TRAINING and EDUCATION
You Make the Call
Each month in “You Make the Call,” we pick a challenging clinical question submitted through the Consult a Colleague program
and post the expert’s response, but we also want to know what you would do. Send in your response to next month’s clinical
dilemma and see how your answer matches up to the expert’s in the next print issue.
This month, Michael Deininger, MD, PhD, discusses treatment for a patient with chronic-phase chronic myeloid leukemia (CML)
whose BCR/ABL transcript levels are rising.
Clinical Dilemma:
A 55-year-old female patient received a diagnosis of chronic-phase chronic myeloid leukemia in April 2016. After treat-
ment with dasatinib 100 mg daily, major molecular response was achieved in January 2017. BCR/ABL1 b2a2 increased
to 0.99 percent by June 2017, and dasatinib was increased to 140 mg daily (BCR/ABL1 kinase domain mutation was
negative). When BCR/ABL reached 0.27 percent in January 2018, she was changed to nilotinib 300 mg twice a day.
BCR/ABL was 0.24 percent in April 2018, and 0.77 percent in June 2018. She is healthy and compliant. What should be
done next?
Consult a Colleague
Through ASH
Expert Opinion
Michael W. Deininger, MD, PhD
Professor and Chief of Hematology and Hematologic Malignancies
Department of Internal Medicine and the Huntsman Cancer Institute
University of Utah
Consult a Colleague is a service for ASH
members that helps facilitate the exchange
of information between hematologists
and their peers. ASH members can seek
consultation on clinical cases from qualified
experts in 11 categories:
• Anemias
• Hematopoietic cell
transplantation
Patients with newly diagnosed chronic phase CML have
several tyrosine kinase inhibitor (TKI) options, includ-
ing imatinib or one of the second-generation (2G)
inhibitors: dasatinib, nilotinib, or bosutinib.
During the initial phase of her TKI therapy, this
patient’s response was optimal, with MMR documented
after nine months. Unusual in this situation, she subse-
quently lost MMR, although she probably maintained a
complete cytogenetic response (CCyR), given that her
BCR-ABL1 transcript remained <1 percent.
At this juncture, it is important to establish whether
the loss of MMR reflects true acquired resistance, lack
of compliance, or a fluctuation in the polymerase chain
reaction testing for the BCR-ABL1 transcript. Re-testing
after 4 to 6 weeks can address such fluctuations and al-
lows reassessment of the transcript levels – and it never
hurts to remind the patient of the virtues of strict adher-
ence to the regimen. Unlike loss of CCyR, loss of MMR
alone is not necessarily a reason to switch therapy. In the
current case, dasatinib was escalated to 140 mg daily, the
maximum dose typically prescribed for accelerated or
blast phase. Surprisingly, there was little improvement
in the BCR-ABL1 level. In fact, a reduction from 0.99 to
0.27 percent is within the variation of BCR-ABL1 testing
in many labs, and the two values are statistically not dif-
ferent. The CML in this patient truly seems to be resistant
even to high doses of a 2G TKI.
In some cases, switching to another 2G TKI is
beneficial, but these tend to be patients in whom
adverse events force the drug’s dose to be lowered. In
this patient, nilotinib did not improve response, with
two values hovering between CCyR and MMR. At this
point, switching to yet another 2G TKI will not help.
Ponatinib, arguably the most potent of the TKIs, might
improve the response, but toxicity concerns could be
prohibitive.
Checking whether a T315I mutation has developed
could be considered, but the likelihood of a positive
result is low, given the stability of BCR-ABL1. Thus,
continued monitoring of residual CML and of cardio-
vascular toxicity of nilotinib would be my preferred
strategy. An honest discussion with the patient that
treatment-free remission in the future is unlikely would
be part of this plan. If, with continued monitoring, her
BCR-ABL rose to >1 percent, one should repeat the
ASHClinicalNews.org
diagnostic workup, including cytogenetics and muta-
tion screening to rule out nilotinib-resistant mutants.
The next step would be treatment with bosutinib, but I
would recommend this only if she had a mutation that
is likely to respond to bosutinib. With no mutations or
with a T315I mutation, one sh