RESUMO
Severe aplastic anemia (SAA) is a marrow failure disorder with high morbidity and mortality. It is treated with bone marrow transplantation (BMT) for those with fully matched donors, or immunosuppressive therapy (IST) for those who lack such a donor, which is often the case for underrepresented minorities. We conducted a prospective phase 2 trial of reduced-intensity conditioning HLA-haploidentical BMT and posttransplantation cyclophosphamide (PTCy)-based graft-versus-host (GVHD) prophylaxis as initial therapy for patients with SAA. The median patient age was 25 years (range, 3-63 years), and the median follow-up time was 40.9 months (95% confidence interval [CI], 29.4-55.7). More than 35% of enrollment was from underrepresented racial/ethnic groups. The cumulative incidence of grade 2 or 4 acute GVHD on day 100 was 7% (95% CI, not applicable [NA]-17), and chronic GVHD at 2 years was 4% (95% CI, NA-11). The overall survival of 27 patients was 92% (95% CI, 83-100) at 1, 2, and 3 years. The first 7 patients received lower dose total body irradiation (200 vs 400 cGy), but these patients were more likely to have graft failure (3 of 7) compared with 0 of 20 patients in the higher dose group (P = .01; Fisher exact test). HLA-haploidentical BMT with PTCy using 400 cGy total body irradiation resulted in 100% overall survival with minimal GVHD in 20 consecutive patients. Not only does this approach avoid any adverse ramifications of IST and its low failure-free survival, but the use of haploidentical donors also expands access to BMT across all populations. This trial was registered at www.clinicaltrials.gov as NCT02833805.
Assuntos
Anemia Aplástica , Doença Enxerto-Hospedeiro , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Transplante de Medula Óssea/efeitos adversos , Estudos Prospectivos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Ciclofosfamida/uso terapêuticoRESUMO
Plasmablastic lymphoma (PBL) is a rare entity, commonly associated with immunosuppressed states such as human immunodeficiency virus (HIV) infection or solid organ transplant. The clinical course is characterized by high relapse rates and a poor prognosis, leading some clinicians to recommend aggressive frontline therapy. However, a specific review of limited stage (LS) PBL patients is not available to evaluate outcomes and justify treatment recommendations. We performed a retrospective review of LS PBL cases to provide insight into this rare disease. Our cohort consisted of 80 stage I or II PBL patients from 13 US academic centers. With a median follow up of 34 months (1-196), the 3-year progression-free survival (PFS) and overall survival (OS) of the entire cohort were 72% (95% CI 62, 83) and 79% (95% CI 70, 89), respectively. The 3-year PFS and OS of patients treated with frontline chemotherapy alone was 65% (95% CI 50, 84) and 71% (95% CI 56, 89), respectively, compared to 85% (95% CI 72, 100) and 96% (95% CI 89, 100), respectively, in patients treated with combined frontline chemotherapy with radiation consolidation. Our data demonstrate favorable outcomes in LS PBL with no improvements in outcome from aggressive frontline treatment including Hyper-CVAD or auto-SCT consolidation. Multivariate regression analysis (MRA) demonstrated improved PFS for patients receiving EPOCH based frontline therapy versus CHOP (HR: 0.23; p = 0.029). Frontline chemotherapy followed by radiation consolidation versus chemotherapy alone appeared to be associated with improved relapse and survival outcomes but did not show statistical significance in MRA.
Assuntos
Infecções por HIV , Linfoma Plasmablástico , Humanos , Linfoma Plasmablástico/terapia , Linfoma Plasmablástico/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de Progressão , Infecções por HIV/tratamento farmacológico , PrognósticoRESUMO
New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.
Assuntos
Brentuximab Vedotin , Lenalidomida , Linfoma Difuso de Grandes Células B , Brentuximab Vedotin/efeitos adversos , Humanos , Imunoconjugados/efeitos adversos , Lenalidomida/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do TratamentoRESUMO
Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor-induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating idelalisib-induced Grade ≥3 irAEs with improved efficacy.
Assuntos
Colite , Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Linfoma Folicular , Linfoma não Hodgkin , Colite/induzido quimicamente , Colite/tratamento farmacológico , Diarreia/induzido quimicamente , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma Folicular/tratamento farmacológico , Linfoma não Hodgkin/patologia , Purinas , Quinazolinonas/efeitos adversosRESUMO
BACKGROUND: Idelalisib is a phosphatidylinositol 3-kinase δ inhibitor approved for relapsed/refractory follicular lymphoma, a type of indolent non-Hodgkin lymphoma (iNHL), and chronic lymphocytic leukemia (CLL). Idelalisib-triggered adverse events (AEs) may be managed with treatment interruption and/or dose reduction, potentially extending therapy duration and increasing the likelihood of continued response. PATIENTS AND METHODS: Post hoc analyses were conducted to evaluate clinical outcomes after AE-induced idelalisib interruption for 125 patients with iNHL and 283 with CLL. RESULTS: Progression-free survival (PFS) was longer for patients with iNHL who experienced ≥ 2 interruptions versus those with 0 interruptions who discontinued idelalisib or study because of AEs (hazard ratio 0.33; P = .0212). Both PFS and overall survival were longer for patients with CLL with ≥ 2 interruptions versus 0 interruptions in those who discontinued therapy because of an AE (hazard ratio PFS 0.50, overall survival 0.41; P < .005). Clinical benefits persisted for patients with CLL who experienced treatment interruption after receiving idelalisib for ≥ 6 months. Supplementing interruption with dose reduction did not worsen clinical outcomes. However, time off therapy of ≥ 8% may diminish the clinical benefit of treatment interruption. CONCLUSION: Idelalisib interruption and dose reduction were associated with enhanced clinical outcomes for patients with relapsed/refractory iNHL or CLL who experienced an AE, supporting this management strategy when indicated.
Assuntos
Antineoplásicos/efeitos adversos , Redução da Medicação/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Purinas/efeitos adversos , Quinazolinonas/efeitos adversos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos RetrospectivosRESUMO
The phase 2 study of idelalisib monotherapy for indolent non-Hodgkin lymphomas (iNHLs) was completed in 2018; final efficacy and safety data with up to 6.7 years long-term follow-up are reported. Patients with iNHL refractory to both rituximab and an alkylating agent were enrolled and received 150 mg idelalisib twice daily (N = 125). Idelalisib resulted in an overall response rate of 57.6% with 34.4% continuing therapy for ≥12 months. The median progression-free survival and duration of response were 11.0 and 11.8 months for follicular lymphoma, 22.2 and 20.4 months for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM), and 6.6 and 18.4 months for marginal zone lymphoma (MZL). Median overall survival after extended follow-up was 48.6 (95% CI 33.9, 71.7) months. Long-term follow-up did not reveal new safety concerns. These data indicate beneficial outcomes with longer follow-up after idelalisib for treatment of iNHL including in patients with LPL/WM and MZL.
Assuntos
Linfoma não Hodgkin , Quinazolinonas , Protocolos de Quimioterapia Combinada Antineoplásica , Seguimentos , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Purinas/efeitos adversos , Quinazolinonas/efeitos adversos , Rituximab/efeitos adversosRESUMO
For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.
Assuntos
Doença de Hodgkin , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Doença de Hodgkin/tratamento farmacológico , Humanos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Projetos Piloto , Transplante Autólogo , Resultado do TratamentoRESUMO
With post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, nonmyeloablative (NMA) HLA-haploidentical (haplo) and HLA-matched blood or marrow transplantation (BMT) have comparable outcomes. Previous reports have shown that discontinuation of immunosuppression (IS) as early as day 60 after infusion of a bone marrow (BM) haplo allograft with PTCy is feasible. There are certain diseases in which peripheral blood (PB) may be favored over BM, but given the higher rates of GVHD with PB, excessive GVHD is of increased concern. We report a completed, prospective single-center trial of stopping IS at days 90 and 60 after NMA PB stem cell transplantation (PBSCT). Between 12/2015-7/2018, 117 consecutive patients with hematologic malignancies associated with higher rates of graft failure after NMA conditioned BMT and PTCy, received NMA PB allografts on trial. The primary objective of this study was to evaluate the safety and feasibility of reduced-duration IS (from day 5 through day 90 in the D90 cohort and through day 60 in the D60 cohort). Of the 117 patients (median age, 64 years; range, 22 to 78 years), the most common diagnoses were myelodysplastic syndrome (33%), acute myelogenous leukemia (with minimal residual disease or arising from an antecedent disorder) (32%), myeloproliferative neoplasms (19%), myeloma (9%), and chronic lymphoblastic leukemia (7%). Shortened IS was feasible in 75 patients (64%) overall. Ineligibility for shortened IS resulted most commonly from GVHD (17 patients), followed by early relapse (11 patients), nonrelapse mortality (NRM) (7 patients), patient/ physician preference (4 patients) or graft failure (3 patients). Of the 57 patients in the D90 cohort, 33 (58%) stopped IS early as planned, and among the 60 patients in the D60 cohort, 42 (70%) stopped IS early as planned. The graft failure rate was 2.6%. After IS cessation, the median time to diagnosis of grade II-IV acute GVHD was 21 days in the D90 cohort and 32 days in the D60 cohort, with almost all cases developing within 40 days. Approximately one-third of these patients resumed IS. All outcome measures were similar in the 2 cohorts and our historical outcomes with 180 days of IS. The cumulative incidence of grade III-IV acute GVHD was low, 2% in the D90 cohort and 7% in the D60 cohort. The incidence of severe chronic GVHD at 2 years was 9% in the D90 cohort and 5% in the D60 cohort. The 2-year overall survival was 67% for both the D90 and D60 cohorts. The 2-year progression-free survival was 47% for the D90 cohort and 52% for the D60 cohort, and the GVHD-free, relapse-free survival was <35% for both cohorts. These data suggest that reduced-duration IS in patients undergoing NMA PBSCT with PTCy is feasible and has an acceptable safety profile. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Assuntos
Doença Enxerto-Hospedeiro , Condicionamento Pré-Transplante , Transplante de Medula Óssea , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Increasingly, adolescent, young adult, and adult children are relied upon as donors for their parents undergoing blood and marrow stem cell transplant. How family functioning impacts donors' decision making and whether haploidentical donor children have unique supportive care needs is unknown. In this qualitative research study, we conducted 15 semistructured telephone interviews among individuals who underwent blood or marrow stem cell donation for their parent. Interviews explored donors' perspectives of the transplant experience across the trajectory from screening through early post-transplant follow-up and elicited unmet needs. Major themes included: (1) perception of choice, (2) act of giving back, (3) burdens of donation, (4) anticipated health benefit to parent, and (5) impact of donation on parent/child relationship. The majority of participants described high family functioning, but strain was also evident. Family functioning rarely was reported as affecting the decision to donate, with all donors expressing a sense of obligation. Participants were overwhelmingly satisfied with their decision and the ability to give back to their parent. Suggestions for the health care team to improve the donation experience focused on increased education about potential delays in screening, better description of possible complications for recipients, and provision of emotional support following donation.
Assuntos
Doadores de Tecidos , Transplante Haploidêntico , Adolescente , Humanos , Adulto Jovem , Doadores Vivos , Núcleo Familiar , Filhos Adultos , AdultoRESUMO
BACKGROUND: Current clinical practices are shifting towards utilizing less invasive biopsy techniques, including fine needle aspiration (FNA) and needle core biopsies. If a patient has a suspected hematologic malignancy, a portion of the FNA sample is typically submitted for flow cytometry (FC) analysis, providing valuable immunophenotypic data. METHODS: FNA specimens were identified via a pathology database search. All cases were morphologic evaluated and a subset of cases were analyzed by FC. RESULTS: 245 hematologic FNA specimens were identified; 84% of these cases had an adequate number of cells for FC analysis, and an unequivocal morphologic diagnosis (benign or malignant) was rendered in 85%. The percentage of cases with an unequivocal diagnosis was statistically significantly higher in those with associated FC than with those without FC (90% vs 58%). Neither FNA technique nor anatomic site affected the likelihood of obtaining an adequate sample for FC analysis and/or rendering a definitive morphologic or unequivocal FC diagnosis. Likewise, tumor subtype did not affect the likelihood of acquiring enough cells for FC analysis, but occasionally resulted in equivocal FC diagnoses or discordant FNA and FC diagnoses. Aggressive B-cell lymphomas and Hodgkin lymphomas were significantly less likely to be detected by FC as compared to low-grade B-cell lymphomas. Discrepancies between FNA and FC diagnoses occurred in 13% of cases. The majority of discrepancies (78%) included FC false negatives, while only 22% of cases had atypical or positive FC with negative FNA. CONCLUSIONS: FNA with associated FC is a powerful diagnostic technique; however, lymphoma subtype may affect diagnostic sensitivity by FC, and therefore, discordant FNA and FC results should be interpreted with caution.
Assuntos
Biópsia por Agulha Fina/métodos , Citometria de Fluxo/métodos , Neoplasias Hematológicas/diagnóstico , HumanosRESUMO
The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
Assuntos
Linfoma Difuso de Grandes Células B , Receptores de Antígenos de Linfócitos T , Adulto , Antígenos CD19 , Humanos , Cinética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
While patients with double-hit lymphoma (DHL) are now frequently treated with intensive front-line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative-intent second-line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression-free/overall survival (PFS/OS) of 2/5·1 months and one-year PFS/OS of 10/19% following the start of second-line therapy. These outcomes may serve as a standard against which future second-line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non-cytotoxic therapies in the second-line setting for these patients.
Assuntos
Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia/terapia , Terapia de Salvação/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Terapia de Salvação/normas , Padrão de Cuidado , Transplante Autólogo/normas , Falha de Tratamento , Adulto JovemRESUMO
PURPOSE: Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma. PATIENTS AND METHODS: Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety. RESULTS: Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common (P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm. CONCLUSION: In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/farmacologia , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Vincristina/farmacologia , Vincristina/uso terapêutico , Adulto JovemRESUMO
PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Isoquinolinas/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Purinas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diarreia/induzido quimicamente , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/efeitos adversos , Estimativa de Kaplan-Meier , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases/metabolismo , Purinas/administração & dosagem , Purinas/efeitos adversos , Rituximab/administração & dosagemRESUMO
Published reports suggest that immune checkpoint inhibitors (ICIs) before allogeneic blood or marrow transplantation (alloBMT) may increase the incidence of graft-versus-host disease (GvHD), immune-related adverse events, and nonrelapse mortality (NRM); this led to the US Food and Drug Administration issuing a "Warning and Precaution" regarding the potential for life-threatening immune-mediated complications associated with alloBMT after nivolumab and pembrolizumab. We retrospectively reviewed the outcomes of 14 consecutive patients who received ICIs as their final salvage therapy before T-cell-replete alloBMT using reduced-intensity conditioning. All patients received posttransplant cyclophosphamide (PTCy), which significantly limits severe GvHD, even in the mismatched-donor setting. There was no grade 3-4 acute GvHD (aGvHD), and all 6 cases of grade 2 aGvHD readily resolved with immunosuppression. No patient experienced veno-occlusive disease of the liver, other immune-related adverse events, chronic GvHD, or NRM. There have been 2 relapses (15-month median follow-up), with 12 of 14 patients remaining alive, well, and progression-free. The only death was a result of disease relapse. Although more experience is needed, our data suggest that concerns over immunologic complications associated with ICIs should not preclude allogeneic bone marrow transplantation with PTCy as GvHD prophylaxis.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Transplante de Medula Óssea , Feminino , Humanos , Ipilimumab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico , Estudos Retrospectivos , Terapia de Salvação/métodos , Transplante Homólogo , Adulto JovemRESUMO
Compared with solvent-based taxanes, nanoparticle albumin-bound (nab®) paclitaxel has demonstrated improved efficacy and tolerability in several solid tumor malignancies. Studies evaluating nab paclitaxel in patients with lymphoma are lacking. In this planned phase-I/phase-II study, we sought to determine the safety and efficacy of nab-paclitaxel in patients with relapsed/refractory (R/R) lymphoma. Eligible patients (R/R to ≥2 prior systemic therapies) received weekly nab-paclitaxel on days 1, 8 and 15 every 28 days. Dosing was initiated at 100 mg/m2 with dose escalations in 25 mg/m2 increments up to 150 mg/m2 in a classic 3 + 3 design. Twenty heavily pretreated patients (median 5 prior regimens), including 65% with refractory disease, enrolled. The maximum dose tested was well tolerated and grade 3/4 hematologic adverse events (neutropenia 25%, thrombocytopenia 20% and anemia 15%) were modest. The overall response rate was 10% with two partial responses, leading to a decision to close the study prematurely.
Assuntos
Albuminas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Linfoma/tratamento farmacológico , Linfoma/patologia , Paclitaxel/uso terapêutico , Adulto , Idoso , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma/diagnóstico por imagem , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. PATIENTS AND METHODS: In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose-limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR). RESULTS: Twenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively. CONCLUSION: Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL.