Mutational Testing an Important Factor in AML Treatment Paradigm, Smith Explains

B. Douglas Smith, MD

B. Douglas Smith, MD

During aTargeted Oncologylive case-based peer perspectives program, B. Douglas Smith, MD, discussed his clinical consideration for the management of acute myeloid leukemia (AML). Smith, professor of oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, explained his treatment decisions during the dinner event in 2 case scenarios of patients with AML.

Case 1

A 65-year-old woman presented to her primary care physician with bruising and fatigue from her daily 3-mile walk. His medical history revealed hypercholesterolemia, which was controlled with atorvastatin (Lipitor). She was diagnosed with acute myeloid leukemia (AML).

At this time, her laboratory findings revealed the following: white blood count (WBC): 2.8 x 10⁹/L; hemoglobin (Hb): 9.1 g/dL; platelets: 40 x 10⁹/L. She had an ECOG performance status of 0. Additionally, her bone marrow biopsy showed that her cytogenetics were normal; blasts percentage: 48%.

Targeted Oncology: What genetic and molecular tests are ordered routinely at your practice?

Smith:Everybody uses a slightly different platform. Unfortunately, some places might struggle with payment. In 2019, I think everyone should be getting some molecular testing on their patients with AML. On average, we know that there will be between 3 to 8 different mutations in every patient. I think there is valuable information there. This patient hadIDH2, RUNX1,andDNMT3Amutations—3 mutations, which is very common in a newly diagnosed leukemia.

Next-generation sequencing (NGS) was completed, which revealed mutations inIDH2,RUNX1, andDNMT3A.

What treatment options would you consider for this patient?

The first choice for someone like this is always a clinical trial. Chemotherapy cytarabine plus idarubicin (7 + 3) plus an inhibitor on a clinical trial would certainly be something worthwhile. It is closed now, but we did have it open. The 7 + 3 combination alone is also available, but it is not approved in the frontline setting for patients withIDH1andIDH2mutations. It is certainly not approved in combination yet, but those trials are currently being done.

What are you likely to recommend?

In this situation, we would be thinking about traditional induction chemotherapy for a patient such as this. Her performance status is great, even if she is a little older. Her cytogenetics are normal and we don’t haveactionablemutations, simply because these drugs aren’t indicated in the frontline setting at this point.

7 + 3 chemotherapy was initiated.

What are your expectations from traditional induction chemotherapy?

This patient was given 7 + 3. When you talk to a 60-year-old patient like this, [you tell them that] the likelihood that this regimen will work is two-thirds of the time. We don’t know exactly what her mutations do individually, but we do expect the induction therapy to work.

What are the adverse events (AEs) associated with this regimen?

When you look at large, retrospective studies, the percentage of mortality ranges from a couple of percentage points to 18%, or even 20% for 30- to 60-day mortality for induction therapy in patients aged more than 60 years. For a patient with a good performance status, I tell people it is around 5%. Patients aged over 70 is when the percentage increases to 12%, 18%, and then 30%. We have significant mortality in that patient population.

The patient did have mucositis and febrile neutropenia, but she ended up getting a remission and went on to get 2 cycles of consolidation therapy. It was a fair success.

Her treatment course was complicated by mucositis and febrile neutropenia. After resolution of her complications, the patient received 2 cycles of intermediate-dose cytarabine consolidation.

Six months after initial diagnosis, she presented with fatigue, aches, and gum bleeding. Her laboratory findings were notable for the following: WBC: 22.8 x 10⁹/L; Hb: 88.1 g/dL; platelets: 28 x 10⁹/L; 20% circulating myeloblasts; absolute neutrophil count (ANC): 450 cells/mL. Her bone marrow biopsy showed hypercellular 80% blast; normal cytogenetics. NGS testing revealed the same mutations inIDH2,RUNX1, andDNMT3A.

What treatment options would you consider for this patient after disease progression?

This person did not go on to transplant, and 6 months later she presented with bleeding. She relapsed pretty early, and the mutations have recurred with this relapse.

The recently approved drug for patients withIDH2mutations in this setting is enasidenib (Idhifa). It definitely takes time to get, but we have not had any trouble getting it paid for. We know that between 10% to 15% of patients with AML will have IDH1orIDH2mutations. They are pretty common mutation, including in people whose disease comes out of myelodysplastic syndrome. You have to know that the mutation results in accumulation of 2-hydroxyglutarate, which blocks differentiation. It is epigenetically driven. The idea is that the cells don’t differentiate normally when you have IDH1orIDH2genesthat are mutated.

For targeted therapy, the approvedIDH2drug is enasidenib. This was from a phase I/II study with an expansion arm that arrived at the idea that the best dose of this drug was 100 mg a day.¹The drug was dosed continually for 28 days, and doses went from 50 mg upward.

Can you provide greater detail about this trial?

The patients on this trial had to have theIDH2mutation. The majority of them had relapsed/refractory AML and were aged over 60. This was an alternative to reinduction with some chemotherapy-based regimen. When you look at the overall response rate, about 40% of patients responded.

Interestingly, it takes a couple of cycles—on average, 2 cycles—until you get a first response. Best response might be closer to 3 or 4 cycles. This should remind you of hypomethylating agents. We used to tell physicians who gave these agents to go through 6 cycles with your patient until you could declare it didn’t work. You had to get through multiple cycles. I tell people now, after 2, 3, or 4 cycles, you should be seeing some change in blood counts if you are headed in the right direction with the hypomethylating agents. I don’t give up until 4 to 6 cycles, but if you see bad blood counts after 3 or 4 cycles, it is not clear that the patient will respond. It is the same with these drugs. You need multiple cycles to make sure you are going in the right direction. And you should be able to see some changes in blood counts by as early as a couple of cycles.

The chance of getting a remission here is probably better than with chemotherapy. That is why we are thinking about targeted therapy. The downside is that the median duration of response is 8 to 9 months. This doesn’t fix everyone, but it does create a window where you can get someone who is in early relapse to stem cell transplant if you didn’t transplant them at the beginning.

Enasidenib was initiated at 100 mg daily and after 3 cycles, the patient had stable disease. Then, after 5 cycles, laboratory results showed the following: peripheral blasts, 15%; ANC, 1.1/mm³red blood count transfusion-free

Can you explain the outcome of stable disease in this patient after starting enasidenib treatment?

A key thing with these drugs is that sometimes you get stable disease. Now we have patients with stable disease with peripheral blasts for 6 to 15 months. They don’t get worse, but they are not in a remission. That is not great for this person who is going to move to transplant, but for a 75-year-old patient who you are keeping stable, that is a reasonably good response. We believe that stable disease is important in these patients.

What are the AEs associated with enasidenib?

The majority of the AEs were grade 1 and grade 2 in the trial. But we think about gastrointestinal upset—including diarrhea, poor appetite, vomiting, hyperbilirubinemia—and liver function test abnormalities. Those tend to be some of the common treatment-related, single-agent AEs.

Two weeks later, she had dyspnea on exertion and mild swelling and a physical exam noted crackle bilaterally. Her Chest x-ray later noted bilateral infiltrates. Additionally, an increased indirect bilirubin of 1.9 mg/dL was noted.

What is the significance of the clinical symptoms experienced by this patient?

In [recent news], there have been 3 reported deaths from differentiation syndrome with this class of drugs. The FDA is up in arms about it. The drug is approved, but this is the number-1 issue. People actually die from it, and you have to be aware of that.

How is differentiation syndrome optimally managed?

Most of the time, you should probably stop the medication. You don’t have to. If you have mild differentiation syndrome and you use steroids, you might be able to leave the patient on the drug. However, when you see this, a lot of people would recommend hospitalizing the patient and giving them a few days of steroids to make sure things normalize. Differentiation syndrome is a big deal and it is worth thinking about.

Dexamethasone 10 mg every other day and antibiotics were started, and her pulmonary symptoms resolved in 1 week. A bone marrow biopsy after 6 cycles showed: morphologic complete response (CR); 2% blasts by flow cytometry; persistence of IDH2 mutation by NGS.

After the patient goes into remission, what would you consider for the next step in treatment?

This patient should go on to an allogeneic stem cell transplantation (alloSCT). In my practice, we would start a donor while we were beginning treatment, and if the patient had an excellent response, the discussion would be: Should we continue therapy—where the responses last 8 to 12 months—or should we move on to transplant after 4 to 5 cycles? Transplant is the curative option for this disease.

The patient was referred for alloSCT.

Case 2

A healthy 48-year-old man who was on no medication visited his primary care physician for flu-like symptoms lasting more than 2 weeks. His laboratory findings were notable for the following: WBC: 56,000 x 10⁹/L (90% blasts); platelets: 85 x 10⁹/L; ANC: 1.5/mm³; liver and cardiac functions within normal limits; bone marrow 65% blasts.

His cytogenetics revealed normal cytogenetic risk by European LeukemiaNet classification. Additioanlly, molecular testing showed the following:NPM1-mutated;FLT3internal tandem duplication (ITD)—positive (low allelic ratio);TP53,ASXL1, andRUNX1wild-type.

What induction therapy would you offer this patient?

When you have a younger person with AML, some data suggest that delays to treatment are not good. When you have an older person with leukemia, data indicate that you probably have 5 days to a week to wait. This is a high-count, proliferative, sick patient who should be treated sooner rather than later. At our practice, we would begin induction therapy at this point to stabilize a patient who is really sick with a high count.

We would treat with them with 200 mg of cytarabine—that was what was given in the RATIFY study—and 60 mg of daunorubicin.²That is what was given in the study, with the FLT3 inhibitor plus chemotherapy. The assumption is that if we find out the patient isFLT3-positive, we would treat them with midostaurin (Rydapt). We get the mutation testing back the same day; however, we would recommend starting induction therapy assuming it was aFLTmutation, although it may [turn out] not [to] be.

Can you explain the RATIFY trial design?

In the RATIFY trial, patients with tyrosine kinase domain or ITD-FLT3mutations were randomized to receive chemotherapy plus midostaurin or chemotherapy plus placebo. They were either consolidated with high-dose cytarabine plus midostaurin or high-dose cytarabine plus placebo. In addition, patients who were eligible were allowed to go on to alloSCT.

The group lined up well with regard to the randomization. When we talk about remission by day 60, midostaurin was a little bit better than placebo, but it was not statistically significant. When we talk about getting into CR during the time between induction therapy and consolidation therapy, it is statistically a little bit different with midostaurin versus placebo.

This is a tricky trial, and we don’t completely understand it. But if you have anFLT3mutation, point or otherwise, we believe that you benefit from the FLT3 inhibitor midostaurin. We don’t understand if it’s because you’re hitting theFLT3mutation or something else. There have also been add-on studies with other drugs, and this one has a strong biological rationale with theFLT3mutation. We do give FLT3 inhibitors in this space thinking that they add to the response that we would expect from chemotherapy and allow patients to do a little bit better.

Do you have a preference when choosing among the FLT3 inhibitors?

I don’t think that one of the original FLT3 inhibitors is [necessarily] the best. When it comes to some of the really selective FLT3 inhibitors, we may find that they are not as good as some of the older ones in this upfront setting. There are going to be data coming.

The patient was treated with 7 + 3 plus midostaurin. Upon count recovery, peripheral blasts approximately day 36 post induction. His bone marrow confirmed refractory disease.

What are your treatment options for this patient after disease progression?

Unfortunately, this patient received midostaurin, but when you repeat them after prolonged cytopenia, he is still loaded with blasts. This is now refractory disease. Your option is another FLT inhibitor versus more chemotherapy.

Gilteritinib (Xospata) is one of the second- or third-generation FLT3 inhibitors forFLT3-mutated refractory/relapsed AML. The approval was based on a study in which patients were randomized to the single-agent inhibitor versus chemotherapy.³What led to the approval of this drug in that study was a CR of only 20%. If this was pancreatic cancer, drugs like this get approved all the time. But in AML, we haven’t had this kind of leeway with the FDA. A lot more data will be coming out on this. We know that ultimately, if we get this into remission, they will go to transplant.

I know that the patient is young, but our bias would be to try to give him an oral inhibitor. In a month or so, if he doesn’t have a response, we would then give chemotherapy. However, we probably wouldn’t give him 7 + 3 again this far out. Twenty percent is not great, but it is a reasonable response rate for someone who is just coming off chemotherapy and is a little bit beaten up.

References:

1. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutantIDH2relapsed or refractory acute myeloid leukemia.Blood. 2017;130(6):722-731. doi: 10.1182/blood-2017-04-779405.
2. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation.N Engl J Med. 2017;377(5):454-464. doi: 10.1056/NEJMoa1614359.
3. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.Lancet Oncol. 2017;18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-3.