The University of Southern California (USC) Norris Comprehensive Cancer Center in Los Angeles presented study results on first-line therapy with tyrosine kinase inhibitors (TKIs) but without PEG-asparaginase in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) at the 2023 Tandem Meetings: Transplantation & Cellular Therapy Meetings of the American Society of Transplantation and Cellular Therapy and the Center for International Blood and Marrow Transplant Research in Orlando, Florida.1 The findings, which included a 3-year overall survival (OS) rate of 89.4% and a 3-year event-free survival (EFS) rate and disease-free survival (DFS) rate of 77%,1 are vital because, despite the development of next-generation TKIs, no optimal treatment strategy exists for Ph+ ALL.
Acute lymphoblastic leukemia cancer cell clusters | Image credit: LASZLO - stock.adobe.com
Different subtypes of ALL are characterized by chromosomal and cytogenetic abnormalities whose identification early on gives clinicians valuable prognostic information prior to treatment start.2 One such abnormality is the presence of Ph.3 The Ph+ subgroup constitutes 20% to 30% of adult patients with ALL, and its incidence increases with age. Historically, adult patients with Ph+ ALL undergoing chemotherapy alone had short DFS rates and dismal outcomes4: Findings from multiple studies showed their 3-year OS rates to be less than 20%.5,6 Routine use of allogeneic hematopoietic stem cell transplant (allo-HSCT) after achieving complete hematologic remission (CHR) was found to significantly improve OS rates and decrease relapse rates compared with chemotherapy alone; as a result, HSCT became standard of care for patients with intermediate and adverse cytogenetic risk.7
In humans, asparagine synthetase (ASNS) is responsible for the conversion of aspartate and glutamine to asparagine and glutamate.8,9 Human ASNS activity is highly responsive to cellular stress, and elevated ASNS protein expression is associated with resistance to asparaginase therapy in childhood ALL.8,9 Findings from randomized studies have shown a survival benefit in children treated with asparaginase-containing regimens.10,11 However, asparaginase is also linked to a host of cardiometabolic toxicities and risk of hypersensitivity.8,9 PEG-asparaginase is polyethylene-linked asparaginase, which has a longer half-life and reduced hypersensitivity, and can be incorporated into frontline treatment of children and younger adults with ALL but not typically in the setting of Ph+ ALL.8,9 The introduction of ABL-specific TKIs in the past decade significantly changed the management of Ph+ ALL in adults. Use of newer-generation TKIs in combination with chemotherapy allowed clinicians to achieve higher rates of CHR in adult and older patients, leading to improved survival rates.10-13 The gold standard of treatment for adult Ph+ B-cell ALL is based on the use of a TKI with or without chemotherapy.14 Likewise, use of next-generation sequencing to detect and monitor minimal residual disease (MRD) has become a first-line approach to enhance treatment.
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Before the introduction of TKIs, the presence of BCR-ABL1 conferred a poor prognosis in patients with ALL.13 A 2017 Surveillance, Epidemiology, and End Results database analysis compared survival in patients with Ph+ and Ph-negative (Ph–) ALL. Despite the availability of TKIs, best long-term outcomes relied on cytotoxic chemotherapy and allo-HSCT.14
Allo-HSCT for patients with Ph+ ALL led to high OS, EFS, and DFS rates, even without PEG. When survival was stratified by transplant status, 3-year OS rate was 100% with allo-HSCT vs 76.9% without allo-HSCT (P = .048), whereas both 3-year EFS and DFS rates with allo-HSCT were, respectively, 100% vs 50.1% without allo-HSCT (P = .033).1
The USC ALL regimen consists of daunorubicin (Cerubidine; Hikma Pharmaceuticals), vincristine (Oncovin; Pfizer), prednisone (Deltasone; Geneyork Pharmaceutical), and methotrexate (Otrexup; Otter Pharmaceuticals) with augmented PEG in patients aged 18 to 60 years. Based on the CCG-1882 regimen, the USC regimen is among other regimens recommended for frontline management of ALL in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Since USC’s last report in 2014, the USC ALL regimen, which consists of 2 induction phases, has been modified, with fractionated doses of cytarabine changed to a single dose, consolidations increased to 6 cycles, altogether with 6 doses of PEG, followed by 6-mercaptopurine (Purinethol; Stason Pharmaceuticals), vincristine, methotrexate, and prednisone maintenance, with the goal of improving outcomes and maintaining tolerable toxicities. Adults with newly diagnosed Ph+ ALL treated between 2016 and 2020 were retrospectively analyzed. Primary objectives were OS and EFS at 3 years, and secondary objectives were rates of complete remission (CR) and CR with incomplete recovery (CRi), MRD by flow cytometry, and presence of BCR-ABL1 fusion transcript by realtime polymerase chain reaction (PCR).
Of the 25 patients with Ph+ ALL in the study, 12 (48%) received blinatumomab (Blincyto; Amgen) for MRD flow positivity, with a median of 3 cycles, and none received inotuzumab ozogamicin (Besponsa; Pfizer). Eleven (44%) underwent allo-HSCT, and none received chimeric antigen receptor T-cell therapy. Of note, 16 (64%) received dasatinib (Sprycel; Bristol Myers Squibb) only, 1 (4%) received imatinib (Gleevec; Novartis), and 8 (32%) received at least 2 TKIs.
The median age at diagnosis was 43.5 years, male and female patients were evenly represented, and the majority of patients (84%) were Hispanic. After first induction, 80% of patients achieved CR/CRi, 4% had refractory disease, 50% had MRD-negative results by flow cytometry, and 24% had undetectable BCR-ABL1 by PCR. After second induction, 90.5% had achieved CR/CRi, none had refractory disease, 56.3% had MRD-negative disease, and 32% had undetectable BCR-ABL1. Overall, 12% had known relapse, none had refractory disease, and 12.5% died.
Kaplan-Meier analysis and log rank tests determined 3-year OS to be at 89.4% and 3-year EFS and DFS rates to be at 77% among patients who received the modified USC ALL regimen without PEG for the management of newly diagnosed Ph+ ALL in combination with a TKI. The patients who received the modified USC ALL regimen without PEG in combination with a TKI were further stratified by the addition of blinatumomab to the regimen. In patients who were given blinatumomab, 3-year OS rate was 87.5% vs 91.7% in patients not given blinatumomab (P = .49). Similarly, the 3-year DFS rate was 80.2% in patients given blinatumomab vs 76.4% in patients not given blinatumomab, and 3-year EFS rate was 80.2% in patients given blinatumomab vs 76.4% in patients not given blinatumomab (P = .8).
The use of the modified ALL regimen without PEG for the management of newly diagnosed Ph+ ALL combined with TKI continued to lead to a high 3-year OS rate at 89.4% and a 3-year EFS and DFS rates at 77%. Study authors stressed the importance of allo-HSCT for patients with Ph+ ALL who received TKI without PEG to achieve high OS, EFS, and DFS. However, they also noted the limitations; it was a single-center, retrospective study with a limited number of patients.
The Role of Clinical Pharmacists
Newer generations of TKIs have unique adverse effects. For example, BCR-ABL inhibitors such as imatinib cause maculopapular rash, facial edema, and, in severe cases, Stevens-Johnson syndrome. But clinical pharmacists can anticipate and manage TKI-related toxicities, overseeing proper dose reduction in cases of acute or delayed toxicity, as well as monitoring patients’ regimen for drug-drug interactions and hold parameters. They can also counsel outpatients to improve medication adherence, thereby sustaining OS, EFS, and DFS for the long term.15
Given the introduction of new TKIs and novel approaches to MRD monitoring, newer studies are warranted to further evaluate the effect of combination TKI and chemotherapy on long-term outcomes. Clinical trials that assess combination of newer-generation TKIs in relapsed/refractory (R/R) Ph+ ALL may be of interest.
Asciminib (Scemblix; Novartis) targets the myristoyl pocket of the BCR-ABL1 TK and was approved in 2021 for the treatment of adults with Ph+ chronic myeloid leukemia in chronic phase (CML-CP) who have been previously treated with at least 2 TKIs and those with Ph+ CML-CP who have the T315I mutation.16,17 Since its approval, published information on the activity of asciminib in patients with R/R Ph+ ALL has been limited to case reports.18
However, a phase 1 clinical trial (NCT03595917) evaluating the safety of asciminib in combination with dasatinib and prednisone in patients with Ph+ ALL is underway. Similarly, the combination of venetoclax (Venclexta; AbbVie, Genentech) and blinatumomab is undergoing a clinical trial (NCT05182385) of patients with R/R ALL. Preclinical studies with venetoclax have also shown synergistic in vitro inhibition and induction of apoptosis with dasatinib or ponatinib (Iclusig; Takeda Pharmaceuticals).19
Recently, the combination of immunotherapy and TKIs as first-line therapy in patients with Ph+ ALL has shed light on older patients with MRD-positive disease. Results from an ongoing phase 2 study (NCT02143414) evaluating the feasibility of combining dasatinib, prednisone, and blinatumomab showed a CHR rate of 92% in the first 25 patients enrolled, with MRD-negative status at day 28 in 38% of patients.20 Findings from the same study reported 3-year DFS and OS rates of 85% and 80%, respectively, with a median follow-up of 1.7 years.20 Similarly, a phase 2 trial (NCT03263572) being conducted at The University of Texas MD Anderson Cancer Center in Houston combines ponatinib and blinatumomab up front during the induction and consolidation phases.21 In the latest update, CHR was attained in 34 of 35 patients with newly diagnosed Ph+ ALL and a 2-year EFS and OS of 93% was reached.21
Substantial progress has been made in the management of Ph+ ALL with the combination of chemotherapy plus TKIs. As rates of CHR and long-term survival have continued to improve, advancement into immunotherapies and treatment regimens without chemotherapy may lead to continued progress and improved standards of care.
About the Authors
Samvel Nazaretyan is a class of 2024 PharmD candidate at the University of Southern California (USC) Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles and a regulatory affairs intern at Intellia Therapeutics.
Vincent Mendiola, MD, is a hematology/oncology fellow at Keck School of Medicine of USC in Los Angeles.
George Yaghmour, MD, is the associate director of allogeneic bone marrow transplant and assistant professor of clinical medicine at the Keck School of Medicine.
Amir Ali, PharmD, BCOP, is a clinical pharmacist specialist and residency program coordinator at USC Norris Comprehensive Cancer Center and an adjunct assistant professor of pharmacy practice at the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
- Mendiola VL, Ly C, Wang J, et al. Updated outcomes in adult Philadelphia-positive acute lymphoblastic leukemia patients using tyrosine kinase inhibitors combined with the modified University of Southern California (USC ALL) regimen without peg-asparaginase in the era of novel agents. Blood. 2022;140(suppl 1):11702-11704. doi:10.1182/blood-2022-164836
- Igwe IJ, Yang D, Merchant A, et al. The presence of Philadelphia chromosome does not confer poor prognosis in adult pre-B acute lymphoblastic leukaemia in the tyrosine kinase inhibitor era - a surveillance, epidemiology, and end results database analysis. Br J Haematol. 2017;179(4):618-626. doi:10.1111/bjh.14953
- Shi T, Huang X, Zhu L, Li X, Li L, Ye X. Adult Ph-positive acute lymphoblastic leukemia-current concepts in cytogenetic abnormalities and outcomes. Am J Cancer Res. 2020;10(8):2309-2318.
- Podgornik H, Doplihar Kebe A, Klun J, et al. Recognition of Philadelphia chromosome-like acute lymphoblastic leukemia as part of routine diagnostic work-up. Int J Lab Hematol. 2022;44(1):142-149. doi:10.1111/ijlh.13698
- Soverini S, Bassan R, Lion T. Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges. J Hematol Oncol. 2019;12(1):39. doi:10.1186/s13045-019-0729-2
- Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008;111,(5):2563-2572. doi:10.1182/blood-2007-10-116186
- Faderl S,Kantarjian HM, Thomas DA, et al. Outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2000;36(3-4):263-273. doi:10.3109/10428190009148847
- Granfeldt Østgård LS, Lund JL, Nørgaard JM, et al. Impact of allogeneic stem cell transplantation in first complete remission in acute myeloid leukemia: a national population-based cohort study. Biol Blood Marrow Transplant. 2018;24(2):314-323. doi:10.1016/j.bbmt.2017.10.019
- Lomelino CL, Andring JT, McKenna R, Kilberg MS. Asparagine synthetase: function, structure, and role in disease. J Biol Chem. 2017;292(49):19952-19958. doi:10.1074/jbc.R117.819060
- Geyer MB, Ritchie EK, Rao AV, et al. Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia. Haematologica. 2021;106(8):2086-2094. doi:10.3324/haematol.2020.251686
- Amylon MD, Shuster J, Pullen J, et al. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia. 1999;13(3):335-342. doi:10.1038/sj.leu.2401310
- Sallan SE, Hitchcock-Bryan S, Gelber R, Cassady JR, Frei E 3rd, Nathan DG. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia. Cancer Res. 1983;43(11):5601-5607.
- Chiaretti S, Foà R. Management of adult Ph-positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2015;2015:406-413. doi:10.1182/asheducation-2015.1.406
- Sasaki K, Kantarjian HM, Short NJ, et al. Prognostic factors for progression in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in complete molecular response within 3 months of therapy with tyrosine kinase inhibitors. Cancer. 2021;127(15):2648-2656. doi:10.1002/cncr.33529
- Ng CY, Chen CB, Wu MY, et al. Anticancer drugs induced severe adverse cutaneous drug reactions: an updated review on the risks associated with anticancer targeted therapy or immunotherapies. J Immunol Res. 2018;2018:5376476. doi:10.1155/2018/5376476
- Hughes TP, Mauro MJ, Cortes JE, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. New Engl J Med. 2019;381(24):2315–2326. doi:10.1056/NEJMoa1902328
- Eide CA, Zabriskie MS, Savage Stevens SL, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell. 2019;36(4):431–443.e5. doi:10.1016/j.ccell.2019.08.004
- Zerbit J, Tamburini J, Goldwirt L, et al. Asciminib and ponatinib combination in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leuk Lymphoma. 2021;62(14):3558-3560. doi:10.1080/10428194.2021.1966787
- Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma. 2017;58(9):1-17. doi:10.1080/10428194.2017.1283032
- Advani A, Moseley A, O’Dwyer K, et al. A Phase 2 study of dasatinib, prednisone, and blinatumomab for older patients with Philadelphia-chromosome (Ph) positive or Ph-like acute lymphoblastic leukemia (ALL) (with dasatinib sensitive fusions/mutations). Blood. 2021;138(suppl 1):3397. doi:10.1182/blood-2021-145529
- Short NJ, Kantarjian H, Konopleva M, et al. Ponatinib and blinatumomab for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: updated results from a phase II study. HemaSphere. 2022;6:15-16. doi:10.1097/01.HS9.0000843352.55138.40