Immunotherapy and AML Remains a Thorny Challenge

Immunotherapy has drastically changed the way physicians treat B-cell malignancies, but one prominent exception is acute myeloid lymphoma (AML). In the case of AML, hematopoietic toxicity has been a consistent problem.

A new review article in the Journal of Clinical Medicine takes a look at recent efforts to get over this hurdle, and the question of whether immunotherapy will ever be a successful option for AML absent the use of stem-cell transplantation.

Corresponding author Georgina J. Clark, PhD, of the University of Sydney, in Australia, and colleagues note that until the past decade there was very little change in the treatment of AML. More recently, advances in the underlying molecular landscape of AML have enabled significant advances.

“However, many of these molecular therapies have limited duration of action when not combined with conventional chemotherapy,” Clark and colleagues write.

Currently, only gemtuzumab ozogamicin (GO) is accepted to treat hematologic malignancies of myeloid origin. However, it has so far had limited success in treating AML, Clark and colleagues write.

A couple of problems are at play.

“Most surface molecules expressed on AML are also expressed on Hematopoietic Stem and Progenitor Cells (HSPC), and potent immunotherapies against traditional AML molecules (CD33 and CD123) have led to hematologic toxicity, both in preclinical models and in clinical trials,” they note. In addition, these surface molecules tend to have complex subclonal architecture and plasticity, making tumor escape “a significant concern.”

One option is to have the patient undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT), which can limit the relapse rate of AML. However, such procedures require conditioning chemotherapy followed by immunosuppression in order to lower the chance of rejection.

“The major limitation is that most patients are not fit for the procedure due to their age at diagnosis and other comorbidities,” the investigators write.

Autogeneic HSCT is also an option, but only in patients without high-risk disease, they note.

Another therapeutic option is vadastuximab talirine (VT), an anti-CD33 antibody drug conjugate (ADC). Clark and colleagues say it has a significant rate of complete remission.

“The potential for significant myelosuppression by targeting CD33 was supported by a dose limiting toxicity (60 ug/kg) of hypocellular marrow in a phase I trial for VT,” they write.

However, prolonged neutropenia and thrombocytopenia were found in patients who achieved complete remission or complete remission with incomplete recovery.

In addition, a phase 3 trial of hypomethylating agents +/- VT was suspended after excess deaths due to infection were observed in the VT arm. With increasingly potent therapeutics available, avoiding hematologic toxicity while remaining effective against AML may require an allo-HSCT as a rescue.”

Clark and colleagues conclude that upcoming trials of AML immunotherapy will need to be carefully conceived given the high risk to patients in the trials.

“Tolerable and effective immunotherapy that can reduce the need for allo-HSCT would constitute a major change in the treatment of AML, but to date this has been elusive,” they say.

As an alternative, Clark and colleagues write that finding a better method to reduce the toxicity of allo-HSCT with immunotherapy would be a significant step forward in and of itself.

Reference

Abadir E, Gasiorowski RE, Silveira PA, Larsen S, Clark GJ. Is hematopoietic stem cell transplantation required to unleash the full potential of immunotherapy in acute myeloid leukemia? J Clin Med. 2020;9(2):554. doi:10.3390/jcm9020554.