Key Studies in Leukemias: Independent Conference Coverage of ASH 2020

Hyper-CVAD Plus Blinatumomab in B-Cell ALL: Background

Eunice S. Wang, MD:
Our final discussion focuses on frontline treatment of newly diagnosed B‑cell ALL in adults. Between 80% and 90% of these individuals achieve CR, but at best only 50% achieve long‑term survival.^[52,53] MRD negativity correlates with a longer duration of response in B‑cell ALL.^[54]

Blinatumomab is a T‑cell–engaging CD3/CD19 bispecific antibody that has demonstrated efficacy in the MRD‑positive setting with high rates of conversion to MRD negativity and prolonged survival.^[55,56] Thus, could the addition of blinatumomab to frontline induction and maintenance therapy enhance these MRD results?

At ASH 2020, Short and colleagues^[57] presented data from a multicenter, single‑arm, open‑label phase II trial evaluating the addition of blinatumomab to a consolidative regimen for newly diagnosed patients with Ph‑negative B‑cell ALL.

Hyper-CVAD Plus Blinatumomab in B-Cell ALL: Study Design and Baseline Characteristics

Eunice S. Wang, MD:
In this trial, blinatumomab was incorporated into 2 phases of frontline therapy.^[57] The first phase was intensive therapy with full-dose hyper‑CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) for up to 4 cycles alternating with methotrexate/cytarabine for up to 4 cycles plus intrathecal chemotherapy and—for patients with CD20-positive disease—rituximab or ofatumumab. This was followed by blinatumomab alone for 4 cycles, then a maintenance phase consisting of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) for 3 cycles alternated with 1 cycle of blinatumomab for a total of 15 cycles. The primary endpoint was RFS with secondary endpoints including ORR, MRD negativity, OS, and safety.

The enrolled patients were relatively young and fit, which was necessary because they were receiving full-dose hyper‑CVAD. The median age was only 37 years and ranged up to 59 years. Nearly all patients had CD20 expression ≥ 50%, meaning they would have received an anti-CD20 antibody in their frontline therapy.

Regarding disease characteristics, 27% had TP53 mutation, 19% were CRLF2 positive by flow cytometry, and 8% each had evidence of KMT2A rearrangement, high hyperdiploidy, and complex karyotype. Overall, this was not a group with completely poor prognoses.

Hyper-CVAD Plus Blinatumomab in B-Cell ALL: Response

Eunice S. Wang, MD:
The response data were highly encouraging. We would expect that 80% to 90% of patients would achieve CR after induction, and in this trial, 81% achieved CR after induction and 100% achieved CR at some point during therapy.^[57] The most intriguing and promising data were for MRD negativity, which was achieved in 33 of 34 patients—giving a rate of MRD negativity at any point after therapy of 97%, although that rate was only 71% after induction.

Hyper-CVAD Plus Blinatumomab in B-Cell ALL: Nonhematologic AEs

Eunice S. Wang, MD:
As would be expected with blinatumomab, 47% of patients experienced an infusion reaction and 32% experienced hyperglycemia, the latter potentially associated with steroids used with this regimen.^[57] The only notable grade 3‑4 AEs were hyperglycemia (21%) and liver function test abnormalities (24%). There was a high rate of blinatumomab-related neurologic events (all grades: 45%; grade 3-4: 13%). CRS occurred in 13% of patients (grade 3-4: 3%). Overall, these AEs appear manageable and consistent with our current practice.

Hyper-CVAD Plus Blinatumomab in B-Cell ALL: Conclusions

Eunice S. Wang, MD:
This was a preliminary analysis and did not present data on the primary endpoint of RFS. However, these early results on tolerability, response, and particularly the MRD‑negativity rate appear promising.

Dr. Cortes, what were your thoughts on these results? Is this an avenue worth actively exploring?

Jorge Cortes, MD:
This appears to be a very promising approach and offers several advantages—most importantly efficacy. With the MRD-negativity rate that high, we would anticipate long‑term survival benefits. It has been quite difficult to improve the outcomes of adult patients with this disease, although TKIs have improved outcomes in certain subsets (eg, Ph‑positive ALL).

Another advantage is that this approach eliminates a great deal of chemotherapy. Notably, the hyper‑CVAD component was shortened from 8 cycles to 4 cycles.

The use of blinatumomab came with the risk of other toxicities, specifically neurotoxicity and CRS, but those events were mostly grade 1-2. Blinatumomab is not an easily administered agent because it requires continuous infusion, but I have found that we have adapted to successfully administering continuous infusions in practice.

I would like to see how this approach performs with specific subsets (eg, Ph‑like). This trial certainly needs more follow-up and more patients, but this is where we are heading in the management of ALL.

Eunice S. Wang, MD:
I agree. Because blinatumomab is an immunotherapy, we can hope that it would be mutation agnostic, similar to what we have seen with other immunotherapies. I am hopeful that patients who have poor karyotype, TP53 mutations, or Ph‑like mutations would preferentially benefit from the addition of blinatumomab, because these patients generally do not benefit from conventional cytotoxic therapy. I would be most interested in seeing the data on patients with poor prognoses.

I also want to see the data on RFS. Would incorporating blinatumomab into this regimen after only 4 cycles of hyper‑CVAD obviate the need to include several cycles of cytotoxic therapy? We are moving toward a potentially chemotherapy‑free regimen for ALL, and this approach is a step in the right direction for younger, fit patients who can tolerate 8 cycles but may not need to if they instead receive long‑term immunotherapy.

Closing Remarks

Eunice S. Wang, MD:
To summarize, ASH 2020 included a wealth of novel data. We are beginning to see more novel therapeutics for AML and biological agents supplant conventional cytotoxic chemotherapy for ALL. We are clearly moving in the direction of targeted immunotherapy for both acute leukemias. Dr Cortes, what was your impression of the CML data at ASH 2020?

Jorge Cortes, MD:
In CML, we have seen the rapid emergence of new agents and new endpoints beyond the traditional morphologic responses. I think we are entering a golden era that is going to help many patients.