Oncology Frontier: Could you please summarize the new treatment in the last 2years for Acute Myeloid Leukemia patients?
Dr Wang: Over the last two years, we have had a number of different therapies and agents that have been approved for the treatment of acute myeloid leukemia here in the United States. These include targeted therapies for specific mutations which are commonly identified in acute myeloid leukemia, specifically FLT3 and IDH1/IDH2 mutations. We have had two drugs approved for FLT3 mutant disease - midostaurin, an oral pan-kinase inhibitor added to intensive chemotherapy for newly diagnosed AML; as well as gilteritinib, a second-generation FLT3 inhibitor approved for monotherapy for patients with relapse and refractory FLT3 mutant AML. In addition, we have had two small molecule inhibitors for IDH1 and IDH2 - ivosidenib is targeted against the IDH1 mutations; and enasidenib is targeted against IDH2 mutations. In addition to that, we have had the reemergence or reapproval of an antibody drug conjugate, gemtuzumab ozogamicin, that is now being added to the upfront intensive chemotherapy setting in combination with 7+3 for patients with favorable and intermediate-risk cytogenetic acute myeloid leukemia. We have also had, most impressively, the addition of a BCL2 inhibitor, venetoclax, added to low-dose cytarabine or hypomethylating agent (HMA) therapy in the treatment of elderly unfit AML >75 years of age. We’ve also had the approval of a targeted stem cell agent, a sonic hedgehog inhibitor, glasdegib, which is also being utilized in combination with low-dose cytarabine for older and unfit newly-diagnosed AML patients. So a number of agents have been approved, and one of the challenges as we manage AML moving forward is what combinations we can use for these patients. In addition to targeted therapy, we also have novel formulations of an older regimen, 7+3 - CPX351 is a liposomal formulation of 7 and 3, specifically cytarabine and daunorubicin, which is being prescribed for the treatment of a very poor subset of AML, secondary AML failing prior myelodysplastic syndrome or therapy-related AML. The last, most recent approval for AML has been the introduction of an oral hypomethylating agent, CC-486. This is the first agent to be approved for use in the maintenance setting after intensive chemotherapy for those individuals with acute myeloid leukemia who are unable to proceed onto allogeneic stem cell transplantation.
Oncology Frontier: Could you please give a brief introduction about how to implement biology, cytogenetics, and molecular markers to refine AML treatment approach?
Dr Wang: In the current era with the diversity and range of novel therapeutics that we have, it is essential that patients undergo cytogenetic and molecular analyses of AML at diagnosis as well as at the time of disease recurrence. How do we use these cytogenetic and molecular features? The identification of specific mutations provides therapeutic as well as prognostic information to guide AML therapy. For example, patients who have favorable or intermediate karyotype are eligible in the intensive chemotherapy regimens for the addition of an antibody drug conjugate, gemtuzumab ozogamicin. The addition of this antibody drug conjugate to standard intensive chemotherapy has been shown to improve the overall survival of favorable cytogenetic-risk AML patients by 20-30%. That is a substantial improvement over the outcomes for 7+3 alone. Similarly, we now have the ability to target FLT3 as well as IDH1 and IDH2 mutations in the upfront and recurrent setting with targeted FLT3 and IDH inhibitors. Of course, identification of those inhibitors is essential for incorporation or use of those agents in the upfront or relapsed and refractory setting. Lastly, the use of molecular mutational markers can tell us information about what therapies not to use. For example, the detection of a mutation in TP53 is universally considered to be a poor prognostic sign, and indicates that the patient will probably respond poorly to treatment both with intensive 7+3 regimens as well as, to some degree, venetoclax-based combination regimens. Identification of a p53 mutation may lead clinicians to pursue alternative therapies including experimental agents targeted against that specific subset, which were presented at the recent Hematology meeting. These p53 mutant AML patients may respond better to treatment with a specific p53 mutant inhibitor, APR-246, or with a specific immunotherapeutic such as magrolimab added to azacitidine in the upfront setting. We do know that identification of some of these mutations can also predict for better response to some regimens we are currently developing. For instance, we know that patients who are older and unfit and who have IDH mutations and/or NPM1 mutations have a very high chance of responding to venetoclax-based HMA regimens in the upfront unfit setting, whereas patients with FLT3 mutant disease may or may not benefit and patients (as mentioned before with p53 disease) have a short overall survival despite high levels of complete remission after initial therapy. To summarize, it is important and essential that all patients undergoing potential therapy for acute myeloid leukemia have cytogenetic and molecular information performed at the time of diagnosis as well as at recurrence. That information is essential for planning future therapy and selecting appropriate agents. Here in the United States, we have recommended that certain pCR-specific mutation analyses for genes such as CEBPA, IDH1, IDH2, NPM1 and FLT3 be performed and expedited within 3-5 days of diagnosis. There are data recently from the German Cooperative Group that delaying therapy particularly in older individuals may be reasonable and feasible and does not impact on outcomes for intensive chemotherapy for those individuals. Waiting for up to a week or even longer to obtain those results is safe and feasible, and the majority of patients don’t have rapidly progressive disease. Lastly, I would emphasize that due to single cell analyses studies and other evaluations of genomic data, there is a significant degree of clonal selection and clonal evolution that occurs over the course of AML therapy. For instance, patients with FLT3 mutations may have them detected at diagnosis and not at relapse, and alternatively, they may not be detected at diagnosis and only picked up at relapse. So it is extremely important to repeat selective genomic analyses at the time of recurrence.
Oncology Frontier: Could you please highlight the latest studies released in ASH for AML?
Dr Wang: Each of the newer targeted therapies is associated with a new array of potential side effects that must be managed carefully in the clinical practice. Just to give an example and a list of possible toxicities. Patients receiving treatment with FLT3 inhibitors , specifically gilteritinib in the relapsed refractory FLT3 mutant setting, may develop abnormalities not only including liver function test abnormalities, but also differentiation syndrome. Differentiation syndrome is something that has been identified following treatment most commonly with drugs used for acute promyelocytic leukemia, but is also a common side effect of novel targeted therapies, specifically IDH1 inhibitors, IDH2 inhibitors and FLT3 inhibitors. Clinical symptoms of this include hypoxia, weight gain, fever, infiltrates, fluid overload and symptoms that could be consistent with acute respiratory distress syndrome (ARDS), pneumonia or congestive heart failure. Patients who do not respond or who have not been identified to have an infectious etiology of these abnormalities should be considered for initiation of steroids (dexamethasone 10mg bid for at least 3-5 days) with potential discontinuation of the targeted therapy if symptoms do not improve. We also know that IDH inhibitors can be associated with other rare phenomena. Ivosidenib has been associated with a rare neurological condition called Guillain-Barré syndrome. Gilteritinib has been associated with a rare neurological syndrome called posterior reversible encephalopathy syndrome. Gemtuzumab ozogamicin, which is added on to upfront conventional chemotherapy for favorable intermediate risk AML, can lead in the setting of an allogeneic stem cell transplantation, to the risk of potentially fatal veno-occlusive disorders. While these are some of the toxicities that clinicians need to be aware of, the most common toxicity that they will experience, particularly for the treatment of older unfit AML patients, is prolonged marrow suppression, which is seen with the combination of the oral BCLA2 inhibitor, venetoclax, added to either low-dose cytarabine or hypomethylating agents. The myelosuppression following the venetoclax addition can last for 3, 4 or 5 weeks. It is recommended when initiating venetoclax that clinicians be aware of the risk of tumor lysis thereby requiring careful dose escalation with the first week of chemotherapy in cycle one. All patients at our center are admitted for cycle one of venetoclax-based therapy based on the risk of tumor lysis, as well as the need for frequent transfusions. Patients typically receiving venetoclax therapy should be seen two or three times a week with a bone marrow check performed after cycle one, day 21-28 for evidence of cytoreductive marrow effects, which could require holding venetoclax to allow for a recovery. All of these toxicities need to be carefully managed as outpatients or inpatients by the treating physician in order to achieve the clinical benefits of these targeted and other therapies.
Oncology Frontier: Could you please give recommendations for the physicians about how to manage the patients who are receiving these new treatments?
Dr Wang: In general, when we treat patients with acute myeloid leukemia in the upfront setting, we look at two criteria. One is the fitness or the ability of the patient to tolerate chemotherapy. And the second is to look at the disease biology. Looking at a patient’s fitness, which is not necessarily determined by age, a determination needs to be made as to whether the individual patient should be offered intensive (cytarabine/anthracycline) versus non-intensive therapy. Achievement of a complete remission following either intensive or non-intensive therapy can be prolonged by different methods and different drugs. Patients achieving a morphological complete response after induction and/or consolidation chemotherapy or not progressing on to an allogeneic stem cell transplantation may now be offered maintenance therapy with an oral azacitidine compound, CC-486. This compound is given 14 out of 28 days continuously while that patient remains in complete remission and while they are continuing to achieve benefit. The phase III QUAZAR study has demonstrated statistically significant prolongation and improvement in overall survival with oral azacitidine maintenance. Patients who are FLT3 mutant at the time of diagnosis who achieve complete remission following intensive induction or consolidation chemotherapy may be continued on maintenance FLT3 inhibitor therapy with benefits as suggested in the RATIFY trial. In addition, we feel that pending clinical trial data may also support the use of FLT3 inhibitors currently being investigated after allogeneic stem cell transplantation in patients that undergo that procedure. For patients receiving venetoclax/HMA or venetoclax/low-dose cytarabine-based therapy, there is a continued need for administration, as far as we know, of both agents indefinitely while patients remain responsive in order to maintain the remission. One question is, is it possible to substitute oral azacitidine for subcutaneous or IV azacitidine in the maintenance setting in these elderly unfit patients. At the current time, there is no evidence that the two drugs can be substituted for IV or subcutaneous. This is not recommended. The trials are currently ongoing. We would strongly discourage patients and clinicians from considering oral azacitidine as a maintenance strategy, other than this specific setting it was approved in.
Oncology Frontier: Could you please introduce some treatment guidelines for patients who achieve remission? If there are different ways for patients to maximize the treatment effect and prolong life expectancy?
Dr Wang: This year’s ASH 2020 meeting was a virtual meeting, and there was a significant amount of new findings and encouraging data presented for treatment of patients with AML. In general, there were three categories of findings that were of interest. Number one. As we move forward with a new array of targeted and non-targeted therapies for AML, one area of great investigation is the use of combinatory regimens. Data presented at the ASH meeting investigated the addition of venetoclax to many other conventional chemotherapy regimens for AML specifically in addition to intensive chemotherapy in the upfront and relapsed and refractory setting. In addition, we saw venetoclax being added to low-dose chemotherapy regimens and combined with other targeted therapies. One of the most interesting venetoclax-based regimens presented was the combination with the FLT3 inhibitor, gilteritinib, for patients with relapsed and refractory FLT3 mutant AML. Response rates with that combination of two oral targeted therapies were greater than 80%, with the majority of those being in morphological leukemia free state without count recovery. Further titration and evaluation of that regimen even in the upfront setting may be worthy of further investigation. In addition, many immunotherapeutic agents appeared to be moving to the forefront in the treatment of relapsed and refractory disease as well as newly diagnosed disease. There was encouraging data with the CD47 magrolimab antibody combination with azacitidine with response rates of 60% or greater both in p53 mutant as well as p53 wild type AML disease in the upfront setting. Data was presented with the bispecific antibody, flotetuzumab, for primary refractory or early relapse AML with encouraging overall response rates of 30%. Lastly, there is a new class of agents that was introduced, a menin-inhibitor. Data that I presented at the ASH 2020 meeting highlighted the preliminary results of an oral menin-inhibitor targeting the MLL rearranged KMT2A epigenetic compound. In early studies, this oral agent was well tolerated at doses up to 400mg with early evidence of clinical activity in a very small subset of 6 out of 8 patients with relapsed and refractory AML. We are looking forward to further combinatorial regimens combining the advantages of the targeted therapies that we have right now and exploring them for greater efficacy. We are also looking forward to the introduction of immunotherapeutics into our standard regimens. That may be particularly attractive both for the treatment of older unfit newly diagnosed AML patients as well as for the eradication of low-grade disease states such as minimal residual disease for our patients moving forward.