Chromosome-positive Acute Lymphoblastic Leukemia Research Articles

Effect of Tyrosine Kinase Inhibitors on 6‐Mercaptopurine Cytotoxicity: Interactions with Equilibrative Nucleobase Transporter 1

Background Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy in children and adolescents in the developed world. The nucleobase analogue 6-mercaptopurine (6-MP) is a key component in the treatment of pediatric ALL, particularly for the maintenance of remission. While most patients tolerate 6-MP well, intra-individual variability between patients continues to complicate attainment of target drug efficacy with low off-target toxicities at standardized doses of 6-MP. Drug transporter expression is a known factor for patient variability in drug response/toxicity. We have recently established that the SLC43A3-encoded transporter, equilibrative nucleobase transporter 1 (ENBT1), is the primary mechanism by which 6-MP enters cells. ENBT1 expression levels in human leukemia cell lines directly correlate with the rate of 6-MP uptake and resulting cytotoxicity. Tyrosine kinase inhibitors (TKI) are used in combination with 6-MP for treating some subtypes of ALL, i.e., Philadelphia chromosome-positive ALL. Previous studies have indicated that TKI can interfere with nucleobase uptake by cells, and thus may compete for ENBT1. Therefore, it is important to establish the existence of potential drug-drug interactions between 6-MP and TKIs that may affect therapeutic efficacy. Hypothesis We hypothesized that TKI can inhibit ENBT1-mediated 6-MP transport and thereby reduce the therapeutic efficacy of 6-MP in ALL cell lines. Methods [3H]Adenine was used in an oil-stop centrifugation assay to assess ENBT1-mediated uptake activity in a SLC43A3-transfected human embryonic kidney 293 (HEK293) cell line in the presence and absence of various TKI. To determine impact on 6-MP toxicity, a well-established human ALL (MOLT-4) cell line was incubated for 48 hours with a range of 6-MP concentrations (78 nM – 1.28 mM), plus or minus a defined concentration of TKI and assessed for their cell viability via the MTT assay. Results An initial screen showed significant inhibition of ENBT1-mediated [3H]adenine uptake by various TKI at 10 μM: gefitinib >> imatinib = dasatinib (one-way ANOVA, F4,26=22, p<0.0001, n=6). Subsequent concentration-inhibition analyses showed a gefitinib IC50 of 5.5 ± 0.8 μM for inhibiting [3H]adenine uptake in MOLT-4 cells (n=5). Gefitinib alone also decreased MOLT-4 cell viability with an EC50 of 90 ± 68 μM (n=5). From these data, 3 μM gefitinib was selected as a concentration that did not affect MOLT-4 cell viability but did inhibit ENBT1-mediated adenine uptake by approximately 30%. Co-administration of 6-MP and 3 μM gefitinib in MOLT-4 cells resulted in a significant 2-fold increase in the cytotoxicity of 6-MP: Control EC50=1.5 ± 0.6 μM vs Gefitinib EC50= 0.72 ± 0.19 μM (unpaired T-test, t8=2.763, p=0.0245. n=5). Conclusion Our results show that TKI can significantly inhibit ENBT1-mediated transport of nucleobases by ENBT1. However, contrary to expectations, gefitinib increased the cytotoxicity of 6-MP. We hypothesize gefitinib inhibits xanthine oxidase, an enzyme that metabolizes 6-MP into an inactive and readily excreted metabolite. Additional work is needed to confirm the mechanism(s) underlying this synergistic effect of gefitinib on 6-MP cytotoxicity.

Clinical Utility of Droplet Digital PCR to Monitor BCR-ABL1 Transcripts of Patients With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Post-chimeric Antigen Receptor19/22 T-Cell Cocktail Therapy

Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) accounts for 20–30% of adult patients with ALL, characterized by translocation of t(9, 22). Tyrosine kinase inhibitors (TKIs) have significantly improved the outcome even though there are still some problems including relapse due to drug-resistant mutations and suboptimal molecular remission depth. Previously, we reported the safety and efficacy of sequential infusion of CD19/22 chimeric antigen receptor T-cell (CAR-T) immunotherapy in the treatment of relapsed/refractory (R/R) B-cell neoplasms including cases with Ph+ ALL. Given possible deeper reaction, more patients were expected to reach optimal minimal residual disease (MRD) response. An alternative method, duplex droplet digital PCR (ddPCR) with high sensitivity was established, which could provide absolute quantification of MRD without the need for calibration curves. Here, we retrospectively collected 95 bone marrow samples from 10 patients with R/R Ph+, who received 19/22 CAR-T-cell cocktail therapy. Notably, sequential molecular remission for more than 3 months (SMR3), a significant indicator based on ddPCR after CAR-T infusion was established, which was defined as a sequential molecular remission for not <3 months with negative MRD. In this cohort, no recurrence was observed in six patients achieving SMR3, where four of whom accepted allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR-T cell regimen. Unfortunately, the other four patients who did not reach SMR3 relapsed, and did not receive extra specific treatment except CAR-T regimen. To sum up, ddPCR may be an alternative, especially when nucleic acid was insufficient in clinical practice. No achievement of SMR3 may be an early warning of potential relapse after CAR-T and indicating the initiation of other therapies including allo-HSCT.

Outcome of patients with chronic myeloid leukemia in lymphoid blastic phase and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with hyper-CVAD and dasatinib.

Dasatinib monotherapy has demonstrated modest clinical activity in chronic myeloid leukemia in lymphoid blastic phase (CML-LBP). The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has dramatically improved with hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in combination with tyrosine kinase inhibitors (TKIs). The authors reviewed 85 patients (23 with CML-LBP and 62 with newly diagnosed Ph-positive ALL) who received hyper-CVAD plus dasatinib. In the CML-LBP cohort, 19 had prior chronic myeloid leukemia as chronic phase (n = 17; 74%), accelerated phase (n = 1; 4%), or myeloid blastic phase (n = 1; 4%); 4 (17%) presented with de novo CML-LBP. The BCR-ABL1 transcript was p210 in 22 patients (96%) and p190 in 1 patient (4%). In the Ph-positive ALL cohort, p210 and p190 transcripts were detected in 13 patients (21%) and 48 patients (77%), respectively. Patients with CML-LBP were less likely to achieve deep molecular remission than patients with Ph-positive ALL: the major molecular response (MMR) rates were 70% and 95%, respectively (P = .007), and the complete molecular response (CMR) rates were 55% and 74%, respectively (P = .16). Survival outcomes were similar for CML-LBP and Ph-positive ALL: the 5-year overall survival (OS) rates were 59% and 48%, respectively (P = .97). Allogeneic stem cell transplantation was associated with a better outcome in CML-LBP (5-year OS rate, 88% vs 57%; P = .04). In Ph-positive ALL, the outcome was driven by deeper molecular remission: the 5-year OS rates were 63% and 25% with CMR and MMR, respectively (P = .002). The outcome of CML-LBP has improved with hyper-CVAD plus dasatinib therapy with survival comparable to that of Ph-positive ALL. Further improvement may be achieved with the use of novel TKIs and targeted agents.

Neurolymphomatosis of the median nerve, optic nerve, L4 spinal nerve root and cauda equina in patients with B-cell malignancies: a case series

BackgroundNeurolymphomatosis is rare. Neoplastic lymphocytes are seen to invade nerves (cranial or peripheral), nerve roots or other related structures in patients with hematological malignancy. It is a separate entity from central nervous system lymphoma. Neurolymphomatosis has most commonly been described in association with B-cell non-Hodgkin lymphoma. Neurolymphomatosis in the context of Burkitt lymphoma and the post-renal transplant setting has not been described before.Case reportsWe report for the first time in the Arabian Gulf countries and nearby Arab states four cases of neurolymphomatosis (one Asian, and the other 3 are from Arabic nationals) occurring between 2012 and 2017 involving the median nerve, optic nerve, nerve root and cauda equina in patients with Burkitt lymphoma, Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma.ConclusionsNeurolymphomatosis is rare and can be difficult to diagnose by biopsy but reliably confirmed by a combined imaging approach. Prior treatment with high-dose dexamethasone might suppress 18F-fluorodeoxyglucose (FDG) activity and decrease the sensitivity of positron emission tomography/computed tomography (PET/CT). The prognosis is generally poor but using high-dose methotrexate as well as high-dose chemotherapy and autologous stem cell transplantation may be an effective way to treat neurolymphomatosis.

Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports

BackgroundThe outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR–ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response.Case presentationPatient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR.ConclusionIn our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

Concomitant use of a dual Src/ABL kinase inhibitor eliminates the in vitro efficacy of blinatumomab against Ph+ ALL

AbstractBlinatumomab is currently approved for use as a single agent in relapsed and refractory acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated via signaling through the T-cell receptor (TCR). There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia chromosome–positive ALL (Ph+ ALL). However, some second- and third-generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual Src/ABL inhibitors with blinatumomab in vitro from both healthy donor samples and primary samples from patients with Ph+ ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells and enhanced production of interferon-γ (IFN-γ). The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation or IFN-γ production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-γ production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples or samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies, highlighting the importance of maintaining T-cell function with targeted therapies.

Analysis of the Different Therapeutic Effects in 21 Ph+ Acute Lymphoblastic Leukemia Children

To analyze the outcomes of the children suffered from philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) treated with tyrosine kinase inhibitor (TKI) plus chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). 21 cases of firstly diagnosed Ph+ALL patients aged <12 year treated with Chinese Childhood Leukemia Group ALL 2008 (CCLG-ALL 2008) protocol form January 2008 and April 2015 were retrospectively analyzed．The patients were divided into two groups, one group was TKI+ chemotherapy group, the other group was allo-HSCT group. Among 21 patients, 17 were male and 4 were female with a median age of 8 years old (range, 4-12 years), the median follow-up time was 30 moths (range, 10-133 months). All the patients were treated with chemotherapy induced by the high-risk project of CCLG-ALL 2008. Among 14 patients treated with TKI plus chemotherapy, nine patients achieved complete remission. During 3 months after treatment, patients without complete molecular response or with the second complete remission and intensity desire of transplantation were treated with allo-HSCT, among 9 patients with allo-HSCT, six patients achieved long term survival. At TKI era, TKI combined with strong chemotherapy can make Ph+ ALL children achieve 5 years event-free survival as campared those treated with allo-HSCT. However, for the patients without complete molecular response persistently and relapsed they can still benefit from allo-HSCT.

Role of BCR-ABL1 isoforms on the prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia in the tyrosine kinase inhibitor era: A meta-analysis.

BCR-ABL1 fusion gene is the driver mutation of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Although the prognostic value of BCR-ABL1 isoforms in Ph+ ALL patients has been investigated in numerous studies in the tyrosine kinase inhibitor (TKI) era, the results were still conflicting. Hence we performed herein the meta-analysis to comprehensively assess the impact of BCR-ABL1 isoforms on the clinical outcomes of Ph+ ALL patients. Systematic literature review was conducted in PubMed, Embase, and Cochrane databases with the data access date up to June 15, 2020. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Furthermore, subgroup analyses were performed to assess the robustness of the associations. Nine studies with a total number of 1582 patients were eligible for this meta-analysis. Combined HRs suggested that p210 was slightly associated with inferior event-free survival (EFS) (HR = 1.34, 95% CI 1.05–1.72). The overall survival (OS) was not significantly affected (HR = 1.15, 95% CI 0.92–1.45). In subgroup analyses, the HRs showed a trend toward adverse impact of p210 on clinical outcomes. However, the confidence intervals were not crossing the null value only in a minority of subgroups including Caucasian studies, first-generation TKI treated cohort and transplant cohort. Our findings suggested that p210 might pose a mild adverse impact on the EFS of Ph+ ALL patients. This effect might be compromised by the use of second- or third-generation TKIs. Further studies are needed to verify our conclusions.

Philadelphia Chromosome-Positive (Ph+) Childhood Acute Lymphoblastic Leukemia: Good Initial Steroid Response Allows Early Prediction of a Favorable Treatment Outcome

Among 4,760 acute lymphoblastic leukemia (ALL) patients enrolled from 1986 to 1995 in two subsequent trials of the BFM and AIEOP study group, 61 patients were found to have Philadelphia chromosome-positive (Ph+) ALL. These patients were analyzed for presenting features and treatment outcome to identify specific prognostic factors. Treatment stratification was based on initial cell mass and early response as determined by blast count in peripheral blood after a 7-day induction prephase with prednisone and one dose of intrathecal methotrexate on day 1. All patients were treated by similar intensive Berlin-Frankfurt-Münster (BFM) protocols. The median age of Ph+ patients was 7.5 years, the median white blood cell count (WBC) was 75 × 109/L, 77% of patients had common ALL, and 29% coexpressed myeloid markers. After a median observation time of 4.2 years, 29 of 61 patients are alive (survival probability [pSUR] at 4 years, 0.49; standard error [SE], 0.06), and 24 of 61 are in first complete remission (CR1; probability of event-free survival [pEFS] at 4 years, 0.38; SE, 0.06). Twenty (35%) of 57 evaluable patients had ≥1,000 leukemic blasts per microliter of blood on day 8 of induction (defined as prednisone-poor-response [PPR]). These patients were older (10.0v 6.88 years; P = .02) and had a higher WBC (144v 29 × 109/L; P = .0016) as compared with patients with prednisone good response (PGR; <1,000 blasts/μL at day 8). Only 2 of 20 patients (10%) with PPR remained in CR1 and alive: 6 patients with PPR did not survive after allogeneic bone marrow transplantation (BMT) due to recurring disease (n = 3) and toxicity (n = 3), and 12 nontransplanted patients died due to progression (n = 5) or relapse (n = 7). In contrast, 26 (70%) of the 37 patients with PGR are alive. Of 18 patients transplanted by allo-BMT, 1 relapsed (now in CR2) and 4 died after BMT. Among the 19 patients with PGR treated by chemotherapy alone, 8 remained in CR1 and 11 relapsed, of which 4 are in CR2 or CR3. The prednisone response emerged as the only independent prognostic factor for survival in Cox regression analysis. Thus, two thirds of Ph+ childhood ALL cases can be identified early by PGR, which, when treated with intensive BFM chemotherapy, with or without BMT, have a significantly lower risk of treatment failure. With a median continuous complete remission (CCR) time of 4.1 years, pEFS for PGR is 0.55 (SE, 0.08) compared with 0.10 (SE, 0.07) in patients with PPR (P = .0001). PGR is also an indicator for treatment responsiveness and durable second remission after relapse, which in turn may provide a second chance for BMT.© 1998 by The American Society of Hematology.

Treatment of Philadelphia chromosome–positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate

AbstractImatinib mesylate, an inhibitor of the Bcr-Abl tyrosine kinase, has modest activity in refractory/relapsed Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL). Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. There were 20 patients who received hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib mesylate followed by imatinib mesylate-based consolidation/maintenance therapy. Of these patients, 11 had de novo disease, 4 were primary failures after induction (without imatinib mesylate), and 5 were in complete remission (CR) after induction (without imatinib mesylate). All 15 patients treated for active disease achieved CR. Within a median of 3.5 months in first CR, 10 patients underwent allogeneic stem cell transplantation (SCT). One patient relapsed after matched related SCT. The other 9 patients remained alive in CR with median follow-up of 12 months after SCT (range, 1+ to 17+ months). Among 10 patients ineligible for (no donor or older age) or refusing allogeneic SCT, 1 patient relapsed after one year. There were 5 patients who remained alive in continuous CR for a median of 20 months (range, 4+ to 24+ months), with 2 older patients dying in CR at 15 and 16 months of comorbid conditions. Molecular CRs were achieved in both groups (SCT or no SCT). Outcome with hyper-CVAD and imatinib mesylate appears better than with prior regimens; continued accrual and longer follow-up of the current cohort is needed. (Blood. 2004;103:4396-4407)

Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy-The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group.

Simple SummaryPhiladelphia chromosome positive acute lymphoblastic leukemia (ALL Ph+) is rare in children, but outcomes are still poor. The aim of our study was to analyze the toxicity events and results of children with ALL Ph+ treated according to the EsPhALL2010 protocol (the European intergroup study of post induction treatment of Philadelphia chromosome positive ALL) in Poland between the years 2012 and 2019. Our treatment outcomes are still disappointing compared to those in other reports. Improvements in supportive care and emphasis placed on the determination of MRD at successive time points, which will impact decisions on therapy, may be required.The treatment of children with Philadelphia chromosome positive acute lymphoblastic leukemia (ALL Ph+) is currently unsuccessful. The use of tyrosine kinase inhibitors (TKIs) combined with chemotherapy has modernized ALL Ph+ therapy and appears to improve clinical outcome. We report herein the toxicity events and results of children with ALL Ph+ treated according to the EsPhALL2010 protocol (the European intergroup study of post-induction treatment of Philadelphia chromosome positive ALL) in 15 hemato-oncological centers in Poland between the years 2012 and 2019. The study group included 31 patients, aged 1–18 years, with newly diagnosed ALL Ph+. All patients received TKIs. Imatinib was used in 30 patients, and ponatinib was applied in one child due to T315I and M244V mutation. During therapy, imatinib was replaced with dasatinib in three children. The overall survival of children with ALL Ph+ treated according to the EsPhALL2010 protocol was 74.1% and event-free survival was 54.2% after five years. The cumulative death risk of the study group at five years was estimated at 25.9%, and its cumulative relapse risk was 30%. Our treatment outcomes are still disappointing compared to other reports. Improvements in supportive care and emphasis placed on the determination of minimal residual disease at successive time points, which will impact decisions on therapy, may be required.

Dasatinib Increases MHCII Surface Levels and Can Synergize with Anti-PD1 Therapy to Increase the Anti-Tumor Effect in a Pre-Clinical Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Model

Anti-PD1 therapy in hematologic malignancies has shown clinically inferior effects when compared to solid tumors.1 However, immunotherapy has been part of the standard of care in the treatment of acute leukemia for over 40 years. Recently, loss of MHCII was shown to be a mechanism of Immune escape in patients with acute myeloid leukemia after stem cell transplantation.2 Here we demonstrate, in pre-clinical models, that responses to anti-PD1 can be enhanced by increased antigen presentation through induction of MHCII. We used a Philadelphia chromosome positive (Ph+) Acute Lymphoblastic Leukemia (ALL) syngeneic mouse model and treated 4 cohorts of mice with the following regimens: 1) vehicle 2) single agent Dasatinib; 3) single agent anti-PD1; 4) combination anti-PD1 + Dasatinib (Figure 1a). Single agent Dasatinib, was highly active against this model compared to vehicle. Although anti-PD1 therapy showed little or no activity as a single agent, when combined with sub-therapeutic doses of Dasatinib, we observed significantly enhanced survival of mice compared to single agent anti-PD1 or to single agent Dasatinib. (Figure 1b) In our mouse model, Dasatinib increased the MHCII on the surface of the antigen presenting cells in the tumor microenvironment, most notably in dendritic cells (CD11c+ cells) from mouse tumor-infiltrating lymphocytes collected from the mice bone marrow after treatment (Fig 1c). To prove whether Dasatinib-induced MHCII expression can occur independently of a tumor microenvironment, we treated antigen presenting cell lines (KG1) with Dasatinib and were able to confirm an increased MHCII expression by flow cytometry and by western blotting. (Fig 1d) Since Dasatinib is approved for the treatment of Philadelphia chromosome positive ALL, CML, and has been used in a variety of other settings in the treatment of both malignant hematology and solid tumors, this data has immediate translational potential. In fact, Dasatinib in combination with anti-PD1 therapy is currently being tested in a variety of phase I/II trials in various kinds of malignancies (NCT04284202, NCT03516279). Here we show that induction of MHCII by Dasatinib may serve as a biomarker and could predict the potential benefit from the combination treatment. Additionally, targeting anti-PD1 following Dasatinib administration may increase response rates of patients treated with Dasatinib, providing a rationale for sequential treatment design in patients with persistent minimal residual disease. Figure 1. (a) C57BL/6J mice were injected via tail vein injection with a transplantable, immunocompetent BCR-ABL+ B-ALL model and treated with vehicle/Dasatinib/or anti-PD1 as described in the schema. (b) Overall survival of the mice treated in the previous experiment. (c) MHCII cell surface expression on dendritic cells (CD11+ cells) from the bone marrow of treated mice. (d) relative Cell surface expression of MHCII in the KG1 cell line (APC cell line) treated with Dasatinib vs. vehicle. (e) protein expression of MHCII in the KG1 cell line (APC cell line) treated with Dasatinib vs. vehicle. 1. Masarova L, Kantarjian H, Ravandi F, Sharma P, Garcia-Manero G, Daver N. Update on Immunotherapy in AML and MDS: Monoclonal Antibodies and Checkpoint Inhibitors Paving the Road for Clinical Practice. Adv Exp Med Biol 2018;995:97-116. W2. Christopher MJ, Petti AA, Rettig MP, et al. Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. New England Journal of Medicine 2018;379:2330-41. Figure Disclosures Koller: Jazz Pharmaceuticals, Inc.: Consultancy. Konopleva:Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Sanofi: Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents &amp; Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; Amgen: Consultancy; Calithera: Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding. OffLabel Disclosure: anti-pd1 therapy in acute lymphoid leukemia

Treatment of Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Using Tyrosine Kinase Inhibitors in Combination with Chemotherapy: A Patient-Centered Benefit-Risk Assessment

BACKGROUND: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL), an aggressive disease with historically poor survival in adults, is treated with tyrosine kinase inhibitors (TKI) plus chemotherapy. Choosing a TKI involves considering a variety of factors, including the benefits and risks of each therapy. This study aims to understand patients' preferences for these benefits and risks, and how this varies between patients. METHODS: In a US-based study conducted between February and April 2020, adult patients (≥ 18 years) with self-reported Ph+ALL (newly diagnosed and relapsed/refractory) completed an online discrete choice experiment (DCE) comprising 12 experimental and 2 internal validity choice tasks. For each task, patients were asked to choose between 2 hypothetical treatments with different levels of benefits and risks. Attributes and levels in the DCE included overall survival (OS, 30-90 months in 5-month increments), duration of remission (DOR, 15-75 months in 5-month increments), risk of a major CV event (0%, 25%, 50%), and risk of myelosuppression (0%, 50%, 100%). A multinomial logit model was used to estimate patients' preferences expressed as weights based on part-worth utilities with 95% CI . A benefit-risk assessment was subsequently conducted to estimate the proportion of patients who would be expected to prefer different TKI profiles. The hypothetical benefit-risk profiles included within this analysis are outlined in Table 1. RESULTS: The DCE was completed by 201 patients. Mean age was 44.8 ± 12.9 years, 17% had ≥2 relapses, 58% were diagnosed &amp;gt;12 months previously, and 67% were in remission. The most common ongoing therapies were dasatinib (24%) and imatinib (18%). Internal validity was high: 88% passed the choice dominance test (where one treatment option was superior for all 4 attributes) and 98% never selected the same option. When selecting a preferred treatment, patients cared the most about a 1-month increase in OS (utility=0.032 [95% CI, 0.021-0.042]) and a 1-month increase in duration of remission (utility=0.017 [95% CI, 0.012-0.023]) and they cared less about reducing the risk of a major CV event by 1% (utility=0.011 [95% CI, 0.008-0.013]) and reducing the risk of myelosuppression by 1% (utility=0.009 [95% CI, 0.008-0.010]). Patients were willing to tolerate a 2.9% (95% CI, 1.78-4.02) increase in risk of a major CV event for 1 additional month of OS, and 1.59% (95% CI, 0.95%-2.24%) increase in risk of a major CV event for an additional 1 month in remission. Figure 1 shows the proportion of patients who would be expected to prefer each of the TKIs, given only the choice between the 4 hypothetical TKIs outlined in Table 1. The results are presented by the overall sample and by subgroups of patients. When the analysis is run for the whole sample, 61.4% of patients are expected to prefer the benefit-risk profile of TKI A, choosing the longer OS and duration of remission, despite the higher CV and myelosuppression risk. However, treatment preference varied between patient subgroups, with greater proportions of patients expected to prefer the benefit-risk profile of TKI A if they had already experienced more than 3 prior lines of Ph+ALL treatment, were in remission, had not relapsed, or had fewer physical limitations. In contrast, other patients were less likely to tolerate higher risks for improvements in remission and survival, such as patients who were diagnosed less than 1 year ago and those who had just started treatment. CONCLUSIONS: Most Ph+ALL patients are willing to accept an increased risk of CV events and myelosuppression in exchange for the improvements in survival and duration of remission generated by frontline treatment. However, risk tolerance varies between patients, with some subgroups of patients being more willing to tolerate increased risks. Consideration of patient specific preferences observed in this study can further assist clinicians in selection of appropriate treatment in discussion with their patients. Disclosures Ashaye: Takeda Pharmaceutical Company Limited: Current Employment, Current equity holder in publicly-traded company. Thomas:Evidera: Consultancy. Dalal:Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical International Company, Cambridge, MA: Current Employment, Current equity holder in private company. Kota:Novartis: Consultancy, Honoraria; Xcenda: Honoraria; Ariad: Honoraria; Pfizer: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Incyte: Honoraria. Krucien:Evidera: Current Employment. Sae-Hau:The Leukemia &amp; Lymphoma Society: Current Employment, Research Funding. Barnhart:Evidera: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Weiss:The Leukemia &amp; Lymphoma Society: Current Employment, Research Funding. Campbell:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Current Employment. Marsh:Evidera: Consultancy.

Optimal Interval for Detection of Molecular Relapse after Stop of Tyrosine Kinase Inhibitor (TKI) in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL) Caliculated By Kinetics of BCR-ABL Transcripts

Background In Ph+ALL patients, prophylactic/maintenance administrations of TKI are used after the protocol treatment. Unlike Chronic myelogenous leukemia (CML), after TKI stopped, there is no consensus about how often to monitor to detect molecular relapse. In the current study, from clinical data of 31 patients we tried to determine the optimal frequency of MRD monitor for better prognosis using a mathematical model. Methods Doubling time (DT) and Growth rate (GR) were retrospectively calculated by the increase of BCR-ABL from 99 kinetic data from 31 patients with Ph+ALL at molecular relapse. Measurement of amount BCR-ABL was performed by RQ-PCR. Mimicking CML, we defined BCR-ABL/ABL ratio of 0.1% as "MR3 (Major molecular response)" and undetectable levels of BCR-ABL transcript as "MR5 (Complete molecular response)". In order to investigate the relationship between tumor burden (BCR/ABL) at the time of MRD detection and prognosis, it was divided into 3 groups, BCR/ABL&amp;lt;0.1% (MR3), 0.1%&amp;lt;BCR/ABL&amp;lt;1% (MR2) and BCR/ABL&amp;gt;1% (MR1). This study was approved by the institutional review committee. Results The doubling time was 1.3 days (GR 0.7%/day) to 95.4 days (70.8%/day) with a median of 12.3 days (5.8%). The rate of increase was compared by three groups of tumor burden. The DT among patients in MR1 was shorter than those in MR3 and MR2 (7.7 days vs 15.2 days in median, t-test p&amp;lt;0.01). There were no differences of DT in sex, age, treatments and BCR/ABL mutation. Most patient had multiple kinetic data and the smallest amount of BCR/ABL was used in each patient. Among 8 patients who showed MR3 (MR3pt) and 11 who showed MR2 (MR2pt), 14 are alive at this analysis, while among 10 patients who showed MR1 (MR1pt), only 1 patient is alive.(Log-rank test, p&amp;lt;0.1) (Figure) Median survival time is 882 days, 330 days and 16 days in MR3pt, Mr2pt and MR1pt, respectively. All patients died of progression of the disease. Finding molecular relapse before MR2 may related to better results. Optimal interval of MRD detection We set several hypotheses to determine the optimal frequency to detect early recurrence of leukemia. We estimated that patients with MR2 and MR5 have 1010 and 107 Ph+ cells in body, respectively. We defined "MR2" and "MR5" as "optimal intervention threshold" and "detection threshold". From our clinical data, we tentatively determined that doubling time of leukemia growth is distributed between 1 day (GR 100%/day) and 100days (0.7%). Also, we assumed that single cell has a relapse potency and the GR is constant during observation in each patient. The number of Ph+ cells in a MR5 patient who would potentially relapse might be distributed between 1 cell and 1 x 107 (MR5). "Success" was defined as if molecular relapse is detected between M5 and MR2 and "Failure" was defined as if detected more than MR2. According to the daily clinical practice, the optimal examination interval is tentatively every 7 days, every 14 days, every 28 days, every 56 days, every 84 days, every 6 months, and every year. First, in order to calculate the growth rate that would be successful at 7-day intervals, the rate of 168%/day for 1 cell to increase 107 (MR5) in 7 days was calculated. This rate is faster than the maximum rate of 100%/day in this study, so an interval of 7 days is good for the initial period. Similarly, at 14-day intervals, 68%/day is calculated, and in this case, it requires 32 days to increase 107 (MR5) from 1 cell. As a result, after 32.7 days, 14-day intervals are acceptable. Similarly, the calculated results for 28 days, 56 days, 84 days, 6 months, and 1 year are shown in the Table. MRD can be found before M3 (success) with 28-day intervals after 65 days, 56-day intervals after 131 days, 84-day intervals after 196 days, 6-month intervals after 419 days and 1-year intervals after 852 days. Conclusion Taken together, soon after stop of TKI, more frequent monitoring of MRD than in "treatment free remission" in CML is needed. The interval can be prolonged with the passage of time. In several patients, hematopoietic stem cell transplantation (HSCT) was possible due to early intervention by changing TKI and chemotherapy. After HSCT, TKI combined with rapid reduction of immune-suppressants and donor lymphocyte infusion successfully related with long term survival. (data will be shown in ASH) Thus, the tight monitoring according to the mathematical model is important. The current strategy may be applied to other leukemia in which MRD monitoring by PCR is established. Disclosures Miyamura: Bristol-Myers Squibb Co., Ltd.:Honoraria;Celgene Co., Ltd.:Honoraria;Daiichi-Sankyo Co., Ltd.:Honoraria;Otsuka Co., Ltd.:Honoraria;Pfizer Co., Ltd.:Honoraria;Novartis Co., Ltd.:Honoraria.Goto:Takeda Pharmaceutical Co., Ltd:Honoraria;Novartis Pharma Co., Ltd.:Honoraria.Morishita:Bristol-Myers Squibb Co., Ltd.:Honoraria.Ozawa:Novartis Co., Ltd.:Honoraria.

The Colony-Stimulating Factor 3 Receptor M696T Mutated in a Patient with Ph+ Acute Lymphoblastic Leukemia

Purpose: Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in a variety of myeloid disorders, such as severe congenital neutropenia (SCN), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and atypical chronic myelogenous leukemia (aCML). Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. We report a case of philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) with the M696T mutation in CSF3R gene and assess the pathogenicity of the CSF3R M696T mutation in Ph+ ALL. Experimental Design: Here we report on a 32-year-old female who presented with asthenia. The initial hematological workup revealed white blood cell (WBC) count of 97 x 109/L (normal range 4-10 x 109/L). There was 84% prolymphocyte in the bone marrow. The immunophenotype of the blasts as judged from flow cytometry was in accordance with a B-ALL. The fusion gene for BCR-ABL P210 was positive. Hot mutation closely related to diseases was: CSF3R (nucleotide change c.2087 T&amp;gt;C, amino acid change p.M696T, mutation frequency 50.4%). Cytogenetic analysis showed 46, XX, t (9;22) (q34;q11). The patient was diagnosed as Ph+ ALL with the CSF3R M696T mutation and achieved Long-term survival after unrelated donor hematopoietic stem cell transplantation. Meanwhile we performed a series of experiments using murine interleukin 3 (IL-3)-dependent Ba/F3 cell line to evaluate the transforming capacity of the CSF3R M696T mutation. The phosphorylation of STAT3 was analyzed by G-CSF dependence assays and immunoblot analysis to evaluate the CSF3R M696T mutation contribution to the tumor transformation ability of Ba/F3 cells. Results: This patient achieved complete remission with chemotherapy in combination with tyrosine kinase inhibitor (TKI) and long-term survival by unrelated donor transplantation. We confirmed the presence of a CSF3R M696T germline mutation in this patient, and the mutation was inherited from her mother. The experiments in vitro result showed the CSF3R M696T mutation harbors marginal contribution to the tumor transformation ability of Ba/F3 cells. CSF3R M696T mutation was neutral in tumor transformation ability. Conclusions: We believe that TKI is still effective in patients with the CSF3R M696T mutation in Ph+ ALL. Donor with CSF3R M696T mutation might still be selected. Disclosures No relevant conflicts of interest to declare.

Low Level BCR-ABL1 Gene Fusion Detected By RT-PCR in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia Does Not Predict Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia at Relapse: A 10-Year Single Institution Study

Background The Philadelphia chromosome t(9;22), a reciprocal translocation between chromosomes 9 and 22, results in the gene fusion BCR-ABL1, and occurs in 2-3% of childhood acute lymphoblastic leukemia (ALL). It is detected using cytogenetic and molecular techniques: karyotype, fluorescence in-situ hybridization (FISH) for t(9;22) and reverse transcription polymerase chain reaction (RT-PCR) for BCR-ABL1. Detection has implications for treatment, with the addition of tyrosine kinase inhibitors to chemotherapy regimens improving outcome. Low level BCR-ABL1 transcripts have been reported in blood of healthy individuals. We have observed this finding in bone marrow in newly diagnosed ALL in the absence of the t(9;22) by karyotype or FISH. The significance of low level positivity at diagnosis has not been determined in the setting of childhood Philadelphia chromosome negative (Ph-) ALL. Here we report, for the first time, the molecular evolutionary characteristics of children and adolescents with low level BCR-ABL1 positivity found at diagnosis to relapse. Methods We reviewed 327 patients aged 0-17 years diagnosed with ALL or Acute Leukemia of Ambiguous lineage (ALAL) at The Children's Hospital at Westmead, Sydney, Australia from 1 January 2010 to 30 June 2020. Those positive for the BCR-ABL1 gene fusion by RT-PCR, and negative for t(9;22) by karyotype or FISH were included. Demographics, cytogenetics at diagnosis and relapse, and outcome data were extracted from the medical record. Qualitative BCR-ABL1 analysis was performed using multiplex RT-PCR, followed by nested PCR, on RNA extracted from diagnostic bone marrow (sensitivity 5x10-6). If positive, quantitation was performed using real-time RT-PCR with results expressed as the ratio of BCR-ABL1 over ABL1 (sensitivity 1x10-5). Each PCR included positive and negative controls. Results Of 313 (96%) evaluable patients diagnosed with ALL or ALAL at our institution in the study period, 54 (17%) were positive by RT-PCR for BCR-ABL1 in diagnostic bone marrow. Seven patients were excluded as they had Ph+ ALL-specific treatment after the detection of t(9;22) by karyotype, FISH or other methods. Forty-seven (15%) children with Ph- ALL had low level BCR-ABL1 detected by qualitative PCR. Demographic and cytogenetic characteristics for these patients are summarized in Table 1. All were diagnosed with ALL, the majority (77%) of precursor B-cell lineage including 2 with infant ALL. The e1a2 transcript was identified in 43 (91%) patients, with other transcript types as follows: e4a2 in 1 (2%), e13a2 in 1 (2%), and splicing variants in 2 (4%). BCR-ABL1 quantitation was performed in 43 (91%) and was quantifiable only in 12 (28%) patients, with a median of 0.0008% (range 0.0003 - 0.095%). Forty-five (96%) patients were treated with Berlin-Frankfurt-Munster ALL chemotherapy regimens. The two infant ALL patients were treated on the Interfant06 trial. One received a bone marrow transplant (BMT) in first remission then died after relapse; the other relapsed and died before BMT. Seven (15%) of 47 relapsed, occurring at a median of 21 months (range 2 - 41 months) after diagnosis. Characteristics of these patients are presented in Table 2. Four patients were tested for BCR-ABL1 by RT-PCR in relapse marrow samples; all were negative. No patient with low level BCR-ABL1 positivity at initial diagnosis was diagnosed with Ph+ ALL at relapse. There was no difference in 5-year relapse-free (80% vs 83%, P = .451) or overall survival (86% vs 91%, P = .368) between children with low level BCR-ABL1 positivity (n=47) and those without (n=259). Conclusion BCR-ABL1 low level positivity detected by RT-PCR in the bone marrow of children with newly diagnosed ALL is a relatively common finding, and did not adversely affect outcome for patients treated for Ph- ALL using a contemporary risk-adapted approach. Importantly, this finding did not influence the molecular evolutionary characteristics at the time of relapse in our patient group. Disclosures No relevant conflicts of interest to declare.

Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients &amp;gt;60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

ZUMA-4: A Phase 1/2 Multicenter Study of KTE-X19 in Pediatric and Adolescent Patients With Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

Background: Although approximately 80% - 85% of patients with acute lymphoblastic leukemia (ALL), the most common childhood malignancy, achieve durable complete remissions (CRs) after initial treatment, the remaining 15% - 20% of patients with relapsed or refractory (R/R) ALL have unfavorable outcomes (Leukemia2018;32:2316-25; N Engl J Med 2015;373:1541-52) and could benefit from effective new therapies. KTE-X19 is an autologous, anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of R/R mantle cell lymphoma and under investigation for additional R/R hematologic malignancies including chronic lymphocytic leukemia, adult ALL, and pediatric B cell ALL and non-Hodgkin lymphoma (NHL). KTE-X19 treatment has shown high rates of CRs, with a manageable safety profile for adult patients with R/R B cell ALL in the Phase 1 portion of ZUMA-3, including those with poor risk factors (J Clin Oncol 2019;37[suppl, abstr]:7006). ZUMA-4 is an ongoing Phase 1/2 study evaluating KTE-X19 in pediatric and adolescent patients with R/R B cell ALL or NHL (NCT02625480). End-of-Phase 1 interim analysis of ZUMA-4 showed the feasibility of KTE-X19 therapy with optimized dosing and adverse event (AE) management strategies for the treatment of pediatric patients with R/R ALL (Pediatr Blood Cancer 2019;66[suppl]:S24). The protocol for Phase 2 of ZUMA-4 has been amended to include broader B cell ALL enrollment criteria with a focus on patients with early relapse associated with poorer outcomes, and an NHL cohort was added. Methods: Key B cell ALL enrollment criteria include age ≤ 21 years, weight ≥ 10 kg, and B cell ALL that is primary refractory, relapsed within 18 months of first diagnosis, R/R after ≥ 2 lines of systemic therapy, or R/R after allogeneic stem cell transplantation at least 100 days prior to enrollment. Criteria for disease burden have been amended to also include patients with minimal residual disease-positive disease at enrollment. Patients with Philadelphia chromosome-positive ALL are eligible if intolerant to tyrosine kinase inhibitor therapy or if R/R after ≥ 2 tyrosine kinase inhibitor therapies. Patients with chronic myelogenous leukemia lymphoid blast crisis or clinically significant infections are not eligible. For B cell NHL, key enrollment criteria include age &amp;lt; 18 years, weight ≥ 10 kg, histologically confirmed diffuse large B cell lymphoma not otherwise specified (DLBCL NOS), primary mediastinal large B cell lymphoma, Burkitt lymphoma (BL), Burkitt-like lymphoma or unclassified B cell lymphomas intermediate between DLBCL and BL, with ≥ 1 measurable lesion. For NHL, disease must be primary refractory, R/R after ≥ 2 lines of systemic therapy, or R/R after autologous or allogeneic stem cell transplantation ≥ 100 days prior to enrollment. Patients with acute graft-versus-host disease or chronic graft-versus-host disease requiring treatment within 4 weeks of enrollment are not eligible. Patients with central nervous system-1 disease (no detectable lymphoblasts in cerebrospinal fluid), with central nervous system-2 disease (detectable disease, but white blood cell count &amp;lt; 5/μL in cerebrospinal fluid) without clinically evident neurologic changes, or who had prior blinatumomab treatment can be included in the ALL and NHL cohorts. Patients with prior CD19-directed therapy, except for blinatumomab, are excluded. Patients receive conditioning chemotherapy with fludarabine 25 mg/m2 on Days −4, −3, and −2 and cyclophosphamide 900 mg/m2 on Day −2 followed by a single infusion of KTE-X19 at a target dose of 1 × 106 anti-CD19 CAR T cells/kg on Day 0. The study has completed the Phase 1 portion and is currently enrolling in Phase 2, with a target accrual of approximately 50 additional patients with ALL and 16 with NHL. For ALL, the primary Phase 2 objective is to evaluate KTE-X19 efficacy as assessed by overall CR rate (CR + CR with incomplete hematologic recovery). For NHL, the primary Phase 2 objective is KTE-X19 efficacy assessment by objective response rate (complete response + partial response). Secondary Phase 2 objectives for ALL and NHL cohorts include safety and tolerability, additional efficacy endpoints, and changes in patient-reported outcome scores. ZUMA-4 is currently recruiting at 23 sites in the United States, Canada, France, and the Netherlands. Disclosures Wayne: Servier: Research Funding; Kite, a Gilead Company: Research Funding. Lee:Amgen Oncology: Consultancy; Kite, a Gilead Company: Research Funding; Juno: Consultancy; Harpoon Therapeutics: Consultancy. Baruchel:Bristol-Myers Squibb: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bellicum: Consultancy. Brown:Novartis: Consultancy; Janssen: Consultancy; Servier: Honoraria; Jazz: Honoraria. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Krueger:Atara: Other: Travel support; Kite, a Gilead Company: Other: Travel support; Novartis: Consultancy, Other: Travel support; no honoraria, Speakers Bureau. Shen:Gilead: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Travel support. Tailford:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Masouleh:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company.

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide

AbstractAllogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.