Novel chemoimmunotherapy approach shows promise for B-cell acute lymphoblastic leukemia in phase 1 study at Fred Hutch

In the first clinical trial of dose-adjusted EPOCH along with inotuzumab ozogamicin (InO) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), Fred Hutch Cancer Center researchers found this combination was well tolerated and produced a high overall response rate (83%). DA-EPOCH is a combination of the chemotherapy drugs etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin. InO is an antibody-drug conjugate, a form of immunotherapy that attempts to deliver chemotherapy directly to cancer cells via a monoclonal antibody. The study, published today in JAMA Oncology, also highlighted that side effects were similar to those commonly seen in people with B-ALL, making the regimen feasible to administer for community oncologists experienced in treating such patients. 

Pursuing better outcomes for more people in more settings

Outcomes for adults with relapsed or refractory B-ALL have historically been poor. Studies like this phase 1 trial may be helpful to reduce health disparities by identifying treatments that are not only more effective but also accessible to more people in a wider range of settings.

Advances like CAR T-cell therapy and the bispecific T-cell engager blinatumomab can be effective against B-ALL, but each has certain limitations. CAR T cells take time to prepare — in some cases, too much time for an acutely ill leukemia patient to wait. They can be given only at a specialized center, like Fred Hutch; they are expensive; and they may cause serious complications. Blinatumomab, which helps healthy T cells kill cancer cells by bringing the two types of cells close together, requires a continuous IV infusion 24 hours a day for 28 days per cycle (potentially for multiple cycles), and it doesn’t work well in patients with a high level of leukemia in their body. 

In contrast, dose-adjusted EPOCH along with inotuzumab ozogamicin, or DA-EPOCH-InO, “is a regimen that can be offered outside specialized centers provided that staff are comfortable with toxic effects germane to patients with acute leukemia,” the researchers wrote in their report. 

Hematologist-oncologist Ryan Cassaday, MD, designed the study. His research and clinical practice focus on adults with ALL, especially those who are older or have relapsed or refractory diseases. 

“While our results need to be validated in a larger study, I believe they are good enough to justify using this approach now in the right situations,” said Cassaday, associate professor in the Clinical Research Division at Fred Hutch and the Division of Hematology and Oncology at the University of Washington. 

“We have used it outside of the clinical trial in select patients, such as those who have a high disease burden and aren’t necessarily great candidates for other options, people whose disease we need to get under control quickly,” he said. “Given the high response rate in the trial and the relatively manageable side effects we observed, we know we can almost assuredly get patients through one or more cycles of DA-EPOCH-InO, bring their disease under better control and then potentially offer them more advanced treatments, like CAR T-cells, blinatumomab or an allogeneic stem cell transplant.”

A novel combination provides hope

The DA-EPOCH-InO study enrolled 24 Fred Hutch patients with at least 5% blood or marrow blasts or one site of disease outside their bone marrow measuring at least 1.5 cm. All had been treated previously for B-ALL, most commonly with chemotherapy. Each patient received DA-EPOCH on days one through five of a 28-day treatment cycle. This regimen has previously been shown to have antileukemia effects. It is typically given in an inpatient hospital.

On days eight and 15, study participants received InO, which can bring about a short remission of B-ALL when given on its own. In the past, it has been tried in combination with other, lower-intensity chemotherapies, leading to some increased survival but also concerns about liver toxicity. The Fred Hutch team hoped InO would perform better when paired with DA-EPOCH. InO can be given by intravenous injection in an outpatient clinic.

To find the maximum tolerated dose of InO along with DA-EPOCH, the first group of patients received the lowest of three InO doses. When dose level 1 was well tolerated, the researchers gave higher doses to subsequent groups. Level 3, the highest planned dose, was confirmed to be the maximum tolerated dose. 

Many patients completed only one or two treatment cycles because this was enough to get their disease into remission, at which point they could transition to another form of therapy intended to sustain the remission, such as a transplant. Some completed as many as four cycles. 

“This study showed that DA-EPOCH-InO was safe and highly active in a heavily pretreated cohort of participants with relapsed or refractory B-ALL,” according to the published report. 

“What’s reassuring is that the type of side effects we saw were not really unique — for example, not some unusual form of heart damage. We didn’t really see any new signals that raised concerns about the safety of this particular combination,” said Cassaday. 

Trial included patients often excluded from research

The team was pleased to see that severe effects from liver toxicity were rare. Only one patient developed sinusoidal obstructive syndrome (SOS), a complication involving damage to blood vessels in the liver, after completing the study and then having an allogeneic transplant. Both InO and transplant independently raise the risk for SOS.

Another valuable aspect of the trial, said Cassaday, was the opportunity to test DA-EPOCH-InO in people with disease primarily outside their bone marrow. Clinical trials for B-ALL often accept only those patients with at least 5% blasts in their marrow. 

“But in people with relapsed or refractory B-ALL, their disease is often growing mainly outside of their bone marrow, so-called extramedullary disease, and they don’t meet that 5% criterion,” said Cassaday. “We allowed patients in that situation on this trial. This meant we could not only be more inclusive but also get a sense of how well this regimen performed in that setting. It’s a relatively under-described situation in the literature because these patients are typically ineligible for trials,” but they are an important segment of the patients who actually need care.

The researchers are considering options to conduct a more definitive study of the same chemoimmunotherapy combination with a larger population of patients to get more precise information about both safety and efficacy.

The phase 1 study was supported by grants from the National Institutes of Health and Pfizer.