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  • 1
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1938-1938
    Abstract: Background: The impact of COVID-19 pandemic has been highly heterogeneous across the globe and different regions within the country. The differences in the outcome of these patients is related to their demographic profile, genetics, socio-economic conditions, and government health policies. Prior to the COVID-19 pandemic, the Healthcare Access and Quality (HAQ) Index for hematological malignancies (HAQ index & lt;30) in a low-middle socio-demographic index(SDI) country like India was less than the mean HAQ index for all other diseases (HAQ index 41) with a significant regional disparity.(1)Several national and international registries from high socio-demographic Index (SDI) countries have reported worse short-term outcomes of coronavirus disease (COVID-19) in patients with hematologic as compared to other solid cancers. The outcomes of COVID-19 in patients with hematologic malignancies from a low-middle SDI country are yet unknown. The COVID-19 Hematologic Cancer registry of India reports these outcomes from India. Methods: Ten tertiary referral hospitals across India reported the demographic, clinical, laboratory, treatment, and outcomes of COVID-19 infection in patients with hematological malignancies. The registry was retrospective from March 21, 2020, and prospective from November 1, 2020, till March 20, 2021. Risk factors associated with severity and mortality were evaluated using the penalised logistic regression and Cox proportional hazards model. Findings: Data from 565 patients was included in this study. Among these, 429 (76%) patients were hospitalized, 186 (33%) patients had moderate/severe COVID-19.There were 116 (20.5%) non-survivors at a mean follow up of 147 (95% CI : 142-153) days. Age & gt;60 years (HR 2·55, 1·23 - 5·27), diagnosis of acute myeloid leukemia (HR 2·85, 1·58 - 5·13), interruption or alteration of anticancer therapy (HR 2·78, 1·65 - 4·68), and post hematopoietic cell transplant status (HR 3·68, 1·82 - 7·45) predicted mortality. In contrast, increasing age [20-40 years (OR 2·54, 1·32 - 4·90), 41-60 years (OR 3·51, 1·84 - 6·71), & gt;60 years (OR 6·04, 3·01 - 12·10), comorbidities such as diabetes mellitus (OR 1·89, 1·18 - 3·04), hypertension (OR 1·94, 1·17 - 3·19), diagnosis of AML (OR 3·70, 2·06 - 6·67), indolent non-hodgkin lymphoma (OR 3·20, 1·68 - 6·09), multiple myeloma (OR 2·88, 1·64 - 5·05), malignancy not being in remission (OR 1·71, 1·12 - 2·60)were significantly associated with severe COVID-19 on univariate analysis. Of these, only increasing age [20-40 years (OR 2·60 (1·31 - 5·15), 40-60 years (OR 3·44, 1.60 - 7·41), more than 60 years (OR 5·70, 2·43 - 13·35)] , AML (OR 2·73, 1·45 - 5·12), and malignancy not being in remission (OR 1·85, 1·18 - 2·89) were significantly associated with severe COVID-19 on multivariable analysis Conclusion: The overall mortality from COVID-19 infection of the entire cohort was 20.5%; the mortality was 46.2% in patients who had moderate to severe disease COVID-19 illness. Similar to previous studies, age, diagnosis of acute myeloid leukemia and a post stem cell transplant status was associated with mortality. In addition, interruption or de-escalation of anticancer therapy during Covid-19 infection was identified as an important factor associated with higher mortality on follow up in the current study. References 1. Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016. Lancet (London, England)2018; 391(10136): 2236-71.Lee AJX, Purshouse K. COVID-19 and cancer registries: learning from the first peak of the SARS-CoV-2 pandemic. Br J Cancer 2021; 124(11): 1777-84. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 2
    In: Blood Cancer Journal, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-01-05)
    Type of Medium: Online Resource
    ISSN: 2044-5385
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 8127-8128
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 4
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 3244-3245
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 5
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2338-2338
    Abstract: In the setting of clinical trials, high cure rates have been reported for acute promyelocytic leukemia (APL) with the chemotherapy-free combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) for low-intermediate risk disease, and with the addition of gemtuzumab ozogamicin or minimal anthracycline for high-risk disease. Despite clear in-vitro synergy between ATO and ATRA, most clinical trial protocols in APL have not used these drugs concurrently beyond induction. There is limited real world data on the use of chemotherapy-free combination of ATO and ATRA with minimal anthracycline use in the treatment of APL, especially in the high risk group. We did a retrospective analysis of the clinical outcomes of patients with newly diagnosed APL treated at our center from January 2015 to May 2020 using concurrent ATO, ATRA and minimal anthracycline in a risk stratified manner. The data was frozen and analyzed as on 1st June 2021. During the study period, 167 patients were diagnosed to have APL at our hospital. Of these, we excluded 5 patients who had presented with relapsed disease and 28 patients who were treated with single agent ATO. The remaining 134 patients were treated with a uniform protocol as summarized in Figure 1a. Figure 1b shows the KM plot for EFS (2 year: 90.8±2.5%) for these 134 patients. For analysis of regimen safety and efficacy, we excluded patients who wished to pursue treatment elsewhere within the first 1 week of treatment (n=7), and patients who had severe infections or life-threatening bleeding at presentation or before therapy initiation and subsequently died (n=4). Thus, a total of 123 patients with newly diagnosed APL were included for further analysis. The median age was 35 years (IQR: 24 to 45 years). Forty-six (37.4%) were females. The median duration of symptoms prior to admission was 14 days (IQR: 7 to 28 days). Sixty-one (49.6%) had high risk APL while the remaining 62 (50.4%) had low-intermediate risk APL. During induction, 28 (22.7%) patients had major bleeding while 5 (4%) patients developed major thrombosis. Sixty-seven (55%) patients had at least one documented infection during induction therapy. The median number of packed red cell concentrates, fresh frozen plasma, platelet rich concentrates and cryoprecipitates transfused during induction therapy was 5 (IQR: 3 to 6.5), 10 (IQR: 3 to 30), 40 (IQR: 23 to 55) and 6 (IQR: 0 to 18) respectively. Nineteen (15.4%) patients developed differentiation syndrome; all were treated with steroids, 8 required transient cessation of treatment and 6 required intensive care. Eight (6.5%) patients died during induction. During induction, grade 3 hepatotoxicity was noted in 8 (6.5%) patients, 10 (8.1%) patients had ATRA related headache or benign intracranial hypertension of which 5 required transient cessation of ATRA, while 11 (8.9%) patients had transient QTc prolongation of which 6 required transient cessation of ATO. Seventeen (13.8%) patients developed symptomatic sensory neuropathy requiring treatment. None required permanent discontinuation of therapy. At a median follow up of 854 days, there were 2 (1.6%) hematologic relapses and no deaths beyond induction therapy. The 2-year OS and EFS for the cohort (n=123) are 93.4% ± 2.3% and 91.6% ± 2.6% respectively (Figure 1c). Two (1.6%) patients have developed second malignancies. In a real world setting, concurrently administered ATO and ATRA with minimal anthracycline use results in excellent long term survival, even in the high risk group. Early deaths due to delayed presentation with infections and life threatening bleeding remain an unmet need for future research along with the need for strategies to reduce treatment-related toxicities. Figure 1 Figure 1. Disclosures Mathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 6
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1400-1400
    Abstract: Combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is currently considered the standard of care in the management of acute promyelocytic leukemia (APL). While APL is considered a highly curable malignancy there is recognition that the outcome in pediatric patients is inferior to that reported in young adults. There have been concerns raised in the past on the potential long term side effects of the use of ATO, especially in a pediatric population. There is limited long term follow up data on the use of ATO in the pediatric population. At our center we have been using ATO based regimens to treat pediatric and adult patients with APL since 1998 and hence we undertook this retrospective analysis to evaluate the long term clinical outcomes and toxicity profile in the pediatric cohort. Data on all consecutive pediatric patients (age ≤18yrs) diagnosed with APL and treated in the Department of Haematology, Christian Medical College, Vellore, from January, 1998 to December, 2017 were included in this retrospective analysis. Of the total 73 patients with age ≤ 18yrs diagnosed during this period, 5 refused treatment and were discharged against medical advice. Treatment in the remaining 68 patients consisted of single agent ATO until 2015 (n=57), as reported previously by us (Mathews et al. Blood 2016). From 2015 combination of ATO, ATRA ± an anthracycline in induction and consolidation was administered in a risk adjusted manner (n=11). The median age was 2 years (range: 2-18) with equal gender distribution (50% each). Sixty two (91.2%) achieved complete hematologic remission (CR), 5 (7.4%) early deaths occurred from intracranial hemorrhage (n=3), neutropenic sepsis (n=1) and pulmonary thrombo-embolism (n=1), one patient did not achieve CR at the end of induction. The median time to CR was 45 days (range: 25- 62). Other acute ATO-related toxicities were low grade, transient and not associated with any mortality (transaminitis = 12 [17.6%]; ATRA like syndrome = 6 [8.8%] ). With a median follow-up of 71 months, the 5 year OS and EFS of pediatric cohort (n=68) was 78.9±5.2% and 61.8±6.4% respectively (Fig 1). Among the 62 patients in CR, 21 (33.9%) relapsed at a median of 18 months (range: 5-126) from the initial diagnosis; 16 bone marrow, 3 bone marrow+CNS and 2 molecular relapses; an additional 2 patients died in remission (one viral encephalitis and another data not available). Nineteen out of 21 (90.5%) patients who relapsed received ATO based re-induction while 2 refused treatment and were discharged at request. Out of the 19 treated patients, all attained second CR. CR was consolidated with an autologous SCT (n=10) or ATO based chemotherapy (n=9). The OS and EFS of the 19 relapsed patients was 72.9±10.4% and 68±10.8% respectively. On long term follow up of this pediatric cohort (median follow up 71 months; 18 (26.5%) 〉 10 years follow up and 37 (54.5%) 〉 5 years follow up) there were no long term renal, hepatic, metabolic complications or second malignancies noted. Our results indicate the high efficacy and long term safety of ATO based regimens in the treatment of children with APL. Even among the relapse pediatric APL patients treated with upfront ATO, salvage chemotherapy with ATO based regimen followed by autologous stem cell transplantation is associated with excellent long term survival and is not associated with any major long term complications. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 7
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3272-3272
    Abstract: Background: Fludarabine based conditioning protocols are increasingly being used for transplant (SCT) in patients with aplastic anaemia (AA) especially in those who have received multiple transfusions. Patients and Methods: Between January 2004 and June 2019, 229 patients with AA and HLA identical sibling donors underwent SCT at CMC Vellore India using Fludarabine [180 mg/m2 over 6 days] and Cyclophosphamide [120 mg/kg over 2 days] . Few patients received low dose ATG [ATGAM 40 mg/kg]. Data on HSCT and outcomes were collected from the institutional database and individual medical records. Results: The median age was 23.9 years (range: 1.5 - 58) including 151 males and 78 females including 78 children (33.4%). Donors were matched sibling (n = 215) or family donors (n = 14). The graft source was Bone marrow in 11 and peripheral blood stem cells in 218. GVHD prophylaxis consisted mainly of cyclosporine and methotrexate mainly with few receiving post-transplant cyclophosphamide. Engraftment occurred in 90% with graft failure in 2.6% and early death in 7.4%. Regimen related toxicity (RRT) was seen in 4.7% and included veno-occlusive disease of liver and hemorrhagic cystitis. Acute GVHD (grade 2-4) occurred in 26.4% while chronic GVHD was seen in 40.3%. The 5 year overall survival (OS) for the entire group is 75.9 + 4.9%. The 5 yr OS was 81.4 + 3.9% for ages 0 - 20, 76.3 + 4.4% for ages 21-40 and 55.3 + 9.3% for ages 〉 40 years. Age 〉 40 years (p = 0.000), presence of fever requiring hospital admission within 4 weeks prior to SCT (p = 0.001) and acute GVHD (p = 0.051) were identified as risk factors associated with a poor outcome on a univariate analysis while on a multivariate analysis, older age and fever continued to remain significant. Conclusion: This is the largest series of patients with AA undergoing SCT using a fludarabine based conditioning and is associated with improved survival following sibling donor HSCT for AA. Presence of fever requiring a hospital admission immediately prior to SCT is associated with poor outcomes. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 8
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2187-2187
    Abstract: Objective: Fanconi anaemia is a genotypically heterogeneous disease. A fast and reliable genetic diagnosis method helps is important for the clinical care of these patients. The objective of this study was to establish a strategy for expeditious molecular diagnosis for the Indian FA patients. Methods: Exome sequencing was performed for 119 FA patients on Illumina HiSeq X system and the data was analysed by Sentieon (v201808.01) to identify germline variants. Single nucleotide variants (SNVs) with an allele frequency of & lt;3% in various population databases including the Indian population database were analysed and annotated using an in-house pipeline. Copy number variants (CNVs) were detected using ExomeDepth (v1.1.10). Long amplicon next-generation sequencing was performed for FANCA and FANCG genes. Gene dosage analysis was performed for the deletions identified by WES in the FANCT/UBE2T gene. Sanger sequencing was performed for the selected variants identified by WES. Results: SNVs associated with FA were identified in heterozygous states in 93 (78%) patients. Of the remaining 20 patients, 8 had homozygous deletions, and twelve were compound heterozygous with deletions and SNVs. We detected deletions in 20 patients: 7 with heterozygous and 12 with homozygous deletions in FANCA, and one with a homozygous deletion in FANCT (UBE2T). MLPA confirmed the deletions in the FANCA gene. The homozygous deletion in the FANCT gene was confirmed by the lack of amplification by PCR using the primers binding to the deleted region. By combining the SNVs and deletions, disease-causing genotypes were identified in 113 of 119 (95%) patients. A large number of our patients (81.5 %) were homozygous (Figure) due to the high rate of consanguinity in the population. FANCA was found to be the most frequently mutated gene in (57.5%) while mutations in FANCG gene accounted for 14.2% of our patients. FANCC mutations were found at a very low frequency (1.8%) in our patients. Although mutations in FANCL are rare in all the populations, 24 (21.2%) patients with FANCL mutations were identified in our study. A previously reported synonymous splicing mutation FANCL c.1092G & gt;A;p.K364= was found in homozygous state in 22 (19.5%) patients. Two other FANCL mutations identified includes a missense mutation c.827C & gt;T; p.Pro281Leu in the homozygous state in one patient and a nonsense mutation c.997C & gt;T; p.Gln333Ter in the compound heterozygous state with the common FANCL c.1092G & gt;A;p.K364= mutation in another patient. Mutations in rarely mutated FA genes included 1 patient each in FANCT/UBE2T and FANCI and two each in FANCJ/BRIP1 and FANCF gene. Based on the comprehensive genotype analysis, we could design an algorithm for FA in the Indian population. ~20% of the FA patients who have FANCL c.1092G & gt;A;p.K364= mutation can be diagnosed by Sanger sequencing. MLPA can detect FANCA deletions (16.5% of the overall mutations). The results from these two tests can be obtained in 48 hours. For those who are negative for the mutations by these two methods, LA-NGS can detect SNVs in the FANCA and FANCG genes, which constitute & gt;55% of the FA mutations in the population. We have tested this algorithm for expedited molecular diagnosis in 27 FA patients and found that the disease genotypes could be established in 94% of the patients in less than two weeks. Conclusion/Clinical applicability: Exome sequencing identified several novel mutations in the FA pathway genes in the FA patients. A cost-effective and time-saving algorithm was explicitly established for molecular diagnosis of FA in the Indian population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 9
    In: Hematology/Oncology and Stem Cell Therapy, King Faisal Specialist Hospital and Research Centre - DIGITAL COMMONS JOURNALS, ( 2021-3)
    Type of Medium: Online Resource
    ISSN: 1658-3876
    Language: English
    Publisher: King Faisal Specialist Hospital and Research Centre - DIGITAL COMMONS JOURNALS
    Publication Date: 2021
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  • 10
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4537-4537
    Abstract: Among transplant related complications, graft versus host disease (GvHD) significantly affects survival among patients undergoing allogeneic hematopoietic stem cell transplantation (aHSCT). There is limited data on GvHD and its impact on outcomes of aHSCT in patients with thalassemia major (TM). We have reviewed the incidence and outcome of GVHD among patients with TM who underwent aHSCT at our center. All patients with TM undergoing their first aHSCT between January 2007 and December 2017 were included in this analysis. Till 2009, all patients received conditioning with busulfan (16mg/kg over 4 days) with cyclophosphamide (200mg/kg over 4 days). From 2010, most patients received treosulfan (42 G/m2 over 3 days) with thiotepa (8mg/Kg for one day) and fludarabine (160mg/m2over 4 days) based conditioning regimen. All patients receiving busulfan conditioning received bone marrow (BM) as the graft while most patients receiving treosulfan conditioning received mobilized peripheral blood stem cells (PBSC). GvHD prophylaxis was with short-course methotrexate (10mg/m2 on day +1, and 7mg/m2 on days 3, 6 and 11) with cyclosporine. Thymoglobulin was added for matched unrelated donors (MUD). GvHD was prospectively recorded and graded according to the Glucksberg classification. Between January 2007 and December 2017, 363 first transplants were done for patients with TM with HLA identical donors. There were 12(3.3%) class 1, 105(28.9%) class 2 and 246(67.8%) class 3 (Pesaro risk stratification), with 115(46.7%) of the latter being high risk (Vellore risk stratification - BBMT, 2007; 13: 889). The median age was 8 years (range: 1-25) with a male predominance (60%). 331 (91.2%) patients had matched related donors (MRD) and 32 (8.8%) had MUDs. Donor gender was mismatched in 207 (57%) of which 129 (35.5%) were female to male transplants. The graft was obtained from the bone marrow in 137 (37.7%) of whom 53 (38.7%) were class III, and from mobilized peripheral blood in 226 (62.3%) of whom 193 (85.4% were class III. 149 (41%) patients developed GvHD - acute GvHD (aGvHD) in 115 (31.7%) and chronic GvHD (cGvHD) in 80 (22%). aGvHD was grade I in 32 patients (27.8%), grade II in 36patients (31.3%), grade III in 16 patients (13.9%) and grade IV in 25 patients (21.7%), while 6 patients (5.2%) had features of overlap GvHD only (oral lichen planus). First line treatment was with steroids in all patients with grade II and above aGvHD (n=83) with 43 (51.8%) of them responding adequately. There were 37 patients (44.5%) who required various second line agents for aGvHD with 20 (24%) receiving more than one immunosuppressive agent. 20 patients (24%) with persistent aGvHD went on to develop cGvHD. Out of the total of 80 patients with cGvHD, 13 (16.3%) had limited and 67 (83.7%) had extensive cGvHD. 26 patients (32.5%) developed de novo cGvHD, 8 (10%) of them after donor lymphocyte infusion (DLI) for potential rejection. The other 46 patients (57.5%) had chronic overlap GvHD following previous aGvHD. Among the different variables evaluated for association with aGvHD (patient/donor age, gender mismatch, MUD vs MRD), none were significant. Among those with MRD, aGVHd occurred in 36/135 patients (26.7%) of patients receiving BM grafts compared to 65/196 patients (33.2%) who received PBSC grafts (p=ns). cGvHD occurred in 23/106 patients (21.7%) in those receiving BM grafts vs 52/171 patients (30.4%) receiving PBSC (p=ns). 30 patients (8.3%) persisted to have cGvHD at last follow-up but only 20 (5.2%) required treatment. Mortality of the whole cohort was 66 (18.2%), out of which 32 (8.8%) were related to GvHD - 24 (6.6%) due to aGvHD and 8 (2.2%) due to cGvHD. At a median follow up of 41 months (range: 0-148), the 5-year and 10-year overall survival (OS) was 81.1±2.1% each for the whole cohort. The 5-year OS of those with grade 2-4 aGvHD was significantly lower than those with grade 0/1 aGvHD (65.7±5.3% vs 85.7±2.2%, p=0.000) [figure 1]. The 5 year OS of those with cGvHD was 88.9% ± 3.8% as compared to those without cGVHD was 96.9% ± 1.2% (P=0.009) [figure 2] . There was no significant difference in OS among those with limited and extensive cGvHD (90.9±3.6% vs 88.4±4.2% (p=ns). Our data shows that, as expected, severe aGvHD and extensive cGvHD significantly lowers survival in patients with TM undergoing aHSCT. However, PBSC graft did not result in higher acute or chronic GVHD compared to BM. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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