conference reporter

Tolerability of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

by Neil P. Shah, MD, PhD

Overview

At the 64th ASH Annual Meeting and Exposition, emerging data underscored the importance of tyrosine kinase inhibitor (TKI) tolerability and dose optimization in achieving favorable long-term outcomes for patients with chronic phase chronic myeloid leukemia (CP-CML).

Following these presentations, featured expert Neil P. Shah, MD, PhD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Shah’s clinical perspectives on these findings are presented here. 

Neil P. Shah, MD, PhD

Edward S. Ageno Distinguished Professorship in Hematology/Oncology
Professor, Department of Medicine
Director, Molecular Medicine Residency Program
University of California, San Francisco
San Francisco, CA

“The availability of multiple TKIs provides patients with a greater variety of treatment options, improving their chances of identifying a drug that is both tolerable and efficacious at a given dose. Nonetheless, a substantial proportion of patients still struggle with either resistance or intolerance to multiple TKIs.”

Neil P. Shah, MD, PhD

TKIs have transformed patient outcomes in CP-CML to the point where these individuals now have a near-normal life expectancy, provided that they adhere to therapy and the molecular monitoring of their disease. Therefore, there is currently a greater emphasis being placed on maintaining quality of life (QOL) by devising strategies to minimize bothersome and severe side effects that can negatively impact adherence and long-term outcomes. The availability of multiple TKIs provides patients with a greater variety of treatment options, improving their chances of identifying a drug that is both tolerable and efficacious at a given dose. Nonetheless, a substantial proportion of patients still struggle with either resistance or intolerance to multiple TKIs.

Optimizing the TKI dose is important for mitigating side effects, maximizing adherence, and achieving favorable long-term outcomes. For many patients who are responding to TKI therapy but are dealing with unpleasant side effects, it is possible to reduce the dose and maintain efficacy. It is critical for physicians to ask their patients about side effects at each visit. The most common are bothersome lower-grade toxicities such as fatigue, musculoskeletal discomfort, gastrointestinal toxicity, and mental fog; however, there are also potentially serious cardiovascular toxicities that are associated with all TKIs aside from imatinib. For example, nilotinib has been associated with accelerated atherogenesis and ponatinib has been linked to thrombosis, although the prothrombotic mechanisms are not well characterized. In the phase 2 PACE study, which was performed in patients with CP-CML and resistance to prior TKIs, ponatinib achieved deep and durable responses, but arterial occlusive events were observed. Post hoc analyses indicated that these events were dose dependent. Further, since many patients with CML are older, age-associated comorbidities such as cardiovascular disease are relatively common. As such, there are ongoing efforts to understand cardiovascular and thrombotic risk in these individuals, as well as any influence that TKIs may have. Examples of this work are included in abstracts 2996 and 4340 from this year's ASH meeting.

In abstract 620, Cortes et al provided a 3-year update from the ongoing OPTIC study (NCT02467270), a phase 2 trial evaluating the efficacy and safety of ponatinib using a novel response-based, dose-adjustment strategy in patients with CP-CML who were resistant to 2 or more TKIs or who harbored the T315I mutation. Results demonstrated the robust longer-term efficacy and an improved and manageable safety profile of ponatinib in a highly resistant CP-CML population. Consistent with results from the primary analysis, a ponatinib starting dose of 45 mg per day with a reduction to 15 mg per day upon attainment of BCR::ABL1 IS results of 1% or lower provided the optimal risk-benefit ratio. It remains to be seen, however, whether this dose reduction strategy will maintain responses in patients with the T315I mutation, who clearly benefit from a starting dose of 45 mg daily. 

The very first of the post-approval dose optimization studies was actually a trial of dasatinib, and now other US Food and Drug Administration (FDA)–approved TKIs are also being studied at doses and schedules that differ from those in the initial registrational trials. Of course, a “one-size-fits-all” approach seems overly simplistic, and it is reasonable to pursue the individual tailoring of doses to maintain efficacy and improve QOL. 

The recently FDA-approved TKI asciminib appears to be quite well tolerated, although more mature data from randomized studies will be required to assess how its profile compares with other TKIs. Unlike the 5 other TKIs that are FDA approved for CML, asciminib targets a distinct pocket within the BCR::ABL1 kinase. This pocket appears to be relatively unique to the ABL1 kinase, and, as a result, asciminib interferes with far fewer kinases than other BCR::ABL1 TKIs in vitro. It is hoped that this will translate to an improved safety profile. 

Some patients with CML who struggle with intolerance can achieve satisfactory disease control with treatment, but at the cost of an unsatisfactory QOL. Anecdotally, for at least a few of these individuals, switching to asciminib has dramatically improved their QOL. The ongoing phase 3 ASC4FIRST study (NCT04971226) is evaluating asciminib vs an investigator-selected TKI in patients with newly diagnosed Philadelphia chromosome–positive CP-CML; however, the design of this study will likely not allow for comparisons between asciminib and individual second-generation TKIs. That is, the comparator consists of a pool of patients treated with the investigators’ choice of TKI, and the extent to which imatinib-treated patients are represented in this pool will impact the rates of response and the cardiovascular toxicity of the comparator.

On the contrary, the present ASC4START trial, a phase 3b study of asciminib vs nilotinib in newly diagnosed patients with CP-CML, is expected to be more informative in this regard (abstract 3021). It is hoped that asciminib will display efficacy in the frontline setting that is equivalent or superior to second-generation TKIs but with an improved safety profile, although several years of follow-up will be necessary to demonstrate this. 

The Australasian Leukaemia Lymphoma Group CML13 ASCEND-CML trial also aims to assess asciminib in the frontline setting. At ASH 2022, Yeung and colleagues reported the interim results of this single-arm study, which revealed favorable tolerability and efficacy as frontline treatment for CP-CML (abstract 79). Notably, the early molecular response rate appears to be higher than what it has been historically with second-generation TKIs, and, if this finding is accurate, it may translate to improved long-term outcomes and higher rates of deep molecular responses that can potentially improve the likelihood of achieving a treatment-free remission. Cytopenia and lipase elevations were the most commonly reported adverse events in this study, although clinically relevant pancreatitis has not been observed. Two patients developed resistance, 1 of whom had a confirmed loss of major molecular response at 9 months after reaching a nadir of 0.067% at 6 months, without evidence of a kinase domain or a myristoyl site mutation, while the other patient transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T (40%), A337V (10%), and P465S (10%), having previously achieved a BCR::ABL1 of 0.37% at 3 months.

References

Aguila S, Cuenca, EJ, Lys MJ, et al. Thrombogenesis mechanisms of high doses of ponatinib in patients with chronic myeloid leukemia (CML) compared to tyrosine kinase inhibitors [abstract 2996]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.

ClinicalTrials.gov. A study of oral asciminib versus other TKIs in adult patients with newly diagnosed Ph+ CML-CP. Updated December 16, 2022. Accessed December 16, 2022. https://clinicaltrials.gov/ct2/show/NCT04971226

ClinicalTrials.gov. Ponatinib in participants with resistant chronic phase chronic myeloid leukemia (CP-CML) to characterize the efficacy and safety of a range of doses (OPTIC). Updated January 13, 2022. Accessed December 16, 2022. https://clinicaltrials.gov/ct2/show/NCT02467270

Cortes JE, Apperley J, Lomaia E, et al. OPTIC primary analysis: a dose-optimization study of 3 starting doses of ponatinib (PON). J Clin Oncol. 2021;39(suppl 15):7000. doi:10.1200/JCO.2021.39.15_suppl.7000

Cortes JE, Deininger MW, Lomaia E, et al. Three-year update from the OPTIC trial: a dose-optimization study of 3 starting does of ponatinib [abstract 620]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.

Cortes JE, Kim D-W, Pinilla-Ibarz J, et al; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med. 2013;369(19):1783-1796. doi:10.1056/NEJMoa1306494

Hochhaus A, Saussele S, Mahon F-X, et al. ASC4START: a phase IIIb, open-label, randomized study of tolerability and efficacy of asciminib versus nilotinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase [abstract 3021]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.

Rousselot P, Mollica L, Guerci‐Bresler A, et al. Dasatinib daily dose optimization based on residual drug levels resulted in reduced risk of pleural effusions and high molecular response rates: final results of the randomized OPTIM DASATINIB trial [abstract S678]. Haematologica. 2014;99(suppl 1):237-238.

Szczepanek E, Chukwu O, Marczyk B, Chłopicki S, Sacha T. The multimodal approach to evaluating cardiovascular risk in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors - the role of endothelial function [abstract 4340]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.

Talpaz M, Saglio G, Atallah E, Rousselot P. Dasatinib dose management for the treatment of chronic myeloid leukemia. Cancer. 2018;124(8):1660-1672. doi:10.1002/cncr.31232

Yeung DT, Shanmuganathan N, Reynolds J, et al. Early and deep molecular responses achieved with frontline asciminib in chronic phase CML – interim results from ALLG CML13 ASCEND-CML [abstract 79]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.


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