Publications by authors named "David Valcárcel"

95 Publications

Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

J Clin Oncol 2021 May 25;39(13):1426-1436. Epub 2021 Mar 25.

Marienhospital Düsseldorf, Düsseldorf, Germany.

Purpose: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia.

Methods: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI).

Results: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 10/L, and absolute neutrophil count was 1.3 × 10/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 16.2 months; = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 10/L.

Conclusion: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.
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http://dx.doi.org/10.1200/JCO.20.02619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099416PMC
May 2021

Ex vivo T-cell depletion vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil as graft-vs-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation.

Eur J Haematol 2021 Jan 18;106(1):114-125. Epub 2020 Oct 18.

Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Objective: To compare the efficacy and safety of CD34+ selected ex vivo T-cell depletion (TCD) vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil (PTCy-Sir-MMF) as graft-vs-host disease (GVHD) prophylaxis.

Methods: We retrospectively included patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either TCD (n = 38) or PTCy-Sir-MMF (n = 91).

Results: Cumulative incidence of neutrophil and platelet recovery was 92% vs 99% (P = .06) and 89% vs 97% (P = .3) in TCD and PTCy-Sir-MMF, respectively. Cumulative incidences of aGHVD grade II-IV, III-IV, and moderate to severe cGVHD were 11% vs 19% (P = .2), 3% vs 2% (P = .9), and 3% vs 36% (P < .001) in TCD and PTCy-Sir-MMF, respectively. The 2-year non-relapse mortality, relapse, disease-free and overall survival were 25% vs 8% (P = .01), 20% vs 16% (P = .2), 55% vs 76% (P = .004), 57% vs 83% (P = .004) for TCD and PTCy-Sir-MMF, respectively. Cumulative incidence of cytomegalovirus and Epstein-Barr infection requiring therapy was 76% vs 40% (P < .001) and 32% vs 0% (P < .001) in TCD and PTCy-Sir-MMF, respectively. PTCy-Sir-MMF platform showed faster T-cell reconstitution.

Conclusions: PTCy-Sir-MMF provides better survival outcomes but is associated with higher risk of cGVHD compared to TCD.
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http://dx.doi.org/10.1111/ejh.13529DOI Listing
January 2021

Analysis of Cell Subsets in Donor Lymphocyte Infusions from HLA Identical Sibling Donors after Allogeneic Hematopoietic Cell Transplant.

Transplant Cell Ther 2021 Jan 26;27(1):53.e1-53.e8. Epub 2020 Sep 26.

Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain.

Donor lymphocytes infusions (DLIs) are a major therapeutic approach to treat relapse and mixed chimerism after allogeneic hematopoietic cell transplant (alloHCT). The impact of the composition regarding different cell subsets in the development of graft-versus-host disease (GVHD) is not fully understood. We performed a cell subsets analysis of 56 DLIs from fully HLA-compatible identical matched sibling donors (MSDs) in 36 alloHCT patients and studied its association with GVHD. A median of one DLI was infused per patient. Fourteen patients (38%) developed GVHD. The cell composition analysis of the first DLI (DLI1) showed that a high dose of B cells (P = .03) and CD27 B cells (P < .01) was associated with GVHD. We identified DLI dose cutoff points for several cell populations above which GVHD was more frequent (CD8 T >3 × 10 cells/kg, CD27 B cells >2.6 × 10/kg, CD27 NK >0.35 × 10 cells/kg, and mononuclear cells >0.83 × 10/kg). Noteworthy, the proportion of CD4 naive T cells (T) or unselected T was not linked with GVHD and a DLI1 containing a higher dose of regulatory T cells was not protective for GVHD. We studied several transplant clinical variables and did not find any association with GVHD. Altogether, this study provides a comprehensive analysis of the cell populations in a DLI from MSDs and identifies potential key cell subsets, which provides insight for the understanding of GVHD after DLI.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.024DOI Listing
January 2021

A decade of changes in management of immune thrombocytopenia, with special focus on elderly patients.

Blood Cells Mol Dis 2021 Feb 20;86:102505. Epub 2020 Sep 20.

Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CB15/00055-CIBERER, Murcia, Spain.

Background: Ten years after their availability, thrombopoietin receptor agonists (TPO-RA) have heralded a paradigm shift in the treatment of immune thrombocytopenia (ITP). This study was aimed to analyze the implementation of current recommendations in the standard practice of adult ITP patients, and how age may influence those changes.

Methods: We included 121 adult patients (> 65 years, n = 54; younger individuals, n = 67) who initiated treatment with TPO-RA between January 2012 and December 2014.

Results: Patients older than 65 years treated with TPO-RA presented at diagnosis with significantly higher platelet counts, less bleeding, and a more prothrombotic profile than younger ones. The high efficacy rates of TPO-RA, preferentially used during the last decade in non-chronic phases, precluded from further therapies in the majority of ITP patients. Their administration was associated with a sharp decline in the last decade in the use of splenectomy and intravenous immunoglobulin, especially in younger ITP individuals.

Conclusion: These results confirm (1) that there is a preferential use of TPO-RAs in elderly ITP patients with fewer bleeding complications but more unfavorable prothrombotic conditions than in younger individuals, and (2) that early use of these agents has been established as an effective therapeutic alternative to other second line therapies.
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http://dx.doi.org/10.1016/j.bcmd.2020.102505DOI Listing
February 2021

A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Cell Transplant in Patients with Myelodysplastic Syndromes.

Biol Blood Marrow Transplant 2020 11 8;26(11):2139-2146. Epub 2020 Aug 8.

Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System-Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes' probability at different time points may aid physicians and patients in their decision regarding HCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609542PMC
November 2020

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report.

Blood Adv 2020 07;4(13):3180-3190

Texas Transplant Institute, San Antonio, TX.

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
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http://dx.doi.org/10.1182/bloodadvances.2019001266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362362PMC
July 2020

Feasibility of thiotepa addition to the fludarabine-busulfan conditioning with tacrolimus/sirolimus as graft vs host disease prophylaxis.

Leuk Lymphoma 2020 08 11;61(8):1823-1832. Epub 2020 Jul 11.

Department of Hematology, Hospital Universitari Vall d'Hebron, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

In classical reduced-intensity conditioning (RIC) regimens, including the fludarabine and busulphan (BF) combination, sirolimus and tacrolimus (SIR-TAC) as graft vs host disease (GVHD) prophylaxis has shown acceptable results. The outcomes of SIR-TAC in a more intense RIC regimen as Thiotepa-fludarabine-busulfan (TBF) have been hardly investigated. This retrospective study included all consecutive patients receiving an allogeneic hematopoietic stem cell transplantation for myeloid malignancies (January 2009-2017) conditioned with either TBF or BF and receiving SIR-TAC. Patients receiving TBF presented higher non-relapse mortality (31.6 vs 12.3%,  = .01), along with shorter overall survival (51.8% vs 77.8%,  < .01) at 2 years than patients treated with BF. There were no significant differences in the cumulative incidence of grade II-IV acute GVHD or moderate-severe chronic GVHD or relapse between both groups. These results suggest that TBF does not seem to improve the traditional RIC BF regimen, at least when associated with SIR-TAC prophylaxis.
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http://dx.doi.org/10.1080/10428194.2020.1788015DOI Listing
August 2020

Posttransplant cyclophosphamide after allogeneic hematopoietic cell transplantation mitigates the immune activation induced by previous nivolumab therapy.

Leukemia 2020 12 11;34(12):3420-3425. Epub 2020 May 11.

Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital (HUVH), Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.

Patients receiving an allogeneic hematopoietic cell transplantation (allo-HCT) after the use of PD-1 inhibitors seem to be at a higher risk of developing acute graft-versus-host disease (aGHVD) through etiopathogenetic mechanisms not fully elucidated. Herein, we investigated the effect of nivolumab administered prior to allo-HCT on the following early T-cell reconstitution and its modulation by the GVHD prophylaxis (tacrolimus/sirolimus vs. posttransplant cyclophosphamide [PTCY]). In all nivolumab-exposed patients we detected circulating nivolumab in plasma for up to 56 days after allo-HCT. This residual nivolumab was able to bind and block PD-1 on T-cells at day 21 after allo-HCT, inducing a T cell activation that was differentially modulated depending on the GVHD prophylactic regimen. Among patients receiving tacrolimus/sirolimus, nivolumab-exposed patients had a higher incidence of severe aGVHD and a more effector T-cell profile compared with anti-PD-1-naïve patients. Conversely, patients receiving PTCY-based prophylaxis showed a similar risk of aGVHD and T-cell profile irrespective of the previous nivolumab exposure. In conclusion, nivolumab persists in plasma after transplantation, binds to allogeneic T cells and generates an increased T-cell activation. This T-cell activation status can be mitigated with the use of PTCY, thus reducing the risk of aGVHD.
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http://dx.doi.org/10.1038/s41375-020-0851-8DOI Listing
December 2020

Deciphering predictive factors for choice of thrombopoietin receptor agonist, treatment free responses, and thrombotic events in immune thrombocytopenia.

Sci Rep 2019 11 13;9(1):16680. Epub 2019 Nov 13.

Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CB15/00055-CIBERER, Murcia, Spain.

Very few data exist on when a particular thrombopoietin-receptor agonist (TPO-RA) is favored in clinical practice for the treatment of patients with immune thrombocytopenia (ITP), about novel risk factors for vascular events (VE) with these drugs, nor about predictive factors for therapy free responses (TFR). We conducted an observational, retrospective, long-term follow-up multicenter study from November 2016 to January 2018 of 121 adult ITP patients initiating TPO-RA between January 2012 to December 2014. Data reflected that a platelet count ≤25 × 10/l at the time when the TPO-RA was initiated was associated with a 2.8 higher probability of receiving romiplostim vs. eltrombopag (P = 0.010). VE on TPO-RA was related to previous neoplasia in patients over 65 years (50% vs. 2.2%, P < 0.001), and to previous splenectomy in younger patients (100% vs. 33%, P = 0.001). Receiving romiplostim as first TPO-RA with no subsequent TPO-RA switching was associated with a 50% likelihood of TFR after 2.9 years of therapy (3.3 years in chronic ITP patients). These real-world data help deciphering some areas of uncertainty, and offer insight into some of the most relevant challenges of ITP which may help clinicians make appropriate treatment decisions in the management of adult ITP patients with TPO-RA.
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http://dx.doi.org/10.1038/s41598-019-53209-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853922PMC
November 2019

Prospective Randomized Study Comparing Myeloablative Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Stem Cell Transplantation for Adults with Hematologic Malignancies.

Biol Blood Marrow Transplant 2020 02 23;26(2):358-366. Epub 2019 Oct 23.

Hematology Department, Hospital Universitari i Politecnic La Fe, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; Centro de Investigación Biomédica en Red de Cancer, Instituto Carlos III, Madrid, Spain.

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P = .04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P = .02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade III-IV, overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P = .8), 9% versus 9% (P = 1), 66% versus 43% (P = .04), and 41% versus 23% (P = .2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P = .06) and 17% versus 23% (P = .5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P = .2), 35% versus 59% (P = .1), and 17% versus 40% (P = .04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT.
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http://dx.doi.org/10.1016/j.bbmt.2019.10.014DOI Listing
February 2020

Spanish Guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia.

Br J Haematol 2020 03 16;188(5):605-622. Epub 2019 Oct 16.

Department of Haematology, Hospital Universitari i Politècnic La Fe, València, Spain.

The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.
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http://dx.doi.org/10.1111/bjh.16175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064979PMC
March 2020

Phase II Study of the ALK5 Inhibitor Galunisertib in Very Low-, Low-, and Intermediate-Risk Myelodysplastic Syndromes.

Clin Cancer Res 2019 12 3;25(23):6976-6985. Epub 2019 Sep 3.

Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

Purpose: Overactivation of TGF-β signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-β receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies.

Patients And Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off.

Results: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4-40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%).

Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1338DOI Listing
December 2019

Chronic graft-versus-host disease could ameliorate the impact of adverse somatic mutations in patients with myelodysplastic syndromes and hematopoietic stem cell transplantation.

Ann Hematol 2019 Sep 16;98(9):2151-2162. Epub 2019 Jul 16.

Hematology Department, University Hospital of Salamanca, IBSAL Institute for Biomedical Research of Salamanca, Paseo de San Vicente, 139, 37007, Salamanca, Spain.

Somatic mutations in patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSTC) are associated with adverse outcome, but the role of chronic graft-versus-host disease (cGVHD) in this subset of patients remains unknown. We analyzed bone marrow samples from 115 patients with MDS collected prior to HSCT using next-generation sequencing. Seventy-one patients (61%) had at least one mutated gene. We found that patients with a higher number of mutated genes (more than 2) had a worse outcome (2 years overall survival [OS] 54.8% vs. 31.1%, p = 0.035). The only two significant variables in the multivariate analysis for OS were TET2 mutations (p = 0.046) and the development of cGVHD, considered as a time-dependent variable (p < 0.001), correlated with a worse and a better outcome, respectively. TP53 mutations also demonstrated impact on the cumulative incidence of relapse (CIR) (1 year CIR 47.1% vs. 9.8%, p = 0.006) and were related with complex karyotype (p = 0.003). cGVHD improved the outcome even among patients with more than 2 mutated genes (1-year OS 88.9% at 1 year vs. 31.3%, p = 0.02) and patients with TP53 mutations (1-year CIR 20% vs. 42.9%, p = 0.553). These results confirm that cGVHD could ameliorate the adverse impact of somatic mutations in patients with MDS with HSCT.
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http://dx.doi.org/10.1007/s00277-019-03751-6DOI Listing
September 2019

Thrombopoietin Receptor Agonists for Severe Thrombocytopenia after Allogeneic Stem Cell Transplantation: Experience of the Spanish Group of Hematopoietic Stem Cell Transplant.

Biol Blood Marrow Transplant 2019 09 29;25(9):1825-1831. Epub 2019 May 29.

Hematology Department, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria Islas Baleares, Palma de Mallorca, Spain.

Persistent thrombocytopenia is a common complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Romiplostim and eltrombopag are the currently available thrombopoietin receptor agonists (TPO-RAs), and some studies with very small numbers of cases have reported their potential efficacy in the allo-SCT setting. The present retrospective study evaluated the safety and efficacy of TPO-RAs in 86 patients with persistent thrombocytopenia after allo-HSCT. Sixteen patients (19%) had isolated thrombocytopenia (PT), and 71 (82%) had secondary failure of platelet recovery (SFPR). TPO-RA therapy was started at a median of 127 days (range, 27 to 1177 days) after allo-SCT. The median initial and maximum administered doses were 50 mg/day (range, 25 to 150 mg/day) and 75 mg/day (range, 25 to 150 mg/day), respectively, for eltrombopag and 1 µg/kg (range, 1 to 7 µg/kg) and 5 µg/kg (range, 1 to 10 µg/kg), respectively, for romiplostin. The median platelet count before initiation of TPO-RA therapy was 14,000/µL (range, 1000 to 57,000/µL). Platelet recovery to ≥50,000/µL without transfusion support was achieved in 72% of patients at a median time of 66 days (range, 2 to 247 days). Eighty-one percent of the patients had a decreased number of megakaryocytes before treatment, showing a slower response to therapy (P = .011). The median duration of treatment was 62 days (range, 7 to 700 days). Grade 3-4 adverse events (hepatic and asthenia) were observed in only 2% of the patients. At last follow-up, 81% of patients had discontinued TPO-RAs and maintained response, and 71% were alive. To our knowledge, this is the largest series analyzing the use of TPO-RAs after allo-SCT reported to date. Our results support the efficacy and safety in this new setting. Further prospective trials are needed to increase the level of evidence and to identify predictors of response.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.023DOI Listing
September 2019

Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms.

Clin Cancer Res 2019 08 1;25(15):4616-4623. Epub 2019 May 1.

Department of Hematology, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBIS)/CSIC/CIBERONC, Universidad de Sevilla, Seville, Spain.

Purpose: The biologically active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (vit D), has immunoregulatory properties via binding vitamin D receptor (VDR). In a prospective trial, we previously reported a reduction in the incidence of chronic GvHD (cGvHD) among patients who received vit D after allogeneic stem cell transplantation (allo-HSCT; Clinical Trials.gov: NCT02600988). Here we analyze the role of patients and donors' VDR SNPs on the immunomodulatory effect of vit D.

Patients And Methods: Patients undergoing allo-HSCT were included in a prospective phase I/II clinical trial (Alovita) in three consecutive cohorts: control (without vit D), low-dose (1,000 IU/day), and high-dose (5,000 IU/day) groups. Vit D was given from day -5 until +100 after transplant. Genotyping of four SNPs of the VDR gene, FokI, BsmI, ApaI, and TaqI, were performed using TaqMan SNP genotyping assays.

Results: We observed a decrease in the incidence of overall cGvHD at 1 year after allo-HSCT depending on the use or not of vit D among patients with FokI CT genotype (22.5% vs 80%, = 0.0004) and among those patients without BsmI/ApaI/TaqI ATC haplotype (22.2% vs 68.8%, = 0.0005). In a multivariate analysis, FokI CT genotype significantly influenced the risk of cGvHD in patients treated with vit D as compared with the control group (HR 0.143, < 0.001).

Conclusions: Our results show that the immunomodulatory effect of vit D depends on the VDR SNPs, and patients carrying the FokI CT genotype display the highest benefit from receiving vit D after allo-HSCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3875DOI Listing
August 2019

Frequency, characteristics, and outcome of PTLD after allo-SCT: A multicenter study from the Spanish group of blood and marrow transplantation (GETH).

Eur J Haematol 2019 Jun 10;102(6):465-471. Epub 2019 Apr 10.

Hospital Clínico de Valencia, Valencia, Spain.

Post-transplant lymphoproliferative disorder (PTLD) is an infrequent complication of allogeneic stem cell transplant (allo-SCT).

Aims: To estimate the frequency and management of PTLD in Spain and to identify prognostic factors influencing outcomes.

Methods: Multicenter, retrospective analysis of allo-SCT performed in 14 transplant units over a 15-year period.

Results: 102 PTLD were diagnosed among 12 641 allo-SCT, leading to an estimated frequency of 0.8%. PTLD was diagnosed at a median of 106 days after SCT. Eighty-seven cases (85%) were diagnosed between 2007 and 2013. At diagnosis, 22% and 17% of the patients had gastrointestinal tract and CNS involvement. Eighty-seven (85%) received rituximab treatment, alone or in combination with immunosuppression reduction, with an ORR of 50.6%. With a median follow-up for survivors of 58 months, the 2-year overall survival (OS) was 33% and the PTLD-related mortality 45%. Age ≥ 40 years, malignant underlying disease, non-response to rituximab, and severe thrombocytopenia or lymphocytopenia at PTLD diagnosis were associated with worse overall survival.

Conclusions: Only a small proportion of allografted patients were diagnosed a PTLD. Its clinical course was highly aggressive, and prognosis poor, especially in those failing rituximab. The prognostic impact found of the platelet, and lymphocyte count at diagnosis requires further confirmation.
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http://dx.doi.org/10.1111/ejh.13226DOI Listing
June 2019

Author Correction: Donor lymphocyte infusions for B-cell malignancies relapse after T-cell replete allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2019 Jul;54(7):1176

Hematology Department, Hospital Universitari Vall d´Hebron, Departament de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain.

In the original version of this article, author 'Lucia López-Corral' was incorrectly listed as 'Lucia López'. This has now been corrected in both the PDF and HTML versions of the article to 'Lucia López-Corral'.
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http://dx.doi.org/10.1038/s41409-019-0471-yDOI Listing
July 2019

Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 05 10;25(5):1022-1030. Epub 2019 Jan 10.

Department of Hematology, Hospital Universitari i Politècnic la Fe, Valencia. Spain; Centro de Investigación Biomédica en Red Cáncer, Instituto Carlos III, Madrid, Spain. Electronic address:

The current study evaluates the clinical effect of sirolimus exposure on the occurrence of cytomegalovirus (CMV) DNAemia necessitating preemptive antiviral therapy. A total of 167 consecutive recipients of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) who received sirolimus- and tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and whose CMV serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with consecutive sirolimus blood levels describing the time to CMV DNAemia-RAT was developed using NONMEM version 7.4. Overall, 122 of 167 patients (73%) were allografted from an unrelated donor, and the donor CMV-serostatus was negative in 51 cases (31%). Fifty-six recipients (34%) developed CMV DNAemia necessitating preemptive therapy, with a cumulative incidence of 36% at a median follow-up of 25 months. Time to CMV DNAemia necessitating preemptive therapy was best described using a Gompertz function. CMV DNAemia necessitating preemptive therapy-predicting factors were antithymocyte globulin-based conditioning regimen (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.1 to 4.1; P < .01) and sirolimus concentration (HR, .94; 95% CI, .87 to .99; P < .01). The risk of CMV DNAemia-RAT decreased by 6% for each 1 ng/mL increase in sirolimus trough concentration. In conclusion, we provide evidence on the association between sirolimus blood concentration and incidence of CMV DNAemia necessitating preemptive therapy in allo-HSCT recipients. Moreover, this study presents the first predictive model describing the time to CMV DNAemia necessitating preemptive antiviral therapy as a function of sirolimus drug concentration.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.012DOI Listing
May 2019

Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group.

Br J Haematol 2019 03 12;184(5):797-807. Epub 2018 Dec 12.

Department of Haematology, Hospital Universitario de Salamanca - IBSAL, CIBERONC, Salamanca, Spain.

We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 × 10 /l and >20 × 10 /l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.
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http://dx.doi.org/10.1111/bjh.15713DOI Listing
March 2019

Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide.

J Clin Oncol 2019 02 4;37(5):367-374. Epub 2018 Dec 4.

3 University Hospital Vall d'Hebron, Barcelona, Spain.

Purpose: Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft.

Methods: Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites.

Results: The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively.

Conclusion: UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.
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http://dx.doi.org/10.1200/JCO.18.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368416PMC
February 2019

Donor lymphocyte infusion for BK virus hemorrhagic cystitis and nephropathy: a case report.

Bone Marrow Transplant 2019 05 5;54(5):772-774. Epub 2018 Dec 5.

Hematology Department. Hospital Universitari Vall d'Hebron, VHIO, Departament de Medicina. Universitat Autònoma de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1038/s41409-018-0402-3DOI Listing
May 2019

Dichotomization of the new revised international prognostic scoring system for a better clinical stratification of patients with myelodysplastic syndromes.

Leuk Lymphoma 2019 06 30;60(6):1522-1527. Epub 2018 Nov 30.

a Department of Hematology , University Hospital Vall d'Hebron, University Autònoma of Barcelona (UAB) , Spain.

In clinical practice, patients with myelodysplastic syndromes (MDS) are usually classified in low or high-risk groups to take therapeutic decisions, conservative for low-risk, whereas active for high-risk. Nevertheless, in the Revised International Prognostic Scoring System (IPSS-R) is not well stated which patients are low or high-risk. This study was aimed to ascertain in 364 MDS patients which IPSS-R threshold better dichotomized in low vs. high-risk. The best dichotomization was obtained with an IPSS-R cut-point of 3. Accordingly, 68% patients were classified as low-risk (median OS, 61.3 months) and 32% as high-risk MDS (median OS, 13.9 months) ( < .001). Interestingly, the intermediate IPSS-R risk patients presented an OS more related to the high IPSS-R than to the low IPSS-R risk group. In conclusion, an IPSS-R cut-point of 3 led to a meaningful stratification in low and high-risk that can be helpful for the clinical management of MDS patients.
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http://dx.doi.org/10.1080/10428194.2018.1542151DOI Listing
June 2019

Thrombotic thrombocytopenic purpura relapse induced by acute hepatitis E transmitted by cryosupernatant plasma and successfully controlled with ribavirin.

Transfusion 2018 11 4;58(11):2501-2505. Epub 2018 Oct 4.

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.

Background: Hepatitis E virus (HEV) can be transmitted by transfusion of any type of blood component, but there are few data on the potential risk of transmitting this virus and the associated complications. We provide evidence that HEV can be transmitted by cryosupernatant plasma, and that HEV infection can act as a trigger for thrombotic thrombocytopenic purpura (TTP).

Study Design And Methods: A patient with a history of TTP treated with plasmapheresis 2 months previously developed jaundice and a TTP exacerbation with purpura, thrombocytopenia, schistocytes, and undetectable ADAMTS-13 activity. He was diagnosed with acute hepatitis E and treated with ribavirin. TTP remitted with remission of HEV infection.

Results: Traceback to determine the source of the infection showed that 1 cryosupernatant plasma among the 99 different blood components used for the patient's last plasmapheresis was positive for HEV RNA, with an estimated viral load of 5000 to 10,000 IU/mL. Phylogenetic analysis proved the transfusion-transmitted route of acute hepatitis E.

Conclusion: In a patient with TTP, acute HEV infection transmitted by cryosupernatant plasma may trigger exacerbation of TTP, which can be controlled on remission of HEV infection with ribavirin.
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http://dx.doi.org/10.1111/trf.14831DOI Listing
November 2018

Usefulness of thrombopoietin receptor agonists for persistent clinically relevant thrombocytopenia after allogeneic stem cell transplantation.

Eur J Haematol 2018 Sep 3;101(3):407-414. Epub 2018 Aug 3.

Hematology Department, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute (IIB Sant-Pau) and José Carreras Leukemia Research Institute, Autonomous University of Barcelona (UAB), Barcelona, Spain.

Objective And Methods: Severe postengraftment thrombocytopenia is a common complication after allogeneic stem cell transplantation (alloSCT). A few studies have suggested that the use of thrombopoietin agonists (TPOa) may be useful in this setting. Our retrospective study is the largest series published to date; we retrospectively evaluated TPOa efficacy and safety in 20 adult alloSCT recipients who received TPOa as a compassionate use for clinically relevant thrombocytopenia.

Results: Twelve of 20 patients (60%) responded, with a 180-day cumulative incidence of successful platelet recovery to ≥30 and ≥50 × 10 /L of 57% (95% CI: 44%-71%) and 32% (95% CI: 18%-46%), respectively, which were reached at a median of 28 and 34 days from the start of therapy. Fifty percent of the responders were able to discontinue the TPOa without recurrence of severe thrombocytopenia and its associated hemorrhagic complications. No serious adverse events were reported. Possible variables associated with higher response to TPOa were as follows: age < 40 years, presence of megakaryocytes in the bone marrow aspirate, and/or prior response to other hematopoietic growth factors.

Conclusion: This study adds further enthusiasm for continued research on the use of these agents for the treatment of persistent thrombocytopenia in alloSCT recipients.
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http://dx.doi.org/10.1111/ejh.13132DOI Listing
September 2018

Impact of mutational studies on the diagnosis and the outcome of high-risk myelodysplastic syndromes and secondary acute myeloid leukemia patients treated with 5-azacytidine.

Oncotarget 2018 Apr 10;9(27):19342-19355. Epub 2018 Apr 10.

Hematology Service, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.

Myelodysplastic syndromes (MDS) are stem cell disorders caused by various gene abnormalities. We performed targeted deep sequencing in 39 patients with high-risk MDS and secondary acute myeloid leukemia (sAML) at diagnosis and follow-up (response and/or relapse), with the aim to define their mutational status, to establish if specific mutations are biomarkers of response to 5-azacytidine (AZA) and/or may have impact on survival. Overall, 95% of patients harbored at least one mutation. and were the most frequently altered genes. Mutations in correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS) in univariate analysis. Patients with mutations were associated with better OS and PFS. Response rate was 55%; but we could not correlate the presence of and mutations with AZA response. Patients with sAML presented more variations than patients with high-risk MDS, and usually at relapse the number of mutations increased, supporting the idea that in advanced stages of the disease there is a greater genomic complexity. These results confirm that mutation analysis can add prognostic value to high-risk MDS and sAML patients, not only at diagnosis but also at follow-up.
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http://dx.doi.org/10.18632/oncotarget.25046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922401PMC
April 2018