Chronic Myeloid Leukemia - Episode 6

Case 2: Relapsed CML With T315I Mutation


Elias Jabbour, MD:Today I’ll present my case of a 44-year-old woman with chronic phase CML [chronic myeloid leukemia] who was diagnosed 4 years ago. At that time, she was offered frontline therapy with nilotinib, 300 mg twice daily. She had a great response. In fact, at 3 months she had 3-log reduction already. In 12 months, she had 4-log reduction with MR4 [molecular response] and maintained her treatment with good tolerance for 4 years. Well, recently she started complaining of fatigue and not feeling well. That prompted her physician to perform a CBC [complete blood count], and the CBC showed the loss of CHR [complete hematologic response] with hyperleukocytosis and left shift, thrombocytopenia, and anemia.

They did a PCR [polymerase chain reaction] of peripheral blood and the PCR showed a ratio of 100% on International Scale. This is what we have from outside, and this woman, with this work-up done, was offered dasatinib therapy at the dose of 100 mg per day. She took the treatment and a few months later, she had a CBC done showing no response with the hyperleukocytosis still of 137,000, anemia, hematocrit of 25%, hemoglobin of 9, and thrombocytopenic. Repeated PCR at 3 months showed a ratio of 90% International Scale. At that time only, she had a bone marrow done, and the bone marrow showed hypercellularity with 20/20 Philadelphia-positive metaphases. At this stage, she did not have transformation because the marrow blasts were below 20%. She had a Sanger sequencing done looking for mutations, and unfortunately, she was identified to have the T315I mutation, known to be resistant to all TKIs [tyrosine kinase inhibitors]. At this stage, she was referred to us for further management. That’s why I presented the case here today at our tumor board to discuss the best approach for this patient.

James K. McCloskey II, MD:Thank you, Elias. Adam, we talked about this a little already, but do you want to tell us our options for mutational testing, and whether maybe at this point a bone marrow biopsy would change our approach or your approach as a hematopathologist?

Adam Bagg, MD:She’s got clear indication of a need for mutational testing based upon how she now presents in what most people would call accelerated phase with more than 10% blasts. So that’s an indication for mutation analysis. As we discussed earlier, the current technology that’s preferred for doing mutational testing is the relatively insensitive Sanger approach in which you need 10%, perhaps closer to 20%, cells with mutations to pick up the mutation.

We’ve discussed that there are more sensitive technologies for mutational analysis, such as next-generation sequencing and other approaches that could be used. Whether it’s necessary in this day and age to do more sensitive testing I think remains unresolved. Given the mutation she has is a particularly bad one, the gatekeeper mutation of T315I, it will almost certainly impact her therapy. Of course, generally speaking, once a patient has been monitored for CML, for the most part, bone marrows are required less frequently perhaps than peripheral blood monitoring. As we know, you can do RT-PCR [reverse transcriptase-polymerase chain reaction], quantitative RT-PCR, to monitor the peripheral blood. There’s no need to do bone marrow tests for that, but the reason for doing a bone marrow test on this patient is as a diagnosis to improve your yield of metaphases and to look for cytogenetic evidence of clonal evolution.

Elias Jabbour, MD:I would add to what Adam mentioned. This woman at 3 months, when she’s failed nilotinib, should have had the bone marrow test done because she had feature of transformation obvious on her blood. She could be in a blast phase disease, but we missed it because she had a PCR of 100%, or she was resistant, and go for single-agent therapy. Had we done a bone marrow test at 3 months and she had transformation, maybe I would have a different approach. I would have used chemotherapy and TKI, and maybe offered transplant. So I think we should repeat the bone marrow test every time we have resistance documented, not only relying on PCR. Because, yes, we need the cytogenetics as well to look at the transformation among the blasts in the bone marrow, as well as looking at the immune phenotype too.

Transcript edited for clarity.