A 40-year-old male patient diagnosed with chronic-phase CML with high risk sokal score in november 2017.
Initial findings:
-Previous history of priapism.
-CBC: hemoglobin 10 g/dL, hematocrit 28 %, WBC 350 ×109/µL (left shift, eosinophils 2 %, basophils 1 %, and blasts 2%), and platelet count of 1500×109/L.
-Severe splenomegaly, 300 mm.
-Bone marrow aspiration and biopsy revealed increased granulocyte precursors, basophils and eosinophils; normal erythroid compartment and normal megakaryocytes; without findings of myelodysplasia; MF1 and 5% of CD34+ cells.
-FISH BCRABL: 100%.
-RqPCR p210: 74%. BCR-ABL (IS)
-Karyotype 46,XY,t(9;22)(q34;q11.2).

He started treatment with Nilotinib (300 mg twice a day) on November 8 with an initial adequate decrease in white blood cells and platelets. 30 days later, he presented with severe thrombocytopenia (10×109/L) and the treatment was stopped. 3-weeks later, the platelet count of the patient was normalized and he re-started Nilotinib (150 mg twice a day). Month 3 evaluation showed the following cytogenetic and molecular response: FISH 60% and RQ-PCR 65%

As platelet counts decreased progressivelly, Nilotinib dose was reduced to 150 mg per day and treatment interrupted due to platelet count of 30×109/L. He has been without treatment for 20 days, does not have anemia or leukocytosis, but the differential count is now with left shift and the platelet count 40×109/L.

My questions are:
-Do you agree to start treatment with another TKI por example dasatinib with an initial dose of 50 mg per day? With which platelet count do you recommend stopping treatment?
-Do you recommend to perform another bone marrow aspiration and biopsy with cytogenetic and molecular evaluation before changing TKI?

Great case with lots of learning points.
Two questions. The first is whether to repeat the bone marrow. The original diagnosis of chronic phase CML with standard cytogenetics is not disputable. The one observation that is not noted, is what was on the bone marrow core biopsy. Was there a lot of fibrosis at diagnosis, something that often makes delivering the therapy difficult? This takes the issue even further, in that unfortunately, many patients in the community, are being started on therapy without bone marrow testing and cytogenetics, purely on the basis of the appearance of the blood and the presence of bcr-abl on molecular screening. This omits a very important predictive test, both in terms of morphology and whether additional chromosomal abnormalities are present at diagnosis. Historically on most of the newly diagnosed studies, problems with recurrent cytopenia despite obvious chemosensitivity and even molecular response, required a repeat bone marrow aspirate and biopsy. What can be answered with this is whether there is ongoing fibrosis, whether the marrow is just empty, or whether there is evidence of an unusual but not unheard of, rapid transformation to accelerated or even blast phase disease. So the answer is yes, repeat the marrow, and if there is a suggestion of morphological transformation, do the cytogenetics again to rule out clonal progression.
The second issue is what to do and guidelines for holding therapy. In the absence of disease progression and fibrosis and the appearance of an empty or hypocellular marrow, then a number of things have been ruled out. Generally, the cytopenias are due to the exquisite disease sensitivity to TKIs. At diagnosis, many individuals with very high counts or who have had disease for a long period of time, only have clonal hemopoiesis, meaning the normal blood cell producing clones are hibernating and blood cells are coming from the Ph-positive clones. TKIs and I mean all TKIs are extremely effective in shutting this down, and only when and if normal clonal hemopoiesis recovers, will blood cell production not be suppressed by the TKI and cytopenias will resolve. So, in other words, a switch in TKI is not the solution generally, as you can expect a similar problem with all.
Usually and depending on your degree of comfort, many people will hold therapy with platelets <50 and neuts <1. If you can monitor the patient much more closely and are comfortable in the case of recurrent cytopenia, these numbers can be a little lower. Confirm of course that the patient is taking nilotinib properly, ie on an empty stomach. Taking it with food can increase absorption as much as 4-fold and hence increase levels significantly. Also make sure that the patient is not taking other medications – prescription, over the counter, naturopathic, social – that may increase the NIL levels.
Personally, I would wait for better count recovery, say to the above parameters and try 150 once daily again, and if counts are sustained, increase the dose as rapidly as tolerated to the usual dose of 300 BID. If counts crash again, DAS could be tried, but even 50 may be too high. This might be a case for considering 20 and escalation rapidly to 50-70 if tolerated. My experience is that a drug switch does not usually work. Recent French/Quebec data suggest that for most patients, the dose of 100 is not needed. If DAS is not tolerated for the same reasons, then there are going to be problems. This is a young man and I would be looking into whether an allograft may be a potential therapy. Persistent cytopenias with off/on therapy usually does not result in great responses, and puts the patient at increased risk for developing bcr-abl mutations or clonal evolution.
Good luck
Jeff

ORIGINAL CASE:

A 40-year-old male patient diagnosed with chronic-phase CML with high risk sokal score in november 2017.
Initial findings:
-Previous history of priapism.
-CBC: hemoglobin 10 g/dL, hematocrit 28 %, WBC 350 ×109/µL (left shift, eosinophils 2 %, basophils 1 %, and blasts 2%), and platelet count of 1500×109/L.
-Severe splenomegaly, 300 mm.
-Bone marrow aspiration and biopsy revealed increased granulocyte precursors, basophils and eosinophils; normal erythroid compartment and normal megakaryocytes; without findings of myelodysplasia; MF1 and 5% of CD34+ cells.
-FISH BCRABL: 100%.
-RqPCR p210: 74%. BCR-ABL (IS)
-Karyotype 46,XY,t(9;22)(q34;q11.2).

He started treatment with Nilotinib (300 mg twice a day) on November 8 with an initial adequate decrease in white blood cells and platelets. 30 days later, he presented with severe thrombocytopenia (10×109/L) and the treatment was stopped. 3-weeks later, the platelet count of the patient was normalized and he re-started Nilotinib (150 mg twice a day). Month 3 evaluation showed the following cytogenetic and molecular response: FISH 60% and RQ-PCR 65%

As platelet counts decreased progressivelly, Nilotinib dose was reduced to 150 mg per day and treatment interrupted due to platelet count of 30×109/L. He has been without treatment for 20 days, does not have anemia or leukocytosis, but the differential count is now with left shift and the platelet count 40×109/L.

My questions are:
-Do you agree to start treatment with another TKI por example dasatinib with an initial dose of 50 mg per day? With which platelet count do you recommend stopping treatment?
-Do you recommend to perform another bone marrow aspiration and biopsy with cytogenetic and molecular evaluation before changing TKI?