Modified Pediatric Regimen Improves Outcomes in Young Adult Patients With Acute Lymphoblastic Leukemia

Using a modified pediatric regimen to treat adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) led to superior outcomes compared with historical adult ALL regimen results, according to a retrospective analysis that evaluated 95 AYAs aged 14 to 39 years. Findings were presented at the eighth annual Society of Hematologic Oncology (SOHO 2020) virtual meeting.¹

Overall, the investigators reported a complete remission (CR) rate of 94.7% with 5 (5.3%) induction failures and 3 (3.2%) induction deaths. At a median follow up of 4.9 years, the 5-year overall survival (OS) was 80% and the 5-year event-free survival (EFS) was 65%. EFS was defined as death from any cause, induction failure, relapse, and second primary malignancy. This is important because outcomes among AYAs with ALL tend to be poor, especially when compared to the improved survival observed in younger children with ALL.²

“The 5-year EFS rate of 65% and an OS rate of 80% in our cohort is promising.” said lead author Saleem Eldadah, MD, consultant hematologist, during the presentation.

Previously, in a systemic review and meta-analysis, Ram R, et al, evaluated AYA patients with ALL who received either a pediatric-related regimen or conventional adult chemotherapy. The investigators found that pediatric-inspired regimens were superior to conventional-adult chemotherapy in AYA ALL patients.³ That analysis included 11 trials that included 2489 patients.

The investigators found that pediatric-inspired regimens were superior to conventional adult protocols in patients who were AYAs with ALL. They noted that patients who were AYAs who received pediatric-based regimens had a lower all-cause mortality rate at 3 years and relapse rates were lower in patients given the pediatric protocols with comparable non-relapse mortality.

In the current study, Eldadah, from the Princess Noorah Oncology Center, Ministry of the National Guard - Health Affairs in Jeddah, Saudi Arabia, said patients received a modified Children’s Cancer Group/Children’s Oncology Group protocol that consisted of induction followed by 8 weeks of augmented consolidation.

Pre-B-ALL patients received 10 infusions of rituximab (Rituxan), followed by blinatumomab (Blincyto) in patients who were minimal residual disease (MRD)-positive after consolidation. Patients received antimicrobial agents prophylactically and were also given granulocyte colony-stimulating factor to address neutropenia.

“Minimal residual disease was assessed by multicolor flow cytometry and positivity was defined by a level greater than 0.01%,” Eldadah said. Patients who had positive central nervous system (CNS) involvement received 24 Gy of cranial radiotherapy, but prophylactic CNS irradiation was not used.

At baseline, 45.3% of patients were over 18 years of age, and 62.1% were male. The majority (75.8%) were pre-B phenotype, and 24.2% were T-cell phenotype. CNS status was negative in 90.5% and positive in 5.3%, and a low percentage of patients (4.2%) had traumatic CNS symptoms.

Cytogenetic analysis revealed that 6.3% of patients were hypodiploid, 14.7% were hyperdiploid, and 24.2% had normal cytogenetics.

Eighty-six patients were evaluated for end-of-induction minimal residual disease (MRD), and of those, 72% achieved MRD negativity. Eldadah noted that all induction deaths were secondary to infection.

Investigators reported that the incidence of relapse was 22.1% (21/95), which included 13 cases of isolated bone marrow relapse, 7 cases of isolated CNS relapse, and 1 combined relapse. A majority of relapsed patients (66.6%) achieved complete remission 2 (CR2), and 28.6% of patients were still alive at last follow up.

Regarding allogeneic stem cell transplant, 16 patients in the whole cohort underwent the procedure. This included 4 patients who were in CR1 and 12 patients who were in CR2.

Six patients died in remission; causes included post-allogeneic stem cell transplant complications (3), sepsis (2), and a traffic accident (1). None of the baseline characteristics impacted OS on univariate/multivariate analysis, said Eldadah.

“When comparing cumulative survival, there was no difference in OS and EFS by age [<18 years vs ≥18 years],” Eldadah said. “Similarly, there was no difference observed based on phenotype, no difference between pre B [precursor B-cell] versus T cell,” he said.

Regarding treatment-related toxicities, venous thromboembolism (VTE) was observed in 16.8% of patients (43.7% were isolated, line-related upper extremity deep venous thrombosis); 13.7% of patients developed symptomatic avascular necrosis (AVN); hyperglycemia developed in 17.8% of patients during induction; and 4.2% of patients developed symptomatic pancreatitis. Grade 3 neuropathy developed in 14.7% of patients.

“AVN and VTE occurred in more than 10% of patients,” Eldadah said. “Using this pediatric ALL protocol in adult patients is feasible, but more work is needed to further improve outcomes and decrease toxicities,” he concluded.

_References:

_{1. Eldadah S, Alsaeed A, Jastaniah W, et al. Sixteen years experience in treating adolescents and young adults (AYA) with Philadelphia negative acute lymphoblastic leukemia (Ph-ALL) with a modified pediatric ALL protocol. Presented at: Eighth Annual Society of Hematologic Oncology (SOHO) meeting; September 9-12, 2020. https://soho.6connex.com/event/AnnualMeeting/login/​}

_{2. Smith EC, Ziogas A, Anton-Culver H. Association between insurance and socioeconomic status and risk of advanced stage Hodgkin lymphoma in adolescents and young adults. Cancer. 2012;118(24):6179-6187. doi:10.1002/cncr.27684}

_{3. Ram R, Wolach O, Vidal L, Gafter-Gvili A, Shpilberg O, Raanani P. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012;87(5):472-478. doi:10.1002/ajh.23149}