Report On Excessive Induction Toxicity in Infants with ALL Enrolled On COG Protocol AALL0631: A Children's Oncology Group Study.

Abstract Abstract 3091 Poster Board III-28 Infants (age ≤ 1 year) with ALL are treated on separate protocols due to distinctive host characteristics and leukemia biology [frequent MLL rearrangements (MLL-r), high relapse rates]. AALL0631 is a treatment protocol for newly diagnosed infant ALL that stratifies patients by age at diagnosis and MLL status into three risk groups: high risk (HR) – age < 90 days, MLL- r; intermediate risk (IR) – age ≥ 90 days, MLL-r; standard risk (SR) – any age, MLL wild-type. All patients receive a common induction chemotherapy course. Post-induction chemotherapy is risk-stratified: SR patients receive relatively less intensive post-induction chemotherapy, and IR and HR patients receive more intensive post-induction chemotherapy and are eligible for randomization to also receive a FLT3 inhibitor (lestaurtinib). AALL0631 induction is based on the predecessor COG P9407 trial. In P9407, excessive induction toxicity was initially encountered, particularly among infants < 90 days of age, prompting changes to induction and prospective safety monitoring rules. A cohort of 142 eligible patients subsequently enrolled (cohort 3, or c3) did not trigger these stopping rules, and enrollment concluded on 10/20/2006. In AALL0631, two changes were made to induction compared to P9407c3: (1) daunomycin dose was reduced 15% to reduce the risk of mucositis; (2) E. coli asparaginase (8 doses over days 4 - 19) was replaced with PEG asparaginase (1 dose on day 4). Four of the first 26 patients enrolled on AALL0631 died of infections during induction, and one patient discontinued protocol therapy during induction due to severe non-fatal toxicity; all toxicities occurred prior to administration of lestaurtinib. This prompted suspension of the protocol on 11/19/2008, and a comprehensive review of induction toxicity for infants treated on AALL0631, P9407c3 and Interfant-99 (a published international cooperative group ALL study with 482 infants enrolled). Differences in Interfant-99 induction compared to COG AALL0631 include: 1) an initial 7 day prednisone-only “prophase” ; 2) 3- to 4-fold lower doses of daunorubicin; 3) use of low dose cytarabine; 4)no use of cyclophosphamide; 5) 2- to 3-fold lower doses of intrathecal methotrexate and cytarabine, and 6) use of native as opposed to PEG L-asparaginase. The details of the 5 severe induction toxicities on AALL0631 are below (Table 1): TABLE 1 Age at dx (days) Type of toxicity Fatal? 1 Infection (fungal – Aspergillus fumigatus) Y 2 Severe hepatotoxicity/hyperbilirubinemia N 92 Infection (fungal – Candida tropicalis) Y 285 Infection (bacterial – Pseudomonas aeruginosa) Y 289 Infection (bacterial – Bacillus species) Y Non-fatal infections have also been prevalent. Table 2 summarizes the grade 3 or greater infectious adverse events (AE) that have been reported during induction therapy on AALL0631. TABLE 2 Organism Type AE Fatal AE % of AE # of Patients % of Patients Bacteria 19 2 76% 15 58% Blood 16 2 64% 13 50% Urine 3 0 12% 2 8% Fungi 4 2 16% 4 15% Viral 2 0 8% 2 8% Totals 25 4 100% 18* 69%* * these are not simple sums, since some patients had multiple AEs Of the 16 bacterial blood isolates, 12 (75%) were gram positive; of these, 6 (50%) were Viridans group streptococci. Since toxicities appeared to vary by age, we analyzed induction deaths by age group as shown in Table 3. Table 3 AALL0631 P9407c3 Both COG Interfant99 Age N Deaths Rate N Deaths Rate N Deaths Rate N Deaths Rate < =30 2 1 50% 6 1 17% 8 2 25% 30 3 10% 0-7 2 1 50% 2 1 50% 4 2 50% 9 2 22% 8-30 0 0 - 4 0 0% 4 0 0% 21 1 5% > 30 24 3 13% 136 5 4% 160 8 5% 452 19 4% ≥ 90 22 3 14% 115 4 4% 137 7 4% 370 nd - Infants ≤ 7 days old have a high risk of induction death with all regimens (overall 31%). For infants ≤ 30 days old, P9407c3 and AALL0631 have a higher induction death rate than Interfant-99 [OR 3.6 (0.5-27), p=.23] although the numbers are small. For infants > 30 days, AALL0631 has a higher induction death rate than P9407c3 [OR 3.7 (0.83-16.8), p=0.1] or Interfant-99 [OR 3.3 (0.89-11.9), p=0.09]. For infants ≥ 90 days, AALL0631 has a higher induction death rate than P9407c3 [OR 4.4 (0.9-21.1), p=0.08]. As a result of this analysis, we decided to make the following major changes to AALL0631: 1) adopt the Interfant-99 induction regimen for all age groups, but dose reduce an additional 25% for infants ≤ 7 days old; 2) enhance supportive care guidelines regarding infection prevention; 3) include a prospective induction death toxicity monitoring plan. Disclosures Zaoutis: Merck & Co.: Research Funding; Cephalon: Research Funding; Enzon: Research Funding.

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