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BACKGROUND: Despite the concurrent use of haploidentical-cord (HCT) and dual cord (DCT) stem cell transplant approaches for over a decade, there have been few comparisons of their outcomes. OBJECTIVES: Our objective in this study is to assess for differences in the outcomes and adverse effects associated with HCTs vs DCTs. STUDY DESIGN: Here we report a retrospective analysis of HCTs and DCTs at our institution. From October 2012 to October 2022, 70 HCT and 133 DCT transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. RESULTS: With a median follow-up of 3.6 years among survivors, there was no difference in overall survival (3 year OS 65% DCT vs 63% HCT, p=1) or relapse free survival (3 year RFS 62% DCT vs 64% HCT, p=0.97) for all patients. Time to neutrophil recovery was faster in HCT recipients (median 17 vs 22 days, p=0.021), with no difference in platelet recovery to 20,000/µL (p=0.12). Median hospitalization for HCT recipients was 20 days versus 24 days for DCT recipients (p<0.0001). Engraftment syndrome treated with steroids occurred in 47/133 (35%) DCT recipients vs 42/70 (60%) HCT recipients (OR 0.37, p-value=0.001). There was a significant increase in grade 3-4 acute graft-versus-host-disease (aGVHD) in haplo-cord recipients (p=0.007), but no difference in grade 2-4 aGVHD (p=0.11), all chronic GVHD (cGVHD) (p=0.9), or moderate-severe cGVHD (p=0.3). CONCLUSIONS: Our outcomes demonstrate faster engraftment and shorter hospitalization in HCTs relative to DCTs, but more engraftment syndrome and higher grade 3-4 aGVHD. When both are options, these factors should guide the choice between HCTs and DCTs.
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Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/genética , Contagem de Leucócitos , Pessoa de Meia-Idade , Masculino , Feminino , Prognóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Quimioterapia de Indução/métodos , Resultado do Tratamento , Adulto Jovem , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.
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Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Mutação , Neoplasia Residual , Nucleofosmina , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Idoso , Masculino , Feminino , Azacitidina/uso terapêutico , Azacitidina/administração & dosagem , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Reação em Cadeia da Polimerase/métodos , Prognóstico , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Adulto , Resultado do TratamentoAssuntos
Transfusão Feto-Materna , Doença Enxerto-Hospedeiro , Complicações na Gravidez , Humanos , Feto/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Feminino , Gravidez , Complicações na Gravidez/imunologia , Transfusão Feto-Materna/complicações , Transfusão Feto-Materna/imunologiaRESUMO
INTRODUCTION: Cytomegalovirus (CMV) can cause significant morbidity and mortality in cord blood transplant (CBT) recipients. Development of CMV-specific cell-mediated immunity (CMV-CMI) has been associated with protection against CMV clinically significant reactivation (CsCMV). In this study, we evaluated CMV-CMI reconstitution during letermovir prophylactic therapy, which prevents CsCMV without complete suppression of CMV reactivation. METHODS: We measured CMV-CMI in CMV-seropositive CBT recipients pre-transplant after Day+90 of letermovir prophylaxis and at Days +180, and +360- post-transplant using a dual color CMV-specific IFNγ/IL2 FLUOROSpot. CsCMV and nonCsCMV reactivations were abstracted from medical records. CsCMV was defined as CMV viral load ≥5,000 IU/ml using a whole blood assay. RESULTS: Among 70 CBT recipients, 31 developed CMV-CMI by Day+90 and an additional eight and five participants by Days +180 and +360, respectively. Thirty-eight participants developed CMV reactivation, including nine with CsCMV. Most reactivations (33 of 38) occurred before Day+180. Early CMV-CMI was present in six out of nine participants with CsCMV, indicating a lack of protection against CsCMV. Moreover, the magnitude of CMV-CMI at Day+90 did not differ between participants with CsCMV and nonCsCMV. CONCLUSION: Approximately 50% of CBT recipients reconstituted CMV-CMI during letermovir prophylactic therapy. However, CMV-CMI did not reach levels protective against CsCMV. Extension of CMV prophylaxis beyond Day+90 may be considered in CMV-seropositive CBT recipients.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Reconstituição Imune , Humanos , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Antivirais/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplantados , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among high relapse risk patients. Between February 2019 and December 2021, we administered post-SCT ven maintenance to 49 AML patients at high-risk for relapse as a prospectively defined off-label practice at our institution. Ven was planned to be administered until 1-year post-SCT. While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively. Our experience demonstrates single agent ven is a safe, tolerable, and feasible maintenance therapy that may improve RFS and OS in high relapse risk post-SCT patients.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Transplante de Células-Tronco , Recidiva , Estudos RetrospectivosRESUMO
Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: i) higher doses of venetoclax are tolerable and more effective, and ii) azacitidine can be discontinued after deep remissions. Forty-two newly diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine+Venetoclax (HiDDAV) Study (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital polymerase chain recation. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400 mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.
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Azacitidina , Leucemia Mieloide Aguda , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasia Residual/tratamento farmacológicoRESUMO
The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease-a major complication of allogeneic HCT-to enable the patient and clinician to assess management options in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Transplante Homólogo , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Condicionamento Pré-Transplante/efeitos adversosRESUMO
Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative approach for patients with acute myeloid leukemia (AML), relapse is a common occurrence. Several strategies, such as choice of conditioning regimen, donor lymphocyte infusions, pharmacologic agents, and cellular therapy approaches, are currently being developed to improve transplantation outcomes. This review outlines some important interventions and considerations to lower the burden of post-transplantation relapse in AML.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Transplante Homólogo , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante , Recidiva , Doença Crônica , Estudos RetrospectivosRESUMO
Background: Acute myeloid leukemia (AML) is associated with poor prognosis, particularly in elderly patients with comorbidities. Combining azacitidine (AZA) with BCL-2 inhibitor venetoclax (VEN) demonstrated significant improvement in outcomes for newly-diagnosed AML patients compared to AZA alone. However, this regimen is myelosuppressive, and the incidence of invasive fungal infections (IFIs) and impact of antifungal prophylaxis are not well defined. Methods: This retrospective cohort study evaluated newly-diagnosed AML patients treated with VEN/AZA at the University of Colorado Hospital from January 2014 to August 2020. Patients with history of prior IFI were excluded. Primary outcome was IFI incidence during VEN/AZA therapy. χ2 and Fisher exact tests assessed the impact of patient demographics, AML-specific risk factors, and receipt of antifungal prophylaxis on IFI incidence. Results: 144 VEN/AZA-treated AML patients were included in the study. 25 (17%) patients developed IFI: 8% (n = 2) "proven," 24% (n = 6) "probable," and 68% (n = 17) "possible" per European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium criteria. There was no statistically significant association between IFI incidence with age, sex, or European LeukemiaNet classification. 10 patients received antifungal prophylaxis; none developed IFI. IFI incidence rate per 1000 patient-days was greatest 0-9 days after starting VEN/AZA, at 8.39. Conclusions: Incidence of "proven" and "probable" IFI in our VEN/AZA-treated AML cohort was 5.6%, in-line with incidence rates reported by recent similar studies. Furthermore, IFI incidence decreased as days from starting VEN/AZA therapy increased.
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Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasia Residual/complicações , Recidiva , Estudos Retrospectivos , SulfonamidasRESUMO
The combination of venetoclax (ven) and azacitidine (aza) has resulted in high response rates in the upfront treatment of AML in patients age > 75 and patients unfit for intensive chemotherapy. Given the poor historical outcomes in patients age ≥ 60 treated with induction chemotherapy, ven/aza has become our institutional preference for the initial treatment of non-core binding factor (CBF) AML patients age ≥ 60. The benefit of allogeneic stem cell transplant (SCT) in patients who achieve response to ven/aza is uncertain. We report outcomes of SCT-eligible patients treated at our center. Between 1/2015 and 1/2020, 119 newly diagnosed non-CBF AML patients age ≥ 60 received ven/aza as initial therapy. 21 patients underwent SCT; 31 additional patients were potentially SCT eligible but deferred SCT. Overall survival (OS) was significantly greater among SCT patients (median survival not reached) versus potentially SCT eligible patients not undergoing SCT (median 518 days) (p = 0.01). Our data suggest that ven/aza followed by SCT in newly diagnosed AML patients older than ≥ 60 results in excellent outcomes and likely improves outcomes over maintenance therapy. Ongoing investigation will further refine the optimal timing of and selection of patients for SCT based on prognostic disease features and response assessments.
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Azacitidina , Leucemia Mieloide Aguda , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Estudos Retrospectivos , SulfonamidasRESUMO
Venetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.
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Azacitidina , Leucemia Mieloide Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sulfonamidas , Adulto JovemRESUMO
BACKGROUND: The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined. METHODS: This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America. RESULTS: Sixty-four patients with proven (nâ =â 47) or probable (nâ =â 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmBâ +â posaconazole (25%), AmBâ +â echinocandin (13%), AmBâ +â isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (nâ =â 28) was associated with a trend toward lower treatment failure compared with AmB (nâ =â 21) (42% vs 64%, Pâ =â .136). CONCLUSIONS: Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmBâ +â azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.
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BACKGROUND: A 30-year-old man underwent double umbilical cord blood transplantation (UCBT) for acute myeloid leukemia (AML) with reduced intensity conditioning. The cords had identical HLA types and were each a 5/6 match to the patient. Following transplantation, cord 2 initially dominated all tested cell populations. At day +306, we observed an unusual reversal of dominance chimerism pattern in which cord 1 instead dominated all tested populations. STUDY DESIGN & METHODS: Polymerase chain reaction (PCR)-based short tandem repeat (STR) assays were performed on the peripheral blood and bone marrow samples. The white blood cell (WBC) populations from the peripheral blood were manipulated for testing to create subpopulations enriched for CD3, CD33, and CD56. RESULTS: Chimerism studies on day +77 showed the following: cord 1: 44%-CD3; 0%-CD33; 16%-CD56; cord 2: 56%-CD3; 100%-CD33; 84%-CD56. Cord 2 initially dominated in all tested cell populations. Chimerism studies performed on post-transplantation day +306 uncovered a reversal of dominance chimerism pattern in which cord 1 now dominated in all cell populations (cord 1: 82%-CD3; >95%-CD33; 67%-CD56; cord 2: 18%-CD3; <5%-CD33; 33%-CD56). Between days +127 and +244, the patient's blood type shifted from B Rh-positive to A Rh-negative. CONCLUSION: The change in the patient's blood type identified a late reversal of dominance chimerism pattern. This is a rare occurrence, previously cited only once, which is inconsistent with published data that early high CD3 counts and unseparated bone marrow chimerism predominance at day +100 predict long-term cord dominance in double UCBT in the vast majority of cases.
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Quimerismo , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/terapia , Leucócitos/metabolismo , Adulto , Tipagem e Reações Cruzadas Sanguíneas , Medula Óssea/metabolismo , Complexo CD3/sangue , Complexo CD3/genética , Antígeno CD56/sangue , Antígeno CD56/genética , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Reação em Cadeia da Polimerase , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/sangue , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genéticaRESUMO
We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
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Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Condicionamento Pré-Transplante , Doadores não RelacionadosRESUMO
Widely-used response criteria, conditional upon count recovery, were developed for acute myeloid leukemia (AML) in the context of intensive chemotherapy (IC). Extending these definitions to continuously-administered venetoclax-based therapies might underestimate responses. Best practices for venetoclax-based therapies mandate interruption after an end-of-cycle 1 bone marrow biopsy shows morphologic remission with cytopenias. We analyzed 435 patients with newly-diagnosed AML and follow-up response assessments. Of the 101 who responded to venetoclax + azacitidine, overall survival for patients whose response was upgraded due to count recovery during a 14-day post-disease assessment period, from complete remission (CR) with incomplete recovery of blood counts to CR, was not different compared to patients who did not need the 14-day period for count recovery. These results were distinct from 138 IC patients. Although sample sizes for the comparison groups were small, and conclusions are exploratory and must be verified, these findings support consideration of new response criteria for venetoclax-based regimens.
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Azacitidina , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , SulfonamidasRESUMO
Although the use of treosulfan (TREO) in conventional donor hematopoietic cell transplantation (HCT) has been extensively evaluated, its use in cord blood transplantation (CBT) for hematologic malignancies has not been reported. Between March 2009 and October 2019, 130 CBT recipients were enrolled in this prospective multicenter phase 2 study. The conditioning regimen consisted of TREO, fludarabine, and a single fraction of 2 Gy total-body irradiation. Cyclosporine and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. The primary end point was incidence of graft failure (GF), and based on risk of GF, patients were classified as low risk (arm 1, n = 66) and high risk (arm 2, n = 64). The median age was 45 years (range, 0.6-65 years). Disease status included acute leukemias in first complete remission (CR; n = 56), in ≥2 CRs (n = 46), and myelodysplastic (n = 25) and myeloproliferative syndromes (n = 3). Thirty-five patients (27%) had received a prior HCT. One hundred twenty-three patients (95%) engrafted, with neutrophil recovery occurring at a median of 19 days for patients on arm 1 and 20 days for patients on arm 2. The 3-year overall survival, relapse-free survival (RFS), transplant-related mortality, and relapse for the combined groups were 66%, 57%, 18%, and 24%, respectively. Among patients who had a prior HCT, RFS at 3 years was 48%. No significant differences in clinical outcomes were seen between the 2 arms. Our results demonstrate that TREO-based conditioning for CBT recipients is safe and effective in promoting CB engraftment with favorable clinical outcomes. This trial was registered at www.clinicaltrials.gov as #NCT00796068.