"Besponsa (inotuzumab ozogamicin) helps patients with relapsed or refractory acute lymphoblastic leukemia (ALL) with a poor prognosis undergo allogeneic stem cell transplantation under positive conditions by increasing the rate of complete remission and MRD-negative achievement compared to conventional chemotherapy," said a local hematologist. 

Adult ALL is an aggressive, rapidly progressive disease with a high acquisition rate of drug resistance to anticancer drugs, resulting in frequent relapse or refractory disease despite continuous chemotherapy and allogeneic stem cell transplantation. These patients account for 50-60 percent of ALL patients and have a poor prognosis, with a five-year survival rate of less than 10 percent.

This is where Pfizer’s Besponsa, the first antibody-drug conjugate in relapsed or refractory ALL, came into play. Besponsa showed improved clinical outcomes compared to conventional chemotherapy.

Notably, Besponsa achieved minimal residual disease (MRD) negativity in 63 percent of patients who achieved complete remission, increasing the allogeneic stem cell transplantation rate by about four times compared to chemotherapy.

Against this backdrop, Korea Biomedical Review met with Professor Lee Seok of the Hematology Department at the Catholic University of Korea St. Mary’s Hospital to learn about the current state of treatment for ALL in Korea and the effectiveness and safety of Besponsa.

Question: A considerable number of adult ALL patients experience relapse after achieving complete remission and have a poor prognosis. What are the factors to consider in mapping out treatment strategies?

Answer: When planning a treatment strategy for relapsed or refractory ALL, we consider the patient’s systemic performance status at diagnosis and relapse, leukemia cell antigen expression and presence of specific genetic abnormalities, extent of disease (percentage of leukemia cells in the bone marrow and extramedullary involvement), early relapse, prior therapy, and donor status. Ultimately, allogeneic stem cell transplantation is considered to improve long-term survival and cure rates while minimizing MRD as little as possible.

Recently, new treatment options, including immunotherapies targeting leukemia cell antigens, such as Besponsa, have emerged. Introducing these therapies has resulted in improved drug toxicity-related mortality and remission rates compared to traditional combination chemotherapy regimens. That, in turn, has made allogeneic stem cell transplantation a viable option for many patients, improving their chances of long-term survival.

Q: We are curious about Besponsa’s pivotal phase 3 clinical trial, the INO-VATE study, which confirmed efficacy and safety in ALL.

A: In the phase 3 INO-VATE study, which included 326 patients with relapsed or refractory ALL, the complete response rate in the Besponsa group was 73.8 percent, compared to 30.9 percent in the chemotherapy group. The allogeneic stem cell transplant rate was also higher in the Besponsa group, with 39.6 percent of patients receiving a transplant compared to 10.5 percent in the chemotherapy group. That represented a 25 percent drop in death risk in the Besponsa group compared to the chemotherapy group.

MRD negativity was also confirmed in 63 percent of patients who achieved complete remission after receiving Besponsa. MRD-negative patients significantly improved survival compared to MRD-positive patients. Among MRD-negative patients, significantly higher survival rates were observed in patients who received Besponsa as a first-line salvage therapy and those who received an allogeneic stem cell transplant.

However, VOD/SOS (hepatic veno-occlusive disease/sinusoidal obstruction syndrome) occurred in 14 percent of patients receiving Besponsa throughout treatment, mainly after allogeneic hematopoietic stem cell transplantation, which warrants continued attention and caution.

These findings confirm that Besponsa provides a bridge to allogeneic stem cell transplantation in relapsed or refractory ALL patients with a poor prognosis, with higher rates of complete remission and MRD negativity than conventional chemotherapy.

Q: Is there any difference between the real-world data and the phase 3 INO-VATE study?

A: In a posthoc analysis of the INO-VATE study, the MRD-negative rate (76.2 percent) and allogeneic stem cell transplant progression rate (46.2 percent) were improved compared to chemotherapy, resulting in improved survival.

In addition, according to “Real World Data from Catholic Hematology Hospital in Korea,” presented at the International Society of Hematology in 2023, Besponsa was administered to 60 relapsed or refractory adult acute lymphoblastic leukemia patients at high risk of treatment failure, with 58.3 percent of patients achieving complete remission. Of these, 75 percent were confirmed MRD-negative and 31.6 percent of patients underwent allogeneic hematopoietic stem cell transplantation in complete remission.

The one-year survival rate for all patients was 24.3 percent, and the one-year survival rate for patients who underwent allogeneic stem cell transplantation was 39.0 percent, while severe VOD/SOS occurred in three patients (5 percent).

Q: Besponsa has shown improvement in MRD negativity. What is the current MRD testing and diagnosis environment in Korea?

A: Currently, the goal of treatment for ALL is shifting to improving cure rates by eliminating MRD. The importance of MRDs in ALL has been demonstrated in numerous domestic and international studies.

In Korea, polymerase chain reaction (PCR), multicolor flow cytometry (MFC), and next-generation sequencing (NGS) have been used to test for MRD in ALL. Fortunately, health insurance coverage for NGS testing for MRD diagnosis has been expanded since January this year, and all MRD tests are now available. This will positively impact improving treatment outcomes for patients in the future.

I believe that MFC and PCR should be performed concurrently with NGS whenever possible when testing for MRD, as studies have reported higher survival rates with MRD negativity on both tests compared to MRD negativity on only one test.

As MRDs are the most important prognostic factors affecting the risk of relapse and death in ALL, they must be explained at the healthcare provider level so that patients know their importance and are proactive in their diagnosis and treatment. More aggressive and continuous MRD screening throughout the entire treatment course is essential.

Q: -How do you use Besponsa in real-world practice?

A: Besponsa is an antibody-drug conjugate that targets and kills the CD22 leukemia cell antigen and has been particularly successful in patients with high levels of leukemia in the bone marrow. These results have been consistent in patients with moderate or low levels of leukemia in the bone marrow.

Specifically, Besponsa has been shown to have a high complete response rate of around 70 percent in patients with a high number of leukemia cells in the bone marrow, early relapse after prior therapy, and extramedullary involvement, making it a viable treatment option for patients who have failed prior therapy and are at high risk.