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In this article, we consider nondiffusive variational problems with mixed boundary conditions and (distributional and weak) gradient constraints. The upper bound in the constraint is either a function or a Borel measure, leading to the state space being a Sobolev one or the space of functions of bounded variation. We address existence and uniqueness of the model under low regularity assumptions, and rigorously identify its Fenchel pre-dual problem. The latter in some cases is posed on a nonstandard space of Borel measures with square integrable divergences. We also establish existence and uniqueness of solution to this pre-dual problem under some assumptions. We conclude the article by introducing a mixed finite-element method to solve the primal-dual system. The numerical examples illustrate the theoretical findings.

The aim of our study was to analyze the potential survival benefit associated with HSCT according to clinico-biological scores which incorporate molecular data (MIPSS70 and MIPSS70+V2) to facilitate decision-making in this context. One transplant (n=241) and one non-transplant cohorts (n=239) were used to test the hypothesis that PMF patients with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. 105 non-transplanted patients could be matched to the 239 transplanted patients. Mean age in transplanted and non-transplanted matched patients was 55.5 and 57.9 years. Blood cell count and DIPSS score distribution were similar in both groups. HSCT was associated with a higher 6-year OS rate in intermediate-2 (60.1% versus 41.5%) and high-risk DIPSS patients (44.4% versus 6.55%), high-risk MIPSS70 (46.5 versus 23.9%), high-risk (73.2% versus 39.7%) or very high-risk MIPSS70V2 (51.8% versus 24%). Intermediate MIPSS70 patients have an advantage of survival with HSCT only when their MTSS were low or intermediate. Transplanted patients had an increased mortality risk the first year but a significant benefit with HSCT after the one-year landmark was observed in higher risk patients. This study confirms that similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies., (Copyright © 2024 American Society of Hematology.)

Acute and chronic graft-versus-host disease (GvHD) are major complications of allogeneic hematopoietic cell transplantation (alloHCT). In vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG) as part of the conditioning regimen prior to alloHCT is frequently used as GvHD prophylaxis, but data on its role in myelofibrosis is scarce. We took advantage of an international collaborative network to investigate the impact of ATLG in myelofibrosis undergoing first alloHCT. We included 707 patients (n = 469 ATLG and n = 238 non-ATLG prophylaxis). The cumulative incidence of acute GvHD grade II-IV was 30% for the ATLG group vs. 56% for the non-ATLG group (P < 0.001). Acute GvHD grade III-IV occurred in 20% vs. 25%, respectively (P = 0.01). Incidence of mild-to-severe chronic GvHD was 49% vs. 50% (P = 0.52), while ATLG showed significantly lower rates of severe chronic GvHD (7% vs. 18%; P = 0.04). GvHD-free and relapse-free survival (GRFS) at 6 years was 45% for the ATLG group vs. 37% for the non-ATLG group (P = 0.02), driven by significantly improved GRFS of ATLG in matched related and matched unrelated donors. No significant differences in risk for relapse, non-relapse mortality, and overall survival were observed. Multivariable modeling for GRFS showed a 48% reduced risk of GvHD, relapse, or death when using ATLG., (© 2024. The Author(s).)

Purpose: Acute myeloid leukemia (AML) is a disease of older patients. Progress in allogeneic hematopoietic cell transplantation (allo-HCT) allowed the delivery of allo-HCT to older patients. We assessed changes over time in transplant characteristics and outcomes in patients with AML ages 65 years and above., Patients and Methods: We identified 7,215 patients with AML (median age 68 years, range 65-80) allografted between 2000 and 2021 in first complete remission (CR1; 64%), second or subsequent remission (CR2+; 14%), or active disease (22%)., Results: Median follow-up was 40 months. The 3-year cumulative relapse incidence (RI) gradually and significantly decreased from 37% to 31%, then to 30% (P = 0.001) over the three time periods (2000-2009; 2010-2014; 2015-2021), whereas nonrelapse mortality (NRM) decreased from 31% and 31% to 27% (P = 0.003). The 3-year leukemia-free survival (LFS) and overall survival (OS) gradually and significantly improved from 32% to 38%, and then to 44% (P = 0.001) and from 37% to 42%, and then to 49% (P = 0.001), respectively. In multivariate analysis, significant improvement in the RI, LFS, and OS were noted after 2015, whereas NRM was not significantly affected. This improvement was observed regardless of disease status at transplant., Conclusions: In older patients with AML, we observed an impressive improvement over time in posttransplant outcomes, mostly attributed to decreased RI rather than decreased NRM, and regardless of disease status at transplant. These large-scale, real-world data can serve as a benchmark for future studies in this setting and indicate that the opportunity for transplant for the elderly should be mandatory and no longer an option., (©2024 American Association for Cancer Research.)

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Oral leukoplakia (OL) is an unfavorable oral disease often resistant to therapy. To this end, cold physical plasma technology was explored as a novel therapeutic agent in an experimental setup., Methods: Biopsies with a diameter of 3 mm were obtained from non-diseased and OL tissues. Subsequently, cold atmospheric pressure plasma (CAP) exposure was performed ex vivo in the laboratory. After 20 h of incubation, biopsies were cryo-conserved, and tissue sections were quantified for lymphocyte infiltrates, discriminating between naïve and memory cytotoxic and T-helper cells. In addition, the secretion pattern related to inflammation was investigated in the tissue culture supernatants by quantifying 10 chemokines and cytokines., Results: In CAP-treated OL tissue, significantly decreased overall lymphocyte numbers were observed. In addition, reduced levels were observed when discriminating for the T-cell subpopulations but did not reach statistical significance. Moreover, CAP treatment significantly reduced levels of C-X-C motif chemokine 10 (CXCL10) and granulocyte-macrophage colony-stimulating factor in the OL biopsies' supernatants. In idiopathically inflamed tissues, ex vivo CAP exposure reduced T-cells and CXCL10 as well but also led to markedly increased interleukin-1β secretion., Conclusion: Our findings suggest CAP to have immuno-modulatory properties, which could be of therapeutic significance in the therapy of OL. Future studies should investigate the efficacy of CAP therapy in vivo in a larger cohort., (© 2023 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

Azacitidine (Aza) combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide (Lena) to act synergistically with Aza/DLI to improve outcome. We, therefore, prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia. Patients were scheduled for eight cycles Aza (75 mg/m2 day 1-7), Lena (2.5 or 5 mg, days 1-21) and up to three DLI with increasing T-cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of myelodysplastic syndromes (n=24), acute myeloid leukemia (n=23) or chronic myelomonocytic leukemia (n=3) received a median of seven (range, 1-8) cycles including 14 patients with 2.5 mg and 36 with 5 mg Lena daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lena dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade 2-4 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lena can be safely added to Aza/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse (clinicaltrials gov. Identifier: NCT02472691).

Background: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking., Objectives: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results., Methods: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed., Results: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts., Conclusions: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease., (Copyright © 2023. Published by Elsevier Inc.)

Patients with acute myeloid leukemia (AML) and nucleophosmin 1 gene mutations (NPM1 mut ) show a favorable prognosis with chemotherapy (CT) in the absence of negative prognostic genetic abnormalities. Between 2008 and 2021 64 patients with NPM1 mut AML received alloHSCT because of additional adverse prognostic factors (1st line), inadequate response to or relapse during or after CT (2nd line). To expand the evidence in alloTX in NPM1 mut AML, clinical and molecular data were retrospectively analyzed with respect to pre-transplant strategies and outcome. Patients with minimal residual disease negative (MRD-) CR at transplant had better 2-y-PFS and 2-y-OS (77% and 88%) than patients with minimal residual disease positive (MRD+) CR (41% and 71%) or patients with active disease (AD) at transplant (20% and 52%). The 2nd line patients with relapse after completing CT responded well to high dose cytarabine based salvage chemotherapy (salvage CT) in contrast to patients relapsing while still on CT (90% vs 20%, P = 0.0170). 2-y-PFS and 2-y-OS was 86% in patients who achieved a 2nd MRD- CR pre alloHSCT. Outcome in NPM1 mut AML depends on disease burden at alloHSCT. Time and type of relapse in relation to CT are predictive for response to salvage CT., (© 2023. The Author(s).)

TP53 mutations (TP53MTs) have been associated with poor outcomes in various hematologic malignancies, but no data exist regarding its role in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HSCT). Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MT in this setting. Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 30 showed a multihit configuration. Median variant allele frequency was 20.3%. Cytogenetic risk was favorable (71%), unfavorable (23%), and very high (6%), with complex karyotype present in 36 patients (10%). Median survival of patients with TP53MT was 1.5 vs 13.5 years for those with wild-type TP53 (TP53WT; P < .001). Outcome was driven by multihit TP53MT constellation (P < .001), showing 6-year survival of 56% for individuals with single-hit vs 25% for those with multihit TP53MT vs 64% for those with TP53WT. Outcome was independent of current transplantation-specific risk factors and conditioning intensity. Similarly, cumulative incidence of relapse was 17% for single-hit vs 52% for multihit vs 21% for TP53WT. Ten patients with TP53MT (20%) presented as leukemic transformation vs only 7 (2%) in the TP53WT group (P < .001). Out of the 10 patients with TP53MT, 8 showed multihit constellation. Median time to leukemic transformation was shorter for multihit and single-hit TP53MT (0.7 and 0.5 years, respectively) vs 2.5 years for TP53WT. In summary, multihit TP53MT represents a very high-risk group in patients with myelofibrosis who are undergoing HSCT, whereas single-hit TP53MT alone showed similar outcome to patients with nonmutated TP53, informing prognostication for survival and relapse together with current transplantation-specific tools., (© 2023 by The American Society of Hematology.)

An improved understanding of relapse kinetics is required to optimize detection and treatment strategies for the post-transplant relapse of myeloid neoplasms. Therefore, we retrospectively analyzed data from 91 patients allografted for MDS (n = 54), AML-MRC (n = 29) and chronic myelomonocytic leukemia (CMML, n = 8), who relapsed after transplant. Patients with early (<12 months, n = 56) and late relapse (>12 months, n = 35) were compared regarding patient-, disease- and transplant-related factors, including karyotype analyses at diagnosis and relapse. After a median follow-up of 17.4 months after relapse, late relapses showed improved outcomes compared with early relapses (2-yr OS 67% vs. 32%, p = 0.0048). Comparing frequency of distinct patient-, disease- and transplant-related factors among early and late relapses, complex karyotype (p = 0.0004) and unfavorable disease risk at diagnosis (p = 0.0008) as well as clonal evolution at relapse (p = 0.03) were more common in early than in late relapses. Furthermore, patients receiving transplant without prior cytoreduction or in complete remission were more frequently present in the group of late relapses. These data suggest that cytogenetics rather than disease burden at diagnosis and transplant-related factors determine the timepoint of post-transplant relapse and that upfront transplantation may be favored in order to delay relapse.

There is no direct evidence to recommend specific conditioning intensities in myelofibrosis undergoing allogeneic hematopoietic cell transplantation, especially in the molecular era. We aimed to compare outcomes of reduced intensity (RIC) or myeloablative conditioning (MAC) transplantation in myelofibrosis with molecular information. The study included 645 genetically annotated patients (with at least driver mutation status available), of whom 414 received RIC and 231 patients received MAC. The median follow-up time from transplantation was 6.0 years for RIC and 9.4 years for MAC. The 6-year overall survival rates for RIC and MAC were 63% (95% confidence interval [CI], 58%-68%) and 59% (95% CI, 52%-66%; P = 0.34) and progression-free survival was 52% (95% CI, 47%-57%) and 52% (95% CI, 45%-59%; P = 0.64). The 2-year cumulative incidence of nonrelapse mortality was 26% (95% CI, 21%-31%) for RIC and 29% (95% CI, 23%-34%) for MAC ( P = 0.51). In terms of progression/relapse, the 2-year cumulative incidence was 10% (95% CI, 5%-19%) for RIC and 9% (95% CI, 4%-14%) for MAC ( P = 0.46). Higher intensity conditioning did not seem to improve outcomes for higher-risk disease, according to mutational, cytogenetic, and clinical profile. In contrast, patients with reduced performance status, matched unrelated donors, and ASXL1 mutations appeared to benefit from RIC in terms of overall survival., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Introduction: Azacitidine (AZA) either single-agent or with donor lymphocytes infusions (DLI) has been used as a salvage treatment for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) relapsing after allogeneic hematopoietic stem cell transplantation (HSCT). To date, the majority of data come from patients relapsed after HSCT from full-matched donors., Methods: We report a multicenter, collaborative, retrospective analysis of 71 patients with hematologic ( n  = 40, 56%) and molecular relapse ( n  = 31, 44%) of myeloid neoplasms after HSCT from alternative donors (mismatched unrelated, n  = 39, 55%; haploidentical, n  = 29, 41%) consecutively treated at three European centers with AZA ± DLI., Results: Median time from HSCT to relapse was 9 months. Additional DLI were given to 33 patients (46%). After a median of four cycles, overall response rate (ORR) was 49% and complete response (CR) rate was 38%. CR lasted for a median of 17 months (range 5-89 months). Median follow-up in the entire cohort was 11 months (range 1-115 months). Event-free survival (EFS) and overall survival (OS) at 1 year were 26% and 53%, respectively. Treatment of molecular relapse granted higher CR rate (65% versus 15%; p   =  0.0001), 1-year EFS (43% versus 13%; p  = 0.006), and 1-year OS (79% versus 34%; p  < 0.001) compared to hematologic relapses. Addition of DLI resulted in significantly higher responses and longer 1-year EFS and OS (Mantel-Byar test, p  = 0.004 and p   =  0.002, respectively). When applied to our cohort, the APSS-R score confirmed its ability to stratify patients into distinct prognostic groups with significantly different response rates ( p   =  0.0005) and survival ( p  < 0.0001). Treatment was well tolerated, with the incidence of late acute and chronic graft-versus-host disease of 27% and 18%, respectively., Conclusion: AZA ± DLI proved feasible and effective in AML and MDS relapsing after HSCT from alternative donors. Despite modest efficacy among hematologic relapses, pre-emptive treatment with AZA ± DLI fared better in molecular relapse. Additional DLI contributed to improving efficacy and ensuring longer survival., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.F. received honoraria from Jazz Pharmaceuticals, served on advisory boards for Medac GmbH and Novartis. B.M. received honoraria from Celgene/BMS, Alexion, Novartis, MSD; travel grants from Celgene/MSD; served on advisory boards for BMS and Jazz Pharmaceuticals. C.M.G. declared consultancy for Janssen, Novartis, and Abbvie. S.T. declared research funding and consultancy for Celgene/BMS. R.C. received travel grants from Jazz Pharmaceuticals and Celgene/BMS; lecturing from Abbvie, Celgene/BMS, and Jazz Pharmaceuticals. MTLS has received travel grants from Neovii Biotech; honoraria from Incyte; served on advisory boards for Novartis and Mallinckrodt Pharmaceuticals. L.C., L.F., V.L., G.R., M.S., A.A., F.F., C.C., B.M., P.J., S.K., M.J.M., S.J., B.A., and C.F. declare no competing financial interests., (© The Author(s), 2022.)

Δ 8 -Tetrahydrocannabinol (Δ 8 -THC) as isomer of the well-known Δ 9 -THC has a similar mode of action, and the potency was estimated to be two thirds compared with Δ 9 -THC. Content of Δ 8 -THC in plant material is low, but formulations containing Δ 8 -THC in high concentrations are gaining popularity. Δ 8 -THC is to be regarded as prohibited substance according to the Prohibited List of the World Anti-Doping Agency (WADA). Contradictory results between initial testing procedure and confirmatory quantitation for 11-Nor-9-carboxy-Δ 9 -tetrahydrocannabinol (Δ 9 -THC-COOH) of a doping control sample gave rise for follow-up testing procedures. After alkaline hydrolysis and liquid-liquid extraction, the sample was analyzed by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) using isocratic elution instead of gradient elution, which is used for standard procedure. Isocratic elution resulted in two peaks instead of one using gradient elution. Both peaks showed same fragmentation. Using certified reference materials, one peak could be assigned to Δ 9 -THC-COOH and the other one with higher intensity to the less common 11-Nor-9-carboxy-Δ 8 -Tetrahydrocannabinol (Δ 8 -THC-COOH) in a concentration of approximately 1200 ng/ml. As complementary method, gas chromatography tandem mass spectrometry (GC-MS/MS) can also be used for identification. Here Δ 8 - and Δ 9 -THC-COOH can be distinguished by chromatography and by fragmentation. Additional investigations of doping control samples containing Δ 9 -THC-COOH revealed the simultaneous presence of Δ 8 -THC-COOH in low concentrations (0.22-8.91 ng/ml) presumably due to plant origin. Percentage of Δ 8 -THC-COOH varies from 0.05 to 2.83%. In vitro experiments using human liver microsomes showed that Δ 8 -THC is metabolized in the same way as Δ 9 -THC., (© 2021 John Wiley & Sons, Ltd.)

To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26-80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10 -3 ) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation., (© 2021. The Author(s).)

Acute myeloid leukemia (AML) is characterized by an expansion of leukemic cells and a simultaneous reduction of normal hematopoietic precursors in the bone marrow (BM) resulting in hematopoietic insufficiency, but the underlying mechanisms are poorly understood in humans. Assuming that leukemic cells functionally inhibit healthy CD34+ hematopoietic stem and progenitor cells (HSPC) via humoral factors, we exposed healthy BM-derived CD34+ HSPC to cell-free supernatants derived from AML cell lines as well as from 24 newly diagnosed AML patients. Exposure to AML-derived supernatants significantly inhibited proliferation, cell cycling, colony formation, and differentiation of healthy CD34+ HSPC. RNA sequencing of healthy CD34+ HSPC after exposure to leukemic conditions revealed a specific signature of genes related to proliferation, cell-cycle regulation, and differentiation, thereby reflecting their functional inhibition on a molecular level. Experiments with paired patient samples showed that these inhibitory effects are markedly related to the immunomagnetically enriched CD34+ leukemic cell population. Using PCR, ELISA, and RNA sequencing, we detected overexpression of TGFβ1 in leukemic cells on the transcriptional and protein level and, correspondingly, a molecular signature related to TGFβ1 signaling in healthy CD34+ HSPC. This inhibitory effect of TGFβ1 on healthy hematopoiesis was functionally corrobated and could be pharmacologically reverted by SD208, an inhibitor of TGFβ receptor 1 signaling. Overall, these data indicate that leukemic cells induce functional inhibition of healthy CD34+ HSPC, at least in part, through TGFβ1, suggesting that blockage of this pathway may improve hematopoiesis in AML., (© 2021 The Authors. STEM CELLS published by Wiley Periodicals LLC on behalf of AlphaMed Press.)