Initial results from a phase II investigation demonstrated that, to date, patients with chronic-phase (CP) chronic myeloid leukemia (CML), who were resistant or intolerant to previous treatment with a tyrosine kinase inhibitor (TKI), achieved a 47% major cytogenetic response rate (MCyR) with the drug, ponatinib.

For patients with the difficult-to-treat T315I mutation — for which currently approved TKIs are largely ineffective &mdash; ponatinib was able to induce a 65% MCyR.

"Robust responses were observed in all patient cohorts, regardless of mutation status or disease stage,” stated study lead investigator, Jorge Cortes, MD, professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.

-generation TKI that was rationally designed to overcome the T315I mutation.

valuation (PACE) trial enrolled chronic patients with CML, regardless of disease phase, as well as patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL), and overall were represented by 1 of 2 categories: Patients resistant or intolerant to previous TKI therapy; and patients with the T315I mutation (N=449). The primary endpoints were MCyR for CP-CML, and major histologic response (MaHR) for accelerated-phase CML (AP-CML) or Ph+ALL. Secondary endpoints looked at safety and tolerability.

All subjects enrolled in the study had previous exposure to currently available, and other investigational TKIs: 16 patients (4%) had been treated with imatinib alone, 172 patients (39%) had been treated with imatinib plus nilotinib or dasatinib, and a majority of 237 patients (53%) had been treated with at least 3 prior TKIs. “Clearly, this is a heavily pretreated population,” said Cortes. Typical responses to prior treatments ranged from 33% for MaHR and 25% for MCyR.

After a median follow-up of 5 months, high levels of responses were observed in all patient types, even in the sickest patients. Participants with AP-CML achieved MaHR of 74%, and MCyR up to 53%; blast-phase-CML, and Ph+ALL patients both achieved MaHR of 37%, and MCyR of 34%, and 37% respectively.  Most notably, patients with the T351I mutation with CP-CML achieved a 33% major molecular response rate.

Few treatment-related adverse events were observed, the most common serious events being thrombocytopenia and neutropenia.

“Ponatinib has the potential to become a promising new treatment option for patients with multirefractory, relapsed CML,” concluded Cortes.

Pierre Laneuville, MD, FRCPC, associate professor at the Department of Medicine and Oncology at McGill University, and the former head of Hematology for the McGill University Health Center, Montreal, sees even greater potential for ponatinib. “If you look at the IRIS study for Gleevec, they had about 20% resistance at 8 years, half of those had mutations. Well, the ponatinib is effective in almost virtually all those mutations.” The argument going forward is that if ponatinib was used up front, 10% of eventual treatment failures with currently available agents could be eliminated outright. “So, that’s potentially quite interesting, and we’ll see if the company pursues that indication. I hope they will.”

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Articles

PACE trial results show patients with previously treated CML achieved a 47% major cytogenetic response rate (MCyR) with ponatinib.

Ponatinib Continues March to Potential Front-line Use in CML

An analysis of data from the Bone Marrow Transplant Survivor Study (BMTSS) suggests that long-term survivors of hematopoietic cell transplantation (HCT) have a much higher risk of chronic psychological, and physical health conditions than was previously assumed.

At 15 years post-transplant, the cumulative incidence of any chronic health condition in survivors was 71%, while the incidence of severe or life-threatening conditions or death was 40%.

“Although we have observed these rather sobering realities for 15-year post-transplant survival,” said study coauthor, Smita Bhatia, MD, MPH, chair of the department of Population Sciences, City of Hope, Duarte, CA, “we need to remember that transplant continues to be life saving, and possibly the only curative option for a large number of our patients with hematologic malignancies.” The focus of the present analysis is to determine the scope of the price paid for these successes.

Previously, Bhatia’s group had shown that patients who had HCT and who had survived 2 or more years were at increased risk of developing a wide range of chronic physical health and psychological conditions. However, as Bhatia noted, there was a lack of information regarding the burden of morbidity for survivors of much longer term.

Using resources offered by the BMTSS, Bhatia and colleagues looked at the psychological and physical health status of 366 patients with >10 years post-transplant survival, and compared these data with survivor siblings. Severity scores ranging from grade 1 (mild) to 5 (death due to chronic health condition) were assigned to each health condition. The Brief Symptom Inventory instrument was used to describe adverse psychological health.

Results for the study cohort showed that the mean age was 22 years at the time of HCT, and 37 years of age for study participation. The mean length of follow-up time was 15 years.

Regarding survivor health, at least one chronic health condition was reported by 74% survivors of HCT, as compared to 29% of the survivor’s siblings (

<0.001). Further, 25% of the survivors reported a severe life-threatening condition, compared to only 8% of their siblings (

Considered on the whole, the analysis showed that survivors had a greater than 5-fold likelihood of developing a severe, potentially life-threatening condition as compared to their age-matched siblings. Incidence of morbidity did not differ by malignancy type.

The most commonly reported severe/life-threatening chronic health conditions included stroke, myocardial infarction, diabetes, musculoskeletal problems, and subsequent malignancies. Survivors also reported a far higher incidence of anxiety and depression than their siblings.

Commenting on the study, HCT transplant specialist, Stephanie Lee, MD, MPH, professor of medicine, University of Washington School of Medicine, Seattle, WA, emphasized the need for greater awareness of the potential confounders of long-term survival. “We have a lot more HCT survivors now than we used to,” she said. “We’re thankful for that of course, but it’s important to realize that once the transplant is over, it’s not really over.” Lee stressed the need for awareness on the part of healthcare providers, their patients, and even third-party payors, of the reality that long-term, aggressive follow-up will be essential in cutting the rates of serious morbidities in patients with HCT.

Bone Marrow Transplant Survivor Study analysis suggests long-term survivors of HCT have high risk of chronic psychological, and physical health conditions

Burden of Morbidity Reported for Long-term Survivors of Hematopoietic Cell Transplantation 

The addition of fractionated doses of gemtuzumab ozogamicin (GO) to a standard chemotherapy regimen improved both event-free, and overall survival (OS) of newly diagnosed patients with acute myeloid leukemia (AML), aged 50 to 70 years, according to results from a Phase III trial reported at the 53rd Annual Meeting of the American Society of Hematology.

“With this research we are encouraged that gemtuzumab may be able to deliver better overall outcomes for these AML patients with limited alternatives,” said lead investigator, Sylvie Castaigne, MD, professor, Department of Hematology at Hôpital de Versailles,Versailles, France.

Gemtuzumab ozogamicin (GO), a humanized monoclonal antibody linked to a cytotoxic agent, is targeted to the CD33 cell surface antigen that is present on roughly 90% of blast cells in AML. When the drug was first developed it was seen as a promising agent in treating AML; however, studies performed after the drug’s approval in 2000 raised questions about excess toxicity. These concerns persisted, and in June of 2010, the manufacturer voluntarily withdrew GO from the US market.

“In its initial development, gemtuzumab was dosed 9 mg/m

,” said Castaigne, “but this dose was so toxic we were unable to combine it with standard chemotherapy.” This led Castaigne and her colleagues to develop a new fractionated regimen. “We give 3 mg/m

 on day 1, 4, and 7, which allows us to combine it with chemotherapy. Using it this way we were able to demonstrate more efficacy,” and with less toxicity than that observed with the 9-mg bolus dose. The approach was validated in 2 previous Phase II trials.  

In the current investigation, the research team at the Acute Leukemia French Association designed a Phase III, prospective, open-label, randomized trial, enrolling treatment naïve, 

 patients with AML, ages 50 to 70 years. Study participants were randomized to 1 of 2 treatment arms — either standard chemotherapy with daunorubicin/ara-C (DC: n=134) or DC plus GO (DCGO, n=137). Study endpoints were event-free survival (EFS), disease-free survival (DFS), OS, and safety over a 3-year follow-up period.

Response rates to treatment were as follows: overall, CR+CRp was achieved in 220/271 patients (77%): 100/134 (75%) in the DC arm (control) versus 110/137 (80%) in the DCGO arm (

=0.31). Significantly, primary resistant AML rate was 29/134 (22%) after DC versus 18/137 (13%) after DCGO (

=0.08). Regarding safety at induction, there were 5/134 (4%) induction deaths in the DC arm and 9/137 (6%) in the DCGO arm (

Adding gemtuzumab to chemotherapy improved event-free and OS of newly diagnosed patients with acute myeloid leukemia.

David Hawk

Articles

Ponatinib Continues March to Potential Front-line Use in CML

Burden of Morbidity Reported for Long-term Survivors of Hematopoietic Cell Transplantation

Minimal Dosing Strategy With Gemtuzumab Ozogamicin Improves Survival in Older Patients With Acute Myeloid Leukemia