Jeremiah Moore, PharmD, BCOP

Chronic Myeloid Leukemia (CML) is a rare myeloproliferative disorder that accounts for approximately 15% of all leukemia cases, with approximately 9000 people projected to receive a diagnosis of the disease in the United States in 2022.1-4 CML is characterized by the translocation between the 

 gene on chromosome 22, forming the constitutively activated 

 fusion gene, which is also known as the Philadelphia chromosome.

Patients with CML are often asymptomatic at diagnosis, or they may present with constitutional symptoms, such as splenomegaly, along with anemia and elevated white blood cells and platelets.

 CML can be further classified into chronic phase (CP-CML), accelerated phase (AP-CML), or blast phase, but the large majority present with CP-CML.

Currently, 6 FDA-approved oral tyrosine kinase inhibitors (TKIs) are available for the treatment of CML. With the introduction of BCR-ABL1 small molecule TKIs, patients with a CML diagnosis can expect a near-normal life expectancy. This scenario means an increased prevalence of CML will likely be a result in the United States, due to the increased number of survivors of the disease present in the country.

As initial therapy for CP-CML, National Comprehensive Cancer Network guidelines recommend either the first-generation TKI imatinib (Gleevec; Novartis) or one of the second-generation agents: bosutinib (Bosulif; Pfizer), dasatinib (Sprycel; Bristol Myers Squibb), or nilotinib (Tasigna; Novartis).

 Additionally, the third-generation TKI ponatinib (Iclusig; Takeda) and the recently approved allosteric ABL1 inhibitor asciminib (Scemblix; Novartis) are options in later lines of therapy.

Imatinib, dasatinib, nilotinib, bosutinib, and ponatinib all target the adenosine triphosphate binding pocket of 

, which leads to inhibition of BCR-ABL1 signaling.

 These agents differ in their BCR-ABL1 potency, toxicity profile, and dosing schedules. Despite a multitude of treatment options, patients may not tolerate treatment or may develop treatment resistance, such as in the case of the T315I mutation, which would necessitate the need for novel therapy options.

Asciminib has a unique mechanism of action: As a STAMP (specifically targeting the ABL myristoyl pocket) inhibitor of BCR-ABL1, it allows for activity in patients with CML who have developed resistance or intolerance to prior therapies.

Based on the results of the CABL001X2101 and ASCEMBL trials (NCT02081378 and NCT03106779), the FDA approved asciminib in October 2021 for patients with CP-CML who were previously treated with 2 or more TKIs, and for adult patients with CP-CML with the T315I mutation. The approval was granted under the accelerated approval process, with continued approval dependent upon longer follow-up.

The CABL001X2101 clinical trial was a phase 1, multicenter, open-label, dose-escalation study that included 141 patients with CP-CML and 9 patients with AP-CML. Participants previously had an inadequate response or unacceptable adverse effects (AEs) from 2 or more BCR-ABL1 TKIs and were treated with asciminib either once or twice daily over a range of doses. Forty-five patients with CP-CML and the T315I mutation received asciminib at 200 mg twice daily. Nineteen of the 45, or 42%, achieved a major molecular response (MMR), defined as 

at less than or equal to 0.1%, at 24 weeks, and 22, or 49%, achieved it at 96 weeks. In a heavily treated population, including those with the T315I mutation, a maximum tolerated dose was not reached and treatment was well tolerated by those with disease activity.

The ASCEMBL clinical trial was a multicenter, randomly assigned, phase 3 clinical trial in which 233 patients with CP-CML who experienced either intolerance or treatment failure after 2 or more TKIs were randomized in a 2:1 ratio to either asciminib 40 mg twice daily or bosutinib 500 mg daily. After a median follow-up of 14.9 months, 25.5% of patients in the asciminib group achieved an MMR vs 13.2% in the bosutinib group at 24 weeks.

In addition, at 24 weeks, 49% in the asciminib group had a 

 less than or equal to 1% vs 23.7% in the bosutinib group. Grade 3 or higher AEs occurred in 50% of the asciminib group vs 60% of the bosutinib group. Finally, 5.8% of the asciminib group discontinued treatment because of toxicity vs 21.1% of patients in the bosutinib group.

The recommended asciminib dosing in CP-CML is 80 mg by mouth once daily or 40 mg by mouth twice daily. In patients with CP-CML with the T315I mutation, the recommended dose is 200 mg by mouth twice daily. Commonly reported AEs among patients include upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, and diarrhea. Common lab abnormalities include low blood counts and elevated cholesterol, pancreatic enzymes, creatinine kinase, and liver enzymes.

Asciminib is an exciting new treatment option with a favorable AE profile in the third-line setting for patients with CP-CML, including those harboring the T315I mutation.

, is a hematology/oncology clinical pharmacy specialist at the University of Rochester Medical Center in New York.

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Articles

Asciminib offers a new option for patients harboring the T315I mutation.

An Overview of the Expanding Treatment Landscape of Chronic Myeloid Leukemia

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy. Approximately 195,000 people in the United States are living with CLL, and an estimated 21,250 new cases and 4320 deaths are predicted for 2021.

“Small lymphocytic lymphoma (SLL)” is used to describe patients with CLL with limited circulating CLL cells.

 The median age of diagnosis is 72 years, and it’s more common in men.

CLL has a heterogeneous presentation and clinical course.

 Treatment options have evolved from chemoimmunotherapy to the use of targeted small molecules that inhibit Bruton tyrosine kinase (BTK), PI3K, and BCL2.

 National Comprehensive Cancer Network guidelines recommend acalabrutinib (Calquence) plus or minus obinutuzumab (Gazyva), ibrutinib (Imbruvica), or venetoclax (Venclexta) plus obinutuzumab as preferred treatment regimens in the first-line setting and acalabrutinib, ibrutinib, or venetoclax plus rituximab (Rituxan) in the second-line or subsequent therapy setting.

BTK inhibitor therapy (acalabrutinib and ibrutinib) provides high response rates and durable remissions but requires continuous therapy.

 These drugs are generally tolerable, but toxicities developing with continuous therapy include bleeding, cardiac arrhythmias, diarrhea, hypertension, and infection.

 Adherence, cost, drug interactions, and resistance can also pose issues.

Venetoclax inhibits the antiapoptotic molecule BCL2, which is highly expressed in CLL cells. Because venetoclax is highly effective, it can cause tumor lysis syndrome. Venetoclax can also cause neutropenia and thrombocytopenia. Recently, 2 clinical trials investigated fixed-duration therapy with venetoclax and a CD20 monoclonal antibody.

The phase 3 MURANO trial randomized 389 patients with relapsed or refractory (R/R) CLL/SLL after at least 1 prior treatment to either bendamustine-rituximab (BR) for 6 months or venetoclax-rituximab for 2 years. The median age of patients was 65 years. After a median follow-up of 23.8 months, the primary end point of progression-free survival (PFS) was not reached in the venetoclax-rituximab arm and was 17 months in the BR arm.

 Grade 3/4 neutropenia and tumor lysis syndrome occurred in 57.7% and 3.1% of patients treated with venetoclax-rituximab, respectively. A longer follow-up showed continued durability of a fixed-duration regimen with a 4-year PFS of 4.6% in the BR arm and 57.3% in the venetoclax-rituximab arm.

The phase 3 CLL14 trial randomized 432 treatment-naive patients with CLL/SLL for 1 year to either chlorambucil (Leukeran)-obinutuzumab or venetoclax-obinutuzumab. The median age was 72 years. After a median follow-up of 28.1 months, the results favored venetoclax-obinutuzumab (HR, 0.35; P < .001 for PFS).

 Grade 3/4 neutropenia occurred in 52.8% of patients, with no cases of tumor lysis syndrome. At a median of 39.6 months, PFS continued to favor venetoclax-obinutuzumab (HR, 0.31; P < .0001).

The findings of the MURANO trial in R/R and the CLL14 trial in patients who are treatment naive for CLL/SLL showed that fixed-duration venetoclax with a CD20 monoclonal antibody is superior to chemoimmunotherapy (BR or chlorambucil-obinutuzumab) and offers a viable treatment option for patients that allows for treatment-free intervals.

The treatment landscape in CLL/SLL is quickly evolving and offers patients multiple options, including but not limited to continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens. Fixed-duration, venetoclax-based combination therapy may be an option for patients who are resistant or do not tolerate BTK inhibitors or prefer fixed-duration therapy. In addition, fixed-duration venetoclax may limit treatment-related adverse effects, cost, and therapy resistance.

is a hematology/oncology clinical pharmacy specialist at the University of Rochester Medical Center in New York.

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12. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948

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14. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5

Patients now have multiple options, including continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens.