Patient SNA is a 48 year old female who has been unwell for the last 5 years.
She has been on hydroxyurea since 2014 (About 3g/day). Her previous 2 BCR-ABL done in two different laboratories did not match. The first lab gave a positive BCR-ABL result and the second laboratory gave a negative BCR-ABL result. The follow has not been good but am informed that the patient has been taking hydroxyurea- getting prescription from one of the local doctors.
She now presents with worsening anaemia, hemoglobin 7.5, her WBC 354.56 with marked granulocytosis and left shift to blast level. Blast count is estimated at 15%. Basophil count is about 3%. Platelet count is 179.
Her repeat BCR-ABL is negative but her peripheral blood picture is consistent with CML- accelerated phase. A bone marrow examination is planned for today.
What are your thoughts on this case?
What other investigations would we recommend for her?

There are three possibilities.
1. This is a case of typical CML, but with a rare transcript that cannot be detected by a standard qPCR. Cytogenetics would be very useful
2. This is a case of typical CML, where the local lab has failed to pick up the transcript (a technical problem)
3. This is a case of atypical CML, Ph neg and BCR-ABL neg.

In case 1 or 2 the disease should be sensitive to a TKI. The hematologic response will be fast.
In case 3, there is no treatment better than hydroxyurea, apart from SCT.
Therefore, I recommend strongly to prescribe a TKI.
In any case, the prognosis is poor, because the disease is in an advanced phase.

Kind regards, Michele

I agree with Michele although I am not as optimistic about a response to TKI at this juncture. If there is one, I believe that it will short lived and in the long run, only allografting may be curative..
This cases raises an important point about the diagnosis and monitoring of CML. Was there a cryptic breakpoint that was not picked up by the local lab? Or as may be the case in many parts of the world including some labs including the Western World, there is a question about the quality of the labs to which the samples were sent. We talk about molecular testing and following bcr-abl, but if a lab is not accurate, cannot give reproducible standardized results, does not have a good degree of sensitivity, and even simply is too far away from the patient so that sample degradation may occur, then molecular testing may not be the way to follow a patient, regardless of the therapy being used. Good FISH or cytogenetics done routinely is preferred to bad molecular testing. These tests may not be as sensitive, but more accurately monitor response. This becomes profoundly important in following the effectiveness of therapy. In the era of the push for TFR, the accuracy and sensitivity of molecular testing, is an absolute to do this responsibly and safely. Excellent papers by Hughes' and Mahon's groups in the last couple of years really outline this. It is not enough to use certain treatments to get responses or discontinue therapy. It needs to be done safely.

Unfortunately in this situation, only bone marrow examination is needed but enough for decision (blast count), but if you have possibility for cytogenetics, do it. In case of Philadelphia chromosome or only +8 or +21 aberration found, the case can be a CML in advanced phase. If you do not have karyotype, even though if you have ability to use imatinib, you should try it at dose of 400mg as treatment test. If patients is sensitive to imatinib (she is imatinib naïve), response of WBC can be fast, within a month, then try to continue treatment with imatinib and to further escalate dose if possible up to 800mg depending on hematological toxicity. Be aware that in imatinib sensitive case, you might have tumour lysis syndrome. In other case if she fails to respond to imatinib, you can use purinetol, araC or any other leukemic treatment available having in mind that platelets are the most problematic issue in management of any chemo in advanced leukemia. Andrija Bogdanovic, Belgrade, Serbia

There is possibility that the Lab was unable to successfully do the BCR-ABL, although that seems less likely, given the very high cell counts. A repeat of this test is crucial at this point. The marrow exam is necessary to confirm Acute leukemia transformation. If the BCR_ABL is negative, and the Marrow has >20% blasts, the diagnosis would then be Acute Leukemia secondary to Chronic Neutrophilic Leukemia. If the BCR_ABL is positive and the marrow blast count is <20%, she should respond to 800mg of Imatinib but if the marrow blast count is >20%, she will need Acute Leukemia treatment plus the TKI.

Was there any monocytosis on the peripheral smear?

Francis Ssali