Ponatinib/Blinatumomab Displays Efficacy as a Chemo-Free, HSCT-Sparing Option in Ph+ ALL

Fadi G. Haddad, MD

The combination of ponatinib (Iclusig®; Takeda) and blinatumomab (Blincyto®; Amgen) induces deep responses and durable remissions in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

Both agents are highly effective in Ph+ ALL. When used together, Fadi G. Haddad, MD, notes that this strategy helps mitigate the need for intensive chemotherapy and allogeneic stem cell transplantation in first remission for these patients. Haddad, a leukemia fellow at The University of Texas MD Anderson Cancer Center, will present updated results from a phase 2 study (oral abstract ALL-424) at 10:31 am on September 28, 2022, during the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).¹

In a phase 2 study, adult patients with newly diagnosed Ph+ ALL (n = 40), relapsed/refractory Ph+ ALL (n = 14), or chronic myeloid leukemia in lymphoid blast phase (n = 6) were treated with the combination of ponatinib and blinatumomab.

Patients were required to have an ECOGperformance status of 0 to 2, total bilirubin ≤ 2x the upper limit of normal (ULN), and alanine aminotransferase and aspartate aminotransferase ≤ 3x the ULN. Those enrolled were given up to 5 cycles of blinatumomab as a continuous infusion at standard doses with ponatinib given at 30 mg daily during cycle 1. Once complete molecular response (CMR) was achieved, the primary end point of the trial, ponatinib was decreased to 15 mg daily. Following the completion of blinatumomab, ponatinib was continued for at least 5 years in the patients who responded. Additionally, 12 doses of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate were administered.

According to Haddad, this chemotherapy-free combination of ponatinib and blinatumomab was shown to be safe and effective in patients with newly diagnosed Ph+ ALL, relapsed/refractory Ph+ ALL, and chronic myeloid leukemia in lymphoid blast phase. Data from this updated analysis shows that this combination has potential as an effective transplant-sparing regimen.

In an interview with The SOHO Daily News before the conference,Haddad discussed the updated results from the combination of blinatumomab and ponatinib in patients with Ph+ ALL presented at SOHO 2022.

The SOHO Daily News: Can you explain the purpose of this trial?

Haddad: Why we are presenting this study and why we believe this is important is because historically, the outcome of patients with Ph+ ALL has been poor with long-term survival around 10% to 15%. Throughout the years, the addition of tyrosine kinase inhibitors [TKIs] to chemotherapy significantly improved the survival of patients to up to 74% at 5 years with the combination of ponatinib and hyper-CVAD chemotherapy [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone].

Based on the clinical activity of single agent blinatumomab in relapsed/refractory ALL, and the efficacy of ponatinib in inducing high rates of CMR and suppressing the emergence of the resistant T315I mutation, we designed this chemotherapy-free regimen that might offer patients higher chances of survival.

What does the design of the study entail?

During the induction phase, blinatumomab is administered for a total of 4 weeks followed by 2 weeks of break, in combination with ponatinib, which is started at the dose of 30 mg. Patients who achieve CMR will have the dose of ponatinib lowered to 15 mg in order to reduce the adverse events associated with ponatinib, in particular cardiovascular adverse events. Responders will proceed with 4 cycles of consolidation (cycle 2 to cycle 5) with blinatumomab at the same dosing schedule and ponatinib. Maintenance consists of ponatinib single-agent given for at least 5 years.

We hope over the coming few years, [that] we’ll have more data and more sensitive testing that will allow us to identify patients who can safely discontinue therapy, and therefore improve on the rates of treatment-free remission similarly to what has been achieved in chronic myeloid leukemia. But we are not there yet. I’m hoping that this will come over the next few years.

What were the main outcome measures?

Among the 40 patients treated in the frontline setting, we had a complete response or complete remission with incomplete count recovery [CR/CRI] of 96%, and a high CMR rate of 87%. This is important because we have established in previous studies that patients who achieve complete molecular response, especially early on, are the patients who do better on the long run. They have a higher survival and lower risk of relapsing, even without the need for allogeneic stem cell transplantation. Being able to achieve high levels of CMR in our patients is a very important end point that will translate into improved long-term survival. We did not have any leukemia-related deaths in this study. Two deaths were observed in this cohort, unrelated to the study drug or to the disease progression.

Another important finding was that only 1 patient in this study proceeded to allogeneic stem cell transplantation because of detectable minimal residual disease. Allogeneic stem cell transplantation has been long considered the standard of care in patients with Ph+ ALL in a curative intent. All remaining patients didn’t undergo transplant and none of them has relapsed so far.

What were some stand out findings of the trial?

Of responses and survival, 87% of our patients achieved a complete molecular response in the frontline cohort overall, but of those, 68% achieved this response after 1 cycle. Achieving an early molecular response is associated with improved survival. With a median follow-up of about 15 months now, we have a 2-year progression-free survival and overall survival rates of 95% both. Again, only 1 patient was transplanted, and the majority of the patients achieved complete molecular response.

Can you discuss the findings of the relapse/refractory cohort examined in the trial?

In patients in the relapsed/refractory cohort we had a CR/CRI of 92%, which is also good. Of the 90% of patients who responded, 79% achieved complete molecular response, which is 4 out of 5 patients who achieved CMR overall. This translated into an overall survival at 1 year of 79%. Even the relapsed/refractory cohort, though small in number, showed good results.

This is a proof of concept that this chemotherapy-free regimen significantly improved the outcomes. Even in those patients who have relapsed/refractory disease, 6 of those patients were able to proceed to stem cell transplant, which is still considered the standard approachin the relapsed setting. This shows that this combination is very promising, either in the frontline setting to induce higher rates of response, longer survival, and prevent patients from having toxicities related to cytotoxic chemotherapy. This reduces and even mitigates the need for allogeneic stem cell transplantation in those patients. On the other hand, in the relapsed/refractory cohort we showed that this combination was proven to be effective and can bridge patients to allogeneic stem cell transplantation as a more curative approach.

What unmet needs still exist in this space?

One thing that may be a next step will be to introduce more sensitive testing in patients with Ph+ ALL. We started doing this at The University of Texas MD Anderson Cancer Center by incorporating more high-sensitive assays such as next-generation sequencing, which can detect leukemia cells at a sensitive level of 10-6.By checking the responses of our patients at this deep level, we can identify which patients are disease-free or who may harbor some minimal disease that wasn’t detected by standard assay. This will help us later to decide which patients can safely discontinue therapy and remain disease-free on the long run.

First, we improved the outcomes through chemotherapy and TKIs, and second, we introduced this chemotherapy-free regimen of blinatumomab plus ponatinib, which improves the remission rates and molecular responses, reduces the adverse events associated with chemotherapy, and reduces the chances of undergoing stem cell transplantation. The next step is to define the patients who can safely discontinue therapy. This way, we would have revolutionized the treatment of Ph+ ALL over the course of 2 decades from a deadly disease to a disease that can be eventually cured.

What do you recommend community oncologists should take away from this presentation?

The key takeaway message is that for patients with Ph+ ALL treated with intensive chemotherapy combinations, potent TKIs are preferred over first- and second-generation TKIs. I will favor using ponatinib rather than first- or second-generation TKIs because most of the patients who relapse have T315I mutations. Using ponatinib can prevent the emergence of this resistant clone.

If oncologists are able to access more novel combinations strategies or refer their patients to receive blinatumomab, this will offer patients higher chances of success with limited toxicity. Again, we have a short follow-up so far on our study, and we’re reporting 1- to 2-year survival rates, but results look encouraging.

What other research are you excited to learn about at SOHO this year?

I’m excited to hear what is coming and what follow-up we have on chimeric antigen receptor [CAR] T-cell therapies and immunotherapies in general. We know that this is a major area of research development and advances in the world of leukemia, and even in hematologic malignancies like lymphoma and myeloma. We have lots of immunotherapies coming, a lot of bispecific combinations, and CAR T-cell therapies that are coming in most fields of hematologic malignancies. This will bring more hope for our patients, more options to reduce the chances of toxic chemotherapy and toxic regimens. This will allow for future combinations that might offer curative approaches.

_REFERENCE

_{1. Haddad FG. Updated results from the phase 2 study of blinatumomab in combination with ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia. Oral abstract ALL-424. Presented at: 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022). September 28-October 1, 2022. Accessed September 28, 2022.}