RESUMO
This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08-0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11-1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.
Assuntos
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Ciclofosfamida , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Condicionamento Pré-Transplante , Humanos , Masculino , Feminino , Condicionamento Pré-Transplante/métodos , Adulto , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Adolescente , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Taxa de Sobrevida , Transplante Homólogo , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/mortalidade , Intervalo Livre de Doença , Estudos Retrospectivos , AloenxertosRESUMO
Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/µL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/µL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/µL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.
Assuntos
Benzoatos , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Hidrazinas , Pirazóis , Humanos , Transplante de Medula Óssea/efeitos adversos , Estudos Prospectivos , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Estudos RetrospectivosRESUMO
OBJECTIVES: Patients with high-risk hematologic diseases require intensive modalities, including high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Haploidentical T-cell-replete transplantation is a logical choice because of the limited availability of matched sibling donors and the prolonged time needed to identify matched unrelated donors in Thailand. METHODS: The clinical outcomes data of 43 patients undergoing allo-HSCT were reviewed. All patients had high-risk hematologic malignancies, were younger than 20 years, and were in complete cytological remission at the time of allo-HSCT. We used two different conditioning regimens: total body irradiation (TBI) combined with cyclophosphamide, fludarabine, and melphalan (n = 23) and thiotepa combined with fludarabine and busulfan (n = 20). All patients received a graft-versus-host disease prophylaxis regimen consisting of cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. RESULTS: There was no difference in engraftment between patients receiving either of the regimens. After a median follow-up of 35.8 (range, 0.6-106.2) months, the overall survival (OS) and event-free survival (EFS) rates were 62.4% and 54.7%, respectively. OS and EFS were comparable between the respective regimens. CONCLUSIONS: We conclude that thiotepa-based conditioning has similar efficacy and tolerability as TBI-based conditioning for haploidentical HSCT with post-transplant cyclophosphamide.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Tiotepa , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Recidiva Local de Neoplasia/tratamento farmacológico , Linfócitos T/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ciclofosfamida/uso terapêutico , Bussulfano/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversosRESUMO
High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.
Assuntos
Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/patologia , Estudos RetrospectivosRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pre transplant immune suppression phase (PTIS) and two courses of dexamethasone (DXM) and fludarabine (FLU) followed by pre transplant conditioning with intravenous FLU busulfan (BU) and post transplant graft-vs.-host disease (GvHD) prophylaxis with cyclophosphamide (CPM), tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia; the 3-year projected overall and event-free survival is over 96.0%, and there have been no secondary graft failures. Of the first 31 patients, we had two graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific human leukocyte antigen (HLA) antibodies [anti-donor specific antibodies (DSAs)], but after adjusting the PTIS to include bortezomib (BORT) and rituximab (RIX) for patients with high titers of anti-DSAs and using pharmacologic dose guidance for BU, we had no graft failures in the last 52 patients. Six (7.0%) of 83 patients developed severe GvHD. We conclude that this is a safe and efficacious approach to allogeneic HSCT in thalassemia.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Talassemia , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Talassemia/tratamento farmacológico , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown. METHODS: Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 µmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 µmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival. RESULTS: Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01). CONCLUSIONS: A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.
Assuntos
Bussulfano , Leucemia Mieloide Aguda , Agonistas Mieloablativos , Síndromes Mielodisplásicas , Condicionamento Pré-Transplante , Idoso , Bussulfano/administração & dosagem , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Agonistas Mieloablativos/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
Acute myeloid leukemia (AML) patients not in remission and beyond first or second complete remission are considered allogeneic stem cell transplant (SCT) candidates. We present 361 patients who underwent SCT from matched related or unrelated donors between 2005 and 2013. The purpose was to identify a subgroup of patients with active disease at the time of transplant that benefit. Cox proportional hazards regression analysis was used for univariate and multivariate analyses to predict overall survival (OS). Variables considered were age, sex, SWOG cytogenetic risk group, bone marrow (BM) and peripheral blood (PB) blast percentage, regimen intensity, and type of AML. At a median of 26 months after transplantation, OS, progression-free survival (PFS), non-relapse mortality, and relapse rates were 26, 24, 23, and 48%, respectively. In a univariate analysis, risk cytogenetics (p < 0.001) and BM blasts >4% (p = 0.006) or any blasts in PB (p < 0.001) indicated worse OS. In a multivariate analysis, patients with <5% BM blasts or absence of circulating blasts and good or intermediate risk cytogenetics had significantly superior OS (46%), PFS (44%), and disease progression at 3 years. Based on these findings, patients not in remission with good or intermediate risk cytogenetics and low blast counts should be considered for SCT.
Assuntos
Medula Óssea/patologia , Aberrações Cromossômicas , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais , Biópsia , Análise Citogenética , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days -3 and -2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days -5 to -2; n = 4) or pharmacokinetic-guided area under the curve of 4000 µmol/min (days -5 to -2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio, .44; 95% CI, .18-1.07; P = .07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Mielofibrose Primária , Idoso , Bussulfano , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Mielofibrose Primária/terapia , Estudos Prospectivos , Condicionamento Pré-Transplante , Vidarabina/uso terapêuticoRESUMO
Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Talassemia , Bussulfano/uso terapêutico , Criança , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Talassemia/terapia , Condicionamento Pré-TransplanteRESUMO
We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T-cell depletion using antithymocyte globulin (ATG) for patients with hematological malignancies. All donor-recipient pairs had high-resolution typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DRB3/4/5 and were matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) had nonpermissive mismatches, in graft-versus-host (GVH) direction, and 167 (17%) had nonpermissive mismatches in host-versus-graft (HVG) direction. Compared with HLA-DPB1 permissive mismatched pairs, nonpermissive GVH mismatched pairs had the highest risk for grade II to IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 1.4; P = .01) whereas matched pairs had the lowest risk (HR, 0.5; P < .001). Grade III to IV aGVHD was only increased with HLA-DPB1 nonpermissive GVH mismatched pairs (HR, 2.3; P = .005). The risk for disease progression was lower with any HLA-DPB1 mismatches, permissive or nonpermissive. However, the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients who were in the intermediate-risk group by the Disease Risk Index (HR, 0.4; P = .001) but no other risk groups. Our results suggest avoidance of nonpermissive GVH HLA-DPB1 mismatches for lowering the risk for grade II to IV and III to IV aGVHD. Permissive or nonpermissive HVG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matches in the intermediate-risk patients to decrease the risk for disease progression.
Assuntos
Cadeias HLA-DRB1 , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Depleção Linfocítica , Linfócitos T , Doença Aguda , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de SobrevidaRESUMO
Busulfan is given in the conditioning regimens preceding hematopoietic stem cell transplantation (HSCT), and plasma levels can be monitored. A targeted, individualized systemic exposure (SE) dose can be achieved by calculating the area under the plasma concentration versus time curve (AUC). The objective of this study was to determine a cutoff value for safety for the AUC for busulfan plasma levels in patients undergoing HSCT. A total of 149 consecutive HSCT patients were studied. After an oral test dose of busulfan, we set target doses of 4000, 5000, or 6000 µMol⸱min/day, and analyzed the AUC of oral or intravenous Bu. These patients were compared with 53 historical control subjects who had received myeloablative conditioning regimen without busulfan pharmacokinetic monitoring. Using a test dose and the administration route had no impact on the sinusoidal obstructive syndrome (SOS) incidence, transplant-related mortality or 1-year overall survival. However, patients receiving busulfan at doses set up at AUC > 5000 had an increased risk to develop SOS after HSCT (hazard ratio 3.39, p = 0.034, 95% CI 1.09-10.52). Adjusting the busulfan dose according to SE levels target dose during conditioning is associated with lower rates of oral severe mucositis and SOS. A cutoff of 5000 µMol⸱min is safe and does not impair survival.
Assuntos
Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Hepatopatia Veno-Oclusiva/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Administração Intravenosa , Administração Oral , Adolescente , Área Sob a Curva , Bussulfano/farmacocinética , Criança , Pré-Escolar , Ensaios Clínicos Controlados como Assunto , Suscetibilidade a Doenças , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/mortalidade , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Prognóstico , Condicionamento Pré-Transplante/métodos , Adulto JovemRESUMO
BACKGROUND: BK polymavirus (BKPyV), a member of the family Polyomaviridae, is associated with increased morbidity and mortality in allogeneic stem cell transplant recipients. METHODS: In our previous retrospective study of 2477 stem cell transplant patients, BKPyV replication independently predicted chronic kidney disease and poor survival. In this study, using the same cohort, we derived and validated a risk grading system to identify patients at risk of BKPyV replication after transplantation in a user-friendly modality. We used 3 baseline variables (conditioning regimen, HLA match status, and underlying cancer diagnosis) that significantly predicted BKPyV replication in our initial study in a subdistribution hazard model with death as a competing risk. We also developed a nomogram of the hazard model as a visual aid. The AUC of the ROC of the risk-score-only model was 0.65. We further stratified the patients on the basis of risk score into low-, moderate-, and high-risk groups. RESULTS: The total risk score was significantly associated with BKPyV replication (P < .0001). At 30 days after transplantation, the low-risk (score ≤ 0) patients had a 9% chance of developing symptomatic BKPyV replication, while the high-risk (score ≥ 8) of the population had 56% of developing BKPyV replication. We validated the risk score using a separate cohort of 1478 patients. The AUC of the ROC of the risk-score-only model was 0.59. Both the total risk score and 3-level risk variable were significantly associated with BKPyV replication in this cohort (P < .0001). CONCLUSIONS: This grading system for the risk of symptomatic BKPyV replication may help in early monitoring and intervention to prevent BKPyV-associated morbidity, mortality, and kidney function decline.
Assuntos
Vírus BK , Transplante de Células-Tronco Hematopoéticas , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Estudos Retrospectivos , Medição de Risco , Transplante de Células-Tronco , TransplantadosRESUMO
The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/administração & dosagem , Adulto , Idoso , Aloenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We studied if the inclusion of early post-stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment-combined with pre-SCT MRD assessment, ELN risk category, and age-improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed.
Assuntos
Leucemia Mieloide Aguda/terapia , Neoplasia Residual/terapia , Transplante de Células-Tronco/efeitos adversos , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Fatores de Risco , Transplante de Células-Tronco/métodos , Adulto JovemRESUMO
We conducted a prospective phase 2 trial of gemcitabine, busulfan and melphalan (Gem/Bu/Mel) with autologous stem cell transplantation (ASCT) in patients with primary refractory or poor-risk relapsed Hodgkin lymphoma (HL) (ie, extranodal relapse or within 1 year of frontline therapy). The trial was powered to detect an improvement in 2-year progression-free survival (PFS) from a historical 50% using a BEAM regimen (carmustine/etoposide/cytarabine/melphalan) to 65%. We compared the study population with all other concurrent patients who were eligible for the trial but instead received the BEAM regimen at our center. No patient received post-ASCT maintenance therapy. The Gem/Bu/Mel trial enrolled 80 patients with a median age of 31 years, 41% with primary refractory HL and 59% with relapsed HL (36% extranodal relapses), and 30% with positron emission tomography (PET)-positive lesions at ASCT. The concurrent BEAM (n = 45) and Gem/Bu/Mel cohorts were well balanced except for higher rates of bulky relapse and PET-positive tumors in the Gem/Bu/Mel cohort. There were no transplantation-related deaths in either cohort. At a median follow-up of 34.5 months (range, 26 to 72 months), Gem/Bu/Mel was associated with better 2-year PFS (65% versus 51%; P = .008) and overall survival (89% versus 73%; P = .0003). In conclusion, our data show that Gem/Bu/Mel is safe, in this nonrandomized comparison yielding improved outcomes compared with a concurrently treated and prognostically matched cohort of patients with primary refractory or poor-risk relapsed HL receiving BEAM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/terapia , Terapia de Salvação/métodos , Adulto , Bussulfano/uso terapêutico , Carmustina/uso terapêutico , Citarabina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Etoposídeo/uso terapêutico , Doença de Hodgkin/mortalidade , Humanos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Terapia de Salvação/mortalidade , Análise de Sobrevida , Transplante Autólogo , Adulto Jovem , GencitabinaRESUMO
In this study, we compared transplantation outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS) who received a CD34+ cell-selected and those who received an unmodified allograft. This analysis initially included 181 patients, 60 who received a CD34+ cell-selected transplant and 121 who received an unmodified transplant. Owing to significant differences in disease characteristics, the analysis was limited to patients with <10% blasts before HSCT (n = 145). Two groups were defined: low risk, with low- and intermediate-risk cytogenetics (CD34+, n = 39; unmodified, n = 46), and high risk: poor and very poor risk cytogenetics (CD34+, n = 19; unmodified, n = 41). In the low-risk group, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) at 1 year post-transplantation was 18% in the CD34+ subgroup versus 41.3% in the unmodified subgroup (P = .015). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of chronic graft-versus-host disease (cGVHD) at 3 years in the 2 subgroups was 5.3% and 56%, respectively (P < .001). At 3 years post-transplantation, relapse, overall survival (OS), and relapse-free survival (RFS) were similar in the CD34+ and unmodified subgroups: 8.1% versus 19.4% (P = .187), 58.5% versus 53.7% (P = .51), and 59.5% versus 52.4% (P = .448). However, the composite outcome combining extensive cGVHD-free status and relapse-free status (CRFS) at 3 years was 59.5% in the CD34+ group versus 19.2% in the unmodified group (P < .001). In the high-risk group, grade II-IV aGVHD at 1 year was 31.6% in the CD34+ subgroup versus 24.4% in the unmodified subgroup (P = .752). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of cGVHD at 3 years in the 2 subgroups was 0% versus 27.6% (P = .013). At 3 years post-transplantation, relapse, OS, RFS, and CRFS in the 2 subgroups were 31.6% versus 69.3% (P = .007), 35.5% versus 14.5% (P = .068), 31.6% versus 10.7% (P = .045), and 31.6% versus 6.1% (P = .001), respectively. Cytogenetic abnormalities at diagnosis and transplant type had significant univariate associations with RFS in the high-risk cohort. Only cytogenetics (P = .03) remained associated with this outcome in a multivariate model. OS was similar in the 2 transplant groups; however, CRFS was superior in the CD34+ cell-selected transplant group.
Assuntos
Antígenos CD34/sangue , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes Mielodisplásicas/terapia , Adulto , Idoso , Aloenxertos/citologia , Aberrações Cromossômicas , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Recidiva , Medição de Risco , Análise de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged <60 years and 4000 µmol/min for patients aged >59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Aloenxertos , Clofarabina , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Irradiação Corporal Total , Adulto JovemRESUMO
Delayed engraftment is a major limitation of cord blood transplantation (CBT), due in part to a defect in the cord blood (CB) cells' ability to home to the bone marrow. Because this defect appears related to low levels of fucosylation of cell surface molecules that are responsible for binding to P- and E-selectins constitutively expressed by the marrow microvasculature, and thus for marrow homing, we conducted a first-in-humans clinical trial to correct this deficiency. Patients with high-risk hematologic malignancies received myeloablative therapy followed by transplantation with 2 CB units, one of which was treated ex vivo for 30 minutes with the enzyme fucosyltransferase-VI and guanosine diphosphate fucose to enhance the interaction of CD34(+) stem and early progenitor cells with microvessels. The results of enforced fucosylation for 22 patients enrolled in the trial were then compared with those for 31 historical controls who had undergone double unmanipulated CBT. The median time to neutrophil engraftment was 17 days (range, 12-34 days) compared with 26 days (range, 11-48 days) for controls (P = .0023). Platelet engraftment was also improved: median was 35 days (range, 18-100 days) compared with 45 days (range, 27-120 days) for controls (P = .0520). These findings support ex vivo fucosylation of multipotent CD34(+) CB cells as a clinically feasible means to improve engraftment efficiency in the double CBT setting. The trial is registered to www.clinicaltrials.gov as #NCT01471067.
Assuntos
Plaquetas/citologia , Sangue Fetal/citologia , Fucose/metabolismo , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Neutrófilos/transplante , Adolescente , Adulto , Idoso , Plaquetas/imunologia , Estudos de Coortes , Selectina E/metabolismo , Estudos de Viabilidade , Feminino , Sangue Fetal/imunologia , Fucosiltransferases/metabolismo , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Células-Tronco Hematopoéticas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Neutrófilos/imunologia , Selectina-P/metabolismo , Transfusão de Plaquetas , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
Our aim was to improve outcome prediction after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia by combining cytogenetic and molecular data at diagnosis with minimal residual disease assessment by multicolor flow-cytometry at transplantation. Patients with acute myeloid leukemia in first complete remission in whom minimal residual disease was assessed at transplantation were included and categorized according to the European LeukemiaNet classification. The primary outcome was 1-year relapse incidence after transplantation. Of 152 patients eligible, 48 had minimal residual disease at the time of their transplant. Minimal residual disease-positive patients were older, required more therapy to achieve first remission, were more likely to have incomplete recovery of blood counts and had more adverse risk features by cytogenetics. Relapse incidence at 1 year was higher in patients with minimal residual disease (32.6% versus 14.4%, P=0.002). Leukemia-free survival (43.6% versus 64%, P=0.007) and overall survival (48.8% versus 66.9%, P=0.008) rates were also inferior in patients with minimal residual disease. In multivariable analysis, minimal residual disease status at transplantation independently predicted 1-year relapse incidence, identifying a subgroup of intermediate-risk patients, according to the European LeukemiaNet classification, with a particularly poor outcome. Assessment of minimal residual disease at transplantation in combination with cytogenetic and molecular findings provides powerful independent prognostic information in acute myeloid leukemia, lending support to the incorporation of minimal residual disease detection to refine risk stratification and develop a more individualized approach during hematopoietic stem cell transplantation.