1. Fuerst, Mark L.

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NEW YORK-Treatment-free remission (TFR) by stopping tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) patients in deep molecular remission (DMR) is ready for prime time, according to an expert who spoke at the 2018 Great Debates & Updates in Hematologic Malignancies.


CML is an increasingly prevalent and survivable cancer, with an incidence of 4,700 patients per year. About 200,000 U.S. patients are now living with CML and projections suggest a 10-times greater steady state number of CML patients in the U.S. by 2050, said Michael Mauro, MD, Leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York.


TKIs became available for CML in 2001, and imatinib, the first-generation TKI, became the poster child for targeted therapy in cancer. Now, five TKIs have been approved with various indications, as well as generic imatinib.


Treatment-Free Remission

Recent treatment guidelines reflect the concept of TFR. The FDA label for the second-generation TKI nilotinib was changed Dec. 22, 2017, to include TFR, with the FDA stating that certain patients with CML may be eligible to stop treatment after sustained response. The National Comprehensive Cancer Network (NCCN) guidelines on TFR recently removed the requirement for no history of resistance to any TKI. The guidelines suggest monitoring CML patients for 12 months, then every 6 weeks for 2 years. NCCN guidelines still recommend bone marrow testing at diagnosis to rule out accelerated phase features relevant to possible TFR, noted Mauro.


"Risk stratification is important and is emerging as a better predictor of overall outcome and dying from CML. Baseline risk is an independent predictor of TFR outcome in several studies. We want precise diagnosis and baseline measurements," said Mauro. He added that with more CML treatment options now patients should be fully informed, including a careful discussion about choice of therapy and the potential for stopping.


Molecular response within the first 18-24 months of therapy is a recognized milestone of response. Those who achieve this response are potential candidates for TFR, he said. Monitoring for response to CML therapy needs improvement. About one in every five patients are not tested for molecular response at 12 months and almost half are not tested for cytogenetic response (CyR), said Mauro. "Guidelines shepherd patients into major molecular response (MMR), but not DMR. We need to maintain patients to have data for TFR," he noted.


Advancing Research

TFR trials have evolved, most requiring treatment duration of TKIs for at least 3 or more years. The eight TFR trials reported in the literature include varying duration and follow-up. The TFR response rate ranges from 45 percent to 65 percent. All the trial data look similar, with similar kinetic relapses and success rates, he stated.


The landmark STIM trial examined long-term follow-up and molecular response. After a median follow-up of 63 months, none of the patients who achieved an MMR had a progressive event. Nearly 100 percent of the patients relapsed (57 of 61 patients), but there were no late relapses. Some 55 of the 57 patients restarted TKI therapy and achieved complete molecular response at a median of 4.2 months. Some patients are off therapy for 10 or more years, said Mauro.


A multivariable analysis found no association with age at diagnosis, prior interferon use, or imatinib duration. "If patients lose response, they can regain it and get back into DMR," he explained.


The duration of DMR has the most impact on the success of cessation of TKIs treatment in CML, according to the EURO-SKI trial. This trial had much less duration TKI needed to enter-only 3 years with 1 year of deep remission. Early relapses were seen, with MMR lost at 6 months. This TFR trial has the longest follow-up, with patients in deep remission at 3 years, he said.


"The right patient for TFR is one who has been on TKI therapy for 5.5 years with deep remission for 3 or more years. Total TKI duration does not make a difference. It's more how long the patient is in deep remission," said Mauro.


The ENESTfreedom trial assessed the potential of TFR following frontline nilotinib in chronic phase CML patients. A total of 190 patients with sustained DMR during the 1-year nilotinib consolidation phase were eligible to stop treatment and entered the TFR phase. The duration of nilotinib prior to TFR was an average 43 months.


At 48 weeks after stopping nilotinib, 98 patients remained in MMR or better. Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8 percent and 88.4 percent, respectively, regained MMR and DMR.


"It may be that patients taking second-generation TKIs might not need as much therapy. The quality of remission may be better," said Mauro, noting this is still in question.


A similar study found patients who took another second-generation TKI, dasatinib, and achieved DMR had high rates of success at maintaining remission after treatment was discontinued. The patients had been on dasatinib for more than 2 years and in DMR for at least 1 year. Molecular response was rescued in all patients once dasatinib was re-initiated. "It's likely 100 percent of patients will regain remission, which is reassuring," he said.


Withdrawal syndrome was seen in eight patients, but was short-lived. This can be treated easily and is not severe, he noted. With imatinib about one-quarter of patients develop TKI withdrawal, primarily musculoskeletal complaints.


There is still an unmet need for a second TFR trial. "About half of TFR attempts fail. It's unclear as to next steps. We need low-risk, low-toxicity options," said Mauro. A CML consortium is now planning to focus on second TFR from the clinical and biologic fronts.


Among the candidates for future CML therapies include a combination of a TKI and the JAK inhibitor ruxolitinib, imatinib plus the allosteric inhibitor ABL001, and a TKI with the vitamin D receptor agonist inecalcitol.


TKI therapy in CML has undergone a paradigm shift to a new era. "Imatinib was the first oral targeted cancer therapy. There was no induction or maintenance, just continuous therapy. TFR is now part of functional care. It's possible to have an increase in minimal residual disease (MRD). We may induce a cure in the face of molecular evidence of disease. Treatment cessation may be sanctioned in the face of MRD-positivity," Mauro concluded.


Mark L. Fuerst is a contributing writer.