A Modified CALGB-10403 in Hispanic Adolescent and Young Adults with Philadelphia -Negative Acute Lymphoblastic Leukemia: Promising Results Despite a High-Rate of Metabolic and Hepatic Toxicities
Authors: Rangel-Patiño Juan , Cabrero Garcia Alvaro , Balderas-Delgado Carolina , Amador Lauro Fabian , Neme Yunes Yvette , Cooke Ana , Rosas Adriana , Demichelis Roberta 
Published: November 2019

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 (&lt;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.