Novel Combination Targeting BCR::ABL1 in Ph+ ALL With TKIs, STAMP-Inhibitor Is Very Well Tolerated

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a subtype of ALL that is characterized by the presence of the Philadelphia chromosome. Ph+ B-cell precursor ALL (BCPALL) is the most prevalent form of ALL in adults and has historically had a poor prognosis prior to tyrosine kinase inhibitor (TKI) usage, which blocks BCR-ABL1 oncoprotein activity.^1,2 The addition of TKIs to the treatment of Ph+ ALL has resulted in better outcomes compared with chemotherapy alone.^3,4 However, despite the development of TKIs and significant advancements in the treatment of Ph+ ALL, relapse can still occur, often due to BCR::ABL1 mutations.⁵

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The need to overcome resistance patterns observed in first- and second-generation TKIs led to the development of ponatinib (Iclusig; Ariad Pharmaceuticals, Inc), a third-generation pan-mutational TKI that inhibits BCR::ABL1. Ponatinib specifically targets gatekeeper mutations like T315I, which are linked to resistance to TKIs in the first and second generations. Ponatinib is known to have toxicity profiles such as cardiotoxicity, hepatotoxicity, and thromboembolic events. New resistance mechanisms also are connected to this medication, both known and unknown.⁶

On Oct. 29, 2021, the FDA approved asciminib (Scemblix; Novartis Pharmaceuticals Corporation), an inhibitor that specifically targets the ABL myristoyl pocket, or STAMP, for the treatment of chronic myeloid leukemia (CML) in the PH+ chronic phase. It is indicated for patients who have received 2 or more TKI treatments or have the T315I mutation. Asciminib effectively suppresses ABL1 kinase activity through allosteric binding, making it the first BCR::ABL1 TKI that does not target the ATP-binding site. Further, asciminib’s allosteric characteristics are anticipated to overcome the set of point mutations that result in resistance to the currently available TKIs and may restore the efficacy of TKIs targeting the ATP-site against compound mutations.⁷

Additionally, studies suggest that the resistance to asciminib in leukemia cells is associated with the overexpression of membrane efflux transporters like ABCG2. This finding supports the strategy of combining asciminib with ponatinib, a TKI that is not regulated by this transporter channel.⁶ Additionally, monoclonal antibodies such as blinatumomab (Blincyto; Amgen Inc) and inotuzumab ozogamicin ([inotuzumab]; Besponsa; Pfizer Inc) have been successfully coupled with TKIs and provide salvage alternatives for achieving complete remission in ALL.^8,9 Other suggested techniques include combining TKIs with the BCR::ABL1 allosteric inhibitor asciminib to boost or restore the activity of TKIs.¹⁰ Although TKIs have substantially improved patients’ survival rates, resistance to these drugs remains a significant clinical problem. This led to development of combination therapies that further enhance the management of Ph+ ALL. However, these combination therapies also present challenges. Unfortunately, a lack of data on drug combinations in ALL has left many clinicians facing challenges when getting the best drugs for their patients with Ph+ ALL.

Recently, however, this study was the first reported safe and highly effective combination of TKI therapy as the backbone in addition to other targeted therapies (in this case inotuzumab).¹

Patient Case

A 28-year-old man with relapsed/refractory Ph+ ALL undergoing chronic hemodialysis presented with chills and leukocytosis. His prior treatment plans included induction with low-intensity chemotherapy (vincristine, dexamethasone, and ponatinib), blinatumomab with dasatinib (Sprycel; Bristol Myers Squibb), and HyperCVAD part B (methotrexate + cytarabine) with dasatinib.

The patient underwent cytoreduction and initiated treatment with inotuzumab ozogamicin at a dose of 0.8 mg/m² on day 1 and 0.5 mg/m² intravenously on days 8 and 15. To address potential hepatotoxicity concerns and interactions with asciminib, 30 mg of ponatinib was administered daily along with the initial administration of inotuzumab. The dosage of asciminib at 40 mg twice daily was added on day 8. Asciminib dosing was chosen considering the absence of a BCR::ABL T315I mutation and the possibility of synergistic effects with ponatinib.

On day 12 of treatment, the patient experienced asymptomatic elevated levels of amylase and lipase at 2 times the upper limit of normal (ULN) and 9 times the ULN, respectively. As a result, ponatinib and asciminib were temporarily discontinued. Once the levels of amylase and lipase returned to below 1.5 times ULN, ponatinib was reintroduced at a dose of 30 mg once daily on day 15, and asciminib was reduced to 40 mg once daily on day 19.¹¹

This adjustment resulted in no significant toxicities, and subsequent assessments on day 22 showed a complete response in the bone marrow with positive minimal residual disease by flow analysis and BCR::ABL1 p190 mutation with levels of 0.0156%. The patient has been maintained on this treatment regimen with good tolerability.¹¹

Case Discussion

Preliminary research indicates that axitinib (Inlyta; Pfizer Inc) and/or asciminib in combination with TKIs targeting the ATP site enhances target inhibition and suppression of resistant outgrowth in Ph+ cell lines and may restore ponatinib’s efficacy against untreatable compound mutants.¹² Gleixner et al carried out a pharmacokinetic study in vitro that exhibited robust synergistic effects on apoptosis and downstream phosphorylation effects of CRKL.¹³

A phase 1 study further illustrated early experiences in clinical trials, in which a combination of asciminib plus ponatinib and prednisone was administered to 12 untreated patients with Ph+ ALL. The primary toxicity reported by investigators was asymptomatic pancreatic enzyme elevation, and following a month of treatment, all patients (10/10) had experienced a complete response. The effectiveness of combination therapies asciminib plus dasatinib or asciminib plus nilotinib (Tasigna; Novartis Pharmaceuticals Corporation) in CML lines was measured through BCR::ABL1 kinase activity by Oruganti et al.¹⁴

Notably, Oruganti et al demonstrated that nilotinib significantly enhances the inhibition activity of asciminib through conformational changes in the inactive state of the protein; however, this was not seen with dasatinib.¹⁵ Despite the fact that they are both second-generation TKIs, nilotinib and bosutinib can only bind to the inactive form of the BCR-ABL1 protein, while dasatinib binds to the active state. Indicating that the TKIs’ ability to bind to the active vs inactive states of the BCR-ABL1 protein may be the molecular basis for the synergistic effects of TKIs and asciminib.

Although not investigated in the study, ponatinib, a third-generation TKI that binds to the inactive state of the BCR-ABL1 fusion oncoprotein, was chosen for combination due to its potential synergistic enhancement with asciminib. The backbone used inotuzumab ozogamicin due to its demonstrated activity in relapsed/refractory ALL and clinical experience when combined with TKIs.¹⁵

Moreover, a case report demonstrated a complete response at 8 months with asciminib and ponatinib in a patient previously treated with GRAAPH-2013 plus ponatinib, blinatumomab, and clofarabine with cyclophosphamide, etoposide, and autologous stem cell transplant.¹⁶ The patient is still receiving combination treatment at 17 months. There is interesting preclinical and early clinical data with TKIs and asciminib in Ph+ ALL. To optimize combination dosing for synergy and TKI-related toxicities, further studies are needed.¹⁶

This study demonstrated the safe combination of asciminib and ponatinib, even in a patient who is dialysis dependent. The first safe and highly effective combination of TKI therapy as the backbone in addition to other targeted therapies (inotuzumab) is shown in this study. Furthermore, this study showcased a patient previously treated with ponatinib who tolerated the novel drug combination of inotuzumab, asciminib, and ponatinib. This combination was used despite limited experience to achieve a good response in the relapsed setting and to proceed to definitive treatment with chimeric antigen receptor T cells.

In the relapsed/refractory setting, the combination of inotuzumab, asciminib, and ponatinib may be used to attempt to achieve a deeper molecular response and avoid emergence of mutations. The combination of these agents is the first case reported and the second to ever showcase the combination of asciminib and ponatinib. The combination is very well tolerated and should be further investigated to define its role.

The Role of Clinical Pharmacists

Clinical pharmacists have a significant role in managing medication therapy, particularly for patients on high-cost complex regimens such as antineoplastics. Pharmacists play a pivotal role in the management of oncologic drug therapies, which are associated with unique toxicity profiles.

A retrospective by Lam et al., investigated the impact of an oncology pharmacist–managed program on medication adherence in patients with CML compared with the standard-care. As a member of a multidisciplinary team, oncology pharmacists play a crucial role in enhancing patient outcomes and medication adherence. Investigators enrolled patients diagnosed with CML who were treated with oral TKIs under the care of oncology pharmacists. The goal was to compare the adherence rates between patients managed by oncology pharmacists and those receiving standard care. The study disclosed that patients under the care of cancer pharmacists demonstrated a higher percentage of adherence to imatinib vs the standardcare group.¹⁷

Additionally, the study analyzed the interventions conducted by pharmacists, including monitoring for adverse events, adjusting TKI doses, detecting drug interactions, conducting laboratory tests, helping with non–CML-related medication choices, and providing financial assistance. The study investigators concluded that the pharmacist-managed oral anticancer therapy program significantly improved TKI adherence rates in patients with CML. The success of the program was accredited to persistent follow-up through routine phone calls as well as secure emails, establishing a trustworthy relationship between oncology pharmacists and patients/families.¹⁷

Another study aimed to evaluate the clinical and financial impacts of an oncology clinical pharmacy specialist–initiated discontinuation process for TKIs in patients with CML. In the analysis, patients with CML who received TKIs from 2 health care systems were evaluated as a part of clinical pharmacy specialist/oncologist discontinuation programs. The results exhibited the significant number of patients who were potential candidates for TKI discontinuation, from which the majority agreed to discontinue therapy. During the follow-up period, most of the patients continued to be off TKI medication, which resulted in significant cost savings. The study signified the effective reduction of financial burden in pharmacistinitiated discontinuation programs on patients and the health care system while providing patient-centered care. However, further research is needed to find cost-saving measures as well as development of tools to help with the discontinuation and monitoring of appropriate candidates.¹⁸

A 3-month study by Lopez-Marin et al addresses the pivotal role of oncology pharmacists in the management of drug interactions in patients starting chemotherapy by reviewing all their medications. Additionally, it was reported that 35% of patients presented with drug interactions and the main actions by the clinical pharmacist were suggestions to alter or stop the drug prescriptions, and these recommendations were followed in 94% of instances. The high incidence of drug interactions in patients diagnosed with cancer, especially involving medications for comorbid conditions are highlighted in this study. Pharmacists are essential in identifying, resolving any potential interactions and optimizing drug therapy for these patients.¹⁹

Furthermore, a study conducted by Coutsouvelis et al., investigated the role of pharmacists in improving cancer therapy outcomes and reducing errors. A total of 9 relevant studies were analyzed, which revealed consistent evidence on the significant role of pharmacists in conducting medication reviews and monitoring, tracking laboratory results, managing adverse events and drug-drug interactions, as well as monitoring patient adherence and providing medication counseling. All of the studies demonstrated that the involvement of pharmacists in cancer care led to fewer errors compared with control groups. This reduction in errors was noted not only in parenteral and oral cancer treatments, but also in supportive medications such as antiemetics.²⁰

By managing these critical aspects, oncology pharmacists contribute significantly to the quality of care for patients diagnosed with cancer. They ensure treatments are not only effective, but also safe and cost-effective. The efficacy of the oncology pharmacist–directed anticancer treatment program has been demonstrated through significantly enhanced TKI adherence rates among patients.

References

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4. Brissot E, Labopin M, Beckers MM, et al. Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. Haematologica. 2015;100(3):392-399. doi:10.3324/haematol.2014.116954

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8. Short NJ, Kantarjian HM, Konopleva M, et al. Combination of ponatinib and blinatumomab in Philadelphia chromosomepositive acute lymphoblastic leukemia: early results from a phase II study. J Clin Onc. 2021;39(suppl 15):7001. doi:10.1200/JCO.2021.39.15_suppl.7001

9. Stock W, Martinelli G, Stelljes M, et al. Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia. Cancer. 2021;127(6):905-913. doi:10.1002/cncr.33321

10. Eadie LN, Saunders VA, Branford S, White DL, Hughes TP. The new allosteric inhibitor asciminib is susceptible to resistance mediated by ABCB1 and ABCG2 overexpression in vitro. Oncotarget. 2018;9(17):13423-13437. doi:10.18632/oncotarget.24393

11. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474-2487. doi:10.1002/cncr.32116

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13. Gleixner KV, Filik Y, Berger D, et al. Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1T315I-compound mutations. Am J Cancer Res. 2021;11(9):4470-4484.

14. Luskin MR, Stevenson KE, Mendez LM, et al. A phase I study of asciminib (ABL001) in combination with dasatinib and prednisone for BCR-ABL1-positive ALL in adults. Blood. 2021;138(suppl 1):2305. doi:10.1182/blood-2021-149225

15. Oruganti B, Lindahl E, Yang J, Amiri W, Rahimullah R, Friedman R. Allosteric enhancement of the BCR-Abl1 kinase inhibition activity of nilotinib by cobinding of asciminib. J Biol Chem. 2022;298(8):102238. doi:10.1016/j.jbc.2022.102238

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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 in Los Angeles.

Elham Mowlavi, is a class of 2024 PharmD candidate at the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.

Arghavan Zolfaghari, is a class of 2024 PharmD candidate at the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.

Jose Tinajero, PharmD, BCOP, is a clinical pharmacist specialist at the City of Hope National Medical Center and areas of specialization include cellular therapies, hematologic malignancies, and hematopoietic stem cell transplantation.