RESUMO
INTRODUCTION: For most adult patients with acute myeloid leukemia, relapse is characteristic of the disease. When allotransplant in first complete remission is administered as consolidative therapy, relapse is still common, affecting 20-40% of recipients. Maintenance of remission with low-dose treatments may hold promise in preventing relapse. AREAS COVERED: Improvements in the detection of clinical and biological variants of disease allow the practitioner to identify which patients, based on disease features, may benefit from therapy directed at residual clonal elements that might contribute to relapse. Along with improvements in methods of detecting residual disease, novel agents are under investigation as a platform in order to maintain remission and may contribute to prolonged survival. In this manuscript, we review literature available through PubMed regarding the use of maintenance therapy, described as post-remission or post-transplant treatment intended to delay or prevent relapse. EXPERT OPINION: Although results of randomized studies are limited, a role for maintenance therapy, particularly directed at molecular targets, in distinct settings of post-remission management is recommended. We also advise that randomized studies of immune therapy along with opportunities for further evaluation of risk-agnostic interventions be a focus of cooperative groups.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , RecidivaRESUMO
Objective: To identify the optimal dose of selinexor in combination with pomalidomide and dexamethasone (SPd). Methods: An analysis of efficacy and safety of 2 once-weekly selinexor regimens (60 mg and 40 mg) with pomalidomide and dexamethasone (SPd-60 and SPd-40, respectively) given to patients with relapsed/refractory multiple myeloma (RRMM) in the STOMP (NCT02343042) and XPORT-MM-028 (NCT04414475) trials. Results: Twenty-eight patients (60.7% males, median age 67.5 years) and 20 patients (35.0% males, median age 65.5 years) were analyzed in the SPd-40 and SPd-60 cohorts, respectively. Overall response rate was 50% (95% confidence interval [CI] 30.6-69.4%) and 65% (95% CI 40.8-84.6%), respectively. Very good partial response or better was reported in 28.6% (95% CI 13.2-48.7%) and 30.0% (95% CI 11.9-54.3%) of patients, respectively. Among 27 responders in both cohorts, the 12-month sustained response rate was 83.3% (95% CI 64.7-100.0%) for SPd-40 and 28.1% (95% CI 8.9-88.8%) for SPd-60. Median progression-free survival was 18.4 months (95% CI 6.5 months, not evaluable [NE]) and 9.5 months (95% CI 7.6 months-NE) for SPd-40 and SPd-60, respectively. Twenty-four-month survival rates were 64.2% (95% CI 47.7-86.3%) for SPd-40 and 51.1% (95% CI 29.9-87.5%) for SPd-60. Treatment-emergent adverse events (TEAEs) included neutropenia (all grades: SPd-40 64.3% versus SPd-60 75.0%), anemia (46.4% versus 65.0%), thrombocytopenia (42.9% versus 45.0%), fatigue (46.4% versus 75.0%), nausea (32.1% versus 70.0%) and diarrhea (28.6% versus 35.0%). Conclusion: The all-oral combination of SPd exhibited preliminary signs of efficacy and was generally tolerable in patients with RRMM. The overall risk-benefit profile favored the SPd-40 regimen.
RESUMO
BACKGROUND: Mucorales infections continue to cause significant morbidity and mortality in immunocompromised hosts despite the advent of new approaches for diagnosis and treatment of fungal infections. We aimed to evaluate risk factors and outcomes of Mucorales infection in solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell therapy recipients. METHODS: This single-center retrospective study included solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell patients with cultures positive for Mucorales. RESULTS: Forty-three patients were included for analysis; 34 solid organ transplant (79%) and 9 hematopoietic stem cell transplant or chimeric antigen receptor T-cell (21%). Infection with Mucorales occurred a median of 184 days after transplant. At the time of diagnosis, 36 patients were on antifungal prophylaxis with the majority receiving posaconazole (53%). Thirty-three had clinically significant disease; 30 received definitive anti-Mucorales therapy and 3 empiric antifungal therapy. Isavuconazole was the most common azole used for treatment in monotherapy recipients. All-cause mortality was 64% and, of these deaths, 18 (75%) were directly related to Mucormycosis. The highest mortality was seen in disseminated and intra-abdominal disease (100%), followed by pulmonary disease (50%). There was no significant association with mortality and transplant type or number of immunosuppressive agents. CONCLUSION: Mucormycosis is an important cause of morbidity and mortality in immunocompromised patients. Breakthrough infection was not uncommon in this study. Data regarding the incidence of infection at approximately 6 months after transplantation can inform prophylaxis and treatment regimens. The spectrum of antifungal regimens used reflects the lack of consensus on ideal regimens for these organisms and a need for more studies.
RESUMO
ABSTRACT: FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and, unlike other inhibitors, is minimally vulnerable to resistance induced by FLT3 ligand. We conducted a phase 1 dose escalation study of oral FF-10101 in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts receiving doses ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. Overall, 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03194685.
Assuntos
Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Feminino , Masculino , Adulto , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Recidiva , Mutação , Resultado do Tratamento , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/efeitos adversos , Adulto JovemRESUMO
Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1-2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Mutação , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/antagonistas & inibidores , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Adulto , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Indução de Remissão , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/genética , Idoso de 80 Anos ou maisRESUMO
Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes. SIGNIFICANCE: Ephrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.
Assuntos
Efrina-B2 , Mieloma Múltiplo , Animais , Humanos , Camundongos , Células Endoteliais/metabolismo , Efrina-B2/genética , Efrina-B2/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptor EphB4/genética , Receptor EphB4/metabolismo , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer. OBJECTIVE: This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. PATIENTS AND METHODS: Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity. RESULTS: As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3-134.2, and 74.8-126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%. CONCLUSIONS: Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).
Assuntos
Neoplasias Hematológicas , Imunoconjugados , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Imunoconjugados/farmacocinética , Adulto , Neoplasias Hematológicas/tratamento farmacológico , Idoso de 80 Anos ou mais , Sistema ASC de Transporte de Aminoácidos , Antígenos de Histocompatibilidade MenorRESUMO
ABSTRACT: Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.
Assuntos
Nitrilas , Mielofibrose Primária , Pirimidinas , Pirrolidinas , Humanos , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/induzido quimicamente , Fosfatidilinositol 3-Quinases , Pirazóis/efeitos adversosRESUMO
ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.
Assuntos
Transfusão de Plaquetas , Humanos , Transfusão de Plaquetas/efeitos adversos , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Lesão Pulmonar Aguda/etiologia , Plaquetas , Estudos Prospectivos , Adulto , Trombocitopenia/etiologia , Doenças Hematológicas/terapiaRESUMO
While the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥ 60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML ≥ 60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-risk, 11% had intermediate-risk, and 78% had adverse-risk AML as defined by ELN. ELN risk was prognostic for overall survival (OS) (P<0.001) but did not stratify favorable-risk from intermediate-risk (P=0.71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (N=316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P<0.05). A "mutation-score" was calculated for each combination of these mutations, assigning adverse-risk patients into two risk groups: -1 to 0 points ("Beat-AML-intermediate") vs 1+ points ("Beat-AML-adverse"). In the final refined risk classification, the ELN favorable- and intermediate-risk groups were combined into a newly defined "Beat-AML-favorable-risk", in addition to mutation scoring within the ELN adverse-risk. This approach redefines risk for older ND AML and proposes refined Beat-AML-favorable- (22%), Beat-AML-intermediate- (41%), and Beat-AML-adverse-risk (37%) groups with improved discrimination for OS (2-year OS: 48% vs 33% vs 11%, respectively, P<0.001; C-index: 0.60 vs 0.55 for ELN), providing patients and providers additional information for treatment decision-making.