The Therapeutic Approach for Relapsed CML - Episode 1

Diagnosis of Relapsed CML and Risk Status

Javier A. Pinilla-Ibarz, MD, PhD:This case is a 64-year-old gentleman with newly diagnosed chronic myeloid leukemia. He presented to his primary physician with left upper quadrant fevers for a while, and at the physical exam, he was found to have a large spleen. His past medical history is remarkable for a long QTC prolongation that is being treated with propranolol, as well as kidney disease with a creatinine clearance of less than 40 ml/min. Lastly, the patient was diagnosed in 2014 with earlier stage non—small cell lung cancer that was treated with surgery and was complicated by pleural effusion as well further thoracentesis procedures. Blood counts performed in this patient show a high WBC, or white blood count, as well increase of platelets, and a decrease on the hemoglobin. Bone marrow is performed and shows classical Philadelphia-positive cells in 20 out of 20 metaphases, as well as a PCR of 90%, BCR-ABL ratio.

His primary oncologist decides to start therapy with imatinib 400 mg once a day, and he’s being followed very closely, trying to see if he’s achieving an NCCN milestone at 3 months. At this point, hisBCRis 10% and his oncologist decides to continue therapy without changing doses of imatinib. Around 6 months of therapy, hisBCRgoes to 6%, which really is defined as a good outcome as per the NCCN milestones. It means every time that patients achieve aBCRof—from the 3 to the 6 months–less than 10%, the patient is doing well. However, the patient has had around 9 months of therapy. HisBCRstarts to go up, and we see a BCR-ABL ratio of 9%.

One year after starting therapy with imatinib 400 mg, theBCRis already 15%, which has prompted his oncologist to perform a bone marrow evaluation as indicated in the NCCN guidelines. At this time, the patient still has 10 out of 20 pH-positive metaphases consistent with lack of complete cytogenetic response at 1 year of therapy. That’s considered a failure. Kinase domain mutation analyses are performed and they are negative for the presence of anyABLmutation. And finally, at this time, new blood counts are performed and this patient reveals a mild leukocytosis with immature forms as the differential, as well with some anemia and normal platelet count.

At 1 year of therapy with imatinib 400 mg once a day, peripheral blood PCR shows 15% and the doctor performs a new bone marrow evaluation that demonstrates 10 out of 20 pH-positive metaphases. At this point, this is considered a lack of complete hematologic response, so he’s a failure by NCCN guideline criteria. His doctor also performs a kinase domain mutation analysis to look for a possibility of the resistance to imatinib, but in this case, there is no kinase domain mutation found. Finally, CBC show normal blood counts with normal hemoglobin, platelets, and white cells.

Every time that we assess a CML patient at diagnosis we try to reestablish the risk stratification, mostly by a so-called score system. In this case, I will have to say that the patient by the criteria and by the physical exam on the peripheral blood can be defined as a high-risk patient.

Transcript edited for clarity.


A Patient With Relapsed CML and Comorbidities

December 2015

  • A 64-year-old male presented to his PCP with symptoms of fever, LUQ pain, and severe fatigue.
  • PMHx:
    • 2012: fainting associated with Long QT syndrome managed on propranolol.
    • 2014: stage 3 kidney disease (GFR; 45 mL/min)
    • 2014: NSCLC, stage IIA squamous histology treated with resection and chemoradiotherapy, pleural effusion managed with thoracentesis
  • PE: spleen palpable 1.5 inches below costal margin
  • CBC:
    • WBCs, 172,000/μL (metamyelocytes, 3%; myelocytes, 6%; basophils, 6%; blasts, 2%;
    • HCT, 30%
    • Platelets, 536,000/μL
    • Hb, 9.9 g/dL
  • Bone marrow biopsy: Ph+ in 20/20 metaphases
  • Q-PCR; BCR-ABL1/ABL1 ratio, 90%
  • The patient was started on therapy with imatinib 400 mg

  • March 2015:BCR-ABL1, 10% Q-PCR
  • June 2015:BCR-ABL1, 6% Q-PCR
  • September 2015:BCR-ABL1, 9% Q-PCR

December 2016:

  • BCR-ABL1, 15% Q-PCR
  • Bone marrow biopsy: Ph+ in 10/20 metaphases
  • Genetic testing was negative for known TKI resistance mutations
  • CBC normal count