RESUMEN
Bosutinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia (CML), and for patients with Ph + chronic phase, accelerated phase, or blast phase CML resistant or intolerant to prior therapy. As is the case for all TKIs approved for treatment of CML, bosutinib is associated with adverse events (AEs) that require appropriate management to ensure adherence to treatment and optimized outcomes. The aim of this review is to provide physicians with updated practical information for the prevention and management of AEs occurring during treatment with bosutinib, including dosing strategies, based on the latest published evidence and clinical experience. Clinical studies and real-world evidence have shown bosutinib has a generally favorable safety profile, which has remained consistent across lines of therapy and in long-term reports. Adjusting the starting dose and/or modifying the dose during treatment with bosutinib are important strategies to manage AEs and improve tolerability, which are recognized within the label and in treatment guidelines. Dosing adjustment strategies to manage AEs are a recognized management approach for other TKIs in the treatment of CML and are not exclusive to bosutinib. In summary, long-term results from clinical trials and emerging real-world evidence demonstrate bosutinib has a safety profile that can largely be managed with treatment modifications and/or supportive care. Increased experience in managing toxicities and by using a personalized dosing approach may further improve adherence and outcomes with bosutinib.
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Compuestos de Anilina , Leucemia Mielógena Crónica BCR-ABL Positiva , Nitrilos , Inhibidores de Proteínas Quinasas , Quinolinas , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/efectos adversos , Nitrilos/uso terapéutico , Nitrilos/efectos adversos , Humanos , Quinolinas/uso terapéutico , Quinolinas/efectos adversos , Quinolinas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
Cytomegalovirus (CMV) reactivation post-allogeneic hematopoietic cell transplantation (post-alloHCT) increases morbidity and mortality. We sought to determine the frequency of CMV seroconversion in patients pre-alloHCT and to investigate the impact on posttransplant outcomes. We retrospectively investigated 752 adult patients who underwent alloHCT at our center from January 2015 to February 2020 before the adoption of letermovir prophylaxis. CMV serology was assessed at consult and pretransplant. The cohort was divided into four groups based on pretransplant CMV seroconversion: negative to positive (Group 1), positive to negative (Group 2), consistently negative (Group 3), and consistently positive (Group 4). Eighty-nine patients (12%) had seroconverted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently seronegative, and 495 (66%) were consistently seropositive pretransplant. For the four CMV serostatus groups, cumulative incidence of CMV reactivation at 6 months posttransplant was 4.5%, 47.1%, 6.6%, and 76.6% for Groups 1, 2, 3, and 4, respectively (p < .0001). No differences between groups were seen regarding Grade III-IV acute graft-versus-host disease (GVHD) (p = .91), moderate/severe chronic GVHD (p = .41), or graft failure (p = .28). On multivariable analysis, there was no impact of CMV serostatus group on overall survival (p = .67), cumulative incidence of relapse (p = .83) or non-relapse mortality. alloHCT patients who demonstrate CMV seroconversion pretransplant from negative to positive have a very low risk of CMV reactivation posttransplant. The observed seroconversion may be due to passive CMV immunity acquired through blood products. Quantitative CMV immunoglobulin G/immunoglobulin M pretransplant may help differentiate between true seroconversion and passively transmitted CMV immunoglobulin.
RESUMEN
Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.
Asunto(s)
Anemia de Diamond-Blackfan , Consenso , Humanos , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Anemia de Diamond-Blackfan/genética , Manejo de la Enfermedad , Trasplante de Células Madre HematopoyéticasRESUMEN
Treosulfan has shown promise in allogeneic hematopoietic cell transplantation (HCT) for its myeloablative properties and low toxicity. In this single-center retrospective propensity score-matched cohort study we compared treosulfan- and busulfan-based conditioning in allogeneic HCT for patients with myelodysplastic syndrome (MDS). This study included 138 adults who underwent allogeneic HCT for MDS or chronic myelomonocytic leukemia at Princess Margaret Hospital, Toronto, from 2015 to 2022. Using propensity score matching, we compared transplant outcomes between 2 well-matched cohorts who received conditioning with either fludarabine-treosulfan (FT) (n = 46) or fludarabine-busulfan with total body irradiation (FBT200) (n = 92). A scoring system based on patient age, Karnofsky performance score, and hematopoietic cell transplant comorbidity index was used to assign patients based on fitness to low-dose (30 g/m2) or high-dose (42 g/m2) treosulfan: 32 (69.6%) received high-dose treosulfan. The racial composition of the 2 groups was similar, with 27.2% and 21.7% of FBT200 and FT recipients, respectively, identifying as non-Caucasian (P = .61). Primary outcomes were analyzed at a median follow-up of 747 days. Of all participants, 116 (84.0%) received graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) and antithymocyte globulin (ATG). Patients who received FT had a superior 2-year overall survival (OS) compared to those who received FBT200: 66.9% (95% confidence interval (CI): 46.1 to 81.2) versus 44.5% (95% CI: 34 to 54.4), hazard ratio (HR): 0.43, 95% CI: 0.22 to 0.84 (P = .013). In multivariate analysis (MVA), only the use of fresh grafts (P = .02) and FT (P = .01) were associated with improved OS. FT was associated with superior 2-year relapse-free survival (RFS) compared to FBT200: 63.1% (95% CI: 42.6 to 77.9) versus 39.1% (95% CI: 29.1 to 49.1), HR: 0.44 (95% CI: 0.24 to 0.81), P = .008. In MVA, the use of fresh grafts (P = .03) and FT (P = .009) were associated with improved RFS. Recipients of FT demonstrated superior 2-year graft-versus-host disease relapse-free survival (GRFS) compared to those who received FBT200: 57.4% (95% CI: 37.8 to 72.8) versus 35.1% (95% CI: 25.5 to 45). In MVA, only FT was associated with superior GRFS (P = .02). FT recipients exhibited markedly superior 1-year event-free survival compared to recipients of FBT200 in univariate analysis (40.3% (95% CI: 25.9 to 54.2) versus 9.2% (95% CI: 4.4 to 16.3), HR: 0.47 (95% CI: 0.30 to 0.72), P < .001) and MVA (P = .004). FT was associated with lower 1-year nonrelapse mortality compared to FBT200 in univariate analysis (9.9% (95% CI: 3.0 to 21.8) versus 29.7% (95% CI: 20.6 to 39.3), HR: 0.41 (95% CI: 0.17 to 0.96), P = .04) and MVA (P = .04). Our study utilized propensity score matching to demonstrate superiority of treosulfan- over busulfan-based conditioning in stem cell transplantation of patients with MDS and is the first to evaluate the performance of treosulfan-based conditioning in combination with ATG and PTCY. As such, it contributes to the increasing body of evidence supporting the safety of treosulfan, even at the dose of 42 g/m2.
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Busulfano , Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Puntaje de Propensión , Acondicionamiento Pretrasplante , Trasplante Homólogo , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/mortalidad , Adulto , Trasplante Homólogo/métodos , Anciano , Enfermedad Injerto contra Huésped , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Irradiación Corporal TotalRESUMEN
The rich history surrounding Diamond-Blackfan anaemia (DBA), originally described in 1938 as congenital hypoplastic anaemia2 reflects the evolution of paediatric haematology. In their paper, the authors1 present the results of a clinical trial using the thrombopoietin-mimetic agent eltrombopag to treat red cell failure in DBA. A low response rate belies the importance of this work. Commentary on: Duncan et al. Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag. Br J Haematol 2024;204:2077-2085.
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Anemia de Diamond-Blackfan , Benzoatos , Hidrazinas , Pirazoles , Anemia de Diamond-Blackfan/tratamiento farmacológico , Humanos , Pirazoles/uso terapéutico , Benzoatos/uso terapéutico , Hidrazinas/uso terapéuticoRESUMEN
BACKGROUND: Blinatumomab, a bispecific monoclonal antibody, effectively controls refractory B cell acute lymphoblastic leukemia (ALL) and promotes measurable residual disease (MRD) negativity. This study investigated the impact of pretransplant blinatumomab on allogeneic hematopoietic cell transplantation (HCT) outcomes in B cell ALL patients. METHODS: We analyzed the effect of pretransplant blinatumomab on transplant outcomes of 117 adults undergoing allogeneic HCT for B cell ALL at Princess Margaret Hospital, Toronto, between 2010 and 2021. Outcomes assessed included overall survival (OS), graft-versus-host disease and relapse-free survival (GRFS), cumulative incidences of relapse (CIR), and nonrelapse mortality (NRM). RESULTS: The median follow-up was 36 months. Thirty-one participants (26.5%) received blinatumomab. Blinatumomab group had higher proportions of individuals with high disease risk index, primary induction failure and was more likely to receive dual T cell depletion with antithymocyte globulin and post-transplant cyclophosphamide. Two-year OS, GRFS, NRM, and CIR in the blinatumomab and nonblinatumomab groups were, respectively: 65.4% versus 45.6% (P = .05), 42.2% versus 17.3% (P = .01), 3.2% versus 43.0% (P = .007) and 34.4% versus 14.4% (P = .02). Blinatumomab was associated with a lower incidence of day-100 grade 2 to 4 and grade 3 to 4 acute graft-versus-host disease (aGVHD): 27.5% versus 56.7% (P = .009), and 10.9% versus 34.7% (P = .04), respectively. Multivariate analysis confirmed the association between pretransplant blinatumomab and improved OS and NRM. CONCLUSIONS: Pretransplant blinatumomab is associated with improved OS and lower risk of NRM in B cell ALL patients undergoing allogeneic HCT, likely reflecting lower burden of treatment-related toxicity in this population. Larger prospective trials are warranted to validate our findings.
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Anticuerpos Biespecíficos , Trasplante de Células Madre Hematopoyéticas , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Trasplante Homólogo , Adulto Joven , Resultado del Tratamiento , Adolescente , Anciano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Enfermedad Injerto contra Huésped , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMEN
Severe aplastic anemia (SAA) is a life-threatening type of aplastic anemia for which allogeneic stem cell transplantation or immunosuppressive therapy are the principal treatment modalities. Only about 25-30% of patients have a matched sibling donor, and finding an unrelated donor in ethnic minorities is a challenge. The use of related haploidentical donor transplants in severe aplastic anemia is uncommon. We would like to report our experience with the first four patients who underwent haploidentical transplants for severe aplastic anemia. This is a retrospective study. We collected data from our transplant database of all haploidentical hematopoietic stem cell transplants for SAA from 1 January 2020 to 31 December 2021. The transplant protocol used was the Hopkins' protocol. There were three patients who underwent haploidentical transplants as primary therapy for SAA. A fourth patient received a haploidentical transplant after immunosuppressive therapy failure. The median age of the patients at transplant was 24 y (range 20-29). All patients were engrafted. Neutrophil engraftment occurred at a median of 21 days (range 17-22). Any active infections resolved with the recovery of blood counts. The median hospitalization time was 27 days (range 22-41). Only one patient had grade 2 acute GVHD involving the skin. There was no chronic GVHD. All patients had complete lymphoid and myeloid donor chimerism on day 60. Based on our experience and the emerging literature, haplo-identical transplantation should be considered for select young patients with SAA who have low chances of responding to immunosuppressive therapy.
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Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Anemia Aplásica/terapia , Estudios Retrospectivos , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/métodosRESUMEN
Due to the remarkable success of tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), allogeneic stem cell transplantation (alloSCT) is not first-line treatment for delivering durable, long-term survival. Consequently, alloSCT is reserved for patients with TKI-resistant or TKI-intolerant chronic phase CML (CP-CML) and advanced phase CML (AP-CML). Advances in transplant technology, such as high-resolution HLA typing, introduction of reduced intensity conditioning and increased alternative donor availability, coupled with improved supportive care, have significantly reduced transplant-related mortality and expanded the pool of transplant-eligible patients. Refinement of conditioning regimens, innovative use of post-transplant cellular and pharmacological therapies, and judicious post-transplant monitoring are important strategies for reducing risk of relapse. Given its potential to cure, alloSCT will invariably remain a key part of the treatment algorithm. This article reviews the data underpinning the role and outcomes of alloSCT and provides an update on current recommendations.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Acondicionamiento Pretrasplante , Trasplante Homólogo , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/métodos , Resultado del Tratamiento , Resistencia a AntineoplásicosRESUMEN
The ideal immunosuppressive agents to complement post-transplant cyclophosphamide (PTCy) in PBSC-based haploidentical hematopoietic cell transplantation (haplo-HCT) remain debated. This study looks at our experience with ATG-PTCy-Cyclosporine (CsA) prophylaxis in PB haplo-HCT since 2015. Between October 2015 and December 2021, 157 adults underwent haploidentical hematopoietic cell transplantation (haplo-HCT) using a GVHD prophylaxis regimen comprising rabbit-ATG, PTCy, and CsA. Among these patients, 76.4% received a total ATG dose of 4.5 mg/kg, and 23.5% received 2 mg/kg. T-cell replete peripheral blood stem cell (PBSC) grafts were infused on day 0. The study reported a median follow-up of 32 months (range 0.3-61.64) for survivors. The cumulative incidence of grade II-IV and grade III-IV acute GVHD at day +100 was 26.3% and 9.5%, respectively. Moderate/severe chronic GVHD at 1 year was 19.9%. The 2-year overall survival (OS) was 49.4%, with a relapse-free survival (RFS) of 44.6%. In multivariate analysis, older patients, and those with high/very-high disease risk indices (DRI) were at higher risk for worse OS and higher non-relapse mortality (NRM). The study confirms that using PTCy and ATG (4.5 mg/kg), alongside CsA is safe and effective in preventing GVHD when using peripheral blood as the stem cell source in haploidentical hematopoietic cell transplantation (haplo-HCT).
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Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Linfocitos T/patología , Acondicionamiento Pretrasplante/efectos adversos , Estudios RetrospectivosRESUMEN
Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Piridazinas , Humanos , Resistencia a Antineoplásicos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Imidazoles/uso terapéutico , Imidazoles/farmacología , Piridazinas/uso terapéutico , Piridazinas/farmacología , Proteínas de Fusión bcr-abl/genética , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
BACKGROUND AND OBJECTIVES: The introduction and widespread use of effective and well-tolerated tyrosine kinase inhibitors for chronic myeloid leukemia have been associated with marked increments in life expectancy and disease prevalence. These changes have been accompanied by elevations in costs of tyrosine kinase inhibitors, which typically must be taken ad vitam after diagnosis and tend to be more expensive than medical therapies for many other hematologic malignancies. The aims of this review included evaluating the potential associations and consequences of healthcare resource utilization and costs of tyrosine kinase inhibitors and possible clinical management approaches to mitigate them. METHODS: A PubMed search of English-language US study reports was conducted that covered the interval of 2001 (US approval of imatinib) through 17 April, 2023 augmented by manual reviews of published bibliographies from the referenced articles and searches of other databases: Google Scholar and Scopus. RESULTS: On the basis of this analysis of chiefly real-world evidence (administrative claims database studies), healthcare resource utilization and costs can be considered indicators of ineffective chronic myeloid leukemia management, including potentially mutation-driven treatment resistance and costly tyrosine kinase inhibitor switches, non-adherence, and suboptimal tolerability, which may culminate in the progression of disease from the chronic to an accelerated or blast phase, with additional excess costs. Costs of tyrosine kinase inhibitors are also associated with reduced treatment adherence. At a willingness-to-pay threshold of $50,000-$200,000 per quality-adjusted life-year, tyrosine kinase inhibitors can be considered cost effective from a US payer perspective. Potential clinical approaches to mitigate costs include regular molecular monitoring with proactive assessments of BCR::ABL1 gene mutations to avoid costly treatment switches, as well as interventions to enhance treatment adherence and tyrosine kinase inhibitor tolerability. CONCLUSIONS: Healthcare resource utilization and costs of chronic myeloid leukemia care may be considered barometers of ineffective management, including mutation-driven tyrosine kinase inhibitor resistance and switching as well as non-adherence and intolerance. Future prospective research is warranted to help determine whether costs can be reduced and other treatment outcomes optimized via more proactive and effective diagnostic interventions (i.e., regular molecular monitoring and proactive mutational testing) and treatment approaches. The strengths and limitations of this review include its emphasis on observational research, which, on one hand, offers a naturalistic "real-world" perspective on current chronic myeloid leukemia management, but, on the other hand, is associational in nature and cannot be used to determine causality and/or its direction.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Mesilato de Imatinib/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Atención a la Salud , Antineoplásicos/uso terapéuticoRESUMEN
The development of the BCR::ABL1 tyrosine kinase inhibitors (TKIs) has transformed Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) from a fatal disease to an often-indolent illness that, when managed effectively, can restore a life expectancy close to that of the normal population. Bosutinib is a second-generation TKI approved for adults with Ph-positive CML in chronic phase, accelerated phase, or blast phase that is resistant or intolerant to prior therapy, and for newly diagnosed Ph-positive chronic phase CML. This review details the efficacy of bosutinib for the treatment of CML in the first- and second-line settings, as well as in third- and later-line settings for high-risk patients resistant or intolerant to at least 2 TKIs. It also outlines bosutinib studies that provide evidence for dose-optimization strategies that can be used to improve efficacy and effectively manage adverse events. The studies that provide evidence for specific patient populations benefiting particularly from bosutinib dose-optimization strategies are also discussed. The well-established, long-term side-effect profile and the potential to make dose adjustments with bosutinib make it an appropriate treatment option for patients with CML. Bosutinib has demonstrated a positive impact on health-related quality of life and an important role in the long-term treatment of patients with CML.
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Compuestos de Anilina , Leucemia Mielógena Crónica BCR-ABL Positiva , Nitrilos , Inhibidores de Proteínas Quinasas , Quinolinas , Humanos , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacología , Nitrilos/uso terapéutico , Nitrilos/farmacología , Quinolinas/uso terapéutico , Quinolinas/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Resultado del TratamientoRESUMEN
In 2015, dual T cell depletion with antithymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) combined with cyclosporine A (CsA) replaced our prior institutional graft-versus-host disease (GVHD) prophylaxis regimen of 4.5 mg/kg ATG, CsA, and mycophenolate mofetil (MMF) (ATG-based) in 10/10 HLA-matched unrelated donor (MUD) peripheral blood allogeneic hematopoietic stem cell transplantation (allo-HCT). The initial ATG dose of 4.5 mg/kg [ATG(4.5)/PTCy] was reduced to 2 mg/kg [ATG(2)/PTCy] in 2018. This study compares the results obtained from 444 adults undergoing MUD allo-HCT at our institution who received ATG(4.5)/PTCy (n = 127) or ATG(2)/PTCy (n = 223) with those who received ATG-based prophylaxis without PTCy (n = 84). The rates of grade II-IV and grade III-IV acute GVHD (aGVHD) at day +100 and moderate/severe chronic GVHD (cGVHD) at 1 year were 35.7%, 21.6%, and 14.7%, respectively, in patients receiving ATG-based prophylaxis without PTCy; 16.5%, 4.9%, and 4.3% in patients receiving ATG(4.5)/PTCy; and 23.3% (P = .004), 8.0% (P < .001), and 14.1% (P =.006) in patients receiving ATG(2)/PTCy. One-year overall survival (OS), nonrelapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) were 69.8%, 25.3%, and 52.0%, respectively, for patients receiving ATG-based prophylaxis without PTCy; 82.7%, 17.3%, and 59.8% for patients receiving ATG(4.5)/PTCy; and 78.3% (P = .446), 14.7% (P = 101), and 56.2% (P = .448) for patients receiving ATG(2)/PTCy. On univariate analyses, the use of ATG(2)/PTCy was associated with a lower risk of NRM (hazard ratio, .54; P = .023) compared with the use of ATG-based prophylaxis without PTCy. ATG(2)/PTCy prophylaxis effectively prevents GVHD and is associated with comparable relapse risk, OS, and GRFS as seen with ATG(4.5)/PTCy and ATG-based prophylaxis without PTCy.
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Suero Antilinfocítico , Ciclofosfamida , Ciclosporina , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Donante no Emparentado , Humanos , Suero Antilinfocítico/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Persona de Mediana Edad , Masculino , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Ciclofosfamida/uso terapéutico , Adulto , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación , Anciano , Trasplante Homólogo , Inmunosupresores/uso terapéutico , Adulto Joven , Resultado del Tratamiento , Antígenos HLA/inmunología , Adolescente , Estudios RetrospectivosRESUMEN
BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality following allogeneic hematopoietic cell transplantation (alloHCT). Letermovir is a novel antiviral agent that prevents CMV reactivation in alloHCT patients, with limited data regarding influence on post-alloHCT outcomes. METHODS: We retrospectively examined 273 alloHCT recipients, 158 in the non-letermovir cohort (NLC), and 115 in the cohort using letermovir prophylaxis (LC). Patients that received letermovir were CMV-seropositive and met criteria for high risk of CMV reactivation. RESULTS: Median start of letermovir was 21 days post-alloHCT, median duration of prophylaxis was 86 days. Letermovir prophylaxis demonstrated a statistically significant reduction in first CMV reactivation (at 200 days post 63.9% in the NLC vs. 35.7% in the LC; p < .001). On univariate analysis at 1 year, overall survival (OS) for NLC was 79.6% and 79.5% for LC (p = .54). Non relapse mortality (NRM) at 1 year for NLC was 12% and 12.3% for LC (p = .69). Cumulative incidence of relapse (CIR) at 1 year was 13.9% for NLC versus 17.1 for the LC (p = .27). On multivariable analysis, there was no significant difference between the two cohorts for OS, NRM, and CIR. CONCLUSIONS: Letermovir prophylaxis started at day +21 post-alloHCT reduced CMV reactivation, with no impact on posttransplant outcomes.
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Acetatos , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Quinazolinas , Humanos , Citomegalovirus , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Receptores de Trasplantes , Estudios Retrospectivos , Canadá/epidemiología , Antivirales/uso terapéuticoRESUMEN
INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is a rare complication of hematopoietic stem cell transplantation (HSCT). Primary prophylaxis for 6-12 months post-HSCT is the standard approach. However, there is no consensus regarding the optimal duration of prophylaxis. METHODS: We identified patients who developed PJP more than 1-year post-HSCT. All patients had previously received 12 months of PJP prophylaxis. PJP was diagnosed based on clinical findings and the detection of P. jirovecii in bronchoalveolar lavage (BAL) using polymerase chain reaction (PCR). The CD4+ T-cell percentage was determined using flow cytometry. Data expressed as median (interquartile range). RESULTS: Ten patients developed PJP at 17.5 months (16-24 months) post-HSCT. PJP diagnosis occurred 5.5 months (3-15 months) after discontinuing prophylaxis. Eight patients received anti-thymocyte globulin (ATG) as graft versus host disease (GVHD) prophylaxis. At diagnosis, only one patient had lymphopenia; all patients had CD4+ T-lymphocyte counts ≥0.2 × 109 /L (median 0.337 × 109 /L). Three patients had concomitant bacterial infections. The clinical presentation was mild; only three required hospitalization, none of them required intensive care and there were no deaths. CONCLUSION: There is a need to develop risk-adapted prophylactic strategies in the contemporary era using ATG-based GVHD prophylaxis.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Pneumocystis carinii , Neumonía por Pneumocystis , Humanos , Neumonía por Pneumocystis/diagnóstico , Neumonía por Pneumocystis/etiología , Neumonía por Pneumocystis/prevención & control , Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre/efectos adversos , Estudios RetrospectivosRESUMEN
Graft-versus host disease (GVHD) is one of the major limitations to allogeneic hematopoietic stem cell transplantation (HCT). Although corticosteroids with calcineurin inhibitors are established first line-therapy for chronic graft-versus-host disease (cGVHD), approximately one-half of cGVHD patients are refractory to corticosteroid therapy. The goal of the present study was to compare treatment outcomes of patients treated with extracorporeal photopheresis (ECP) and best available therapy (BAT) as third-line or beyond treatment for cGVHD. Using propensity score matching (PSM), treatment outcomes were compared between ECP-treated patients (n = 74) and a historical cohort of cGVHD patients treated with BAT (n = 132). By adjusting for unbalanced risk factors between the groups, including GVHD severity at the start of therapy, acute GVHD history, and baseline corticosteroid dose, 62 patients were balanced and selected for PSM. In the PSM cohort, the ECP group showed a 12-month failure-free survival (FFS) rate of 70.1% versus 32.5% in the BAT group (P < .0001; hazard rate [HR], .214), and 93.1% 12 months' overall survival (OS) rate of 93.1% versus 68.1% in the BAT group (P = .0249; HR, .3811); multivariate analysis confirmed ECP's superior FFS and OS compared with BAT. Generalized linear model analysis showed faster tapering of corticosteroids and higher rates of prednisone discontinuation in the ECP versus BAT PSM groups in the first 6 months. The ECP group also had a higher percentage of prednisone discontinuation, by 6% at month 0, by 14.9% at month 3, and by 22.5% at month 6. The current study demonstrates superior FFS, OS, and steroid tapering efficacy for ECP compared with BAT as third-line therapy or beyond in cGVHD patients.
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Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Fotoféresis , Humanos , Prednisona , Fotoféresis/efectos adversos , Puntaje de Propensión , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Corticoesteroides/uso terapéuticoRESUMEN
PURPOSE: Allogeneic stem cell transplant (allo-HSCT) patients are at risk of malnutrition and weight loss from impaired oral intake resulting from gastrointestinal toxicities, dysgeusia, and psychological effects. METHODS: A retrospective review of 264 adult patients transplanted at Princess Margaret Cancer Centre who achieved relapse-free survival up to 3 months after allo-HSCT was performed. RESULTS: Overall incidence of patients who experienced WL (WL) ≥ 10% from HSCT to 3-month post-transplant was 45.9% and from HSCT to 6 months was 56.6%. Patients with ≥ 10% WL from allo-HSCT at 3 months and 6 months had similar 2-year overall survival (OS) compared to those with < 10% WL, 55.7% vs 62.8% (HR = 1.38, p = 0.11) and 71.1% vs 77.2% (HR = 1.37, p = 0.27), respectively. Patients with ≥ 10% WL 3 and 6 months from allo-HSCT also had similar 2-year relapse-free survival (RFS) compared to those with < 10% WL, 48.1% vs 55.8% (HR = 1.26, p = 0.22), and 62.7% vs 69.8% (HR = 1.29, p = 0.31), respectively. The 2-year transplant-related mortality (TRM) was higher for those with ≥ 10% WL from allo-HSCT to 3 months, 35.4% vs 16.9% (HR = 2.39, p = 0.0007) and 6 months, 22% vs 8% (HR = 3.1, p = 0.0034). Although statistical significance was not observed for OS or RFS, patients who experienced ≥ 10% WL 3- and 6-months post allo-HSCT experienced higher 2-year TRM. These results highlight the importance of early intervention and close monitoring of weight post allo-HSCT. CONCLUSION: Approaches to WL post allo-HSCT should be multifaceted and include members of the interdisciplinary team in order to decrease TRM.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Desnutrición , Adulto , Humanos , Disgeusia , Trasplante de Células Madre , Pérdida de Peso , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
BACKGROUND: Extracorporeal photopheresis (ECP) is recommended as a second- or later-line therapy for chronic GvHD (cGvHD). Benefits include reasonable response with avoidance of intense systemic immunosuppression, which can translate into lowering the risk of systemic toxicity and opportunistic infection. METHODS: We evaluated 75 patients treated with ECP for cGvHD from 2007 to 2021 at Princess Margaret Cancer Centre, and analyzed overall response rate (ORR) and clinical benefit (CB) at 3, 6 and 12 months plus other long-term treatment outcomes. RESULTS: With a median follow-up of 72 months, a gradual increase in ORR was noted over time: 21% (16 out of 75 patients), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. Gradual increase in CB was also observed over time with CB rate of 23% (17/75), 62% (39/63), and 76% (35/46) at months 3, 6 and 12, respectively. A total of 27 failures (36%) were noted, due to: 1) ECP resistance requiring switch to other therapy (n = 14, 19%), 2) non-relapse mortality (n = 10, 13%), 3) relapse of primary disease (n = 1, 1%) or 4) ECP procedure-related complication (n = 1, 1%, line infection), with 20 deaths (27%) observed. Failure-free survival (FFS) and overall survival (OS) rates were 68.3% and 85.9% at 12 months, respectively. After starting ECP, the proportions of patients who completely discontinued steroids were 17%, 32%, and 64% at months 3, 6 and 12, respectively. CONCLUSION: ECP is an effective treatment option for heavily pre-treated cGvHD patients.