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Graft versus tumor relies on tumor-associated antigens (TAAs) that are presented to donor T cells via human leukocyte antigens (HLAs). The HLA evolutionary divergence (HED) between alleles of a single individual can dictate the ability to present TAAs. The impact of HED in haploidentical donor transplantation (HIDT) has not been studied. We studied the effect of HED on transplant outcomes following HIDT. We analyzed 322 consecutive recipient/donor pairs with a median follow-up of 57.2 months. Pairwise divergence of HLA class I and II showed that HLA-B, -DRB1, and -DQB1 contributing most to mean HED. The mean HED was class I 6.85 (HLA-A 7.08, -B 8.24, and -C 5.07), class II 8.58 (HLA-DRB1 10.97, -DQB1 10.06 and -DPB1 4.06). A high HED in class I mismatched recipient/donor haplotype (RD MM) was significant for worse DFS (HR 1.11, p = 0.020), and relapse (HR 1.11, p = 0.02). Also, a high HED in RD MM HLA-B haplotype had worse OS (HR 1.07, p = 0.02), DFS (HR 1.09, p = 0.002), higher relapse (HR 1.10, p = 0.003), and similar NRM to low HED. The multivariate analysis showed that high HED in RD MM HLA-B (≥7.8 vs <7.8) had worse DFS (HR 1.53, p = 0.01), higher relapse (HR 1.61, p = 0.024), and similar NRM and OS.
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Following conventional graft-versus-host disease (GVHD) prophylaxis, the development of acute and/or chronic GVHD is associated with lower relapse rates. However, the effects of GVHD on relapse and non-relapse mortality following post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis have not been well studied. To this end, we analyzed the impact of acute and chronic GVHD following PTCy-based haploidentical donor transplantation (HIDT). The analysis included 335 consecutive HIDT recipients transplanted at a single institution between 2005 and 2021. Landmark analysis (LA) and time-dependent multivariable analysis (MVA) were utilized to study the impact of GVHD development on transplant outcome. Landmarks were defined as Day +100 for acute GVHD and one-year for chronic GVHD. Recipient characteristics included a median age of 50 (19-80) years, most commonly transplanted for acute leukemia[/MDS [242]. PBSC was the graft source in 81%, and regimen intensity was myeloablative in 49%. Median follow-up was 65 (23-207) months. In landmark analysis, development of grade 3 to 4 acute GVHD (versus 0-1) was associated with inferior 3-year overall survival (OS 47% versus 64%, P = .041), due to higher NRM (25% versus 10%, P = .013). In contrast, development of grade 2 acute GVHD had no significant effect on NRM or survival. When restricted to acute leukemia/MDS patients, development of grade II acute GVHD was associated with improved OS (79% versus 58%, P = .027) and a trend towards lower relapse (24% versus 36%, P = .08). Development of moderate-to-severe chronic GVHD resulted in significantly higher NRM (15% versus 4%, P = .010), but had no impact on relapse, DFS or OS. In Cox multivariate analysis (MVA), grade 3 to 4 acute GVHD and moderate-to-severe chronic GVHD were both associated with significantly higher NRM (HR 3.38, P < .001 and HR3.35, P < .001, respectively). In addition, grade 3 to 4 acute GVHD predicted worse OS (HR 1.80, P = .007) and DFS (HR 1.55, P = .041). In contrast, relapse was not impacted by acute or chronic GVHD in MVA. Grade 2 acute GVHD was not associated with transplant outcome in MVA. In summary, both grade 3 to 4 acute and moderate-to-severe chronic GVHD were associated with higher NRM after PTCy-based HIDT, without an effect on relapse risk. Methods of early identification of such patients in order to augment GVHD prophylaxis are clearly needed.
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The presence of an HLA-DPB1 nonpermissive mismatch (NPMM) by the TCE-3 model has been associated with improved survival following haploidentical donor transplantation (HIDT) using post-transplantation cyclophosphamide (PTCy). With the development of a revised model (TCE-Core) that further separates TCE-3 "group 3" alleles into "core" (C) and "noncore" (NC) alleles, a formerly permissive mismatch (PMM) resulting from group 3 alleles in both donor and recipient is now considered a C-NPMM if 1 or more of those alleles is NC. We aimed to study the additional effect of HLA-DPB1 C-NPMM according to the TCE-Core algorithm, as well as the directional vector of the mismatch, on outcomes following HIDT. To this end, we analyzed 242 consecutive HIDT recipients with acute leukemia or myelodysplastic syndrome who underwent transplantation between 2005 and 2021 (median age, 51 years; range, 19 to 80 years). The median follow-up was 62 months (range, 23 to 199 months). Of the 136 HIDTs classified as PMM by TCE-3, 73 were reclassified as a C-NPMM by the TCE-Core algorithm, of which 36 were in the graft-versus host (GVH) vector (37 were host-versus-graft [HVG] only). Given comparable survival between conventional NPMM and C-NPMM, GVH/bidirectional were analyzed together (nonpermissive). HVG-only C-NPMM were combined with HLA-DPB1-matched and PMM (permissive) because of similar outcomes. The presence of a TCE-Core-defined nonpermissive HLA-DP mismatch resulted in superior 5-year overall survival (OS) (66% versus 47%) and disease-free survival (DFS) (60% versus 43%). Compared to the conventional TCE-3 algorithm, TCE-Core identified a higher percentage of nonpermissive transplants (38% versus 23%) and better discriminated outcomes between nonpermissive and permissive status, with a larger difference in survival outcomes using TCE-Core compared to TCE-3 (OS Δ, 18.3% versus 12.7%; DFS Δ, 16.5% versus 8.5%). In multivariable analysis (MVA), a nonpermissive TCE-Core mismatch led to improved OS (hazard ratio [HR], .54; P = .003) and DFS (HR, .62; P = .013), largely due to decreased relapse risk (HR, .63; P = .049). In contrast, nonrelapse mortality (NRM) and graft-versus-host disease (GVHD) outcomes were not significantly impacted. In summary, the presence of nonpermissive TCE-Core HLA-DP mismatch strongly predicts survival following PTCy-based HIDT, owing to a reduction in relapse risk without a corresponding increase in GVHD or NRM. As a donor selection tool, TCE-Core appears to better discriminate HIDT outcomes while at the same time identifying a larger percentage of the potential donor pool.
Assuntos
Recidiva , Transplante Haploidêntico , Humanos , Pessoa de Meia-Idade , Adulto , Feminino , Masculino , Idoso , Adulto Jovem , Cadeias beta de HLA-DP/genética , Cadeias beta de HLA-DP/metabolismo , Idoso de 80 Anos ou mais , Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/mortalidade , Alelos , Doença Enxerto-Hospedeiro/imunologiaRESUMO
The development of chronic graft-versus-host disease (GVHD) in 1-year survivors after matched related or unrelated hematopoietic cell transplantation was shown to be associated with higher nonrelapse mortality (NRM) and worse overall survival (OS). The impact of chronic GVHD requiring immunosuppression (IS) for recipients of haploidentical transplantation (HIDT) with post-transplantation cyclophosphamide (PTCy) who have survived to 1 year post-transplantation has not been studied previously and was investigated for this analysis. A total of 322 adult patients who underwent HIDT at our center were included in this study. The effect of IS-free status on post-transplantation outcomes was assessed. The median follow-up for survivors was 63.9 months (range, 18.3 to 165 months). A total of 163 patients (65%) were IS-free at 1 year post-HIDT. Baseline characteristics of this group were similar to those of patients still requiring IS, except for higher percentages of female donor-male recipient pairs (28% versus 15%; P =.03) and female donors (48% versus 30%; P =.008). Logistic regression to identify patients more likely to be on IS at 1 year post-HIDT identified the use of a female donor as a significant risk factor (odds ratio, 2.11; P = .009). In a Cox regression analysis, patients requiring IS at 1 year post-transplantation had higher NRM (hazard ratio [HR], 4.18; 95% confidence interval [CI], 1.80 to 6.72; P < .001) and showed a trend toward worse disease-free survival (DFS) (HR, 1.59; 95% CI, .95 to 2.66; P =.08), with no impact on OS (HR, 1.44; 95% CI, .90 to 2.31; P = .13) or relapse (HR, .77; 95% CI, .37 to 1.61; P = .49). These results indicate that use of a female donor is a significant risk factor for requiring IS at 1 year post-HIDT. Additionally, chronic GVHD requiring IS at 1-year post-HIDT no significant effect on relapse but is associated with higher NRM and a trend toward worse DFS.
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Ciclofosfamida , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Imunossupressores , Transplante Haploidêntico , Humanos , Ciclofosfamida/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Adulto , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Adulto Jovem , Adolescente , Idoso , Fatores de Risco , Estudos Retrospectivos , Seguimentos , Terapia de Imunossupressão/métodosRESUMO
Identifying plasma biomarkers early after allo-HCT may become crucial to prevent and treat severe aGvHD. We utilized samples from 203 allo-HCT patients selected from the Blood & Marrow Transplant Clinical Trials Network (BMT CTN) to identify new biomarker models to predict aGvHD and overall mortality. Two new biomarkers (Gal-3 and LAG-3), and previously identified biomarkers (ST2/IL33R, IL6, Reg3A, PD-1, TIM-3, TNFR1) were screened. Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population [AUC: 0.602; P = 0.045] while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning [P = 0.028] but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD [159.1 ng/mL vs 222.0 ng/mL; P = 0.046]. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4). In conclusion, the combination of Gal-3 alone or in combination with LAG-3, and PD-1 is a new informative model to predict aGvHD development and overall non-relapse mortality after allo-HCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Galectina 3 , Receptor Celular 2 do Vírus da Hepatite A , Receptor de Morte Celular Programada 1 , Proteína 1 Semelhante a Receptor de Interleucina-1 , Receptores Tipo I de Fatores de Necrose Tumoral , Biomarcadores , Bancos de Espécimes BiológicosRESUMO
Acute myeloid leukemia (AML), an aggressive malignancy with unmet medical need, lacks immunotherapeutic options. CD123, the cellular receptor for interleukin-3, expressed in AML is an attractive target for tumor-specific therapy. Vibecotamab (XmAb14045), a humanized bispecific antibody, monovalently binds both CD3 and CD123 to recruit cytotoxic T cells to kill CD123+ tumor cells. This phase 1 study's primary objectives were safety and tolerability and identification of a maximum tolerated dose/recommended dose for use as monotherapy in patients with relapsed/refractory AML. Identification of a recommended phase 2 vibecotamab dose comprised 3 step-up doses (Week 1), which were noted to reduce cytokine response syndrome (CRS), followed by weekly dosing (1.7 µg/kg, Cohort -1D). In 16 of 120 patients, at least 1 treatment-emergent adverse event was classified as a dose-limiting toxicity. CRS, the most common adverse event (59.2%), managed with premedication, were mostly ≤grade 2. A secondary objective was assessment of efficacy in patients with CD123-expressing leukemias. A total of 10 of 111 (9.0%) efficacy-evaluable patients with AML achieved an overall response of morphologic leukemia-free state or better with an overall objective response rate (ORR) of 9.0%. Response was only observed in patients receiving a target dose of 0.75 µg/kg or higher (n = 87) in which the efficacy-evaluable ORR was 11.5%. Response was associated with lower baseline blast counts in blood and bone marrow (<25%) suggesting potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT02730312.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Subunidade alfa de Receptor de Interleucina-3 , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doenças Mieloproliferativas-Mielodisplásicas , Neoplasias , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Esplenomegalia , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida , Doadores não Relacionados , Doença Aguda , Recidiva , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/terapia , América do Norte , Condicionamento Pré-Transplante/métodosRESUMO
Allogeneic transplant remains the best postremission therapy for patients with nonfavorable risk acute myeloid leukemia (AML). However, some patients are ineligible because of psychosocial barriers, such as lack of appropriate caregiver support. We hypothesized that immune checkpoint inhibition after autologous transplant might represent effective postremission therapy in such patients. We conducted a phase 2 study of autologous transplantation followed by administration of pembrolizumab (8 cycles starting day +1). Twenty patients with nonfavorable AML in complete remission were treated (median age, 64 years; CR1, 80%); 55% were non-White and adverse-risk AML was present in 40%. Treatment was well tolerated, with only 1 nonrelapse death. Immune-related adverse events occurred in 9 patients. After a median follow-up of 80 months, 14 patients remain alive, with 10 patients in continuous remission. The estimated 2-year LFS was 48.4%, which met the primary end point of 2-year LFS >25%; the 2-year overall survival (OS), nonrelapse mortality, and cumulative incidences of relapse were 68%, 5%, and 46%, respectively. In comparison with a propensity score-matched cohort group of patients with AML receiving allogeneic transplant, the 3-year OS was similar (73% vs 76%). Patients in the study had inferior LFS (51% vs 75%) but superior postrelapse survival (45% vs 14%). In conclusion, programmed cell death protein-1 blockade after autologous transplant is a safe and effective alternative postremission strategy in patients with nonfavorable risk AML who are ineligible for allogeneic transplant, a context in which there is significant unmet need. This trial was registered at www.clinicaltrials.gov as #NCT02771197.
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Leucemia Mieloide Aguda , Receptor de Morte Celular Programada 1 , Humanos , Pessoa de Meia-Idade , Transplante Autólogo , Leucemia Mieloide Aguda/terapia , Indução de Remissão , Transplante HomólogoRESUMO
To develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.
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Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Humanos , Estados Unidos , Pessoa de Meia-Idade , Prognóstico , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/terapia , Transplante Homólogo , Doadores não Relacionados , Doença Crônica , RecidivaRESUMO
Few patients with nonfavorable risk (NFR) acute leukemia and myeloid dysplasia syndrome (AL/MDS) undergo allogeneic transplantation (HCT). We assessed whether this could be improved by integrating HCT/leukemia care and the use of haploidentical donors. Of 256 consecutive patients aged <75 years who received initial therapy at our center for NFR AL/MDS from 2016 to 2021, 147 (57%) underwent planned HCT (70% for patients aged <60 years). In the logistic regression analysis, age (OR 1.50 per 10-year increment; P < .001) and race (Black vs White [OR 2.05; P = .023]) were significant factors for failure to receive HCT. Reasons for no HCT included comorbidities (37%), poor KPS, lack of caregiver support, refractory malignancy (19% each), and patient refusal (17%). Lack of donor or insurance were rarely cited (3% each). In older patients (≥60 years), comorbidities (49 vs 15%; P < .001) and KPS (25% vs 10%; P = .06) were more common, and lack of caregivers was less common (13% vs 30%; P = .031). In Black vs White patients, lack of caregivers (37% vs 11%; P = .002) was more frequent. The median time from initial treatment to HCT was 118 days and was similar for Black and White patients. Landmark analysis showed that HCT within 6 months of the initial treatment produced better survival. Multivariable analysis showed that HCT resulted in a significant survival benefit (HR 0.60; P = .020). With the above approach, most of the currently treated patients aged <75 years can access planned HCT. Black patients remain at greater risk of not receiving HCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Idoso , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/patologia , Leucemia Mieloide Aguda/patologia , Transplante Homólogo , Síndromes Mielodisplásicas/terapiaRESUMO
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for blood or marrow transplantation (BMT). In this collaboration across North America, we retrospectively analyzed outcomes of first BMT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN), an otherwise incurable hematological neoplasm. We included 120 patients, 38% of non-White/Caucasian ethnicity, across 15 centers with median age at BMT 62.5 years. The median follow-up is 2.4 years. Graft failure was reported in 6% patients. At 3-years, nonrelapse mortality (NRM) was 25%, relapse 27%, grade 3-4 acute graft versus host disease (GVHD) 12%, chronic GVHD requiring systemic immunosuppression 14%, progression-free survival (PFS) 48% and overall survival (OS) 56%. On multivariable analysis, statistically significant associations included older age at BMT (per decade increment) with NRM (sdHR 3.28, 95%CI 1.30-8.25), PFS (HR 1.98, 95% 1.13-3.45) and OS (HR 2.01, 95% CI 1.11-3.63), presence of mutation in EZH2/RUNX1/SETBP1 with relapse (sdHR 2.61, 95%CI 1.06-6.44), and splenomegaly at BMT/prior splenectomy with OS (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for BMT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Disease-related factors including splenomegaly and high-risk mutations dominate outcomes following BMT.
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Early autologous hematopoietic cell transplantation (AHCT) with post-transplant maintenance therapy is standard of care in multiple myeloma (MM). While short-term quality of life (QOL) deterioration after AHCT is known, the long-term trajectories and symptom burden after transplantation are largely unknown. Toward this goal, a secondary analysis of QOL data of the BMT CTN 0702, a randomized controlled trial comparing outcomes of three treatment interventions after a single AHCT (N = 758), was conducted. FACT-BMT scores up to 4 years post-AHCT were analyzed. Symptom burden was studied using responses to 17 individual symptoms dichotomized as 'none/mild' for scores 0-2 and 'moderate/severe' for scores of 3 or 4. Patients with no moderate/severe symptom ratings were considered to have low symptom burden at 1-year. Mean age at enrollment was 55.5 years with 17% African Americans. Median follow-up was 6 years (range, 0.4-8.5 years). FACT-BMT scores improved between enrollment and 1-year and remained stable thereafter. Low symptom burden was reported by 27% of patients at baseline, 38% at 1-year, and 32% at 4 years post-AHCT. Predictors of low symptom burden at 1-year included low symptom burden at baseline: OR 2.7 (1.8-4.1), p < 0.0001; older age: OR 2.1 (1.3-3.2), p = 0.0007; and was related to being employed: OR 2.1 (1.4-3.2), p = 0.0004). We conclude that MM survivors who achieve disease control after AHCT have excellent recovery of FACT-BMT and subscale scores to population norms by 1-year post-transplant, though many patients continue to report moderate to severe severity in some symptoms at 1-year and beyond.
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Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Qualidade de Vida , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante AutólogoRESUMO
Steroid refractory acute graft-versus-host disease (SR aGvHD) is a major limitation of successful allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal photopheresis (ECP) has been used to treat SR aGvHD effectively and with low treatment related toxicity. In this study, we retrospectively analyzed the outcomes of 103 Steroid Refractory aGvHD (SR aGvHD) patients to identify factors associated with improved outcomes including the use of ECP. A total of 79 patients received ECP as part of their SR aGVHD treatment compared to 24 patients who did not. Both groups had similar aGVHD grade and maximum organ stage at onset of aGVHD and treatment initiation. Patients in the group that received ECP had better OS (p = 0.01), DFS (p = 0.008), lower relapse (p = 0.05) and similar NRM compared to the group that did not receive ECP. Patients that received ECP treatment also had shorter hospital stays in the first 180 days after onset of SR aGvHD (20 vs. 38 days, p = 0.03). Multivariable analysis for OS indicated patient CMV status (CMV+ versus CMV-, HR 2.34, CI 1.16-4.69), regimen intensity (Myelo vs. non-Myeloablative, HR 0.39, CI 0.20-0.75), and the use of ECP (ECP vs. no ECP, HR 0.39, CI 0.20-0.75) were associated with OS. In summary, the use of ECP in the treatment of SR aGvHD results in improved overall survival secondary to lower relapse rates compared to other therapeutic modalities that do not incorporate ECP.
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Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Fotoferese , Humanos , Estudos Retrospectivos , Fotoferese/métodos , Doença Aguda , Recidiva Local de Neoplasia/tratamento farmacológico , Esteroides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Crônica , Infecções por Citomegalovirus/tratamento farmacológicoRESUMO
The role of NK cell alloreactivity on outcomes after T cell-replete haploidentical donor transplantation (HIDT) remains uncertain. After transplantation, newly formed NK cells are licensed through interactions of donor inhibitory KIR (iKIR) and NKG2A receptors with their cognate ligands on recipient cells. Donor NKG2A recognizes HLA-E bound by recipient HLA class I leader peptides, a process requiring methionine (M) at position -21 of the leader sequence. An rs1050458C/T dimorphism results in approximately 40% of individuals expressing at least one copy of -21M HLA-B (M/M or M/T [M+]), allowing ligand expression. We assessed the impact of recipient HLA-B-leader genotype (M+ versus M- [T/T]) and HLA-C-group iKIR missing ligand (ML, C1C1/C2C2 versus C1C2) on relapse and disease-free survival (DFS) in recipients of post-transplantation cyclophosphamide (PTCy)-based HIDT. Based on preclinical data, we hypothesized that the relative impact of each variable may depend on disease lineage (lymphoid versus myeloid). To this end, we analyzed outcomes of 322 consecutive PTCy-based HIDT recipients with hematologic malignancy who underwent transplantation at a single institution using standardized supportive care measures with mature follow-up (median 45 months). Primary endpoints were relapse and DFS of patients based on HLA-B-leader genotype and HLA-C-group iKIR ML. Planned subgroup analysis included patient with lymphoid versus myeloid malignancy. M+ HLA-B-leader genotype and HLA-C-group iKIR ML were seen in 42% and 49% of recipients, respectively. The presence of a recipient M+ B-leader (versus M-) improved overall survival (OS) and DFS and lowered cumulative incidence of relapse (CIR), an effect primarily seen in lymphoid malignancies (80% versus 51%, 72% versus 41%, 16% versus 42%, respectively). In contrast, myeloid malignancy patients benefited most from HLA-C-group iKIR ML with better OS and DFS and lower CIR (67% versus 51%, 64% versus 44%, 25% versus 45%, respectively). Multivariate analysis confirmed the disease-specific associations of improved relapse/DFS with M+ HLA-B-leader in lymphoid malignancy (hazard ratio [HR] 0.20, P < .001/HR 0.34, P <.001) and HLA-C-group iKIR ML in myeloid malignancy (HR 0.44, P = .004/HR 0.54, P = .009). Neither HLA-B-leader nor iKIR ML was associated with the incidence of non-relapse mortality or acute or chronic graft-versus-host disease. Two distinct NK cell education pathways predict relapse and DFS after HIDT-PTCy in a disease-specific manner: the presence of recipient M+ HLA-B-leader genotype improves outcome in patients with lymphoid malignancies, whereas HLA-C-group iKIR ML improves outcome in patients with myeloid malignancies. These findings strengthen the essential role of NK cells for optimal GVL in the context of HIDT-PTCy and may suggest different approaches to improving transplant outcome depending on disease type.
Assuntos
Antígenos HLA-B , Antígenos HLA-C , Recidiva Local de Neoplasia , Transplante Haploidêntico , Ciclofosfamida/uso terapêutico , Genótipo , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Humanos , Ligantes , Recidiva Local de Neoplasia/diagnóstico , Receptores KIRRESUMO
Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine, and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was the day 100 complete response rate. Sixty-five patients with a median (range) age of 59 (40-69) years underwent transplantation from 2015 to 2020. Other characteristics included Karnofsky performance status <80%, hematopoietic cell transplantation-comorbidity index ≥3, International Staging System III, and high-risk fluorescein in situ hybridization (FISH) in 35%, 46%, 26%, and 44%, respectively. ASCT after BeEAM was well tolerated, and there were no non-relapse deaths through 1 year after transplantation. Although at least 1 nonhematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. The day 100 response rate was ≥CR1 and ≥ very good partial response (VGPR1) in 40% and 89%, respectively. With a median follow-up of 44 (13-70) months, the 3-year overall survival was 92%, 96%, and 90% for all patients and those with standard- and high-risk FISH, respectively. The corresponding values for 3-year progression-free survival was 57%, 72%, and 40%, respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen before up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan in the front-line setting may be warranted.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Cloridrato de Bendamustina/uso terapêutico , Citarabina/uso terapêutico , Quimioterapia Combinada/efeitos adversos , Etoposídeo/uso terapêutico , Humanos , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia , Transplante AutólogoRESUMO
Bortezomib-based triplet regimens-specifically bortezomib, lenalidomide, and dexamethasone (VRD) and bortezomib, cyclophosphamide, and dexamethasone (VCD)-are the 2 most common induction regimens used in transplantation-eligible patients with newly diagnosed multiple myeloma (NDMM), with conflicting data on comparative efficacy and outcomes in this population. We compared long-term outcomes of patients with NDMM receiving VRD induction and those receiving VCD induction prior to autologous stem cell transplantation (ASCT). Patients registered with the Center for International Blood and Marrow Transplant Registry were included if they had undergone ASCT for MM within 6 months of diagnosis between January 2013 and December 2018, received VRD or VCD induction, and achieved a pretransplantation partial or better response. Of 1135 patients, 914 received VRD and 221 received VCD. The patients receiving VCD were more likely to have renal impairment and International Staging System (ISS) stage III disease and less likely to receive full-dose melphalan (200 mg/m2) conditioning (69% versus 80%; P < .001). Very good partial response rates pretransplantation, post-transplantation, and at best response were not significantly different in the 2 groups. Maintenance use was more common after VRD induction (88% versus 76%; P < .001), with lenalidomide the most common agent (80% versus 63%). Patients in the VRD group had a higher rate of renal recovery (74% versus 43%; P < .001), possibly due to a rapid reduction of light chains in the VRD group or improvement in renal function with VCD, which allowed a switch over to VRD, as patients who switched were classified in the VRD group. Patients receiving VRD had better survival on univariate analysis, with a median progression-free survival (PFS) from transplantation of 44.6 months versus 34.1 months (P = .004) and median 5-year overall survival (OS) of 79% versus 60% (P < .001). Multivariate analysis showed no significant survival difference, with a hazard ratio for VCD versus VRD induction of 1.22 (95% CI, 0.96 to 1.55; P = .10) for PFS and 1.33 (95% CI, 0.93 to 1.92, P = .12) for OS. Maintenance use was independently associated with superior PFS and OS, along with ISS stage, cytogenetics, and pretransplantation response (PFS only). In patients with MM undergoing upfront ASCT after VRD or VCD induction, no independent survival difference was seen based on the induction therapy received after adjusting for other prognostic factors. The use of maintenance treatment was uniformly associated with superior outcomes. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Quimioterapia de Indução , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Transplante AutólogoRESUMO
The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLA-matched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P ≤ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P ≤ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (≤18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Sangue Fetal , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Irmãos , Doadores não RelacionadosRESUMO
We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41-74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6-75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59-81), 44% (95% CI 29-59), and 30% (95% CI 17-43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14-34) and 31% (95% CI 17-47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02-20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68-14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3-4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14-70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study.