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ABSTRACT: We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.
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Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Humanos , Mielofibrose Primária/terapia , Mielofibrose Primária/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Condicionamento Pré-Transplante/métodos , Idoso , Doença Enxerto-Hospedeiro/etiologia , Doadores de Tecidos , Sistema de Registros , Doadores não RelacionadosRESUMO
ABSTRACT: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with PV include advanced age, TE history, and elevated hematocrit. Although an association of TE with elevated white blood cell (WBC) counts has been suggested by retrospective studies, this relationship needs further validation. The prospective observational study of patients with polycythemia vera in US clinical practices (REVEAL) study collected prospective clinical data from 2510 patients with PV with a median follow-up of 44.7 months (range, 2-59 months) from enrollment. Using time-dependent covariate Cox proportional hazards models, blood counts were individually modeled with sex, age, disease duration, TE history at enrollment (baseline covariates), and treatment (time-dependent covariate). Analysis of 2271 participants identified 142 TEs in 106 patients. Significant associations with initial TE occurrence during the study period were observed for hematocrit level >45% (hazard ratio [HR], 1.84; 95% confidence interval [95% CI], 1.234-2.749; P = .0028) and WBCs >11 × 109/L (HR, 2.35; 95% CI, 1.598-3.465; P < .0001). Elevated WBC count was significantly associated with initial TE occurrence in both low-risk and high-risk PV. When hematocrit was controlled at ≤45%, WBC count >12 × 109/L was significantly associated with TE occurrence (HR, 1.95; 95% CI, 1.066-3.554; P = .0300). The results support incorporation of WBC count into PV risk stratification and studies of treatment strategies, and indicate the importance of controlling both hematocrit and WBC count in disease management. This trial was registered at www.clinicaltrials.gov as #NCT02252159.
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Policitemia Vera , Trombose , Humanos , Policitemia Vera/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Trombose/etiologia , Fatores de Risco , Contagem de LeucócitosRESUMO
CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing.
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Antifúngicos , Transplante de Células-Tronco Hematopoéticas , Humanos , Voriconazol/uso terapêutico , Antifúngicos/uso terapêutico , Farmacogenética , Citocromo P-450 CYP2C19/genética , Estudos Retrospectivos , GenótipoRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.
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Transplante de Células-Tronco Hematopoéticas , Transtornos Mieloproliferativos , Humanos , Pessoa de Meia-Idade , Transplante Homólogo , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Transtornos Mieloproliferativos/patologia , Doença Crônica , Recidiva , Células Dendríticas/patologiaRESUMO
The rapid pace of drug development in hematology has led to multiple approvals for myelofibrosis (MF) and polycythemia vera (PV) in recent years. Moreover, there are many innovative agents and combinations being explored for myeloproliferative neoplasms (MPNs). In the past year, there have been several advances in MF, PV, and essential thrombocythemia. In MF, investigational approaches are focusing on strategies to optimize inhibition of signal transduction (including JAK inhibition), modify epigenetics, enhance apoptosis, target DNA replication, transform host immunity, and/or alter the tumor microenvironment. In PV, ropeginterferon alfa-2b has been introduced to the market in the United States, and data continue to accumulate to support the safety and efficacy of this treatment. Hepcidin mimesis is also emerging as a novel way to treat erythrocytosis. In essential thrombocythemia, ropeginterferon alfa-2b is being evaluated, as are therapies to modify epigenetics and inhibit CALR. The enhanced focus on MPNs brings hope that our field can improve morbidity and mortality in this group of diseases.
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Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Humanos , Estados Unidos , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Transdução de Sinais , Microambiente TumoralRESUMO
The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnósticoRESUMO
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doenças Mieloproliferativas-Mielodisplásicas , Neoplasias , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Esplenomegalia , Transplante de Células-Tronco Hematopoéticas/métodos , Ciclofosfamida , Doadores não Relacionados , Doença Aguda , Recidiva , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/terapia , América do Norte , Condicionamento Pré-Transplante/métodosRESUMO
To develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.
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Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Humanos , Estados Unidos , Pessoa de Meia-Idade , Prognóstico , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/terapia , Transplante Homólogo , Doadores não Relacionados , Doença Crônica , RecidivaRESUMO
Purpose: Cancer patients are at high risk of developing severe illness from SARS-CoV-2 infection, but risk is lowered with receipt of COVID-19 vaccine. COVID-19 vaccination uptake among previously infected cancer patients may be influenced by an assumption of natural immunity, predicted weak immune response, or concerns about vaccine safety. The objective of this study was to evaluate COVID-19 vaccine uptake trends in cancer patients previously infected with SARS-CoV-2. Materials and Methods: Medical records of 579 sequential cancer patients undergoing active treatment at Levine Cancer Institute who tested positive for COVID-19 between January 2020 and January 2021 were evaluated. Patients who died prior to vaccine eligibility were excluded from the analysis. Demographic, clinical, and COVID-19 related characteristics were analyzed to identify prognostic factors for COVID-19 vaccine uptake as this information could be important for health policy design for future pandemics. Results: Eighty-one patients died prior to the availability of COVID-19 vaccines. The acceptance rate of COVID-19 vaccination among 498 previously infected cancer patients was 54.6%. Of the patients with known vaccination dates, 76.8% received their first vaccine by April 17th, 2021. As of November 30, 2021, 23.7.% of eligible patients were boosted. In univariate models, older age, female sex, higher income, solid tumor cancer type, and hormone therapy were significantly associated with higher vaccine uptake, while Hispanic/Latino ethnicity was significantly associated with lower vaccine uptake. In a multivariable model, age (OR 1.18, 95% CI 1.10-1.28; p < 0.001), female sex (OR 1.80, 95% CI 1.22-2.66; p = 0.003), and higher income (OR 1.11, 95% CI 1.01-1.22; p = 0.032), were predictive of COVID-19 vaccine uptake. Conclusions: Overall, vaccine uptake was low among our cohort of previously infected cancer patients. Older age, female sex, and higher income were the only variables associated with COVID-19 vaccine uptake within this vulnerable patient population.
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Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Adulto , Humanos , Adolescente , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/terapia , Bussulfano/uso terapêutico , Melfalan , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Condicionamento Pré-Transplante , Vidarabina/uso terapêuticoRESUMO
Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD-CD38hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Humanos , Animais , Camundongos , Recidiva Local de Neoplasia/complicações , Aminopiridinas/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Esteroides/uso terapêutico , Quinase Syk/uso terapêuticoRESUMO
Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell's C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Crônica , Adulto , Humanos , Pessoa de Meia-Idade , Medula Óssea , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/terapia , Mutação , Prognóstico , IdosoRESUMO
We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Transplante Homólogo , Condicionamento Pré-Transplante , Recidiva Local de Neoplasia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos RetrospectivosRESUMO
This study aimed to identify a recommended phase II dose and evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary clinical activity of JNJ-63709178, a CD123/CD3 dual-targeting antibody, in patients with relapsed or refractory acute myeloid leukemia. Intravenous (i.v.) and subcutaneous (s.c.) administration of JNJ-63709178 were evaluated. The i.v. infusions were administered once every 2 weeks (cohorts 1-5 [n = 17]) or twice weekly (cohorts 6-11 [n = 36]). A twice-weekly s.c. dosing regimen with step-up dosing was also studied (s.c. cohorts 1-2 [n = 9]). Treatment-emergent adverse events (TEAEs) greater than or equal to grade 3 were observed in 11 (65%) patients in cohorts 1-5 and 33 (92%) patients in cohorts 6-11. At the highest i.v. dose (4.8 µg/kg), 5 (71%) patients discontinued treatment due to TEAEs. For s.c. administration (n = 9), eight (89%) patients experienced TEAEs greater than or equal to grade 3 and injection site reactions (≤ grade 3) emerged in all patients. At 4.8 µg/kg (i.v. and s.c.), the mean maximum serum concentrations were 30.3 and 3.59 ng/ml, respectively. Increases in multiple cytokines were observed following i.v. and s.c. administrations, and step-up dosing strategies did not mitigate cytokine production or improve the safety profile and led to limited duration of treatment. Minimal clinical activity was observed across all cohorts. The i.v. and s.c. dosing of JNJ-63709178 was associated with suboptimal drug exposure, unfavorable safety profiles, limited clinical activity, and inability to identify a recommended phase II dose.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Subunidade alfa de Receptor de Interleucina-3/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
The treatment landscape for acute myeloid leukemia (AML) has changed substantially in recent years. The introduction of newer therapies, including oral agents, less myelosuppressive agents, and parenteral regimens suitable for outpatient administration, has made it feasible for select patients to receive therapy in the outpatient setting and in community practices. Thorough patient evaluation (including molecular testing), planned supportive care (eg, transfusion support, antimicrobial prophylaxis), and vigilant patient monitoring (for tumor lysis syndrome and adverse events) by a multidisciplinary team are required for successful management of patients both in the community and at specialized leukemia centers. Some patients are unable or unwilling to travel to larger academic centers for treatment, and treatment of AML in the community setting may have potential advantages compared to less conveniently located academic/leukemia centers. This includes reduction of financial hardship for patients and their families and often better opportunities for family/caregiver support. Additionally, partnership between community practices and academic/leukemia centers is often crucial to optimizing AML management for many patients, as collaboration may facilitate access to additional expertise and trials, multidisciplinary teams for supportive care, easier transition to hematopoietic cell transplantation, and access to sophisticated molecular testing. In this review, we discuss AML treatment and management in the community setting, available therapies, and circumstances in which a referral to and co-management with an academic/leukemia center is more strongly recommended.
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Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by clonal expansion of myeloid blasts. It is the most common type of acute leukemia in adults, including elderly patients, and has historically been associated with poor outcomes in this age group. Here, we present the case of an 80-year-old woman with newly diagnosed AML with myelodysplasia-related changes. She was treated with a total of five cycles of azacitidine, two cycles as monotherapy followed by three cycles in combination with venetoclax. Therapy was stopped due to cytopenias and declining performance status. Bone marrow aspirate and biopsy immediately following treatment and again approximately four months later did not show any morphologic, immunophenotypic, or cytogenetic evidence of leukemia. The patient's clinical and performance status improved significantly with time. Follow-up labs more than three years following the completion of treatment reveal continued hematologic remission. A short treatment course of azacitidine and venetoclax with close monitoring may lead to durable responses in some patients. Further studies are necessary to determine which patients might be appropriate for treatment suspension or discontinuation while in remission.
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PURPOSE: Patients with hematologic malignancies are extremely vulnerable to financial toxicity (FT) because of the high costs of treatment and health care utilization. This pilot study identified patients at high risk because of FT and attempted to improve clinical outcomes with comprehensive intervention. METHODS: All patients who presented to the Levine Cancer Institute's Leukemia Clinic between May 26, 2019, and March 10, 2020, were screened for inclusion by standardized two question previsit survey. Patients screening positive were enrolled in the comprehensive intervention that used nurse navigators, clinical pharmacists, and community pro bono financial planners. Primary outcomes were defined as improvement in mental and physical quality of life in all patients and improvement in overall survival in the high-risk disease group. RESULTS: One hundred seven patients completed comprehensive intervention. Patients experiencing FT had increased rates of noncompliance including to prescription (16.8%) and over-the-counter medications (15.9%). The intervention resulted in statistically significantly higher quality of life when measured by using Patient-Reported Outcomes Measurement Information System physical (12.5 ± 2.2 v 13.7 ± 1.8) and mental health scores (11.4 ± 2.2 v 12.4 ± 2.2; all P < .001). In patients with high-risk disease (as determined by using disease-specific scoring systems), risk of death in those receiving the intervention was 0.44 times the risk of death in those without the intervention after adjusting for race, and treatment with stem-cell transplant, oral chemotherapy, or immunotherapy (95% CI, 0.21 to 0.94; P = .034). CONCLUSION: Screening and intervention on FT for patients with hematologic malignancies is associated with increased quality of life and survival.
Assuntos
Neoplasias Hematológicas , Qualidade de Vida , Estresse Financeiro , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Projetos Piloto , Inquéritos e QuestionáriosAssuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Citarabina , Daunorrubicina , Hospitalização , Humanos , Leucemia Mieloide Aguda/etiologia , SulfonamidasRESUMO
This phase 1 b study evaluated the safety, efficacy, and pharmacokinetics of atezolizumab in combination with guadecitabine in patients with relapsed/refractory (R/R) or first-line acute myeloid leukemia (AML). Patients received atezolizumab 840 mg (days [D] 8 and 22) and guadecitabine 60 mg/m2 (D1 and D5) over 28-day cycles. Sixteen patients (median age 73.0 years) enrolled (R/R cohort, n = 11; first-line cohort, n = 5). All patients reported at least 1 AE; 15 patients (93.8%) reported grade ≥ 3 AEs, and 15 patients (93.8%) reported SAEs. Fourteen of the 16 patients (87.5%) died during the trial period due to disease progression (8/14) or AEs (6/14), hence the study was terminated early. One patient (from the R/R AML cohort) achieved a response (CR with incomplete platelet recovery) with a DOR of 27.8 months at study termination. Atezolizumab plus guadecitabine had limited clinical activity in AML and an overall unfavorable benefit-risk profile at the investigated dose levels.