Differential diagnosis of bone marrow failure syndromes guided by machine learning.

The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in patients with severe pancytopenia. Conversely, the misdiagnosis of inherited bone marrow failure (BMF) can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affected family member as a stem cell donor. To predict the likelihood of patients having acquired or inherited BMF, we developed a 2-step data-driven machine-learning model using 25 clinical and laboratory variables typically recorded at the initial clinical encounter. For model development, patients were labeled as having acquired or inherited BMF depending on their genomic data. Data sets were unbiasedly clustered, and an ensemble model was trained with cases from the largest cluster of a training cohort (n = 359) and validated with an independent cohort (n = 127). Cluster A, the largest group, was mostly immune or inherited aplastic anemia, whereas cluster B comprised underrepresented BMF phenotypes and was not included in the next step of data modeling because of a small sample size. The ensemble cluster A-specific model was accurate (89%) to predict BMF etiology, correctly predicting inherited and likely immune BMF in 79% and 92% of cases, respectively. Our model represents a practical guide for BMF diagnosis and highlights the importance of clinical and laboratory variables in the initial evaluation, particularly telomere length. Our tool can be potentially used by general hematologists and health care providers not specialized in BMF, and in under-resourced centers, to prioritize patients for genetic testing or for expeditious treatment.

Haematopoietic cell transplantation for 106 infants and preschoolers with acquired and inherited bone marrow failures.

Aplastic anaemia in infants and young children presents unique challenges due to high prevalence of inherited bone marrow failure syndromes (IBMFS) in this age group. The objective of this study is assessing clinical characteristics and outcomes of haematopoietic cell transplantation in children ≤5 years with bone marrow failure syndromes. We analysied 106 patients (66% males), median age 4.6 years, including 40 with Fanconi anaemia (FA), 32 with Acquired Severe Aplastic anaemia (aSAA), 15 with Diamond-Blackfan Anaemia, 11 with Amegakaryocytic Purpura and 8 with other IBMFS. Molecular testing was limited (39%), with 25.4% confirmed genetically. Retrospective longitudinal study across three paediatric transplantation centres (1982-2020). Overall survival (OS) was 76.4% over a median 10-year follow-up. OS rates were similar between aSAA and IBMFS (FA 77.5%, other IBMFS 76.5%). Transplant-related mortality (TRM) was lower in aSAA (9.4%) compared with IBMFS (16.2%). Recent years showed improved outcomes, with TRM declining post-2010. Choice of stem cell source impacted OS, favouring bone marrow over umbilical cord, but showing encouraging results with haploidentical. Late complications were common, including endocrine-metabolic issues and delayed neuropsychomotor development. Diagnosing and managing bone marrow failures in young children pose significant challenges. Despite advancements in transplant practices, ongoing vigilance and comprehensive care are necessary to improve long-term survival rates.

Hematopoietic cell transplantation for telomere biology diseases: A retrospective single-center cohort study.

BACKGROUND: Telomere biology diseases (TBD) result from defective telomere maintenance, leading to bone marrow failure. The only curative treatment for aplastic anemia related to TBD is a hematopoietic cell transplant (HCT). Although reduced-intensity conditioning (RIC) regimens decrease transplant-related mortality, non-hematological phenotypes represent a major challenge and are associated with poor long-term follow-up outcomes. OBJECTIVE: To describe the outcome of TBD patients transplanted for marrow failure. STUDY DESIGN: This is a retrospective, single-center study describing the outcomes of 32 consecutive transplants on 29 patients between 1993 and 2019. RESULTS: The median age at transplantation was 14 years (range, 3-30 years). Most patients received a RIC regimen (n = 28) and bone marrow (BM) from an unrelated donor (n = 16). Four patients received a haploidentical transplant. Chimerism was available for 27 patients with a median time to neutrophil recovery of 20 days (13-36 days). Primary graft failure occurred in one patient, whereas second graft failure occurred in two. Acute GVHD grade II-IV and moderate to severe chronic GVHD occurred in 22% of patients at risk. Fourteen patients were alive after HCT at the last follow-up (median, 6 years; 1.4-19 years). The 5-year overall survival was better after matched sibling donor (MSD) transplantation compared to other hematopoietic stem cell sources (88.9% vs. 47.7%; p = .05; CI = 95%). Overall, 15 patients died after HCT, most of them (n = 11) after the first year of transplant, due to non-hematological disease progression or complication of chronic GVHD. CONCLUSIONS: Hematopoietic cell transplantation is a potentially curative treatment option for TBD, nonetheless the poor outcome reflects the progression of non-hematologic disease manifestations, which should be considered when transplantation is indicated.

Ocular Manifestations in Patients with Fanconi Anemia: A Single-Center Experience Including 106 Patients.

OBJECTIVES: To describe the prevalence of acquired ocular manifestations in patients with Fanconi anemia (FA) and to describe and correlate the congenital ocular malformations with the genetic subtypes of the disease. STUDY DESIGN: This is a cross-sectional observational study of 106 consecutive patients with confirmed diagnosis of FA who were followed at the Hematopoietic Stem Cell Transplantation (HSCT) Service at the Federal University of Paraná, Curitiba, Parana, Brazil. Participants underwent a complete ophthalmologic evaluation and 84 patients underwent ocular ultrasound examination. This study was conducted between November 2014 and August 2017. RESULTS: The patients ranged in age from 6 months to 43 years of age. Microphthalmia was the most common congenital ocular abnormality (95.2%). A decrease in anthropometric measurements was observed, including palpebral fissure length (78/103 patients [76.5%]), microcornea (48/103 patients [46.6%]), and ptosis (31/103 patients [30.1%]). We identified a new ophthalmic condition in 15 patients with FA, that is, epiretinal tissue on the optic disc. The genetic subtype was identified in 78 patients (79.6%), the FA-A subtype was most prevalent (50%). The most common acquired ocular manifestation (non-graft-versus-host disease [GVHD] related) in patients who did not undergo HSCT (n = 44) was limbal neovascularization (13.6%), whereas in patients who underwent HSCT (n = 62), the GVHD-related manifestation was ocular GVHD (51.6%). The most frequent symptom of ocular GVHD was keratoconjunctivitis sicca (29%). CONCLUSIONS: Several ocular manifestations were identified in patients with FA.

Kidney complications in 107 Fanconi anemia patients submitted to hematopoietic cell transplantation.

Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure, cancer predisposition, and multiple systemic malformations, including congenital abnormalities of the kidney and urinary tract (CAKUT). Hematopoietic cell transplantation (HCT), the only potentially curative treatment for the hematological complications of FA, may precipitate acute kidney injury (AKI) and hypertension. We retrospectively investigated 107 FA patients who underwent HCT between 2009 and 2017. We investigated the incidence and risk factors of AKI within 100 days after HCT in a cohort of FA patients, and kidney function and hypertension over 2-year follow-up.The incidence of AKI (mainly stage I) was 18.7%. Patients aged ≥ 11 years at transplantation showed a higher risk of AKI (OR 3.53). The eGFR was 60-90 mL/min/1.73 m2 in 53 (49.5%), 55 (51.4%), 50 (50.5%), 50 (51%), and 46 (59.7%) patients before HCT, at 100 days, 6 months, 1 year, and 2 years. Within the first 100 days after HCT, hypertension was observed in 72% of the patients and was associated with cyclosporine therapy. Most (62.3%) patients had stage 2 hypertension. CAKUT was observed in 33.7% of the patients and was associated with both hypertension (86%) and diminished kidney function but not with AKI.Conlusion: Although AKI, a commonly known HCT complication, was mild in this study, the prevalence of chronic kidney disease (CKD), as well as the high incidence of hypertension, specially associated with CAKUT point out the importance of kidney care in short and long-term follow up of FA patients. What is Known: • Fanconi anemia (FA) is the most frequent inherited bone marrow failure in children, and 30% of cases have congenital anomalies of kidney (CAKUT). • Acute kidney injury and hypertension after hematopoietic cell transplantation (HCT) may impact the outcomes.. What is New: • Despite the presence of CAKUT and stage 2 CKD in 33.7% and 50% of the patients, respectively, AKI was mild and transitory after HCT in FA patients. • CAKUT in FA patients was associated with lower kidney function and hypertension after HCT.

Analysis of baseline characteristics, disease burden and long-term follow-up of 167 patients with Paroxysmal Nocturnal Hemoglobinuria at a single center in Brazil.

Paroxysmal nocturnal hemoglobinuria (PNH) can occur as a hemolytic form or small PNH clone found in a patient with bone marrow failure. METHODS: Describe Brazilian retrospective PNH cohort and identify the impact of disease burden on long-term follow-up. RESULTS: 167 patients, mean age at diagnosis 28.4 (7.1-71.2 years), four years mean interval between onset of cytopenia/aplasia diagnosis and PNH clone detection. Patients were divided into 15 Classic PNH, 55 Hemolytic PNH with bone marrow hypoplasia (PNH/AA), and 97 Subclinical PNH (sc-PNH). Hypocellular bone marrow was found in 89.2%; 55 had hemoglobinuria and 22 thrombosis during monitoring. WBC PNH clone correlated with RBC PNH clone, LDH and cytopenia. Subclinical patients had lower median lower RBC clone (2.0% vs 24.0% vs 57.8%) and WBC clone (11.7% vs 58.8% vs 81.2%) than PNH/AA and Classic PNH, respectively. PNH granulocyte clone was 89.1% in thrombotic patients. Ten-year overall survival 80.4% and mortality in transplanted patients 9.6%. Sepsis was mortality cause in subclinical PNH (16/18, 88.8%), and thrombosis in hemolytic PNH (11/13, 84.6%). CONCLUSION: Large PNH clones and LDH burden were associated with increased hemolysis and thrombosis risks, while young patients were associated with small PNH clones and subclinical form of the disease. Knowledge of the patient profile, the low risk associated with HSCT, and the use of long-term IST may be instrumental in the clinical management of PNH in restricted-resources countries.

Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia.

By combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clinical outcomes of patients treated with all-trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on fms-like tyrosine kinase-3-internal tandem duplication mutational status; the ΔNp73/TAp73 expression ratio; and ID1, BAALC, ERG, and KMT2E gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score, 3; range, 0-10). ISAPL modeling identified 2 distinct groups of patients, with significant differences in early mortality (P < .001), remission (P = .004), overall survival (P < .001), cumulative incidence of relapse (P = .028), disease-free survival (P = .03), and event-free survival (P < .001). These data were internally validated by using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances for a cure.

Outcomes after Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Patients with Primary Immunodeficiency Diseases.

Allogeneic hematopoietic stem cell transplantation (HCT) can cure primary immunodeficiency diseases (PID). When a HLA-matched donor is not available, a haploidentical family donor may be considered. The use of T cell-replete haploidentical HCT with post-transplantation cyclophosphamide (haplo-PTCy) in children with PID has been reported in few case series. A donor is usually readily available, and haplo-PTCy can be used in urgent cases. We studied the outcomes of 73 patients with PID who underwent haplo-PTCy, including 55 patients who did so as a first transplantation and 18 who did so as a salvage transplantation after graft failure of previous HCT. The median patient age was 1.6 years. Most of the children were male (n = 54) and had active infection at the time of transplantation (n = 50); 10 children had severe organ damage. The diagnosis was severe combined immunodeficiency (SCID) in 34 patients and non-SCID in 39 (Wiskott-Aldrich syndrome; n = 14; chronic granulomatous disease, n = 10; other PID, n = 15). The median duration of follow-up of survivors was 2 years. The cumulative incidence of neutrophil recovery was 88% in the SCID group and 84% in non-SCID group and was 81% for first transplantations and 83% after a salvage graft. At 100 days, the cumulative incidence of acute GVHD grade II-IV and III-IV was 33% and 14%, respectively. The majority of patients reached 200/µL CD4+ and 1000/µL CD3+ cell counts between 3 and 6 months. The estimated 2-year overall survival was 66%; it was 64% for SCID patients and 65% for non-SCID patients and 63% for first HCT and 77% for salvage transplantations. Twenty-five patients died, most of them due to infection early after transplantation (before 100 days). In conclusion, haplo-PTCy is a feasible procedure, can cure two-thirds of children with PID, and can be used as rescue treatment for previous graft failure. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Impact of CD34 Cell Dose and Conditioning Regimen on Outcomes after Haploidentical Donor Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide for Relapsed/Refractory Severe Aplastic Anemia.

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.

Hematopoietic cell transplantation for Diamond Blackfan anemia: A report from the Pediatric Group of the Brazilian Bone Marrow Transplantation Society.

OBJECTIVES: The aim of this study was to analyze the outcomes of children with Diamond-Blackfan anemia (DBA) treated in Brazil with hematopoietic cell transplantation (HCT). METHODS: We performed a retrospective analysis of 44 pediatrics patients transplanted between 1990 and 2018. The median age of patients was 5 years, and 57% were male. Twenty-five received their first HCT from an HLA-matched sibling donor (MSD), 12 from a HLA matched unrelated bone marrow donor (MUD 10/10, n = 12) and 7 other HLA mismatched donors (MMD). RESULTS: After a median follow-up of 4 years, estimate 5-year overall survival (OS) for the entire cohort was 70%, 80% for MSD group, 73% for MUD, and 29% for MMD. Thirty-eight out of the 44 evaluable patients engrafted successfully. Primary and secondary graft failure was observed in five and three patients, respectively. Rates of grade II-IV and III-IV acute graft-versus-host disease (aGVHD) were 25% and 18%, respectively. Nine patients developed chronic GVHD (cGVHD). CONCLUSION: Overall survival rates observed after HLA matched donors transplant for DBA were comparable to those reported from higher-income countries and international registries.

The challenge of long-term follow-up of survivors of childhood acute leukemia after hematopoietic stem cell transplantation in resource-limited countries: A single-center report from Brazil.

With the number of long-term HSCT survivors steadily increasing, attention needs to be focused on the late complications and quality of life. We therefore analyzed the outcome of 101 pediatric patients (<18 years old at the time of HSCT) transplanted for acute leukemia between 1981 and 2015 at Complexo Hospital de Clínicas, Federal University of Paraná, Brazil, and who survived at least two years after HSCT. The median follow-up was 5.9 years (2.0-29.0); median age at follow-up was 17.5 years (2.98-39.0). The 5-year cumulative incidence of relapse was 27.5% (95% CI 18.6%-36.4%). Two-year cumulative incidence of chronic GVHD was 21.8% (95% CI 13.7%-29.8%). Of the 101 patients, 72 patients (71.3%) presented with late effects. Those surviving longer after HSCT experienced more complications. Patients who received TBI-based regimen developed more late effects (P = .013) and more endocrinological complications (P = .024). Endocrinological complications were the most common late sequelae found in this study. For childhood survivors, quality of life was not influenced by age (at HSCT or at last visit), time from HSCT, gender, donor, or GVHD. For survivors that no longer were children, only age at last visit impacted financial domain measures, irrespective of gender, donor, or GVHD. The current study confirms the high burden late complications after pediatric HSCT have on the survivors and underlines the importance of extended follow-up.

Allogeneic Bone Marrow Transplants for Pediatric Severe Aplastic Anemia: Real-world Data comparing Matched Related and Unrelated Donors in a Developing Country. Retrospective study on behalf of the Pediatric Hematopoietic Stem Cell Transplant Working Group of the Brazilian Bone Marrow Transplantation Society (SBTMO) and the Brazil-Seattle Consortium (Gedeco).

In this study, we report on major MRD or URD BMT outcomes in pediatric patients with SAA in Brazil. This was a retrospective study, which included 106 patients ≤18 years old who received a first BMT for SAA. All patients received bone marrow as graft source from an MRD (n = 69) or a URD (n = 37). Conditioning regimen was non-myeloablative in 73.6% of cases, and GVHD prophylaxis comprised a calcineurin inhibitor plus methotrexate in 89.6% of patients. After a median follow-up of 4.5 years after BMT, 81 patients are alive, with a 4-year OS of 77% and no statistically significant difference between the MRD and URD groups (82% vs. 69%, respectively; P = .08). Grade III-IV aGVHD at 6 months and cGVHD at 2 years were observed in 8% and 14% of cases, respectively, and were not statistically different between the groups. Twenty-five (23%) patients died at a median of 2.9 months after BMT. Our study showed that 4-year OS after BMT was not statistically different between MRD and URD recipients. This study shows that the outcomes of pediatric patients transplanted for SAA with a URD in Brazil are approaching those of MRD transplants. In contrast, OS after MRD BMT was lower than we would expect based on previous reports. The wide range of preparatory regimens used by the study centers highlights the need for standardized protocols for these children. Our findings provide a benchmark for future studies focused on improving BMT outcomes in this setting in Brazil.

Transplantation of Hematopoietic Stem Cells for Primary Immunodeficiencies in Brazil: Challenges in Treating Rare Diseases in Developing Countries.

The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant.

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Children and Adolescents with Fanconi Anemia.

We describe haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PT-CY) for 30 patients with Fanconi anemia (FA). Twenty-six patients were transplanted upfront, and the preparatory regimens included fludarabine 150 mg/m2 + total body irradiation 200 to 300 cGy ± CY 10 mg/kg without (n = 12) or with rabbit antithymocyte globulin (r-ATG) 4 to 5 mg/kg (n = 14). Four patients were rescued after primary or secondary graft failure after related or unrelated donor transplantation with the above regimen with (n = 2) or without r-ATG (n = 2). PT-CY at 25 mg/kg/day (total dose, 50 mg/kg) followed by cyclosporine and mycophenolate mofetil was given to all patients. All patients engrafted in the subgroup of patients who did not receive r-ATG (n = 14), but their transplant course was complicated by high rates of acute and chronic graft-versus-host disease (GVHD), and only 8 patients are alive. In the subgroup that received r-ATG (n = 16), 14 patients had sustained engraftment, severe GVHD rates were lower, and 13 patients are alive. Hemorrhagic cystitis occurred in 50% of patients, whereas cytomegalovirus reactivation occurred in 75%. One-year overall survival for the entire cohort was 73% (95% CI, 64% to 81%), and all surviving patients achieved full donor chimerism. In conclusion, haploidentical donor transplantation with PT-CY is a suitable option for FA patients without a matched related or unrelated donor.

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia.

The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.

Observational study of multiple myeloma in Latin America.

Relatively little is known about the outcomes of multiple myeloma in Latin America, a world region where incorporation of novel agents is generally slow. In the current retrospective-prospective study, we aimed to describe the patterns of care and treatment results in five Latin American countries. Between April 2007 and October 2009, patients who had been diagnosed from January 2005 to December 2007 were registered at 23 institutions from Argentina, Brazil, Chile, Mexico, and Peru. We divided patients into two cohorts, according to transplantation eligibility, and analyzed them with regard to first-line treatment and overall survival (OS). We analyzed a total of 852 patients, 46.9 % of whom were female. The median follow-up was 62 months. Among transplantation-ineligible patients (N = 461), the mean age was 67.4 years, approximately one third of patients received a thalidomide-based treatment in the first line, and the median OS was 43.0 months. Transplantation-eligible patients (N = 391) had a mean age of 54.7 years and a median OS of 73.6 months. Autologous transplantation was performed in 58.6 % of the patients for whom this procedure was initially planned and in only 26.9 % of the overall patients. Our long-term results reflect the contemporary literature for patients with multiple myeloma treated with autologous transplantation and thalidomide-based regimens in clinical trials and observational studies. However, further efforts are needed to approve and incorporate novel agents in Latin American countries, as well as to increase access to transplantation, in order to achieve the expected improvements in patient outcomes.

Long-term Survival, Organ Function, and Malignancy after Hematopoietic Stem Cell Transplantation for Fanconi Anemia.

We report on long-term survival in 157 patients with Fanconi anemia (FA) who survived 2 years or longer after their first transplantation with a median follow-up of 9 years. Marrow failure (80%) was the most common indication for transplantation. There were 20 deaths beyond 2 years after transplantation, with 12 of the deaths occurring beyond 5 years after transplantation. Donor chimerism was available for 149 patients: 112 (76%) reported > 95% chimerism, 27 (18%) reported 90% to 95% chimerism, and 8 (5%) reported 20% to 89% donor chimerism. Two patients have < 20% donor chimerism. The 10- and 15-year probabilities of survival were 90% and 79%, respectively. Results of multivariate analysis showed higher mortality risks for transplantations before 2003 (hazard ratio [HR], 7.87; P = .001), chronic graft-versus-host disease (GVHD) (HR, 3.80; P = .004) and squamous cell carcinoma after transplantation (HR, 38.17; P < .0001). The predominant cause of late mortality was squamous cell carcinoma, with an incidence of 8% and 14% at 10 and 15 years after transplantation, respectively, and was more likely to occur in those with chronic GVHD. Other causes of late mortality included chronic GVHD, infection, graft failure, other cancers, and hemorrhage. Although most patients are disease free and functional long term, our data support aggressive surveillance for long periods to identify those at risk for late mortality.

Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib.

Patients in complete cytogenetic response (CCyR) with detectable BCR-ABL1 after ≥2 years on imatinib were randomized to nilotinib (400 mg twice daily, n = 104) or continued imatinib (n = 103) in the Evaluating Nilotinib Efficacy and Safety in clinical Trials-Complete Molecular Response (ENESTcmr) trial. By 1 and 2 years, confirmed undetectable BCR-ABL1 was achieved by 12.5% vs 5.8% (P = .108) and 22.1% vs 8.7% of patients in the nilotinib and imatinib arms, respectively (P = .0087). Among patients without molecular response 4.5 (BCR-ABL1(IS) ≤0.0032%; MR(4.5)) and those without major molecular response at study start, MR(4.5) by 2 years was achieved by 42.9% vs 20.8% and 29.2% vs 3.6% of patients in the nilotinib and imatinib arms, respectively. No patient in the nilotinib arm lost CCyR, vs 3 in the imatinib arm. Adverse events were more common in the nilotinib arm, as expected with the introduction of a new drug vs remaining on a well-tolerated drug. The safety profile of nilotinib was consistent with other reported studies. In summary, switching to nilotinib enabled more patients with chronic myeloid leukemia in chronic phase (CML-CP) to sustain lower levels of disease burden vs remaining on imatinib. This trial was registered at www.clinicaltrials.gov as #NCT00760877.

Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL.

Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.

BCR-ABL mutations in chronic myeloid leukemia treated with tyrosine kinase inhibitors and impact on survival.

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.