Faculty Bibliography

Background/Objectives: Nelarabine (Nel) is a T-cell specific agent, FDA approved for patients who have failed at least two regimens. COG AALL0434 evaluated the safety and efficacy of Nel when incorporated into COG augmented BFM (ABFM) chemotherapy in newly diagnosed patients with T-ALL. Design/Methods: AALL0434 enrolled 1,895 patients (2007-2014) and included a 2 x 2 pseudo-factorial randomization using the ABFM regimen. Patients were randomized to receive escalating dose methotrexate with pegaspargase (CMTX) or High Dose MTX (HDMTX). Intermediate and high-risk patients with T-ALL were randomized to +/-six 5-day courses of Nel 650 mg/m²/day during Consolidation (2), Delayed Intensification (1) and Maintenance (3). The intermediate and high risk patients received prophylactic (1200 cGy) or therapeutic (1800 cGy, CNS3) cranial irradiation. Patients with induction failure were non-randomly assigned to HDMTX+Nel. Results: For all randomized patients, the 4-year disease-free survival (DFS) and overall survival (OS) rates were 84.3 +/-1.1% and 90.2 +/-0.9%. The 4-year DFS rate for patients with T-ALL randomized to Nel (N=323) vs no Nel (N=336) was 88.9 +/-2.2% vs 83.3 +/-2.5%, (p=0.0332). Among patients with T-ALL randomized to CMTX the 4-year DFS for Nel (N=147) vs no Nel (N=151) was 92.2 +/-2.8% vs 89.8 +/-3.0%, p=0.3825. For those randomized to HDMTX, 4-year DFS was 86.2 +/-3.2% with Nel (N=176) vs 78.0 +/-3.7% without Nel (N=185), p=0.024. Differences between DFS in a 4-arm comparison were highly significant (P = 0.002), with no significant interactions between MTX and Nel randomizations (p=0.41). Patients with induction failure (N=43) assigned to HDMTX/Nel had a 4-year DFS of 54.8 +/-8.9%. Overall toxicity and neurotoxicity were acceptable and not significantly different between all four arms. Conclusions: COG AALL0434 showed outstanding overall outcomes for patients with T-cell malignancy with Nel improving DFS for children and young adults with T-ALL

Purpose Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. Patients and Methods COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. Results AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. Conclusion AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with NCI high-risk (HR) ALL as defined by age and initial white blood cell count, or intermediate risk as defined by minimal residual disease response, is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors (TKIs). The prevalence, outcome and potential for targeted therapy of Ph-like ALL in NCI standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled on the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, 67 patients with either BCR-ABL1 (n=6) or ETV6-RUNX1 (n=61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted RT-PCR assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%) and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared to non Ph-like ALL (82.4±3.6% vs. 90.7±1.0%, P = .0022), with no difference in overall survival (93.2±2.4% vs. 95.8±0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features, and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

PEGylated asparaginase (pegaspargase) can be administered via intramuscular (IM) injection or intravenous (IV) infusion with a hypersensitivity reaction (HSR) incidence ranging 3-41%. We evaluated grade >/=3 HSRs when given IM vs. IV on six Children's Oncology Group (COG) leukemia trials (2003-2015) to determine differences in HSR rates. 54,280 doses were administered to 16,534 patients. Considering all doses of pegaspargase during induction, consolidation, and delayed intensification, grade >/=3 HSR rate with IM injection was 5.4% (n = 482/8981) compared to 3.2% for IV (n = 245/7553) (p < .0001). If only the second and third doses of pegaspargase were analyzed, where the majority of grade >/=3 HSRs occur, the rate following IM injection was 10.1% (n = 459/4534) compared to 5.0% (n = 222/4443) for IV (p < .0001). On standardized treatment protocols conducted by the COG during 2003-2015, grade >/=3 HSR rates to pegaspargase occurred less frequently with IV infusion than IM injection.

Minimal residual disease (MRD) after initial therapy is integral to risk stratification in B-precursor and T-precursor acute lymphoblastic leukemia (B-ALL, T-ALL). Although MRD determines depth of remission, remission remains defined by morphology. We determined the outcomes of children with discordant assessments of remission by morphology vs. flow cytometry using patients age 1-30.99 years enrolled on Children's Oncology Group ALL trials who underwent bone marrow assessment at the end of induction (N = 9350). Morphologic response was assessed locally as M1 (<5% lymphoblasts; remission), M2 (5-25%), or M3 (>25%). MRD was centrally measured by flow cytometry. Overall, 19.8% of patients with M2/M3 morphology had MRD < 5%. M1 with MRD ≥ 5% was less common in B-ALL (0.9%) than T-ALL (6.9%; p < 0.0001). In B-ALL, M1/MRD ≥ 5% was associated with superior 5-year event-free survival (EFS) than M2/MRD ≥ 5% (59.1% ± 6.5% vs. 39.1% ± 7.9%; p = 0.009), but was inferior to M1/MRD < 5% (87.1% ± 0.4%; p < 0.0001). MRD levels were higher in M2/MRD ≥ 5% than M1/MRD ≥ 5% patients. In T-ALL, EFS was not significantly different between M1/MRD ≥ 5% and M2/MRD ≥ 5%. Patients with morphologic remission but MRD ≥ 5% have outcomes similar to those who fail to achieve morphological remission, and significantly inferior to those with M1 marrows and concordant MRD, suggesting that flow cytometry should augment the definition of remission in ALL.

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.9% of presumed sporadic B-ALL, identifying 28 unique variants in 45 children. The majority of variants adversely affected IKZF1 function and drug responsiveness of leukemic cells. These results identify IKZF1 as a leukemia predisposition gene, and emphasize the importance of germline genetic variation in the development of both familial and sporadic ALL.

Efficacy of therapeutic strategies relative to patient- and family-centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at-home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.