Newly Diagnosed CML - Addressing Primary Resistance

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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 a case with newly diagnosed chronic myeloid leukemia, and when we will address a primary resistance.

The clinical presentation of the case is a male, 57 years old, who presented to the local ER with a recent history of left upper quadrant side abdominal pain, poor appetite, night sweats, and weight loss of 20 pounds in the last 2 months. Past medical history is remarkable for COPD secondary to a history of smoking. The physical exam revealed splenomegaly of 12 cm under the left costal margin.

Laboratory findings include a complete blood count with white cell blood counts of 155,000 and hemoglobin of 10.8 and platelets of 650,000. Differential include 20% of segmented cells, 28% of band, 14% of myelocyte, 13% of promyelocyte, 8% of basophils, 6% of eosinophils, 4% of lymphocytes, and 9% of blasts. Peripheral blood qualitative RT-PCR is positive for BCR-ABL. The peripheral FISH also was performed for BCR-ABL and was positive in 90% of the cells analyzed.

So, the first question that we face, which diagnostic test would you add at this point:

  1. HLA testing,
  2. BCR-ABL mutation screening,
  3. CAT scan of abdomen and pelvis with contrast,
  4. bone marrow aspiration with cytogenetics, or
  5. quantitative PCR for BCR-ABL?
When we discuss any patient with possible newly diagnosed CML, the bare minimum that we need to really do as we did the history and physical exam including the spleen size and complete blood count, but I think it is very important as the question stated bone marrow aspirate with marrow differential is essential for the diagnosis. On doing so, combination of cytogenetics will be very important to really recognize what kind of CML are we dealing with, if it has any other chromosomal abnormalities, has any other characteristics that make us think that this patient is really in an advanced phase.

So, I think it is important to remember that we should not treat leukocytosis with imatinib, rather to confirm the diagnosis first; of course optionally, the bone marrow biopsy. The FISH is optional as well as the PCR, but it is very mandatory in case of Ph-negative karyotype as any cryptic translocations. Flow cytometry is not really important but can be done usually in case patients present with accelerated phase or blast phase.

So, in order to establish a diagnosis, I think it is important to establish the phase of the disease. So, think about accelerated phase when you have low platelets, bone marrow or blood blast of more than 15%, high basophils, myelocyte more than 30%, as well as blasts more than 30%. In this regard, establishing Sokal risk score is very useful and you can use any calculator available online to really find low-, intermediate-, or high-risk Sokal score.

So, in this case, the bone marrow aspiration was done, and there was hypocellular bone marrow with the left shift, 7% of blasts, and 5% of basophils. The cytogenetic revealed a -Y 45, XY 9;22 in 20 out of 20 metaphases. Positional analysis also confirmed these 90% of cells were positive for BCR-ABL, and the quantitative PCR using international scale was 89%. Sokal and Hasford score assessment was defined as high risk. You see here these -y may leave us suspicious about the severity of the disease but in fact -y has not been associated with bad outcomes. Rather, they reflect in this case is the high-risk Sokal score.
The staging is complete – this patient has chronic phase CML with a high Sokal risk (2.61).

So, the question at this point is: At this stage, how you will proceed? You will

  1. do an allogeneic bone marrow transplant,
  2. imatinib 400 mg q.d.,
  3. dasatinib 100 mg q.d.,
  4. nilotinib 300 mg b.i.d., or
  5. imatinib 100 mg q.d.
As you see here, the b, c, and d are the currently available therapeutics that are approved by the FDA for the frontline therapy of patient with CML. So, what is even important considering that you decide either of imatinib, nilotinib, or dasatinib, which three of them will be very good options. It will be to really follow a patient.

In this case, the patient was started on imatinib 400 mg q.d., but a workup of three months following initiation of therapy revealed RT-PCR for BCR-ABL by international scale of 15%, and the patient can achieve a complete hematological response. The workup of 6 months included PCR of 9% by international scale, but the bone marrow of this patient reveals 17 out of 20 Ph-positive metaphases. At the 12th month, the PCR was 4% by international scale, and the bone marrow revealed still significant proportion of 12 out of 20 metaphases with ABL kinase domain negative.

So, at this point, how you will proceed for now? Will you continue the allogeneic bone marrow transplant, consider increasing the dose of imatinib to 100 mg or switch to dasatinib 100 mg a day, nilotinib 400 mg twice a day, or bosutinib 500 mg q.d., or even ponatinib 45 mg once a day as the last option?
[Note: On December 20, 2013, ponatinib has been reinstated by the US FDA with update to the labeling and a REMS program.]

At this point, it is important to really follow the recommendation of the NCCN and the followup of the three of the gears that are currently available on the website, and all these are based on the 3-month evaluation data from Hammersmith and from the German data who provide very important information regarding the low probability of progression-free survival as well as overall survival in patients who did not achieve BCR-ABL by the international scale of less than 10% by 3 months.

All these are based on the 3‐month evaluation data from Hammersmith and from the German data who provide very important information regarding the low probability of progression‐free survival as well as overall survival in patients who did not achieve BCR‐ABL by the international scale of less than 10% by 3 months.

This is from Hammersmith,and from the German data who provide very important information regarding the low probability of progression‐free survival as well as overall survival in patients who did not achieve BCR‐ABL by the international scale of less than 10% by 3 months.

It is important for us to start to remember all these things and definitions so we can really have a good understanding. In this case, the patient already was at 12 months and really did not achieve a complete cytogenetic response which really by the NCCN will for sure be a case for switching to second generation TKI. Of course, if the patient is being treated initially with imatinib 400 mg, the options that are currently available and endorsed by the NCCN are nilotinib 400 mg twice a day, dasatinib 100 mg once a day, bosutinib 500 mg once a day.

Always remain current with side effects of the various TKIs approved and used in this setting and educate their patients to report any of these side effects should they occur.

Last modified: December 23, 2013
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