As a leukemia expert, I’m fortunate to live in a time when we’re making major progress. We can say with good confidence that the cure for acute lymphoblastic leukemia (ALL) will eventually happen in our lifetime. It’s an exciting time because we have the tools to accomplish this goal, and we have ongoing trials that are already leading to very promising results.
One example is the treatment of Philadelphia chromosome (Ph)-positive ALL. Historically, Ph-positive ALL was a disease with a poor prognosis. Long-term survival rates were only 10%, and only those patients who were lucky enough to get a transplant had a long-term survival rate of 30%. Then, in the early 2000s we saw the approval of imatinib, the first tyrosine kinase inhibitor (TKI). TKI approval was revolutionary in the treatment of Ph-positive ALL and chronic myeloid leukemia (CML). When combined with chemotherapy, TKIs showed even better patient outcomes, and patients were able to undergo transplant in better shape when TKIs were administered early on.
As maintenance, post-transplant TKIs have proven to be extremely effective as well. Still, survival in the long run was limited to 50% with imatinib and second-generation TKIs.
There are several reasons why that is the case. First, we know the outcome is dependent on achieving a complete molecular remission (CMR). Second, we know resistance was driven by the emergence of certain mutations, among them T315I, that can drive resistance to the first- and second-generation TKIs. Third, despite the progress in transplantation, the treatment-related mortality remains non-negligible.
Therefore, in 2010 we hypothesized that if we can improve the CMR rate and suppress the emergence of the kinase domain T315I mutations, we can improve the outcome of this disease.
Ponatinib is a BCR-ABL inhibitor that was shown to be extremely effective in CML, more potent than other TKIs, and it can suppress the emergence of the T315I mutation. We designed a new regimen combining the hyper-CVAD chemotherapy backbone with ponatinib. With this combination, we’ve shown that we can improve both the three-month CMR rate and the six-year overall survival rate to 75%. We’ve also shown that patients who did not receive a transplant performed better than those who did. For the first time, we’re questioning the role of transplant in this disease.
We then asked if we could identify the patients who may or may not need transplant. Since the three-month molecular response is an important milestone for transplant, we performed a landmark analysis at a different time point. The analysis showed that CMR at three months predicts for the best outcome regardless of the TKI a patient receives. However, even if a patient reaches CMR, approximately 25% of patients can relapse or progress.
The next step was to ask which patients are achieving CMR and not relapsing. In other words, can we triage patients by those who should go for transplant and those who should not? It turned out that patients who did receive ponatinib were able to achieve CMR and did not relapse.
Then, we aimed to reduce and eliminate the need for chemotherapy. Blinatumomab, a bispecific T-cell engager, has shown activity in relapsed or refractory disease. If it works and is better than chemotherapy, then why still go for chemotherapy? So, we designed a chemotherapy-free treatment, a combination of ponatinib and blinatumomab. We gave 12 doses of intrathecal chemotherapy to prevent any central nervous system disease.
By doing so, we’ve shown that most patients do respond well. In fact, the time to response is quite fast: patients achieved CMR within four weeks. The four-week CMR rate was 67%, and it was 88% at three months. We treated 60 patients, and our strategy involved no chemotherapy at all. Instead, we treated patients with immunotherapy and TKIs. The three-year survival rate is 95%. These are the best results ever obtained.
At the same time, ponatinib was compared with other TKIs in a randomized trial and has shown an improvement in outcomes and better responses when compared with imatinib. Ponatinib is a legitimate frontline therapy.
The combination of blinatumomab and ponatinib is a true chemotherapy-free regimen. What are the implications of such a regimen? Not only improving survival in our patients, but we know that intensive chemotherapy and transplant are problematic for a lot of them. Due to the complexity of our health care system and the complexity of ALL therapy, a lot of patients do not receive optimal care and therefore cannot sustain long-term therapy.
By offering a highly targeted finite therapy—five to six months with a three-year survival of 95%—we can have a major impact on our society. Patients can be cured and resume their normal life without any long-term toxicities.
In summary, we went from survival of 10% to 90% and from full-fledged chemotherapy and transplant to a chemotherapy-free, highly targeted regimen. This approach can serve as a model for how personalized therapy can improve the cure rate and the survival of our patients. We’re very fortunate to have such therapy, and I hope that it will be confirmed and become the standard of care around the world.
Elias Jabbour, MD, is a Professor in the Department of Leukemia at the MD Anderson Cancer Center.