Pivotal phase II trial of ponatinib in patients with chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-Month Follow-up of the PACE trial

Researchers have discovered that ponatinib, a new oral tyrosine-kinase inhibitor (TKI), can silence a deadly mutation in chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukaemia (Ph+ALL).

CML and Ph+ALL are leukaemias caused by an abnormality known as the Philadelphia chromosome that produces the cancer-causing gene BCR-ABL.

This gene provides the DNA code to produce the BCR-ABL tyrosine-kinase, a protein found on the leukaemia cell surface critical to its development.

TKIs such as imatinib, dasatinib, and nilotinib, which bind to the protein and "turn off" its signal, have been revolutionary in the treatment of leukaemia and have quickly become standard first-line therapies for CML and Ph+ALL.

Despite this success, no targeted treatment option exists for approximately 5 to 20 percent of CML and Ph+ALL patients with the "gatekeeper" T3151 BCR-ABL mutation, which makes them resistant to available TKIs.

The only treatment alternative is a haematopoietic stem cell transplant which has toxic side effects. Ponatinib, the first targeted therapy that has emerged for these hard-to-treat patients, has demonstrated excellent activity against the T3151 mutation in early clinical trials.

High levels of response have also been observed in patients with other mutations or with no mutations who have experienced resistance or intolerance to two or all three available TKIs.

Given these promising results, researchers conducted a pivotal Phase II trial assessing the drug.

A team of researchers from the United States and Europe enrolled 449 patients with CML and Ph+ALL who were either resistant or intolerant (R/I) to dasatinib or nilotinib or had the T3151 mutation.

Patients were assigned into six cohorts based on their disease resistance or genetic profile and then treated with ponatinib. Nearly all of the patients were previously treated with two of the available TKIs (imatinib, dasatinib, and/or nilotinib) or with all three TKIs.

The primary endpoint of the study was major cytogenetic response (>65% of cells are normal) within 12 months of treatment for those with chronic phase CML and major hematologic response (normal white blood cell counts) within six months after treatment for those with advanced-phase CML or Ph+ALL.

Major cytogenetic response was observed in 55 percent of all chronic-phase CML patients (50% of R/I patients and 70% with T3151 mutation), and major hematologic response was observed in 58 percent of patients with accelerated-phase CML (57% of R/I patients and 50% with T3151 mutation) and 34 percent of those with blast-phase CML/ Ph+ALL (35% of R/I patients and 33% with T3151 mutation).

The similar response rates observed in patients with and without the T3151 mutation build on previous evidence and imply that ponatinib is a TKI that may work across a wide range of mutations associated with TKI resistance and also in instances where mutations are not detected.

Remarkably, complete cytogenetic response (no Ph+ cells measured in the body) was achieved in 46 percent of patients with chronic phase CML, with higher response rates observed in patients who were exposed to fewer prior TKIs and those with shorter disease duration.

The therapy was also well tolerated in all cohorts, as evidenced by the minimal toxicities observed. The most common adverse events observed were skin toxicity (including rash or dry skin), elevation of pancreatic enzymes and/or pancreatitis, and myelosuppression (a side effect of cancer treatment that lowers blood cell count).

At the time of analysis, 52 percent of patients remained on the therapy. These results demonstrate ponatinib’s efficacy in CML and Ph+ALL patients with no other viable treatment options.

“This therapy may be able to transform highly fatal forms of leukaemia into a curable disease in these patients – we have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients,” said Jorge Cortes, MD, lead author, Professor of Medicine, Deputy Chair of the Department of Leukemia, and Chief of the CML and AML Sections at The University of Texas MD Anderson Cancer Center in Houston. “Our next step is to test ponatinib’s potential as an initial therapy in an attempt to prevent the occurrence of relapse that may decrease the prospects of a normal lifespan for patients.”