Impact of payment source, referral site, and place of residence on outcomes after allogeneic transplantation in Mexico.

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.

Increasing access to transplantation through telemedicine and patient navigation.

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.

Lactate dehydrogenase as a hematopoietic stem cell mobilization biomarker in autologous transplantation

ABSTRACT 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.

Comparison of CD4+/CD8+ Lymphocytic Subpopulations Pre- and Post-Antituberculosis Treatment in Patients with Diabetes and Tuberculosis.

Is there a CD4+ and CD8+ immunity alteration in patients with pulmonary tuberculosis (TB) and diabetes (DM) that does not recover after antituberculosis treatment? This prospective comparative study evaluated CD4+ and CD8+ lymphocytic subpopulations and antituberculosis antibodies in patients with diabetes and tuberculosis (TB-DM), before and after antituberculosis treatment. CD4+ T cell counts were lower in patients with TB-DM compared to those with only TB or only DM, and these levels remained low even after two months of anti-TB treatment. Regarding the CD8+ T cell analysis, we identified higher blood values in the DM-only group, which may be explained by the high prevalence of latent tuberculosis (LTBI) in patients with DM. IgM antituberculosis antibodies levels were elevated in patients with only TB at baseline, and 2 months post-anti-TB treatment, IgG did not express any relevant alterations. Our results suggest an alteration in CD4+ immunity in patients with TB-DM that did not normalize after antituberculosis treatment.

Real-world practice of acute leukemia intrathecal chemotherapy administration: A Mexican nationwide survey

ABSTRACT Introduction: Intrathecal chemotherapy is a mainstay component of acute lymphoblastic leukemia treatment. In Mexico, there is a considerable practice variability in aspects, such as the manner of preparation and the administration technique. Objective: Our objective was to describe the different techniques used for the application of ITC and review the existing recommendations in the literature. Method: A cross-sectional, nationwide survey study was conducted by an electronic questionnaire sent to hematologists and oncologists in Mexico. We collected demographic data, personal experience, intrathecal chemotherapy techniques, drug preparation and postprocedural conduct. Results: We received 173 responses. Twenty percent had an anesthesiologist administering sedation and pain management. The platelet count considered safe was 50 × 109/L in 48% of the participants. In 77% (n = 133) of the cases, the conventional needle with stylet used was, 49% did not receive any added diluent in the intrathecal chemotherapy and only 42% were recommended to rest in a horizontal position for more than 30 min. Conclusion: We identified a considerable variation in the administration of intrathecal chemotherapy across the hematologists in Mexico. We discuss the implications and opportunities in reducing the variation in our setting, highlighting the unmet need to establish guidelines that should be evaluated by the Mexican professional society to produce a position paper regarding practice standardization.

Acute Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The Good, the Bad, and the Ugly of Isolated Extramedullary Relapse in a Latin American Population.

Hematopoietic stem cell transplantation (HSCT) is an effective therapy for acute leukemia (AL). Relapse represents the main cause of mortality. Isolated extramedullary relapse (iEMR) is atypical and has been related to better outcomes. Here we describe the clinical characteristics and outcomes of AL relapse after HSCT in our study population and analyze the impacts of different types of relapse on survival outcomes. This retrospective, multicenter study included 124 patients age ≥15 years with AL who underwent HSCT between 2004 and 2019. At diagnosis, 66.1% of the patients had lymphocytic AL, 19.7% presented with high-risk features, and 18.5% had extramedullary disease (EMD). At HSCT, 83.1% of the patients were in complete remission (CR), and 44.8% had negative measurable residual disease (MRD). The vast majority of donors were related (96%), including 48.4% HLA-matched and 47.6% haploidentical. Myeloablative conditioning was provided to 80.6% of patients. The median overall survival (OS) was 15 months (95% confidence interval [CI] 9.9 to 20.1 months). Factors associated with improved OS were adolescent and young adult (AYA) patient (P = .035), first or second CR (P = .026), and chronic graft-versus-host disease (GVHD) (P < .001). Acute GVHD grade III-IV (P = .009) was associated with increased mortality. The median relapse-free survival was 13 months (95% CI, 7.17 to 18.8 months); early disease status (P = .017) and chronic GVHD (P < .001) had protective roles. Sixty-eight patients (55%) relapsed after HSCT, with a median time to relapse of 6 months (95% CI, 3.6 to 8.4 months). iEMR was reported in 16 patients (23.5%). The most commonly involved extramedullary sites were the central nervous system and skin. Compared to patients with bone marrow relapse, all patients with iEMR had a diagnosis of acute lymphoid leukemia (P = .008), and 93.8% belonged to the AYA group; regarding pre-HSCT characteristics, iEMR patients had higher rates of negative MRD (P = .06) and a history of EMD (P = .009). Seventy-seven percent of relapsed patients received additional treatment with curative intent. The median OS after relapse (OSr) was 4 months (95% CI, 2.6 to 5.4 months). Factors related to increased OSr included lymphoid phenotype (P = .03), iEMR (P = .0042), late relapse (≥6 months) (P = .014), receipt of systemic therapy including second HSCT (P < .001), and response to therapy (P < .001). Rates of relapse and iEMR were higher than those previously reported in other studies. Advanced disease, reduced-intensity conditioning, and a diminished graft-versus-leukemia effect were factors influencing these findings. At relapse, presenting with iEMR after 6 months and receiving intensive therapy with adequate response were associated with better outcomes. Our results strongly suggest that a personalized approach to treating patients with HSCT is needed to counterbalance specific adverse factors and can positively impact clinical outcomes.

Lactate dehydrogenase as a hematopoietic stem cell mobilization biomarker in autologous transplantation.

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.

Orbital myeloid sarcoma treated with low-dose venetoclax and a potent cytochrome P450 inhibitor.

CASE REPORT: We report the first case of orbital myeloid sarcoma that was successfully treated with a standard venetoclax dose of 25%. A 38-year-old man with acute myeloid leukemia (AML) post-haplo-hematopoietic stem cell transplantation (HSCT) presented with a nine-month history of progressive right proptosis and a visual acuity deficit. The patient was treated with venetoclax (100 mg orally on days 1-28), cytarabine (40 mg subcutaneously, days 1-10), and itraconazole (100 mg twice daily orally on days 1-28). MANAGEMENT AND OUTCOME: The present case report shows that using cytochrome P450 (CYP) inhibitors is a helpful strategy to reduce the cost of expensive treatments. DISCUSSION: There are limited data on the use of CYP inhibitors as a strategy to reduce the costs of expensive drugs (i.e. venetoclax). This approach has some advantages over standard dose venetoclax (400 mg/day) such as significantly reduced costs (which is relevant for patients in low-income countries). In this case, we used itraconazole-a potent CYP3A4 inhibitor-which can theoretically reduce the dose to 100 mg/day without losing serum therapeutic concentrations.

Real-world practice of acute leukemia intrathecal chemotherapy administration: A Mexican nationwide survey.

INTRODUCTION: Intrathecal chemotherapy is a mainstay component of acute lymphoblastic leukemia treatment. In Mexico, there is a considerable practice variability in aspects, such as the manner of preparation and the administration technique. OBJECTIVE: Our objective was to describe the different techniques used for the application of ITC and review the existing recommendations in the literature. METHOD: A cross-sectional, nationwide survey study was conducted by an electronic questionnaire sent to hematologists and oncologists in Mexico. We collected demographic data, personal experience, intrathecal chemotherapy techniques, drug preparation and postprocedural conduct. RESULTS: We received 173 responses. Twenty percent had an anesthesiologist administering sedation and pain management. The platelet count considered safe was 50 × 109/L in 48% of the participants. In 77% (n = 133) of the cases, the conventional needle with stylet used was, 49% did not receive any added diluent in the intrathecal chemotherapy and only 42% were recommended to rest in a horizontal position for more than 30 min. CONCLUSION: We identified a considerable variation in the administration of intrathecal chemotherapy across the hematologists in Mexico. We discuss the implications and opportunities in reducing the variation in our setting, highlighting the unmet need to establish guidelines that should be evaluated by the Mexican professional society to produce a position paper regarding practice standardization.

Cytochrome P450 inhibition to decrease dosage and costs of venetoclax and ibrutinib: A proof-of-concept case study.

The inhibition of cytochrome P450 (CYP) enzymes is the most frequent cause of drug-drug interactions. Many safe, inexpensive and widely available therapeutic drugs can inhibit CYP enzymes (e.g., azoles). Also, the specific potency of inhibition and the targeted CYP enzyme have been well described (e.g., itraconazole strongly inhibits CYP enzyme 3A4 and, in turn, CYP3A4 metabolizes venetoclax and ibrutinib). CYP enzyme inhibitors increase the plasma concentration of other drugs via shared metabolic pathways. We herein present the effects of inhibiting CYP enzymes with itraconazole-venetoclax for the treatment of refractory acute myeloid leukaemia, as well as itraconazole-ibrutinib to treat steroid-refractory acute graft vs. host disease in the same patient. Both of the patient's conditions responded completely. This appears to be a feasible strategy that decreases treatment costs by 75%. Previous Food and Drug Administration recommendations and clinical data support these subsequent dose reductions. Eleven months after the transplant, the patient remains in complete response and with no minimal residual disease. Another patient had been effectively treated before with CYP enzyme inhibition prior to venetoclax-itraconazole administration for orbital myeloid sarcoma. Thus, this case study furthers information on the CYP enzyme inhibition strategy when associated with another costly drug, ibrutinib. The CYP enzyme inhibition strategy could be applied to many more anticancer drugs (e.g., ruxolitinib and ponatinib) and facilitate the availability of expensive oncological treatments in low- and middle-income countries. Also, this strategy could be further generalized by using different CYP enzyme inhibitors with varied pharmacokinetic and pharmacodynamic properties (i.e., grapefruit, azoles and clarithromycin).

Hematopoietic stem cell transplantation activity in Mexico during the COVID19 pandemic: on the way to recovery.

OBJECTIVE: To analyze the number of HSCTs performed in 2019 vs. 2020 and report the status of transplant centers (TCs) during and a year after the COVID-19 pandemic. METHODS: We performed a comprehensive cross-sectional nationwide study including active TCs interrogating HSCT activity from 2019 through September 2021. An electronic survey was sent to TCs and consisted of items regarding the number and characteristics of procedures performed and were compared yearly. Changes to their institutions' transplant policies and practices during the COVID19 pandemic were also documented. Fifty centers were invited to participate, 33 responded. RESULTS: Most TCs were part of the public health system (63.7%). Almost half are in the country's capital, Mexico City (45.5%). Most centers performed <10 procedures per year. The number of HSCTs decreased from 835 in 2019-505 in 2020 (p < .001), representing a 40% reduction in transplant activity. The monthly transplant rate in 2021 increased to 58.3, compared to 42 in 2020 and close to 69.5 in 2019 (p < .001). All types of HSCTs decreased excluding haploidentical transplants. All institutions treated patients with COVID19, and over two-thirds experienced some form of hospital reconversion. Transplant activity stopped completely in 23 TCs (70%) during the pandemic with a median closure duration of 9.9 months (range, 1-21). In 2021, 9.1% of TCs remained closed, all of them in the public setting. CONCLUSION(S): The limited transplant activity in Mexico decreased significantly during the pandemic but is recovering and nearly in pre-pandemic levels.

Diagnosis and treatment of acute lymphoblastic leukemia in Latin America.

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.

Oseltamivir as rescue therapy for persistent, chronic, or refractory immune thrombocytopenia: a case series and review of the literature.

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.

Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America.

Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America.Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML.Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100-600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7-15.5) and 8 months (95% CI 4.8-11.2).Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials.Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.

Desensitization to Brentuximab Vedotin after anaphylaxis in refractory Hodgkin's lymphoma.

INTRODUCTION: Brentuximab vedotin (BV) is a monoclonal antibody that targets CD30 antigen. It is indicated for the treatment of CD30 + lymphomas and classical Hodgkin lymphoma (HL), including advanced (stage III-IV) untreated disease, relapsed/refractory disease, and consolidation after autologous hematopoietic stem cell transplantation. In clinical trials the incidence of a hypersensitivity reaction is 1.2%. CASES REPORT: We present 3 cases of patients with refractory HL and anaphylaxis to the administration of BV ( Table 1). Symptoms are analyzed using a grading system described by Brown (2004) and a desensitization protocol was performed with a total dose of 100 mg of BV in 4 solution bags with an initial concentration of 1:1000 of total dose for cases of severe anaphylaxis, and desensitization of 3 solution bags with baseline concentration of 1: 100 for cases of moderate anaphylaxis. MANAGEMENT & OUTCOME: Intradermal skin tests were positive. Before desensitization, premedication with methylprednisolone and chlorphenamine was administered, as well as fluid therapy with 0.9% physiological solution at 100 cc/hour at induction stage, 250 cc/hour at maintenance stage, and increased to 500 cc/hour in case of hypersensitivity reaction. DISCUSSION: Drug desensitization in 12 or 16 steps allows tolerable administration of brentuximab vedotin after moderate to severe anaphylaxis. The favorable response to treatment of these patients may indicate that desensitization is a viable strategy for patients with relapsed or refractory HL.