Moving Beyond Transplant and Chemotherapy for Ph+ ALL

Advances have been accomplished in the management of adults with acute lymphoblastic leukemia (ALL) thanks to immune therapy and tyrosine kinase inhibitors (TKIs). Patients with Philadelphia chromosome-positive (Ph+) ALL have historically had very poor outcomes, with long-term survival dismal at around 10%. At one time, the only way to improve the outcome was transplantation. Then, around the year 2000, TKIs became available. When added to chemotherapy, they improved outcomes and led to more patients receiving transplants, with survival around 40% to 50%.

We started with imatinib in combination with low-dose chemotherapy or intensive chemotherapy and transplantation. Then we moved to dasatinib. One study compared dasatinib to imatinib in the pediatric setting and showed that dasatinib is better than imatinib therapy.

Still, the standard of care has been to continue to transplant in the vast majority of patients. But how can we get a better outcome? We know that when we give TKIs, chemotherapy, and transplant, the outcome depends on two things. Number one is deep molecular remission, or a complete molecular remission (CMR). Number two, with first- and second-generation TKIs, is that resistance is driven by acquisition of the T315I mutation. Therefore, to improve outcomes, we need to deepen responses with a higher rate of CMR, as well as suppress the emergence of T315I mutation.

A drug that can respond to these two concerns is ponatinib, which can induce deeper responses and suppress the emergence of T315I mutations. Therefore, we moved beyond the regular TKIs to use ponatinib in combination with chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine]).

In a phase II study, 86 patients were treated and followed for a median of five-plus years. The overall CMR rate was 84% and 75% at three months. Long-term survival was around 75%.

But, how can we do better? How can we alleviate the need for chemotherapy? How can we further improve outcomes? We moved from chemotherapy to immune therapy using an approach with blinatumomab, which is known to be effective in relapsed/refractory Ph+ ALL and in combination with TKIs.

We moved this combination into the frontline so we can spare patients from intensive chemo­therapy. We hope to further improve that outcome. In the D-ALBA trial, patients received low-dose steroid and dasatinib for three months; from month four and onward, blinatumomab was added for at least two cycles. With this combination, the CMR rate was up to 40%, and the overall deep molecular response rate was 60%. With long-term follow-up reported at the European Hematology Association Congress, at 40 months, three-year survival was around 77%. The proof here is that we can spare the need for chemotherapy and use the combination of blinatumomab and TKI. Of note, half of the patients received subsequent allogeneic hematopoietic stem cell transplantation.

Can we improve the outcome without the need for chemotherapy and transplantation?

We designed a phase II study where 35 patients received blinatumomab and ponatinib. Patients received concomitant ponatinib with five cycles of blinatumomab, and then maintenance with ponatinib only in addition to 12 intrathecal chemotherapy administrations. The ponatinib dose was 30 mg per day upfront, then reduced to 15 mg daily once CMR was obtained. Within four weeks, 65% achieved CMR. Within two cycles, 86% achieved CMR. Only one patient received transplantation. Within a median follow-up of one year, the two-year survival rate is 95%, which is a major breakthrough.

Compared with the D-ALBA trial, we administered blinatumomab concomitantly with ponatinib from the start of therapy with only one patient proceeding to transplantation. Of course, we have to wait for more mature data to confirm this standard of care.

What we learned from this study is that we can spare the need for chemotherapy. We can spare the need for transplant and move into chemotherapy-free regimens. Ponatinib is now being tested against imatinib in combination with chemotherapy, but the combination with blinatumomab is very encouraging.

In conclusion, we went from intensive chemotherapy and transplant to what we call chemotherapy-free regimens. That is revolutionary in ALL therapy, where survival has climbed from 10% to 95%.

Elias Jabbour, MD, is a Professor in the Department of Leukemia, Division of Cancer Medicine, at MD Anderson Cancer Center in Houston.