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In: Bone Marrow Transplantation, Springer Science and Business Media LLC, Vol. 55, No. 6 ( 2020-06), p. 1137-1146

Type of Medium: Online Resource

ISSN: 0268-3369 , 1476-5365

URL: Article

DOI: 10.1038/s41409-020-0791-y

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2004030-1

In: Journal of Hematology, Elmer Press, Inc., Vol. 10, No. 1 ( 2021), p. 35-39

Type of Medium: Online Resource

ISSN: 1927-1212 , 1927-1220

URL: Article

DOI: 10.14740/jh761

Language: English

Publisher: Elmer Press, Inc.

Publication Date: 2021

detail.hit.zdb_id: 2662519-2

In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 3 ( 2020-03), p. S221-S222

Type of Medium: Online Resource

ISSN: 1083-8791

URL: Article

DOI: 10.1016/j.bbmt.2019.12.540

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 3056525-X

detail.hit.zdb_id: 2057605-5

In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 3 ( 2020-03), p. S354-S355

Type of Medium: Online Resource

ISSN: 1083-8791

URL: Article

DOI: 10.1016/j.bbmt.2019.12.182

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 3056525-X

detail.hit.zdb_id: 2057605-5

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 20-20

Abstract: Introduction: Haploidentical bone marrow transplant (haplo-BMT) with post-transplant cyclophosphamide (PTCy) provides near universal donor availability and curative potential for individuals with severe sickle cell disease (SCD). However, a recently recognized late-effect following allogeneic hematopoietic cell transplant is new-onset post-transplant diabetes mellitus type II (PTDM), which occurs in up to 50% of patients and is associated with a three-fold increase in mortality (Griffith et al BBMT 2011, Engelhardt et al BBMT 2019). Known risk factors for PTDM include older age, total body irradiation, and non-Caucasian ethnicity. Studies have shown that pre-transplant insulin resistance and enhanced immune cell alloreactivity are other important contributing factors (Engelhardt et al Blood 2011). To our knowledge, the incidence of PTDM following haplo-BMT with PTCy for SCD has not been characterized, in a population which is predominantly African-American, with a crude prevalence of diabetes mellitus type II of 16.4 (14.7-18.2), and thus represents an unmet need. We hypothesized that the ethnicity and chronic inflammatory state that exists in individuals with SCD contributes to an increased risk of PTDM and may be associated with worse transplant-related outcomes. Methods: We analyzed a multi-center cohort of 33 patients with SCD who underwent haplo-BMT with PTCy. All patients received the reduced-intensity conditioning as shown in Figure 1. Ten patients (31%) had preconditioning with hydroxyurea, azathioprine and hyper-transfusion. Patients with existing diabetes mellitus or follow-up time less than one year were excluded. PTDM was defined as any random single blood glucose level of & gt; 200 mg/dL between D0 and D+100 of transplant. Baseline patient and transplant-related variables were analyzed. Immune subsets were analyzed by flow cytometry at one, two, three, six, and twelve months post-haplo-BMT. Results: The median age at transplant was 11.5 years. Median at age last follow up was 16 years. Baseline and transplant-related data are summarized in Table 1. No patients experienced primary graft failure, while three patients had secondary graft failure at a median of 87 days (range 60-604 days) following haplo-BMT (Table 1). Donor chimerism at 6 months and 1 year was & gt;95% for myeloid and lymphoid lineages for all patients. Fourteen patients (44%) developed PTDM at a median time of 18 days (range 3-40 days), though only three (21%) were treated with corticosteroids prior to the development of PTDM (Table 1). In the PTDM cohort, the median time to corticosteroid use was 22 days. Sixteen patients required corticosteroids for any indication (13 PTDM, 3 non-PTDM), with a median time of administration of 32 days. The starting dose in prednisone equivalents in both groups was 1 mg/kg. All four deaths occurred in the PTDM cohort. The cumulative incidence of grade II-IV acute GVHD was 6/33 (18%). One patient (3%) developed grade IV acute GvHD of the skin and gut, while moderate-severe chronic GvHD developed in six patients (18%). The median time to acute GvHD was 36 days for the entire cohort (36 days for PTDM group, 37.5 days for non-PTDM group). Quantitative reconstitution of CD8 T-cells was significantly lower at one and two months post-haplo-BMT for PTDM compared to non-PTDM patients. CD4 subsets tended to be lower in the PTDM cohort. No significant difference was seen for CD56 cellular subsets at any time period. Conclusion: PTDM is a frequent occurrence following haplo-BMT for SCD and developed prior to corticosteroid exposure. Early T-cell reconstitution may impact glucose homeostasis. Prospective studies with longer follow up are needed to determine the clinical implications in transplant survivors following allogeneic hematopoietic cell transplant for SCD. Disclosures Dholaria: bms: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J & J: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-143039

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Expert Review of Hematology, Informa UK Limited, Vol. 12, No. 9 ( 2019-09-02), p. 733-752

Type of Medium: Online Resource

ISSN: 1747-4086 , 1747-4094

URL: Article

DOI: 10.1080/17474086.2019.1642103

Language: English

Publisher: Informa UK Limited

Publication Date: 2019

In: World Journal of Oncology, Elmer Press, Inc., Vol. 11, No. 1 ( 2020), p. 33-36

Type of Medium: Online Resource

ISSN: 1920-4531 , 1920-454X

URL: Article

DOI: 10.14740/wjon1241

Language: English

Publisher: Elmer Press, Inc.

Publication Date: 2020

detail.hit.zdb_id: 2548989-6

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2922-2922

Abstract: Background: Patients with TP53 MUT MDS/AML experience poor clinical outcomes with high rates of disease recurrence and short overall survival (OS). Characterization of these individuals' post-HCT mortality is uniquely challenging due to competing risks from disease relapse and treatment toxicity. Transplant registries contain high-level outcomes data, however, there is a lack of detailed data in molecularly defined subsets of diease. This analysis was undertaken to bridge this gap. Methods: Allogeneic HCT recipients between 1/2014 and 12/2018 were retrospectively studied. Key inclusion criteria were TP53 MUT by NGS or deletion of chromosome 17/17p by FISH/cytogenetics. The primary outcome of non-relapse mortality (NRM) was defined as death from any cause other than disease with relapse as competing risk. Secondary outcomes for this analysis were OS, cumulative incidence of relapse (CIR), and relapse free survival (RFS). Relapse was defined as relapse/progression with NRM as competing risk. Results: 384 TP53 MUT MDS/AML patients were analyzed. 55% of patients were transplanted for AML, 41% received myeloablative conditioning (MAC), 39% had secondary MDS/AML, and 26% received prior chemo and/or radiation therapy (XRT). Median time from HCT to last follow-up was 321 days (range 8-2,385 days). Mutational data was available in 264 patients and cytogenetic data was available in 368 patients; 78% of patients had a complex karyotype (CK), 82% had TP53 missense mutations, and 74% had bi-allelic targeting of the TP53 gene. The incidence of all-grade acute and chronic GVHD (cGVHD) was 52% and 31%, respectively. One and 2 year OS was 48.5% and 30.9%, respectively. Estimated CIR at 1 and 2 years was 49% and 54.9%, respectively. The 1 year NRM was 13.7% and 2 year NRM was 18.1%. In multivariate analysis (MVA), there was no association between NRM and the clinical, molecular, or genetic features of TP53 MUT MDS/AML. HCT diagnosis of MDS (HR: 0.67, 95% CI: 0.46-0.97, p: 0.036), mono-allelic TP53 MUT (HR: 0.6, 95% CI: 0.39-0.94, p: 0.023), achievement of full donor PB chimerism (HR: 0.33, 95% CI: 0.14-0.85, p: 0.022), BM chimerism (HR: 0.33, 95% CI: 0.18-0.60, p: 0.003), and cGVHD (HR: 0.35, 95% CI: 0.23-0.51, p: & lt;0.001) correlated with lower rates of relapse while CK predicted for increased relapse (HR: 2.5, 95% CI: 1.49-4.19, p: 0.001). Inferior OS was associated with CK (HR: 1.84, 95% CI: 1.19-2.85, p: 0.006) and history of prior chemo/XRT (HR: 1.84, 95% CI: 1.01-1.93, p: 0.006) whereas high KPS (HR: 0.98, 95% CI: 0.97-1, p: 0.046), mono-allelic TP53 mutations (HR: 0.52, HR: 0.36-0.77, p: 0.001), full donor PB chimerism (HR: 0.36, 95% CI: 0.19-0.68, p: 0.002), BM chimerism (HR: 0.3, 95% CI: 0.19-0.49, p: & lt;0.001), and cGVHD (HR: 0.36, 95% CI: 0.18-0.36, p: & lt;0.001) were associated with improved OS. In subgroup analysis, history of chemo and/or XRT increased NRM in AML (HR: 4.24, 95% CI: 1.35-13.39, p: 0.014). Pre-HCT TP53 MUT persistence by NGS (HR: 3.59, 95% CI: 1.43-9, p: 0.007) predicted for post-HCT relapse whereas pre-HCT CR (HR: 2.93, 95% CI: 1.54-5.59, p: 0.001) and full donor BM chimerism (HR: 0.14, 95% CI: 0.05-0.38, p: & lt;0.001) were associated with lower rates of relapse. High KPS (HR: 0.96, 95% CI: 0.98-0.99, p: 0.021) and cGVHD (HR: 0.3, 95% CI: 0.16-0.56, p: & lt;0.001) corresponded with improved OS. Prior chemo/XRT was associated with shorter OS (HR: 2.11, 95% CI: 1.06-4.18, p: 0.033) No significant NRM associations were identified in MDS. CK (HR: 5.04, 95% CI: 1.95-13.01, p: & lt;0.001) and RIC/NMA conditioning intensity (HR: 2.54, 95% CI: 1.26-5.1, p: 0.009) increased risk of post-HCT relapse while full donor BM chimerism (HR: 0.15 95% CI: 0.08-0.31, p: & lt;0.001), full donor PB chimerism (HR: 0.17, 95% CI: 0.17, p: & lt;0.001), and cGVHD (HR: 0.17, 95% CI: 0.07-0.42, p: & lt;0.001) reduced this risk. OS was improved with mono-allelic mutations (HR: 0.54, 95% CI: 0.32-0.96, p: 0.034), full donor BM (HR: 0.24, 95% CI: 0.12-0.71, p: & lt;0.001), PB (HR: 0.29, 95% CI: 0.09-0.3, p: 0.007) chimerism, and cGVHD (HR: 0.16, 95% CI: 0.09-0.3, p: & lt;0.001). Conclusions: From this large multi-institutional cohort of TP53 MUT myeloid neoplasms, we report a low NRM rate, likely due to high rates of post-HCT relapse/progression. These data demonstrate associations between bi-allelic TP53m/CK and post-HCT outcomes. Our work highlights the importance donor chimerism after HCT and provides new understanding of the importance of chronic GVHD in TP53 MUT MDS/AML. Figure 1 Figure 1. Disclosures Byrne: Karyopharm: Research Funding. Logan: Amgen, Pfizer, AbbVie: Consultancy; Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding. Lee: CareDx: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Fresensius Kabi: Consultancy; Jazz,: Consultancy; Incyte: Research Funding. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Jimenez: Takeda: Research Funding; AbbVie: Research Funding. Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Bhatnagar: Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Cell Therapeutics: Honoraria, Research Funding; Kite: Honoraria; Karyopharm: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Research Funding. Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Mishra: Novartis: Research Funding. Savona: BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-154151

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2277-2277

Abstract: Background: Children and adolescents with sickle cell disease (SCD) are at significant risk for cerebral infarction and neurocognitive deficits. In a quantitative meta-analysis, Prussien et al. (2019) showed that school-aged children with SCD display significant deficits in full scale IQ, verbal reasoning, perceptual reasoning, executive function, and processing speed relative to the normative mean in sibling and healthy controls, with mean standard scores ranging from 82.38 to 87.51. Quantitative reviews have also shown that deficits in cognitive function in this population also increase with age (Prussien et al., 2019; Schatz et al., 2002). Few studies have investigated whether therapeutic interventions to prevent cerebral infarction impact progressive neurocognitive benefits in individuals with SCD. Four studies to date have assessed the effect of bone marrow transplantation (BMT) on cognition in SCD, and findings show that full scale IQ remained stable after transplant (Neha Bhatnagar et al, 2011; Bockenmeyer et al., 2013; King et al., 2019; Woodard et al., 2005). King et al., also found that verbal IQ and performance IQ also remain stable. However, these findings are based on very small samples, and replication is necessary across multiple domains of cognition including various transplant approaches. We hypothesize that successful related haploidentical BMT (haplo-BMT) in individuals with SCD will result in stable to improved neurocognitive function. Method: In a select cohort of patients who underwent reduced intensity conditioning haplo-BMT with post-transplant cytoxan for SCD as part of an international learning collaborative. Neurocognitive assessments were conducted 2-3 months prior and 12 months post-transplant. All participants were administered age-appropriate Wechsler scale of intelligence (i.e., Wechsler Intelligence Scale for Children - Fourth Edition for children ages 6 to 16 years and the Wechsler Adult Intelligence Scale - Fourth Edition for adolescents over age 18 years). The transplant data base was used to assess baseline demographics and transplant related outcomes. Descriptive statistics was used to evaluate pre- and post-transplant cognitive function. Only participants who completed both pre- and post-transplant cognitive assessments were included for analysis. Results: All sixteen patients had sickle cell anemia (Hb SS), and completed both pre- and post-transplant cognitive assessments. Indication for transplant included stroke 56% (9/16), silent infarcts 63% (10/16) and both in 50% (8/16) (Table 1). Results show that despite disease severity, the current sample of adolescents demonstrated greater scores in verbal reasoning, perceptual reasoning, and executive function relative to prior meta-analytic findings for school-aged children (Prussien et al., 2019). Findings from repeated measures t tests (Table 2), showed no significant difference in mean scores pre- and post-transplant in verbal reasoning (pre = 91.44, post = 90.69, d = .09, p = .641), perceptual reasoning (pre = 91.56, post = 86.12, d = .57, p = .066), working memory (pre = 93.56, post = 86.19, d = .46, p = .158), and full scale IQ (pre = 84.50, post = 86.00, d = .20, p = .694); however, mean scores for processing speed were significantly greater post-transplant relative to pre-transplant (pre = 79.81, post = 86.31, d = .49, p = .023). Conclusions: Neurocognitive function outcomes are stable to improved following haplo-BMT with post-transplant cytoxan in children and adolescents with SCD. Future studies should evaluate long-term neurocognitive function outcomes in SCD patients undergoing haplo-BMT compared to age-matched cohorts on best supportive care. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124769

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3686-3686

Abstract: Introduction: Hematopoietic cell transplantation (HCT) is the only curative therapy for sickle cell disease (SCD), though is not widely utilized due to inadequate donor availability. Our center has previously reported improved outcomes with a reduced intensity, haploidentical bone marrow transplant (haplo-BMT) with post-transplant Cytoxan and thiotepa (de la Fuente et al, Biol Blood Marrow Transplant 2019). All patients treated with this protocol require red blood cell (RBC) support for anemia. Alloimmunization to minor RBC antigens can be a barrier to therapies including HCT, especially in those patients with multiple antibodies or those requiring rare RBC units. We report on our experience thus far in seven patients with SCA on this protocol. Materials and Methods: After IRB approval, we report in a cohort of 10 patients who completed haplo-BMT with our ongoing platform (ClinicalTrials.gov Identifier: NCT01850108). Phenotypic matching of RBCs beyond ABO and Rh(D) is necessary since patients with SCD commonly produce antibodies against minor RBC antigens, which can result in transfusion reactions such as delayed hemolysis and hyperhemolysis. Our institutional practice is to obtain minor RBC phenotyping on both the patient and their donor prior to transplant. The blood bank provides RBCs that are phenotypically matched for Rh and Kell antigens regardless of antibody status. If a patient has a history of an antibody or a positive screen, the blood bank provides extended phenotypic matching to include Fya, Fyb, Jka, Jkb, and MNS if possible. Outcomes data were analyzed using the CIBMTR database and EMR. Results: A total of 10 patients underwent haplo-BMT, 7 for sickle cell anemia and 3 for beta thalassemia major. Two patients had alloantibodies prior to haplo-BMT, both of whom had SCA. Three patients were ABO identical with their donor; five patients received minor ABO incompatible transplants, and two received major ABO incompatible transplants. Indications for transplant included transfusion dependence (5 patients), cerebrovascular accidents (4 patients), recurrent pain crises (1 patient), visual impairment (1 patient), and seizures (1 patient). The median recipient age at transplant was 17.8 years for the 8 males and 2 females included. Median donor age was 37.5 years, including 4 males and 6 females, with 7 parental donors and 3 sibling donors. No grade 1 acute graft-versus-host disease (GvHD) was noted, though 30% (3/10) had grades II-IV disease. Limited chronic GvHD occurred in 20% (2/10) patients, without any cases of extensive disease. A median of 3.5 RBC (range 0 - 14) transfusions and a median of 10 (range 1 - 24) platelet transfusions were required from date of transplant until neutrophil engraftment. None of the patients had delayed erythroid engraftment. Conclusion: We report successful haploidentical HCT in 7 patients with sickle cell anemia. Providing appropriate phenotypically matched RBCs is especially important in the era of emerging cures for sickle cell anemia, including gene therapy and haploidentical HCT. Alloimmunization is an understudied barrier to HSCT and must be carefully assessed when planning for HCT or other curative therapies required RBC transfusion support. 1. de la Fuente J, Dhedin N, Koyama T, et al. Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Sickle Cell Anemia: Results of an International Learning Collaborative. Biol Blood Marrow Transplant 2019;25:1197-1209. 2. Bolanos-Meade J, Fuchs EJ, Luznik L, et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 2012;120:4285-91. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131942

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7