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Targeting AML: The Latest Advances

Sangeetha Venugopal, MD, MS, discussed the evolving landscape of acute myeloid leukemia treatment as well as unmet needs among these patients.

Sangeetha Venugopal, MD, MS

Patients with acute myeloid leukemia (AML) have benefited from recent advancements in treatment. The advent of drugs targeting specific genetic mutations, such as FLT3, IDH1, IDH2, NPM1, and KMT2A, as well as improved methods for genetic testing have changed the landscape for physicians and the patients they treat. Still, questions remain on how to best optimize treatment protocols.

In an interview with Targeted OncologyTM for Leukemia and Lymphoma Awareness Month, Sangeetha Venugopal, MD, MS, assistant professor of medicine in the leukemia program, the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, discussed the evolving landscape of AML treatment as well as unmet needs among these patients.

Targeted Oncology: What are some of the unmet needs among patients with AML?

Microscopic examination revealing red blood cells, white blood cells, neutrophils, eosinophils: ©AkuAku - stock.Adobe.Com

Venugopal: AML [is mainly] an older age group [of] patients. The median age of diagnosis is 69 years, but that does not mean that it does not occur in younger patients. The treatment that revolutionized the survival outcomes in older patients is hypomethylating agents in combination with venetoclax [Venclexta]. We can give this treatment indefinitely, meaning there is no stopping point. What I would like to know, and most of the patients would like to know, is if there is a stopping point for this treatment? And if that is the case, what are the subgroups where we can stop treatment? I am sure it is a selected subgroup of patients who with whom we can stop treatment.

How has the treatment of AML evolved in the last 10 or so years?

I started my fellowship in 2017, and 2017 was the first year that saw the approval of midostaurin [Rydapt], which targets FLT3 mutations. Since then, we have had several drugs approved for special molecular subsets, and that has changed the treatment landscape of AML immeasurably.

Especially for FLT3, we now have now 3 drugs that target the mutation because it is one of the most common molecular subgroups. Those are midostaurin, which targets both FLT3 [internal tandem duplication (ITD)] and [tyrosine kinase domain (TKD)], gilteritinib [Xospata], which targets the FLT3 ITD and TKD, and quizartinib [Vanflyta], which targets FLT3 ITD.

We have a couple of other [targets], including IDH1, and we have 2 medications to that target the IDH1 mutation. One is ivosidenib [Tibsovo], and the other is olutasidenib [Rezlidhia], which was approved recently. For IDH2, we have enasidenib [Idhifa].

The other exciting aspect that I am looking forward is that we have a new kid in the block, which is a Menin inhibitor, and that targets against NPM1 mutation and KMT2A rearrangements. I am looking forward to how this is going to play out for Menin inhibitors.

How do you go about assessing the best course of treatment for a patient? At what point does molecular testing come into the process?

The molecular landscape of AML is dynamic, so we do genetic testing at diagnosis, because we incorporate FLT3 inhibitors on day 8. We need to know the genetic makeup of the AML before we decide on whether we are going to add a FLT3 inhibitor or not, and FLT3 inhibitors are added in frontline treatments. We [do molecular testing] at diagnosis to incorporate the molecularly targeted treatment, and we do it at remission, which is treatment assessment of the bone marrow at the end of the first cycle of treatment, to know if the molecular aberration is still present or absent. That would help us decide how the how the prognosis is going to be, because some of these patients may be going to transplant. In those patients, we want to make sure that they do not have any of these molecular aberrations left to give a best possible outcome for transplant. After that, we do molecular testing at any time the AML relapses in a patient, mainly because we need to know the dominant clone that is driving this leukemia. Was this the same molecular aberration that was present at diagnosis, or is this something new that will affect the management?

What role does measurable residual disease [MRD] play in determining treatment?

We measure the residual disease by 2 ways. One is through flow cytometry, and the other is specific testing for molecular subgroups. Looking at the measurable residual disease, we want to look at a deeper level than the morphology and the pulse sequencing. The measurable residual disease needs a depth of at least 10-5.

The reason why we are looking at measurable residual disease is because it predicts the outcomes in long-term outcomes. For example, in a patient with core binding factor leukemia, if we track the measurable residual disease by, especially for the [inversion 16] and RUNX1-RUNX1T1 translocation, and when we track it, we can find if, at some point, they lose that response. For example, all along it is negative, and suddenly we see something like popping up which is positive, even though it is low-level positive. Then we increase the frequency to see if we can intervene before there is a frank morphological relapse. Right now, we do not intervene if it is just molecular relapse; however, we monitor the MRD more frequently than usual if we see that the level of MRD is rising.

Who do you consider referring for transplant with AML?

All patients must be referred for evaluation for hematopoietic cell transplant, regardless of the age, because sometimes the biological age may not matter. Sometimes, the biological age may be lesser than the chronological age. I do think that all patients would benefit from referral for hematopoietic cell transplant.

REFERENCE: Venugopal S, Sekeres MA. Contemporary management of acute myeloid leukemia: a review. JAMA Oncol. Published online August 8, 2024. Doi:10.1001/jamaoncol.2024.2662

Novel Treatment Regimen Yields Promising Response In Advanced-phase Chronic Myeloid Leukemia

According to researchers at The University of Texas MD Anderson Cancer Center, 80% of patients with previously untreated or relapsed/refractory advanced-phase chronic myeloid leukemia (CML)—including both accelerated or myeloid blast phases of the disease—or Philadelphia chromosome-positive acute myeloid leukemia (AML) achieved a bone marrow remission when treated with a novel combination of decitabine, venetoclax and ponatinib.

Findings from the Phase II clinical trial, published in The Lancet Haematology, represent an important step forward for patients with advanced-phase CML, who tend to have poor outcomes. Limited data on a standard-of-care approach to treating the disease, highlights the need for investigations into additional therapeutics.

"Over the last decade, there have been very few studies that evaluated a regimen to treat this rare disease and identify a potential standard-of-care treatment," said principal investigator Nicholas Short, M.D., associate professor of Leukemia.

"It is important that we get these patients into a state of marrow remission as this will allow them to be considered for a stem cell transplant. We were able to achieve this response in 80% of patients on this trial."

A total of 20 patients were enrolled in the trial, with 14 having myeloid blast-phase CML, four with accelerated-phase CML, and two with Philadelphia chromosome-positive AML.

Overall, 50% of patients achieved a complete remission or complete remission with an incomplete hematological recovery, and an additional 30% of patients achieved a morphologic leukemia-free state. Responses were seen even in patients who had received multiple prior therapies and in those with high-risk cytogenetic or molecular features.

"For this trial, we were able to build on previous preclinical and clinical research conducted at MD Anderson, which identified synergy between the BCL-2 inhibitor, venetoclax and the BCR::ABL1 tyrosine kinase inhibitor, ponatinib," Short said. "This knowledge led us to consider this novel treatment regimen for this aggressive disease."

The researchers observed expected side effects, which were consistent with previous studies with the drugs. Common side effects include neutropenia, rash and nausea.

The trial is ongoing and enrolling additional patients. MD Anderson researchers are also conducting additional studies building on the approach of adding targeted therapies into new combinations for patients with advanced-phase CML.

More information: Nicholas J Short et al, Decitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial, The Lancet Haematology (2024). DOI: 10.1016/S2352-3026(24)00250-3

Citation: Novel treatment regimen yields promising response in advanced-phase chronic myeloid leukemia (2024, September 18) retrieved 21 September 2024 from https://medicalxpress.Com/news/2024-09-treatment-regimen-yields-response-advanced.Html

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Several Resources I Counted On During Treatment For AML

Before receiving treatment for acute myeloid leukemia, I made it a point to take advantage of all the resources that were available to me.

When I was admitted to Moffitt Cancer Center for treatment to arrest my acute myeloid leukemia, I was walked through several hospitalization orientation steps. Thankfully, I had my brother at my side. Later I was blessed with a bevy of helpful social workers.

The process can be distressing and emotional. From the get-go, the treatment center required insurance, billing information, medical records, radiology images and pathology slides (for some patients with cancer), informed consent and a list of medications. There was training on the use of a patient portal to access records, messages, appointments, resources and more.

The touchier topics are approached. Do you want to give someone power of attorney? Do you wish to complete advance directives? Do you need to create a will? Do you need financial assistance?

When you're in a state of bewilderment, and perhaps even physical pain, all these steps can be daunting.

Take a breath.

Caregivers and social workers are godsends. Though genuinely empathetic, social workers are less emotionally affected by your diagnosis and can therefore focus on processes. Lean on them.

My social worker helped my caregiver and me execute forms, including the power of attorney and advanced directive. She provided a list of institutions that could help financially and emotionally. She advised me to submit my social security application. Honestly, I think she did a whole lot more, but I just have a lousy memory. I do know this: She listened. A lot. (Are all social workers born with a sweet voice?)

The list of resources for financial aid was long and remarkable. I reached out to The Lymphoma & Leukemia Society with my social worker's help and submitted a request to take advantage of their insurance co-pay program. I was bewildered and delighted that they paid a large portion of every monthly insurance premium! They are now in my will.

There were numerous other foundations that provided grants to help with the housing and transportation and other expenses for patients and caregivers. I was hospitalized during the COVID-19 pandemic and there were grants for one time relief help. Almost all my applications were approved. The list had at least 15 resources for financial aid.

Emotional help was also abundant at Moffitt Cancer Center — they had therapy dogs visit select patients. Cellists played music in common areas. Coffee and treats were shared with patients and caregivers in the surgical areas. Volunteers visited patients in infusion centers. I was in the bone marrow transplant ward and could not leave the unit, but for other patients, there was an art room with art supplies and instructors. There was a library and a chapel. There were support groups no matter where you were being treated.

My social worker introduced me to Imerman Angels. Even though I did not reach out at the time, I am now an Angel, myself. Through their unique matching process, Imerman Angels can connect you with a custom-selected Mentor Angel whose life experience and cancer story were much the same as yours. Sometimes we don't want to share our feelings with loved ones. We may even disagree with our caregivers on a topic. Sometimes patients don't have remaining family or someone nearby who can be by their side. I remember wanting to talk about death, but not with my family members! The mentor can be an ear for anything you wish to share.

American Cancer Society Hope Lodge communities offer a home away from home for people facing cancer and their caregivers when cancer treatment is far away. A Ronald McDonald House program can help reduce stress and financial burden for families when they must travel far from home to access medical care for their child.

I remember getting treatment. I remember the cellist. I don't remember struggling with forms or worrying about bills! Thanks to my social workers, caregivers, charitable foundations, institution-provided education, volunteers and support groups, I was able to focus on getting better. And I did.

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