Komrokji Reveals Therapeutic Strategies for Patients with AML

Rami S. Komrokji, MD, recently discussed the treatment considerations and decisions he makes when treating patients with acute myeloid leukemia. Komrokji, professor of oncologic sciences, University of South Florida, and vice chair of the Department of Hematologic Malignancies, Moffitt Cancer Center, explained his treatment decisions based on 2 case scenarios during a <em>Targeted Oncology</em> live case-based peer perspectives presentation.

Rami S. Komrokji, MD

Rami S. Komrokji, MD, recently discussed the treatment considerations and decisions he makes when treating patients with acute myeloid leukemia. Komrokji, professor of oncologic sciences, University of South Florida, and vice chair of the Department of Hematologic Malignancies, Moffitt Cancer Center, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

A 67-year-old man received standard chemotherapy for diffuse large B-cell lymphoma 3 years prior. He had hypertension, which was controlled with amlodipine. He was later diagnosed with acute myeloid leukemia (AML).

Lab findings showed: white blood count, 15 x 109/L; serum creatinine, 1.5 mg/dL; normal liver function tests; and left ventricle ejection fraction, 50%. He had an ECOG performance status of 1.

What are your general impressions of this case?

This is a case of cytophilic AML. The gentleman has a history of diffuse large B-cell lymphoma previously treated with chemotherapy, which we would assume would be CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab (Rituxan). He developed leukemia 3 years after, which is typically what we see in what we call type 2 therapy-related AML or myelodysplastic syndrome (MDS). This happens within a few years of exposure to chemotherapy, patients will present with AML or higher-risk MDS. Classically, they may have an 11q23 chromosome abnormality.

Additionally, the patient has hypertension and some mild renal impairment, but seems to have a good ejection fraction and a good performance status. That will open different options of treatment for the patient.

We do see 2 types of therapy-related MDS or AML. There is 1 type we call type 1, which we see with alkylating agents many years after transplant. Type 2 we see with topoisomerase II inhibitors, such as anthracyclines, and that usually happens within a few years where patients present with AML. [Based on that], this looks like the type 2-therapy related AML.

What additional workup would you order?

The patient presented with leukocytosis where there seemed to be a blast on the peripheral blood. A bone marrow biopsy must be obtained with cytogenetics. And, nowadays, we include molecular data. This includes somatic mutations, such asFLT3,NPM1,P53mutations, which are important in these patients specifically, andIDH1,IDH2,andDNMT3Amutations.

If there are additional concerns, one would look into disseminated intravascular coagulation, obtaining PIT, PTT, and uric acid levels to make sure the patient is not having hyperuricemia.

What are the options for therapy for this patient?

I believe the options are either less intensive therapy with hypomethylating agents versus intensive chemotherapy. Hypomethylating agents can be an option for patients with therapy-related AML and MDS, especially if they have a poor performance status, they are not fit for chemotherapy, or in cases where there is a complex karyotype, with several monosomies and aP53mutation. The advantage of [hypomethylating agents] is that patients will get it as an outpatient treatment, with less adverse events (AEs) than intensive chemotherapy. The disadvantage is that it takes longer to work and the complete response (CR) rate may not be as high as with intensive chemotherapy.

If the option is intensive chemotherapy, it’s usually based on patient performance status, absence of very complex karyotype, orP53mutation. Nowadays, we have a couple of options. The standard chemotherapy, the 3+7, which we have done for many years, and now cytarabine/daunorubicin (CPX351; Vyxeos) is approved for these patients.

What would you recommend for this patient?

The patent is 67 years old, has reasonable performance status, no major comorbidities at this point, and I think that this patient would probably be a candidate for allogeneic transplant down the road. That being said, I would go with an induction strategy with intensive chemotherapy. And, in this case, based on the FDA approval, I would use the liposomal cytarabine/daunorubicin.

What kind of supportive care would you offer?

Patients need infection prophylaxis, so they would be on prophylactic antibiotics for infection. They would also need blood product support, in terms of red blood cells and platelets. Additionally, they need hydration. If they have hyperglycemia treatment, for the care after the induction, the patient would be hospitalized because it is intense care for that patient.

The patient received treatment with liposomal cytarabine/daunorubicin, but his course was complicated by febrile neutropenia. After induction, laboratory findings showed: <5% marrow blasts, neutrophil count (>1400/&micro;L), and platelets 60,000/&micro;L.

What are your general impressions after the patient experiences disease progression?

The patient received liposomal cytarabine/daunorubicin. He developed febrile neutropenia, which is expected. Afterwards, he had less than 5% marrow blasts, the neutrophil count was more than 1400, and the platelet count was 60,000.

Would you offer this patient consolidation therapy?

We would offer this patient consolidation therapy. In general, the consolidation strategy in AML could be with either chemotherapy or allogenic stem cell transplant. In this patient, we would think of allogenic transplant. If the patient did not have a donor or was excluded from transplant, then there is room for consolidation. Sometimes, if the timing of the transplant was 3 to 4 months, down the road one would consider a consolidation therapy.

What supportive care would you offer this patient?

In terms of supportive care with consolidation therapy, it would be similar to the induction phase. However, the consolidation treatment can be done outpatient. Those patients can be seen on a regular basis to receive their infusions and antibiotic prophylaxis, but it can be done outpatient.

Why would cytarabine/daunorubicin be a desirable option for consolidation therapy based on the phase III study?

The CPX-351 is a molecule that combines both cytarabine and daunorubicin in a pegylated form. It affects the molar ratio that the leukemia cells kill. It has been through phase I and II studies. In the phase II study, there was a signal that maybe there is an overall survival (OS) [benefit in] patients that had therapy-related AML or MDS, or those who had AML from MDS.

The phase III study was designed to look at patients aged 60 to 75 that were candidates for intensive chemotherapy that either had therapy-related AML or AML with a history of MDS, AML with a history of de novo MDS, or MDS with karyotype or epigenetic changes.1Patients received either 3+7 or the CPX351.

The baseline characteristics between those 2 groups were similar. More than a third of the patients were above the age of 70 in both arms. Additionally, on both arms, half of the patients had poor risk cytogenetics by the National Comprehensive Cancer Network criteria. One-third of those patients had received prior hypomethylating agents.

In terms of response rate and efficacy, the CR as well as CR with incomplete blood count recovery rate was higher with CPX351 than 3+7. The OS was statically significantly better for patient that received the CPX351, with a median OS of 9.56 months compared with 5.95 months, which was still seen even when [looking at patients who underwent] transplant. Those patients that had CPX351 were more able to proceed to transplant, so it was a bit better of a bridge to transplant.

In terms of toxicity and safety, the 30 and 60-day mortality rates were less with the CPX351 compared to the 3+7. The AEs noted were similar to what was seen in terms of intensive chemotherapy, neutropenia, sepsis, and the classic AEs that we see with intensive chemotherapy. The count recovery has approximately a 7-day delay with CPX351, however, the 30 and 60-day mortality was not increased. We do see more distinguished rash with CPX351. But, in general, the AE profile was very similar to the 3+7 arm, with less 30 and 60-day mortality rates.

Case 2

A 75-year-old female was diagnosed with AML. She had normal cytogenetics;IDH2R140,RUNX1, andDNMT3Amutations.

The patient was started on 3+7 induction chemotherapy, but her treatment course was complicated by mucositis and febrile neutropenia. After resolution of her complications, she received 2 cycles of intermediate-dose cytarabine consolidation.

What are your general impressions of this patient?

This is a 75-year-old gentleman who had AML, normal cytogenetics. Next-generation sequencing (NGS) testing showedRUNX1andIDH2mutations. He was originally treated with 3+7, as was expected. The course was complicated by mucositis and febrile neutropenia. Then he went on to receive 2 cycles of intermediate-dose cytarabine as consolidation therapy.

Do you routinely test forIDH1/IDH2mutations?

We obtain NGS testing in those patients that includes theIDH1/IDH2mutations. Nowadays, in the relapsed/refractory AML setting, those could be targeted mutations. Whether they need to be tested in every patient upfront or not, it may not change their current management. Although, this could change with some of the newer treatments. They may have higher responses in patients especially with theIDH1/IDH2mutations.

When should testing be performed?

I think it should be performed if one would consider changing the treatment based on what I said before. For example, in the relapsed/refractory setting or upfront where there is data suggesting that those patients could be combined with hypomethylating agents plus IDH1/IDH2 inhibitors, or hypomethylating agents plus venetoclax (Venclexta). However, it is still under investigation as to whether you test it as part of an NGS panel or separately. At our institution, we test them as part of the panel.

Six months after her initial diagnosis, she presented with fatigue, aches, and gum bleeding. Lab findings showed leukocytosis, 20% circulating myeloblasts; and absolute neutrophil count, 450 cells/mL. A bone marrow biopsy was performed, showing hypercellular 80% blast and normal cytogenetics. NGS revealed recurrentIDH2-mutated AML, but no other mutations were detected.

What are your impressions of this patient after progression?

This patient received consolidation as I mentioned previously, and then 6 months later had some symptoms. Unfortunately, findings showed that he had relapsed disease with leukocytosis, 20% circulating myeloblasts, and his ANC was 450 cells/mL. A bone marrow biopsy was done and showed 80% blast, he had normal cytogenetics, and theIDH2mutation was detectable.

What are the therapeutic strategies for this patient at this point?

Only patients who relapse within 1 year are considered early relapsed AML. Intensive chemotherapy could be an option for some of those patients. However, the duration of the first response is what dictates chances of achieving a secondary remission. The patient has a short-lived response. And with a patient who is 75, who is probably not going to proceed to allogeneic stem cell transplant, the value of intensive chemotherapy could be discussed. Especially in the setting of early relapsed AML.

Other options are the approved enasidenib (Idhifa). Enasidenib is an IDH1 inhibitor that is approved by the FDA for patients who have relapsed/refractory AML withIDH2mutation. That is a reasonable option for this patient. In terms of clinical trials, there are clinical trials combining IDH2 inhibitors with hypomethylating agents in the relapsed setting that could be reasonable. There are data on hypomethylating agents or low-dose cytarabine with venetoclax, suggesting that patients with anIDH2mutation may have a high response. Those would be reasonable clinical trials for this patient.

We see around 5% to 10% of patients with AML have anIDH1mutation and 10% to 15% have anIDH2mutation. Those mutations are typically mutually exclusive for other methylating mutations, such as theTET2mutation. [IDH1/2mutations are] thought to be an early oncogenic event in AML and lead to methylation and impair cellular differentiation.

Enasidenib is the selective oral inhibitor for theIDH2mutation. There was a phase I/II study with a dose escalation phase, and there was an expansion of the study with a 100-mg dose.2There were different cohorts in the phase I expansion study, including patients above or below the age of 60, and those above 60 if they had a relapse after transplant, or below 60 excluding patients who had transplant, an untreated cohort of patients, and a smaller cohort that included patients with MDS. The expansion phase of the phase II study was based on refractory/relapsed AML.

Around 20% of the patients achieved a CR with a little bit more patients achieving stable disease and other clinical benefits. The time to first response was 1.9 months. The duration of response was 5.8 months. Those that achieved a CR had a longer duration of response. Again, the treatment is oral and relatively well tolerated. The main AEs were gastrointestinal, as well as myelosuppression. It is important to note that a differentiation-like syndrome has been reported in patients treated with enasidenib, with leukocytosis on the peripheral blood, and some blasts seen that sometimes would require additional hydroxyurea (Hydrea) or steroids, however, it is not a sign of progression of the disease.


  1. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trials of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary AML).J Clin Oncol. 2016;34(suppl 15; abstr 7000). doi: 10.1200/JCO.2016.34.15_suppl.7000.
  2. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant-IDH2relapsed or refractory acute myeloid leukemia.Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405.