Expert Highlights Developments in Myeloid Malignancies

Suman Kambhampati, MD

Myelodysplastic syndromes (MDS), precursors to acute myeloid leukemia (AML), are underdiagnosed, according to Suman Kambhampati, MD.

“Early referrals to a hematologist and proper diagnostics are the key aspects of promotion for MDS awareness,” said Kambhampati, adding that clinical trials are also a vital aspect of proper diagnostics and developing efficacious treatments that reduce the risk of disease progression.

One such study is the ongoing, phase III MEDALIST trial (NCT02631070), which is looking at luspatercept, a novel fusion protein that inhibits TGF- family ligands in patients with very low-, low-, and intermediate-risk MDS. Data from the phase II PACE-MDS Extension study showed 77% of patients with high transfusion burden saw a decrease of ≥4 units red blood counts over 8 weeks with luspatercept treatment; 89% of patients with low transfusion burden saw an increase in hemoglobin ≥1.5 g/dL for ≥8 weeks.

OncLive: Please provide an overview of the treatment landscape of MDS.

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Kambhampati, co-medical director of the Blood Cancer Program at Sarah Cannon Cancer Institute, detailed available treatments for MDS and ongoing clinical trials investigating targeted treatments in myeloid malignancies.Kambhampati: The 2 main features in MDS are low blood counts and the risk of transforming into AML; those are the 2 broad areas of therapeutic focus. When it comes to low blood counts, we primarily deal with anemia, thrombocytopenia, low platelets, and risk for infections due to low neutrophil counts. MDS is categorized into low- and high-risk disease. Low-risk MDS is often characterized by low blood counts, and the focus in that category is mostly improving blood counts and giving growth factors to stimulate blood production.

In patients for whom that isn't successful, we’re focusing our attention on clinical trials and research. A lot of research is being done to overcome barriers in blood production in patients who are failing growth factor therapy. There is this new class of drugs called TGF- ligand trap agents, such as luspatercept, and they’re showing some remarkable efficacy in patients with low-risk MDS.

Can you share some of the data we have seen with venetoclax myeloid malignancies?

In high-risk MDS, unfortunately, we have not made big strides. We continue to look for new agents. There are some new agents that look extremely appealing, such as venetoclax and IDH2 inhibitors. We are going to see more emphasis on mutational profiling and targeted therapies in MDS. The broad theme that is evolving now is improving the quality of life of patients with low-risk MDS and prolonging the survival of patients with high-risk MDS. What is unique about venetoclax (Venclexta) is that it overcomes a key rate-limiting molecular vent in myeloid malignancies. That is common for many malignancies, but in myeloid malignancies in particular, we see lack of chemotherapy efficacy due to the TP53 mutation. Venetoclax can work downstream of p53 and lead to the restoration of chemotherapy responsiveness; that's the holy grail of cancer therapy.

Is the development of modern immunotherapy approaches in MDS headed toward chimeric antigen receptor (CAR) T-cell therapy?

It’s remarkably successful in patients with high-risk AML who were traditionally treated with nonintensive chemotherapy approaches. We didn't see a big difference in their overall survival (OS), but now we're seeing a remarkable prolongation of their OS. The treatment is not trivial and there are significant side effects that need to be monitored, but they are a step forward in the field of myeloid malignancies.The immune therapies are still very early in MDS. Unlike solid tumors, myeloid malignancies are slightly more diverse and molecularly complex. Immune therapies are still finding their space in MDS. Whatever research has come out of early trials gave us a hint of response, but not a clear path or signal to effective therapies. A lot of research still needs to be done in finding the right space in myeloid malignancies, particularly in MDS and AML.

What are the difficulties in MDS with regard to proper diagnosing and staging?

As for CAR T cells, the complexity of MDS and AML is such that we do not have a predominant molecule that could be targetable. However, there is some research coming out with dominant molecules, such as CD123, that could be a target to immune therapies. We are probably going to see some new research looking at those dominant molecules as a target for CAR T cells. The key to MDS diagnosis is referral to a hematologist. There was a paper published several years ago from the National Institutes of Health group suggesting that MDS is underdiagnosed. A big part of that is lack of referrals to a hematologist. The advocacy groups—such as the Aplastic Anemia & MDS International Foundation, as well as Leukemia & Lymphoma Society—are doing a fabulous job in spreading awareness about MDS, but it is still an underdiagnosed condition.

What are some ongoing studies at Sarah Cannon Research Institute?

The key is early referral. Bone marrow is often needed. In fact, that's a must to diagnose MDS. Bone marrow helps not only with the diagnosis of MDS, but also in staging MDS with the broad classifications like the International Prognosis Scoring System (IPSS) and Revised IPSS. We're going to see more of an increase in the number of patients with MDS in the United States and worldwide. With more awareness, research, and events like this, there’s clearly going to be a lot of emphasis on MDS research. We are going to do some really exciting trials in MDS and AML. There are some new clues that intrigue us about how to improve the effectiveness of existing therapies, such as azacitidine and decitabine, using simple methods. Sarah Cannon Research Institute is going to take the lead on some of these trials and be the coordinating center for them. The scope of research is such that it could be paradigm changing.

Giagounidis A, Platzbecker U, Germing U, et al. Luspatercept treatment leads to long term increases in hemoglobin and reductions in transfusion burden in patients with low or intermediate-1 risk myelodysplastic syndromes (MDS): preliminary results from the phase 2 PACE-MDS Extension Study. Blood. 2015;126(13):92.