The Addition of Asciminib and Removal of Omacetaxine Mark Notable CML NCCN Guideline Updates

Neil P. Shah, MD, PhD

One of the most immediate practice-changing updates to the NCCN Clinical Practice Guidelines in Oncology for chronic myeloid leukemia (CML) published in 2024 was the addition of asciminib (Scemblix), according to Neil P. Shah, MD, PhD, chair of the CML NCCN guidelines. Shah added that the elimination of omacetaxine from the guidelines following its discontinuation in the US by the manufacturer also represented a notable recent change.

“The good news is that for the most part the NCCN guidelines inform insurance companies of what is standard practice, and they will usually comply,” Shah said in an interview with OncLive^®. “There have been some rare cases where [challenges occur]; for instance, up until recently, asciminib was only approved in the third line and beyond settings based upon its superiority to bosutinib [Bosulif] in a randomized phase 3 study [NCT03106779]. You would think that a patient would not have to take bosutinib if they previously received 2 TKIs and had resistance or intolerance. Nonetheless, there have been cases where asciminib was denied because a patient had not yet taken bosutinib despite the fact that the patient had received 2 prior TKIs, and this of course makes no sense.”

The Most Notable NCCN Revisions inCML:¹

• For the primary treatment of chronic phase CML:
  • Asciminib was added as a preferred treatment option for patients with any risk score (category 1)
• For advanced phase CML:
  • Allosteric TKI was added before asciminib
  • Asciminib was added
  • Omacetaxine was removed
• A new section was added: “Special Considerations for the Use of TKI Therapy”
• For early treatment response milestones:
  • BCR::ABL1 greater than 1% to 10% at 12 months: yellow changed to orange.
  • For yellow; possible TKI resistance:
    • Consider bone marrow cytogenetics analysis to assess for major cytogenetic response (MCyR) at 3 months or complete cytogenetic response (CCyR) at 12 months was removed from clinical considerations
    • Consider evaluation for allogeneic hematopoietic cell transplantation (HCT) was removed from recommendations
  • A new category was added: orange
    • Evaluate patient adherence and drug interactions, consider BCR::ABL1 kinase domain mutational analysis, and consider bone marrow cytogenetic analysis to assess for CCyR at 12 months were added to clinical considerations
    • Consider switching to an alternate TKI or continue the same TKI if CCyR is achieved was added to recommendations
• For treatment recommendations based on BCR::ABL1 mutation profile:
  • Omacetaxine was removed
• For allogeneic HCT:
  • Omacetaxine was removed from additional therapy

In the interview, Shah highlighted key recent changes to the CML NCCN Guidelines and detailed anticipated data as well as research for 2025. Shah is the Edward S. Ageno Distinguished Professorship in Hematology/Oncology at UCSF and a professor in the Department of Medicine at UCSF in San Francisco, California.

OncLive: What recent NCCN guideline updates have had an immediate influence on how you practice in CML?

Shah: First and foremost, there is an updated indication of asciminib for newly diagnosed patients with [Philadelphia chromosome–positive] chronic phase CML. In late October 2024, the FDA approved asciminib as a frontline option, so it is now included as an option along with the other 4 approved TKIs. This is immediately affecting practice.

Other changes that have occurred are related to the treatment milestone guidelines. In the past, [for] the yellow category, which refers to possible TKI resistance, there were categories at both 3 months and 12 months. Now there’s only a category at 3 months, and this refers to patients who do not meet the 3-month treatment milestone. We had previously suggested consideration of a bone marrow biopsy to determine if the patient had achieved a MCyR, which is defined as 35% or fewer Philadelphia chromosome-containing metaphases out of 20 analyzed. We’ve removed this because we feel that as long as patients are approaching this milestone, it’s reasonable to continue until 6 months to see if they reach the [molecular response] transcript level [of] less than 10%. The yellow category at 12 months has been eliminated, but in its place there’s a new orange category where there is the suggestion to perform a bone marrow biopsy at this time point if the CCyR level is approaching the milestone response level of 1% but [is] not yet there.

Additionally, on this page of the guidelines, there’s been a footnote added to the green category in recognition of the observation that outcomes in patients who have a transcript level of less than [or equal to] 10% at 12 months are very good. Although, we ideally want to get patients down to 1%, as long as patients are below 10%, I believe we can be reassured that their outcomes are likely to be very close to the excellent outcomes achieved in patients who are at or below the 1% [level] at 12 months. One can [also] defer bone marrow transplant evaluation unless the transcript level is greater than 10% at 12 months, in light of the excellent outcomes [experienced] for patients with [levels] less than or equal to 10% at 12 months.

Asciminib was recently added as an option for [advanced] phase CML and omacetaxine has been removed as a treatment option from the guidelines because it is no longer being supplied by the manufacturer.

The last thing of note is that we’ve added M244V as a contraindicated mutation for asciminib. This is a mutation that we know is resistant to imatinib [Gleevec]. Unexpectedly, we found it confers resistance to asciminib, and patients who have this as a preexisting mutation following prior therapy with imatinib should not be treated with asciminib.

What is key to note for community oncologists who are adapting to recent guideline changes?

Based on data at the present time in patients with low-risk disease, we don’t feel that any particular TKI is preferred unless there’s a strong indication to ultimately achieve a deep response and try to stop therapy, in which case one can make the case for a second-generation drug or the allosteric inhibitor asciminib.

Bear in mind that the treatment guideline cutoffs that are used in the milestone responses don’t imply binary outcomes. In other words, if a patient is just above the 1% [level] vs just below the 1% [level] at 12 months, their long-term outlook is almost identical. Keep that in mind and don’t necessarily panic [based on level].

The other thing I would say which doesn’t necessarily pertain to recent guideline updates is that major molecular response and failure to achieve a major molecular response should absolutely not be considered a failure; if patients are at a 1% or below [level], they have just as good of a long-term outlook as if they get to that major molecular response milestone. Even though this is an end point in many of the clinical trials examining TKIs, its clinical meaning is debatable.

Is there anything that can be done on a physician level to correct issues with the insurance system when implementing guideline changes?

In my personal experience, I’ve had to deal with time consuming physician-to-physician or peer-to-peer calls to try to override or get the insurance companies to reconsider, and we’re all quite busy. I don’t have a good answer to that. It baffles me that an FDA-approved indication is not covered by an insurance company. I don’t know of ways that we can try to approach that, [but] it would be wonderful if these issues could be resolved.

Are guideline changes something that you routinely incorporate into new patient discussions, and if so, how do you typically approach that?

If I have patients on therapy and I’ve been following them and there are guideline changes that pertain to them, I will absolutely bring those up as appropriate. In a newly diagnosed [patient] scenario, I’ll always mention the most important treatment milestones and include in that a discussion of the treatment options as specified by the guidelines. I also refer patients to the NCCN CML patient guidelines, which are available at www.nccn.org, and these nicely provide background about the disease, its monitoring, the treatment options, and the milestone response achievements; they can help patients become very literate about their disease and proactive about the management. These are updated from time to time and were recently updated as well.

What changes do you anticipate coming up in 2025 for additional guideline updates?

We know a lot about resistance mechanisms and specific mutations that are problematic for most of the TKIs. With asciminib being a relatively new addition, we’re still learning about problematic resistance conferring mutations, and we’re likely to see that number [of mutations] grow, and that’s going to be reflected in the guidelines.

Additionally, there are recently published data from my laboratory and others that have found that a subset of patients with CML who have atypical transcripts, [such as] b3a3, [have] variants that are highly resistant to asciminib, although these patients do respond beautifully to the prior 5 approved TKIs. We will likely modify the guidelines to convey this information so that patients are not exposed unnecessarily to asciminib treatment with no chance of response.

I believe that we will continue to consider whether to recommend looking for myeloid gene mutations through myeloid gene mutation panels at the time of diagnosis and/or at the time of resistance or progression. These panels can be useful for monitoring progress to therapy in patients with acute myeloid [diseases], but also can provide some important prognostic information in patients with myeloproliferative neoplasms [such as] polycythemia vera, essential thrombocythemia, and primary myelofibrosis. There are emerging data to suggest that they may be important for patients with CML. We’re still waiting for more data, but that’s something we’re going to continue to monitor, and [it] may make its way into the guidelines sometime soon.

Lastly, one of the important things we have to begin to grapple with, and CML may be the first disease setting in which this issue is becoming prominent, is the cost disparity between therapies that may be relatively similar or basically equivalent in activity. Of course, imatinib has been available in a generic formulation for years, and relatively recently, has been made available very cheaply through an online generic pharmacy. Dasatinib became available in September of 2024 in a generic formulation in the US for the first time, [and] at this moment the cost is not particularly that much lower, from my understanding, compared with the brand name drug.

But if in the not-too-distant future that becomes a very inexpensive option, we have to start grappling with the societal costs and whether to incorporate that into our recommendations. If we have several therapies that are considered to be equivalent—and that currently is the case looking at second generation drugs and asciminib for newly diagnosed chronic phase CML—it would be reasonable to recommend [alternatives] in the setting of therapeutic equivalents based on cost differences alone. If they are especially substantial [cost differences], we might consider preferring a cheap generic option to the expensive brand name alternatives. [This is] not necessarily based on the patient’s out-of-pocket costs, but the societal cost that we that we all pay for.

Reference

1. NCCN. Clinical Practice Guidelines in Oncology. Chronic myeloid leukemia, version 2.2025. Accessed November 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf