Publications by authors named "Robert Peter Gale"

355 Publications

RBC distribution width predicts thrombosis risk in polycythemia vera.

Leukemia 2021 Sep 8. Epub 2021 Sep 8.

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

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http://dx.doi.org/10.1038/s41375-021-01410-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424620PMC
September 2021

Cell therapy of chronic lymphocytic leukaemia: Transplants and chimeric antigen receptor (CAR)-T cells.

Blood Rev 2021 Sep 1:100884. Epub 2021 Sep 1.

Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom. Electronic address:

There is substantial progress in the therapy of chronic lymphocytic leukaemia (CLL), much of it the result of new drug development. As such the definition of high-risk CLL is changing. Nevertheless, few persons with CLL are cured with current therapy. Two types of cell therapies of CLL are currently being evaluated or re-evaluated in the context of these advances: haematopoietic cell transplants and chimeric antigen receptor (CAR)-T-cells. We discuss the potential role of these cell therapies in the context of the evolving therapy topography of CLL including how these therapies work and who, if anyone, is an appropriate candidate for cell therapy.
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http://dx.doi.org/10.1016/j.blre.2021.100884DOI Listing
September 2021

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

Front Immunol 2021;12:706186. Epub 2021 Aug 17.

Public Health Sciences and Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans.

Objective: Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings.

Methods And Results: We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies.

Conclusions: Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.706186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416151PMC
September 2021

Clinical Relevance of (rs3025039) +936 C>T Polymorphism in Primary Myelofibrosis: Susceptibility, Clinical Co-Variates, and Outcomes.

Genes (Basel) 2021 Aug 20;12(8). Epub 2021 Aug 20.

Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnostics, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Foundation, 27100 Pavia, Italy.

We evaluated the association of rs3025039 polymorphism with clinical co-variates and outcomes in 849 subjects with primary myelofibrosis (PMF) and 250 healthy controls. Minor T-allele frequency was higher in subjects with compared with those without (18% vs. 13%; = 0.014). In subjects with , the TT genotype was associated at diagnosis with lower platelet concentrations ( = 0.033), higher plasma LDH concentration ( = 0.005), higher blood CD34-positive cells ( = 0.027), lower plasma cholesterol concentration ( = 0.046), and higher concentration of high-sensitivity C-reactive protein ( = 0.018). These associations were not found in subjects with PMF without . In subjects with the TT genotype, risk of death was higher compared with subjects with CC/CT genotypes (HR = 2.12 [1.03, 4.35], = 0.041). Finally, the TT genotype was associated with higher frequency of deep vein thrombosis in typical sites (12.5% vs. 2.5%; OR = 5.46 [1.51, 19.7], = 0.009). In conclusion, in subjects with PMF, the rs3025039 CT or TT genotypes are more common in those with than in those without mutation and are associated with disease severity, poor prognosis, and risk of deep vein thrombosis.
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http://dx.doi.org/10.3390/genes12081271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393853PMC
August 2021

A SAS macro for estimating direct adjusted survival functions for time-to-event data with or without left truncation.

Bone Marrow Transplant 2021 Aug 19. Epub 2021 Aug 19.

Medical College of Wisconsin, Milwaukee, WI, USA.

There are several statistical programmes to compute direct adjusted survival estimates from results of the Cox proportional hazards model. However, when used to analyze observational databases with large sample sizes or highly stratified treatment groups such as in registry-related datasets, these programmes are inefficient or unable to generate confidence bands and simultaneous p values. Also, these programmes do not consider potential left-truncation in retrospectively collected data. To address these deficiencies we developed a new SAS macro %adjsurvlt() able to produce direct adjusted survival estimates based on a stratified Cox model. The macro has improved computational performance and is able to handle left-truncated and right-censored time-to-event data. Several mechanisms were implemented to improve computational efficiency including choosing matrix operations over do-loops and reducing dimensions of co-variate matrices. Compared to the latest SAS macro, %adjsurvlt() used < 0.1% computational time to process a dataset with 100 treatment cohorts and a sample size of 20,000 and showed similar computational efficiency when analyzing left-truncated and right-censored data. We illustrate use of %adjsurvlt() to compare retrospectively collected survival data of 2 transplant cohorts.
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http://dx.doi.org/10.1038/s41409-021-01435-2DOI Listing
August 2021

Is the Sokal or EUTOS long-term survival (ELTS) score a better predictor of responses and outcomes in persons with chronic myeloid leukemia receiving tyrosine-kinase inhibitors?

Leukemia 2021 Aug 19. Epub 2021 Aug 19.

Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, PR China.

Data from 1661 consecutive subjects with chronic-phase chronic myeloid leukemia (CML) receiving initial imatinib (n = 1379) or a 2-generation tyrosine-kinase inhibitor (2G-TKI; n = 282) were interrogated to determine whether the Sokal or European Treatment and Outcome Study for CML (EUTOS) long-term survival (ELTS) scores were more accurate responses and outcome predictors. Both scores predicted probabilities of achieving complete cytogenetic response (CCyR), major molecular response (MMR), failure- and progression-free survivals (FFS, PFS), and survival in all subjects and those receiving imatinib therapy. However, the ELTS score was a better predictor of MR, MR, and CML-related survival than the Sokal score. In subjects receiving 2G-TKI therapy, only the ELTS score accurately predicted probabilities of CCyR, MMR, MR, FFS, and PFS. In the propensity score matching, subjects classified as intermediate risk by the ELTS score receiving a 2G-TKI had better responses (p < 0.001~0.061), FFS (p = 0.002), and PFS (p = 0.03) but not survival. Our data suggest better overall prediction accuracy for the ELTS score compared with the Sokal score in CML patients, especially those receiving 2G-TKIs. People identified as intermediate risk by the ELTS score may benefit more from initial 2G-TKI therapy in achieving surrogate endpoints but not survival, especially when a briefer interval to stopping TKI therapy is the therapy objective.
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http://dx.doi.org/10.1038/s41375-021-01387-yDOI Listing
August 2021

Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improve Transplantation Outcomes in Older Patients with Myelodysplastic Syndromes.

Transplant Cell Ther 2021 Aug 14. Epub 2021 Aug 14.

Department of Hematology/Oncology, Hospital Infantil Universitario Nino Jesus, Madrid, Spain.

Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival (OS) was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.08.007DOI Listing
August 2021

Is race important in genomic classification of hematological neoplasms?

Hematol Oncol 2021 Aug 14. Epub 2021 Aug 14.

MDS and MPN Centre, Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

In recent years, genome-based classifications for hematological neoplasms have been proposed successively and proved to be more accurate than histologic classifications. However, some previous studies have reported the racial differences of genetic landscape in persons with hematological neoplasms including myelodysplastic syndromes (MDS), which may cause a genomic classification based on a particular ethnic group does not operate in other races. To determine whether race plays an important role in the genomic-based classification, we validated a newly proposed genomic classification of MDS (J Clin Oncol.2021; JCO2001659), which was based on a large European database, in Chinese patients from our center. Our results showed significant differences between Chinese and European patients including proportion of each group to overall cohort when applying this novel genomic classification. Our data indicate that a genomic classification of hematological neoplasms probably should be revised according to specific genetic features in different races.
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http://dx.doi.org/10.1002/hon.2909DOI Listing
August 2021

Improving prediction accuracy in acute myeloid leukaemia: micro-environment, immune and metabolic models.

Leukemia 2021 Aug 7. Epub 2021 Aug 7.

Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China.

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http://dx.doi.org/10.1038/s41375-021-01377-0DOI Listing
August 2021

Toward the Cure of Acute Lymphoblastic Leukemia in Children in China.

JCO Glob Oncol 2021 07;7:1176-1186

Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

This study explored results of therapy of children with acute lymphoblastic leukemia (ALL) in China, recent progress, and challenges. Included are a survey of therapy outcomes of ALL in Chinese children nationwide, comparison of these data with global ALL therapy outcomes, analyses of obstacles to improving outcomes, and suggestions of how progress can be achieved. Therapy outcomes at many Chinese pediatric cancer centers are approaching those of resource-rich countries. However, nationwide outcomes still need improvement. Obstacles include suboptimal clinical trials participation, children without adequate health care funding, human resource shortages, especially physicians expert in pediatric hematology and oncology, and social-economic disparities. We suggest how these obstacles have been and continue to be remedied including expanded access to protocol-based therapy, improved supportive care, health care reforms, recruitment of trained personnel, and international collaborations. China has made substantial progress treating children with ALL. We envision even better outcomes in the near future.
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http://dx.doi.org/10.1200/GO.21.00049DOI Listing
July 2021

Professor Anton Hagenbeek 1948-2021: Father of MRD and lymphoma expert.

Bone Marrow Transplant 2021 Aug 19;56(8):2038-2039. Epub 2021 Jul 19.

Department of Hematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.

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http://dx.doi.org/10.1038/s41409-021-01375-xDOI Listing
August 2021

Clonal Megakaryocyte Dysplasia with Normal Blood Values Is a Distinct Myeloproliferative Neoplasm.

Acta Haematol 2021 Jul 19:1-8. Epub 2021 Jul 19.

Department of Immunology and Inflammation, Center for Haematology Research, Imperial College London, London, United Kingdom.

Introduction: In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity.

Methods: This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis.

Results: Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41-54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. JAK2V617F was present in 10 subjects and CALR mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40-160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5-4.0) and 5.0 events (4.6-5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis.

Conclusion: Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values.
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http://dx.doi.org/10.1159/000517207DOI Listing
July 2021

Granulocyte transfusions in haematopoietic cell transplants and leukaemia: the phoenix or beating a dead horse?

Bone Marrow Transplant 2021 Sep 3;56(9):2046-2049. Epub 2021 Jul 3.

Department of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, USA.

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http://dx.doi.org/10.1038/s41409-021-01399-3DOI Listing
September 2021

Will New Drugs Replace Transplants for Chronic Lymphocytic Leukaemia?

J Clin Med 2021 Jun 7;10(11). Epub 2021 Jun 7.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London SW7 2BX, UK.

Transplants have been used to treat chronic lymphocytic leukemia (CLL) for more than 35 years. Use has been restricted to <1 percent of highly selected persons typically failing concurrent conventional therapies. As therapies of CLL have evolved, so have indications for transplantation and transplant techniques. The data that we review indicate that transplants can result in long-term leukemia-free survival in some persons but are associated with substantial transplant-related morbidity and mortality. We discuss the mechanisms underlying the anti-leukemia effects of transplants including drugs, ionizing radiations, immune-mediated mechanisms and/or a combination. We discuss prognostic and predicative covariates for transplant outcomes. Importantly, we consider whether there is presently a role of transplants in CLL and who, if anyone, is an appropriate candidate in the context of new drugs.
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http://dx.doi.org/10.3390/jcm10112516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201027PMC
June 2021

Mental Health in Persons With Chronic Myeloid Leukemia During the SARS-CoV-2 Pandemic: The Need for Increased Access to Health Care Services.

Front Psychiatry 2021 8;12:679932. Epub 2021 Jun 8.

Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China.

Mental health problems in the general population have been reported during the SARS-CoV-2 pandemic; however, there were rare data in persons with chronic myeloid leukemia (CML). Therefore, we performed a cross-sectional study on mental health evaluated using the 9-item Patient Health Questionnaire (PHQ-9; depression), the 7-item Generalized Anxiety Disorder (GAD-7; anxiety), and the 22-item Impact of Event Scale-Revised (IES-R; distress), including subscales of avoidance, intrusion, and hyper-arousal in persons with CML, non-cancer persons, and immediate family members of persons with cancer as controls (≥16 years) by an online survey. Data from 3,197 persons with CML and 7,256 controls were collected. In multivariate analyses, CML was significantly associated with moderate to severe depression (OR = 1.6; 95% Confidence Interval [CI], 1.4, 1.9; < 0.001), anxiety (OR = 1.4 [1.1, 1.7]; = 0.001), distress (OR = 1.3 [1.1, 1.5]; < 0.001), and hyper-arousal (OR = 1.5 [1.3, 1.6]; < 0.001). Moreover, delay in regular monitoring was significantly associated with depression (OR 1.3 [1.0, 1.7]; = 0.024), anxiety (OR = 1.3 [1.0, 1.8]; = 0.044), avoidance (OR = 1.2 [1.0, 1.4]; = 0.017), and intrusion (OR = 1.2 [1.0, 1.4]; = 0.057); tyrosine kinase-inhibitor dose reduction or discontinuation, depression (OR = 1.9 [1.3, 2.8]; = 0.001), distress (OR = 2.0 [1.4, 2.8]; < 0.001), avoidance (OR = 1.6 [1.2, 2.1]; = 0.004), intrusion (OR = 1.6 [1.1, 2.1]; = 0.006), and hyper-arousal (OR = 1.3 [1.0, 1.8]; = 0.088). We concluded that persons with CML during the SARS-CoV-2 pandemic have worse mental health including depression, anxiety, and distress symptoms. Decreasing or stopping monitoring or dose resulted in adverse mental health consequences.
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http://dx.doi.org/10.3389/fpsyt.2021.679932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217438PMC
June 2021

Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures.

J Radiol Prot 2021 Jun 16. Epub 2021 Jun 16.

Hematology Research Centre, Imperial College London, 11693 San Vicente Boulevard, #335, Los Angeles, California, 90049, UNITED STATES.

Therapy of acute, high-dose whole-body exposures of humans to ionizing radiations is a complex medical challenge. Since 1944 more than 400 radiologic accidents have been registered with more than 3,000 substantial radiation exposures and 127 fatalities. There are several potential interventions including supportive care, transfusions, preventative or therapeutic anti-infection drugs, molecularly-cloned myeloid growth factors and hematopoietic cell transplants. We discuss the use of the granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) to treat acute high-dose ionizing radiation exposures. Considerable data in experimental models including monkeys indicate use of these drugs accelerates bone marrow recovery and in some but not all instances increases survival. In 10 accidents since 1996, 30 victims received G-CSF alone or with other growth factors. 26 victims survived. In 7 accidents since 1986, 28 victims received GM-CSF alone or with other growth factors. 18 victims survived. However, absent control or data from randomized trials, it is not possible to know with certainty what role, if any, receiving G-CSF or GM-CSF was of benefit. Given the favorable benefit-to-risk ratio of molecularly-cloned myeloid growth factors, their use soon after exposure to acute, high-dose whole-body ionizing radiations is reasonable.  .
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http://dx.doi.org/10.1088/1361-6498/ac0bffDOI Listing
June 2021

NK-/T-cell lymphomas.

Leukemia 2021 09 11;35(9):2460-2468. Epub 2021 Jun 11.

Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, PR China.

Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein-Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. Its pathogenesis is complex and incompletely understood. Lymphoma cells are transformed from NK- or T-cells, sometimes both. EBV-infection and subsequent genetic alterations in infected cells are central to NKTL development. Hemophagocytic syndrome is a common complication. Accurate staging is important to predict outcomes but there is controversy which system is best. More than two-thirds of NKTL lympohmas are localized at diagnosis, are frequently treated with radiation therapy only and have 5-year survival of about 70 percent. Persons with advanced NKTLs receive radiation therapy synchronously or metachronously with diverse multi-drug chemotherapy typically including L-asparginase with 5-year survival of about 40 percent. Some persons with widespread NKTL receive chemotherapy only. There are few data on safety and efficacy of high-dose therapy and a haematopoietic cell autotransplant. Immune therapies, histone deacetylase (HDAC)-inhibitors and other drugs are in early clinical trials. There are few randomized controlled clinical trials in NKTLs and no therapy strategy is clearly best; more effective therapy(ies) are needed. Some consensus recommendations are not convincingly evidence-based. Mechanisms of multi-drug resistance are considered. We discuss these issues including recent advances in our understanding of and therapy of NKTLs.
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http://dx.doi.org/10.1038/s41375-021-01313-2DOI Listing
September 2021

Emil J Freireich and Baruch Spinoza: birds of a feather?

Bone Marrow Transplant 2021 07 20;56(7):1768-1769. Epub 2021 May 20.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

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http://dx.doi.org/10.1038/s41409-021-01273-2DOI Listing
July 2021

Cost-Effectiveness of Post-Autotransplant Lenalidomide in Persons with Multiple Myeloma.

Mediterr J Hematol Infect Dis 2021 1;13(1):e2021034. Epub 2021 May 1.

Center for the Study of Myelofibrosis, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy.

Considerable data indicate post-transplant lenalidomide prolongs progression-free survival and probably survival after an autotransplant for multiple myeloma (MM). However, optimal therapy duration is unknown, controversial and differs in the EU and US. We compared outcomes and cost-effectiveness of 3 post-transplant lenalidomide strategies in EU and US settings: (1) none; (2) until failure; and (3) 2-year fixed duration. We used a Markov decision model, which included six health states and informed by published data. The model estimated the lenalidomide strategy given to failure achieved 1.06 quality-adjusted life years (QALYs) at costs QALY gained of €29,232 in the EU and $133,401 in the US settings. Two-year fixed-duration lenalidomide averted €7,286 QALY gained in the EU setting and saved 0.84 QALYs at $60,835 QALY gained in the US setting. These highly divergent costs QALY in the EU and US settings resulted from significant differences in post-transplant lenalidomide costs and 2nd-line therapies driven by whether post-transplant failure was on or off-lenalidomide. In Monte Carlo simulation analyses which allowed us to account for the variability of inputs, 2-year fixedduration lenalidomide remained the preferred strategy for improving healthcare sustainability in the EU and US settings.
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http://dx.doi.org/10.4084/MJHID.2021.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114895PMC
May 2021

Why chronic myeloid leukaemia cannot be cured by tyrosine kinase-inhibitors.

Leukemia 2021 08 17;35(8):2199-2204. Epub 2021 May 17.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

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http://dx.doi.org/10.1038/s41375-021-01272-8DOI Listing
August 2021

Systematic review and meta-analysis of tocilizumab in persons with coronavirus disease-2019 (COVID-19).

Leukemia 2021 06 17;35(6):1661-1670. Epub 2021 May 17.

Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

We performed a meta-analysis to determine safety and efficacy of tocilizumab in persons with coronavirus disease-2019 (COVID-19). We searched PubMed, Web of Science and Medline using Boolean operators for studies with the terms coronavirus OR COVID-19 OR 2019-nCoV OR SARS-CoV-2 AND tocilizumab. Review Manager 5.4 was used to analyze data and the modified Newcastle-Ottawa and Jadad scales for quality assessment. We identified 32 studies in 11,487 subjects including three randomized trials and 29 cohort studies with a comparator cohort, including historical controls (N = 5), a matched cohort (N = 12), or concurrent controls (N = 12). Overall, tocilizumab decreased risk of death (Relative Risk [RR] = 0.74; 95% confidence interval [CI], 0.59, 0.93; P = 0.008; I = 80%) but not of surrogate endpoints including ICU admission (RR = 1.40 [0.64,3.06]; P = 0.4; I = 88%), invasive mechanical ventilation (RR = 0.83 [0.57,1.22]; P = 0.34; I = 65%) or secondary infections (RR = 1.30 [0.97,1.74]; P = 0.08; I = 65%) and increased interval of hospitalization of subjects discharged alive(mean difference [MD] = 2 days [<1, 4 days]; P = 0.006; I = 0). RRs of death in studies with historical controls (RR = 0.28 [0.16,0.49; P < 0.001]; I = 62%) or a matched cohort (RR = 0.68 [0.53, 0.87]; P = 0.002; I = 42%) were decreased. In contrast, RRs of death in studies with a concurrent control (RR = 1.10 [0.77, 1.56]; P = 0.60; I = 85%) or randomized (RR = 1.18 [0.57,2.44]; P = 0.66; I = 0) were not decreased. A reduced risk of death was not confirmed in our analyses which questions safety and efficacy of tocilizumab in persons with COVID-19.
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http://dx.doi.org/10.1038/s41375-021-01264-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127467PMC
June 2021

JAK-inhibitors for coronavirus disease-2019 (COVID-19): a meta-analysis.

Leukemia 2021 09 14;35(9):2616-2620. Epub 2021 May 14.

Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

We analyzed reports on safety and efficacy of JAK-inhibitors in patients with coronavirus infectious disease-2019 (COVID-19) published between January 1st and March 6th 2021 using the Newcastle-Ottawa and Jadad scales for quality assessment. We used disease severity as a proxy for time when JAK-inhibitor therapy was started. We identified 6 cohort studies and 5 clinical trials involving 2367 subjects treated with ruxolitinib (N = 3) or baricitinib 45 (N = 8). Use of JAK-inhibitors decreased use of invasive mechanical ventilation (RR = 0.63; [95% Confidence Interval (CI), 0.47, 0.84]; P = 0.002) and had borderline impact on rates of intensive care unit (ICU) admission (RR = 0.24 [0.06, 1.02]; P = 0.05) and acute respiratory distress syndrome (ARDS; RR = 0.50 [0.19, 1.33]; P = 0.16). JAK-inhibitors did not decrease length of hospitalization (mean difference (MD) -0.18 [-4.54, 4.18]; P = 0.94). Relative risks of death for both drugs were 0.42 [0.30, 0.59] (P < 0.001), for ruxolitinib, RR = 0.33 (0.13, 0.88; P = 0.03) and for baricitinib RR = 0.44 (0.31, 0.63; P < 0.001). Timing of JAK-inhibitor treatment during the course of COVID-19 treatment may be important in determining impact on outcome. However, these data are not consistently reported.
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http://dx.doi.org/10.1038/s41375-021-01266-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119232PMC
September 2021

The paradox of haematopoietic cell transplant in Latin America.

Bone Marrow Transplant 2021 May 13. Epub 2021 May 13.

FUNDALEU, Buenos Aires, Argentina.

Hematopoietic cells transplants are technically complex and expensive imposing a huge burden on health care systems, especially those in developing countries and regions. In 2017 > 4500 transplants were done in 13 Latin American countries with established transplant programmes. We interrogated data on transplant rate, cost, funding source, hospital type, Gini coefficient and the United Nations Development Programme Inequality-Adjusted Human Development Index to determine co-variates associated with transplant development. Transplant rates varied almost 30-fold between the 13 countries from 345 in Uruguay to 12 in Venezuela with a regional transplant rate 7-8-fold lower compared with the US and EU. We found significant correlations between higher transplant cost, public funding, transplants in private hospitals with transplant rate. Low cost per transplant regardless of payor and transplants done in public hospitals were associated with low transplant rates. In contrast, high cost per transplant funded by the government and transplants done in private hospitals were associated with high transplant rates. Surprisingly, we found transplant rates were higher when transplants cost more, when they were done in private for-profit hospitals and payed for with public funds. These data give insights how to increase transplant rates in Latin America and other developing regions.
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http://dx.doi.org/10.1038/s41409-021-01321-xDOI Listing
May 2021

A prognostic immune risk score for diffuse large B-cell lymphoma.

Br J Haematol 2021 Jul 3;194(1):111-119. Epub 2021 May 3.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China.

We constructed a prognostic score for persons with diffuse large B-cell lymphoma (DLBCL) based on infiltrating immune cells. Data of 956 consecutive subjects were retrieved from the Gene Expression Omnibus database and assigned to training (GSE10846, n = 305) or validation (GSE87371 n = 206 and GSE117556 n = 445 combined) cohorts. Proportions of non-lymphoma cells in the sample were inferred using the ESTIMATE algorithm. An immune risk score was constructed comprised of eight types of non-lymphoma immune cells calculated using the CIBERSORT algorithm. Five-year survival of subjects with an immune risk score ≤ 0·45 in the training cohort was better than that of subjects with a score > 0·45 (hazard ratio [HR] = 3·99; 95% confidence interval [CI] = 2·74, 5·82; P < 0·001). HR in the validation cohort was HR = 2·17 (1·47, 3·21; P < 0·001). Enrichment analyses indicated correlations with genes controlling immune-related biological processes and pathways. A nomogram comprised of the immune risk score and most covariates including age, lactate dehydrogenase concentration (LDH), lymphoma-type (germinal centre B cell [GCB] versus non-GCB), Eastern Cooperative Oncology Group performance status (ECOG-PS) and rituximab therapy had a C-statistic of 0·76 compared with C-statistics of 0·69 and 0·69 for the International Prognostic Index (IPI) and Revised International Prognostic Index (R-IPI). These data indicate the immune risk score is an accurate, independent survival predictor in persons with DLBCL.
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http://dx.doi.org/10.1111/bjh.17478DOI Listing
July 2021

Economics influences therapy decisions in chronic myeloid leukaemia: should it?

J Cancer Res Clin Oncol 2021 Apr 22. Epub 2021 Apr 22.

Department of Immunology and Inflammation, Centre for Haematology Research, Imperial College London, London, SW7 2AZ, UK.

The question whether economic considerations should influence therapy decisions in persons with chronic myeloid leukaemia (CML) is complex touching on many metrics other than medicine including the perceptions, attitudes, and motivations of physicians, patients, their families, and payors', allocation of health care resources, and others. We discuss metrics whereby physicians, patients, and payors make CML therapy choices in settings where cost and availability are or are not considerations. We conclude that economic considerations strongly influence therapy decisions in CML. Whether this should be so and what impact it has on outcomes is also considered. Absent definitive data proving which therapy strategy is best allowing economic considerations to operate may not be as unreasonable or unethical as it appears. In some settings, it may be the best approach. However, because TKIs markedly prolong survival and may even cure some persons with CML, TKI therapy should be available to everyone with CML.
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http://dx.doi.org/10.1007/s00432-021-03607-5DOI Listing
April 2021

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Sep 16;56(9):2108-2117. Epub 2021 Apr 16.

Haematology Research Centre, Department of Immunology and Inflammation, Imperial College London, London, UK.

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
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http://dx.doi.org/10.1038/s41409-021-01261-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425595PMC
September 2021

Impact of socio-demographic co-variates on prognosis, tyrosine kinase-inhibitor use and outcomes in persons with newly-diagnosed chronic myeloid leukaemia.

J Cancer Res Clin Oncol 2021 Apr 9. Epub 2021 Apr 9.

National Clinical Research Center for Hematologic Disease, Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South Street, Beijing, 100044, China.

Purpose: Define the impact of socio-demographic co-variates on outcomes of persons with newly-diagnosed chronic phase chronic myeloid leukaemia (CML).

Methods: Data of 961 consecutive subjects with newly-diagnosed CML were integrated for these outcomes in multi-variable Cox regression analyses after adjusting for confounders and interactions.

Results: Elder age was associated with less use of a 2nd generation TKI as initial therapy. Household registration, comorbidity(ies) and education level were associated with use of a generic rather than branded TKI as initial therapy. Subjects with lower education level were more likely to be diagnosed with CML because of leukaemia-related symptoms. Rural registration and lower education level were also associated with a greater likelihood of switching TKI-therapy. Lower education level was associated with lower likelihood of achieving MMR [HR = 0.8 (0.7, 0.9), p = 0.002], MR [HR = 0.8 (0.7, 1.0), p = 0.055], and poor FFS [HR = 1.7 (1.3, 2.5); p < 0.001], PFS [HR = 2.0 (1.1, 5.0); p = 0.014], CML-related survival [HR = 2.5 (1.0, 10.0); p = 0.060] and survival [HR = 2.5 (1.0, 10.0); p = 0.043]. Males had lower rates of MMR and MR and worse FFS, but not survival compared with females. Being married was associated with a higher rate of MR, fewer failures, progressions, and deaths.

Conclusion: Socio-demographic co-variates have a strong impact on therapy choice and responses in persons with newly-diagnosed CML, including circumstances of diagnosis, risk category and prognosis, use of initial TKI, switching TKIs, response to TKI-therapy, and outcomes.
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http://dx.doi.org/10.1007/s00432-021-03624-4DOI Listing
April 2021

Impact of Pretransplantation Renal Dysfunction on Outcomes after Allogeneic Hematopoietic Cell Transplantation.

Transplant Cell Ther 2021 05 26;27(5):410-422. Epub 2021 Feb 26.

Abramson Cancer Center, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania.

Renal dysfunction is a recognized risk factor for mortality after allogeneic hematopoietic cell transplantation (alloHCT), yet our understanding of the effect of different levels of renal dysfunction at time of transplantation on outcomes remains limited. This study explores the impact of different degrees of renal dysfunction on HCT outcomes and examines whether the utilization of incremental degrees of renal dysfunction based on estimated glomerular filtration rate (eGFR) improve the predictability of the hematopoietic cell transplantation comorbidity index (HCT-CI). The study population included 2 cohorts: cohort 1, comprising patients age ≥40 years who underwent alloHCT for treatment of hematologic malignancies between 2008 and 2016 (n = 13,505; cohort selected given a very low incidence of renal dysfunction in individuals age <40 years), and cohort 2, comprising patients on dialysis at the time of HCT (n = 46). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. The patients in cohort 1 were assigned into 4 categories-eGFR ≥90 mL/min (n = 7062), eGFR 60 to 89 mL/min (n = 5264), eGFR 45 to 59 mL/min (n = 897), and eGFR <45 mL/min (n=282)-to assess the impact of degree of renal dysfunction on transplantation outcomes. Transplantation outcomes in patients on dialysis at the time of alloHCT were analyzed separately. eGFR <60 mL/min was associated with an increased risk for nonrelapse mortality (NRM) and requirement for dialysis post-HCT. Compared with the eGFR ≥90 group, the hazard ratio (HR) for NRM was 1.46 (P = .0001) for the eGFR 45 to 59 mL/min group and 1.74 (P = .004) for the eGFR <45 mL/min group. Compared with the eGFR ≥90 mL/min group, the eGFR 45 to 59 mL/min group (HR, 2.45; P < .0001) and the eGFR <45 mL/min group (HR, 3.09; P < .0001) had a higher risk of renal failure necessitating dialysis after alloHCT. In addition, eGFR <45 mL/min was associated with an increased overall mortality (HR, 1.63; P < .0001). An eGFR-based revised HCT-CI was also developed and shown to be predictive of overall survival (OS) and NRM, with predictive performance similar to the original HCT-CI. Among 46 patients on dialysis at alloHCT, the 1-year probability of OS was 20%, and that of NRM was 67%. The degree of pretransplantation renal dysfunction is an independent predictor of OS, NRM, and probability of needing dialysis after alloHCT. An eGFR-based HCT-CI is a validated index for predicting outcomes in adults with hematologic malignancies undergoing alloHCT. The outcomes of alloHCT recipients on dialysis are dismal; therefore, one should strongly weigh the significant risks of being on hemodialysis as a factor in determining alloHCT candidacy.
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http://dx.doi.org/10.1016/j.jtct.2021.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168834PMC
May 2021

VEXAS syndrome in myelodysplastic syndrome with autoimmune disorder.

Exp Hematol Oncol 2021 Mar 19;10(1):23. Epub 2021 Mar 19.

State Key Laboratory of Experimental Haematology, Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly-described adult-onset inflammatory syndrome characterized by vacuoles in myeloid and erythroid precursor cells and somatic mutations affecting methionine-41 (p.Met41) in UBA1. The VEXAS syndrome often overlaps with myelodysplastic syndromes (MDS) with autoimmune disorders (AD). By screening the UBA1 gene sequences derived from MDS patients with AD from our center, we identified one patient with a p.Met41Leu missense mutation in UBA1, who should have been diagnosed as MDS comorbid with VEXAS syndrome. This patient respond poorly to immune suppressive drugs. Patients with MDS and AD who have characteristic vacuoles in myeloid and erythroid precursor cells should be screened for UBA1 mutation, these patients are likely to have VEXAS syndrome and unlikely to improve with immunosuppressive drugs and should be considered for other alternative therapies.
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http://dx.doi.org/10.1186/s40164-021-00217-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976711PMC
March 2021
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