RESUMO
Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 10(6) in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8(+) TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4(+) and CD8(+) TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4(+)/CD8(+) TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Memória Imunológica , Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Linfócitos T/transplante , Adulto , Idoso , Antígenos CD19/metabolismo , Contagem de Células , Terapia Combinada/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células B/imunologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Autólogo , Adulto JovemRESUMO
Current conditioning regimens provide insufficient disease control in relapsed/refractory acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with active disease. Intensification of chemotherapy and/or total body irradiation (TBI) is not feasible because of excessive toxicity. Total marrow and lymphoid irradiation (TMLI) allows for precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement, while sparing normal tissue. We conducted a phase I trial in 51 patients (age range, 16 to 57 years) with relapsed/refractory acute leukemia undergoing HSCT (matched related, matched unrelated, or 1-allele mismatched unrelated) with active disease, combining escalating doses of TMLI (range, 1200 to 2000 cGy) with cyclophosphamide (CY) and etoposide (VP16). The maximum tolerated dose was declared at 2000 cGy, as TMLI simulation studies indicated that >2000 cGy might deliver doses toxic for normal organs at or exceeding those delivered by standard TBI. The post-transplantation nonrelapse mortality (NRM) rate was only 3.9% (95% confidence interval [CI], .7 to 12.0) at day +100 and 8.1% (95% CI, 2.5 to 18.0) at 1 year. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 43.1% (95% CI, 29.2 to 56.3) and for grade III and IV, it was 13.7% (95% CI, 6.9 to 27.3). The day +30 complete remission rate for all patients was 88% and was 100% for those treated at 2000 cGy. The overall 1-year survival was 55.5% (95% CI, 40.7 to 68.1). The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy with a low 100-day and 1-year NRM rate and no increased risk of GVHD with higher doses of radiation.
Assuntos
Medula Óssea/efeitos da radiação , Leucemia/terapia , Irradiação Linfática , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta à Radiação , Etoposídeo/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Terapia de Salvação/métodos , Análise de Sobrevida , Adulto JovemRESUMO
Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus-based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non-T-carriers were associated with higher blood levels (P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were associated with higher blood levels than CYP3A5*1/*1 (P = .002). By multivariable analysis, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were independently associated with decreased acute GVHD compared with CYP3A5*1/*1, after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM.
Assuntos
Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/uso terapêutico , Farmacogenética/métodos , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adolescente , Adulto , Idoso , Criança , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Adulto JovemRESUMO
The occurrence of additional cytogenetic abnormalities (ACAs) is common in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but is of unknown significance in the tyrosine kinase inhibitor (TKI) era. We retrospectively analyzed data from a consecutive case series of adults with Ph+ ALL who had undergone allogeneic hematopoietic cell transplantation (alloHCT) at City of Hope between 2003 and 2014. Among 130 adults with Ph+ ALL who had TKI therapy before alloHCT, 78 patients had available data on conventional cytogenetics at diagnosis and were eligible for outcomes analysis. ACAs were observed in 41 patients (53%). There were no statistically significant differences in median age, median initial WBC count, post-HCT TKI maintenance, or disease status at the time of transplant between the Ph-only and ACA cohorts; however, the Ph-only cohort had a higher rate of minimal residual disease positivity at the time of HCT. Three-year leukemia-free survival (79.8% versus 39.5%, P = .01) and 3-year overall survival (83% versus 45.6%, P = .02) were superior in the Ph-only cohort compared with the ACA cohort, respectively. Monosomy 7 was the most common additional aberration observed in our ACA cohort (n = 12). Thus, when TKI therapy and alloHCT are used as part of adult Ph+ ALL therapy, the presence of ACAs appears to have a significant deleterious effect on outcomes post-HCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Risco , Irmãos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Doadores não RelacionadosRESUMO
This multicenter prospective phase II study examines the activity and tolerability of brentuximab vedotin as second-line therapy in patients with Hodgkin lymphoma that was relapsed or refractory after induction therapy. Brentuximab vedotin (1.8 mg/kg) was administered i.v. on day 1 of a 21-day cycle for a total of 4 cycles. Patients then proceeded to autologous hematopoietic cell transplantation (AHCT), if eligible, with or without additional salvage therapy, based on remission status after brentuximab vedotin. The primary endpoint was overall response rate (ORR). Secondary endpoints were safety, stem cell mobilization/collection, AHCT outcomes, and association of CD68(+) with outcomes. Of 37 patients, the ORR was 68% (13 complete remission, 12 partial remission). The regimen was well tolerated with few grade 3/4 adverse events, including lymphopenia (1), neutropenia (3), rash (2), and hyperuricemia (1). Thirty-two patients (86%) were able to proceed to AHCT, with 24 patients (65%) in complete remission at time of AHCT. Thirteen patients in complete remission, 4 in partial remission, and 1 with stable disease (49%) received AHCT without salvage combination chemotherapy. CD68 expression did not correlate with response to brentuximab vedotin. The median number of stem cells mobilized was 6.0 × 10(6) (range, 2.6 to 34), and median number of days to obtain minimum collection (2 × 10(6)) was 2 (range, 1 to 6). Brentuximab vedotin as second-line therapy is active, well tolerated, and allows adequate stem cell collection and engraftment. For Hodgkin lymphoma patients with relapsed/refractory disease after induction therapy, second-line brentuximab vedotin, followed by combination chemotherapy for residual disease, can effectively bridge patients to AHCT.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Imunoconjugados/administração & dosagem , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin , Criança , Esquema de Medicação , Feminino , Mobilização de Células-Tronco Hematopoéticas , Doença de Hodgkin/imunologia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Hiperuricemia/etiologia , Hiperuricemia/patologia , Imunoconjugados/efeitos adversos , Linfopenia/etiologia , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/patologia , Estudos Prospectivos , Recidiva , Indução de Remissão , Terapia de Salvação , Análise de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1-14 along with 375 mg/m(2) of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.
Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/efeitos adversos , Antineoplásicos/efeitos adversos , Progressão da Doença , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Injeções Intravenosas , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Linfopenia/induzido quimicamente , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Rituximab , Análise de Sobrevida , Trombose/induzido quimicamente , Trombose/patologia , VorinostatRESUMO
We previously reported that brentuximab vedotin (BV) enabled successful reduced-intensity allogeneic hematopoietic cell transplantation (RIC-alloHCT) in patients with relapsed Hodgkin lymphoma, after a median follow-up of 14.4 months. We now provide an updated report on 21 patients who were treated from 2009 to 2012 with BV before RIC-alloHCT with a uniform fludarabine/melphalan conditioning regimen and donor source after a median follow-up of 29.9 months. We have also retrospectively compared the patient characteristics and outcomes of these BV-pretreated patients to 23 patients who received fludarabine/melphalan RIC-alloHCT without prior BV, in the time period before the drug was available (2003 to 2009). Patients who were treated with BV before RIC-alloHCT had a lower median hematopoietic cell transplantation-specific comorbidity index and a reduced number of peri-transplantation toxicities. There were also improvements in 2-year progression-free survival (59.3% versus 26.1%) and cumulative incidence of relapse/progression (23.8% versus 56.5%).
Assuntos
Doença de Hodgkin/terapia , Imunoconjugados/uso terapêutico , Adulto , Brentuximab Vedotin , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante , Adulto JovemRESUMO
Brentuximab vedotin induces an overall response rate of 75% in patients with relapsed/refractory Hodgkin lymphoma, but its impact on future allogeneic transplantation (allo-HCT) is not known. We retrospectively examined the records of 18 patients with relapsed/refractory Hodgkin lymphoma who were treated on brentuximab vedotin clinical trials to evaluate the efficacy and safety of subsequent reduced-intensity allo-HCT. Seventeen patients had previous autologous transplant; 6 were in complete remission, and 8 were in partial remission before allo-HCT with 12 grafts from unrelated or mismatched donors. The 1-year overall survival was 100%, progression-free survival was 92.3%, and nonrelapse mortality was 0% (median follow-up, 14 months). The incidence of acute GVHD was 27.8% and chronic GVHD was 56.3%. Brentuximab vedotin before reduced-intensity allo-HCT does not appear to adversely affect engraftment, GVHD, or survival and may provide sufficient disease control to enable reduced-intensity allo-HCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/terapia , Imunoconjugados/uso terapêutico , Adulto , Brentuximab Vedotin , Contagem de Células , Resistencia a Medicamentos Antineoplásicos/fisiologia , Células-Tronco Hematopoéticas/citologia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
Posttransplantation thrombotic microangiopathy (TMA) is a multifactorial complication of allogeneic hematopoietic cell transplantation (allo-HCT) whose incidence is increased with the use of a sirolimus plus tacrolimus (SIR/TAC) regimen for acute graft-versus-host disease (aGVHD) prophylaxis. We evaluated the incidence and possible risk factors for TMA in a case series of 177 patients who received allo-HCT using SIR/TAC-based GVHD prophylaxis. The patients received either a sibling donor graft (n = 82) or a matched unrelated donor graft (n = 95). Within the first 100 days post-HCT, 30 patients (17%) were diagnosed with TMA, and an additional 9 patients (5%) were classified as probable TMA cases. The median time to onset of TMA was 4.6 weeks (range, 1.6-10.6 weeks). Thirty-four patients developed both TMA and aGVHD, with the majority (81%) developing aGVHD first. Multivariate analysis identified the following factors as associated with increased risk of TMA: day 14 serum sirolimus level ≥9.9 ng/mL (hazard ratio [HR], 2.19; 95% confidence interval [CI], 1.13-4.27; P = .02), presence of previous aGVHD grade II-IV (HR, 3.04; 95% CI, 1.38-6.71; P < .01), and fully myeloablative conditioning (HR, 3.47; 95% CI, 1.60-7.53; P < .01). These risk factors for TMA suggest that when using a SIR/TAC regimen for GVHD prophylaxis, careful monitoring and adjustment of the sirolimus dosage is critical, particularly in patients with active aGVHD.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Sirolimo/efeitos adversos , Tacrolimo/efeitos adversos , Microangiopatias Trombóticas/etiologia , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagem , Microangiopatias Trombóticas/induzido quimicamente , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Recent studies demonstrate an increased risk of second primary malignancies (SPMs) in patients with multiple myeloma (MM) receiving maintenance lenalidomide after autologous stem cell transplantation (ASCT). We explored the possibility of other risk factors driving post-ASCT SPMs in patients with MM through analysis of our large transplantation database in conjunction with our Long-Term Follow-Up Program. We conducted a retrospective cohort study of 841 consecutive patients with MM who underwent ASCT at City of Hope between 1989 and 2009, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during, and after ASCT. Median duration of follow-up for the entire cohort was 3.4 years (range, 0.3-19.9 years). Sixty cases with a total of 70 SPMs were identified. The overall cumulative incidence of SPMs was 7.4% at 5 years and 15.9% at 10 years when nonmelanoma skin cancers (NMSCs) were included and 5.3% at 5 years and 11.2% at 10 years when NMSCs were excluded. Multivariate analysis of the entire cohort revealed associations of both older age (≥55 years; relative risk, 2.3; P < .004) and race (non-Hispanic white; relative risk, 2.4; P = .01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend toward increased risk (odds ratio, 3.5; P = .15); however, an insufficient number of patients were treated with lenalidomide to allow us to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables but was accompanied by loss of statistical significance. This large single-institution analysis identified associations between race and older age and increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that might not be restricted to lenalidomide.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mieloma Múltiplo/cirurgia , Segunda Neoplasia Primária/etiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Autólogo/efeitos adversos , Adulto JovemRESUMO
We analysed the long-term outcomes of 60 multiple myeloma patients who underwent reduced intensity allogeneic stem cell transplantation between August 2000 and March 2008. Regimens included fludarabine and melphalan conditioning (flu-mel regimen) for allogeneic haematopoietic cell transplant (HCT) or a planned tandem regimen consisting of high-dose melphalan conditioning for autograft followed by low-dose total body irradiation conditioning for allogeneic HCT (auto-allo regimen). Donors included human-leucocyte-antigen-matched siblings (n = 55) or matched unrelated donors (n = 5). With a median follow-up of 9·8 years, 7-year overall survival (OS) and progression-free survival (PFS) were 60% and 31%, respectively. By multivariate Cox regression analysis, disease status of complete response (CR) or partial response (PR) at transplant and the presence of chronic graft-versus-host disease were significantly associated with improved OS. Only disease status was significantly associated with improved PFS. We noted a surprising number of very late relapses, with six patients (10%) relapsing between 6 and 12 years post-transplant. Among the six late relapse patients, all were transplanted within 14 months of diagnosis, five had normal karyotypes, and five were in CR/PR. Our data provide additional evidence that, while survival may be extended by reduced intensity allogeneic transplant, ultimately, it may not offer a cure.
Assuntos
Mieloma Múltiplo/cirurgia , Transplante de Células-Tronco de Sangue Periférico/estatística & dados numéricos , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea/estatística & dados numéricos , Terapia Combinada , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Doadores Vivos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Modelos de Riscos Proporcionais , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Irradiação Corporal TotalRESUMO
This phase 1/2 study assessed the augmentation of reduced-intensity conditioning (RIC) with total marrow and lymph node irradiation (TMLI), for peripheral blood stem cell transplantation, in patients with advanced hematologic disease. The regimen consisted of fludarabine 25 mg/m(2) per day for 5 days, melphalan 140 mg/m(2) for one day, and TMLI radiation at 150 cGy/fraction in 8 fractions over 4 days. Eligible patients were over 50 years old and/or had compromised organ function. Median age of the 33 evaluable patients was 55.2 years. Eighteen events of nonhematologic grade III or higher toxicities occurred in 9 patients. Day 30 and day 100 mortalities were 3% and 15%, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 days after transplantation. Long-term toxicities occurred in 2 patients: hypokalemia and tremor, both grade III, on days 370 and 361 after transplantation. Fourteen patients died, 7 of relapse-related causes and 7 of non-relapse-related causes. With a median follow-up for living patients of 14.7 months, 1-year overall survival, event-free survival, and non-relapse-related mortality were 75%, 65%, and 19%, respectively. Addition of TMLI to RIC is feasible and safe and could be offered to patients with advanced hematologic malignancies who might not otherwise be candidates for RIC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/efeitos da radiação , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Linfonodos/efeitos da radiação , Transplante de Células-Tronco de Sangue Periférico , Adolescente , Adulto , Idoso , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Criança , Estudos de Viabilidade , Feminino , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/patologia , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Taxa de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto JovemRESUMO
PURPOSE: A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II. RESULTS: The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22-72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05-0.48; P = 0.001). CONCLUSIONS: Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD. See related commentary by El Marabti and Abdel-Wahab, p. 694.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Receptores de Antígenos Quiméricos , Humanos , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Linfócitos T/imunologia , Linfoma de Células B/tratamento farmacológico , Antígenos CD19/imunologiaRESUMO
We conducted a matched-cohort analysis of autologous transplant conditioning regimens for diffuse large cell lymphoma in 92 patients treated with either radioimmunotherapy (RIT) or total body irradiation (TBI)-based conditioning regimens. The RIT regimen consisted of 0.4 mCi/kg of (90)Y-ibritumomab tiuxetan plus BEAM (BCNU, etoposide, cytarabine, melphalan). The TBI-based regimen combined fractionated TBI at 1200 cGy, with etoposide and cyclophosphamide. Five factors were matched between 46 patient pairs: age at transplant ±5 years, disease status at salvage, number of prior regimens, year of diagnosis ±5 years, and year of transplantation ±5 years. Patients in the TBI group had higher rates of cardiac toxicity and mucositis, whereas Z-BEAM patients had a higher incidence of pulmonary toxicity. Overall survival at 4 years was 81.0% for the Z-BEAM and 52.7% for the TBI group (P = .01). The 4-year cumulative incidence of relapse/progression was 40.4% and 42.1% for Z-BEAM and TBI, respectively (P = .63). Nonrelapse mortality was superior in the Z-BEAM group: 0% compared with 15.8% for TBI at 4 years (P < .01). Our data demonstrate that RIT-based conditioning had a similar relapse incidence to TBI, with lower toxicity, resulting in improved overall survival, particularly in patients with ≥2 prior regimens.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Difuso de Grandes Células B/terapia , Radioimunoterapia/métodos , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total/métodos , Adulto , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , Estudos de Coortes , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/radioterapia , Linfoma Difuso de Grandes Células B/cirurgia , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/uso terapêutico , Rituximab , Terapia de Salvação/métodos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Irradiação Corporal Total/efeitos adversos , Adulto JovemRESUMO
We report feasibility and response results of a phase II study investigating prolonged weekly bortezomib and dexamethasone followed by thalidomide and dexamethasone as maintenance therapy after single autologous stem cell transplantation (ASCT) in patients with multiple myeloma. Within 4 to 8 weeks of ASCT, patients received weekly bortezomib and dexamethasone for six cycles, followed by thalidomide and dexamethasone for six more cycles. Thalidomide alone was continued until disease progression. Forty-five patients underwent ASCT. Forty patients started maintenance therapy; of these, 36 patients received four cycles, and 32 completed six cycles of maintenance bortezomib. Of these 40 patients, nine (22%) were in complete response (CR) before ASCT, 13 (32%) achieved CR after ASCT but before bortezomib maintenance therapy, and 21 (53%) achieved CR after bortezomib maintenance therapy. Nine patients not previously in CR (33%) upgraded their response to CR with bortezomib maintenance. At 1 year post-ASCT, 20 patients achieved CR, and two achieved very good partial response. Twenty-seven patients experienced peripheral neuropathy during bortezomib therapy, all grade 1 or 2. Our findings indicate that prolonged sequential weekly bortezomib, dexamethasone, and thalidomide maintenance therapy after single ASCT is feasible and well tolerated. Bortezomib maintenance treatment upgraded post-ASCT CR responses with no severe grade 3/4 peripheral neuropathy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: Acute lymphoblastic leukemia (ALL) is a heterogeneous disease, for which treatment guidelines are still evolving. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapeutic modality for ALL, and this review describes the recent studies and current practice patterns concerning the who, when, and how of allo-HCT in the management of ALL. RECENT FINDINGS: Allogeneic stem cell transplantation is the treatment of choice for patients with ALL after first relapse and is also recommended for high-risk patients in first complete remission (CR1). Minimal residual disease evaluation and monitoring is developing as an important prognostic factor and could guide physicians in determining which patients, especially those with standard risk, might require transplant. Tyrosine kinase inhibitor (TKI) therapy allows a much higher proportion of Philadelphia-chromosome-positive ALL patients to attain remission and proceed to transplant with improved results; posttransplant TKI maintenance therapy may also provide survival benefit. Reduced-intensity conditioning regimens are a reasonable alternative for patients who would otherwise be ineligible for transplant because of age or comorbidity. SUMMARY: For patients with high-risk features, there is general agreement that allo-HCT in CR1 is a potentially curative option; however, there is no consensus on early transplant for standard-risk patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doença Aguda , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Agonistas Mieloablativos/uso terapêutico , Neoplasia Residual , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Transplante HomólogoRESUMO
The controversy surrounding private banking of umbilical cord blood units (CBU), as a safeguard against future malignancy or other life-threatening conditions, raises many questions in pediatric clinical practice. Recent favorable experiences with autologous transplantation for severe aplastic anemia using privately stored CBU, suggested a possible utility. While private banking is difficult to justify statistically or empirically, there may exist rare cases where autologous transplant of stored umbilical CBU could be beneficial. The reality of privately banked CBU and the possibility for future discovery of additional indications for autologous cord blood transplant, motivated us to re-examine our attitudes towards private cord blood banking.
Assuntos
Anemia Aplástica/terapia , Bancos de Sangue/provisão & distribuição , Sangue Fetal , Transplante de Células-Tronco Hematopoéticas , Privatização/estatística & dados numéricos , Humanos , Transplante AutólogoRESUMO
BACKGROUND: Transplant-associated thrombotic microangiopathy (TMA) syndromes are reported to occur with increased frequency in transplant patients treated with siroliumus combined with a calcineurin inhibitor. We performed a retrospective study of all pediatric transplant patients at City of Hope who were administered combined tacrolimus/sirolimus (TAC/SIR) to determine the occurrence of TMA. PROCEDURE: This analysis includes 41 consecutive patients between the ages of 2 and 20 (median age 9.1) who received an allogeneic hematopoietic stem cell transplant from any source and also received TAC/SIR for prevention or treatment of GVHD. Of those 41 patients, 20 received TAC/SIR as GVHD prohpylaxis and were designated the preventative group (PG), while 21 received TAC/SIR as treatment for GVHD and were designated the therapy group (TG). TMA occurrence in both groups was documented from day -1 of transplant to day 60 for the PG, and until 30 days after last dose for the TG. TMA was defined according to 2005 consensus criteria. RESULTS: Five of twenty patients in the PG, and five of twenty one in the TG, experienced TMA, with an overall rate of 23.8% for the population. All ten patients with TMA showed elevated levels of TAC, SIR or both and nine of ten suffered from organ injury due to regimen-related toxicity or GVHD. CONCLUSION: Physicians should exercise caution in the use of TAC/SIR in pediatric patients due to a high rate of TMA. It is not recommended for heavily pre-treated patients and peak levels of TAC/SIR must be very carefully controlled.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/efeitos adversos , Sirolimo/efeitos adversos , Tacrolimo/efeitos adversos , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Imunossupressores/administração & dosagem , Masculino , Estudos Retrospectivos , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagem , Fatores de Tempo , Transplante HomólogoRESUMO
Lymphomas with central nervous system (CNS) involvement confer a worse prognosis than those without CNS involvement, and patients currently have limited treatment options. T cells genetically engineered with CD19-targeted chimeric antigen receptors (CAR) are effective against B-cell malignancies and show tremendous potential in the treatment of systemic lymphoma. We aimed to leverage this strategy toward a more effective therapy for patients with lymphoma with CNS disease. NOD-scid IL2Rgammanull (NSG) mice with CNS and/or systemic lymphoma were treated with CD19-CAR T cells via intracerebroventricular (ICV) or intravenous (IV) injection. CAR T cells isolated after treatment were rigorously examined for phenotype, gene expression, and function. We observed that CAR T cells infused ICV, but not IV, completely and durably eradicated both CNS and systemic lymphoma. CAR T cells delivered ICV migrated efficiently to the periphery, homed to systemic tumors, and expanded in vivo, leading to complete elimination of disease and resistance to tumor rechallenge. Mechanistic studies indicated that ICV-delivered CAR T cells are conditioned by exposure to cerebrospinal fluid in the ICV environment for superior antilymphoma activity and memory function compared with IV-delivered CAR T cells. Further analysis suggested that manipulating cellular metabolism or preactivating therapeutic CAR T cells with antigen ex vivo may improve the efficacy of CAR T cells in vivo Our demonstration that ICV-delivered CD19-CAR T cells had activity against CNS and systemic lymphoma could offer a valuable new strategy for treatment of B-cell malignancies with CNS involvement.
Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia Adotiva/métodos , Linfoma/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/metabolismo , Animais , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Injeções Intravenosas , Injeções Intraventriculares , Linfoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.