During a <em>Targeted Oncology </em>case-based peer perspectives program, Elias Jabbour, MD, discussed his clinical considerations for the management of chronic myeloid leukemia in chronic phase. Jabbour explained his treatment decisions during the live event based on a case scenario of a patient with CML-CP.
Elias Jabbour, MD
During aTargeted Oncologycase-based peer perspectives program, Elias Jabbour, MD, discussed his clinical considerations for the management of chronic myeloid leukemia in chronic phase (CML-CP). Jabbour, a professor in the Department of Leukemia at the University of Texas MD Cancer Center, explained his treatment decisions during the live event based on a case scenario of a patient with CML-CP.
A 64-year-old man presented to his primary care physician with symptoms of fever, left upper-quadrant pain, and severe fatigue. In 2012, he fainted due to QT syndrome, which was managed with propranolol. In 2014, he was diagnosed with stage III kidney disease (glomerular filtration rate, 45 mL/min) and nonsmall cell lung cancer (NCSLC; stage IIa squamous histology), which was treated with resection and chemoradiotherapy; pleural effusion managed with thoracentesis.
His physical exam revealed that his spleen was palpable 1.5 inches below costal margin. The patient was referred to hematology based on his laboratory findings: white blood count (WBC), 172,000/mcL (metamyelocytes, 3%; myelocytes, 6%; basophils, 6%; blasts, 2%); hematocrit (HCT), 30%; platelets, 536,000/mcL; hemoglobin (Hb), 9.9 g/dL. His bone marrow evaluation showed Philadelphia chromosome positive (Ph+) in 20/20 metaphases. Additionally, a quantitative-polymerase chain reaction revealed his BCR-ABL1/ABL1 value was 90% IS. The patient was later diagnosed with CML-CP.
Describe the patient’s risk status and how it affects your treatment decision.
This patient is asymptomatic and has a high WBC, and his spleen is 1.5 inches below the costal margin. With any score you use, this is going to be high-risk disease. Patients with CML are often asymptomatic. In the United States, 75% of patients will come in to see you with low-risk disease by any score. Few, such as this patient, will have a high WBC and high-risk disease.
All the scoring systemsSokal, Hasford, and European Treatment and Outcome Study—were established before the tyrosine kinase inhibitors (TKIs) were invented. However, we know that they do correlate with patient responses, which does affect your treatment decision. This man is a high-risk patient. What would you prescribe? You might decide to prescribe dasatinib (Sprycel) because of the risk features. The insurance will ask for a co-pay of $1000 per month. If you give him imatinib, however, they will not ask for anything. Does this justify your decision? Overall, there is no survival difference.
In my practice, I would try to convince the insurance company to cover dasatinib or nilotinib (Tasigna). There is an up-front risk of transformation, which is higher with imatinib (Gleevec) compared with the newer drugs. On a larger scale, the difference is not significant, and it does not affect overall survival. If I have to pay $1000, I cannot make the case to pay it because I want to avoid the 2% transformation rate with imatinib; however, all conditions equal, I would favor dasatinib, nilotinib, or even bosutinib in the frontline setting.
What challenges are presented when patients have multiple comorbidities?
This is not a typical patient. People may say that his multiple cancers may limit my options of TKIs. However, 1 thing that is for sure is that TKIs do no create an increase of other cancers. We look at the database as a whole, and there is no increase in incidences of cancer. The only TKI where you do not have to look at an electrocardiogram for QT syndrome is bosutinib (Bosulif). All the other TKIs’ package inserts will tell you to check for that.
In December 2014, the patient was started on therapy with imatinib 400 mg/day. In March 2015, his BCR-ABL1/ABL1 value was 10% IS and by June 2015, it decreased to 6% IS. In September 2015, however, his BCR-ABL1/ABL1 increased to 9% IS.
In December 2016, his BCR-ABL1/ABL1 value was 75% IS and a bone marrow evaluation revealed Ph+ in 19/20 metaphases. His Sanger sequencing was negative for known TKI resistance mutations. Laboratory findings were notable for the following: WBC, 184,000/mcL (metamyelocytes, 5%; myelocytes, 6%; basophils, 5%; blasts, 3%); HCT, 40%; platelets, 124,000/mcL; Hb, 11.9 g/dL.
How would you characterize the patient’s response to imatinib?
Three months down the road, the BCR-ABL1/ABL1 is down to 10%, which is excellent. At 6 months, it is down to 6%. We continue to tell him to take his drugs and not miss a dose, but in September 2015, he comes in with 9% BCR-ABL1/ABL1. This may tell me that he is not taking his medicine. The first thing you should do when you see the BCR-ABL1/ABL1 going up is ask the patient if they are taking the drug. We waited it out, and the patient did well for a while.
In December 2016, he comes to see us and has a BCR-ABL1/ABL1 of 75%, and he has progressed. We should check for mutations at this point because when you fail, you can acquire change in the amino acid domain that the drug will not find. In this case, no mutations were detected. At this point, he has lost his response fully.
Does the fact that the patient has no known mutations affect your thinking about next steps?
Patients who don’t have mutations tend to do worse than those that do. However, it does not affect anything. If the patient has the mutation, then you have to choose your drug based on the mutation profile. If there are no mutations, you can go with any agent based on the patient’s comorbidities and your affinities.
How would the patient’s medical history factor into treatment choice?
One thing to be careful about at this point is that he had lung cancer, and he had pleural effusions in his past medical history. Therefore, he may be at a higher risk of pleural effusion. We should keep that in mind, but it is not an absolute deprecation.
He had long QT syndrome, which does not make me comfortable with using nilotinib. He had kidney disease, which does not affect any TKI response. Bosutinib, however, can increase the creatinine levels a little bit at the beginning, and you can have diarrhea and/or dehydration. Dasatinib compared with nilotinib and imatinib can cause more thrombocytopenia. If this patient is on clopidogrel (Plavix), for example, you can have heightened bleeding.
What options are available for this patient?
In somebody who has a history of lung chronic obstructive pulmonary diseasebecause they were a smoker prior to their lung cancer—with a QT segment of concern, high-dose imatinib does not help. The right drug to prescribe is bosutinib, and you give loperamide (Imodium) with that because the rate of diarrhea is 80% in the first 2 days. But that is fine.
The patient was treated with bosutinib and at 3 months, he achieved a complete hematologic response (CHR) however, he lost his CHR at 6 months. No kinase domain mutation was encountered.
What would you do after he loses his response tobosutinib?
This man is truly resistant, and the best drug right now to get him to respond is ponatinib (Iclusig). For this scenario, to give dasatinib after failing bosutinib would produce an overall response rate (ORR) of just 20% or less. Additionally, the dasatinib profile is similar to that of bosutinib, from the perspective of molecular profiling. Nilotinib post bosutinib is the worst drug option. I would have given imatinib, nilotinib, dasatinibbut I would not have done the reverse.
There was a meta-analysis, and when you compare ORRs with a second-generation TKI, the best response rate is 24%. If you give ponatinib, you are at 56% to 60%. if you want the patient to live longer, your best bet is to give ponatinib. You are limited in your choices here.
The patient was treated with ponatinib.
At what dose do you start ponatinib?
The label is for 45 mg per day; however, I do not do this. This is 1 of the examples of where the FDA approves a drug and we do not use it as approved. I use it at 30 mg or possibly even 15 mg. The reason I use it at a lower dose is to avoid complicationsmainly, vascular events.
It is an expensive drug because when it was first approved, the company came with 15-mg and 45-mg pills and priced them the same. When vascular events started to happen [at the higher dose] and we started to dose reduce the patients, a lot of patients started using 30 mg, and that is when you take 2 tabs of 15 mg. In Europe, the government forced them to drop the price of the 30-mg tablets, which cost the same as the 15-mg and 45-mg tablets. In the United States, you can do whatever you want because it is a free market, and they priced the 15 mg pills the same as the 45-mg tablets because now we buy two 15-mg tablets. It becomes double the price. There was a bill that went to floor for Medicare, Medicaid, and other big payers to be able to negotiate with pharma to lower the prices; however, this bill did not get the vote.
What is the potential to transition to a lower dose based on achieving a long-term remission?
My goal when I’m treating a patient who has a good response is to lower the dose and maintain them at 15 mg. Usually, this does happen within 3 months of therapy.
What would be your approach to next-line therapy if the CML relapses?