Research To Practice

Method

Recognizing and managing suspected differentiation syndrome on menin inhibitors

Maintain a high index of suspicion for differentiation syndrome in any patient starting a menin inhibitor: for revumenib, onset is roughly within one to two weeks; for ziftomenib it can occur later, up to one to two months, because of its longer half-life. Patients should come in for evaluation immediately if they develop fever, joint aches, bone aches, chest pain, trouble breathing, or rash. Workup includes checking blood counts for rising white count and differentiating cells, evaluating kidney function and joint/bone aches, obtaining a chest x-ray for pleural or pericardial effusions, and performing an echocardiogram if a pericardial effusion is found. At any suspicion, give high-dose dexamethasone 10 mg twice daily for three days regardless of symptom improvement — stopping steroids

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Method described by Dr Ghayas Issa

Method preserved for inspection; not a verified protocol.

Consequential creator advice requires independent verification before Today can promote it.

Method

Steroid management of suspected differentiation syndrome: dexamethasone 10 mg twice daily for three days

Dr Ghayas Issa advises that at any suspicion of differentiation syndrome, give high-dose steroids: dexamethasone 10 milligrams twice a day for three days, regardless of whether symptoms improve, because the goal is to prevent the syndrome from recurring. A dose of steroids can be diagnostic — patients often feel 100% better with the first dose, confirming you're on the right track. Because differentiation syndrome can be deadly, it is better to err on the side of giving steroids than to wait to confirm the diagnosis and risk it being too late to correct.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Method described by Dr Ghayas Issa

Method preserved for inspection; not a verified protocol.

Consequential creator advice requires independent verification before Today can promote it.

Method

Workup of suspected differentiation syndrome on menin inhibitors

Dr Ghayas Issa outlines the evaluation for suspected differentiation syndrome: check the blood count for an increase in white count (sometimes associated with differentiation); look at whether leukemia cells are turning into normal cells; a chest x-ray may be done because pleural or pericardial effusions can occur; an echo may be performed if there is a pericardial effusion; and kidney function should be evaluated.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Method described by Dr Ghayas Issa

Method preserved for inspection; not a verified protocol.

Consequential creator advice requires independent verification before Today can promote it.

Method

Evaluating suspected differentiation syndrome

Dr Ghayas Issa describes the workup for suspected differentiation syndrome: check blood counts for an increase in white count (sometimes associated with differentiation) and look for leukemia cells turning into normal cells; obtain a chest x-ray because pleural or pericardial effusions can occur; perform an echocardiogram if there is a pericardial effusion; and check kidney function.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Method described by Dr Ghayas Issa

Method preserved for inspection; not a verified protocol.

Consequential creator advice requires independent verification before Today can promote it.

Recommendation

Give high-dose dexamethasone at any suspicion of differentiation syndrome rather than waiting for diagnostic certainty

Dr Ghayas Issa recommends that at any suspicion of differentiation syndrome, high-dose dexamethasone 10 milligrams twice a day for three days should be given regardless of whether symptoms improve. Because differentiation syndrome can be deadly, it is better to err on the side of steroids than to wait for diagnostic certainty and risk it being too late to correct. A single dose often makes patients feel 100% better, which can serve as diagnostic confirmation, and stopping steroids early risks the syndrome recurring.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Recommendation from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Recommendation

Stem cell transplant consolidation is key to durable response on menin inhibitors

The key factor for improving durability of response in relapsed/refractory AML patients on menin inhibitors is consolidation with a stem cell transplant.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Recommendation from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Principle

Maintain high suspicion for differentiation syndrome; timing differs by agent (revumenib 1-2 weeks, ziftomenib up to 1-2 months)

Dr Ghayas Issa advises maintaining a high index of suspicion for differentiation syndrome in any patient on a menin inhibitor when they start treatment. For revumenib, it occurs roughly within one to two weeks; for ziftomenib it can occur up to a month or two months after starting, related to the drug's longer half-life.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Claim from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Recommendation

Err on the side of continuing menin inhibitors when patients derive benefit without clear progression

Dr Ghayas Issa explains that menin inhibitors are epigenetic therapies that take a little more patience; if the patient is deriving benefit and there is no clear progression, he would err on the side of keeping the menin inhibitor to see if it eventually turns into a full response.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Recommendation from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Principle

Stem cell transplant consolidation is key to durable response in relapsed/refractory disease on menin inhibitors

Dr Ghayas Issa advises that the key factor for improving durability of response — hopefully cure — in relapsed/refractory disease treated with menin inhibitors is consolidation with a stem cell transplant.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Claim from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Recommendation

Repeat mutational analysis at relapse

Repeat mutational analysis should be done on all patients at relapse to find targeted therapies. In about 5% of cases NPM1 is lost at relapse, so the analysis matters; KMT2A is detected at relapse in 100% of cases, so repeat analysis is probably less important for KMT2A — though some KMT2A-rearranged cases can be missed at diagnosis, which is another reason to test at relapse. If a patient acquires a FLT3 mutation at relapse, the treatment would be different.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Recommendation from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Recommendation

Give IT chemo prophylaxis with menin inhibitors unless combined with high-dose cytarabine

When treating patients with menin inhibitors without high-dose cytarabine combination, give prophylaxis with IT chemo to prevent CNS leukemia, since menin inhibitors do not cross the blood-brain barrier.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Recommendation from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Recommendation

Standard of care and count control before HMA/venetoclax

The standard of care for NPM1-mutated monocytic AML is HMA plus venetoclax. It is very important to try to reduce the count before starting HMA and venetoclax; hydroxyurea (hydrea) can be used to control leukocytosis before starting the regimen.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Recommendation from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Report

Menin inhibitors do not cross the blood-brain barrier; IT chemo prophylaxis is important to prevent CNS leukemia

Dr Ghayas Issa states that menin inhibitors are small molecules that do not cross the blood-brain barrier, so they would not prevent CNS leukemia. In patients treated with menin inhibitors without high-dose cytarabine combination, it is very important to give prophylaxis with IT chemo to prevent CNS leukemia.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Claim from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Principle

Patients on menin inhibitors should seek evaluation for fever, aches, chest pain, breathing trouble, or rash

Dr Ghayas Issa tells his staff and patients — giving them a card about menin inhibitors — that if they have any fever, joint aches, bone aches, chest pain, trouble breathing, or rash, they should come in and get evaluated.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Claim from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Recommendation

Consider menin inhibitors for KMT2A-rearranged or NPM1-mutant leukemias

Think of menin inhibitor therapies for KMT2A-rearranged leukemias or NPM1-mutant leukemias. Dr Issa hopes these therapies will be broadly available soon for all patients who could benefit.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Recommendation from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Creator perspective

Menin inhibitors do not cross the blood-brain barrier and do not prevent CNS leukemia

Dr Ghayas Issa explains that menin inhibitors are small molecules that do not cross the blood-brain barrier and therefore would not prevent CNS leukemia; when not combined with high-dose cytarabine, it is very important to give prophylaxis with IT chemo to prevent CNS leukemia.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Claim from Dr Ghayas Issa

Consequential creator advice requires independent verification before Today can promote it.

Creator perspective

Differentiation syndrome is caused by leukemia cells turning back into normal cells when differentiation arrest is lifted

Dr Ghayas Issa explains that differentiation syndrome is caused by leukemia cells turning back into normal cells when the differentiation arrest is lifted by drugs such as IDH inhibitors, arsenic, FLT3 inhibitors, or menin inhibitors.

Research To Practice · Acute Myeloid Leukemia — An Interview with Dr Ghayas Issa on the Role of Menin Inhibitors

Claim from Dr Ghayas Issa