Management of Accelerated Phase CML Patient

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Javier Pinilla-Ibarz, MD, PhD
Associate Professor
Department of Oncologic Sciences
College of Medicine
University of South Florida
Tampa, Florida

Today we are going to discuss the management of accelerated phase chronic myeloid leukemia in one patient. We are going to start with a rather classical clinical presentation where a female 62 years old was presented to the local emergency room with a recent history of left upper side abdominal pain, poor appetite, night sweats, and weight loss of 20 pounds in the last 2 months. Past medical history in this case was remarkable for cholelithiasis. The physical exam revealed splenomegaly of 15 cm under left costal margin.

Laboratory findings that included complete blood counts revealed white cell blood counts of 150,000, hemoglobin of 10.8, platelets of 350,000 with the differential of 20% segmented cells, 28% bands, 14% myelocytes, 13% promyelocytes, 8% basophils, 6% eosinophils, 4% lymphocytes, and 9% blasts. Bone marrow aspiration revealed hypocellular bone marrow with left shift, 7% of blasts, and 5% of basophils.  Cytogenetics include 46 XY with a 9;22 translocation in 20 out of 20 metaphases, and the FISH revealed 90% of cells positive for BCR-ABL with quantitative RT-PCR by international scale of 89%. Once again, the classical Sokal or even Hasford score with assessment of this patient is classified as high risk.

We will talk a little more what happened with this patient. The local oncologist started therapy with imatinib 400 mg a day with initial very good tolerance besides occasional leg cramps. After 4 weeks of therapy, the patient achieved a complete hematologic response, and a bone marrow examination performed in 6 months showed a minor cytogenetic response and a 12-month new bone marrow showed a complete cytogenetic response. PCR for BCR-ABL in 18 months was 0.8 by international scale on this type over the time, but the patient was followed 12 months later. A followup CBC was abnormal which really appeared suspicious, that something was going on with this patient.

So at this point, the laboratory findings and workup of the patient revealed a complete blood count with a white cell blood count of 210,000, hemoglobin 9.5, and platelets 75,000. Low platelets outside the early phase of therapy with CML always should prompt us to really think about something is going wrong with our patients and really prompt immediate workup. Differential counts revealed 15% segmented cells, 18% bands, 8% myelocytes, 18% promyelocytes, 21% basophils, 6% eosinophils, and 14% of blasts. PCR for BCR-ABL in the peripheral blood revealed 70%. Peripheral blood FISH for BCR-ABL was positive in 100% of the cells analyzed. Bone marrow aspiration was performed based on the recent findings and showed hypocellular bone marrow with left shift and 17% of blasts. Cytogenetics revealed as 47 XX with trisomy 8 on isochromosome 17. Both of these are red flags in terms of clonal evolution. ABL kinase domain mutation was negative for the presence of any possible mutation and responsible for resistance of imatinib in this case.

So once again, the question that we are facing is what we do with this patient as you may see already has features of accelerated phase as per the blast count, the low platelets, and the bone marrow assessment.  So, will you do allogeneic bone marrow transplant as soon as possible or you will include one of the drugs currently available for the treatment of CML after imatinib failure? 

Of course, the drugs available these days are bosutinib 500 mg once a day, dasatinib 140 mg once a day, and nilotinib 400 mg twice a day including ponatinib 45 mg once a day.

Now all of these TKIs come with benefits and risks and you must be aware of them. Since there was a great deal of focus on safety issues regarding ponatinib leading to a temporary withdrawal from the market, followed by a reintroduction to market with an updated prescribing sheet and boxed warnings, here are just a few important points.  You should review the new indication sheet and boxed warnings and be familiar with them. As a reminder, ponatinib is a kinase inhibitor indicated for the: Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with ponatinib. The optimal dose of ponatinib has not been identified. In clinical trials, the starting dose of ponatinib was 45 mg administered orally once daily. However, 59% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy. Start dosing with 45 mg once daily. You should consider reducing the dose of ponatinib for CP CML and AP CML patients who have achieved a major cytogenetic response. Consider discontinuing ponatinib if response has not occurred by 3 months (90 days). Ponatinib may be taken with or without food. Tablets should be swallowed whole. You should familiarize yourself with the dose-modification for myelosuppression, hepatic toxicity, pancreatitis and elevation of lipase as well as those recommended when ponatinib is used with strong CYP3A inhibitors 

See: www.accessdata.fda.gov/drugsatfda_docs/label/2013/203469s007s008lbl.pdf as partial reference.

So at this point, we will have to discuss the pros and cons of all these drugs to really ensure based on also recommendation of NCCN Guidelines to really start to treat the patient with a drug that can really allow patient to be salvaged.

Nevertheless, I am considering that this patient already failed the imatinib and already had a clonal evolution. The patient also should be considered for allogeneic bone marrow transplantation consultation because upon response of drugs this patient should be evaluated for the possibility to have allogeneic bone marrow transplant in case needed.

Of course, early prognostic factor has achievement of a very good complete cytogenetic response, so even like less than 10% by PCR by international scale in 3 months may point out to a patient who may have chances to really stay a longer period time on TKI, but nevertheless in younger patient, I think this is also mandatory to make sure that we discuss the transplant options upon failure of imatinib and even more in case of the patient having accelerated phase.

Last modified: February 3, 2014
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