 This is Patient Profile 1. This is a 62-year-old woman who has a history of a prior malignancy, a triple-negative breast cancer for which she received neoadjuvant chemotherapy, including several cycles of anthracycline-based drugs, breast-conserving surgery, and then follow-up radiation therapy followed by adjuvant capecitabine and potential hormonal therapy. She has a long history of being treated for this solid tumor malignancy. Other than that, she’s relatively well. She has some hyperlipidemia, which is well controlled.

Despite taking some time off for her medical treatment, she continues to work full time as a teacher and remains active. About 4 years after completion of her adjuvant chemotherapy, she unfortunately presents with some persistent nosebleeds to her primary care doctor. He performs laboratory work, showing significant abnormalities. Her white blood cell count is now elevated at 24,000 per mm3, with evidence of abnormal cells constituting 20% of the peripheral blood. She has a hemoglobin of 7.1 g/dL and a platelet count that’s decreased to 43,000 per mm3. Creatinine is off slightly, at 1.5 mg/dL. Otherwise, her liver function tests are normal, and a recent echocardiogram as part of our cardiac work-ups showed a normal ejection faction. In your office, she looks great. She’s a little fatigued, but otherwise, her ECOG performance status is 1.

On examination, she has some evidence of recent nosebleeds, scattered bruises, and petechiae due to low platelets, but she’s otherwise well with a normal cardiopulmonary examination. However, a bone marrow biopsy confirms a diagnosis of a therapy-related or secondary AML [acute myeloid leukemia] with 40% myeloblasts. Her cytogenetics are normal with evidence on a rapid mutational profile of only a 

 Should we back up for a second? Do you agree that this patient has secondary AML? If so, why?

 The diagnosis of a secondary therapy-related AML is mostly because of the clinical history. As you mentioned, we have evidence of specific mutations that are tied to the biology of the underlying disease. But in this case, even without the mutational profile, she has developed an acute myeloid leukemia in the setting of prior myelotoxic chemotherapy, giving her a clinical diagnosis of therapy-related AML. Do you disagree with that? What are your thoughts? Do people need to keep doing that mutational profile to confirm that, or can they just do it based on history?

 With history, she definitely has secondary AML. But this brings up 1 of the issues I mentioned in my starting remarks: we don’t know her cytogenetics. It could be normal. Her mutational profile is pretty benign. A 

 mutation doesn’t put her into the Dr Coleman Lindsley secondary category. 

 is epigenetic but not a chromatin-remodifying enzyme. This patient might have a better prognosis than we think. Obviously, cytogenetics could be bad. It’s at the right time frame to get what I call the worst flavor of secondary AML.

There are 2 types of secondary AML. There’s the alkylating agent type, which this patient may have. Then there’s epipodophyllotoxin type, which occurs with a shorter incubation period and tends to have an MLL [mixed-lineage leukemia] rearrangement, which in general fares a little better than the alkylating agent type that was first described after MOPP [mechlorethamine, vincristine, procarbazine, prednisone] chemotherapy. This patient definitely has secondary AML by history, but may have a better prognosis than the average patient with secondary AML. We aren’t told the cytogenetics, but the 

 isn’t that bad. We don’t know the VAF [variant allele frequency] for the 

 mutation. If it’s a low VAF, it could even be a 

 mutation. This patient may have a pretty good prognosis.

Videos

Two experts review a patient profile and discuss whether the patient meets the criteria for secondary acute myeloid leukemia (AML).

Patient Profile 1: Patient with Secondary Acute Myeloid Leukemia

 program on improving outcomes in newly diagnosed acute myeloid leukemia [AML] and translating evidence to clinical practice. My name is Dr Richard Stone, and I’m a professor of medicine at Harvard Medical School, the chief of staff at Dana-Farber Cancer Institute, and director of translational research in the leukemia division of medical oncology at Dana-Farber Cancer Institute in Boston, Massachusetts. I’m joined by my colleague Dr Eunice Wang. I welcome my good friend and colleague to introduce herself.

 Thank you, Rich. I’m delighted to be here to participate in this program. My name is Dr Eunice Wang from the Roswell Park Comprehensive Cancer Center [in Buffalo, New York], where I’m with the leukemia service and the department of medicine. I’m delighted to share my treatment approach for AML.

 Welcome, and thank you for joining us in what we hope will be an enlightening discussion. We’re going to discuss advances in the treatment of newly diagnosed acute myeloid leukemia and its impact on clinical practice. We’ll present 2 hypothetical patient cases and discuss our treatment approach to illustrate how we incorporate recent data in our practice. Let’s get started.

At least 1 of these cases, if not both of them, will have secondary AML. This term isn’t used with the utmost precision when talking about cases. But in general, there are different flavors of secondary AML. One flavor of secondary AML is treatment-related AML. These folks have had hints of cancer chemotherapy for another neoplasm, whether chemotherapy or radiation, and now they have a myeloid malignancy. Not all those patients are the same. We know from DNA sequencing of cytogenetics, which can define the biology of the disease, that some of these patients may be more treatable than others. Certainly, such patients are enriched with what we’d consider mild dysplasia-related changes, such as abnormalities of chromosome 5 and 7 in complex karyotypes as well as adverse mutations, such as 

Another type of secondary AML is seen in patients who have had a prior episode of myelodysplasia, ideally documented, who now have AML. Most of those patients have what we call secondary or myelodysplasia-related cytogenic and particularly molecular abnormalities, as was shown by many doctors, especially Dr Coleman Lindsley, who showed that a lot of patients with AML who have a prior history of MDS [myelodysplastic syndrome] have certain mutations that are usually in chromatin-remodeling enzymes or spliceosome genes. Some patients who have never had a known history of MDS have secondary AML mutations. Whether those should be considered secondary AML without a history of MDS is open for debate.

The notion of secondary AML is enriched for adverse prognostic features, but not every patient has adverse prognostic features. This is a distinction to de novo AML, where there’s no history of MDS. In general, those patients are more likely to have what we call pan-AML mutations, normal cytogenetics, or favorable cytogenetics. But as I mentioned a few seconds ago, some patients with de novo AML really have secondary AML, at least biologically, so that’s a bit of a challenge.

With most patients with secondary AML—at least the ones who have less than ideal prognosis, which is the majority—what are our treatment goals? It depends on patient age, comorbidities, and philosophy about what our treatment goals would be. If a patient is reasonably young, under age 75, we might even have cure as the goal. If cure is the goal in general, a patient with adverse chromosomes or secondary AML mutations are only going to be cured if they can get to a stem cell transplant.

In general, when someone presents with 1 of these adverse AML cases, we’d consider some form of induction chemotherapy. We’ll talk in a few minutes about the possibilities for induction or initial chemotherapy. Then the goal would be to do a stem cell transplant. We know that stem cell transplants can be difficult in the subgroup of patients with secondary AML with 

 mutations, but it’s still there as a goal for many of those patients, although it’s a distant, difficult-to-achieve goal for those with 

There’s also a question about how our practice has changed since COVID-19. With COVID-19 receding, we’re somewhat back to the way we were pre–COVID-19. But during COVID-19, more patients were being treated at community oncology centers. They couldn’t or wouldn’t come to the tertiary care centers, even now with the advent of the HMA [hypomethylating agent] venetoclax as an initial therapy for many patients with AML. That’s a combination that, while not completely benign, certainly lends itself to being given to the community because it isn’t as myelointensive as standard 3+7–based regimens. We need to make sure our community oncologists are aware of how to manage that chemotherapy and deal with the adverse effects.

Plus, we have targeted agents like IDH1 inhibitors, IDH2 inhibitors, and FLT3 inhibitors. Maybe those need to be managed in a different way from how we’re used to treating patients with AML with 3+7 alone. During COVID-19, some of the patients were pretty far along when they got to see the doctors, but I’m happy to report that we seem to be back into the same level of disease that patients have when they come to the doctor. Eunice, do you want to make additional comments about secondary AML?

 My only comment is that it appears that we’re seeing more cases of secondary AML over time, in part because of the overall aging of the general population, and that people are living longer and developing secondary myeloid processes. I also think that as we treat more patients who have other malignancies, cancers, and conditions with things like cytotoxic agents, CAR [chimeric antigen receptor] T-cell therapy, and transplants, the subset of patients who have therapy-related AML, which is a subset of secondary AML, has also been increasing. That’s partially the result of our success in other areas that we’re starting to see that continue to rise.

 Those are fantastic points, Eunice, and I agree with all of them.

Richard Stone, MD, and Eunice Wang, MD, define secondary acute myeloid leukemia treatment goals and how treatment has been affected by the COVID-19 pandemic.

Secondary Acute Myeloid Leukemia (AML): Overview

Eunice Wang, MD, the chief of the Leukemia Service at Roswell Park Comprehensive Cancer Center, discusses the potential impact of menin inhibitors on the treatment of acute myeloid leukemia (AML).

Menin inhibitors potentially represent the next forefront of targeted treatment for patients with AML, according to Wang. Previously, positive results have been observed with other targeted therapies, such as the 

-targeting antibody-drug conjugate gemtuzumab ozogamicin (Mylotarg), 

 inhibitors midostaurin (Rydapt) and gilteritinib (Xospata), and 

 inhibitors ivosidenib (Tibsovo) and enasidenib (Idhifa), Wang says. Most recently, older patients with AML have also been found to benefit from a 

-targeted treatment approach, Wang notes.

As such, menin inhibitors show potential as a treatment option for patients with 

 rearrangements, Wang adds. Additionally, menin inhibitors could be combined with other targeted treatment options to further enhance outcomes, Wang concludes.

Eunice Wang, MD, discusses the potential impact of menin inhibitors on the treatment of acute myeloid leukemia.


Dr. Wang on the Potential Impact of Menin Inhibitors in AML

Eunice Wang, MD, chief, Leukemia Service, Roswell Park Comprehensive Cancer Center, discusses preliminary findings from the ongoing KOMET-001 trial (NCT04067336) in relapsed/refractory acute myeloid leukemia (AML).

The first-in-human, open-label, phase 1/2a study is evaluating the oral, selective menin inhibitor KO-539. Currently, the study has enrolled 12 patients to 1 of 4 dosing cohorts. At the data cutoff, 1 patient was enrolled to the 50 mg cohort, 1 patient was enrolled to the 100 mg cohort, 6 were enrolled to the 200 mg cohort, and 4 were enrolled to the 400 mg cohort, Wang says. 

Notably, preliminary findings showed that all adverse effects (AEs) observed were mild, reversible, and did not result in treatment discontinuation. Grade 3 or higher AEs​, reported in 1 patient each, included pancreatitis, increased lipase, decreased neutrophil count, tumor lysis syndrome, and deep vein thrombosis. Grade 1 or 2 AEs included nausea,, rash, and diarrhea. No AEs common with other drugs in this category, such as QT prolongation, were observed. Additionally, no drug-drug interactions or limitations with coadministration of CYP3A4 inhibitors were noted, Wang concludes.

Eunice Wang, MD, discusses preliminary findings from the ongoing KOMET-001 trial in relapsed/refractory acute myeloid leukemia. 








  Dr. Wang on Preliminary Findings From the KOMET-001 Trial in Relapsed/Refractory AML 

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses the results of the combination of crenolanib plus chemotherapy in a study of patients with acute myeloid leukemia (AML).

The novel FLT3 inhibitor crenolanib was evaluated in combination with standard chemotherapy for patients with AML up to 60 years old who are

-mutant. The quality of the remissions observed in this population were very good, says Wang, as 15 out of 16 patients in remission were minimal residual disease (MRD)-negative. Of the evaluable patients, the overall survival was 79% after almost 18 months, and the rate of relapse was 16% after a median follow-up of about 15 months, Wang adds.  

These numbers compare favorably to the data seen with the RATIFY trial, which lead to the approval of midostaurin (Rydapt) for the treatment of adult patients with newly diagnosed

-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses the results of the combination of crenolanib plus chemotherapy in a study of patients with acute myeloid leukemia.

Dr. Wang on Results With Crenolanib Plus Chemotherapy in AML

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses treatment options for patients with 

About one-third of patients with AML will have disease characterized by a 

mutation, says Wang. Prior studies have shown that these patients have a worse clinical outcome overall, with a shorter period of disease-free survival and higher recurrence rates.

In April 2017, the FDA approved the oral kinase inhibitor midostaurin (Rydapt) for the treatment of adult patients with newly diagnosed 

-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Since midostaurin was developed, many companies have been focusing oral kinase inhibitors in an effort to create a more specific and potent agent, Wang says.

A study was presented at the 2017 ASH Annual Meeting evaluated the safety, feasibility, and efficacy of the novel FLT3 inhibitor crenolanib in combination with standard chemotherapy for patients with AML up to 60 years old who are 

-mutant. The addition of crenolanib to chemotherapy was safe and well tolerated, Wang says. Of the patients evaluated, 29 (72%) achieved a complete response (CR) after 1 cycle of induction with cytarabine/anthracycline and crenolanib.

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses treatment options for patients with FLT3-mutated acute myeloid leukemia.
 

Dr. Wang Discusses Treatment Options for FLT3-Mutated AML

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses the combination of crenolanib and cytarabine/anthracycline chemotherapy in patients with acute myeloid leukemia (AML).

A study presented at the 2017 ASH Annual Meeting evaluated the safety, feasibility, and efficacy of the novel FLT3 inhibitor crenolanib in combination with standard chemotherapy for patients with AML up to 60 years old who are 

-mutant. Patients were enrolled onto the study if they were newly diagnosed and untreated.

When looking at these patients, the results showed that the addition of crenolanib to chemotherapy was safe and well tolerated, Wang says. Of the patients evaluated, 29 (72%) achieved a complete response (CR) after 1 cycle of induction with cytarabine/anthracycline and crenolanib. Additionally, 3 patients achieved a CR after re-induction or after treatment with high-dose cytarabine or hematopoietic stem cell transplant. The adverse events were not significantly different than expected, said Wang.

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses the combination of crenolanib and cytarabine/anthracycline chemotherapy in patients with acute myeloid leukemia.

Dr. Wang Discusses Crenolanib Plus Chemotherapy in AML

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses 

 mutations in acute myeloid leukemia (AML).

-mutated AML, crenolanib was combined with standard chemotherapy. There was an initial high response rate, and the drug was fairly well tolerated.

There is a lot of heterogeneity in the FLT3 mutations that AML patients can present with, says Wang. Additionally, there are data suggesting that these mutations can predict resistance to other TKIs.

Eunice Wang, MD, chief, Leukemia Service, professor of Oncology, Departments of Medicine and Immunology, Roswell Park Cancer Institute, discusses FLT3 mutations in acute myeloid leukemia.

Eunice Wang, MD

Articles