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&rsquo;s being followed very closely, trying to see if he&rsquo;s achieving an NCCN milestone at 3 months. At this point, his

is 10% and his oncologist decides to continue therapy without changing doses of imatinib. Around 6 months of therapy, his

goes to 6%, which really is defined as a good outcome as per the NCCN milestones. It means every time that patients achieve a

offrom the 3 to the 6 months&ndash;less than 10%, the patient is doing well. However, the patient has had around 9 months of therapy. His

starts to go up, and we see a BCR-ABL ratio of 9%.

One year after starting therapy with imatinib 400 mg, the

is 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&rsquo;s considered a failure. Kinase domain mutation analyses are performed and they are negative for the presence of any

mutation. 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&rsquo;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.

Diagnosis of Relapsed CML and Risk Status

Today we are very fortunate to have several options for the treatment of newly diagnosed chronic phase chronic myeloid leukemia. There are 3 agents approved for frontline therapy. The first is imatinib, the second one is nilotinib, and the third one is dasatinib.

When we really discuss with our patient initial therapy for treatment of chronic phase chronic myeloid leukemia, it&rsquo;s very important to really have the feedback of our patient in terms of dosing as well as to really take into consideration any potential comorbid condition the patient may experience or have experienced before as this may predispose them to have complications to specific drugs that we&rsquo;re going to prescribe.

So, it&rsquo;s important to take into consideration the past medical history of a patient who we really start therapy, or we need to decide to change therapy, with a tyrosine kinase inhibitor. In this case, the patient has a history of long QTC. There&rsquo;s also history of current kidney disease, as well history of lung cancer treated with surgery, but also complicated by pleural effusion of thoracentesis. In this regard, all these comorbid conditions may really make us choose certain drugs or preferentially certain drugs versus others, at least considering that some of the drugs that we are currently use for the treatment of chronic myeloid leukemia may have complications such as pleural effusion and prolonged QTC, or even they may, in the long run in some cases, potentially decrease glomerular filtration.

The treatment of chronic myeloid leukemia in older patients is challenging and this is because of the multiple comorbid conditions that are very well studied, that most of the patients with CML are 60 to 65 years old presenting, as well as many, many times the polypharmacy that these patients are receiving. These are very, very important factors to consider at the time for which TKIs may be better tolerated, but also very important as predictors of potential side effects of each of the drugs that we are going to prescribe.

The patient on this case was treated with imatinib. Although we know that imatinib is a good frontline drug for the treatment of patients with chronic myeloid leukemia, we also know that the trial has been performed. And comparing imatinib with a second-generation TKI, one of the advantages to really treat patients with a high-risk Sokal score is that they have less progression during the first year and they achieve faster and deeper response. In this case, although no one can say that is contraindicated, the decision to really use a second-generation TKI should have be discussed with the patient because they may have some advantage in terms of better response during this first year.

In any patient who we decide to start treatment with a tyrosine kinase inhibitor, it is also important to take into consideration all these comorbid conditions. So, it&rsquo;s very important to really control any abnormalities and any other comorbidities that can really increase the toxicity of the drugs that we&rsquo;re going to prescribe. In this case, it&rsquo;s important to really have a close collaboration with the primary physician, even with the cardiologist, to really work as a team and to try to avoid comorbid conditions that can affect the toxicity of the drugs that we&rsquo;re going to prescribe.

Treatment Approach for Relapsed CML

The patient response to imatinib is always assessed at 3 months. In this case, the patient had a 10% PCR, under the limit of what the patient should have. However, his doctor decided to waitand many, many times we do&mdash;to the 6-month mark to really see if his 10% PCR continued to decrease, which will be the best outcome for most of the patients. At 6 months, this patient experienced a 6% PCR level.

However, at 9 months, we start to really see that his PCR goes back to 9%. And finally, at 1 year of therapy, it&rsquo;s very clear that this patient has failed therapy, based on a bone marrow evaluation and the persistence of 10 out of 20 pH-positive metaphases in the bone marrow. This is really considered a lack of complete cytogenetic response that is the optimal outcome at 1 year of therapy. So, in this case, we should consider this patient as a failure to imatinib therapy. And of course we, at this point, need to really understand why this patient failed.

So his doctor prescribed and performed these kinase mutation tests to assess if there is any able mutation responsible for the lack of activity of imatinib. In this case, as it has happened on many occasionsat least in 50% of the time&mdash;there was no mutation found that can really justify this lack of response to imatinib.

Any time that a patient relapses or lacks to achieve the wild milestone as per the NCCN guidelines, a kinase domain mutation should be performed. Kinase domain mutations evaluate the presence of specific mutations in the

part of the BCR-ABL protein. That will enable tyrosine kinases to really bind and effectively treat the patient. In this case, there are several mutations that have been described over the last years. Many of them can really be a lack of importance. However, a specific mutation at some point may respond to one drug versus another drug. It&rsquo;s well characterized. However,

is a mutation for which none of the tyrosine kinase inhibitors, except ponatinib, are effective in the treatment of this condition. Other mutations, like

, can also be managed with other drugs. Unfortunately, the presence of a mutation may predict the onset of new mutations later on, which is something that needs to be taken into consideration.

Once a patient fails imatinib at frontline, they have multiple options for the treatment as a second line. We are lucky enough to really have at least 4 drugs available for the treatment of this patient, and even if we cannot, in some cases, have a chemotherapy drug that is very, very rarely used in the setting. The drugs will be nilotinib, dasatinib, bosutinib, and ponatinib. And the choice of any of these drugs will be for the potential comorbid conditions. The efficacy of these drugs is best in patients with resistant CML, or at least to refractory to imatinib.

Relapsed CML: Mutation Testing and Therapy Choices

There is no doubt that all the drugs that we are going to prescribe for patients who fail from frontline imatinib can be used in this setting. Ponatinib is one of the choices. I think it&rsquo;s something that we discuss with patients after frontline failure. It&rsquo;s true that ponatinib may be indicated many, many times after failure of second-generation TKIs, so we know that in this setting, it has the higher effectivity. However, you may consider, in certain situations, to reuse ponatinib as a second-line therapy. Because of the cardiovascular toxicity associated with this drug, sometimes you have to really weigh the risk benefit to really introduce these early on rather to wait until patients fail a second-generation TKI. In this case, your choices will be nilotinib, bosutinib, or dasatinib. However, it&rsquo;s important to emphasize that in this specific case, all of these 3 drugs may be associated with side effects that this patient has a history of. For example, prolonged QTC. Although prolonged QTC is a class effect, this patient had this problem previously. And not only for nilotinib, rather for all the TKIs, it is something that needs to be taken into consideration and really looked after.

The second one is the problems with the history of lung cancer and pleural effusion. Although it&rsquo;s not really clear the problems of pulmonary function in this patient, dasatinib may, in patients like that, induce or predispose patients to really have farther pleural effusion. So, this is an important factor to be considered.

Finally, bosutinib is very well tolerated in this setting. In some casesand in the long, long follow-ups&mdash;it may be associated with decrease of renal function, so it&rsquo;s something that also needs to be taken into consideration. Finally, ponatinib after this consideration may be an option, but obviously, it&rsquo;s important to produce or to recommend dose modification because 45 mg, the current dose approved by the label, may be extremely toxic in patient like him. So, lower doses of 30 mg, with even more decrease of the dose when the response is achieved, may be recommended to substantially decrease the potential toxicities, including the cardiovascular toxicity, that have been associated with this drug.

In my experience of treating a chronic phase CML with ponatinib, it&rsquo;s important to consider the dosing. Once again, the current approved dose to start a therapy is 45 mg. However, we know that this dose sometimes exposed patients to certain toxicities. They may ask to reduce the dose immediately. This is the reason that many of my colleagues, including myself, start at the dose of 30 mg to really see a better tolerance. We know that ponatinib, today, is the more potent tyrosine kinase inhibitor that we have available. We know that it&rsquo;s able to suppress any kinase or mutation present in the patient, and also produce a substantial response in patients who don&rsquo;t have a kinase main mutation responsible for the resistance. This is the reason why ponatinib should be considered for the treatment of patients who have resistant CML, who are really failing frontline or second-line second-generation tyrosine kinase inhibitors, and always taking into consideration dose reduction from the very beginning. The patient can achieve responses that can be seen very, very fast with this drug in order to decrease, significantly, the toxicities that these drugs may be associated with in the long run.

Rationale for TKI Therapy in Relapsed CML

In the PACE trial, patients with chronic phase CML were started on 45 mg, but upon encountering toxicities and by recommendation of the FDA, many of the patients, if not all, were reduced to 30 mg and 50 mg doses. Currently, with more than 5 years of follow-up, patients who were dose reduced are still enjoying very durable responses. Not only complete cytogenetic response, but also major molecular responses and even deeper responses. So, it&rsquo;s important to take this into consideration. In this case, the recommendation in my patient is 30 mg of ponatinib daily. As soon as the response is achieved, maybe at 3 months, maybe at 6 months, try to really go to a lower dose from 50 mg. That is a dose that can be easily tolerated, if it&rsquo;s already tolerated at 30 mg, but also is associated with less long-term cardiovascular toxicities and is also able to produce durable responses.

We have been discussing in this case that there are many options for second-line introduction of tyrosine kinase inhibitors. We&rsquo;ve discussed 4 drugs: nilotinib, dasatinib, bosutinib, and ponatinib. Of course, the third-line choice is going to depend on what is going to be the second-line choice. However, we know that in the case of ponatinib, the later we use a very powerful drug like this, the responses are going to be lower. So, I think it&rsquo;s important to take this fact into consideration. And although it is very standard these days to use a second-line TKI before the introduction of ponatinib, in certain patients, they may lower the efficacy of ponatinib in the long run. However, something that needs to be discussed between patients and doctors, as well as evaluated, always, is the potential risk benefit of the introduction of these powerful drugs associated with some toxicities.

The Therapeutic Approach for Relapsed CML

Diagnosis of Relapsed CML and Risk Status

Treatment Approach for Relapsed CML

Relapsed CML: Mutation Testing and Therapy Choices

Rationale for TKI Therapy in Relapsed CML

Dose Reduction and Third-Line Therapy for CML