The Deciding Factors for CML Treatment

Michael J. Mauro, MD:So, here we have a case of a middle-aged woman, 48 years old, diagnosed with chronic ACML (atypical chronic myeloid leukemia). Her case was fairly typical in that she did have some splenomegaly, her blood counts were quite abnormal—with a markedly elevated white blood cell count—she had some anemia, mild change in her platelet counts, although still in the normal range. There were 6% blasts in the blood, which is notable. Typical cytogenetics that showed 100% pH positivity, and molecular studies were consistent with the BCR profusion at a level above 100% on the international scale.

She represents a dilemma of how to treat a newly diagnosed CML patient: Which medications do we choose and how do we navigate? She was started on dasatinib therapy, 100 mg per day, after a discussion of multiple choices, and she actually did well. She had, within 6 months, a major molecular response and then, within a year, a deeper molecular remission, and continued along that path for several years.

When we think about a patient who is newly diagnosed with CML, we probably ought to take a step back and do what’s called a risk stratification or risk assessment. Traditionally, that is looking at the disease parameters. And ironically, a bone marrow study isn’t necessary, at least looking at historic risk stratification, to do that. The blood counts, the physical exam findings, and the patient’s age all can be put into different models. These models have evolved, the original being the Sokal score, but with time, the Hasford, or the Euro, scoring, and even scores that incorporate survival, have been developed, which really helped us project how well a patient will do and then perhaps how to choose therapy.

There are some thoughts and different guidelines whether a high-risk patient should have different therapy than a low-risk patient, although I think there’s debate over that. But that is one part of the risk assessment. I think the other is to look at the patient as a whole, look at their medical status and their comorbid illnesses. That has become increasingly important as we choose therapy and navigate patients on therapy: Looking at toxicity and risk benefits of different changes in therapy or even initial choices.

So, we have 3 approved agents for the frontline setting. We may have more as time passes, but in a higher-risk patient of younger age, I think it’s very reasonable to pursue a second-generation BCR-ABL tyrosine kinase inhibitor like dasatinib. And that’s what was chosen in this patient, which I think is very practical. And in turn, the patient did well. The important milestones are noted in the case, and I think that’s the next step after risk stratification: Decision-making and initial therapies, of course, to make sure the patient moves along their treatment journey promptly and meets the appropriate milestone.

In digging a little bit deeper into this case, there were multiple different choices for her, and one could consider imatinib, erlotinib, or dasatinib, currently, for a newly diagnosed CML patient. I think, again, her risk stratification put her in a higher risk category if you calculate her risk by historic models. She calculates as a higher-risk patient. The things that would probably make that true are the increase in blast in the blood, the enlargement in the spleen, and perhaps, a bit, her younger age.

So, I think imatinib offers a good response in a patient like this. There are differences in high-risk versus intermediate-risk or lower-risk patients from our original data from the Irish trial. And if you look at data from our second-generation trials used in the frontline setting compared to trials like the ENESTnd trial and the DASISION trial, there were advantages across the board, but they may be slightly greater advantages for patients who have higher-risk disease.

We didn’t hear much about her comorbid illness status. I think that would have been an important line of questioning. Did she have cardiovascular disease? Does she have cardiopulmonary disease, diabetes, or any health conditions that require careful attention that potentially could be exacerbated by treatment choice? Assuming those weren’t the case, I think in the end, dasatinib for a younger patient with high-risk disease represents a good choice and is expected to bring a patient into rapid molecular response, something called “early molecular response,” within 3 to 6 months. And then hopefully, prompt cytogenetic response within 12 to 18 months and deeper molecular response within generally 18 months or beyond. And as we see, this patient actually responded quite quickly with major molecular response within the first year and a deeper molecular response as the months continued.

Transcript edited for clarity.

Case: A Younger Patient With Relapsed CML

May 2013

• A 48-year-old female was diagnosed with CP-CML with a splenomegaly, 3.2 cm below the costal margin
• Laboratory values:
  • WBCs, 157,000/μL
  • HCT, 30% hematocrit
  • Platelets, 359,000/μL
  • Myeloblasts, 6%
• Bone marrow biopsy: Ph+ in 20/20 metaphases
• Q-PCR, showed a BCR-ABL1/ABL1 ratio of 176%
• The patient was started on dasatinib 100 mg; she achieved MMR after 6 months, and a deeper molecular remission (>MR4) after 12 months on therapy and remained in remission for 3 years

December 2016

• The patient complained of increasing fatigue and weight loss.
• Q-PCR showed a significant increase in BCR-ABL1 transcript ratio (to 50% IS)
• Bone marrow biopsy; 80% cellularity, 18/20 Ph+ metaphases
• Mutation testing showed the presence of T315I
• CBC WNL
• The patient was started on ponatinib 45 mg daily
• She developed grade 3 thrombocytopenia; the ponatinib dose was reduced to 30 mg daily

March 2017

• Cytogenetics, 3/20 Ph+ metaphases
• BCR-ABL1 transcript ratio, 5%

June 2017

• BCR-ABL1 transcript ratio, 0.75%.

October 2017

• BCR-ABL1 transcript ratio, 0.01% and no T315I mutation was detected