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.
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.
Pharmacy Times: Call for Papers
Pharmacy Times Oncology EditionTM and Pharmacy Times Health-System EditionTM are seeking to expand our current coverage offerings to include peer reviewed research on clinical topics and treatment of different disease states.
The publications are seeking to focus on a wide range of therapeutic categories in the oncology and health-system pharmacy space to educate readers and translate innovative clinical discoveries into improved health outcomes for patients. This new focus on clinical research seeks to accelerate adaptation of new therapeutics, techniques, and technologies from the publication’s pages to the clinical setting.
The clinical manuscripts sought will examine different treatments for and management of the different disease states and pharmacologic interventions. Of particular interest are papers that highlight the role of the pharmacist within the overall health care team and provide insight into the impact pharmacists have on patient outcomes. These submissions will be peer-reviewed and published in upcoming editions of Pharmacy Times Oncology Edition and Pharmacy Times Health-System Edition.
Some clinical topics of interest include:
- Antimicrobial Stewardship
- HIV and Pre-exposure Prophylaxis
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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
Newer-Generation TKIs
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.
