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ISSN / EISSN : 0006-4971 / 1528-0020
Published by: American Society of Hematology (10.1182)
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Oriana Miltiadous, , Hana Andrlova, , Chi L Nguyen, Marina Burgos da Silva, Sarah Lindner, John Slingerland, Paul Giardina, Annelie Clurman, et al.
Published: 21 January 2022
Abstract:
Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2,067 stool samples and flow-cytometry data from 2,370 peripheral blood samples drawn from 894 allogeneic HCT patients, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early post-transplant period was associated with worse CD4 T cell recovery. Our observations suggest that the intestinal bacteria - or the factors they produce - can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.
Ivy Elizabeth Abraham, Garth H Rauscher, , William Pearse, Priya Rajakumar, , Ahmed Aleem, Ami Dave, Sushma Bharadwaj, Koosha Paydary, et al.
Published: 21 January 2022
Abstract:
Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic white (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult AML patients from six urban cancer centers and revealed inferior survival among NHB (HR=1.59, 95% CI: 1.15, 2.22) and Hispanic (HR=1.25, 95% CI: 0.88, 1.79) compared to NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across six composite variables: structural racism (census tract disadvantage, affluence and segregation), tumor biology (ELN risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization) and ICU admission during intensive chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, as well as treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.
Ye-Jun Wu, Hui Liu, Qiao-Zhu Zeng, Yi Liu, Jing-Wen Wang, Wen-Sheng Wang, Jia- Feng, He-Bing Zhou, Qiu-Sha Huang, Yun He, et al.
Published: 20 January 2022
Blood, Volume 139, pp 333-342; https://doi.org/10.1182/blood.2021013393

Abstract:
The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥ 30 × 109/L confirmed on at least two separate occasions (at least 7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07 to 0.36). Sustained response (SR), defined as maintenance of a platelet count > 30 x 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04 to 0.35). The 2 most common AEs for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288.
, , Ashley Alesia McCook, Jeremy Michael Sen, Christian M. Barlow, , , , Michael A. Spinner, Ranjana Advani, et al.
Published: 20 January 2022
Blood, Volume 139, pp 413-423; https://doi.org/10.1182/blood.2021012888

Abstract:
Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.
Richard Coffey, Chun-Ling Grace Jung, Joseph Daniel Olivera, Gabriel Karin, Renata C. Pereira, ,
Published: 20 January 2022
Blood, Volume 139, pp 439-451; https://doi.org/10.1182/blood.2021014054

Abstract:
The hormone erythroferrone (ERFE) is produced by erythroid cells in response to hemorrhage, hypoxia, or other erythropoietic stimuli, and it suppresses the hepatic production of the iron-regulatory hormone hepcidin, thereby mobilizing iron for erythropoiesis. Suppression of hepcidin by ERFE is believed to be mediated by interference with paracrine bone morphogenetic protein (BMP) signaling that regulates hepcidin transcription in hepatocytes. In anemias with ineffective erythropoiesis, ERFE is pathologically overproduced, but its contribution to the clinical manifestations of these anemias is not well understood. We generated 3 lines of transgenic mice with graded erythroid overexpression of ERFE and found that they developed dose-dependent iron overload, impaired hepatic BMP signaling, and relative hepcidin deficiency. These findings add to the evidence that ERFE is a mediator of iron overload in conditions in which ERFE is overproduced, including anemias with ineffective erythropoiesis. At the highest levels of ERFE overexpression, the mice manifested decreased perinatal survival, impaired growth, small hypofunctional kidneys, decreased gonadal fat depots, and neurobehavioral abnormalities, all consistent with impaired organ-specific BMP signaling during development. Neutralizing excessive ERFE in congenital anemias with ineffective erythropoiesis may not only prevent iron overload but may have additional benefits for growth and development.
, , Hartmut Döhner
Published: 20 January 2022
Blood, Volume 139, pp 323-332; https://doi.org/10.1182/blood.2021011304

Abstract:
Patients with acute myeloid leukemia (AML) have conventionally received more "intense" therapy than patients with myelodysplastic syndromes (MDS). Although less intense therapies are being used more often in AML, the AML-MDS dichotomy remains, with the presence of ≥ 20% myeloblasts in marrow or peripheral blood generally regarded as defining AML. Consequently, patients with 19% blasts are typically ineligible for AML studies, with patients with 21% blasts ineligible for MDS studies. Here we cite biologic and clinical data to question this practice. Biologically, abnormalities in chromosome 3q26,and mutations in NPM1, and FLT3, regarded as AML-associated, also occur in MDS. The genetic signatures of MDS, particularly cases with 10-19% blasts (MDS-EB2), resemble those of AML following a preceding MDS ("secondary AML"). Mutationally, secondary AML appears at least as similar to MDS-EB2 as to de novo AML. Patients presenting with de novo AML but with secondary-type AML mutations, appear to have the same poor prognoses associated with clinically defined secondary AML. Seattle data indicate that after accounting for European LeukemiaNet (ELN) 2017 risk, age, performance status, clinically secondary AML, and treatment including allogeneic transplant, patients with WHO-defined AML (n=769) have similar rates of OS, EFS and CR/CRi as patients with MDS-EB2 (n=202). We suggest defining patients with 10-30% blasts ("AML/MDS") as eligible for either AML or MDS studies. This would permit empirical testing of the independent effect of blast percentage on outcome, allow patients access to more therapies, and potentially simplify the regulatory approval process.
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