Immunotherapy at the Forefront of ALL Treatment, Expert Says

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 = .0004).

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 <.001).

“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

Although not yet approved for elderly patients, chimeric antigen receptor (CAR) T-cell therapy has generated excitement for treating pediatric and young adult patients. Tisagenlecleucel (Kymriah) was the first FDA approved CAR T-cell therapy in August 2017 for patients up to age 25 years with relapsed/refractory B-cell precursor ALL that is refractory or in second or later relapse, based on the results of the ELIANA trial.⁴

Of the 75 patients who received a single infusion treatment on the phase II trial, 60% had a CR and all of these patients were MRD-negative, with 95% achieving MRD-negativity by day 28. The overall response rate was 81%.

Studies are now considering which patients will benefit most from CAR T-cell therapy. In a phase I single-institution study, Memorial Sloan Kettering Cancer Center (MSK) assessed the long-term follow-up for adults with relapsed/refractory B-cell precursor ALL (n = 53) who received an infusion of autologous T cells expressing 19-28z CAR, which were manufactured by MSK.⁵ With a median follow-up of 29 months (range, 1-65), patients with low disease burden who received the CD19-directed CAR T-cell therapy had a median OS of 20.1 months compared with 12.4 months among patients with a high disease burden.

Patients with high disease burden were also associated with a higher risk of severe cytokine release syndrome (P = .004) and neurotoxic effects (P = .0002).

“The question really is who are the best patients for CAR T cells. This was something that was looked at by the Sloan Kettering group,” added Daver. “They did a number of analyses, but the one they found that really helped to separate our outcome with CAR T-cell therapy was the disease burden. When you pick people who have low disease burden, less than 5%, which is usually an MRD-positive group…you see the impact of the CAR T-cell [therapy] was very significant.”

Several concerns still exist, however, with giving CAR T-cell therapy. Nearly all patients (95%) on the ELIANA trial experienced an any-grade treatment-related adverse event (TRAE) with tisagenlecleucel, and nearly three-quarters of patients experienced grade 3/4 TRAEs. Additionally, 40% of patients experienced neurologic events within 8 weeks of infusion, with 13% of patients experiencing grade 3 neurological events that were managed with best supportive care.

Seventy-nine percent of patients experienced cytokine release syndrome (CRS), of which 21% was grade 3 and 27% was grade 4. CRS occurred within 3 days of treatment (range, 1022) and lasted for a median of 8 days (range, 1-36).

Another concern is the duration of time between treatment. “One of the things that we are thinking about is to reduce the logistics or duration [of] time many patients have to wait,” Daver said. Off-the-shelf’ CAR T cells can significantly shorten the duration and have been proven to be just as affective. He noted that this therapy should be administered only by the highly experienced. “This is not something that can be done in the community or even, I would say, the smaller academic centers. At this time, large academic centers are the ones that are able to do this.”

References

1. Kantarjian, HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozagamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753. doi: 10.1056/NEJMoa1509277.
2. Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimum residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(5):1522-1531. doi: 10.1182/blood-2018-08-798322.
3. Jabbour E, Ravandi F, Kebriaei P, et al. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative acute lymphoblastic leukemia: a phase II clinical trial. JAMA Oncol. 2018;4(2):230-234. doi: 10.1001/jammaoncol.2017.2380.
4. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults in b-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi: 10.1056/NEJMoa1709866
5. Park JH, Riviere I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449-459. doi: 10.1056/NEJMoa1709919.