Standardizing Optimal Diagnostic Procedures and Monitoring Strategies in CML

Sudipto Mukherjee, MD, PhD, MPH

Although TKIs remain the mainstay of treatment for patients with chronic myeloid leukemia (CML), nuances in the diagnosis, monitoring, and long-term outcomes of patients require better implementation and standardization.

“CML is a disease where there is an embarrassment of riches as far as treatments go,” said Sudipto Mukherjee, MD, PhD, MPH. “However, things have been changing over the past few years that affect patient monitoring and outcomes. Even though we have had so much success with CML, a lot of patients don’t get appropriate diagnostic work up.”

During the 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Mukherjee, a clinical assistant professor in the Department of Medicine, School of Medicine, Case Western Reserve University, and physician in the Department of Hematology and Medical Oncology at Cleveland Clinic Cancer Center, provided detail as to some of these nuances and the optimal management of patients with CML.

Standardizing a Multi-Step Diagnostic Procedure in CML

All patients with CML require a physical examination to palpate and record their baseline spleen size at the time of diagnosis, said Mukherjee. Additionally, all patients should have a complete blood count with differential.

Additionally, performing a bone marrow aspiration and biopsy at diagnosis can determine the metaphase cytogenetics of a patient’s disease and whether any additional chromosomal abnormalities (ACAs) that can influence prognosis are present. Moreover, testing a patient’s blast count in their bone marrow can inform their disease stage.

Potential ACAs include loss of Y chromosome, trisomy 8, Philadelphia chromosome amplification or duplication, 17q insertion, deletion 7q, and 3q26 rearrangement. More than half (54%) of patients with newly diagnosed CML have 1 ACA, 20% have 2 ACAs, and 26% have more than 2, said Mukherjee. Notably, patients who harbor ACAs have poorer prognoses compared with patients who do not.¹

Finally, with regard to the diagnostic process, fluorescence in situ hybridization or qualitative multiplex reverse transcription polymerase chain reaction (RT-PCR) testing should be completed to test for BCR-ABL1 mutations.

Results from these tests will inform risk stratification. Further stratification using the Sokal Index for Chronic Myelogenous Leukemia, the EUTOS Score for Chronic Myelogenous Leukemia, the Hasford Score, and/or the EUTOS Long-Term Survival Score should be done prior to treatment.

TKIs Continue to Impress in Chronic and Advanced CML, Though Toxicities Inform Selection

TKIs remain the standard treatment option for patients with chronic-phase CML, said Mukherjee. Currently, imatinib (Gleevec), bosutinib (Bosulif), dasatinib (Sprycel), and nilotinib (Tasigna) are approved for the first-line treatment of patients with newly diagnosed disease; however, selecting between the agents is not always a clear choice.

Potential drug-drug interactions, risk-benefit analysis of existing comorbid conditions and potential toxicities, and the goals of treatment, such as survival and/or treatment-free remission (TFR), should be considered when selecting between TKIs.

Additionally, a conversation with the patient is needed so that they may weigh their options and express their own preference, Mukherjee explained. “Once-a-day dosing versus twice-daily dosing interferes with meals. Those are big issues that patients [should understand] because it can interfere with their daily life,” said Mukherjee.

In the advanced-phase setting, higher-dose TKIs, ponatinib (Iclusig), or acute myeloid leukemia (AML)–like or acute lymphoblastic leukemia (ALL)–like chemotherapy induction plus a TKI may be considered. Although these regimens have not been compared head-to-head, the ultimate goal of therapy in advanced-phase CML is to make patients eligible for an allogeneic hematopoietic stem cell transplant (allo-HSCT).

Toxicity is a primary consideration that is used to inform TKI selection because each agent is associated with a unique set of potential adverse effects (AEs).

Although cardiovascular toxicities can be a concerning AE, they have not been widely investigated in clinical trials, said Mukherjee. As such, routine cardiovascular risk assessment for certain patients with CML who are receiving TKIs is recommended.

Among all the approved TKIs in CML, common AEs include myelosuppression, increased transaminase level, rash, and fatigue.

More specifically, imatinib, which appears to be the least thrombogenic TKI, is associated with AEs, such as edema, myalgia, and gastrointestinal effects, like diarrhea and nausea. Potential AEs with bosutinib include diarrhea, nausea, and vomiting. Pleural or pericardial effusions, bleeding, and pulmonary arterial hypertension are associated with dasatinib use. Finally, nilotinib may cause increased pancreatic enzymes, indirect hyperbilirubinemia, hyperglycemia, QT prolongation, and cardiovascular events.

In the advanced-phase setting, ponatinib may cause increased pancreatic enzymes, hypertension, skin toxicities, and thrombotic events.

“Of all the available TKIs, ponatinib has, by far, the highest [rate of] thrombogenicity,” explained Mukherjee. “Up to a quarter of all patients on ponatinib can develop a blood clot or a vaso-occlusive event. This tends to be dose dependent.”

Understanding a Patient’s Molecular Response to TKIs

“Although all the [TKIs] are very effective, the challenge now is how to monitor these patients,” said Mukherjee. “Patients do not need regular bone marrow biopsies because we can run quantitative RT-PCR on peripheral blood.”

With this, BCR-ABL1 analysis showed that the log reduction in BCR-ABL1 determines the level of response in patients. Patients with a molecular response of 4 log reduction, or 0.01% IS, or greater are considered to have achieved a deep molecular response.

“Unless a patient achieves a complete molecular response, they cannot [enroll on] a TFR trial.” Mukherjee added.

Moreover, 3 months is an important marker to determine whether a patient may be having a poor response to TKI therapy. However, it is important to continue the patient on the same TKI for up to 6 months because data have shown that outcomes at 6 months can be improved, even in patients who had a poor response at 3 months, explained Mukherjee.

Deciding When to Switch a TKI

A patient who becomes intolerant to 1 TKI despite frequent interruptions or dose reductions may be switched to another. A TKI switch may also be necessary in patients who progress on their TKI as indicated by greater than 10% ISat 6 months or later, inability to reach a complete cytogenetic response (CCyR) at 12 or 18 months, loss of complete hematologic response or CCyR at any time point, loss of major molecular response at any time point, or clonal evolution of metaphase cytogenetics.

Prior to switching TKIs due to intolerance or failure, it is important to check again for drug-drug interactions. For example, some patients receive proton-pump inhibitors that interact with most of the available TKIs.

Compliance should also be established; non-compliance has been shown to have negative effects on outcomes. Patients should also undergo a repeat bone marrow biopsy and a BCR-ABL kinase mutation analysis, which can confirm disease stage and identify acquired mutations.

At the time of switching, TKI selection should be based on prior TKI/s exposure, drug-drug interaction, and risk-benefit analysis.

Additionally, TKI selection should be informed by the patient’s mutational profile, as the presence of certain mutations indicate sensitivity or non-sensitivity to some TKIs. For example, patients with T315I mutations should receive ponatinib, allo-HSCT, or other investigational drugs. Patients with V299L, T315A, or, F317L/V/I/C mutations should be considered for nilotinib versus dasatinib, while those with Y253H, E255K/V or F359V/C/I mutations should be considered for dasatinib versus nilotinib. Patients with any other mutation may receive high-dose imatinib or, dasatinib or nilotinib.

Patients who require a second TKI switch may receive any of the remaining TKIs that they have not yet been treated with. These patients may also undergo an allo-HSCT, which is recommended.

Patients with advanced-phase disease or blast crisis who progress on or become intolerant to 2 TKIs can receive any of the TKIs that had not been previously used; however, ponatinib should be used in cases of T315I mutations. Additionally, these patients could undergo allo-HSCT or receive induction chemotherapy to make them eligible for allo-HSCT.

The Ultimate Goal of TFR in CML

For eligible patients, achieving a TFR holds significant benefit for patients with CML, said Mukherjee.

“[TKIs] can be prohibitively expensive for some patients,” said Mukherjee. “Also, the [AEs] can be numerous and very disabling. [Finally], in young females of reproductive age who have CML [and] achieve [TFR], we can safely discontinue the TKI and allow the pregnancy to proceed normally.”

Treatment needs to induce a deep molecular remission before patients are eligible to discontinue treatment.

Although there is some controversy surrounding which patients with chronic-phase CML are ideal for treatment discontinuation, factors such as non-high Sokal score at diagnosis, typical BCR-ABL transcript at diagnosis, past history of chronic-phase only, optimal response to first-line TKI therapy, over 8 years duration of all TKI therapy, depth of deep molecular response of at least 4.5 log reduction, and more than 2 year duration of deep molecular response monitored in a standardized laboratory are factors that likely indicate a patient is a candidate for treatment discontinuation.

“The paradigm is changing in the treatment and monitoring [of patients with CML], and how we assess patient outcomes. The goal is to take patients off treatment while maintaining quality of life and keeping them in remission,” Mukherjee concluded.

Reference

Mukherjee S. Institutional perspectives in cancer webinar on chronic myeloid leukemia. September 21, 2020. Accessed October 27, 2020.