CML Clinical Case Scenario Neil Shah, MD, PhD Edward S. Ageno Distinguished Professor in Hematology/Oncology Leader, Hematopoietic Malignancies Program Helen Diller Family Comprehensive Cancer Center at UCSF San Francisco, California
A 34-year old man is referred for recently discovered leukocytosis of 244K He was found to have palpable splenomegaly, 8 cm below the left costal margin His differential was notable for the presence of 6% basophils, immature granulocytes, and 8% blasts Bone marrow biopsy reveals a hypercellular marrow with 6% blasts and an M:E ratio of 10:1, consistent with a myeloproliferative disorder Cytogenetics reveal t(9;22) in all 20 metaphases analyzed. The BCR-ABL transcript level is 68% by PCR on the International Scale He has two siblings, and no other medical history, and would like to know how he should be treated
Which therapeutic options are most appropriate? Bone marrow transplantation as soon as possible, with the use of TKI until pretransplant workup can be completed Definitive treatment with imatinib 400 mg daily Definitive treatment with dasatinib 100 mg daily Definitive treatment with nilotinib 300 mg bid Definitive treatment with bosutinib 500 mg daily Definitive treatment with ponatinib 45 mg daily Imatinib 400 mg daily, dasatinib 100 mg daily, or nilotinib 300 mg bid (each could be considered appropriate) Imatinib 400 mg daily, dasatinib 100 mg daily, nilotinib 300 mg bid, or bosutinib 500 mg daily (each could be considered appropriate)
Which therapeutic options are most appropriate? Bone marrow transplantation as soon as possible, with the use of TKI until pretransplant workup can be completed Definitive treatment with imatinib 400 mg daily Definitive treatment with dasatinib 100 mg daily Definitive treatment with nilotinib 300 mg bid Definitive treatment with bosutinib 500 mg daily Definitive treatment with ponatinib 45 mg daily Imatinib 400 mg daily, dasatinib 100 mg daily, or nilotinib 300 mg bid (each could be considered appropriate) Imatinib 400 mg daily, dasatinib 100 mg daily, nilotinib 300 mg bid, or bosutinib 500 mg daily (each could be considered appropriate)
The patient initiates imatinib 400 mg daily, which he tolerates generally well, with the exception of mild nausea, peripheral edema and occasional muscle cramps One month later, CBC reveals a complete hematologic response (CHR), and his spleen is no longer palpable He visits your office 3 months after initiating imatinib, and continues to have a CHR
At 3 months, what tests do you recommend? CBC/diff and chem panel alone CBC/diff and chem panel along with a bone marrow biopsy and aspiration CBC/diff and chem panel along with peripheral blood for quantitative PCR assessment of BCR-ABL All of the above CBC/diff and chem panel along with peripheral blood for quantitative PCR assessment of BCR-ABL with a bone marrow and aspiration only if the PCR test reveals failure to meet the desired 3-month milestone
At 3 months, what tests do you recommend? CBC/diff and chem panel alone CBC/diff and chem panel along with a bone marrow biopsy and aspiration CBC/diff and chem panel along with peripheral blood for quantitative PCR assessment of BCR-ABL All of the above CBC/diff and chem panel along with peripheral blood for quantitative PCR assessment of BCR-ABL with a bone marrow and aspiration only if the PCR test reveals failure to meet the desired 3-month milestone
PCR is performed at 3 months, and reveals a BCR- ABL/ABL ratio of 27% (International Scale)
Based upon his PCR result, you: Tell him that no bone marrow assessment is necessary, and it is reasonable to continue imatinib 400 mg daily Tell him that no bone marrow assessment is necessary, but he should switch to dasatinib, nilotinib or bosutinib, or have his imatinib dose escalated Tell him that a bone marrow biopsy and aspiration should be performed at this time, and believe any metaphase response is satisfactory at this time Tell him that a bone marrow biopsy and aspiration should be performed at this time, and believe a metaphase response of 65% Ph+ would be satisfactory Tell him that a bone marrow biopsy and aspiration should be performed at this time, and believe a metaphase response of 35% Ph+ would be satisfactory Tell him that he will need to undergo allo-sct
Based upon his PCR result, you: Tell him that no bone marrow assessment is necessary, and it is reasonable to continue imatinib 400 mg daily Tell him that no bone marrow assessment is necessary, but he should switch to dasatinib, nilotinib or bosutinib, or have his imatinib dose escalated Tell him that a bone marrow biopsy and aspiration should be performed at this time, and believe any metaphase response is satisfactory at this time Tell him that a bone marrow biopsy and aspiration should be performed at this time, and believe a metaphase response of 65% Ph+ would be satisfactory Tell him that a bone marrow biopsy and aspiration should be performed at this time, and believe a metaphase response of 35% Ph+ would be satisfactory Tell him that he will need to undergo allo-sct
He is disappointed to learn that he must undergo another bone marrow biopsy procedure at this time. He has interacted with other CML patients online, and knows that some of them have initiated either nilotinib or dasatinib as their first-line therapy. He asks whether he might have been less likely to require a bone marrow procedure at this time had he started either nilotinib or dasatinib rather than imatinib
You inform him that: Nilotinib and dasatinib were approved for first-line treatment based upon superior cytogenetic and molecular response rates at 12 months, and there are no data to suggest that they achieve a higher rate of desirable molecular milestone achievement at 3 months Nilotinib and dasatinib were approved for first-line treatment based upon superior cytogenetic and molecular response rates at 12 months, and while there are data to suggest that they achieve a higher rate of desirable molecular milestone achievement at 3 months, there is no documented clinical benefit Nilotinib and dasatinib were approved for first-line treatment based upon superior cytogenetic and molecular response rates at 12 months, and they achieve a higher rate of desirable molecular milestone achievement at 3 months, which is associated with significantly improved overall survival
You inform him that: Nilotinib and dasatinib were approved for first-line treatment based upon superior cytogenetic and molecular response rates at 12 months, and there are no data to suggest that they achieve a higher rate of desirable molecular milestone achievement at 3 months Nilotinib and dasatinib were approved for first-line treatment based upon superior cytogenetic and molecular response rates at 12 months, and while there are data to suggest that they achieve a higher rate of desirable molecular milestone achievement at 3 months, there is no documented clinical benefit Nilotinib and dasatinib were approved for first-line treatment based upon superior cytogenetic and molecular response rates at 12 months, and they achieve a higher rate of desirable molecular milestone achievement at 3 months, which is associated with significantly improved overall survival
His bone marrow assessment reveals the presence of the Ph chromosome in 9/20 (45%) of metaphases. There is no evidence of a drug-resistant BCR-ABL kinase domain mutation. He is switched to nilotinib 400 mg twice daily. You inform him of the adverse events associated with nilotinib, including rash, QT prolongation, pancreatitis, and peripheral arterial occlusive events Three months after initiating nilotinib, his BCR-ABL level is 6% (IS). Six months later, the value is 0.06% (IS).
Six months later, quantitative PCR for BCR-ABL reveals an increased level of is 2.3% (IS). He states he has been adherent with medication. You repeat the test and the value is 4.1% (IS). Bone marrow biopsy reveals the presence of a Ph chromosome in 1/20 metaphases. A BCR-ABL kinase domain mutation analysis reveals the presence of a Y253H mutation.
Which of the following treatment options is most reasonable? Imatinib 800 mg daily Dasatinib 100 mg daily Nilotinib 600 mg twice daily Bosutinib 500 mg daily Ponatinib 45 mg daily Dasatinib 100 mg daily, nilotinib 300 mg bid, bosutinib 500 mg daily, or ponatinib 45 mg daily (each could be considered appropriate) Dasatinib 100 mg daily or bosutinib 500 mg daily (either could be considered appropriate) Allo-SCT
Which of the following treatment options is most reasonable? Imatinib 800 mg daily Dasatinib 100 mg daily Nilotinib 600 mg twice daily Bosutinib 500 mg daily Ponatinib 45 mg daily Dasatinib 100 mg daily, nilotinib 300 mg bid, bosutinib 500 mg daily, or ponatinib 45 mg daily (each could be considered appropriate) Dasatinib 100 mg daily or bosutinib 500 mg daily (either could be considered appropriate) Allo-SCT
You decide to switch him to dasatinib 100 mg daily
You inform him that potential side effects of dasatinib to be aware of include all of the following EXCEPT: Headache Pleural effusion Peripheral arterial occlusive events Pulmonary arterial hypertension QT Prolongation Peripheral arterial occlusive events and pulmonary arterial hypertension Peripheral arterial occlusive events and QT prolongation
You inform him that potential side effects of dasatinib to be aware of include all of the following EXCEPT: Headache Pleural effusion Peripheral arterial occlusive events Pulmonary arterial hypertension QT Prolongation Peripheral arterial occlusive events and pulmonary arterial hypertension Peripheral arterial occlusive events and QT prolongation
Which treatment options would be most reasonable if instead of Y253H, his tumor had had a T315I mutation? Imatinib 800 mg daily Dasatinib 140 mg daily Nilotinib 600 mg twice daily Bosutinib 500 mg daily Ponatinib 45 mg daily Allo-SCT Ponatinib 45 mg daily or allo-sct
Which treatment options would be most reasonable if instead of Y253H, his tumor had had a T315I mutation? Imatinib 800 mg daily Dasatinib 140 mg daily Nilotinib 600 mg twice daily Bosutinib 500 mg daily Ponatinib 45 mg daily Allo-SCT Ponatinib 45 mg daily or allo-sct
He is reluctant to proceed with allosct at this time, and is leaning toward starting ponatinib 45 mg daily. He asks if there are any significant toxicities that he should be aware of. You tell him that: Pleural and pericardial effusions are common and need to be monitored Arterial thrombotic events occur in a substantial proportion of patients Life-threatening bleeding has been seen in 4% of chronic phase CML cases QT prolongation and sudden death are listed as black box warnings
He is reluctant to proceed with allosct at this time, and is leaning toward starting ponatinib 45 mg daily. He asks if there are any significant toxicities that he should be aware of. You tell him that: Pleural and pericardial effusions are common and need to be monitored Arterial thrombotic events occur in a substantial proportion of patients Life-threatening bleeding has been seen in 4% of chronic phase CML cases QT prolongation and sudden death are listed as black box warnings