Long-Term Data, Novel Regimens Showcase Progress in ALL

Madhuri Vusirikala, MD

The combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) plus ponatinib (Iclusig) continued to demonstrate sustained responses in adult patients with newly diagnosed Philadelphia chromosome—positive acute lymphoblastic leukemia (ALL), according to long-term safety and efficacy results of a phase II study presented at the 2019 ASH Annual Meeting.

"Prior to the [introduction of the] TKIs, patients with Philadelphia chromosome—positive ALL were typically recommended for transplant because it was the only [curative] option," said Madhuri Vusirikala, MD. "Now, we have seen improved responses without transplant with the addition of TKIs."

In December 2012, ponatinib was granted FDA approval to treat adults with chronic myeloid leukemia and Philadelphia chromosome—positive ALL.

Additional studies exploring this combination—as well as the addition of other agents, such as blinatumomab (Blincyto)—in the frontline setting may allow patients with Philadelphia chromosome—positive ALL to obtain deeper responses while reducing the need for chemotherapy.

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Vusirikala, a professor of internal medicine in the Division of Hematology/Oncology at the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center, discussed recent changes in the treatment paradigm of ALL, based on data from the 2019 ASH Annual Meeting.

OncLive: What practice-changing studies in ALL were presented at the 2019 ASH Annual Meeting?

Vusirikala: Investigators from The University of Texas MD Anderson Cancer Center presented on the combination of hyper-CVAD and ponatinib. Although these data had been presented before, updated data [were presented at the 2019 ASH Annual Meeting], which continued to show that this combination has better response rates. They were able to avoid transplant for this subgroup of high-risk patients. It appears that a subgroup of patients who receive hyper-CVAD and ponatinib and go on to transplant have a worse prognosis than patients who continue on ponatinib without transplant.

Other studies looked at new combinations. [For example], the combination of our 2 approved agents in the relapsed/refractory setting, inotuzumab ozogamicin (Besponsa) and blinatumomab, with chemotherapy is showing a lot of promise for patients who are older and unable to undergo high-dose chemotherapy.

Another study looked at the combination of navitoclax and venetoclax (Venclexta). Venetoclax is approved in chronic lymphocytic leukemia and other low-grade lymphoid malignancies, and it has a big role in acute myeloid leukemia. In ALL, the combination is now showing good response rates in patients with relapsed/refractory disease. It could [provide] a bridge toward allogeneic stem cell transplant.

What factors allow venetoclax to have synergism with navitoclax in ALL?

It has to do with the effectiveness of venetoclax on B-cell receptors. As we know, B-cell ALL is a B-cell malignancy. Patients seem to have good responses with the combination, and some achieved minimal residual disease (MRD)—negative disease.

How has the role of MRD evolved in ALL?

MRD [should be] your primary endpoint when treating a patient. The BLAST study looked at blinatumomab in patients who have MRD-positive ALL. A large percentage of those patients are able to achieve MRD-negative disease with blinatumomab. Then they undergo transplant and are cured.

Beyond blinatumomab, what do you do for patients with MRD-positive disease?

Data are looking at agents post transplant to reduce the risk of relapse. We know that patients who [have] MRD-negative [disease] have a much better outcome with transplant. However, a subset of [patients with] MRD-positive [disease] can undergo transplant and be cured.

We can take [patients with MRD-positive disease] to transplant, but [it is important] to be cognizant that they have a high risk of relapse. Implementing strategies, such as lymphocyte infusions or giving blinatumomab or inotuzumab ozogamicin posttransplant, may [yield better outcomes posttransplant].

What is the future of blinatumomab?

Blinatumomab is being used up front, as it is a highly effective agent in ALL. [At UT Southwestern Medical Center], the ECOG-ACRIN 1910 trial is looking at blinatumomab upfront in patients with ALL and was recently completed. Patients who have MRD-positive disease after 2 cycles of induction chemotherapy are automatically enrolled to receive blinatumomab. Patients with MRD-negative ALL at the end of induction intensification were randomized to receive blinatumomab versus no blinatumomab. This trial is going to tell us whether a role exists for blinatumomab in patients who have MRD-negative disease at the end of induction therapy. Blinatumomab is also being looked at in the pediatric setting.

One fear with blinatumomab post transplant is [the potential for] an increased risk of graft-versus-host disease (GVHD) because blinatumomab is an immune-based therapy. [Thus far], there does not appear to be an increased risk of GVHD with blinatumomab for a select group of patients. Of course, [the agent] should not be given to patients with recurring GVHD.

How has the role of transplant evolved in ALL?

ALL is a different disease in adults compared with pediatric patients. One group of patients [encompasses] adolescents and young adults; the cutoff age of young adults is variable. In most clinical trials, the cutoff age is 39 years, whereas it can be as high as 50 years in some European studies.

If you use a pediatric-inspired regimen in B-cell ALL, you have a high chance of curing patients, but the role of transplant is not very clear.

On the other hand, Philadelphia chromosome—like ALL is a whole new entity that we are still learning about. We know there are targetable markers for this disease. The BCR-ABL and JAK-STAT pathways are involved. As such, many pediatric and adult patient studies are looking at the use of ruxolitinib (Jakafi) and dasatinib (Sprycel) for the up-front treatment of these patient subsets. With time, we will know whether a role exists for transplant in this disease group. In Philadelphia [chromosome]–positive ALL, we are shying away from transplant, especially in patients who have MRD-negative [disease].

Another study from The University of Texas MD Anderson Cancer Center group looked at MRD status of patients with Philadelphia chromosome—positive ALL after 3 months’ post treatment with hyper-CVAD and a TKI. If the patient has MRD-positive disease, they may benefit from transplant.

[At UT Southwestern Medical Center], our strategy is to treat all patients with [Philadelphia chromosome—positive ALL] with hyper-CVAD and a TKI. At the end of induction, we perform a bone marrow biopsy to see whether they are in a complete molecular response. If so, we give maintenance therapy with 2 years of vincristine, steroids, and indefinite TKIs. If they have MRD-positive disease, we take them to transplant.

Short NJ, Kantarjian HM, Ravandi F, et al. 283 Long-term safety and efficacy of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019;134(suppl 1):283. doi:10.1182/blood-2019-125146.