Background: Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). Chemotherapy with Hyper-CVAD has been widely used with poor outcomes, with a 3-year overall survival (OS) of 25.7% in this group of age. In low-and middle-income countries (LMIC), limitations in supportive care such as low access to neutrophil stimulant agents, antifungal prophylaxis and limited intensive care access, may increase treatment-related mortality. On the other hand, reports suggest that specific high-risk subgroups may be more frequent in Hispanic patients from Mexico and Central America. We hypothesize that the use of a less-myeloablative regimen, based on L-asparaginase could overcome the bad outcomes previously reported. Methods We modified the original CALGB 10403 based on local drug-access. We include patients with newly diagnosed Philadelphia-negative B- or T-cell ALL between 14-49 years from 4 centers in Mexico and one in Guatemala. We modified the regimen as following: replaced pegaspargase by E. Coli asparaginase, thioguanine by 6-mercapatopurine and incorporate rituximab 375mg/m2 for 6 doses in CD20 positive patients. After the first interim analysis (October 2019), we replaced the prednisone by dexamethasone during induction. Minimal residual disease (MRD) was assessed by flow cytometry after induction and after first consolidation. We considered high-risk karyotype if MLL-rearrangements, complex or hypodiploid and high-white blood cell count (WBC) if >30 x10 3/mcL for B-ALL or >100 x10 3/mcL for T-ALL. The main objective was to evaluate OS and as secondary objectives to evaluate complete response (CR) rate, relapse-free survival (RFS) and to assess the safety of this regimen. Results From January 2017 to December 2020, 95 patients have been enrolled with a median age of 23 years (range 14-49). One third (34.6%) had overweight and 11.7% were obese. The majority (92.6%) had a B-cell ALL and a normal karyotype (81.2%). The median WBC was 18.4 x10 3/mcL (0.2-427.7) and 40.9% had a high-WBC. During induction, adverse events (AE) included grade 3/4 elevated bilirubin (21.1%), transaminases (14.7%), hyperglycemia (14.7%), hypofibrinogenemia (44.2%), thrombosis (10.5%), hypersensitivity (2.2%) and pancreatitis (2.1%). During consolidation, AE included grade 3/4 hepatic toxicity (18.9%), hypertriglyceridemia (14.8%), thrombosis (5.3%) and pancreatitis (2.1%). Neutropenic fever occurred in 55.8% during induction (grade 4: 31.5%), and in 32.9% during consolidation (grade 4/5: 5.3%). A dose adjustment due to AE was required in 22.1% during induction and in 23.2% during consolidation. The induction related-mortality (IRM) rate was 7.4% The CR rate was 87.8%. After-induction, MRD was <0.01% in 39.1%, 0.01-0.1% in 39.1% and > 0.1% in 24.6%. Post-consolidation MRD was only measured in 43 patients and was <0.01% in 37.2%. During follow-up, 26.7% relapsed: 62.5% bone marrow (BM) relapses, 25.0% central nervous system (CNS) relapses and 12.5% CNS + BM relapses. Eight patients (8.4%) received an allogeneic-stem cell transplant (HSCT) as consolidation. The 2-year OS was 72.1%. The post-induction MRD <0.1% was associated with a better OS (figure 1A) (HR: 0.17 (95%CI: 0.06-0.55), p=0.003) and a high-WBC with an inferior OS (figure 1B) (HR: 4.13 (95%CI: 1.68-10.14), p=0.002). The 2-year RFS was 65.2%. The post-induction MRD <0.1% was associate with a better RFS (figure 1C) (HR: 0.19 (95%CI: 0.07-0.50), p=0.001) and a high-WBC and overweight / obesity with an inferior RFS (HR: 4.08 (95%CI: 1.71-9.73), p=0.001 and 2.50 (95%CI: 1.06-5.86), p=0.036 respectively) (figure 1D). Conclusions: The adoption of modified CALGB10403 regimen in Central America based on local resources is feasible. It is associated with a significant improvement in the OS and decrease in IRM when compared with previous reports. Despite a very high-rate of hepatic and metabolic toxicities, these were manageable. As reported by other groups, MRD, high-WBC and overweight/obesity are associated with poor outcomes. Despite being encouraging results, a significant number of patients persist with positive MRD and the main cause of dead is disease progression. Access to cellular therapies, and BiTes is cost restricted in LMIC. Hence, we should generate strategies to intensify treatment in MRD positive patients and expand transplant access to overcome outcomes. Figure 1 Figure 1. Disclosures Rangel-Patiño: Bristol: Consultancy; Abbvie: Speakers Bureau. Ceniceros: Amgen: Speakers Bureau. Espinosa: Amgen: Speakers Bureau; Janssen: Consultancy; Pfizer: Consultancy. Amador: Abbvie: Consultancy, Speakers Bureau; Bristol: Consultancy. Cabrero Garcia: Takeda: Speakers Bureau; Abbvie: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Astellas: Consultancy; BD: Speakers Bureau. Inclan-Alarcon: Janssen: Speakers Bureau; Boehringer: Speakers Bureau. Neme Yunes: Janssen: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Meillon-García: Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Astellas: Consultancy. Apodaca: Sanofi: Consultancy; Asofarma: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Demichelis: Bristol/Celgene: Consultancy, Speakers Bureau; Astellas: Consultancy; Gilead: Consultancy; ASH: Research Funding; Abbvie: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz: Consultancy.
Background: Distinct diagnostic assays and algorithms are employed by contemporary pathologists when seeking to identify lymphoma. There is a paucity of data on the degree of concordance between pathologists diagnosing lymphoma and its subtypes in different institutional settings in Latin America. The objective of this study was to assess the concordance between lymphoma diagnoses made via tissue biopsy by local pathologists and after review of these specimens by more specialized hematopathologists. Methods: This prospective, noninterventional and multicenter study was conducted at seven sites in Mexico from January 2017 to October 2017. Eligible biopsy samples were from patients with a previous diagnosis of lymphoma on lymph node biopsy or a diagnosis of extranodal lymphoma, with adequate tissue preservation and adequate amount of tissue for the review analysis. Patients receiving either chemotherapy or corticosteroids before sampling of tissue biopsies were excluded. Seven sites representing local pathologists and three hematopathologists participated in the study. The same biopsy tissues reviewed by the local pathologists were also sent to the hematopathologists participating in this study. Physicians in charge of patients' treatment decided whether to make any changes to a patient's treatment decision when comparing diagnosis results from the local pathologists and hematopathologists. The concordance in diagnosis results were classified into 3 categories: diagnostic agreement (i.e. the local pathologist and hematopathologist diagnoses concurred), minor discrepancy (i.e. there was a difference in diagnosis but it didn't change the treatment decision) and major discrepancy (i.e. there was a difference in diagnosis and it changed the treatment decision based on guidelines from the National Comprehensive Cancer Network). Results: Of 111 samples received, 105 met eligibility criteria for full review by hematopathologists and were included for full analysis. The median (range) patient age was 53 (16-94) years. More specimens were obtained from women (n = 57; 54.3%). A total of 53 (50.5%) patients were recruited from private institutions and the remaining (52; 49.5%) from public institutions. Within the 105 biopsies, a total of 89 cases were diagnosed as lymphoma by hematopathologists, including non-hodgkin's lymphoma (NHL; n = 72; 68.6%) and hodgkin's lymphoma (HL; n = 17; 16.2%). The most common subtype of NHL diagnosed was diffuse large B cell lymphoma (DLBCL), with a total of 32 cases. Diagnostic agreement was observed in 23 (21.9%) biopsies, minor discrepancies in 32 (30.5%) biopsies and major discrepancies in 50 (47.6%) biopsies, indicating treatment decisions changed in 47.6% of the total cases. Subtypes of lymphoma that local pathologists and hematopathologists most commonly found in diagnostic agreements were DLBCL (8/23; 34.8%) and HL (6/23; 26.1%), potentially due to their higher prevalence in the overall studied samples. Three types of error from the local pathologists were observed in major discrepancies, including ambiguity or lack of full diagnosis (27/50; 54%), a change from malignant to benign lesion (11/50; 22%) and a change of the type of neoplasm (12/50; 24%). Hematopathologists reported more immunohistochemical disease markers per tissue specimen: a median of 8.7 and a mode of 8 compared to a median of 5 and a mode of 0 for local pathologists. The diagnostic concordance varied across the seven study sites; the rate of major discrepancies ranged from 0% to 100% and the rate of diagnostic agreement ranged from 0% to 81.8%. The local pathologist from only one site received formal training in hematopathology and reported no major discrepancies. When excluding results from this site, the diagnostic agreement was observed in 14 (14.9%) biopsies, minor discrepancies in 30 (31.9%) biopsies and major discrepancies in 50 (53.2%) biopsies. Conclusions: This study showed that physicians from the seven study sites in Mexico changed their original treatment decisions that were initially based on local pathologist's diagnosis in nearly one-half (47.6%) cases after they reviewed the hematopathologist's diagnosis. In addition, there was a wide variation in the percentage of diagnostic agreements and discrepancies among different study sites, where sites with more experienced pathologists demonstrated a lower rate of diagnosis discrepancies in the diagnosis of lymphoma. Disclosures Solano: Janssen: Honoraria, Research Funding. Arteaga:Janssen: Honoraria, Research Funding. Martinez Hernandez:Janssen: Honoraria, Research Funding. Cabrero Garcia:Janssen: Honoraria, Research Funding. Gomez-Almaguer:AbbVie: Consultancy; Novartis: Consultancy. Lopez:Janssen: Honoraria, Research Funding. Perez:Janssen: Honoraria, Research Funding. Maldonado:Janssen: Honoraria, Research Funding. Bernal:Janssen: Honoraria, Research Funding. Osorno:Janssen: Honoraria, Research Funding. Fernandez:Janssen: Employment. Barreyro:Janssen: Employment. Regalado:Janssen: Employment. Herrera-Rojas:Janssen: Employment.
Introduction The COVID-19 pandemic has affected the entire world. Health systems have been affected in such a way that patients with diseases other than COVID-19 have suffered serious consequences. In Latin America, the disease has emerged in a fragile system with more disparities, making our patients more vulnerable. Acute leukemia patients have a high risk of severe COVID-19 disease. Various expert recommendations have emerged with the aim of minimizing the risk of COVID-19 without affecting leukemia-related outcomes. However, multiple logistical issues tangentially associated with the pandemic have also appeared, potentially limiting the quality of management of these patients. The objective of this study was to register treatment modifications associated with the COVID-19 pandemic and its short-term consequences in Latin American countries. Methods We included patients older than 14 years, from 14 centers of 4 Latin American countries (Mexico, Peru, Guatemala and Panama), with the diagnosis of acute leukemia, who were on active treatment since the first case of COVID-19 was documented in each country. We documented their baseline characteristics and followed the patients prospectively until July 15, were data-cutoff for this pre-planned analysis was performed. The primary outcome was the incidence of COVID-19 disease and its complications. Secondary outcomes included treatment and consult modifications, and cause of death during the study period. Logistic regression was performed to determine factors associated with COVID-19 and all-cause mortality. Results We recorded the information of 635 patients: 58.1% Ph-negative ALL, 25.7% AML, 9% APL and 7.2% Ph+ALL. The median age was 35 years (14-90 years); 58.8% were consideredf high-risk patients. The majority were on CR (68.3%) receiving consolidation or maintenance therapy, while 14.5% were newly diagnosed and 17.2% with relapsed/refractory disease. The majority (91.8%) were treated in centers that were also receiving COVID-19 patients, 40.2% in centers were patients could not be electively hospitalized for leukemia treatment because of the COVID-19 pandemic. The COVID-pandemic led to treatment-modifications in 40.8% of the cases. Reasons for modifications were associated with logistical issues (22.4%), medical decisions (15.1%) or patient choice (3.3%). The most frequent modification was chemotherapy delay (17.3%) followed by regimen modification (13.4%) and dose-reductions (10.1%). (Figure 1) 83 patients (13.1%) developed COVID-19 disease, the majority mild-moderate disease (54.2%), 27.7% severe disease and 18.1% critically ill; 27.7% required mechanical ventilation and 37.7% died from COVID-19 disease, representing 4.9% of the entire cohort. We identify as risk factors for COVID-19 disease the presence of active leukemia (newly diagnosed or relapsed) (OR 3.46 [95% CI: 2.16-5.5], p<0.001), high-risk leukemia (OR 1.63 [95% CI: 1.54-4.52], p<0.001) and being treated in a center were elective hospitalization was possible (OR 2.17 [95% CI 1.29-3.67], p=0.004). Treatment modifications, appointment prolongations or the use of virtual consultation were not associated with a reduction in the risk of COVID-19. On the other hand, 16.7% of patients died during period analyzed due to leukemia (57.5%), COVID-19 (29.2%) or treatment related-mortality (13.2%). Independent factors associated with mortality were AML vs. ALL (OR 1.89 [95% CI: 1.12-3.18], p=0.016), relapsed-refractory disease (OR 8.34 [95% CI: 4.83-14.41], p<0.001), induction/consolidation vs. maintenance therapy (OR 2.20 [95% CI: 1.25-3.18], p<0.001) and the use of virtual consultation (OR 0.35 [95% CI: 0.13-0.94] p=0.037). (Table 1) Discussion/Conclusions The COVID-19 pandemic led to significant modifications in the standard of care treatment of patients with acute leukemia. The incidence of COVID-19 disease in acute leukemia patients was considerable and more than a third of the patients with acute leukemia and COVID-19 disease died. Despite a short-follow up, 16.7% of the patients died and leukemia-related deaths were the most frequent. In low- and middle-income countries with fragile health systems, the collateral damage for patients with acute leukemia may be just as important as the direct consequences of COVID-19. Disclosures Alvarado: Roche: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau. De la Peña-Celaya:Amgen: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Perez:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Gomez-Almaguer:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Background: Acute lymphoblastic leukemia (ALL) represents 51% of acute leukemias in adults in Mexico. Poor outcomes have been reported, with a 3-year overall survival (OS) of 25.7% in the group of adolescents and young adults (AYA). In ALL, Hispanic ethnicity has been associated with more high-risk features and more treatment-related toxicity. Recently the results of the pediatric-inspired regimen CALGB 10403 in AYA ALL-patients have been published with encouraging results. We modified the original regimen based on the drug-access in Mexico and we incorporate Rituximab in CD20 positive patients. Methods We included patients with newly diagnosed B- or T-cell ALL between 17 and 45 years. Patients with Philadelphia chromosome-ALL were excluded. We enrolled patients from 4 centers in Mexico. We replicated the CALGB 10403 protocol, with the following modifications: replaced pegaspargase (2,500 IU/m2) with E. Coli asparaginase (6,000 IU/m2/day for 6 doses in alternate days). During the delayed intensification we replaced thioguanine 60mg/m2/day with 6-mercapatopurine 60mg/m2/day. We incorporated rituximab 375mg/m2 at D1 and D29 during remission consolidation, D1 and D21 in interim maintenance and D1, D29 and D50 in delayed intensification. The central nervous system (CNS) prophylaxis was given as a triple-drug (methotrexate 12.5mg, cytarabine 60mg and dexamethasone 8mg), with a total of 11 intratecal administrations, 7 during the induction/consolidation courses and 4 during maintenance. Minimal residual disease (MRD) was assessed by flow cytometry after induction and after first consolidation. The aims of this study were to evaluate complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and to assess the safety of this regimen. Result From January 2017 to May 2019 thirty-eight patients (23 men, 15 women) have been enrolled. Median follow-up is 11 months (range 1-30). Median age is 23 years (range 18-41). The 100% of patients are of Hispanic ethnicity. Obesity (BMI≥30) was reported in 18%. Thirty patients had an evaluable karyotype: 83% were normal, and 13% with MLL-rearrangements. The majority were B-cell ALL (90%), and 10% were T-cell ALL. Median WBC was 19.5 x103/mcL (range: 0.7-427.7) and 32% had hyperleukocytosis. Among the B-cell ALL patients, 53% were CD20 positive. CNS disease was presented at diagnosis in only one patient (3%). Thirty-three patients (86%) achieved CR, thirty (81%) after the first induction and three after the extended induction therapy. There was only one death during induction therapy (2.6%). After induction, 41% had negative MRD (<0.01%). Grade 3 /4 hepatic toxicity was reported in 58% patients, hyperglycemia in 24% and hypertriglyceridemia in 34%. The rest of toxicities are summarized in Table 1. During induction ten patients (19%) required dose adjustment because of toxicity. During consolidation, 42% required treatment modifications because of toxicity. After induction, we had no treatment-related mortality. At the last follow-up twenty-three patients continue in the protocol. Four patients already received Allo-SCT. The relapse-rate is 31.2% with half of these patients with CNS-disease at relapse. Nine patients have died: one during induction, six with progression or refractory disease and one after Allo-SCT. The 18-months PFS and OS rates were 80% and 84%, respectively. Median PFS is 23 months (CI 95% 17 to 29 months), and median OS was not been reached. Negative-MRD after induction was associated with excellent outcomes: 18-months OS 100% vs. 45.3%, p=0.008 (figure 1). Obesity was associated with worse OS (18-month 22% vs. 80%, p=0.03) and PFS (22% vs. 79.1%, p=0.026) Conclusion: Mexican patients treated with a modified CALGB 10403 protocol had similar response rates than reported in the original protocol but with more toxicity, mainly hepatic and metabolic. However, induction-related mortality was low and we had no treatment-related toxicity after induction. We presume that the high-rate of toxicities can be related with the genetic and environmental metabolic risk factors plenty described in our population. The modified CALGB showed encouraging results in this Hispanic population, hence we have to explore lower dose schedule based in patient characteristics and asparaginase levels. Disclosures Neme Yunes: Abbvie: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau. Demichelis:Abbvie: Speakers Bureau; Celgene: Speakers Bureau; AMGEN: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Shire: Speakers Bureau.
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