RESUMEN
Haploidentical hematopoietic cell transplantation (HCT) using glucocorticoids for acute graft-versus-host disease prophylaxis (GC-haplo) may become a curative treatment option for nonremission acute myeloid leukemia (AML). This retrospective study aimed to identify pre-HCT predictors of survival in a cohort of 97 nonremission AML treated with GC-haplo in Hyogo Medical University Hospital between 2010 and 2020. Relapse and primary induction failure included in 70 (72%) and 27 (28%) patients, respectively. Sixty-one patients (63%) had undergone previous HCT. Multivariate analysis revealed that ≤ 6 months' duration between first complete remission (CR1) and first relapse (Rel1) (CR1-Rel1 interval) (hazard ratio 2.11, 95% confidence interval [CI] 1.15-3.89, P = 0.016) and serum albumin before starting the conditioning treatment of ≤ 3.5 g/dL (hazard ratio 1.80, 95%CI 1.09-2.96, P = 0.022) as risk factors for overall survival. Among three groups categorized according to serum albumin and CR1-Rel1 interval, the best 3-year overall survival was observed in patients with albumin > 3.5 g/dL and CR1-Rel1 interval > 6 months or primary induction failure (50.2%, 95%CI 28.9%-68.3%, P < 0.001), revealing that survival could be predicted using albumin and past CR duration in patients with very high-risk AML not in remission before GC-haplo.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Trasplante Haploidéntico/efectos adversos , Estudios Retrospectivos , Inducción de Remisión , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Recurrencia , Albúmina Sérica , Esteroides/uso terapéutico , Acondicionamiento PretrasplanteRESUMEN
Hematopoietic cell transplantation (HCT) for hematologic malignancies with non-remission disease and/or prior post-transplant relapse have poor relapse-free survival. We previously demonstrated the efficacy of haploidentical reduced-intensity HCT regimen with glucocorticoid-based graft-versus-host disease (GVHD) prophylaxis. We recently showed a possible association between rabbit antithymocyte globulin (rATG) exposure and acute GVHD (aGVHD) risk, leading to hypothesize that optimization of rATG exposure may further improve this regimen. We retrospectively examined the exposure-response association of rATG and key clinical outcomes post haploidentical HCT. We subsequently developed an individualized rATG dosing that optimizes rATG exposure using a previously developed population pharmacokinetic model. Of the 103 patients analyzed, the median age was 47 years (range: 17-70) and majority had a non-remission disease prior to HCT (88%). rATG concentration on day 0 of HCT (Cday_0 ) was the strongest predictor of Grade 2-4 aGVHD through day +100. Patients with Cday_0 ≥ 20 µg/mL had an approximately 3-fold lower risk of Grade 2-4 aGVHD (hazard ratio [HR]: 0.32, 95% confidence interval [CI]: 0.16, 0.62) and Grade 3-4 aGVHD (HR: 0.33, 95% CI: 0.16, 0.68) as well as an approximately 2-fold lower risk of overall mortality (HR: 0.47, 95% CI: 0.28, 0.77) and relapse (HR: 0.50, 95% CI: 0.26, 0.94). In conclusion, this reduced-intensity haploidentical HCT regimen with exposure-optimized rATG may provide a promising option to patients undergoing high-risk HCT for hematologic malignancy. The developed rATG dosing warrant prospective validation.
Asunto(s)
Suero Antilinfocítico , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Persona de Mediana Edad , Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Adolescente , Adulto Joven , AncianoRESUMEN
Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.
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Immune reconstitution after human leukocyte antigen (HLA)-mismatched (haploidentical) hematopoietic stem cell transplantation (haplo-HCT) can significantly influence long-term outcomes. The three possible HLA haplotypes after transplantation are: one carried by both the patient and the donor (shared HLA), one by donor only (donor-specific HLA), and one by patient only (host-specific HLA), and the donor T cells remain restricted to one of these three haplotypes. Understanding the presence of donor T cells restricted to each haplotype may provide more detailed insights into post-transplant immune response and potentially provide valuable information for the development of chimeric antigen receptor T cell or T cell receptor T cell constructs. In this study, patients or donors with HLA-A24 or HLA-A2 were tested with HLA-A*24:02- and A*02:01-restricted cytomegalovirus (CMV)-specific tetramers for detecting the respective HLA-restricted T cells. Sixty-four samples from 40 patients were assayed. More than half of the patients at day 90 and all patients by day 900 had shared HLA-restricted T cells. After day 90, half of the patients had donor-specific HLA-restricted T cells, but no host-specific HLA-restricted T cells were found. In the comparative analysis of the transplant types, shared HLA-restricted T cells were positive in all three categories: haplo-HCT (50%), 2-haplo-mis-HCT (75%), and spousal HCT (67%). Furthermore, donor-specific HLA-restricted T cells demonstrated positivity in haplo-HCT at 57% and in 2-haplo-mis-HCT at 60%, with a threshold of 0.01%. Donor-specific HLA-restricted T cells for spousal HCT were not examined due to the lack of an appropriate HLA combination for the tetramers. The presence of shared HLA-restricted T cells explains the host defense after HLA-haploidentical transplantation, while the presence of donor-specific HLA-restricted T cells may account for host defense against hematotropic viruses, such as CMV. However, this study failed to detect host-specific HLA-restricted T cells, leaving the host defense against epitheliotropic viruses unresolved, thus requiring further investigation.
RESUMEN
In HLA haploidentical stem cell transplantation, patients and donors usually share one HLA haplotype and have one different HLA haplotype (hetero-to-hetero). However, there are rare cases of transplantation from HLA homozygous donors to heterozygous recipients (homo-to-hetero), resulting in mismatches only in the graft-versus-host direction. We previously reported that homo-to-hetero transplants have a lower survival rate in a mouse model than hetero-to-hetero transplants due to stronger graft-versus-host disease (GVHD) but inferior graft-versus-leukemia effect. To examine whether homo-to-hetero transplant effects also occur in humans, we retrospectively compared the results of 59 homo-to-hetero and 4,539 hetero-to-hetero cases in the Japanese transplant registry data. The results showed no statistical difference between the homo-to-hetero and hetero-to-hetero groups in the cumulative incidences of neutrophil engraftment (83.1% vs 89.0%), acute GVHD II-IV (36.8% vs 38.8%), III-IV (16.8% vs 17.4%), chronic GVHD (32.7% vs 30.7%), relapse (52.9% vs 49.0%), and non-relapse mortality (31.6% vs 28.2%). In contrast, overall survival was significantly lower in the homo-to-hetero group than in the hetero-to-hetero group (12.6% vs 26.2%, p = 0.0308). The inferior effect of homo-to-hetero transplantation on overall survival remained significant in multivariate analyses.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Humanos , Estudios Retrospectivos , Trasplante Haploidéntico/efectos adversos , Tasa de Supervivencia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a currative treatment modality for diffuse large B-cell lymphoma (DLBCL) because of the intrinsic graft-versus-lymphoma effect. However, limited information is available regarding which patients with relapsed or refractory DLBCL are likely to benefit from allo-HSCT. We retrospectively analyzed data from 1268 DLBCL patients who received allo-HSCT. The overall survival and progression-free survival (PFS) rates were 30.3% and 21.6% at 3 years, respectively. Multivariate analysis revealed that stable or progressive disease at transplantation, male patient, poorer performance status at transplantation, and shorter intervals from previous transplantation were associated independently with a lower PFS. Four prognostic factors were used to construct a prognostic index for PFS, predicting 3-year PFS of 55.4%, 43.7%, 20.4% and 6.6%, respectively. The prognostic model predicted relapse rates following allo-HSCT accordingly (P < 0.0001), whereas did not predict transplantation-related mortality (P = 0.249). The prognostic index can identify a subgroup of DLBCL patients who benefit from allo-HSCT and it is worthwhile to evaluate whether this model is also applicable to patients undergoing allo-HSCT in cases of relapse after chimeric antigen receptor engineered T-cell therapy, although the application of allo-HSCT has been declining with the increase of novel immunotherapies.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Humanos , Masculino , Estudios Retrospectivos , Recurrencia Local de Neoplasia/terapia , Linfoma de Células B Grandes Difuso/terapia , RecurrenciaRESUMEN
Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Enfermedad Injerto contra Huésped/etiología , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Recurrencia Local de Neoplasia , Factores de Riesgo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
Prognosis for patients undergoing hematopoietic cell transplantation (HCT) has been improving. Short-term survival information, such as crude survival rates that consider deaths immediately after the transplantation, may not be sufficiently useful for assessing long-term survival. Using the data of the Japanese HCT registry, the net survival rate of patients who survived for a given period was determined according to age, disease, and type of transplant. We included a total of 41,716 patients who received their first allogeneic hematopoietic cell transplantation between 1991 and 2015. For each disease, age group, graft source subcategory, net survival was calculated using the Pohar-Perme method, and 5-year conditional net survival (CS) was calculated. Ten-year net survivals of total patient cohort were 41.5% and 47.4% for males and females, respectively. Except for myelodysplastic syndrome, multiple myeloma, and adult T-cell leukemia/lymphoma, 5-year CS for 5-year transplant survivors exceeded 90%. CS was especially high for aplastic anemia, of which was over 100% for children and younger adults receiving cord blood, suggesting that these patients have similar longevity to an equivalent group from the general population. These findings provide useful information for long-term survival, and can serve as benchmark for comparisons among registries, including other cancers.
RESUMEN
Background: Human T-cell leukemia virus type I (HTLV-1) is a retrovirus known to cause adult T-cell leukemia/lymphoma (ATL). There are few reports on hematopoietic stem cell transplantation (HSCT) for HTLV-1 carriers with diseases other than ATL. Methods: A total of 25,839 patients (24,399 adults and 1440 children) with pre-transplant HTLV-1 serostatus information recorded in the Japanese National Survey Database who had undergone their first HSCT were analyzed. We investigated the overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT in relation to HTLV-1 serologic status. Findings: Three hundred and forty-eight patients were HTLV-1 antibody carriers. The number of HTLV-1 carriers and noncarriers among adult patients who received allogeneic HSCT (allo-HSCT) or autologous HSCT (auto-HSCT) was 237/15,777 and 95/8920, respectively, and was 16/1424 among pediatric patients who received allo-HSCT. No pediatric HTLV-1 carrier recipients undergoing auto-HSCT were identified. There were no significant differences between HTLV-1 carriers and non-carriers regarding stem cell source, disease risk, or HCT-CI score prior to allo-HSCT. Multivariate analysis of OS (P = 0.020) and TRM (P = 0.017) in adult patients showed that HTLV-1 positive status was a significant prognostic factor. In children, TRM was significantly higher (P = 0.019), but OS was not significantly different. In adult patients who underwent auto-HSCT, HTLV-1 positive status was not a significant prognostic factor. In adult allo-HSCT patients, cytomegalovirus reactivation was significantly more common in HTLV-1 carriers (P = 0.001). Interpretation: HTLV-1 antibody positivity was shown to have a poor prognosis in OS and TRM after allo-HSCT in adult patients and in TRM after allo-HSCT in pediatric patients. Funding: This work was supported in part by the practical research programs of the Japan Agency for Medical Research and Development (AMED) under grant number 17ck0106342h0001.