AML Trial Halted Due to COVID-19 Pandemic
March 30, 2020 09:08pm
By Lisa Astor
Stuart L. Goldberg, MD, discussed the management of patients with acute myeloid leukemia as well as those with myelodysplastic syndrome.
Stuart L. Goldberg, MD
With the success of many novel agents introduced into the treatment landscape in the past year, the management of acute myeloid leukemia (AML) has undergone a significant transformation, says Stuart L. Goldberg, MD.
Last year saw the FDA approval of gemtuzumab ozogamicin (Mylotarg), CPX-351 (Vyxeos), midostaurin (Rydapt), and enasidenib (Idhifa) for the treatment of patients with AML. Additionally, the FDA granted a priority review to ivosidenib (AG-120) for the treatment of patients with relapsed/refractoryIDH1-mutant AML.
Additionally, venetoclax (Venclexta) was granted an FDA breakthrough therapy designation in July 2017 for use in combination with low-dose cytarabine in treatment-naïve elderly patients with AML who are ineligible for intensive chemotherapy.
Although there has been much success in this field, Goldberg said that the focus needs to be put on elderly patients, as well as patients with myelodysplastic syndrome (MDS), a precursor to AML. In contrast to AML, MDS has experienced little success in the last decade, Goldberg said.
In an interview withTargeted Oncology, Stuart, a hematologist in the Division of Leukemia at John Theurer Cancer Center, and chief scientific officer of Cota, discussed the management of patients with AML as well as those with MDS.
TARGETED ONCOLOGY:How has the management of patients with AML evolved?
Goldberg:Prior to 2017, the management and evaluation of patients with AML was relatively simple. We would decide whether the patient was fit or unfit for therapy, and if they were fit, we would offer them standard induction chemotherapy. We have done that for 40 years. The management of AML has changed dramatically in the past year with the approval of several new agents. AML is no longer a simple disease; it is complex, and the evaluation needs to be done properly so that we can select the right patient for the right therapy.
TARGETED ONCOLOGY:Can you speak to how these new approvals have impacted the field?
Goldberg:This has truly been a banner year with the FDA approval of 4 new agents. Also, we have seen the use of other approved agents in AML that are showing efficacy in the elderly population. The field has become fairly complex; you need to do a very good workup because each of our agents are geared toward a specific subtype.
AML is an extremely complex disease at a genetic and chromosomal level. Up until now, we have used chromosomes mostly to determine whether a patient should get a bone marrow transplant or if they should get consolidation chemotherapy for risk stratification. However, with the introduction of the molecular tests, we can now give targeted therapies.
When I see a brand-new patient, I have to look at their history. Do they have a history of myelodysplastic changes or secondary AML? In that case, I might be using CPX-351. I have to look and see if they have a genetic alteration ofFLT3, because then I might be using a FLT3 inhibitor upfront such as midostaurin, or we may want to think about some of the experimental agents in the second-line setting. If they have anIDHmutation, we now have a drug forIDH2, and we will probably soon have one forIDH1. If the patient has a core-binding factor, a common chromosome abnormality, there may be a role for gemtuzumab ozogamicin. Each of these new drugs have a specific area where they seem to be shining.
TARGETED ONCOLOGY:Could chimeric antigen receptor (CAR) T-cell therapy have potential in this field?
Goldberg:The whole field of oncology is changing with the development of immunotherapies, which to date have not been very successful in AML or MDS. We do see the development of CAR T cells as a potential future [option]. It has already shown promise in lymphomas and myeloma, and we have targets on myeloid cells such as CD33 that may be a potential target for CAR T cells in AML. The work is fairly early, but there may be a future for CAR T cells in relapsed patients, similar to what we have seen in acute lymphocytic leukemia in patients who have relapsed after bone marrow transplant.
TARGETED ONCOLOGY:Venetoclax in combination with low-dose cytarabine has shown promise. Could you share some insight on that?
Goldberg:Most of the focus this past year has been on the development of new agents which have been used for the younger, healthier, fit patients. However, we desperately need agents to treat the older, unfit patients. In the past few years, we have used hypomethylating agents such as 5-azacitidine or decitabine, and sometimes low-dose cytarabine.
One of the most exciting developments in the elderly population is the data that have come out about the addition of venetoclax to either hypomethylating agents or low-dose cytarabine. There was a paper from researchers at The University of Texas MD Anderson Cancer Center on it in combination with hypomethylating agents, and at the 2017 ASH Annual Meeting we saw how it could be combined with low-dose cytarabine.
When you look at the combination, we are using the standard doses of our gentle drugshypomethylating agents and low-dose cytarabine. Venetoclax is extremely well tolerated, and more importantly, we are seeing a 60% complete response rate. This is pretty much unheard of with low-dose therapies. We are hoping that this may be a big step forward for the elderly patient who is not appropriate for aggressive induction chemotherapy.
TARGETED ONCOLOGY:Can you discuss the current treatment approach for relapsed/refractory patients?
Goldberg:Once a patient with leukemia relapses, and if you are trying to cure the patient, the goal is transplant. We have years of experience of trying to get them to transplant safely with less toxicities, but it has been a challenge. We don't have a standard second go-to therapy. However, we do have a couple developments in targeted therapies, such as second-generation FLT3 inhibitors and IDH1/2 inhibitors, which are well tolerated and allow the patient to have good quality of life, and potentially get them to transplant. Now we have gemtuzumab ozogamicin, which has been brought back. It may not be appropriate in the pretransplant setting, because it may raise the risk of veno-occlusive disease, but for patients not going to transplant, it may offer a lower-dose solution.
TARGETED ONCOLOGY:What is the current treatment landscape of MDS?
Goldberg:Although there is a lot of excitement about what has happened in the past year in AML, we have gone another year without developing anything new for MDS. The therapeutic options continue to be fairly limited. There are a couple drugs on the horizon.
We spent the last year understanding preleukemia, or pre-MDS, with the idiopathic cytopenias of uncertain significance (ICUS). These are the patients who, as hematologists, we all see. They come in with a cytopenia and we have done the workup, but we cannot figure out what they have. It turns out that most of them will not actually have MDS, and if we follow them long enough, most of them will actually do very well.
We also have clonal hematopoiesis of indeterminate potential (CHIP). This is where we have done the workup and the patient has a mild anemia, but the cytogenetics are abnormal. This is sort of the flip side of ICUS. These patients are a little bit more worrisome.
Then, there is clonal cytopenia of uncertain significance (CCUS). This is where the patient has low blood counts and bad genetics, but not the dysplasia to call it MDS. We have spent some time defining these characteristics in patients who might develop MDS in the future, but unfortunately, we still do not have treatments for them. This at least gives us a little more guidance on who we should watch and how we should follow them.
TARGETED ONCOLOGY:What is the greatest unmet need you would like to see addressed in both AML and MDS?
Goldberg:One of the greatest unmet needs is treating AML in the elderly. Despite all of this encouraging data, survival for the elderly patient has not changed in the last 20 to 30 years. We know that AML is a disease traditionally of the elderly. We have made some great headway this past year with new drugs, but we are still focused on the fit patients. Hopefully, the potential addition of venetoclax will help the elderly patients.