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Tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myeloid leukemia (CML) over the last two decades. However, some patients still do not achieve an adequate response to these drugs, and hematopoietic stem cell transplantation (HSCT) is indicated in this scenario. We present the results of a 20-year follow-up study of 70 patients who underwent transplantation after TKI failure. The primary objective of this study was to evaluate overall survival (OS) and the secondary objective was to evaluate the outcomes of relapse-free survival (RFS), GVHD-free, relapse-free survival (GFRS) and the incidences of relapse (RI), non-relapse mortality (NRM), acute and chronic GVHD. Median survival was 11 years, with a 1-year OS of 70% (57.8 to 79.3) and a 5-year OS of 57.7% (45.1 to 68.5). The estimated 5-year OS was not different for CP1 (60%) versus advanced stages (45%); P = .60. The degree of response immediately before transplantation was directly associated with worse outcomes [HR 5.89 (1.19-29.16); P = .03] for patients with only a hematological response compared with patients with a cytogenetic or molecular response. This study corroborates the potential of HSCT in the scenario of therapeutic failure and highlights the role of molecular or cytogenetic response as a potential target to be achieved before transplantation., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Bloodstream infections are a leading cause of death in patients who undergo hematopoietic stem cell transplantation (HSCT) and are more severe when caused by multidrug-resistant (MDR) bacteria. This study proposed to investigate if colonization by MDR bacteria negatively affects the clinical outcomes in hematological patients after HSCT, as well as to evaluate possible risk factors for death due to bacteremia by the same colonizing agent., Methods: A single-center retrospective cohort study was conducted with 405 hematological patients submitted to a single HSCT procedure between 2015 and 2021. Patients were classified as colonized (n = 132) or noncolonized (n = 273) based on the surveillance cultures from D-30 to D+30 of transplantation, and their relevant clinical and laboratory data were collected until D+100., Results: Colonization by MDR bacteria increased blood culture positivity by all micro-organisms and also specifically by MDR bacteria, with a more pronounced effect when caused by carbapenemase-producing Klebsiella pneumoniae. Patients colonized with carbapenem-resistant K. pneumoniae had increased overall mortality (HR = 4.07, 95% CI 1.85-8.91, P = .0005) and had prolonged hospital length of stay in the context of autologous transplantation. Risk factors for death due to bacteremia by the same colonizing agent were neutropenia, colonization by carbapenem-resistant K. pneumoniae and use of high-dose total body irradiation in conditioning., Conclusion: Hematological patients colonized by MDR bacteria presented a higher incidence of bloodstream infections, and colonization by carbapenemase-producing K. pneumoniae was associated with reduced overall survival., (© 2023 Wiley Periodicals LLC.)

Graft failure (GF) is one of the major concerns after allogeneic hematopoietic cell transplantation (allo-HCT) and remains a significant cause of morbidity and mortality. Although previous reports have associated the presence of donor-specific HLA antibodies (DSAs) with an increased risk of GF after unrelated donor allo-HCT, recent studies have failed to confirm this association. We sought to validate the presence of DSAs as a risk factor for GF and hematologic recovery in the unrelated donor allo-HCT setting. We retrospectively evaluated 303 consecutive patients who underwent their first unrelated donor allo-HCT at our institution between January 2008 and December 2017. DSA evaluation was performed using 2 single antigen bead (SAB) assays; DSA titration with 1:2, 1:8, and 1:32 dilutions; C1q-binding assay; and absorption/elution protocol to assess possible false-positive DSA reactivity. The primary endpoints were neutrophil and platelet recovery and GF, and the secondary endpoint was overall survival. Multivariable analyses were performed using Fine-Gray competing risks regression and Cox proportional hazards regression models. The median patient age was 14 years (range, 0 to 61 years), 56.1% were male, and 52.5% underwent allo-HCT for nonmalignant disease, Eleven patients (3.63%) were DSA-positive, including 10 with preexisting DSAs and 1 with post-transplantation de novo DSAs. Nine patients had 1 DSA, 1 patient had 2 DSAs, and 1 patient had 3 DSAs, with a median mean fluorescent intensity (MFI) of 4334 (range, 588 to 20,456) and 3581 (range, 227 to 12,266) in LABScreen and LIFECODES SAB assays, respectively. Overall, 21 patients experienced GF, including 12 with primary graft rejection, 8 with secondary graft rejection, and 1 with primary poor graft function. The cumulative incidence of GF was 4.0% (95% confidence interval [CI], 2.2% to 6.6%) at 28 days, 6.6% (95% CI, 4.2% to 9.8%) at 100 days, and 6.9% (95% CI, 4.4% to 10.2%) at 365 days. In the multivariable analyses, DSA-positive patients had significantly delayed neutrophil recovery (subdistribution hazard ratio [SHR], .48; 95% CI, .29 to .81; P = .006) and platelet recovery (SHR, .51; 95% CI, .35 to .74; P = .0003) compared to patients without DSAs. In addition, only DSAs were significant predictors of primary GF at 28 days (SHR, 2.78; 95% CI, 1.65 to 4.68; P = .0001). The Fine-Gray regression also demonstrated that the presence of DSAs was strongly associated with a higher incidence of overall GF (SHR, 7.60; 95% CI, 2.61 to 22.14; P = .0002). DSA-positive patients with GF had significantly higher median MFI values than DSA-positive patients who achieved engraftment in the LIFECODES SAB assay using neat serum (10,334 versus 1250; P = .006) and in the LABScreen SAB at 1:32 dilution (1627 versus 61; P = .006). All 3 patients with C1q-positive DSAs failed to engraft. DSAs were not predictive of inferior survival (HR, .50; 95% CI, .20 to 1.26; P = .14). Our results validate the presence of DSAs as a significant risk factor for GF and delayed hematologic recovery after unrelated donor allo-HCT. Careful pretransplantation DSA evaluation may optimize unrelated donor selection and improve allo-HCT outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Fanconi anaemia is a challenging disease to manage, and haematopoietic stem-cell transplantation (HSCT) is the treatment of choice for the haematological complications related to this disease. Over these past two decades, we have observed a substantial improvement in survival outcomes after matched related and unrelated donor HSCT, even for patients living in low-income and middle-income countries. Long-term overall survival is still suboptimal because of the risk of malignancies and other disease-related complications. For patients without well matched donors, alternative donor transplantation using mismatched related donors is an option but is historically associated with a high incidence of graft failure and graft-versus-host disease (GVHD). Herein we discuss the development of a HSCT programme for Fanconi anaemia in our centre in Curitiba, Brazil. Because ex vivo, T-cell depletion is unavailable in our country, we adapted the haploidentical donor transplantation platform using post-HSCT cyclophosphamide to overcome graft failure and GVHD associated with HLA-mismatched donor transplantation. The withdrawal of pre-HSCT cyclophosphamide reduced the severity of mucositis and did not interfere with engraftment. The addition of serotherapy improved overall survival by decreasing the incidence of severe acute and chronic GVHD. Although we have improved overall survival and expanded access to HSCT for Fanconi anaemia, our patients face many challenges, especially viral reactivation and GVHD disease, that merit attention. We acknowledge that there is a learning curve to adopt the haploidentical approach for Fanconi anaemia to low-resourced settings, and this Brazilian experience might require further modifications along with national and international collaborations to be implemented in other countries., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) has been recognized as a major risk factor for graft failure (GF) after haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (haplo-PTCy). However, the role of DSAs in salvage haplo-PTCy for rescuing patients with nonmalignant disorders (NMDs) has not yet been reported. The present study retrospectively analyzed 22 patients with NMDs who underwent salvage haplo-PTCy from January 2008 to December 2017. The median age at the time of the rescue haplo-PTCy was 9 years (range, 1-26 years). Median time from the first transplant to second haplo-PTCy was 56 days (range, 37-591 days). Among all patients, six (27.3%) had DSAs, with a median DSA strength (mean fluorescence intensity [MFI]) of 5201 (range, 1412-11,543) in the first DSA testing. In addition, the median DSA MFI was 2672 (range, 832-10,498) before the bone marrow infusion. Overall, GF occurred in 5 (25%) of the 20 assessable patients. Three of four (75%) patients with DSAs experienced GF versus 2 of 16 (12.5%) DSA-negative patients (P = 0.032). The median DSA MFI for patients with GF was 6437 (range, 1412-10,498) versus 1845 (range, 832-2672) for those who engrafted or had early death (P = 0.030). One-year event-free survival was significantly lower in DSA-positive patients than in those without DSAs (16.7% vs. 62.5%, P = 0.002). DSA-negative patients had an acceptable 1-year survival of 62.5%. In conclusion, this study suggests that DSAs may be associated with deleterious outcomes after salvage haplo-PTCy in patients with NMDs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Severe aplastic anemia (SAA) is a life-threatening disease that can be cured with allogeneic cell transplantation (HCT). Haploidentical donor transplantation with post-transplantation cyclophosphamide (haplo-PTCy) is an option for patients lacking an HLA-matched donor. We analyzed 87 patients who underwent haplo-PTCy between 2010 and 2019. The median patient age was 14 years (range, 1 to 69 years), most were heavily transfused, and all received previous immunosuppression (25% without antithymocyte globulin). Almost two-thirds (63%) received standard fludarabine (Flu)/cyclophosphamide (Cy) 29/total body irradiation (TBI) 200 cGy conditioning, and the remaining patients received an augmented conditioning: Flu/Cy29/TBI 300-400 (16%), Flu/Cy50/TBI 200 (10%), or Flu/Cy50/TBI 400 (10%). All patients received PTCy-based graft-versus-host disease (GVHD) prophylaxis. Most grafts (93%) were bone marrow (BM). The median duration of follow-up was 2 years and 2 months. The median time to neutrophil recovery was 17 days. Primary graft failure occurred in 15% of the patients, and secondary or poor graft function occurred in 5%. The incidences of grade II-IV acute GVHD was 14%, and that of chronic GVHD was 9%. Two-year overall survival and event-free survival (EFS) were 79% and 70%, respectively. EFS was higher for patients who received augmented Flu/Cy/TBI (hazard ratio [HR], .28; P = .02), and those who received higher BM CD34 cell doses (>3.2 × 10E6/kg) (HR, .29; P = .004). The presence of donor-specific antibodies before HSCT was associated with lower EFS (HR, 3.92; P = .01). Graft failure (HR, 7.20; P < .0001) was associated with an elevated risk of death. Cytomegalovirus reactivation was frequent (62%). Haploidentical HCT for SAA is a feasible procedure; outcomes are improved with augmented conditioning regimens and BM grafts with higher CD34 cell doses., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Patients with severe aplastic anemia (SAA) who fail immunosuppressive therapy have a dismal prognosis. Hematopoietic stem cell transplantation (HSCT) from an unrelated donor (URD) is one of the most effective treatment options. Two institutions have independently adopted a post-transplantation cyclophosphamide (PTCy) approach for patients with SAA undergoing HSCT from a URD. Thirteen patients were included, 11 of whom had been treated with immunosuppressive therapy. Eight patients had a mismatched URD. All patients were conditioned with fludarabine, cyclophosphamide, and total body irradiation, in various dosage combinations. PTCy was given at a dose of 100 mg/kg. Two patients died, and overall survival was 85% at 2 years. All patients engrafted, but 1 patient developed secondary graft failure. Of the 11 patients alive after 2 years, 9 had complete donor chimerism. All surviving patients were transfusion-independent. Ten patients (77%) had cytomegalovirus reactivation, and 2 patients had more than 1 reactivation. No Epstein-Barr virus reactivation or post-transplantation lymphoproliferative disease was observed. Four patients had mild hemorrhagic cystitis. In summary, our findings show that PTCy is a promising treatment for patients with SAA undergoing URD HSCT., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to describe the periodontal profile of -candidates for allogeneic hematopoietic stem cell transplantation., Methods: This cross-sectional prospective study was performed from March 2014 to March 2015. After an initial interview, eligible individuals were evaluated by the following clinical parameters: visible plaque, bleeding on probing, probing depth, and clinical attachment level at six sites per tooth, excluding third molars., Results: Thirty-six candidates for allogeneic hematopoietic stem cell transplantation (HSCT) were clinically assessed. Eight (22%) patients were diagnosed with gingivitis and 21 (58%) of them with periodontitis. The gingival bleeding was statistically correlated with the percentage of sites with visible plaque (p < 0.0001; r = 0.630) and did not correlate with the number of platelets (p = 0.643, r = -0.082)., Conclusions: The candidates for allogeneic HSCT studied showed a high prevalence of periodontal diseases with unmonitored local infection before transplantation., (© 2017 Special Care Dentistry Association and Wiley Periodicals, Inc.)

Purpose: Although the relevance of dental intervention before transplant is recognized, many patients are undergoing transplantation without receiving dental care. The objective of this study was to identify the searching profile, access, and use of dental services by candidates to hematopoietic stem cell transplantation (HSCT), and the difficulties faced by those candidates., Methods: All candidates for an allogeneic HSCT from a bone marrow transplant unit were invited to take part in this research from March 2014 to March 2015. A questionnaire was developed consisting of five sections with questions about personal information, hematologic disease, access to dental services, and history of dental treatment, patient's preferences, and knowledge., Results: One hundred and ten candidates for allogeneic HSCT participated in this study. Fifty-five participants received professional oral care in the previous year of interview. The majority of patients (64 %) went to a dentist not linked to transplant staff, and private dental service was the most visited (42 %). To visit a dentist during the previous year was statistically associated with the habit of going to a dentist outside the hospital (p < 0.001), which was statistically associated with the family income (p = 0.001). The main barriers to access to dental treatment were lack of guidance (66 %), apprehension (45 %), and lack of confidence (29 %) in an "external" dentist., Conclusions: Most of the barriers seem to be associated to lack of confidence and information among patients and professionals, as well as a lack of parameters for scheduling or referrals to dental care, especially for those with a low-socioeconomic background.

Reduced fertility is one clinical manifestation among other well known Fanconi anemia features. Most recipients of allogeneic hematopoietic stem cell transplantation suffer from secondary infertility owing to gonadal damage from myeloablative conditioning. In order to evaluate the rate of pregnancy in Fanconi anemia transplanted patients, we performed a retrospective analysis of female patients transplanted in 15 centers from 1976 to 2008. Among 578 transplanted Fanconi anemia patients, we identified 285 transplanted females of whom 101 patients were aged 16 years or over. Ten became pregnant (4 twice). Before hematopoietic stem cell transplantation all had confirmed Fanconi anemia diagnosis. Median age at transplantation was 12 years (range 5-17 years). Conditioning regimen consisted of cyclophosphamide with or without irradiation. During follow up, 5 of 10 patients presented signs of ovarian failure. Among those, 2 patients spontaneously recovered regular menses, and 3 received hormonal replacement therapy. Pregnancy occurred from four to 17 years after hematopoietic stem cell transplantation. Three patients had preterm deliveries, one patient had a hysterectomy for bleeding. All 14 newborns had normal growth and development without congenital diseases. In conclusion, recovery of normal ovarian function and a viable pregnancy is a realistic but relatively rare possibility even in Fanconi anemia patients following hematopoietic stem cell transplantation. Mechanisms of fertility recovery are discussed.