Stuart L. Goldberg, MD

Question

Do any patient or disease factors affect whether you assign newly diagnosed patients with chronic myeloid leukemia (CML) to receive a particular tyrosine kinase inhibitor (TKI)? Do high-risk cytogenetics affect your treatment decision?

Answer

CML treatment represents a true success story, with most patients diagnosed today expected to live normal lifespans. There are currently 4 approved first line TKIs, each yielding complete cytogenetic remission rates by the end of the first year exceeding 70% and 5-year survival rates exceeding 90%.

When choosing a first-line TKI it is important to consider CML disease factors. The Sokal scoring system (which includes age, spleen size, platelet count, and peripheral blast percentage) is predictive for response to TKI therapy.¹ Randomized clinical trials demonstrated that, among patients with intermediate- or high- risk Sokal scores, the second-generation TKIs (bosutinib, dasatinib, nilotinib) all result in higher rates of molecular remission rates and, more importantly, lower rates of clinical disease progression than those seen with imatinib.^2-4

These findings have led the National Comprehensive Cancer Network (NCCN) guidelines to prefer second-generation agents in these higher-risk disease categories. Variant and additional cytogenetic abnormalities also have a negative impact on outcomes and may warrant consideration of second-generation agents.⁵ In lower-risk disease, imatinib remains a reasonable first-line option.

Since patients will be treated with TKIs for many years, it is also critical to consider patient factors to maximize adherence and tolerability. Although all of the TKIs have generally favorable toxicity profiles, there are important differences, which may guide treatment selection.

Given the potential for pulmonary toxicity with dasatinib, this agent may not be preferred in patients with a history of lung diseases. Nilotinib, with its potential for QTc prolongation, metabolic effects and need for fasting, and pancreatitis, may not be an optimal choice for individuals with arrhythmias, diabetes, or history of alcohol diseases. Bosutinib, with its higher rate of diarrhea and liver-associated enzyme elevations, may not be an optimal choice for patients with inflammatory bowel or liver diseases. Imatinib, with increased risks of fluid retention and periorbital edema, may not be favored in patients with heart failure or patients for whom appearance is important.

To maximize adherence, the predictability of the patient’s schedule, whether fasting or twice daily dosing can be accomplished easily, may also weigh into decision-making.

Question

Is cost typically a major issue for patients you encounter? How do you advise patients about managing the long-term costs of TKI therapy?

Answer

Financial toxicity may be an important consideration in the management of CML. A survey by the Cancer Support Community and the Leukemia and Lymphoma Society found that nearly half of patients with CML spend at least $100 monthly, a quarter spend more than $250, and 15% spend more than $500.⁶

Although generic imatinib has entered the market and resulted in price cuts, out-of-pocket expenses still can be formidable, especially for patients on Medicare who may not qualify for pharmaceutical company support. In my practice every patient with CML meets with our social support team to discuss the costs of their medications. This may be particularly important for patients with “good insurance,” who may not realize that they qualify for industry sponsored programs.

I also revisit the issue of out-of-pocket expenses when patients achieve deep molecular responses — as a possible reason to consider TKI discontinuation or to consider switching to lower-cost generic imatinib for long-term maintenance.

Question

If patients develop resistance or intolerance to multiple TKIs, what other treatment strategies do you use?

Answer

The availability of multiple TKI agents as salvage strategies makes it incumbent on physicians to monitor patients with CML appropriately. The NCCN guidelines recommend quarterly polymerase chain reaction (PCR) testing for the first year and for at least 2 years after a molecular response has been achieved; thereafter monitoring may be less frequent. Patients who fail to meet the time-based milestones, or show evidence of a rising PCR, need to be assessed and considered for alternative treatments.

Poor adherence to TKI therapy is the major cause of failure to meet response milestones or loss of cytogenetic response.⁷ A potential tip-off of lack of adherence is a rapid rise in PCR values, as resistance frequently results in a more protracted pattern. Before launching into expensive molecular evaluations or changing TKIs, it is imperative to have frank discussions with patients who are not achieving optimal responses.

Once adherence is confirmed, a search for a potential cause of resistance then becomes appropriate. Changes in absorption or drug interactions may interfere with TKI effectiveness. Examples include antacid use or gastric bypass surgery. ABL-kinase domain mutations, however, are the most common cause of resistance. Since many commercial labs hold specimens, in my practice if a patient has a rising PCR value (or fails to meet a time-based milestone), I contact the laboratory and add-on the ABL-mutation study from the original sample, shortening the evaluation period.

If the patient’s sample is not available, it is important not to stop the “ineffective” TKI before obtaining the ABL-mutation study, to prevent overgrowth of wild-type BCR-ABL transcripts, which might obscure results. If a mutation is detected, the choice of TKI can be rationally determined. The NCCN guidelines list preferred TKI agents for the major ABL mutations.

Intolerance may also necessitate treatment change. As with the initial selection, a full reassessment of patient comorbidities and preferences may be helpful in choosing the next agent to avoid similar intolerances. Although TKIs may share toxicities profiles, most reactions are non-cross intolerant — for example rashes are common with all, but any given patient may have this toxicity with one agent but not the others.⁸

The most difficult intolerances are severe cytopenias, as these may be cross-tolerant (a single patient having difficulty with multiple TKIs). In my practice for cytopenias I have used dose reduction, (off-label) eltrombopag, and, rarely, allogeneic transplantation.⁹

Question

What do you advise pregnant women or males/females of reproductive potential before initiating TKI therapy? Can pregnancy be successful while taking TKIs?

Answer

Although TKIs do not appear to affect male fertility or pregnancy outcomes, I advise my male patients to, if possible, delay attempting conception until achieving at least a molecular remission and then to temporarily discontinue therapy for a month, resuming TKIs after at most 3 months.

Pregnancy issues in female CML patients are more difficult, as the TKIs are associated with increased risks of spontaneous abortions and congenital abnormalities. For women desiring to become pregnant, it is important to achieve as deep a molecular response as possible (major molecular response, preferably) before conception.¹⁰ If an unplanned pregnancy occurs, and the TKI is stopped immediately, the majority of pregnancies have been successful and thus discontinuation of pregnancy is not mandatory.

The goal of CML treatment is to prevent clinical disease progression (to accelerated or blast phase), so I observe patients off treatment until loss of hematologic response. At that point interferon at 3 to 6 million units several times per week can be added. Pegylated interferon should be avoided. In the third trimester, hydroxyurea can be added. Low-dose aspirin or heparin may be required for extreme thrombocytosis.¹¹

Question

What molecular markers determine whether you allow patients to discontinue treatment? How long, for example, do patients need to show major molecular response before discontinuation is feasible? How and how often do you monitor patients thereafter?

Answer

With tyrosine kinase therapy, many patients are able to achieve deep molecular remissions. The natural extension is to ask if patients can be safely discontinued from therapy and maintained in a state of “treatment free remission (TFR).”¹²

Clinical trials involving over 2000 patients have demonstrated that between 40% and 60% of appropriately selected patients may discontinue TKIs permanently. The NCCN guidelines (and a recent FDA [US Food and Drug Administration] indication) have endorsed this option. To be eligible for treatment-free remission (TFR), patients must achieve a molecular response of at least a 4-log reduction (PCR 0.01% IS) and maintain this suppression for a minimum of 2 years. Higher success with TFR has been noted among patients with remissions of 5 years. A history of accelerated or blast phase is, however, considered a contraindication to TFR attempts.

The most important feature in attempting TFR is close molecular monitoring. In my practice I perform PCR testing monthly during the first year, bimonthly during year 2, and quarterly thereafter. A loss of major molecular response triggers reinstitution of TKI therapy. The vast majority of failures occur within the first 6 months of TFR, with rare relapses after 1 year. Patients may experience a withdrawal syndrome consisting musculoskeletal pain and/or pruritus, which typically resolves by 3 months.¹³