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3.
Cancer ; 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38809547

RESUMEN

BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes. METHODS: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m2 and anthracyclines during induction/consolidation. RESULTS: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486). CONCLUSION: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower.

4.
Blood Adv ; 8(12): 3237-3245, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38607399

RESUMEN

ABSTRACT: The introduction of posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy-based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.


Asunto(s)
Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Trasplante Haploidéntico , Humanos , Persona de Mediana Edad , Adulto , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/mortalidad , Masculino , Femenino , Adolescente , Anciano , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto Joven , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología , Trasplante Haploidéntico/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Ciclofosfamida/uso terapéutico
5.
Oncotarget ; 15: 220-231, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38484153

RESUMEN

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.


Asunto(s)
Busulfano , Leucemia Mieloide Aguda , Sulfonamidas , Vidarabina/análogos & derivados , Humanos , Busulfano/farmacología , Tiotepa/uso terapéutico , Cladribina/farmacología , Leucemia Mieloide Aguda/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Combinación de Medicamentos , Línea Celular Tumoral , Apoptosis
6.
Bone Marrow Transplant ; 59(6): 832-837, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38443706

RESUMEN

Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.


Asunto(s)
Rechazo de Injerto , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Aloinjertos , Masculino , Femenino , Adulto , Quimera por Trasplante , Trasplante Homólogo/métodos
7.
Clin Lymphoma Myeloma Leuk ; 24(5): e196-e204, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38403505

RESUMEN

BACKGROUND: Maintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results. MATERIALS AND METHODS: We conducted a single center retrospective matched-control analysis with the study group (5-azacitidine [AZA] group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression. RESULTS: The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04). CONCLUSION: AZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset.


Asunto(s)
Antimetabolitos Antineoplásicos , Azacitidina , Leucemia Mieloide Aguda , Quimioterapia de Mantención , Síndromes Mielodisplásicos , Azacitidina/administración & dosificación , Progresión de la Enfermedad , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Antimetabolitos Antineoplásicos/administración & dosificación , Estudios Retrospectivos , Estudios de Casos y Controles , Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Trasplante de Células Madre Hematopoyéticas , Quimioterapia de Mantención/métodos , Quimioterapia de Mantención/normas , Supervivencia sin Progresión , Resultado del Tratamiento
9.
Am J Hematol ; 99(4): 562-569, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38314663

RESUMEN

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.


Asunto(s)
Benzoatos , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Hidrazinas , Pirazoles , Humanos , Trasplante de Médula Ósea/efectos adversos , Estudios Prospectivos , Trasplante de Células Madre Hematopoyéticas/métodos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Estudios Retrospectivos
10.
Am J Hematol ; 99(5): 836-843, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38400519

RESUMEN

Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Inotuzumab Ozogamicina , Estudios Prospectivos , Recurrencia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Alquilantes , Acondicionamiento Pretrasplante/métodos
11.
Nat Med ; 30(3): 772-784, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38238616

RESUMEN

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neoplasias , Receptores Quiméricos de Antígenos , Animales , Ratones , Humanos , Receptores Quiméricos de Antígenos/genética , Interleucina-15 , Células Asesinas Naturales , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19 , Proteínas Adaptadoras Transductoras de Señales
12.
Blood Adv ; 8(5): 1128-1136, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38266155

RESUMEN

ABSTRACT: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Among patients aged 18 to 25 years, disease risk index (DRI; 31% with high/very high DRI vs 12% low/intermediate DRI; P = .03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1; P = .03) were the strongest predictors of VOD. Incidence of VOD in patients aged >25 years of age consistently ranged between 3% and 5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase, alanine aminotransferase) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared with those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors of VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Enfermedades Vasculares , Humanos , Adolescente , Adulto , Anciano , Estudios Retrospectivos , Incidencia , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Factores de Riesgo , Ciclofosfamida/efectos adversos , Enfermedades Vasculares/etiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/complicaciones
13.
Am J Phys Med Rehabil ; 103(8): 710-715, 2024 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-38207179

RESUMEN

INTRODUCTION: Physical rehabilitation is increasingly incorporated throughout the allogeneic hematopoietic stem cell transplant journey for older adults. OBJECTIVE: This study aimed to describe physical medicine and rehabilitation-related diagnoses, exercise barriers, and management recommendations for older adults before allogeneic hematopoietic stem cell transplant. DESIGN: Fifty physical medicine and rehabilitation consults as part of the Enhanced Recovery-Stem Cell Transplant multidisciplinary prehabilitation program at a comprehensive cancer center were retrospectively reviewed. RESULTS: Many physical medicine and rehabilitation-related diagnoses (173), exercise barriers (55), and management recommendations (112) were found. Common diagnoses were musculoskeletal dysfunction (more commonly back, shoulder, then knee) ( n = 39, 23%) and fatigue ( n = 36, 21%). Common exercise barriers were also musculoskeletal dysfunction (more commonly back, knee, then shoulder) (total n = 20, 36%) and fatigue ( n = 20, 36%). Most patients ( n = 32, 64%) had one or more exercise barriers. Common physical medicine and rehabilitation management recommendations were personalized exercise counseling ( n = 37, 33%), personalized nutrition management ( n = 19, 17%), body composition recommendations ( n = 17, 15%), medications ( n = 15, 13%), and orthotics and durable medical equipment ( n = 8, 7%). CONCLUSIONS: Routine physical medicine and rehabilitation referral of older allogeneic hematopoietic stem cell transplant patients for prehabilitation resulted in the identification of many rehabilitative needs and substantial additional management recommendations. Increased early, collaborative prehabilitation efforts between physical medicine and rehabilitation and allogeneic hematopoietic stem cell transplant teams to optimize care for these patients is recommended.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Femenino , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Cuidados Preoperatorios/métodos , Trasplante Homólogo , Medicina Física y Rehabilitación , Ejercicio Preoperatorio , Grupo de Atención al Paciente , Atención Ambulatoria
14.
BMC Cancer ; 23(1): 1258, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38124057

RESUMEN

BACKGROUND: There is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). METHODS: Patients aged 0-39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed. RESULTS: Two hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6-39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03). Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0-196.6) months after ASCT, and SPM was the cause of death in five (50%) of them. CONCLUSIONS: CAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/terapia , Linfoma no Hodgkin/terapia , Trasplante de Células Madre/efectos adversos , Trasplante Autólogo , Resultado del Tratamiento
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