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Recombinant Erwinia asparaginase (JZP458) in ALL/LBL: complete follow-up of the Children's Oncology Group AALL1931 study
Maese, Luke; Loh, Mignon L; Choi, Mi Rim; Agarwal, Shirali; Aoki, Etsuko; Liang, Yali; Lin, Tong; Girgis, Suzette; Chen, Cuiping; Roller, Shane; Chandrasekaran, Vijayalakshmi; Iannone, Robert; Silverman, Lewis B; Raetz, Elizabeth A; Rau, Rachel E
Children's Oncology Group study AALL1931 investigated the efficacy and safety of recombinant Erwinia asparaginase (JZP458) in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma and hypersensitivity reactions/silent inactivation to Escherichia coli-derived asparaginases. Each pegylated Escherichia coli asparaginase dose remaining in a patient's treatment plan was replaced by intramuscular (IM) or IV JZP458 (6 doses) administered Monday/Wednesday/Friday (MWF). Three IM cohorts (1a [25 mg/m2 MWF], n = 33; 1b [37.5 mg/m2 MWF], n = 83; 1c [25/25/50 mg/m2 MWF], n = 51) and 1 IV cohort (25/25/50 mg/m2 MWF, n = 62) were evaluated. The proportion (95% confidence interval [CI]) of patients maintaining nadir serum asparaginase activity (NSAA) levels of ≥0.1 IU/mL at the last 72 (primary end point) and 48 hours during course 1 was 90% (95% CI, 81-98) and 96% (95% CI, 90-100) in IM cohort 1c, respectively, and 40% (95% CI, 26-54) and 90% (95% CI, 82-98) in the IV cohort. Population pharmacokinetic modeling results were comparable with observed data, predicting the vast majority of patients would maintain therapeutic NSAA levels when JZP458 is administered IM or IV 25 mg/m2 every 48 hours, or IM 25/25/50 mg/m2 MWF, or with mixed IM and IV administration (IV/IV/IM 25/25/50 mg/m2 MWF). Drug discontinuation occurred in 23% and 56% of patients in the IM and IV cohorts, respectively; 13% and 33% because of treatment-related adverse events (mainly allergic reactions and pancreatitis). JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules based on combined observed and modeled data with a safety profile consistent with other asparaginases. This trial was registered at www.ClinicalTrials.gov as #NCT04145531.
PMCID:11742576
PMID: 39454281
ISSN: 2473-9537
CID: 5781652
A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia
Xu, Jason; Chen, Changya; Sussman, Jonathan H; Yoshimura, Satoshi; Vincent, Tiffaney; Pölönen, Petri; Hu, Jianzhong; Bandyopadhyay, Shovik; Elghawy, Omar; Yu, Wenbao; Tumulty, Joseph; Chen, Chia-Hui; Li, Elizabeth Y; Diorio, Caroline; Shraim, Rawan; Newman, Haley; Uppuluri, Lahari; Li, Alexander; Chen, Gregory M; Wu, David W; Ding, Yang-Yang; Xu, Jessica A; Karanfilovski, Damjan; Lim, Tristan; Hsu, Miles; Thadi, Anusha; Ahn, Kyung Jin; Wu, Chi-Yun; Peng, Jacqueline; Sun, Yusha; Wang, Alice; Mehta, Rushabh; Frank, David; Meyer, Lauren; Loh, Mignon L; Raetz, Elizabeth A; Chen, Zhiguo; Wood, Brent L; Devidas, Meenakshi; Dunsmore, Kimberly P; Winter, Stuart S; Chang, Ti-Cheng; Wu, Gang; Pounds, Stanley B; Zhang, Nancy R; Carroll, William; Hunger, Stephen P; Bernt, Kathrin; Yang, Jun J; Mullighan, Charles G; Tan, Kai; Teachey, David T
Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.
PMID: 39587259
ISSN: 2662-1347
CID: 5780312
Reply to: Accurate Determinants of Outcome in ALL
Chang, Ti-Cheng; Chen, Wenan; Qu, Chunxu; Cheng, Zhongshan; Elsayed, Abdelrahman; Pounds, Stanley B; Shago, Mary; Rabin, Karen R; Raetz, Elizabeth A; Devidas, Meenakshi; Cheng, Cheng; Angiolillo, Anne; Baviskar, Pradyuamma; Borowitz, Michael; Burke, Michael J; Carroll, Andrew; Carroll, William L; Chen, I-Ming; Harvey, Richard; Heerema, Nyla; Iacobucci, Ilaria; Wang, Jeremy R; Jeha, Sima; Larsen, Eric; Mattano, Leonard; Maloney, Kelly; Pui, Ching-Hon; Ramirez, Nilsa C; Salzer, Wanda; Willman, Cheryl; Winick, Naomi; Wood, Brent; Hunger, Stephen P; Wu, Gang; Mullighan, Charles G; Loh, Mignon L
PMID: 39715469
ISSN: 1527-7755
CID: 5767332
Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children
Gupta, Sumit; Rau, Rachel E; Kairalla, John A; Rabin, Karen R; Wang, Cindy; Angiolillo, Anne L; Alexander, Sarah; Carroll, Andrew J; Conway, Susan; Gore, Lia; Kirsch, Ilan; Kubaney, Holly R; Li, Amanda M; McNeer, Jennifer L; Militano, Olga; Miller, Tamara P; Moyer, Yvonne; O'Brien, Maureen M; Okada, Maki; Reshmi, Shalini C; Shago, Mary; Wagner, Elizabeth; Winick, Naomi; Wood, Brent L; Haworth-Wright, Tara; Zaman, Faraz; Zugmaier, Gerhard; Zupanec, Sue; Devidas, Meenakshi; Hunger, Stephen P; Teachey, David T; Raetz, Elizabeth A; Loh, Mignon L
BACKGROUND:B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes. METHODS:We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or high risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival. RESULTS:The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a high relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone. CONCLUSIONS:Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or high risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).
PMID: 39651791
ISSN: 1533-4406
CID: 5762342
Azacitidine as epigenetic priming for chemotherapy is safe and well-tolerated in infants with newly diagnosed KMT2A-rearranged acute lymphoblastic leukemia: Children's Oncology Group trial AALL15P1
Guest, Erin M; Kairalla, John A; Devidas, Meenakshi; Hibbitts, Emily; Carroll, Andrew J; Heerema, Nyla A; Kubaney, Holly R; August, Margaret A; Ramesh, Sidharth; Yoo, Byunggil; Farooqi, Midhat S; Pauly, Melinda G; Wechsler, Daniel S; Miles, Rodney R; Reid, Joel M; Kihei, Cynthia D; Gore, Lia; Raetz, Elizabeth A; Hunger, Stephen P; Loh, Mignon L; Brown, Patrick A
Infants less than 1 year old diagnosed with KMT2A-rearranged (KMT2A-r) acute lymphoblastic leukemia (ALL) are at high risk of remission failure, relapse, and death due to leukemia, despite intensive therapies. Infant KMT2A-r ALL blasts are characterized by DNA hypermethylation. Epigenetic priming with DNA methyltransferase inhibitors increases the cytotoxicity of chemotherapy in preclinical studies. The Children's Oncology Group trial AALL15P1 tested the safety and tolerability of five days of azacitidine immediately prior to the start of chemotherapy on day six, in four post-induction chemotherapy courses for infants with newly diagnosed KMT2A-r ALL. The treatment was welltolerated, with only two of 31 evaluable patients (6.5%) experiencing dose-limiting toxicity. Whole genome bisulfite sequencing of peripheral blood mononuclear cells (PBMCs) demonstrated decreased DNA methylation in 87% of samples tested following five days of azacitidine. Event-free survival was similar to prior studies of newly diagnosed infant ALL. Azacitidine is safe and results in decreased DNA methylation of PBMCs in infants with KMT2A-r ALL, but the incorporation of azacitidine to enhance cytotoxicity did not impact survival. Clinicaltrials.gov identifier: NCT02828358.
PMID: 38867582
ISSN: 1592-8721
CID: 5669242
Daratumumab in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: DELPHINUS Study
Bhatla, Teena; Hogan, Laura; Teachey, David Trent; Bautista, Franciso; Moppett, John P; Velasco, Pablo; Micalizzi, Concetta; Rossig, Claudia; Shukla, Neerav Narendra; Gilad, Gil; Locatelli, Franco; Baruchel, André; Zwaan, Michel; Bezler, Natalie S; Rubio-San-Simón, Alba; Taussig, David; Raetz, Elizabeth A; Mao, Zhengwei J; Wood, Brent; Alvarez Arias, Diana; Krevvata, Maria; Nnane, Ivo; Bandyopadhyay, Nibedita; Lopez Solano, Lorena; Dennis, Robyn M; Carson, Robin; Vora, Ajay
Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) have poor outcomes compared with newly diagnosed, treatment-naïve patients. The phase 2, open-label DELPHINUS study evaluated daratumumab (16 mg/kg intravenously) plus backbone chemotherapy in children with relapsed/refractory B-cell ALL (n=7) after ≥2 relapses and children and young adults with T-cell ALL (children, n=24; young adults, n=5) or LL (n=10) after first relapse. The primary endpoint was complete response (CR) in the B-cell ALL (end of Cycle 2) and T-cell ALL (end of Cycle 1) cohorts, after which patients could proceed off study to allogeneic hematopoietic stem cell transplant (HSCT). Seven patients with advanced B-cell ALL received daratumumab with no CRs achieved; this cohort was closed due to futility. For the childhood T-cell ALL, young adult T-cell ALL, and T-cell LL cohorts, the CR (end of Cycle 1) rates were 41.7%, 60.0%, and 30.0%, respectively; overall response rates (any time point) were 83.3% (CR+CR with incomplete count recovery [CRi]), 80.0% (CR+CRi), and 50.0% (CR+partial response); minimal residual disease-negativity (<0.01%) rates were 45.8%, 20.0%, and 50.0%; observed 24-month event-free survival rates were 36.1%, 20.0%, and 20.0%; observed 24-month overall survival rates were 41.3%, 25.0%, and 20.0%; and allogeneic HSCT rates were 75.0%, 60.0%, and 30.0%. No new safety concerns with daratumumab were observed. In conclusion, daratumumab was safely combined with backbone chemotherapy in children and young adults with T-cell ALL/LL and contributed to successful bridging to HSCT. This trial was registered at www.ClinicalTrials.gov as NCT03384654.
PMID: 39158071
ISSN: 1528-0020
CID: 5680452
Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study
Rheingold, Susan R; Bhojwani, Deepa; Ji, Lingyun; Xu, Xinxin; Devidas, Meenakshi; Kairalla, John A; Shago, Mary; Heerema, Nyla A; Carroll, Andrew J; Breidenbach, Heather; Borowitz, Michael; Wood, Brent L; Angiolillo, Anne L; Asselin, Barbara L; Bowman, W Paul; Brown, Patrick; Dreyer, ZoAnn E; Dunsmore, Kimberly P; Hilden, Joanne M; Larsen, Eric; Maloney, Kelly; Matloub, Yousif; Mattano, Leonard A; Winter, Stuart S; Gore, Lia; Winick, Naomi J; Carroll, William L; Hunger, Stephen P; Raetz, Elizabeth A; Loh, Mignon L
Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children's Oncology Group frontline ALL trials (1996-2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.
PMID: 39261601
ISSN: 1476-5551
CID: 5690472
Reply to C.T. Matava et al [Letter]
Alexander, Sarah; Kairalla, John A; Gupta, Sumit; Hibbitts, Emily; Weisman, Hannah; Anghelescu, Doralina; Winick, Naomi J; Krull, Kevin R; Salzer, Wanda L; Burke, Michael J; Gore, Lia; Devidas, Meenakshi; Embry, Leanne; Raetz, Elizabeth A; Hunger, Stephen P; Loh, Mignon L; Hardy, Kristina K
PMID: 39047217
ISSN: 1527-7755
CID: 5705602
Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia
Narang, Sonali; Ghebrechristos, Yohana; Evensen, Nikki A; Murrell, Nina; Jasinski, Sylwia; Ostrow, Talia H; Teachey, David T; Raetz, Elizabeth A; Lionnet, Timothee; Witkowski, Matthew; Aifantis, Iannis; Tsirigos, Aristotelis; Carroll, William L
Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions.
PMCID:11358475
PMID: 39198446
ISSN: 2041-1723
CID: 5701942
Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia
Chang, Ti-Cheng; Chen, Wenan; Qu, Chunxu; Cheng, Zhongshan; Hedges, Dale; Elsayed, Abdelrahman; Pounds, Stanley B; Shago, Mary; Rabin, Karen R; Raetz, Elizabeth A; Devidas, Meenakshi; Cheng, Cheng; Angiolillo, Anne; Baviskar, Pradyuamna; Borowitz, Michael; Burke, Michael J; Carroll, Andrew; Carroll, William L; Chen, I-Ming; Harvey, Richard; Heerema, Nyla; Iacobucci, Ilaria; Wang, Jeremy R; Jeha, Sima; Larsen, Eric; Mattano, Leonard; Maloney, Kelly; Pui, Ching-Hon; Ramirez, Nilsa C; Salzer, Wanda; Willman, Cheryl; Winick, Naomi; Wood, Brent; Hunger, Stephen P; Wu, Gang; Mullighan, Charles G; Loh, Mignon L
PURPOSE/OBJECTIVE:Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS/METHODS:To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS:in high-hyperdiploid ALL. CONCLUSION/CONCLUSIONS:Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.
PMID: 39121442
ISSN: 1527-7755
CID: 5696962