Is Hepatic Toxicity during Induction Chemotherapy a Real Problem in Hispanic Young Adults with Acute Lymphoblastic Leukemia?

Introduction In Mexico, 51% of acute leukemias in adults are acute lymphoblastic leukemia (ALL). In resource-constrained settings, adults with ALL have poor outcomes with a high treatment related mortality and long-term overall survival (OS) around 20%.

Currently, the use of pediatric inspired regimens (PIR) has allowed to achieve better long-term outcomes. Obesity and metabolic syndrome represent highly prevalent comorbidities in the Hispanic population, which, like the ethnic group itself, have been described as risk factors related to the development of hepatic toxicity with the use of PIR.

Despite the high rate of hepatic toxicity during induction, hepatic failure is very rare and there is not enough evidence about the clinical consequences of this toxicity.

Methods A single center observational retrospective study, including adults with ALL aged between 18- 50 years, who received induction chemotherapy between January 2015 and March 2020. A comparative study of the sociodemographic, clinical and laboratory characteristics in patients with and without hepatotoxicity was carried out.

The aims of this study were to evaluate the impact of the hepatic toxicity during induction chemotherapy in terms of complete response (CR) rate, induction-related mortality, OS and associated risk factors.

Results A total of 90 patients were included, with a median age of 25 years (IQR 20-36), 60% men. Most had normal karyotype (38%), 13% Ph positive and 3% with rearrangement in KMT2A. B-cell phenotype corresponded to 93% of the cases and 77% were considered as high risk. Hyperleukocytosis was present in 44%. Most patients (64%) had abnormal liver chemistry at diagnosis, though most of these corresponded to a mild elevation with less than 2xULN and only 13% to an elevation >3xULN. Baseline lipid profile was determined in 46/90 patients, of which the majority had dyslipidemia at diagnosis (76.7%), with mixed dyslipidemia being the most frequent in 56%. 46% were obese or overweight, and only 4% had diabetes. Steatosis was evaluated by abdominal ultrasound or computed tomography, and it was present in 11% at diagnosis. Regarding the type of induction therapy, 42% received a PIR and 58% an adult regimen.

Most patients presented some type of induction-related toxicity (98%), with grade 3 toxicity being the most frequent in 48%. Hepatotoxicity of any grade occurred in 82% and grade 3 or 4 in 31% being the most common hyperbilirubinemia in 61%, followed by transaminitis in 54%. Among other frequent toxicities: febrile neutropenia in 63%, septic shock in 29% and hypofibrinogenemia in 75% (42/56). Treatment regimen was adjusted due to toxicity in 18%.

No statistically significant differences were found between the frequency of grade 3 / 4 hepatotoxicity and the type of regimen (40% pediatric vs 25% adult p 0.14), nor for the presence of comorbidities studied such as obesity (36 vs. 28% p=0.37), dyslipidemia (30% vs. 36%, p=0.70) and diabetes (50 % vs. 30% p=0.40). Risk factors for grade 3 / 4 hepatotoxicity were: steatosis (OR 6.5 95%, CI 1.55-27.7, p=0.005) and hypofibrinogenemia (OR 4.95 95%, CI 0.98-24.9, p=0.03).

In terms of clinical impact and outcomes, there was no difference between the frequency of induction-related mortality and grade 3 / 4 hepatic toxicity (25% vs. 26%, p=0.69), nor for septic shock (42% vs. 26% p=0.14) or admission to intensive care unit (44% vs. 28% p=0.22). Although, the frequency of CR was higher in patients who presented grade 3/ 4 hepatotoxicity than those who did not (93% vs. 69% p=0.01). Hepatic toxicity was independently associated a higher CR rate (OR 4.8, CI 1.4-16.5, p=0.012).

Finally, the median OS in patients with grade 3 / 4 hepatotoxicity during induction was 54.2 months vs. 34.7 months (p=0.24).

Conclusions The frequency of hepatic toxicity during ALL induction chemotherapy in young Mexican adults is high regardless of the regime type (pediatric vs. adult), however, its presentation does not seem to imply an unfavorable impact on clinical outcomes, such as higher induction-related mortality and lower overall survival. In addition, there seems to be a trend towards a better treatment response even when dose adjustment is required due to treatment-related toxicity, probably as a reflection of the treatment intensity and effectiveness.

Rangel-Patiño:Abbvie: Consultancy, Speakers Bureau. Demichelis:Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Teva: Consultancy; Gilead: Consultancy; ASH: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.