In an interview with Oncology Learning Network, Pamela S. Becker, MD, PhD, Professor, Hematology Division, University of Washington School of Medicine, Seattle, discussed the clinical significance and potential implications of a study examining the use of gemtuzumab ozogamicin in patients with relapsed or refractory acute myeloid leukemia (AML).

The results of the study in which Dr Becker was a co-investigator were presented at the 2018 ASH Annual Meeting.

Transcript

Hello, I am Dr. Pamela Becker, Professor of Medicine in the Division of Hematology of the Institute of Stem Cell and Regenerative Medicine at the University of Washington in Seattle.

We conducted this extended access trial because of data that suggested that gemtuzumab ozogamicin could be effective in certain groups, such as favorable-risk or even intermediate-risk AML. The drug had been initially FDA-approved and then the approval status was rescinded a few years ago.

There were a number of publications including the group at the MRC, where it was clear that there were subgroups of patients that were responding to this. And in fact, there is meta-analysis that was published by the MRC Group.

Hills et al. describes that there is improvement in overall survival at 5 years in patients with favorable cytogenetics and also in intermediate cytogenetics. The patients with adverse cytogenetics did not appear to benefit from the addition of this drug.

There was also pediatric literature by our colleagues at Seattle Children's Hospital. Pollard et al. had shown that there were subsets of patients that had improved, event-free survival. And the response appeared to be associated with keratogenic expression level of CD33 via the AML cells.

In addition, a colleague of mine from Fred Hutchinson Cancer Research Center, Dr. Soheil Meshinchi, has been able to identify splice variants that were better or worse response rates.

So for all these reasons, where we thought there was a target population that could benefit from the addition of this drug, and also, because we suddenly did not have the drug available because the FDA had withdrawn its approval, we have sought to pursue this expanded access trial.

In particular, the patients who were studied were those who had acute promyelocytic leukemia (APL) or AML with favorable-risk cytogenetics initially, and then we later expanded to other risk groups. The patients were also both adult and pediatric.

We studied 44 patients, 32 of which were adult and 12 were pediatric; 42 had relapsed disease and 2 refractory disease. We had patients undergo treatment with combination of gemtuzumab ozogamicin with many different regimens.

They included intensive regimens, such as FLAG-IDA (which is fludarabine, Ara-C, G-CSF, and idarubicin) or G-CLAM (which is G-CSF, cladribine, Ara-C, mitoxantrone), as well as less-intensive regimens, such as azacytidine.

The most common toxicities were documented infections and fevers—as would be the case with any salvage injection regimens for AML.

We allowed flexibility in terms of the dosing, so that the options would be 3 mg/m2 for 1 or 2 doses in addition to chemotherapy, or 9 mg/m2 with split dosing over a period of 8 days with no single dose greater than 3 mg/m2. In addition, for APL, 9 mg/m2 dose as a single agent or in combination with regimens was also permitted.

Our most significant outcomes were obtained with patients who received more intensive chemotherapy regimens.

We found that for patients who had more intense regimens, the complete remission rate without minimal residual disease was 25%, and complete remission with incomplete count recovery 47% with the more intensive regimens as compared to 19% with less-intense regimens. These results are not particularly surprising.

We also found that we had a majority of patients who had favorable or intermediate-risk cytogenetics, and we did have responses in all groups.

The overall response rate for the patients who had the more intensive regimen was 78% total complete remission, plus complete remission with incomplete count recovery compared to the less intensive where the overall total was only 44%.

In addition, patients with fewer prior therapies had higher response rates, and the highest response rates were seen in the patients with favorable cytogenetics.

Given the results in this expanded access group of patients, we're interested in continuing the study. And at our institution, we're actually now directly studying the addition of gemtuzumab ozogamicin to our G-CLAM regimen; so that study is now enrolling.

In addition, we have a new study that's recently opened where we're adding gemtuzumab ozogamicin for patients who have minimal residual disease. We'll be doing correlative studies for this minimal residual disease study, where in my laboratory we'll be examining the level of expression of CD33, which is the target of gemtuzumab ozogamicin.

My colleague, Dr Meshinchi at the Fred Hutchinson Cancer Research Center, will be studying the splice variants. We hope to be able to correlate our responses in the patients with minimal residual disease with these levels and perhaps be able to predict which patients might respond for the future.

There are other innovative approaches that are being used now to further study gemtuzumab in various other groups so that we'll be able to hopefully define the best regimens to use in combination with gemtuzumab ozogamicin, and also again focus on which patients might derive the most benefit.

Lastly, everyone is always concerned about the risk of sinusoidal obstruction syndrome (SOS), which is a complication after allogeneic transplant, and as many of the patients (after achieving remission with our relapse regimens) go on to allogeneic transplant, which is potentially curable therapy.

Our abstract also reported that we had 2 pediatric patients who developed SOS that occurred >60 days from dosing with the gemtuzumab ozogamicin, and there were no adult patients who developed this complication. This will of course be a focus in the ongoing studies at our institution and at others as to what the incidence of this so-called SOS—this entity, which is a liver complication that's associated with high bilirubin level after transplant—what the incidence of that complication might be.

But we do believe based on published studies, as well as our own experience, that when these fractionated doses and lower doses of 3 mg/m2 per dose are used rather than the 9 mg/m2 dose that had initially been used as a single dose, that the toxicity is reduced. And that there's less incidence of significant SOS post-allogeneic transplant.

I just wanted to also relate to you that gemtuzumab ozogamicin was the first antibody to CD33 that was studied and FDA-approved, and now reapproved in particular groups of patients by the FDA. Now this drug will be able to be used in select patients.

There are also a number of other investigational antibodies to CD33 that have been under study. Some of them are now combining in the bispecific antibodies, a region which is directed against CD33, as well as includes an antibody against antigens on T-lymphocytes that may improve the response rate to these antibodies.

So there's been additional technological development, and not only will the antibody to CD33 be involved in some of these bispecific antibodies, but also antibodies to other cell surface markers. So I believe that while gemtuzumab ozogamicin was the first prototype of the use of antibodies in AML, now there are many such antibodies under investigation.

Hopefully, this will enrich the armamentarium of immunotherapy approaches to AML.

In addition, there are now the cellular therapy approaches to treat AML that are under investigation. These will also similarly target antigens on AML.

So even though this was the first antibody, there's now been a rapid and enlarging expanded approach to immunological therapy of AML.