1. Fuerst, Mark L.

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NEW YORK-New therapeutic options for chronic myelogenous leukemia (CML) patients who fail to respond to all available tyrosine kinase inhibitors (TKIs) are now under investigation.


"At present, we have five oral, small molecular kinase inhibitors approved in the U.S. for Philadelphia chromosome-positive CML. This is a spoil of riches, with more drugs on the way," said Michael J. Mauro, MD, Leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York, at the 2018 Great Debates & Updates in Hematologic Malignancies meeting.


Mauro outlined what approaches clinicians should take for the failing CML patient. Polymerase chain reaction (PCR) at diagnosis is very important. "It's like a timing chip when you run a race-where did you start? Early response at 3 months should be on track, 10 times lower than at the start. Complete cytogenetic response (CyR) is very important and protective. Major molecular response (MMR) adds further protection. Deep molecular response aims for 10,000 times lower response than at the start."


The goal is to get CML patients into deep remission. "Patients will miss every milestone if they don't make molecular response. CyR is like the cake, and MMR is the icing on the cake. If they don't achieve MMR, they don't retain CyR," he said. Based on intuition, PCR must become negative to cure disease.


Aside from being a launching point for treatment-free remission trials, complete molecular response does not add value for CML patients. "We look more for 4-log reduction in BCR-ABL transcripts," he noted.


Emerging toxicity is an important concern. "Imatinib is a very clean drug and has the best toxicity profile. Nilotinib has vascular events, dasatinib [includes] pulmonary arterial hypertension, bosutinib [has] mild renal effects, and ponatinib [has] vascular events. Vascular events require attention," said Mauro.


Post-imatinib second-generation TKIs offer similar benefits, each with a slight difference in progression-free survival, ranging from 64 percent with nilotinib to 80 percent with dasatinib. Two-year overall survival is about 90 percent for all second-generation TKIs.


If a patient fails a second-line TKI, the option is to switch to an alternate second-generation TKI or switch to the third-generation drug ponatinib. "We usually achieve a higher rate of CyR with ponatinib. Recycling second-generation TKIs is less successful," he stated. Omacetaxine remains an option in patients with complex disease who need to be stabilized.


Point mutations account for the vast majority of resistance to TKIs. More than 100 mutations have been described in imatinib and subsequent generation TKI-treated patients. Only a handful of mutations account for the vast majority (about 85%) of clinically observed mutations. Single and compound mutations are found in the same subset of 12 key positions, said Mauro.


Both the European LeukemiaNet and National Comprehensive Cancer Network recommend ABL kinase domain mutational analysis. "At diagnosis in chronic phase is not a good time to do mutational analysis. Wait until you see smaller disease volume. A good time to look for mutations is when a patient loses response or does not achieve MMR," he explained.


The likelihood of mutation testing will influence TKI choice. "Multiple mutations often hide complex mixtures of single and compound mutants. It's hard to differentiate polyclonal mutations from two different clones from compound mutations because there is more than one mutation from the same clone," Mauro noted.


Managing CML is more of a marathon than a sprint, and patient adherence is of utmost importance. A study of pharmacy record analysis of 4,043 patients prescribed imatinib found patient adherence was estimated at 75 percent; only 41 percent of patients had more than 90 percent adherence.


"If patients look to gain MMR, they need to take 90 percent of the drug," he said. "Adherence and the achievement of MMR are the only independent predictors for outcome. Poor adherent patients have a higher probability of losing complete CyR and achieving a lower event-free survival."


He presented a practical approach to a patient with resistance or intolerance to TKI. "First, determine the disease phase, prior TKI exposure, and mutational status. Select mutations may support the role of specific second-generation TKIs. More detailed assays are not routinely incorporated, such as deep sequencing," said Mauro.


Next, balance therapy risk and toxicity potential with known comorbidities. Are there true contraindications? Does risk outweigh benefit expected from therapy? Can the risk be mitigated or anticipated? he asked.


Novel New Agents

Several new agents show promise in CML. The fourth-generation TKI ABL001, which allosterically inhibits BCR-ABL kinase activity, is the most advanced. It was developed to gain greater BCR-ABL inhibition, with activity against BCR-ABL mutations conferring resistance to TKIs. This small molecule inhibitor has the potential to combine with TKIs for greater pharmacological control of BCR-ABLs since it binds at a different ABL kinase.


Initial studies show responses in CML patients treated with single-agent twice daily ABL001 with 3 or more months of exposure. A planned phase III, multicenter, open-label randomized study will compare ABL001 with bosutinib in 222 CML patients previously treated with two or more TKIs.


PF-114 is a novel third-generation inhibitor of BCR-ABL developed in the Soviet Union that is a close structural analog of ponatinib. It was rationally designed to avoid inhibition of numerous off-target kinases and potentially avoid life-threatening side effects. In a 24-patient study, the pharmacokinetics was good and there was a low level of myelosuppression and limited biochemical adverse events and cardiovascular toxicity. Chronic phase patients achieved an 80 percent response rate. A phase II, multicenter international study is planned.


K0706 is another novel BCR-ABL TKI. It is designed for patients who are refractory or intolerant to TKIs and not suitable for ponatinib. Studies show evidence of hematologic response and CyR at 3-6 months.


Stem cell transplant is still an option in advanced phase CML. However, in chronic-phase and accelerated-phase CML, there is no early gain in overall survival with stem cell transplant versus ponatinib therapy, Mauro noted. "CML is highly treatable and functional cure appears feasible. New options and new drugs are on the horizon."


Mark L. Fuerst is a contributing writer.