Teachey, David T.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Acute Lymphoblastic Leukemia (ALL) were developed as a result of meetings convened by a multidisciplinary panel of pediatric ALL experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. The NCCN Guidelines for pediatric ALL focus on risk assessment and stratification of risk-adapted therapy; treatment strategies for BCR::ABL1 (Philadelphia chromosome [Ph])-negative and BCR::ABL1-positive B-cell lineage, T-cell lineage, and infant ALL; and supportive care considerations. This selection from the NCCN Guidelines for pediatric ALL focuses on the diagnosis of and management of pediatric T-ALL.

Abstract Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children’s Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

Abstract Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6‐cyclin D complex that regulates cell cycle progression. Procedure The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four‐drug re‐induction chemotherapy in children and young adults with relapsed/refractory B‐ and T‐cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1–3) and subsequently combined with re‐induction chemotherapy. This two‐part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose‐limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T‐ALL and three among seven patients with B‐ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with re‐induction chemotherapy was well tolerated with a RP2D of 50 mg/m 2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. Procedure The Children’s Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug reinduction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently combined with reinduction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) followed by an expansion pharmacokinetic (PK) cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or PK expansion cohorts and overall rates of grade 3/4 non-hematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with reinduction chemotherapy was well tolerated with a RP2D of 50 mg/m 2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

PURPOSE To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( P = .412) and OS ( P = .600). CONCLUSION Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal; the primary goal of T-ALL/T-LL treatment is to prevent relapse. AALL1231 was a COG phase 3 clinical trial that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone +/- the proteasome inhibitor bortezomib during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). Bortezomib was tested in frontline therapy based on strong preclinical data and data in relapse on COG AALL07P1. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphologic and minimal residual disease (MRD) at end induction and end consolidation (T-ALL) and radiographic response (T-LL). To eliminate cranial radiation (CXRT) in all pts, (except VHR: Day 29 M3 marrow or EOC MRD >0.1% or pts with overt CNS leukemia at diagnosis, CNS3), the aBFM backbone was modified to use dexamethasone (dex) as the sole corticosteroid and an extra pegaspargase dose was added in both induction and DI, following the MRC strategy. IR pts received a second interim maintenance (IM) phase (one Capizzi MTX; one HD-MTX). Following consolidation, VHR pts received 3 BFM high-risk intensification blocks in lieu of IM. Results: AALL1231 accrued 847 patients (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure in 2017 when COG AALL0434 established that nelarabine (NEL) improved DFS in T-ALL (AALL1231 did not include NEL). The 3-year EFS for Arm A (no bortezomib) vs Arm B (bortezomib) were 81.7±2.4% and 85.1±2.2 % (HR=0.782, p=0.074) (3/31/20 data cut-off; see Table 1 for additional outcomes). SR and IR pts, who account for 95% of pts, had significantly improved EFS on Arm B as compared with Arm A. Yet, VHR patients had improved EFS on Arm A. Patients with T-LL had improved EFS and OS with bortezomib: 3-year EFS (76.5±5.9% vs 88.3±4.5%; p = 0.01); 3-year OS (78.0±5.8% vs 89.5±4.2%, p = 0.007). A similar improvement in EFS and OS was not seen in T-ALL; however, with longer follow-up this may change. No excess toxicity was seen on Arm B. A dex-based Induction did result in lower MRD rates; more T-ALL pts on AALL1231 had Day 29 MRD <0.1% as compared with AALL0434 which used a prednisone-based Induction (AALL1231 Arm A: 69.6%; Arm B: 72.2%; AALL0434: 64.6%; p = 0.02). However, this did not translate into improved survival. Indeed OS, but not EFS was worse on AALL1231 than AALL0434. On-going analyses are investigating the increased mortality on AALL1231, but preliminary analyses suggest a combination of increased toxic deaths and overall poor outcome in the VHR group. On AALL0434, 90.8% of T-ALL pts received CXRT. On AALL1231, 9.5% of subjects were scheduled to receive CXRT (CNS3 T-ALL/T-LL: 5.7%; VHR T-ALL: 4.1%). A comparison of AALL0434 pts that received CXRT with similar AALL1231 pts not receiving CXRT on AALL1231 demonstrated similar EFS (p = 0.14) and OS (p = 0.42) (Table 2). CNS relapse rates were higher in these pts on AALL1231 (4.5%) as compared with AALL0434 (1.7%), but overall relapse rates were the same (6.5% vs 6.4%). Notably the benefit of NEL in AALL0434 was due to reduction of CNS relapses. 128 AALL1231 pts came off protocol therapy after the study was closed for physician or patient/parent choice. Data collection is underway to understand the reasons for removal, including if it was to receive NEL. Conclusions: Outcomes for SR and IR pts with T-ALL and T-LL treated with bortezomib were excellent despite the elimination of prophylactic CXRT. Bortezomib significantly improved 3-year EFS for these groups, comprising ~95% of pts. Outcomes for VHR pts were dismal and worse on the bortezomib arm. T-LL pts had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. This is the first trial to demonstrate an OS benefit for de novo pediatric T-LL with a new agent; however, longer follow-up is needed. Therapy intensification allowed elimination of CXRT in the majority of pts without excessive relapse. These results should be interpreted cautiously as the 3-yr OS on AALL1231 was inferior to AALL0434. Nevertheless, incorporating bortezomib into standard therapy for de novo T-LL appears advantageous. Future COG T-ALL/T-LLy trials will build on the positive findings from AALL0434 and AALL1231, balancing intensity while mitigating toxicity to maintain high cure rates without routine cranial radiation. (MLL, SPH, EAR contributed equally) Disclosures Teachey: Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy; Sobi: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Galardy:Abbott: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Hermiston:Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Shimano:Novartis: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. McKay:Immunogen: Current Employment. Bollard:Mana Therapeutics: Other: IP. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. OffLabel Disclosure: Bortezomib for the treatment of acute lymphoblastic leukemia under an IND

Background: Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (B-ALL, T-ALL, B-LLy and T-LLy), the outcome of patients with primary resistant or relapsed disease remains very poor, particularly for children with second or greater relapses and with T-cell disease. Deregulation of cell cycle machinery is essential for both the induction and progression of ALL (Sicinska et al. Cancer Cell 4:451-61, 2003). Additionally, targeting cell cycle regulators CDK4 and 6 efficiently suppresses ALL growth and disease progression in vivo (Sawei et al. Cancer Cell 22:452-65, 2012) and this effect is augmented by conventional chemotherapy. These data provided the rationale for investigating the CDK4/6 inhibitor palbociclib in relapsed/refractory ALL and LLy. Preliminary results from the ongoing Children's Oncology Group (COG) AINV18P1 trial are reported. Methods: Patients aged 1-30 years with first or greater isolated or combined marrow relapses of T-ALL or T-LLy and second or greater relapses of B-ALL or B-LLy are eligible for COG AINV18P1 (NCT03792256). Patients with refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are also eligible. This is a 2-part study conducted at selected COG sites. In Part 1 of the study (dose determination), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy (Table 1). Study treatment consisted of a single cycle of therapy. A starting palbociclib dose of 50 mg/m2/dose was explored with one dose de-escalation (35 mg/m2/dose) using the rolling six design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Part 2 (expansion cohort) is accruing 6 additional patients (pts) at the MTD for further assessment of the safety and feasibility of combination therapy. Dose-limiting toxicities (DLTs), defined as hematologic and non-hematologic toxicities exceeding baseline toxicities observed with re-induction chemotherapy alone, are assessed throughout the treatment cycle. The primary aims of the study are safety, determination of the MTD/RP2D and assessment of palbociclib pharmacokinetics (PK). Secondary aims are assessment of the biological and preliminary clinical activity of combination therapy in this patient population. Results: As of June 30, 2020, 8 pts have enrolled; 6 in Part 1 and 2 in Part 2. All 6 pts in Part 1 completed one full cycle (32 days) of protocol therapy. The median (range) age of pts is 10 (6-21) years and 62% are male (Table 2). Three pts had T-ALL, 4 B-ALL and 1 T-LLy. Pts received a median (range) of 2 (1-6) prior chemotherapy regimens and 2 pts underwent prior allogeneic stem cell transplant. All 6 pts in Part 1 experienced grade 3-4 toxicities, most commonly hematologic: anemia (3 pts), neutropenia (5 pts) and thrombocytopenia (4 pts). Three pts had grade 3 infections and one pt had grade 3 hyperbilirubinemia, which resolved. No hematologic or non-hematologic DLTs were observed at the 50 mg/m2/dose of palbociclib in Part 1 and accrual to the expansion phase of the trial at this dose continues. PK and pharmacodynamic studies assessing cell cycle inhibition are also ongoing. Conclusions: Palbociclib in combination with 4-drug re-induction chemotherapy is safe and well tolerated in children and young adults with relapsed/refractory ALL and LLy. Further assessment of the feasibility and activity of combination therapy is ongoing in the expansion phase of this trial. Disclosures Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Teachey:La Roche: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sobi: Consultancy. Norris:Merck: Other: Travel funding. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. OffLabel Disclosure: This study includes off-label use of palbociclib in children and young adults with relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.

Abstract Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.