Publications by authors named "Jacob Rowe"

267 Publications

CNS Involvement in AML at Diagnosis is Rare and does not Affect Response or Survival: Data from 11 ECOG-ACRIN Trials.

Blood Adv 2021 Oct 1. Epub 2021 Oct 1.

Mayo Clinic, Rochester, Minnesota, United States.

Central nervous system (CNS) involvement in newly diagnosed acute myeloid leukemia (AML) patients is rare and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive ECOG-ACRIN clinical trials for newly diagnosed AML patients. 3240 patients with AML were analyzed and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies where LP was done at the discretion of the investigator (0.86% vs. 1.41%, p=0.18). There was no significant difference in the complete remission (CR) rate between patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs. 59.3-60%). The median overall survival (OS) of CNS-positive patients, other EMD or no EMD was 11.4, 11.3 and 12.7 months, respectively. There was no difference in OS between patients with CNS involvement and those with other EMD (HR 0.96, adjusted p=0.84) or no EMD (HR 1.19, adjusted p=0.44). In conclusion, the reported incidence of CNS involvement of newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis does not appear, in and of itself, to portend for a poor prognosis for either achieving an initial CR or OS.
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http://dx.doi.org/10.1182/bloodadvances.2021004999DOI Listing
October 2021

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Blood Adv 2021 Sep 22. Epub 2021 Sep 22.

University of Texas Southwestern Medical Center, Dallas, Texas, United States.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.
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http://dx.doi.org/10.1182/bloodadvances.2021004881DOI Listing
September 2021

Consolidation in AML: Abundant opinion and much unknown.

Blood Rev 2021 Aug 5:100873. Epub 2021 Aug 5.

Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.

Consolidation therapy forms the backbone of post-remission therapy for AML and is uniformly accepted as an integral part of therapy designed to achieve long-term survival. The need for post-remission therapy was initially described over four decades ago and has since undergone many variations in terms of dosage, number of cycles and intensity of therapy. There is much empiricism in the current understanding of consolidation therapy and much that has not been rigorously studied. This review will consider the many aspects of consolidation therapy, focusing on the number of cycles, differences between young and older adults, first and subsequent remission as well as therapy prior to an allogeneic transplant. Emphasis will be given to differentiate strategies that are clearly evidence-based from those that have been incorporated into standard of care while bypassing the need for rigorous data-driven approaches. Finally, consideration will be given to the current ability to assess the minimal measureable residual disease and the impact that this may have on therapeutic paradigms, including superseding many of the time-honored prognostic features.
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http://dx.doi.org/10.1016/j.blre.2021.100873DOI Listing
August 2021

Proton-gated coincidence detection is a common feature of GPCR signaling.

Proc Natl Acad Sci U S A 2021 Jul 6;118(28). Epub 2021 Jul 6.

Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136;

The evolutionary expansion of G protein-coupled receptors (GPCRs) has produced a rich diversity of transmembrane sensors for many physical and chemical signals. In humans alone, over 800 GPCRs detect stimuli such as light, hormones, and metabolites to guide cellular decision-making primarily using intracellular G protein signaling networks. This diversity is further enriched by GPCRs that function as molecular sensors capable of discerning multiple inputs to transduce cues encoded in complex, context-dependent signals. Here, we show that many GPCRs are coincidence detectors that couple proton (H) binding to GPCR signaling. Using a panel of 28 receptors covering 280 individual GPCR-Gα coupling combinations, we show that H gating both positively and negatively modulates GPCR signaling. Notably, these observations extend to all modes of GPCR pharmacology including ligand efficacy, potency, and cooperativity. Additionally, we show that GPCR antagonism and constitutive activity are regulated by H gating and report the discovery of an acid sensor, the adenosine A2a receptor, which can be activated solely by acidic pH. Together, these findings establish a paradigm for GPCR signaling, biology, and pharmacology applicable to acidified microenvironments such as endosomes, synapses, tumors, and ischemic vasculature.
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http://dx.doi.org/10.1073/pnas.2100171118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285908PMC
July 2021

Efficacy and Safety Profile of Ivosidenib in the Management of Patients with Acute Myeloid Leukemia (AML): An Update on the Emerging Evidence.

Blood Lymphat Cancer 2021 22;11:41-54. Epub 2021 Jun 22.

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

The isocitrate dehydrogenase enzyme, catalyzing isocitrate conversion to α-ketoglutarate (αKG) in both the cell cytoplasm and mitochondria, contributes to the production of dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as a reductive potential in various cellular processes. gene mutations are revealed in up to 20% of the patients with acute myeloid leukemia (AML). A mutant IDH enzyme, existing in the cell cytoplasm and possessing neomorphic activity, converts αKG into oncometabolite R-2-hydroxyglutarate (R-2-HG) that accumulates in high amounts in the cell and inhibits αKG-dependent enzymes, including epigenetic regulators. The resultant alteration in gene expression and blockade of differentiation ultimately lead to leukemia development. Myeloid differentiation capacity can be restored by obstruction of the mutant enzyme, inducing substantial reduction in R-2-HG levels. Ivosidenib, a potent selective inhibitor of mutant , is a differentiating agent shown to be clinically effective in newly diagnosed AML (ND-AML) and relapsed/refractory (R/R) AML harboring this mutation. The drug is approved by the Food and Drug Administration (FDA) as a single-agent treatment for R/R AML. Significance of mutated targeting and a potential role of ivosidenib in AML management, when used either as a single agent or as part of combination therapies, will be reviewed herein.
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http://dx.doi.org/10.2147/BLCTT.S236446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235936PMC
June 2021

Prognostic effect of gender on outcome of treatment for adults with acute myeloid leukaemia.

Br J Haematol 2021 Jul 17;194(2):309-318. Epub 2021 Jun 17.

Mayo Clinic, Rochester, MN, USA.

There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi-institutional treatment studies from March 1984 to November 2008. Kaplan-Meier estimates were used to estimate event-time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two-sided tests. Non-APL female patients had a significantly better overall (OS) but not disease-free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.
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http://dx.doi.org/10.1111/bjh.17523DOI Listing
July 2021

Enhancer Hijacking Drives Oncogenic Expression in Lineage-Ambiguous Stem Cell Leukemia.

Cancer Discov 2021 Jun 8. Epub 2021 Jun 8.

Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of , a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to . Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed allele and association of with activated hematopoietic progenitor cell -regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of driven by diverse structural alterations, including superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0145DOI Listing
June 2021

Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.

Blood 2021 Sep;138(11):948-958

Leukaemia Research Cytogenetics Group, Newcastle University Translational and Clinical Research Institute, Newcastle-upon-Tyne, United Kingdom.

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.
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http://dx.doi.org/10.1182/blood.2020010144DOI Listing
September 2021

Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia.

Nat Cancer 2020 Nov 19;1(11):1113-1127. Epub 2020 Oct 19.

Institute for Cancer Genetics, Columbia University, New York, NY, USA.

Multi-agent combination chemotherapy can be curative in acute lymphoblastic leukemia (ALL). Still, patients with primary refractory disease or with relapsed leukemia have a very poor prognosis. Here we integrate an in-depth dissection of the mutational landscape across diagnostic and relapsed pediatric and adult ALL samples with genome-wide CRISPR screen analysis of gene-drug interactions across seven ALL chemotherapy drugs. By combining these analyses, we uncover diagnostic and relapse-specific mutational mechanisms as well as genetic drivers of chemoresistance. Functionally, our data identifies common and drug-specific pathways modulating chemotherapy response and underscores the effect of drug combinations in restricting the selection of resistance-driving genetic lesions. In addition, by identifying actionable targets for the reversal of chemotherapy resistance, these analyses open novel therapeutic opportunities for the treatment of relapse and refractory disease.
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http://dx.doi.org/10.1038/s43018-020-00124-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011577PMC
November 2020

Perspectives on current survival and new developments in AML.

Authors:
Jacob M Rowe

Best Pract Res Clin Haematol 2021 03 31;34(1):101248. Epub 2021 Jan 31.

Department of Hematology, Rambam Health Care Campus, Shaare Zedek Medical Center, 12 Shmuel Bait St, Jerusalem, IL, 9103102, Israel. Electronic address:

The past three years have witnessed remarkable progress in acute myeloid leukemia (AML). The approval and development of targeted therapies and novel agents has improved outcomes for patients with traditionally poor survival rates. This review has summarized the survival impact of chemotherapy-based regimens in AML and described recent advances that will be of significance in the near future.
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http://dx.doi.org/10.1016/j.beha.2021.101248DOI Listing
March 2021

Predictable cholesterol binding sites in GPCRs lack consensus motifs.

Structure 2021 05 27;29(5):499-506.e3. Epub 2021 Jan 27.

Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, RMSB 6078A, Miami, FL 33136, USA; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA; University of Miami Institute for Data Science and Computing, Miami, FL 33136, USA. Electronic address:

A rich diversity of transmembrane G protein-coupled receptors (GPCRs) are used by eukaryotes to sense physical and chemical signals. In humans alone, 800 GPCRs comprise the largest and most therapeutically targeted receptor class. Recent advances in GPCR structural biology have produced hundreds of GPCR structures solved by X-ray diffraction and increasingly, cryo-electron microscopy (cryo-EM). Many of these structures are stabilized by site-specific cholesterol binding, but it is unclear whether these interactions are a product of recurring cholesterol-binding motifs and if observed patterns of cholesterol binding differ by experimental technique. Here, we comprehensively analyze the location and composition of cholesterol binding sites in the current set of 473 human GPCR structural chains. Our findings establish that cholesterol binds similarly in cryo-EM and X-ray structures and show that 92% of cholesterol molecules on GPCR surfaces reside in predictable locations that lack discernable cholesterol-binding motifs.
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http://dx.doi.org/10.1016/j.str.2021.01.004DOI Listing
May 2021

The evolution and mechanism of GPCR proton sensing.

J Biol Chem 2021 Jan-Jun;296:100167. Epub 2020 Dec 13.

The Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA; The Department of Tumor Biology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida, USA; The Institute for Data Science Computing, University of Miami, Coral Gables, Florida, USA. Electronic address:

Of the 800 G protein-coupled receptors (GPCRs) in humans, only three (GPR4, GPR65, and GPR68) regulate signaling in acidified microenvironments by sensing protons (H). How these receptors have uniquely obtained this ability is unknown. Here, we show these receptors evolved the capability to sense H signals by acquiring buried acidic residues. Using our informatics platform pHinder, we identified a triad of buried acidic residues shared by all three receptors, a feature distinct from all other human GPCRs. Phylogenetic analysis shows the triad emerged in GPR65, the immediate ancestor of GPR4 and GPR68. To understand the evolutionary and mechanistic importance of these triad residues, we developed deep variant profiling, a yeast-based technology that utilizes high-throughput CRISPR to build and profile large libraries of GPCR variants. Using deep variant profiling and GPCR assays in HEK293 cells, we assessed the pH-sensing contributions of each triad residue in all three receptors. As predicted by our calculations, most triad mutations had profound effects consistent with direct regulation of receptor pH sensing. In addition, we found that an allosteric modulator of many class A GPCRs, Na, synergistically regulated pH sensing by maintaining the pK values of triad residues within the physiologically relevant pH range. As such, we show that all three receptors function as coincidence detectors of H and Na. Taken together, these findings elucidate the molecular evolution and long-sought mechanism of GPR4, GPR65, and GPR68 pH sensing and provide pH-insensitive variants that should be valuable for assessing the therapeutic potential and (patho)physiological importance of GPCR pH sensing.
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http://dx.doi.org/10.1074/jbc.RA120.016352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948426PMC
August 2021

BL-8040 CXCR4 antagonist is safe and demonstrates antileukemic activity in combination with cytarabine for the treatment of relapsed/refractory acute myelogenous leukemia: An open-label safety and efficacy phase 2a study.

Cancer 2021 Apr 3;127(8):1246-1259. Epub 2020 Dec 3.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML.

Methods: Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23).

Results: BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts.

Conclusions: The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia.
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http://dx.doi.org/10.1002/cncr.33338DOI Listing
April 2021

Forward into the second century of Haematologica.

Authors:
Jacob M Rowe

Haematologica 2020 11 1;105(11):2498. Epub 2020 Nov 1.

Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.

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http://dx.doi.org/10.3324/haematol.2020.271767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604556PMC
November 2020

A novel PrECOG (PrE0901) dose-escalation trial using eltrombopag: enhanced platelet recovery during consolidation therapy in acute myeloid leukemia.

Leuk Lymphoma 2020 09 30;61(9):2191-2199. Epub 2020 May 30.

Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.

High-dose cytarabine (HiDAC) consolidation for acute myeloid leukemia (AML) induces transient profound myelosuppression and potential morbidity/mortality. PrE0901 was a phase I multi-center trial evaluating the safety/toxicity of eltrombopag in AML patients receiving HiDAC consolidation. We used a standard 3 + 3 design employing a unique dose-escalation/de-escalation strategy. One hundred four patients were screened, 54 declined participation, 35 were deemed medically ineligible, and 14 were treated on study. Three patients were treated in cohorts 1-4 and two were treated in cohort 5. Eltrombopag + HiDAC was well-tolerated and no dose-limiting toxicities were observed. Median time to platelet recovery of all patients treated was 22.5 (range 16-43) days. Observationally, eltrombopag 150 mg once daily starting on day 3 of consolidation demonstrated the fastest and most consistent platelet recovery (median 19 days). Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression.
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http://dx.doi.org/10.1080/10428194.2020.1762878DOI Listing
September 2020

Venetoclax is safe and efficacious in relapsed/refractory AML.

Leuk Lymphoma 2020 09 18;61(9):2221-2225. Epub 2020 May 18.

Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.

Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% ( = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.
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http://dx.doi.org/10.1080/10428194.2020.1761964DOI Listing
September 2020

Survival following allogeneic transplant in patients with myelofibrosis.

Blood Adv 2020 05;4(9):1965-1973

Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Carolinas HealthCare System, Charlotte, NC.

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.
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http://dx.doi.org/10.1182/bloodadvances.2019001084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218417PMC
May 2020

CRISPR-addressable yeast strains with applications in human G protein-coupled receptor profiling and synthetic biology.

J Biol Chem 2020 06 1;295(24):8262-8271. Epub 2020 May 1.

Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA

Genome stability is essential for engineering cell-based devices and reporter systems. With the advent of CRISPR technology, it is now possible to build such systems by installing the necessary genetic parts directly into an organism's genome. Here, we used this approach to build a set of 10 versatile yeast-based reporter strains for studying human G protein-coupled receptors (GPCRs), the largest class of membrane receptors in humans. These reporter strains contain the necessary genetically encoded parts for studying human GPCR signaling in yeast, as well as four CRISPR-addressable expression cassettes, landing pads, installed at known safe-harbor sites in the yeast genome. We showcase the utility of these strains in two applications. First, we demonstrate that increasing GPCR expression by incrementally increasing GPCR gene copy number potentiates Gα coupling of the pharmacologically dark receptor GPR68. Second, we used two CRISPR-addressable landing pads for autocrine activation of a GPCR (the somatostatin receptor SSTR5) with its peptide agonist SRIF-14. The utility of these reporter strains can be extended far beyond these select examples to include applications such as nanobody development, mutational analysis, drug discovery, and studies of GPCR chaperoning. Additionally, we present a BY4741 yeast strain created for broad applications in the yeast and synthetic biology communities that contains only the four CRISPR-addressable landing pads. The general utility of these yeast strains provides an inexpensive, scalable, and easy means of installing and expressing genes directly from the yeast genome to build genome-barcoded sensors, reporter systems, and cell-based factories.
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http://dx.doi.org/10.1074/jbc.RA120.013066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294089PMC
June 2020

How we treat older patients with acute myeloid leukaemia.

Br J Haematol 2020 12 30;191(5):682-691. Epub 2020 Apr 30.

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

After decades when intensive chemotherapy remained the only effective anti-acute myeloid leukaemia (AML) treatment, a torrent of novel, less toxic agents are about to revolutionise AML therapy. Prolonged remissions with good quality of life become achievable for many patients previously considered only for palliative care because they could not tolerate intensive therapy. As treatment options multiply, the importance of genetic profile is recognised, even for advanced-age patients for whom cure is unlikely. With lack of randomised comparative trials for most treatment regimens, one can only extrapolate data from existing studies to make evidence-based decisions. We herein present seven common clinical scenarios illustrating the complexity of treating older AML patients and describe our approach to their management. In each case, up-to-date data on relevant agents to be offered to a particular patient are discussed. The current review is limited to the drugs, available and approved in the Western world and many promising agents, still under investigation, are not discussed.
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http://dx.doi.org/10.1111/bjh.16701DOI Listing
December 2020

At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial.

Br J Haematol 2020 10 27;191(1):37-43. Epub 2020 Mar 27.

University College London, London, UK.

Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37-144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five-year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse.
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http://dx.doi.org/10.1111/bjh.16616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687130PMC
October 2020

Pharmacological prophylaxis of infection in pediatric acute myeloid leukemia patients.

Expert Opin Pharmacother 2020 Feb 8;21(2):193-205. Epub 2020 Jan 8.

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

: Pediatric patients treated for acute myeloid leukemia (AML) are at high risk of developing severe infectious complications. The choice of an optimum supportive treatment should be based on local epidemiology, as well as intensity and toxicity of the anti-leukemic therapy applied.: This review presents an overview of recently published studies focusing on the prevention of infection in pediatric AML patients. PubMed has been systematically searched for clinical trials, reviews, and meta-analyses published in the last 10 years. The focus of this article will be limited to primary prophylaxis only, while secondary prophylaxis is beyond the scope of the current review.: Although anti-bacterial agents may decrease the bacterial infection burden, there is no consensus regarding prophylactic use. To that end, there is a need for further randomized controlled trials to establish the precise role of anti-bacterial prophylaxis in pediatric AML patients. The prophylactic use of anti-fungal agents is strongly recommended for all AML patients. Since the contribution of hematopoietic growth factors to improved survival has not been demonstrated, they should not be routinely applied. Decisions regarding an appropriate prophylactic strategy should be taken in collaboration with the infectious disease experts and pharmacology team.
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http://dx.doi.org/10.1080/14656566.2019.1701654DOI Listing
February 2020

Will new agents impact survival in AML?

Authors:
Jacob M Rowe

Best Pract Res Clin Haematol 2019 12 18;32(4):101094. Epub 2019 Oct 18.

Technion, Israel Institute of Technology, Haifa, Israel; Department of Hematology, Rambam Health Care Campus, Haifa, Israel; Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Hematology, Shaare Zedek Medical Center, 12 Shmuel Bait St, Jerusalem, IL, 9103102, Israel. Electronic address:

In recent years, several drugs-including midostaurin, gilteritinib, and gemtuzumab ozogamicin, to name a few-have been approved or reapproved in the United States to treat patients with acute myeloid leukemia (AML). Yet survival rates for younger patients had improved with chemotherapy alone even before the approvals of these new agents. This begs the question whether the new therapies will actually have a positive impact on survival. The 5-year survival rate for older patients has also risen, again without the addition of these new agents. The challenge will be to incorporate new therapies and use them where they will have the greatest impact-major work for clinicians and researchers alike.
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http://dx.doi.org/10.1016/j.beha.2019.101094DOI Listing
December 2019

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

Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia: A Center for International Blood and Marrow Transplant Research Study.

Biol Blood Marrow Transplant 2020 03 25;26(3):472-479. Epub 2019 Oct 25.

The Blood and Marrow Transplant Group of Georgia, Northside Hospital, Atlanta, Georgia.

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358778PMC
March 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

Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study.

Mycoses 2019 Dec 22;62(12):1140-1147. Epub 2019 Oct 22.

Infectious Diseases Unit, Shaare-Zedek Medical Center, affiliated with Hebrew University Medical School, Jerusalem, Israel.

Background: Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases.

Objectives: Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment.

Methods: Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software.

Result: Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD.

Conclusions: The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.
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http://dx.doi.org/10.1111/myc.13001DOI Listing
December 2019

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2019 11 22;25(11):2113-2123. Epub 2019 Aug 22.

Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota Medical Center, Minneapolis, MN.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.014DOI Listing
November 2019

Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission.

Blood Adv 2019 06;3(12):1826-1836

The Blood and Marrow Transplant Program, Northside Hospital, Atlanta, GA.

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy-based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival ( = .15), leukemia-free survival ( = .50), nonrelapse mortality ( = .16), relapse ( = .90), or grade II-IV acute GVHD ( = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease-donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy-based Haplo-HCT vs MSD using calcineurin inhibitor-based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.
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http://dx.doi.org/10.1182/bloodadvances.2019000050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595262PMC
June 2019

Efficacy outcomes in the treatment of older or medically unfit patients with acute myeloid leukaemia: A systematic review and meta-analysis.

Leuk Res 2019 07 21;82:36-42. Epub 2019 May 21.

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Israel; The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.

Older and medically unfit patients with acute myeloid leukaemia (AML) who are unsuitable for standard induction therapy have limited treatment options. A meta-analysis was performed with two objectives: 1) to describe outcomes for patients treated with hypomethylating agents, either decitabine or azacitidine, or low-dose cytarabine (LDAC) and 2) to describe the effect of age (<75 vs ≥75) on the remission rates. Thirteen published multi-centre studies in 1822 patients were identified where patients were treated with hypomethylating agents or LDAC. A random effects meta-analysis was performed to provide a pooled estimate of efficacy for the following endpoints: complete remission (CR), overall response rate (CR + complete remission with incomplete white blood cell recovery [CRi]), relapse free survival (RFS), overall survival (OS), and 60-day mortality. For all endpoints apart from RFS, there was significant unexplained between-trial variability (I > 64%). The pooled estimates of average outcome across studies were 15% (95% CI: 12%-19%) for CR; 22% (95% CI: 18%-26%) for overall response rate; 8.8 months (95% CI: 7.7 m-10.0 m) for median RFS; 6.3 months (95% CI: 5.3 m-7.4 m) for median OS and 21% (95% CI: 18%-25%) for 60-day mortality. The odds of response were 1.85 times higher (95% CI: 1.3-2.7) among patients who were <75 compared to those who were older.
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http://dx.doi.org/10.1016/j.leukres.2019.05.007DOI Listing
July 2019
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