Abstract: Although outcomes for patients with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for relapsed or refractory T-ALL remain less than 10%. While mechanisms mediating chemotherapy resistance in these patients remain incompletely understood, resistance to glucocorticoids (GC), a central component of therapy, may be particularly important. GC resistance occurs more commonly than resistance to other chemotherapeutic agents in ALL. Additionally, newly diagnosed patients that fail to rapidly clear their peripheral leukemic blasts during an upfront window of prednisone (prednisone poor response) have a poorer outcome, suggesting differences in GC sensitivity may exist at diagnosis. Here, we develop an in vitro assay to model the early prednisone response. Using primary, pre-treatment human T-ALL samples, we demonstrate that individual T-ALLs have distinct intrinsic GC sensitivity thresholds at diagnosis and that this threshold can predict end induction MRD. To interrogate potential mechanisms of GC resistance, we use a panel of patient-derived xenografts (PDX) generated from diagnostic T-ALLs. We find that intrinsic GC resistance is uniformly seen in T-ALLs that arise at the early thymic progenitor (ETP) stage as well as in a subset of non-ETP T-ALLs. Removal of IL7 from the media or inhibition of IL7/JAK/STAT signaling with the JAK1/2 inhibitor ruxolitinib or a novel JAK3 inhibitor, JAK3i, reverses GC resistance in ETP and a subset of the non-ETP T-ALL. This effect is drug specific, since IL7 does not offer protection from death induced by other agents. IL7-dependent GC resistance can be predicted by hyper-responsiveness to IL7 stimulation. Mechanistically, the combination of dexamethasone and ruxolitinib alters the balance between BCL2 and BIM in IL7-dependent, but not IL7-independent, GC resistant T-ALL samples. Together, these data support a model where IL7, a cytokine with leukemogenic properties that is normally present in lymphopoietic niches, contributes to intrinsic GC resistance in a subset of T-ALL samples. This environmentally induced GC resistance may be reversed with IL7/JAK/STAT pathway inhibition. This could result in an augmented leukemotoxic effect of GC treatment, potentially enhancing efficacy of glucocorticoids in a subset of patients and justifying exposure to the toxic side effects of GCs. Disclosures Taunton: Global Blood Therapeutics: Equity Ownership; Kezar Life Sciences: Equity Ownership, Research Funding; Pfizer: Research Funding; Principia Biopharma: Consultancy, Equity Ownership; Circle Pharma: Consultancy, Equity Ownership; Cell Design Labs: Consultancy, Equity Ownership. Wood:Juno: Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Teachey:Novartis: Research Funding.

Abstract: Daratumumab is effective against T-ALL in human xenograft models. CD38 is a novel target with broad potential in the treatment of T-ALL.

Abstract: 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 & gt;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 & lt;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

Abstract: 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.

Abstract: The Children’s Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients. PATIENTS AND METHODS The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/μL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible. RESULTS At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups ( P = .29) or by treatment regimen ( P = .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients. CONCLUSION COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.

Abstract: Targeted immunotherapy has become critical for the successful treatment of many forms of cancer, particularly therapeutic antibodies with cytotoxic abilities. No safe and effective immunotherapies have been developed for T-cell acute lymphoblastic leukemia (T-ALL). CD38 is a transmembrane glycoprotein found on the cell surface of activated T cells, terminally differentiated B cells, but relatively low levels on normal lymphoid and myeloid cells. Daratumumab (dara) (Darzalex, Janssen Biotech, Inc.) is a human IgG1κ monoclonal antibody that binds to a unique CD38 epitope and was recently FDA approved for the treatment of refractory multiple myeloma. In order to ensure CD38 is a relevant target in T-ALL and surface expression does not change with chemotherapy, we evaluated CD38 expression by flow cytometry (FACS) from 21 patients with T-ALL (10 early T-cell precursor (ETP) and 11 non-ETP) at diagnosis and after one month of induction chemotherapy. All of the samples had detectable CD38 expression which did not change significantly after induction (mean CD38 MFI at diagnosis vs end-induction: 3.27 log vs 3.19 (S.I.; p = 0.25). Therefore we hypothesized that targeting CD38 with dara would be effective against T-ALL. In order to test this hypothesis, we xenografted primary ALL blasts from 15 different patients, including 7 with ETP-ALL and 8 with non-ETP T-ALL. Mice were randomized to dara (200 μg /mouse intraperitoneally (IP) weekly) vs control (isotype control at 200 μg/mouse IP weekly; 5 mice per arm for each sample) after they developed & gt;1% peripheral blood (pb) blasts by FACS. Disease burden was assessed by FACS enumeration of pb blasts weekly and splenic blasts at sacrifice. We demonstrate striking efficacy of dara monotherapy in 6 of 7 ETP-ALL samples with reduction of pb and splenic blasts. Mice treated with high disease burden from 5 of the 8 non-ETP samples were moribund immediately after dara injection, possibly from aggregates of antibody bound to tumor cells leading to pulmonary embolism or tumor lysis, and were therefore inevaluable. We have since repeated the experiments for 3 of the samples, treating the mice after injection but before detectable engraftment of peripheral blasts. Dara was effective in all 3 samples. Experiments are ongoing for the other 2 samples. Overall, we have found Dara was effective in 4 of 6 evaluable non-ETP T-ALL samples. In summary, we found dara is a highly effective novel monotherapy for T-ALL in preclinical models. Based on these results, we are developing an early phase trial for children and young adults with relapsed/refractory T-ALL. Note: This abstract was not presented at the meeting. Citation Format: Karen Lee Bride, Tiffaney Vincent, Soo-Yeon L. Im, Tori Fuller, Theresa Ryan, David M. Barrett, Shannon L. Maude, Mignon L. Loh, Michelle L. Hermiston, Stephan A. Grupp, Brent L. Wood, David T. Teachey. Preclinical efficacy of daratumumab in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2642. doi:10.1158/1538-7445.AM2017-2642

Abstract: Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.

Abstract: ETP-ALL, a high-risk subtype of T-ALL, is characterized by aberrant activation of the JAK/STAT signaling pathway. The JAK1/2 inhibitor ruxolitinib demonstrates robust activity in patient-derived xenograft models of ETP-ALL.