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Chimeric Antigen Receptor T-cell (CAR-T) therapies are transforming the treatment of B-cell lymphoproliferative disorders and multiple myeloma, yet global access challenges and barriers for their implementation persist. Global access disparities persist, particularly for persons living in low and middle-income countries and for underserved populations in high income countries. In this review we address patient-related factors including age, comorbidities, fitness, race and ethnicity, and geographic location for CAR-T access. Also, we review disease-related and health system barriers like disease biology, potential for short and long-term toxicity, insurance access, referrals, supply and manufacturing, regulation, costs and treatment center capacity. Lastly, alternatives for overcoming these barriers exemplified by research efforts worldwide are discussed, emphasizing the need for a multifaceted approach from all stakeholders to improve global accessibility and ensure equitable access and improved outcomes for patients worldwide.
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Acute myeloid leukemia (AML) is the most frequent indication for allogeneic hematopoietic cell transplantation (alloHCT) worldwide; social and health system barriers limit its access. We performed an observational retrospective analysis in Mexico to analyze factors limiting alloHCT in fit patients with AML. With a median follow-up of 11.8 months, 301 patients were included, with a median age of 42; 33.5% were classified as adverse risk. Despite 215 patients (92.5%) achieving complete remission, only 103 (34%) had HLA-typing: 44.5% had a matched-sibling donor (MSD), 32% a haploidentical donor, and 23.5% had no donor. Only 23.5% of patients had an HCT consult; merely 36 underwent an HCT: 30 alloHCT, and six an autologous HCT. Age ≥ 60 years, HCT-CI score ≥ three, and the absence of a local transplant program negatively influenced HLA typing likelihood. Patients with an MSD had a higher alloHCT likelihood. The cumulative incidence of transplant (CIT) and relapse (CIR) at 6 and 12 months was 7.3% and 13.8%, 8.2% and 13%, respectively. A lack of HLA-typing was associated with a lower CIT (p < 0.001) and higher CIR (p = 0.033) (HR 11.72, CI 95% 4.39-31.27, p < 0.001), while the presence of an MSD was associated with a higher CIT (p = 0.002) (HR 4.22, CI 95% 1.89-9.44, p < 0.001). The main reasons hindering alloHCT are the lack of access to HLA-typing tests and the absence of an MSD. A national donor registry and improved HLA-typing accessibility are critical for increasing alloHCT access in Mexico.
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OBJECTIVE: To document the results of outpatient hematopoietic stem cell transplantation (HSCT) from the peripheral blood (PB) of sibling donors without anti-thymocyte globulin (ATG) in the conditioning regimen. MATERIAL AND METHODS: Patients from a low-income population with severe AA who received a PB, unmanipulated sibling HLA-identical HSCT between 2000 and 2020 at a single institution were studied. Survival was the primary outcome. RESULTS: Forty-one transplants were performed. Time between diagnosis and transplant was five months (1-104). Median age was 37 (range, 4-61) years; 25 (61 %) recipients were males and 32 (78 %) had treatment failure, 9 (22 %) have not received treatment. ATG was administered in 5 (12.2 %) cases; the graft source was PB in 38 (92.7 %) transplants. Twenty-six (63.4 %) transplants were carried out in the outpatient setting. Infections developed in 14 (34.1 %) patients. Primary graft failure (GF) occurred in 3 (7.3 %) patients. The 15-year OS was 81 %, EFS was 77.4 %. Patients with high pre-HSCT transfusion burden had lower OS (p = 0.035) and EFS (p = 0.026). Previous treatment failure and age were not associated with lower OS (p = 0.115, p = 0.069) or EFS (p = 0.088, p = 0.5, respectively). CONCLUSIONS: HLA-identical T-cell replete outpatient HSCT from the PB of sibling donors for AA patients using ATG-free conditioning offers excellent long-term survival.
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BACKGROUND: The impact of social determinants of health in allogeneic transplant recipients in low- and middle-income countries is poorly described. This observational study analyzes the impact of place of residence, referring institution, and transplant cost coverage (out-of-pocket vs government-funded vs private insurance) on outcomes after allogeneic hematopoietic stem cell transplantation (alloHSCT) in two of Mexico's largest public and private institutions. AIM: To evaluate the impact of social determinants of health and their relationship with outcomes among allogeneic transplant recipients in Mexico. METHODS: In this retrospective cohort study, we included adolescents and adults ≥ 16 years who received a matched sibling or haploidentical transplant from 2015-2022. Participants were selected without regard to their diagnosis and were sourced from both a private clinic and a public University Hospital in Mexico. Three payment groups were compared: Out-of-pocket (OOP), private insurance, and a federal Universal healthcare program "Seguro Popular". Outcomes were compared between referred and institution-diagnosed patients, and between residents of Nuevo Leon and out-of-state. Primary outcomes included overall survival (OS), categorized by residence, referral, and payment source. Secondary outcomes encompassed early mortality, event-free-survival, graft-versus-host-relapse-free survival, and non-relapse-mortality (NRM). Statistical analyses employed appropriate tests, Kaplan-Meier method, and Cox proportional hazard regression modeling. Statistical software included SPSS and R with tidycmprsk library. RESULTS: Our primary outcome was overall survival. We included 287 patients, n = 164 who lived out of state (57.1%), and n = 129 referred from another institution (44.9%). The most frequent payment source was OOP (n = 139, 48.4%), followed by private insurance (n = 75, 26.1%) and universal coverage (n = 73, 25.4%). No differences in OS, event-free-survival, NRM, or graft-versus-host-relapse-free survival were observed for patients diagnosed locally vs in another institution, nor patients who lived in-state vs out-of-state. Patients who covered transplant costs through private insurance had the best outcomes with improved OS (median not reached) and 2-year cumulative incidence of NRM of 14% than patients who covered costs OOP (Median OS and 2-year NRM of 32%) or through a universal healthcare program active during the study period (OS and 2-year NRM of 19%) (P = 0.024 and P = 0.002, respectively). In a multivariate analysis, payment source and disease risk index were the only factors associated with overall survival. CONCLUSION: In this Latin-American multicenter study, the site of residence or referral for alloHSCT did not impact outcomes. However, access to healthcare coverage for alloHSCT was associated with improved OS and reduced NRM.
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BACKGROUND: Hematopoietic cell transplantation (HCT) is a promising treatment for hematological diseases, yet access barriers like cost and limited transplant centers persist. Telemedicine-based patient navigation (PN) has emerged as a solution. This study presents a cost-free PN telemedicine clinic (TC) in collaboration with the National Marrow Donor Program. AIM: to assess its feasibility and impac on HCT access determined by the cumulative incidence of transplantation. METHODS: In this single-center cohort study, patients of all ages and diagnoses referred for HCT participated. Two transplant physician-navigators established patient relationships via video calls, collecting medical history, offering HCT education and recommending pretransplant tests. The analysis involved descriptive statistics and intent-to-transplant survival assessment. RESULTS: One hundred and three patients were included of whom n = 78 were referred for allogeneic HCT (alloHCT), with a median age of 28 years. The median time from initial contact to the first consult was 5 days. The cumulative incidence of transplantation was 50% at 6 months and 61% at 12 months, with varying outcomes based on HCT type. Notably, 49 patients were not transplanted, primarily due to refractory disease, progression or relapse (57.1%). Autologous HCT candidates and physician referrals were correlated with higher transplant success compared to alloHCT candidates and patients who were not referred by a physician. CONCLUSION: Our pretransplant TC was feasible, facilitating access to HCT. Disease relapse posed a significant barrier. Enhancing timely physician referrals should be a focus for future efforts.
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Objectives: Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been reported to be between 0% and 30%. In 2018, we identified a pGF incidence of 35% in our pediatric haplo-HSCT recipients with hematologic malignancies, which motivated us to enact changes to the conditioning regimen.Methods: We performed a single-center prospective, pre-post study of consecutive patients under 16 years with hematologic malignancies, from January 2015 to December 2022 who received a haplo-HSCT. Twenty-six pediatric patients received a haplo-HSCT before September 2018 (G1) and 36 patients after (G2). The main conditioning regimen for G1 was myeloablative with Flu/Cy/Bu, and for G2 the main regimen was reduced intensity Flu/Cy/Mel/TBI2.Results: Nine patients (35%) in G1 had primary graft failure, while in G2 there were no patients with pGF. The median follow-up for G1 was 15.9 months, and for G2 was 24.8 months, with an estimated overall survival at 12 months of 63% (95% CI 47-76) versus 85% (95% CI 73-93), and at 24 months of 47% (95% CI 31-64) versus 70% (95% CI 54-82) respectively (p = .007).Conclusion: After September 2018 conditioning regimen modifications were implemented with the objective of reducing primary failure, consisting mainly of switching from busulfan to melphalan as the alkylating agent of choice, and adding, when clinically possible TBI. Primary failure has been significantly reduced in our institution since then.
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Neoplasias Hematológicas , Melfalan , Humanos , Criança , Estudos Prospectivos , Transplante Haploidêntico , BussulfanoRESUMO
OBJECTIVES: We have analyzed the association of delayed both diagnosis and treatment of persons with MS with the long-term results of patients given autologous hematopoietic stem cell transplantation (aHSCT). METHODS: Patients with MS referred to the HSCT-Mexico program were included in the study; in 103, detailed pre- and post-transplant evolution could be recorded. Two groups of patients were analyzed according to the time of evolution between the onset of symptoms and the definite diagnosis of MS: more than 8 months (delayed diagnosis, DD), or less than 8 months (non-delayed diagnosis, NDD). The progression of MS was assessed by changes in the expanded disability status scale (EDSS). RESULTS: The time elapsed between the onset of symptoms and the correct diagnosis was lower for the NDD group (1.55 vs. 35.87 months, p<0.05). Both groups of patients showed a similar EDSS score at diagnosis (1.5 vs. 1.5); however, the EDSS at the time of the transplant was higher in the DD group (4.5 vs. 3.0, p=0.3) and the response of the EDSS score to the transplant was significantly better for the NDD group, the last EDSS scores being 2.5 vs. 4.25 (p=0.03). Both groups of patients responded to aHSCT by diminishing the EDSS, but the response was significantly better in the NDD group. CONCLUSIONS: These data indicate that both the pre-transplant progression of the disease and the response to aHSCT were significantly worse in the DD group. An early diagnosis and an early aHSCT intervention are critical for a good prognosis, in terms of lowering and stabilizing the motor disability in MS patients given autografts.
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Diagnóstico Tardio , Progressão da Doença , Transplante de Células-Tronco Hematopoéticas , Esclerose Múltipla , Transplante Autólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Masculino , Adulto , Esclerose Múltipla/terapia , Esclerose Múltipla/diagnóstico , Pessoa de Meia-Idade , Fatores de Tempo , México , Adulto Jovem , Avaliação da Deficiência , Resultado do TratamentoRESUMO
BACKGROUND: HLA compatibility predicts allogeneic hematopoietic cell transplant (allo-HCT) and graft-versus-host disease (GvHD) outcomes. There is insufficient information regarding GvHD outcomes for outpatient HLA-identical and haploidentical-HCT employing reduced-intensity conditioning (RIC). RESEARCH DESIGN AND METHODS: We compare GvHD outcomes between donor types and report risk factors associated with GvHD. Stem cell source was T-cell replete peripheral blood. GvHD prophylaxis was post-transplant cyclophosphamide (PT-CY), mycophenolic acid, and calcineurin inhibitors for haploidentical (n = 107) and oral cyclosporine (CsA) plus methotrexate i.v. for HLA-identical (n = 89) recipients. RESULTS: One hundred and ninety-six HCT transplant patients were included. aGvHD and cGvHD frequency were similar between HCT types. aGvHD severity was comparable, but severe cGvHD was less frequent in the haploidentical group (p = .011). One-hundred-day cumulative incidence (CI) of aGvHD for haploidentical and HLA-identical was 31% and 33% (p = .84); 2-year CI of cGvHD was 32% and 38% (p = .6), respectively. Haploidentical recipients had less steroid-refractory cGvHD (p = .043). Patients with cGvHD had less 2-year relapse (p = .003); both aGvHD and cGvHD conferred higher OS (p = .010 and p = .001), respectively. Male sex was protective for steroid-refractory cGvHD (p = .028). CONCLUSIONS: Acute and chronic GvHD rates were comparable between HLA-identical and haploidentical transplant groups. cGvHD severity was lower in the haploidentical group.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pacientes Ambulatoriais , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/epidemiologia , Ciclofosfamida/uso terapêutico , Esteroides , Condicionamento Pré-Transplante/efeitos adversosRESUMO
BACKGROUND: While second-generation tyrosine kinase inhibitors (TKI) revolutionized treatment for patients with chronic myeloid leukemia (CML) who developed a suboptimal response to imatinib, many patients in developing countries are fixed to the latter due to socioeconomic barriers. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. METHODS: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to a standard dose of imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights. Our primary outcome was overall survival (OS) at 150 months. Our secondary outcomes were disease-free survival (DFS) at 150 months and adverse events. RESULTS: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. No difference was found in the 150-month overall survival risk (RR: 95% CI 0.91, 0.55-1.95, P-value = .77; RD: -0.04, -0.3 to 0.21, P-value = .78) and disease-free survival (RR: 1.02, 95% CI 0.53-2.71, P-value = .96; RD: 0.01, -0.26 to 0.22, P-value = .96). There was also no difference in the incidence of adverse events in either group. CONCLUSION: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. If impossible, however, our findings suggest that patients treated with high-dose imatinib have a similar overall survival and disease-free survival prognosis to patients receiving a second-generation TKI.
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Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Hispânico ou Latino , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Estudos Retrospectivos , Substituição de MedicamentosRESUMO
Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1-21, itraconazole 100 mg twice daily from days 1-21, and azacytidine 100 mg subcutaneously, once daily from days 1-7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25-73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.
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OBJECTIVE: to review the current diagnostic and therapeutic landscape of AML in Latin America as a reflection of other low- and middle-income countries and regions of the world. Encompassing both acute promyelocytic and non-promyelocytic disease types. METHODS: We reviewed the literature and study registries concerning epidemiological features of patients with AML/APL treated in Latin America, as well as evaluated diagnostic and genetic stratification and patient fitness assessment challenges, the importance of early mortality and supportive care capacity, intensive and non-intensive chemotherapy alternatives, consolidation, and maintenance strategies including novel agents and hematopoietic stem cell transplantation. RESULTS: Although most of the current technologies and treatment options are available in the region, a significant fraction of patients have only limited access to them. In addition, mortality in the first weeks from diagnosis is higher in the region compared to developed countries. CONCLUSIONS: Disparities in access to technologies, supportive care capacity, and availability of novel agents and HSCT hinder results in our region, reflecting barriers common to other LMICs. Recent developments in the diagnosis and treatment of this disease must be implemented through education, collaborative clinical research, and advocacy to improve outcomes.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína , América Latina/epidemiologia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
INTRODUCTION: Pre-apheresis peripheral blood CD34+ cell count (PBCD34+) is the most important predictor of good cell mobilization before hematopoietic stem cell transplantation, albeit flow cytometry is not always immediately available. Identification of surrogate markers can be useful. The CD34+ cells proliferate after mobilization, resulting in elevated lactate dehydrogenase (LDH) activity and correlating with the PBCD34+ count. OBJECTIVE: To determine the LDH cut-off value at which adequate CD34+ cell mobilization is achieved and its diagnostic yield. MATERIALS AND METHODS: A total of 103 patients who received an autologous stem cell transplantation (ASCT) between January 2015 and January 2020 were included. Demographic and laboratory characteristics were obtained, including complete blood count, pre-apheresis PBCD34+ and LDH levels. Receiver operating characteristic (ROC) curves were performed to identify the optimal serum LDH activity cut-off points for ≥ 2 and ≥ 4 × 106 cells/kg post-mobilization CD34+ count and their diagnostic yield. RESULTS: A post-mobilization serum LDH cut-off value of 462 U/L yielded a sensitivity (Se) = 86.8% (positive predictive value [PPV] = 72.7%), a pre- and post-mobilization serum LDH difference cut-off value of 387 U/L, an Se = 45.7% (PPV = 97%) and an LDH ratio of 2.46, with an Se = 47.1% (PPV = 97%) for an optimal mobilization count (CD34+ ≥ 4 × 106). CONCLUSION: The LDH measurement represents a fast and affordable way to predict PBCD34+ mobilization in cases where flow cytometry is not immediately available. According to the LDH diagnostic yield, it could be used as a surrogate marker in transplant centers, supporting the CD34+ count, which remains the gold standard.
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BACKGROUND: B-cell acute lymphoblastic leukemia is frequent in Hispanic adolescents and young adults. Outcomes of implementation of pediatric-inspired regimens in low-and middle-income countries are not well known. METHODS: In this study we treated 94 adolescents and young adults with a local BFM regimen designed to be affordable with the use of native L-asparaginase and mitoxantrone administered in an outpatient fashion, and the of BCR/ABL and measurable residual disease (MRD) determined by high sensitivity flow cytometry for risk stratification. RESULTS: Induction mortality was 11%; 25% of patients had to abandon treatment or be transferred to another health system. Two-year overall (OS) and event free survival (EFS) were 61.5% and 49.8%, MRD-negative patients had a 24-month OS of 85.6% vs. 69.6% (p = .024) and EFS of 76% vs. 45.5% (p = .004). Patients older than 40 years and those who abandoned treatment had worse EFS. Overall drug costs in our regimen were 52% lower than those of CALGB10403. CONCLUSION: The treatment of AYAs with ALL with an outpatient focus was implemented successfully at a reduced cost. Genetic risk assessment, treatment abandonment and lack of access to novel therapies remain major barriers for improving outcomes.
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Pacientes Ambulatoriais , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Humanos , Adulto Jovem , Intervalo Livre de Doença , Asparaginase/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prognóstico , Resultado do TratamentoRESUMO
OBJECTIVE: to discuss the status and challenges associated with the management of acute lymphoblastic leukemia (ALL) in Latin America. METHODS: This review summarizes various insights gained from information regarding diagnostic approaches and treatment strategies in adult patients with ALL in Latin American Countries. RESULTS: Information regarding ALL in Latin America is scarce; however, many efforts have been made to overcomes these barriers. Nevertheless, major obstacles to successful treatment in Latin America and LMIC remain poor adherence, abandonment of treatment, and lack of supportive therapy and new therapeutic agents. CONCLUSION: Further improvements in survival should be pursued by developing more Latin American registries, forming cooperative groups, developing educational models to facilitate earlier diagnosis and prevention of complications, better support therapy and management of infections, and adapting treatment strategies.
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Países em Desenvolvimento , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , América Latina/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
INTRODUCTION: Primary immune thrombocytopenia (ITP) is an acquired bleeding disorder. Conventionally, first-line ITP therapy aims to obtain a rapid response and stop or decrease the risk of bleeding by increasing the platelet count. At this point, the duration of the response, the tolerability, and the long-term safety of pharmacologic interventions are considered less of a priority. Combination treatments that simultaneously address multiple disease mechanisms are an attractive strategy to increase efficacy in acute ITP therapy. In this review, we discuss the treatment of newly diagnosed ITP patients, emphasizing the use of new combinations to benefit from their synergy. AREAS COVERED: This article summarizes conventional treatment, recent and novel combinations, and COVID-19 management recommendations of newly diagnosed ITP patients. EXPERT OPINION: The key areas for improvement consider the long-term effects of conventional first-line therapy, reducing relapse rates, and extending responses to achieve long-term remission. Although corticosteroids remain a first-line therapy, restricting their use to avoid toxicity and the increasing use of rituximab and TPO-RAs in the first three months after diagnosis open the landscape for future interventions in frontline therapy for ITP. First-line therapy intensification or synergistic drug combination offers a potential and realistic shift in future treatment guidelines.
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COVID-19 , Púrpura Trombocitopênica Idiopática , Trombocitopenia , COVID-19/terapia , Humanos , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/terapia , Rituximab/uso terapêuticoRESUMO
Immune thrombocytopenia (ITP) is an autoimmune disease that results from antibody-mediated platelet destruction and impaired platelet production. Novel therapies have emerged in the last decade, but 15-20% of patients will relapse or fail and require further therapy. We performed a prospective, single-arm intervention study on seven patients with chronic, persistent, or refractory ITP from the Hospital Universitario "Dr. José E González", in Monterrey, Mexico between 2015 and 2019. Eligible patients received oral oseltamivir 75 mg twice daily for 5 days and were followed up for six months. Most patients received a median of three distinct therapies (range 2-6). Four patients (57.1%) received combined therapy. The median time for any response was 55.5 days (range = 14-150). All patients responded at some point in time (ORR = 100%, six had a proportion of loss of response [PR], and one achieved [CR]). Six months after oseltamivir administration, three patients (42.9%) maintained a response, and one patient had a CR (14.3%). Oseltamivir was well tolerated with a good overall response rate and was useful for treating chronic ITP. We observed an initial increase in the number of platelets; however, this response was not maintained.