Naval Daver, MD
Major advancements in immunotherapy are at the forefront of treatment for patients with acute lymphoblastic leukemia (ALL), according to Naval G. Daver, MD.
“[There are] 3 major backbone therapies right now in ALL in the immune area [and] there are more coming,” said Daver, associate professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, during a presentation at the 2nd Annual Live Medical Crossfire®
: Hematologic Malignancies meeting in New York.
Although immunotherapy shows promise, Daver advised that the use of tyrosine kinase inhibitors should still be considered, particularly for patients with Philadelphia chromosome–positive ALL.Novel Agents Versus Standard-of-Care Chemotherapy
Inotuzumab ozogamicin (Besponsa) was approved by the FDA in August 2017 for the treatment of adults with relapsed or refractory B-cell precursor ALL. The antibody–drug conjugate is composed of a monoclonal antibody that targets CD22, which is expressed on leukemic blasts in more than 90% of patients with ALL, and is linked to a cytotoxic agent.
The phase III INO-VATE trial, which the approval was based on, compared inotuzumab ozogamicin with investigator’s choice of standard intensive chemotherapy.1
Of the 218 randomized patients included in the primary analysis, 80.7% of patients had a complete remission (CR) or complete remission with incomplete platelet recovery (CRi) in the inotuzumab ozogamicin arm (n = 109), with a median overall survival (OS) of 7.7 months. In contrast, only 29.4% achieved a CR/CRi in the chemotherapy arm (n = 109) with a median OS of 6.2 months. The 2-year OS for patients in the inotuzumab ozogamicin arm was more than doubled compared with those in the chemotherapy arm (22.8 vs 10.0 months; P
Among those who had a CR/CRi, 78.4% of patients in the inotuzumab ozogamicin group achieved minimum residual disease (MRD)–negativity, compared with 28.1% in the chemotherapy group (P
“This trial shows you 2 things: 1) how bad chemotherapy does in the salvage population, and 2) this drug was much more effective,” Daver explained. “If you look at the tail of the curve, at 2 as well as 3 years, you are getting 15% to 20% more [patients] alive at those marks, which I think is important, because it [shows] a durability component beyond the median.”
The second novel agent in a head-to-head study with standard-of-care chemotherapy was blinatumomab (Blincyto), a bispecific monoclonal antibody constructed that enables CD3-positive T cells to recognize and eliminate CD19-positive acute ALL blasts. Most recently, the FDA granted an accelerated approval in March 2018 to blinatumomab for the treatment of adult and pediatric patients with B-cell precursor ALL who are in remission but are MRD-positive.
In the randomized phase III TOWER study, patients with Philadelphia chromosome–negative relapsed/refractory B-cell precursor ALL in the blinatumomab arm (n = 271) had a 34% CR rate with a median OS of 7.7 months, compared with a 16% CR rate in the standard chemotherapy arm (n = 134) with only a 4.0-month median OS.2
Additionally, in the blinatumomab arm, there was no difference in OS or recurrence-free survival between those who received allogeneic hematopoietic stem cell transplant (allo-SCT) versus those who did not. Among those who achieved a CR, 76% of patients in the blinatumomab obtained MRD-negativity status, versus 48% who received standard chemotherapy.
“These people were MRD-positive, then got blinatumomab with the intent of making them MRD-negative. And in about 80% of patients, the drug successfully eradicated MRD and was also associated with a significant median OS benefit. And a number of patients were able to go to allo-SCT.”Combination Therapies on the Horizon
A recent study has looked at the potential for combining novel agents in ALL with standard chemotherapy. In the single-arm, phase II trial, adults with relapsed/refractory Philadelphia chromosome–negative ALL (n = 59) achieved a CR rate of 59% when treated with inotuzumab ozogamicin plus low-intensity chemotherapy, referred to as mini-HCVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2
for 4 doses), as salvage therapy.3
Among the 46 (78%) of patients who responded, the MRD-negativity rate was 82% and 26 (44%) went on to receive allo-SCT. Of note, veno-occlusive disease (VOD) occurred in 9 patients (15%). Similar combinations are being studied in elderly patients with ALL, which also show significant responses.CAR T-cell Therapy Gains Traction