The U.S. Food and Drug Administration (FDA) has eased the selection of drugs for the treatment of chronic granulocytic leukemia (CML) and a class of acute lymphoblastic leukemia with a Ph chromosome (Ph+ ALL). The current drug approval was granted for ponatinib (trade name Iclusig), a multikinase inhibitor that has been shown to be effective in a large number of patients with both of these diseases.
In clinical treatment, patients with both leukemias can have a strong response to imatinib (Gleevec) and the second-generation drugs nilotinib (Tegretolide) and dasatinib (Beryl). This class of drugs works by inhibiting a protein-complex kinase on leukemia cells, specifically the abnormal BCR-ABL protein that causes the disease.
However, 30-40% of patients with CML are resistant to imatinib. And only 40-50% of these patients are treated effectively with nilotinib and dasatinib.
“The effectiveness of ponatinib will substantially improve treatment outcomes for the majority of patients with CML and Ph+ ALL who are resistant to previous complexine kinase inhibitor therapy.” So says Professor Jorge Cortes, M.D., of the Leukemia Research Unit at The University of Texas Medical Branch Anderson Cancer Center.
Cortes added, “We can observe a clinical response in patients regardless of their mutation status or stage of disease. This is a new and valuable treatment option for leukemia patients.”
A new drug that fills a therapeutic gap
Punatinib is the third drug approved by the FDA in the past four months for the treatment of CML and Ph+ ALL, giving oncologists a wide range of options when treating this patient population.
Clinical trials for all three approved drugs are being spearheaded by Cortes. The other two drugs are bersutinib (bersulide) and omadecitabine (Neorubicin). Clinical trials for the three previously approved CML therapies were also led by Cortes and other Leukemia Research staff.” Having as many treatments as possible to treat the tumor is very important to us because it is extremely rare that a single drug or combination therapy works for all patients. ” Cortes said.
“These new drugs fill different gaps in treatment, so they can serve our patients in different ways,” Cortes said. “We want to provide effective treatment options for all of them,” Cortes said. “
Punectinib (Iclusig)
Developed by ARIAD Pharmaceuticals, ponatinib is designed to combat refractory mutations. The most prominent of these is the T35I mutation, which can be expressed in up to 20 percent of patients, thus preventing other complexine kinase inhibitors from binding to the binding site of the mutant protein.
Cortes presented a pivotal Phase II clinical trial at the 54th Annual Meeting and Convention of the American Society of Hematology in Atlanta, GA, in early December of this year. The trial showed that ponatinib produced a response in early-stage CML as well as accelerated and acute CML – the most severely mutated and difficult-to-treat advanced CML.
At an interim follow-up of 15 months for patients with early-stage CML, 149 of 267 (56%) had a predominantly cytogenetic response (cells with Ph chromosomes ≤35%), with 46% of those followed showing a complete cytogenetic response (no cells with Ph chromosomes in the bone marrow).
Of the 64 patients with chronic-phase CML with T315I mutations, 45 (70%) exhibited a predominantly cytogenetic response, of which 66% achieved a complete cytogenetic response. The proportion of patients with CML in the accelerated and acute phases with a predominantly hematologic response (majority of CML cells in the blood were reduced) was 57% and 34%, respectively.
Bersutinib (Bersulide)
Bersutinib, which received FDA approval in September, is a second-generation complexine kinase inhibitor that counteracts many of the BCR-ABL mutations that cause resistance. There is an exception, however, and that is the T315I mutation, and only ponatinib is effective in treating this mutation.
“The effect of bersutinib is comparable to that of dasatinib and nilotinib,” Cortes said. “The clear difference between bersutinib and the other two drugs is that it acts only on BCR-ABL and SRC, inhibiting their expression with better activity specificity, which makes it less likely to have serious drug side effects.”
For example, bersutinib does not cause cardiotoxicity or pancreatitis that can be caused by other complexine kinase inhibitors.” When we are trying to choose an appropriate drug for a patient, bersutinib is a good choice. For those patients with other complications or concomitant conditions, it may be their best option,” Cortes said.
Known by the trade name bersutinib, it was introduced to the market by Pfizer Inc.
Omasitaxin (Synephrine)
Omasitaxin’s mechanism of action is completely different from that of the other five complex kinases (inhibitors). It works by blocking the synthesis of abnormal BCR-ABL protein, rather than inhibiting BCR-ABL protein activity.
“This is an important therapeutic option for patients who have failed with other complex kinase inhibitors and for those who cannot tolerate other complex kinase inhibitors,” Cortes said. “A small number of such patients need to get a good outcome by seeking new treatments.”
Omasetasine is a synthetic version of a clinically used drug (hypertrigonelline) that has been used for years to treat CML, and it originated as an evergreen found in China. Although it does not inhibit the activity of abnormal proteins like ponatinib and other drugs, Omasitaxin inhibits the expression of BCR-ABL protein and acts against drug-resistant CML – including T315I mutant CML.
Its trade name is Neoreb, and the drug is marketed by Teva Pharmaceuticals, Israel. Clinical trials combining omadacytasine and a complexine kinase inhibitor are planned.
Next: Personalized treatment to eradicate CML
Prior to the FDA approval of Gleevec (imatinib), the 5-year survival rate for CML patients was only about 50 percent. Now, with these three previously approved drugs, the 5-year survival rate for CML patients has reached 90%. Of these, Gleevec (imatinib) and Tegretol (nilotinib) were brought to market by Novartis Pharmaceuticals of Switzerland, and Beryl was put on the market by Bristol-Myers Squibb of Germany.
That said, we still face a number of significant challenges, Cortes cautioned. “We need to identify which patients each drug is indicated for. For example, which types of patients are treated well with imatinib, and which patients need the new drug as a starting agent?” He said, “Currently, our choice of therapeutic drug for each patient starts with imatinib, dasatinib or nilotinib.”
In addition, although current therapeutic agents have reduced CML to extremely low or even non-detectable levels, most patients must still adhere to their medications to prevent relapse. “We want to be informed of an exact and certain time when a patient reaches that level where the disease will not relapse and thus stop treatment.”
“To be able to achieve this goal, we must develop a reliable tool to help us determine the clinical treatment endpoint at which the disease is completely eradicated and the majority of patients are cured with effective treatment,” Cortes said. “There is still much work to be done in these two areas of current research.”