Reinduction Regimen Effective in Late Marrow-Relapsed Pediatric ALL

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In the CALL-0603 study of 44 patients with first marrow-relapsed childhood acute lymphoblastic leukemia, the second complete remission (CR2) rate was 72.7% for a chemotherapy regimen that included a reduced dose of idarubicin.

Investigators working in South Korea assigned patients to a reinduction regime that included prednisolone, vincristine, L-asparaginase, and 10 mg/m2 of weekly idarubicin. The idarubicin dose was adjusted according to degree of myelosuppression.

More than half of the patients (54.2%) with early relapse and 95.0% of patients with late relapse had CR2 <24 weeks after initial diagnosis (P = .002). Investigators called the results for early relapsers “suboptimal.”

“This study showed a favorable CR2 rate due to reduced toxicity during reinduction treatment of marrow-relapsed pediatric ALL,” they wrote. “The CR2 rate of late relapsers was excellent, whereas that of early relapsers was unsatisfactory. Thus, a more effective induction treatment involving new agents should be considered for early relapsers. In addition, CR2 achievement was not translated into sustained remission in most patients. Thus, future trials are required to optimize the post-induction treatment and improve the long-term outcomes.” Approximately 20% of patients with childhood ALL relapse during or after frontline treatment. Prognosis following bone marrow relapse of pediatric ALL is very poor, and relapsed ALL is one of the major causes of childhood cancer death. Challenges in the treatment of marrow-relapsed ALL include failure to achieve CR2, risk of induction death, and short-sustained second remission during postremission treatment. Consequently, one way to improve outcomes for patients with marrow-relapsed ALL is the development of a safer, more effective reinduction platform.

Reinduction therapy usually consists of a 4-week regimen of prednisone, vincristine, L-asparaginase, and an anthracycline. Idarubicin is a second-generation anthracycline that has been used to treat acute myeloid leukemia and relapsed ALL.

The reported maximum-tolerated dose of idarubicin is 12.5 mg/m2. However, a previous Korean pilot study showed that dosage was unacceptably toxic and had an inferior CR2 rate to a modified dose of 10 mg/m2 per week due to a higher toxic death rate. Investigators in CALL-0603 sought to improve the CR2 rate by reducing toxic death during a reinduction attempt with a modified dose of idarubicin and to evaluate the long-term outcomes of Korean children with relapsed ALL.

Patients aged 1 to 21 years with a first isolated or combined marrow-relapsed ALL enrolled from 2006 to 2009. Individuals with B-precursor and T-cell ALL were included, whereas those with mature B-cell ALL and Down syndrome were excluded. Patients who had undergone prior allogeneic hematopoietic stem cell transplantation (HSCT) were eligible.

The reinduction protocol consisted of daily oral 60 mg/m2 prednisolone for 28 days, weekly IV 1.5 mg/m2 vincristine, thrice-weekly IM 6000 IU/m2 L-asparaginase for a total of 9 doses, and 10 mg/ m2 idarubicin on days 0, 7, 14, and 21. Idarubicin was discontinued if the absolute neutrophil count was <500/μL or the platelet count was <50,000/μL on day 14 or 21.

For postinduction treatment, at a median follow-up duration of 99 months, 5-year event-free survival (EFS) was 22.2% ±6.4% and overall survival (OS) was 27.3% ±6.7 for all patients. EFS was 4.2% ±4.1% and OS was 8.3% ±5.6% for early relapsers. For late relapsers, EFS was 43.8% ±11.4% and OS was 50.0% ±11.2%.

Nineteen patients received 20 mg/m2 idarubicin, 22 patients received 30 mg/m2, and 3 patients received 40 mg/m2. The median dose was 30 mg/m2. Patients who received 30 mg/m2 or more of idarubicin were significantly more likely to display bone marrow relapse on day 14 than those who received 20 mg/m2 of idarubicin (27.8% vs 0.0%; P = .038).

Investigators observed no significant difference in the CR2 rate between the 20 mg/m2 and 30 mg/m2 or more doses (70.0% vs 75.0%, P = .736). Time from initial diagnosis to relapse of less than 24 months was a significant predictor of failure to achieve CR2 (P = .002). Site of relapse, age at relapse, risk group allocation at initial diagnosis, and cytogenetic aberrations were not significantly associated with the probability of achieving CR2.

Forty-three patients completed 4 weeks of reinduction treatment, and 1 died during reinduction therapy. Five patients achieved remission with extended treatment, resulting in a final CR2 rate of 84.1%.

Thirty-eight patients had available bone marrow data on day 7 and/or day 14 and could be segregated into 3 cohorts: rapid early response (n = 11), slow early response (n =15), and induction failure (n = 12).

Early time point of relapse and slow early response to reinduction chemotherapy were significantly related to poor EFS. All patients in the rapid early response cohort had early response verses 33.3% ±15.7% in the slow early response cohort and 0% in the induction failure group (P <.001). Early response during reinduction treatment was a significant prognostic factor for late relapsers, but it was not significant for early relapsers (P = .113).

EFS rates were not different between patients who received chemotherapy or allogeneic HSCT as a consolidative treatment (20.5% ±12.0% vs 29.2% ±9.3%; P = .354). However, EFS among early relapsers who had CR2 (n = 17) was significantly superior for those who received allogeneic HSCT (0.0% vs 8.3%; P = .003). EFS was similar for late relapsers who had CR2 (n = 20) for both consolidation treatments (50.0% ± 17.7% vs 50.0% ±14.4%; P = .649).

Koh, KN, Im, HJ, Kim H, et al. Outcome of reinduction chemotherapy with a modified dose of idarubicin for children with marrow-relapsed acute lymphoblastic leukemia: Results of the Childhood Acute Lymphoblastic Leukemia (CALL)-0603 study. J Korean Med Sci. 2017;32(4):642-649. doi: 10.3346/jkms.2017.32.4.642.