jun 18.

Sourasky Medical Center, Institute of Hematology, Tel-Aviv, Israel.

The incidence of systemic diffuse large B cell lymphoma (DLBCL) concurrently involving the central nervous system (CNS) at diagnosis, is very low and data regarding the clinical course of these patients are scarce. We investigated characteristics, efficacy of treatment regimens including consolidative autologous stem cell transplantation and outcome of patients presenting with concomitant systemic and CNS DLBCL. The records of 44 patients, diagnosed between 2004 and 2017, who fulfilled the inclusion criteria, were retrospectively reviewed. CNS involvement was diagnosed as solely parenchymal in 41%, solely leptomeningeal in 43%, and paranchymal with leptomeningeal in 11% of the patients. Induction regimens were anthracycline-based combined with high-dose methotrexate (HD-MTX) in 80% (n = 35) of patients, anthracycline-based combined with intrathecal MTX in 3, cytarabine-based (without antracyclines) in 2, HD-MTX in 1 and palliative in three. Five of 41 patients treated with chemotherapy died of treatment-related toxicity, all due to infections. Nineteen patients had consolidative autologous transplantation. Overall response rate following induction was 80% (complete responses 66% and partial responses 15%). All relapses (n = 11) occurred within less than 2 years. Within a median follow-up of 26.8 months, 3-years projected overall survival (OS) and progression free survival rates for the entire cohort were 56% ± 8.3 and 42% ± 8.9, respectively. In multivariate analysis, RCHOP-HD MTX-based induction [HR = 0.228, (0.054-0.964)], administration of 3.5 g/m MTX [HR = 0.735 (0.620-0.871)], and attaining CR following induction [HR = 0.185, (0.051-0.667)] predicted longer OS. RCHOP-HD MTX can provide prolonged remissions in DLBCL patients presenting with concomitant systemic and CNS involvement whereas role of autograft remains uncertain.
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http://dx.doi.org/10.1002/ajh.25558DOI Listing
September 2019

Superior outcome of patients with favorable-risk acute myeloid leukemia using consolidation with autologous stem cell transplantation.

Leuk Lymphoma 2019 10 3;60(10):2449-2456. Epub 2019 Apr 3.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus , Haifa , Israel.

Autologous stem cell transplantation (ASCT), intensifying anti-leukemic effects without significant treatment-related mortality (TRM), is particularly appealing in AML with favorable genetic/molecular profile. This study retrospectively evaluated the outcomes of post-remission treatment in consecutive favorable-risk AML patients. Sixty-six patients were included: 32 had mutated NPM1/wild-type FLT-ITD, 16 had t(8:21) and 18 - inv(16). Forty patients received chemotherapy alone, 26 underwent ASCT upfront. In time-dependent analysis, the ASCT group demonstrated higher relapse-free (RFS) ( = .001) and overall survivals (OS) ( = .0007). The 1-year RFS and OS were 44.2% vs 88% and 71% vs 96% for chemotherapy and ASCT, respectively. The corresponding TRM was 4/40 (10.0%) and 0/26 (0%), with relapse rates of 70.0% and 19.2% ( = .0002). In multivariate analysis, ASCT was associated with superior OS and RFS. In conclusion, ASCT offers significantly superior RFS and OS in favorable-risk AML in first complete remission. These data support the recent resurgence of interest in ASCT for AML.
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http://dx.doi.org/10.1080/10428194.2019.1594214DOI Listing
October 2019

Characteristics and outcomes of young adults with Philadelphia-negative myeloproliferative neoplasms.

Eur J Haematol 2019 Jun 25;102(6):504-508. Epub 2019 Apr 25.

Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Objective: Approximately 10% of Philadelphia (Ph)-negative myeloproliferative neoplasms (NPM) are diagnosed at young adulthood. We aim to define the features of this group.

Methods: A multicenter retrospective study, including patients 18-45 years of age, diagnosed with Ph-negative MPN between 1985 and 2017.

Results: One hundred nine patients were included, 37 with polycythemia vera (34%), 54 with essential thrombocytosis (50%), 15 with primary myelofibrosis (PMF) (14%), and 3 with MPN unclassifiable (3%). Median age was 33 years and 62 (57%) were females. During a median follow-up of 8 years, 39 patients (37%) had at least one thrombotic event. 30/39 of events were venous (77%), 23/30 of which were splanchnic (77%). In 14/39 (36%), thrombosis preceded MPN diagnosis. In a multivariable analysis, only splenomegaly predicted for thrombosis (HR 5.6, CI: 1.4-22). The 10-year risk for secondary myelofibrosis was similar for ET and PV (0.13 vs 0.19, P = 0.51). The 10-year risk for leukemic transformation or mortality was significantly higher for PMF (0.3, P = 0.04).

Conclusions: The risks of mortality and of progression to MF/leukemia in young adults are similar to older population. Thrombotic events are frequently a presenting sign with a high incidence of venous, in particular splanchnic, events.
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http://dx.doi.org/10.1111/ejh.13232DOI Listing
June 2019

Baseline Chest Computed Tomography for Early Diagnosis of Invasive Pulmonary Aspergillosis in Hemato-oncological Patients: A Prospective Cohort Study.

Clin Infect Dis 2019 10;69(10):1805-1808

Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israeli Institute of Technology, Haifa, Israel.

Invasive pulmonary aspergillosis (IPA) has dire consequences in hemato-oncological patients. We report our experience with performing routine baseline chest computed tomography for early diagnosis of IPA. We found high rates of proven or probable IPA diagnosed on admission among patients with newly diagnosed acute myeloid leukemia.
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http://dx.doi.org/10.1093/cid/ciz194DOI Listing
October 2019

Severe cytomegalovirus enterocolitis developing following daratumumab exposure in three patients with multiple myeloma.

Eur J Haematol 2018 Aug 18. Epub 2018 Aug 18.

Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel.

Objectives: The risk of cytomegalovirus (CMV) reactivation in multiple myeloma (MM) patients treated with bortezomib-based induction regimens is increased following autologous stem cell transplantation (ASCT). There is paucity of data regarding the risk of CMV infections in MM patients who did not receive bortezomib and ASCT.

Methods: We herein report three cases of heavily pretreated MM patients, receiving daratumumab-containing combination regimens, in whom ASCT had been performed long ago and who recently developed severe CMV-related gastrointestinal disease.

Results: All the three patients had a prolonged CMV disease course requiring a long-term antiviral treatment. All the patients suffered from CMV colitis. One patient had concurrent CMV duodenitis and another patient had a concurrent CMV retinitis.

Conclusion: Novel myeloma treatments prolong patient survival and more patients with profound immunosuppression following multiple lines of therapies are seen in clinical practice. These patients may present with opportunistic infections that were rare in the past. Our findings suggest a possible association between daratumumab therapy (in combination with other immunosuppressive therapies) and severe CMV gastrointestinal disease. A longer follow-up is needed to explore long-term side effects of novel agents like daratumumab in newly diagnosed as well as heavily pretreated MM patients.
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http://dx.doi.org/10.1111/ejh.13164DOI Listing
August 2018

Semaphorin-3A inhibits multiple myeloma progression in a mouse model.

Carcinogenesis 2018 10;39(10):1283-1291

Cancer Research Center, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Previous studies revealed that progression of multiple myeloma (MM) is associated with downregulation of semaphorin-3A (sema3A) expression in bone marrow endothelial cells. We therefore determined if serum sema3A concentrations are correlated with MM progression and if sema3A can affect MM progression. We find that the concentration of sema3A in sera of MM patients is strongly reduced and that the decrease is correlated with disease progression. A similar depletion is found in patients having acute myeloid leukemia and acute lymphoblastic leukemia but not in cancer forms that do not involve the bone marrow such as in colon cancer. Expression of a modified sema3A [furin-resistant sema3A (FR-sema3A)] stabilized against cleavage by furin-like proprotein convertases in CAG MM cells did not affect their behavior in-vitro. CAG cells injected into the tail vein of severe combined immunodeficient (SCID) mice home to the bone marrow and proliferate, mimicking MM disease progression. Disease progression in mice injected with CAG cells expressing FR-sema3A was inhibited, resulting in prolonged survival and a lower incidence of bone lesions. Histological examination and fluorescence-activated cell sorting analysis revealed that FR-sema3A expression reduced the infiltration of the CAG cells into the bone marrow, reduced bone marrow necrosis and reduced angiogenesis induced by the MM cells in the bone marrow. Our results suggest that measurement of sema3A serum concentrations may be of use for the diagnosis and for the monitoring of malignancies of the bone marrow such as MM. Furthermore, our results suggest that FR-sema3A may perhaps find use as an inhibitor of MM disease progression.
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http://dx.doi.org/10.1093/carcin/bgy106DOI Listing
October 2018

Treatment patterns and clinical outcomes in high-risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi-center retrospective study.

Am J Hematol 2018 06 28;93(6):810-815. Epub 2018 Apr 28.

Tel-Aviv Sourasky medical Center, Israel.

Del17p is a genomic imbalance occurring in ∼7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved ≥ VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches.
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http://dx.doi.org/10.1002/ajh.25098DOI Listing
June 2018

Community-acquired respiratory infections are common in patients with non-Hodgkin lymphoma and multiple myeloma.

Support Care Cancer 2018 Jul 9;26(7):2425-2431. Epub 2018 Feb 9.

Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.

Purpose: Available data suggest that respiratory infections are associated with increased morbidity and mortality in patients hospitalized due to acute leukemia and allogeneic stem cell transplantation (allo-SCT). However, the precise incidence, risk factors, and severity of respiratory infection, mainly community-acquired, in patients with lymphoma and multiple myeloma (MM) are not fully determined. The current study aimed to investigate risk factors for respiratory infections and their clinical significance in patients with B cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) in the first year of diagnosis.

Methods: Data of consecutive patients diagnosed with NHL or MM and treated at the Rambam Hematology Inpatient and Outpatient Units between 01/2011 and 03/2012 were evaluated. Information regarding anticancer treatment, incidence and course of respiratory infections, and infection-related outcomes was analyzed.

Results: One hundred and sixty episodes of respiratory infections were recorded in 103 (49%) of 211 (73-MM, 138-NHL) patients; 126 (79%) episodes were community-acquired, 47 (29%) of them required hospitalization. In univariate analysis, age < 60 years, MM diagnosis, and autologous SCT increased the respiratory infection risk (P = 0.058, 0.038, and 0.001, respectively). Ninety episodes (56% of all respiratory episodes) were examined for viral pathogens. Viral infections were documented in 25/90 (28%) episodes, 21 (84%) of them were community-acquired, requiring hospitalization in 5 (24%) cases. Anti-flu vaccination was performed in 119 (56%) patients. Two of the six patients diagnosed with influenza were vaccinated.

Conclusions: Respiratory infections, including viral ones, are common in NHL and MM. Most infections are community-acquired and have a favorable outcome. Rapid identification of viral pathogens allows avoiding antibiotic overuse in this patient population.
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http://dx.doi.org/10.1007/s00520-018-4079-3DOI Listing
July 2018

How Do Hunter-Gatherer Children Learn Subsistence Skills? : A Meta-Ethnographic Review.

Hum Nat 2017 Dec;28(4):367-394

Department of Psychology, University of Cambridge, Free School Lane, Cambridge, CB2 3RQ, UK.

Hunting and gathering is, evolutionarily, the defining subsistence strategy of our species. Studying how children learn foraging skills can, therefore, provide us with key data to test theories about the evolution of human life history, cognition, and social behavior. Modern foragers, with their vast cultural and environmental diversity, have mostly been studied individually. However, cross-cultural studies allow us to extrapolate forager-wide trends in how, when, and from whom hunter-gatherer children learn their subsistence skills. We perform a meta-ethnography, which allows us to systematically extract, summarize, and compare both quantitative and qualitative literature. We found 58 publications focusing on learning subsistence skills. Learning begins early in infancy, when parents take children on foraging expeditions and give them toy versions of tools. In early and middle childhood, children transition into the multi-age playgroup, where they learn skills through play, observation, and participation. By the end of middle childhood, most children are proficient food collectors. However, it is not until adolescence that adults (not necessarily parents) begin directly teaching children complex skills such as hunting and complex tool manufacture. Adolescents seek to learn innovations from adults, but they themselves do not innovate. These findings support predictive models that find social learning should occur before individual learning. Furthermore, these results show that teaching does indeed exist in hunter-gatherer societies. And, finally, though children are competent foragers by late childhood, learning to extract more complex resources, such as hunting large game, takes a lifetime.
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http://dx.doi.org/10.1007/s12110-017-9302-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662667PMC
December 2017

Ruxolitinib for the management of myelofibrosis: Results of an international physician survey.

Leuk Res 2017 10 10;61:6-9. Epub 2017 Aug 10.

Department of Haematology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.

Background: Ruxolitinib is established as treatment for symptomatic myeloproliferative neoplasm (MPN)-associated myelofibrosis. The strict inclusion and exclusion criteria and dose modification rules that applied to the COMFORTI and II studies that led to the licensing of ruxolitinib are not always applicable to routine clinical practice. Thus physicians now face decisions regarding ruxolitinib use that were not addressed in these pivotal trials.

Methods: We performed an online survey of hematologists practicing in Europe, Israel, the United Kingdom and the United States. Demographic details regarding the physicians and their practice as relates to MPNs were collected. Management decisions pertaining to the use of ruxolitinib were obtained regarding 10 clinical scenarios relating to anemia, thrombocytopenia, frailty, infection and lack or loss of response to ruxolitnib in MF patients.

Results: 140 physicians responded to the survey. There were marked differences regarding their decisions for ruxolitinib administration in MF patients with or developing anemia or thrombocytopenia. Similarly there was little consensus regarding management of patients refractory or losing a response to ruxolitinib. There were differences between "MPN-focused" and "non-MPN-focused" physicians in certain areas.

Conclusion: Physician practices regarding management of MF patients experiencing ruxolitinib-related toxicities or in whom response to the drug is lost was variable. This was true of "MPN-focused" and "non-MPN-focused" physicians in certain cases. Physician education and experience in using ruxolitinib may improve patient management.
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http://dx.doi.org/10.1016/j.leukres.2017.08.002DOI Listing
October 2017

Allogeneic stem-cell transplantation for myelofibrosis.

Curr Opin Hematol 2017 Nov;24(6):475-480

aDepartment of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa bDepartment of Hematology, Shaare Zedek Medical Center, Jerusalem cRuth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Purpose Of Review: Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative therapy for myelofibrosis. The number of HSCTs performed for this indication has been steadily increasing over the past years, even after the approval of the Janus kinase (JAK) inhibitor, ruxolitinib. This increase may be attributed to improved patient selection based on new prognostic molecular markers, more frequent use of matched unrelated donors, secondary to better (high-resolution) human leukocyte antigen typing and supportive care. Ruxolitinib approval raises new questions regarding the role of JAK inhibitors in the transplant setting.

Recent Findings: The current review summarizes recent updates on HSCT in myelofibrosis. Predictors for transplant outcomes, and specific considerations related to myelofibrosis patient selection for HSCT (e.g. molecular risk stratification) are reviewed. In addition, this review will consider management of myelofibrosis patients in the peritransplant period, including the role of ruxolitinib in the pretransplant period, pre and posttransplant splenomegaly, transplant protocols, posttransplant follow-up of minimal residual disease and interventions in the event of poor engraftment.

Summary: HSCT remains a highly relevant treatment option for myelofibrosis in the era of JAK inhibitors. Recent advances may contribute to a refined definition of HSCT eligibility and identification of the optimal transplantation time, conditioning protocols and posttransplant management.
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http://dx.doi.org/10.1097/MOH.0000000000000381DOI Listing
November 2017

Integration of CT-Based Measurements into Surveillance PET/CT in Patients with Diffuse Large B Cell Lymphoma.

Isr Med Assoc J 2016 Jul;18(7):411-417

Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background: Despite the lack of clinical studies supporting the use of routine surveillance FDG-positron emission tomography (PET) in patients with diffuse large B cell lymphoma (DLBCL) who achieved remission, many centers still use this strategy, especially in high risk patients. Surveillance FDG-PET computed tomography (CT) is associated with a high false positive (FP) rate in DLBCL patients.

Objectives: To investigate whether use of specific CT measurements could improve the positive predictive value (PPV) of surveillance FDG-PET/CT.

Methods: This retrospective study included DLBCL patients treated with CHOP or R-CHOP who achieved complete remission and had at least one positive surveillance PET. CT-derived features of PET-positive sites, including long and short diameters and presence of calcification and fatty hilum within lymph nodes, were assessed. Relapse was confirmed by biopsy or consecutive imaging. The FP rate and PPV of surveillance PET evaluated with/without CT-derived measurements were compared.

Results: Seventy surveillance FDG-PET/CT scans performed in 53 patients were interpreted as positive for relapse. Of these studies 25 (36%) were defined as true-positive (TP) and 45 (64%) as FP. Multivariate analysis found long or short axis measuring ≥ 1.5 and ≥ 1.0 cm, respectively, in PET-positive sites, International Prognostic Index (IPI) ≥ 2, lack of prior rituximab therapy and FDG uptake in a previously involved site, to be independent predictors of true positive surveillance PET (odds ratio 5.4, 6.89, 6.6, 4.9, P < 0.05 for all).

Conclusions: PPV of surveillance PET/CT may be improved by its use in selected high risk DLBCL patients and combined assessment of PET and CT findings.
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July 2016

Comparison of engraftment following different stem cell mobilization modalities in patients with multiple myeloma treated with a uniform induction regimen containing bortezomib, cyclophosphamide and dexamethasone.

Ann Hematol 2017 Mar 24;96(3):461-467. Epub 2016 Dec 24.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8, Ha'Aliya Street, 31096, Haifa, Israel.

Bortezomib-based induction followed by autologous stem cell transplantation is a common treatment for multiple myeloma (MM). Stem cell (SC) mobilization with granulocyte-colony stimulating factor (G-CSF) alone has become an alternative to G-CSF combined with chemotherapeutic agents. This study aimed to compare the efficacy of the two mobilization modalities following induction with a uniform regimen containing bortezomib, cyclophosphamide and dexamethasone (VCD). We retrospectively evaluated results of SC mobilization using either G-CSF alone or combined with high-dose cyclophosphamide (HD-CY) in MM patients after VCD induction. The primary endpoints of the study were engraftment and mobilization-associated toxicity. Parameters of stem cell collection, transplantation and engraftment were assessed. Data of 92 patients were analyzed [56 (61%) mobilized with HD-CY + G-CSF and 36 (39%) with G-CSF only]. HD-CY + G-CSF provided a higher number of CD34 + cells (15.9 vs 8.1 × 10/kg, p = 0.001) with fewer apheresis sessions. However, while no adverse events were observed in patients receiving G-CSF alone, nine patients (16%) receiving HD-CY + G-CSF developed neutropenic fever requiring hospitalization. Although a greater number of cells was transplanted following mobilization with HD-CY + G-CSF, neutrophil and platelet engraftment and duration of transplant-related hospitalization were similar in both cohorts. G-CSF alone provided a sufficient SC amount, without exposing patients to additional toxicity. While HD-CY + G-CSF resulted in a superior SC yield in MM patients induced with VCD, this advantage should be balanced against adverse effects of this mobilization regimen.
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http://dx.doi.org/10.1007/s00277-016-2897-2DOI Listing
March 2017

Site Formation Processes and Hunter-Gatherers Use of Space in a Tropical Environment: A Geo-Ethnoarchaeological Approach from South India.

PLoS One 2016 26;11(10):e0164185. Epub 2016 Oct 26.

Department of Archaeology and Anthropology, University of Cambridge, Cambridge, United Kingdom.

Hunter-gatherer societies have distinct social perceptions and practices which are expressed in unique use of space and material deposition patterns. However, the identification of archaeological evidence associated with hunter-gatherer activity is often challenging, especially in tropical environments such as rainforests. We present an integrated study combining ethnoarchaeology and geoarchaeology in order to study archaeological site formation processes related to hunter-gatherers' ways of living in tropical forests. Ethnographic data was collected from an habitation site of contemporary hunter-gatherers in the forests of South India, aimed at studying how everyday activities and way of living dictate patterns of material deposition. Ethnoarchaeological excavations of abandoned open-air sites and a rock-shelter of the same group located deep in the forests, involved field observations and sampling of sediments from the abandoned sites and the contemporary site. Laboratory analyses included geochemical analysis (i.e., FTIR, ICP-AES), phytolith concentration analysis and soil micromorphology. The results present a dynamic spatial deposition pattern of macroscopic, microscopic and chemical materials, which stem from the distinctive ways of living and use of space by hunter-gatherers. This study shows that post-depositional processes in tropical forests result in poor preservation of archaeological materials due to acidic conditions and intensive biological activity within the sediments. Yet, the multiple laboratory-based analyses were able to trace evidence for activity surfaces and their maintenance practices as well as localized concentrations of activity remains such as the use of plants, metals, hearths and construction materials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164185PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082661PMC
June 2017

Management of extreme thrombocytosis in myeloproliferative neoplasms: an international physician survey.

Ann Hematol 2017 Jan 13;96(1):87-92. Epub 2016 Oct 13.

Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.

Extreme thrombocytosis (ExT) has been associated with an increased bleeding risk in myeloproliferative neoplasm (MPN) patients and is included in the high risk category in treatment guidelines. Treatment of patients with ExT has not been studied in prospective trials. To study physicians' approaches to ExT, we distributed a web based questionnaire with clinical case scenarios to 202 members of MPN working groups. Cases included low thrombotic risk essential thrombocythemia (ET) with either JAK2V617F or CALR mutation, polycythemia vera with ExT either with or without leukocytosis, an ET patient needing urgent orthopedic surgery, and a poorly controlled ET patient with acute cerebral venous sinus thrombosis. Responses were received from 90 physicians (45 %) and were variable in most case scenarios. Country of practice had the most significant influence on physician response. The USA and Israel physicians responded similarly in most cases and differently to the Europe physicians. Treatment of asymptomatic JAK2V617F positive ET and target platelet count on cytoreduction were significantly influenced by physician years of experience. Responses were not influenced by the volume of MPN practice or by whether MPN was considered a major interest by the physician. Our results show a lack of consensus on how to manage MPN patients with ExT. Randomized controlled trials properly designed to address these questions are needed.
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http://dx.doi.org/10.1007/s00277-016-2826-4DOI Listing
January 2017