USC ALL Induction Regimen Combined With Newer TKIs Is Safe, Effective for Patients With Ph+ Disease

Acute lymphoblastic leukemia (ALL) is a type of blood and bone marrow cancer identified by the rapid and uncontrolled growth of immature lymphocytes and their precursor cells. As reported by the American Cancer Society, ALL is the second most prevalent form of acute leukemia, with approximately 6000 new cases identified annually across the nation.¹ The various subtypes of ALL are distinguished by significant chromosomal and cytogenetic irregularities. Detecting these cytogenetic anomalies early in the diagnostic process enables clinicians to gather vital prognostic information before starting therapy.²

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The Philadelphia chromosome (Ph), a result of the t(9;22) translocation, is an abnormality characterized by the presence of the BCR-ABL1 rearrangement.³ Approximately 20% to 30% of adult patients with ALL are Ph positive (Ph+), and risk of the chromosomal translocation occurrence increases with age. Adult patients with Ph+ ALL who undergo chemotherapy alone experience short disease-free survival (DFS) rates and poor outcomes.⁴

Numerous studies have indicated that adults with Ph+ ALL who receive only chemotherapy face 3-year overall survival (OS) rates of less than 20%.^5,6 By contrast, the incorporation of allogeneic hematopoietic stem cell transplant (HSCT) after achieving complete hematologic remission has been proven to significantly enhance OS rates and reduce relapse rates compared with chemotherapy alone. Because of the poor outcomes associated with chemotherapy alone, HSCT has become the standard of care for patients with both intermediate and adverse cytogenetic risk.⁷

Using Tyrosine Kinase Inhibitors

ABL-specific tyrosine kinase inhibitors (TKIs) have transformed Ph+ adult ALL treatment, demonstrating higher complete hematologic remission rates and improved survival when combined with chemotherapy. The gold standard for treating adult Ph+ ALL involves TKIs with or without chemotherapy, and next-generation sequencing is increasingly employed for minimal residual disease (MRD) detection and monitoring to improve outcomes.^8,9

A standard multiagent therapy regimen, which consists of cytotoxic chemotherapy and allogeneic HSCT for remission, may still be utilized. However, a 2017 Surveillance, Epidemiology, and End Results database study compared Ph+ and Ph-negative ALL patient survival during the TKI era, with results showing improved survival rates with the administr-tion of TKIs. That said, newer research is still needed to evaluate combined TKI and chemotherapy strategies on long-term outcomes.¹⁰

Clinicians continue to seek the best approach for treating Ph+ ALL, with data showing that certain second-generation TKIs demonstrate superior efficacy compared with first-generation TKIs.¹¹ Researchers at the University of Southern California (USC) have released updated results from a retrospective study involving the modified USC ALL induction regimen without pegaspargase (PEG; Oncaspar; Servier IP UK Ltd) combined with TKIs. This study consisted of a retrospective chart review analysis of adolescent and young adult/adult patients with ALL treated at our single-center institution using a modified USC ALL frontline approach.

The modified USC ALL treatment regimen primarily consists of second-generation TKIs, such as dasatinib (Sprycel; Bristol Myers Squibb). First-generation TKIs, such as imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corporation), have demonstrated significant efficacy in treating Ph+ ALL; however, the development of resistance and limited efficacy against certain kinase domain mutations led to the introduction of second-generation TKIs,including dasatinib and nilotinib (Tasigna; NovartisPharmaceuticals Corporation).¹²

Additionally, blinatumomab (Blincyto; Amgen Inc), a bispecific T-cell engager, may be incorporated into the patient’s treatment regimen. After initial treatment, the patient may also be offered allogeneic HSCT, resulting in high OS, event-free survival (EFS), and DFS rates.¹³

The USC ALL protocol has resulted in favorable outcomes, contributing to increased patient survival rates. Further, the USC ALL regimen has been very well tolerated among patients, and this success was attained even without the use of PEG.

The investigation involved male and female patients 18 years and older who received a diagnosis of Ph-negative ALL between January 1, 2016, and December 31, 2021, and who received treatment at our institution using the pediatric-based USC ALL front-line protocol. This USC ALL treatment plan was based on the pediatric protocol CCG-1882 ALL. The USC ALL regimen includes daunorubicin, vincristine,cytarabine, methotrexate, and prednisone without the use of augmented PEG in patients aged 18 to 60 years.¹⁴

Patients received 75 mg/m² of cytarabine on days 1 through 4, 8 through 11, 29 through 32, and 36 through 39 of the second induction phase. Changes to the cytarabine dosage were made in conjunction with the pharmacy department. Additionally, because of adverse events (AEs) from combining PEG and TKIs, PEG for patients with Ph+ ALL was excluded.¹⁴

Confirmed diagnosis of Ph+ ALL by USC pathologists was necessary for patients to be included in this study. Patients who had prior induction therapy but remained refractory according to immunohistochemistry were also included. The investigators determined that any patient who had not undergone the modified USC ALL induction regimen at any point during their treatment would be excluded from the study. Further, data collection primarily relied on the use of electronic medical records at the USC facility.

The retrospective study completed at USC included 25 patients with Ph+ ALL. The patient population was predominantly Hispanic (84%); among these patients, 64% had received dasatinib only, 0.04% had received imatinib, and 32% had received at least 2 TKIs.

After the first round of induction, 80% of patients achieved complete response (CR) or incomplete response (CRi), 4% were refractory, and 50% showed MRD negativity by flow cytometry. Additionally, 24% of patients had undetectable BCR-ABL1 levels as measured by polymerase chain reaction. Following a second induction, 90.5% achieved CR/CRi, no patients were refractory, and 56.3% showed MRD negativity by flow cytometry, with 32% having undetectable BCR-ABL1 polymerase chain reaction levels.

In this study, we also introduced updated information from our institution on incorporating TKIs into our modified USC ALL pediatric-based protocol without PEG as the primary treatment for patients with Ph+ ALL. The 3-year OS rate for patients was 89.4%, with EFS and DFS rates at 77%.

When examining patients based on MRD negativity as assessed by flow cytometry after induction, the 3-year OS rate was 100% vs 76.9% for patients who were MRD positive (P = .048), and the 3-year DFS and EFS rates were 100% and 50.1% for MRD positivity and negativity, respectively (P = .033). Furthermore, when comparing survival rates by allogeneic stem cell–transplant status, the 3-year OS rate with trans-plant was 100% vs 76.9% without (P = .048), and the 3-year EFS/DFS rate was 100% vs 50.1%, respectively (P = .033).

The results of this study demonstrate that the toxicities associated with the use of newer TKIs and blinatumomab are generally tolerable. The investigators observed no instances of hypersensitivity reactions and a relatively low occurrence of grade 3/4 toxicities, such as febrile neutropenia.

The study findings further indicate that using the USC ALL induction regimen in combination with newer TKIs continues to yield positive outcomes for patients with Ph+ ALL. These results also emphasize the importance of transplants in achieving better survival rates for this patient population.

Integrating TKIs into the treatment plans of patients with a recent Ph+ ALL diagnosis has resulted in better remission rates, an increased likelihood of undergoing allogeneic SCT, and extended survival vs chemotherapy alone. Further, attainment of complete molecular remis-sion in the early stages remains crucial for patients with Ph+ ALL because it identifies patients with an excellent prognosis for long-term survival who may not require allogeneic SCT. Ultimately, combining second-generation TKIs with either intensive or low-intensity chemotherapy was shown to result in higher complete molecular remission rates than imatinib-based regimens, which inturn contributed to improvedoutcomes and reduced dependence onallogeneic SCT.¹⁵

A 2016 study demonstrated that second-generation TKIs dasatinib and nilotinib showed superior molecular response, progression-free survival, and OS compared with first-generation TKI imatinib in patients with newly diagnosed Ph+ ALL. Further, second-generation TKIs exhibited a higher rate of deep molecular response (BCR-ABL1 transcripts < 0.01%) and complete cytogenetic response compared with imatinib. Additionally, the study reported a lower rate of disease progression and improved OS rates with the use of second-generation TKIs.¹²

Conclusion

Overall, our study’s results indicate that the USC ALL induction regimen combined with newer TKIs is an effective and safe treatment strategy for patients with Ph+ ALL. The findings also emphasize the importance of achieving MRD flow cytometry negativity, which is a crucial factor in monitoring and predicting survival outcomes in ALL.¹⁶

When monitoring the AEs of second-generation TKIs, pharmacists can play a critical role. Mild to moderate nonhematologic AEs after the use of second-generation TKIs have been reported, including rash, headache, nausea, and increased serum bilirubin and lipase levels.¹⁷

Based on their assessment, pharmacists can recommend adjustments to the dose of the medication or suggest alternative medications to reduce the severity of adverse effects. Overall, the involvement of pharmacists in the management of second-generation TKIs can help ensure that patients receive optimal care and achieve the best possible outcomes.^18,19

In conclusion, our study has demonstrated that the modified USC ALL regimen could be a promising treatment option for patients with Ph+ ALL. Data from other studies support the findings regarding the improved efficacy with second-generation TKIs. Nonetheless, the limited sample size, single-center nature, and predominantly Hispanic population restrict the broader applicability ofthese findings.

References

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About the Authors

Amir Ali, PharmD, BCOP, is a clinical pharmacist specialist at the University of Southern California (USC) Norris Comprehensive Cancer Center and an adjunct assistant professor of pharmacy practice at USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences (School of Pharmacy) in Los Angeles.

Amin Khudari, is a PharmD candidate at the USC School of Pharmacy; research coordinator in the lab of Paul M. Beringer, PharmD, at the USC School of Pharmacy; and a pharmacy assistant at Adventist Health White Memorial in Azusa, California.

Vincent Mendiola, MD, is a hematology/oncology fellow at Keck Medicine of USC.

George Yaghmour, MD, is the associate director of allogeneic bone marrow transplant and assistant professor of clinical medicine at Keck School of Medicine of USC.

Samantha Shi, PharmD, BCOP, is a pharmacy manager and the postgraduate year 2 residency director at the USC Norris Comprehensive Cancer Center.

Hien Tang, PharmD, BCOP, is a pharmacy manager at the USC Norris Comprehensive Cancer Center.

Harry Shamamian, PharmD, MBA, FACHE, is the director of pharmacy services at Norris Cancer Hospital and Clinics, Investigational Drug Service at Keck Medicine of USC.