Third-Generation TKI Most Promising Option for Ph+ ALL

Elias Jabbour, MD

Tyrosine-kinase inhibitors (TKIs) have considerably improved survival outcomes for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), said Elias Jabbour, MD, who discussed these advances during his presentation at the recent 2016 Chemotherapy Foundation Symposium.

“In the old days, the only way to cure these patients was to go through autologous stem cell transplantation (ASCT), and a lot of patients were not eligible,” said Jabbour, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “The big change came when we added TKIs to chemotherapy.”

Now, numerous TKI options are available for Ph+ ALL, including imatinib mesylate (Gleevec), dasatinib (Sprycel), and ponatinib (Iclusig). Jabbour reviewed the history of TKI use in Ph+ ALL and the emerging promise of first-line ponatinib in combination with chemotherapy. He also discussed the potential of blinatumomab (Blincyto), a bispecific T-cell engager, which he said could eliminate the need for ASCT.

It’s been a decade since imatinib and dasatinib were approved for relapsed Ph+ ALL. Both drugs have made a significant impact in the treatment of disease, but challenges still remain, said Jabbour. “When dasatinib became available, we tried that in combination with chemotherapy,” he said. “We saw responses of 90% and survival at 3 years of 60% to 70%. Unfortunately, with dasatinib, we did still see more relapses happening.”

Ponatinib, which is currently FDA-approved for Ph+ALL that is resistant or intolerant to prior TKI therapy, has significant promise, said Jabbour. “Ponatinib is a very potent TKI compared to all the previous TKIs,” he said. In a phase II, single-arm study, ponatinib, in combination with hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone), was investigated by researchers at MD Anderson in previously untreated Ph+ ALL.¹ Patients who had received fewer than 2 courses of previous chemotherapy with or without TKIs also were eligible. Jabbour was the lead author on the trial.

The study enrolled and treated 37 patients from Nov 1, 2011, to Sept 1, 2013. The 2-year event-free survival rate was 81% (95% 4, 64%—90%). Grade III and above toxicities included infections during induction (54%), increased aspartate aminotransferase and alanine aminotransferase concentration (38%), thrombotic events (8%) myocardial infarction (8%), hypertension (16%), skin rash (22%), and pancreatitis (16%). Two patients died from myocardial infarction potentially related to treatment; another patient died from myocardial infarction related to sepsis.

The dose was adjusted based on toxicities, said Jabbour. “Ponatinib was given at the beginning at 45 mg per day. This dose was problematic because of vascular events,” he said. “We decided to reduce the dose and give only 45 mg for the first course and then 30 mg for course number 2. Once the patient achieves a complete molecular remission (CMR), we drop to 15 mg per day.”

Following that trial, an additional randomized trial, in which Jabbour also was an author, was conducted comparing HCVAD and dasatinib with HCVAD and ponatinib for the front-line treatment of Ph+ ALL. The study analyzed data on 110 patients from 2 consecutive, prospective, phase II clinical trials. The patients in those trials were all diagnosed with Ph+ ALL and received either dasatinib (n = 63) or ponatinib (n = 47).²

A propensity score analysis was used to match 41 patients from the dasatinib cohort with similar patients from the ponatinib cohort. Based on this propensity score matching, the 3-year event-free survival (EFS) rates for patients treated with HCVAD plus ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P = .04), and the 3-year overall survial (OS) rates were 83% and 56%, respectively (P = .03). An inverse probability of treatment weighting (IPTW) analysis using prematching cohorts demonstrated that patients treated with HCVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response (CR), major molecular response at CR and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus ponatinib was associated with longer EFS (P = .003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib. “When we compared ponatinib to dasatinib, we showed that [ponatinib] is superior,” said Jabbour.

What’s Next

Additional research investigated whether ASCT, still a standard of care for patients with PH+ ALL, is necessary in the era of effective TKIs, such as ponatinib. “We did an assessment to see if patients can be cured without transplantation,” said Jabbour. “We decided to look at the impact of CMR at different time points and we found that if patients achieve a CMR with treatment they do well, but if they don’t achieve a CMR the outcome is worse and they require transplantation. Therefore, today in our treatment strategy, we treat to achieve CMR, because if that occurs patients have a good outcome, and ponatinib is the best TKI in that sense.”The next question to be tackled is whether chemotherapy could eventually be removed from the PH+ ALL treatment paradigm, said Jabbour. Blinatumomab offers a promising alternative option to chemotherapy, he said.

In a phase II study, blinatumomab monotherapy demonstrated a CR or CR with partial hematological recovery (CRh) rate of 36% in patients with relapsed/ refractory Ph+ ALL. Of those with a CR/CRh, 88% tested negative for minimal residual disease. A quarter of patients went on to receive subsequent stem cell transplant and the median OS was 7.1 months.³ These findings suggest that blinatumomab may be an effective combination with ponatinib, said Jabbour, athough further research is needed.

“It is possible that we may be able to eventually stop using chemotherapy,” he said. “Blinatumomab has shown that some patients respond very well. Therefore, our next step is to combine blinatumomab with ponatinib to improve CMR, minimize relapse concern, get rid of chemotherapy, and cure these patients. I think the outlook is very bright in PH+ ALL.”

References:

1. Jabbour E, Kantarjian H, Ravandi F. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015;16(15):1547-1555. doi/10.1016/ S1470-2045(15)00207-7.
2. Sasaki K, Jabbour E, Ravandi F. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome- positive acute lymphoblastic leukemia: A propensity score analysis. Cancer. Published July 2016. doi: 10.1002/cncr.30231
3. Martinelli G, Dombret H, Chevallier P, et al. Complete molecular and hematologic response in adult patients with relapsed/refractory (R/R) Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia (ALL) following treatment with blinatumomab: results from a phase 2 single-arm, multicenter study (ALCANTARA). Presented at: 57th American Society of Hematology Annual Meeting; December 5-8, 2015; Orlando, FL. Abstract 679.