Tag: Acute Myeloid Leukemia

Acute Myeloid Leukemia: Who Is an Appropriate Candidate for ONUREG® (azacitidine) Tablets?

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Written by: Thomas E Boyd, MD, Texas Oncology
Content Sponsored by: Bristol-Myers Squibb Company (BMS)

 

 

Dr. Boyd is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Acute myeloid leukemia (AML) is a deadly disease with most new cases affecting patients aged 65–74 years old.1 The 5-year relative survival rate for AML is 29.5%1, highlighting a need for treatment approaches that improve survival.2 Patient- and disease-related characteristics, including medical fitness, age, cytogenetic and molecular testing, and risk of adverse events, often determine treatment options.3

After careful consideration of all factors, patients can be treated with either a higher-intensity chemotherapy option or a lower-intensity therapy option, and in some cases, additional cycles of consolidation therapy may follow the higher-intensity chemotherapy option.4 Helping patients achieve remission and keeping them there is a major goal of initial induction therapy. Continued treatment of AML in first remission may improve overall survival; however, relapse due to residual AML cells is still a major concern.2 In 764 patients with AML aged 60–85 years old who received induction therapy, ~50% relapsed within 1 year and ~80% relapsed within 5 years.5 A goal of continued treatment for AML is extending overall survival (OS) in patients who have achieved first remission.2 In some instances, extending OS can be achieved with a hematopoietic stem cell transplant; but not all patients are eligible or choose to go down this treatment route.3

ONUREG® is the first and only FDA-approved therapy indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.6 The efficacy and safety of ONUREG® was evaluated in the Phase 3 multicenter, randomized, double-blind placebo-controlled QUAZAR® AML-001 study.6 Eligible patients were ages 55 years or older, diagnosed with AML, were within 4 months of achieving first CR or CRi with intensive induction chemotherapy, and may have received consolidation therapy.6 Efficacy was established by OS, where ONUREG® demonstrated >2 years median OS for patients with AML in first remission as compared to placebo (24.7 months in the treatment arm vs 14.8 months in the placebo arm, hazard ratio (HR) 0.69, 95% confidence interval (CI): 0.55-0.86; P=0.0009).6 The most common adverse reactions (ARs, ≥ 10%) associated with ONUREG® treatment were nausea, vomiting, diarrhea, fatigue/asthenia, constipation, pneumonia, abdominal pain, arthralgia, decreased appetite, febrile neutropenia, dizziness, and pain in extremity.6 Serious ARs occurred in 15% of patients who received ONUREG®, and the most common Grade 3/4 ARs are shown in the table below.6

Who is an appropriate candidate for ONUREG®? The following hypothetical examples will review some of the characteristics to consider when deciding if a patient could be appropriate for ONUREG®.

Patient A is a 67-year-old retired accountant who is active and generally healthy. Their hypertension is well managed with medication, and they have no other comorbidities. Despite no family history of leukemia or hematologic abnormalities, Patient A has just been diagnosed with de novo AML not otherwise specified with intermediate-risk cytogenetics and no actionable mutations. Their hematologist prescribes intensive induction chemotherapy with the standard 7+3 regimen, and Patient A went into first remission.

Patient A is generally healthy with a well-managed comorbidity, which results in their treatment with intensive induction chemotherapy followed by first remission. Patient A is a candidate for transplant but declines one due to concerns over graft-versus-host disease. Since Patient A chose not to proceed to transplant, then ONUREG® may be an option for them.

Patient B is a 70-year retired nurse who lives alone, with family nearby. They were recently diagnosed with AML and received 7+3 chemotherapy followed by one round of consolidation. Patient B tolerated their treatment as well as could be expected and achieved first complete remission. While they are eligible for transplant, they declined and have been under observation by their doctor for the past few months. Patient B received and tolerated intensive induction chemotherapy, achieved first remission, and declined transplant, an intensive curative option. This makes them a potential candidate for continued treatment with ONUREG®.

Ultimately, the treating physician will make the final decision, but ONUREG® is indicated as a continued treatment of adult patients with AML who achieved first CR or CRi following intensive induction chemotherapy and are not able to complete intensive curative therapy.6 Understanding a patient’s disease and journey can help set them on the path where appropriate towards a continued treatment that has demonstrated an overall survival benefit in the QUAZAR® AML-001 study.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
ONUREG® is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS
Risks of Substitution with Other Azacitidine Products
Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG® are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG® may result in a fatal adverse reaction. Treatment with ONUREG® at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG® for intravenous or subcutaneous azacitidine.
Myelosuppression
New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG®. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG® due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS)
In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG® or placebo. 107 received a median of 5 cycles of ONUREG® 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG® arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG® for MDS have not been established. Treatment of MDS with ONUREG® is not recommended outside of controlled trials.
Embryo-Fetal Toxicity
ONUREG® can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG® and for at least 3 months after the last dose.
ADVERSE REACTIONS
Serious adverse reactions occurred in 15% of patients who received ONUREG®. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG®.
Most common (≥10%) adverse reactions with ONUREG® vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION
There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG® and for 1 week after the last dose.

Please see full Prescribing Information for ONUREG®.

References
1. National Cancer Institute. SEER Cancer Statistics Factsheets: Acute Myeloid Leukemia. http://seer.cancer.gov/statfacts/html/amyl.html. Accessed April 21, 2021.
2. Medeiros BC, Chan SM, Daver NG, Jonas BA, Pollyea DA. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am J Hematol. 2019;94:803-811.
3. Medeiros BC, Satram S. Real world treatment patterns and comparative effectiveness among elderly patients with acute myeloid leukemia in the United States. Ann Hematol Oncol. 2020;7(1):1283.
4. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487-494.
5. Büchner T, Berdel WE, Haferlach C, et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol. 2009;27(1):61-69.
6. ONUREG®® [Prescribing Information]. Summit, NJ: Celgene Corporation; 2021.

© 2021 Celgene Corporation.
ONUREG® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company.
QUAZAR® is a registered trademark Celgene Corporation, a Bristol-Myers Squibb company.
12/21 2011-US-2100198

Long Term Survival Benefit with Maintenance ONUREG® in AML Patients

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SUMMARY: The American Cancer Society has estimated that in 2021, 20,240 new cases of Acute Myeloid Leukemia (AML) were diagnosed in the United States and 11,400 patients died of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5 year Overall Survival (OS) in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

Cytotoxic chemotherapy for AML often consists of induction therapy to achieve remission, followed by consolidation therapy. However, standard induction chemotherapy achieves Complete Remission in only 40-60% of AML patients older than 60 years of age, and majority of these patients will eventually relapse. This had been attributed to clonal evolution and epigenetic reprogramming, leading to aberrant DNA methylation, and persistence of leukemia-initiating cells.

Longer duration of first remission is associated with better survival outcomes. Postremission maintenance therapies to prevent early AML relapse has been an area of active research with little progress made until now. Patients with AML who are under age 55 with high-risk cytogenetics, in first clinical remission,are considered for allogeneic Hematopoietic Stem Cell Transplantation (HSCT), as this has shown to offer survival advantage over conventional chemotherapy. This therapeutic option however is not feasible for many elderly patients.

Oral Azacitidine (ONUREG®) is a hypomethylating agent that has a distinct pharmacokinetic as well as pharmacodynamic profile from the parenteral Azacitidine preparation, and can be administered in extended dosing schedules (for 14-21 days per 28-day treatment cycle) to sustain therapeutic activity.

ONUREG® is the first and only FDA-approved therapy indicated for continued treatment of adult patients with AML who achieved first Complete Remission (CR) or Complete Remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy, and are not able to complete intensive curative therapy.

This FDA approval was based on an International, double-blind, placebo-controlled, Phase III QUAZAR AML-001 trial, in which ONUREG® was evaluated as maintenance therapy in patients with AML, who were in first remission after intensive chemotherapy. Eligible patients were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for Hematopoietic Stem Cell Transplantation. Patients (N=472) were randomly assigned to receive ONUREG® 300 mg orally (N=238) or placebo (N=234), once daily for 14 days of a 28-day cycle. The median age was 68 years. The Primary end point was Overall Survival (OS). Secondary end points included Relapse Free Survival (RFS) and Health-Related Quality of Life.

At the time of the primary analysis in 2019, with a median follow up of 41.2 months, maintenance treatment with ONUREG® significantly prolonged median OS, when compared to placebo (24.7 months versus 14.8 months; P<0.001). The median RFS was also significantly longer with ONUREG® than with placebo (10.2 months versus 4.8 months; P<0.001). These survival benefits were demonstrated in most treatment subgroups. Further, with a median follow up of 51.7 months, the median OS remained unchanged, and the median OS with oral ONUREG® was 24.7 months versus 14.8 months with placebo (HR=0.69; P=0.0008). The 3-year OS rates in the experimental and control arms were 37.4% and 27.9%, respectively and at 5 years were 26.2% and 19.2%, respectively. Overall Quality of life was preserved while on treatment with ONUREG®. The most common adverse reactions associated with ONUREG® treatment were nausea, vomiting, diarrhea, abdominal pain, constipation, fatigue/asthenia, febrile neutropenia and pneumonia.

The authors concluded that maintenance treatment with ONUREG® was associated with significantly longer Overall and Relapse Free Survival when compared to placebo, among elderly patients with AML, who were in remission after chemotherapy. This survival benefit was maintained with one additional year of follow up. The researchers added that these updated data suggests that maintenance therapy with ONUREG® provides a sustained, long term Overall Survival benefit in elderly patients with AML in first remission.

Long-Term Overall Survival (OS) with Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC): Updated Results from the Phase 3 QUAZAR AML-001 Trial. Wei AH, Döhner H, Sayar H, et al. Blood. 2021;138(suppl 1):871. doi:10.1182/blood-2021-147501.

VENCLEXTA® (Venetoclax)

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The FDA on October 16, 2020, granted regular approval to VENCLEXTA® (Venetoclax) in combination with Azacitidine, Decitabine, or Low-Dose Cytarabine (LDAC), for newly diagnosed Acute Myeloid Leukemia (AML) in adults, 75 years or older, or who have comorbidities precluding intensive induction chemotherapy. VENCLEXTA® was initially granted accelerated approval for this indication in November 2018. VENCLEXTA® is a product of AbbVie Inc. and Genentech Inc.

ONUREG® (Azacitidine tablets)

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The FDA on September 1, 2020, approved ONUREG® for continued treatment of patients with Acute Myeloid Leukemia who achieved first Complete Remission (CR) or Complete Remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy, and are not able to complete intensive curative therapy. ONUREG® is a product of Celgene Corporation.

VIDAZA® plus VENCLEXTA® for Elderly patients with AML

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SUMMARY: The American Cancer Society estimates that in 2020, 19,940 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,180 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS), when compared to conventional care regimens, in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. The combination of VIDAZA® and VENCLEXTA® in a previously published Phase Ib study was highly efficacious, with significant responses, duration of response and Overall Survival benefit.VENCLEXTA_MOA

VIALE-A is a Phase III, multicenter, randomized, double-blind, placebo-controlled confirmatory trial, conducted to evaluate the efficacy and safety of a combination of VIDAZA® and VENCLEXTA®, as compared with VIDAZA® plus placebo (the control regimen), in previously untreated patients with AML, who were ineligible for intensive induction therapy. In this study, 431 patients (N=431) with previously untreated AML were randomly assigned in a 2:1 ratio to receive either VIDAZA® plus VENCLEXTA® (N=286), or VIDAZA® plus placebo (N=145). Enrolled patients were ineligible for standard induction chemotherapy because of coexisting conditions, 75 years of age or older, or both.

All patients received VIDAZA® 75 mg/m2 subcutaneously or IV on days 1 through 7 of every 28-day cycle. Patients in the study group also received VENCLEXTA® 100 mg orally on day 1 and 200 mg on day 2 and target dose of 400 mg on day 3, and continued daily until day 28 during cycle 1, to mitigate Tumor Lysis Syndrome. The dose of VENCLEXTA® was initiated at 400 mg daily in all subsequent 28-day cycles. In the control group, a matching placebo was administered orally, once daily, in 28-day cycles. The median patient age was 76 years. Secondary AML was reported in 25% of the patients in the VIDAZA® plus VENCLEXTA® group and in 24% of the patients in the control group, and poor cytogenetic risk was reported in 36% and 39%, respectively. All the patients were hospitalized on or before day 1 of cycle 1 and for at least 24 hours after receiving the final dose of VENCLEXTA®, in order to receive prophylaxis against the Tumor Lysis Syndrome and for monitoring. The Primary endpoint was Overall Survival (OS). The Secondary end points included Complete Remission (CR) rates, composite Complete Remission (Complete Remission or Complete Remission with incomplete hematologic recovery), RBC and platelet transfusion independence, and Quality of Life according to Patient-Reported Outcomes.

At a median follow up of 20.5 months, the median OS was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.66; P<0.001). VIDAZA® plus VENCLEXTA® combination resulted in a CR rate of 36.7% versus 17.9%; P<0.001 and composite CR of 66.4% versus 28.3%; P<0.001, when compared to the control regimen. Most responses were seen after the first 28-day cycle. The median time to first response was 1.3 versus and 2.8 months respectively, duration of CR was 17.5 months versus 13.3 months and median duration of composite CR was 17.5 months in the VIDAZA® plus VENCLEXTA® group and 13.4 months in the control group. RBC transfusion independence occurred in 59.8% of the patients in the VIDAZA® plus VENCLEXTA® group and in 35.2% of those in the control group (P<0.001), and platelet transfusion independence occurred in 68.5% and 49.7% (P<0.001), respectively. The benefits with VIDAZA® plus VENCLEXTA® were noted in almost all molecular subgroups compared to the control regimen. The response rates were highest among patients with FLT3 mutations (72.4% versus 36.4%, P=0.02) and those with IDH1 or IDH2 mutations (75.4 % versus 10.7%, P<0.001), respectively. The incidence of febrile neutropenia was higher in the VIDAZA® plus VENCLEXTA® group than in the control group. Infections of any grade occurred in 85% of the patients in the VIDAZA® plus VENCLEXTA® group and in 67% of those in the control group, and serious Adverse Events occurred in 83% and 73%, respectively.

It was concluded that among previously untreated patients with AML who were ineligible for intensive chemotherapy, those who received VIDAZA® plus VENCLEXTA® had significantly longer Overall Survival and higher remission rates, compared to those who received VIDAZA® alone. Whether VIDAZA® plus VENCLEXTA® will replace conventional induction chemotherapy for AML, remains to be seen.

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. DiNardo CD, Jonas BA, Pullarkat V, et al. N Engl J Med 2020; 383:617-629

IDHIFA® plus VIDAZA® Significantly Improves Complete Remission and Overall Response in Newly Diagnosed IDH2-Mutated AML

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SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

IDHIFA® (Enasidenib) is a selective, oral, small molecule inhibitor of mutated IDH2 protein that promotes myeloid cell differentiation. IDHIFA® indirectly reduces DNA methylation by suppressing the oncometabolite, 2-HydroxyGlutarate, thereby restoring function to Alpha-Ketoglutarate-dependent TET family enzymes. IDHIFA® was approved in the US in 2017 for the treatment of adult patients with relapsed or refractory Acute Myeloid Leukemia (AML), with an IDH2 mutation. Further, treatment with single agent IDHIFA® resulted in an Overall Response Rate (ORR) of 31% and a Completer Response (CR) rate of 18% in patients with newly diagnosed AML. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS) when compared to conventional care regimens in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. In vitro studies demonstrated that a combination of IDHIFA® and VIDAZA® enhance cell differentiation and apoptosis.

Based on this preclinical data and early clinical trials, an open label, Phase I/II study was conducted comparing a combination of IDHIFA® and VIDAZA® with single agent VIDAZA® in patients with newly diagnosed IDH2 mutated AML, who are not candidates for intensive chemotherapy. The authors reported the first interim outcomes from the randomized, Phase II portion of this ongoing study. The Phase II portion of the trial enrolled 101 patients with newly diagnosed IDH2-mutant AML who were ineligible to receive intensive chemotherapy. Patients had an ECOG PS score of 2 or less and were randomized in a 2:1 ratio to receive IDHIFA® plus VIDAZA® or VIDAZA® alone in repeated 28-day cycles. All patients received VIDAZA® 75 mg/m2/day SC for the first 7 days of each treatment cycle, whereas patients randomized to IDHIFA® plus VIDAZA® also received IDHIFA® 100 mg orally QD continuously. The median patient age was 75 years, and 78% in the combination group and 90% in the VIDAZA® only group had intermediate-risk cytogenetics respectively, and 18% and 10% had poor-risk cytogenetics. The median number of treatment cycles was 8. The Primary endpoint was Overall Response Rate (ORR), which included Complete Remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), Partial Remission (PR), and Morphologic Leukemia-Free State (MLFS), per modified IWG 2003 AML response criteria. Mutant IDH2 Variant Allele Frequencies (VAF) in bone marrow mononuclear cells was assessed by digital PCR.

It was noted that the ORR were significantly higher with combination treatment vs VIDAZA® alone (71% versus 42% respectively, P=0.0064) and the CR rates were 53% versus 12% (P=0.0001). The time to first response was about 2 months in each treatment group and the median Duration of Response was 24.1 months with the combination treatment and 12.1 months with VIDAZA® alone. Responses were observed in patients with RAS pathway co-mutations, which have been usually associated with resistance to IDHIFA® monotherapy. The maximal mutant IDH2 VAF suppression from baseline was significantly greater with the combination treatment versus single agent VIDAZA® (median –69.3% versus –14.1% respectively, P=0.0004). Treatment related Grade 3-4 Adverse Events occurring in 10% or more of patients in the combination group were neutropenia, thrombocytopenia, anemia, febrile neutropenia and IDH differentiation syndrome.

It was concluded that a combination of IDHIFA® plus VIDAZA® was associated with significantly improved Complete Remission and Overall Response Rates, with significant mutant IDH2 Variant Allele Frequencies reductions, compared with VIDAZA® alone, in patients with newly diagnosed IDH2-mutant AML. Further the combination treatment was generally well tolerated, with a safety profile similar to that reported for monotherapy with either of these two agents. Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. DiNardo CD, Schuh AC, Stein EM, et al. Presented at 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 643.

Single Agent XOSPATA® for FLT3 Mutated AML

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SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.

Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.MUTATED-FLT3-INDUCES-LIGAND-INDEPENDENT-PATHWAY-ACTIVATION

The Fms-Like Tyrosine kinase 3 (FLT3) is a cytokine receptor tyrosine kinase in the PDGF family of growth factor receptors. It is located on the cell surface (transmembrane) of early hematopoietic stem and progenitor cells and regulates their proliferation and differentiation. It plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. FLT3 mutations occur most often as Internal Tandem Duplications (FLT3-ITD) or point mutations at codon D835 (FLT3-Tyrosine Kinase Domain or TKD). Approximately 80% of AML patients with a FLT3 mutation will have the FLT3-ITD, and about 15% will have both FLT3-ITD and FLT3-TKD, and about 5% will have FLT3-TKD alone. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations are predicted to have poor outcomes with shorter remission duration and significantly decreased leukemia-free and Overall Survival. FLT3-TKD can confer resistance to other Tyrosine Kinase Inhibitors and frequently do not respond to salvage chemotherapy.

XOSPATA® (Gilteritinib) is a highly selective oral FLT3/AXL Tyrosine Kinase Inhibitor with activity against both FLT3-ITD and FLT3-TKD mutations. Tyrosine Kinase AXL has been implicated in FLT3 inhibitor resistance. Another FLT3 inhibitor, RYDAPT® (Midostaurin), is also approved, but in combination with standard Cytarabine and Daunorubicin-based chemotherapy for patients with newly diagnosed FLT3-mutated AML. However, for patients with relapsed or refractory AML, RYDAPT® has not conferred durable clinical benefit as a single agent. Unlike XOSPATA®, RYDAPT® is a not selective and is a multikinase inhibitor and inhibits FLT3, PDGFR, c-KIT (CD 117), VEGFR, and protein kinase C. Single-agent XOSPATA®, in a phase 1-2 study, resulted in a 41% composite Complete Remission rate (Complete Remission with or without normal hematologic recovery), among patients with relapsed or refractory FLT3-mutated AML. Based on this information, the authors conducted a multicenter, randomized trial comparing XOSPATA® with conventional salvage chemotherapy regimens in patients with relapsed or refractory FLT3-mutated AML.

The ADMIRAL trial is an international, multicenter, randomized, Phase III study in which 371 patients with relapsed or refractory FLT3 mutated AML were randomly assigned in a 2:1 ratio to receive either XOSPATA® 120 mg orally once daily or salvage chemotherapy, in 28-day cycles. The median age was 62 years, approximately 60% of the patients had relapsed AML and 39% had primary refractory disease. Over 85% of patients had received previous induction therapy with Anthracyclines but not FLT3 inhibitors. The two Primary end points were Overall Survival and the percentage of patients who had Complete Remission with full or partial hematologic recovery. Secondary end points included Event-Free Survival (freedom from treatment failure – relapse or lack of remission or death) and the percentage of patients who had Complete Remission. The median duration of follow up for Overall Survival was 17.8 months.

The median Overall Survival in the XOSPATA® group was significantly longer than that in the chemotherapy group (9.3 months versus 5.6 months) with a 36% reduction in the risk of death, compared to salvage chemotherapy (HR for death=0.64; P<0.001). The median Event-Free survival was 2.8 months in the XOSPATA® group and 0.7 months in the chemotherapy group (HR for treatment failure or death=0.79). The percentage of patients who had Complete Remission with full or partial hematologic recovery was 34.0% in the XOSPATA® group and 15.3% in the chemotherapy group and the Complete Remission rates were 21.1% and 10.5%, respectively. The median Overall Survival as well as Complete Remission rates were similar among those with FLT3 ITD mutations alone and those with FLT3 TKD mutations, when treated with XOSPATA®. Further, longer survival was observed with XOSPATA® than with chemotherapy across all cohorts of patients with co-mutations, particularly in those patients with double mutation (DNMT3A and NPM1), and baseline levels of AXL expression did not influence survival with XOSPATA®. Serious adverse events occurred less frequently in the XOSPATA® group than in the chemotherapy group and the most common adverse events of Grade 3 or higher were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).

It was concluded that treatment with single agent XOSPATA® resulted in significantly longer Overall Survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. Perl AE, Martinelli G, Cortes JE, et al. N Engl J Med 2019; 381:1728-1740

XOSPATA® (Gilteritinib)

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The FDA on May 29, 2019 approved the addition of overall survival data in labeling for XOSPATA®, indicated for adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FLT3 mutation, as detected by an FDA-approved test. XOSPATA® is a product of Astellas Pharma US, Inc.

FDA Approves TIBSOVO® for Newly Diagnosed AML Patients Ineligible for Intensive Chemotherapy

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SUMMARY: The FDA on May 2, 2019, approved TIBSOVO® (Ivosidenib) for newly-diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 (Isocitrate DeHydrogenase-1) mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. The American Cancer Society estimates that for 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior Myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone.MOA-of-Ivosidenib

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations. TIBSOVO® is an oral, targeted, small-molecule inhibitor of mutant IDH1. The FDA in July, 2018, approved TIBSOVO® for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation.

The present first line approval by the FDA was based on an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839)of single-agent TIBSOVO®, for newly-diagnosed AML patients, with an IDH1 mutation detected by an FDA-approved IDH1 Assay. In this study, 28 patients were included and these patients were at least 75 years old, or had comorbidities that precluded the use of intensive induction chemotherapy. For comorbidities, enrolled patients met at least one of the following criteria – baseline ECOG PS of 2 or more, severe cardiac or pulmonary disease, hepatic impairment with Bilirubin more than 1.5 times the upper limit of normal, or Creatinine Clearance less than 45 mL/min. The median age was 77 years and 79% had therapy-related AML or AML with Myelodysplasia-related changes. Patients received TIBSOVO® 500 mg orally daily until disease progression, development of unacceptable toxicity, or hematopoietic stem cell transplantation. Efficacy was based on the rate of Complete Remission (CR) or Complete Remission with partial hematologic improvement (CRh) rate, the duration of CR+CRh, and the conversion rate from transfusion dependence to transfusion independence. CRh was defined as less than 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets more than 50,000/microliter and ANC more than 500/microliter).

In this trial, TIBSOVO® demonstrated a CR+CRh rate of 42.9%, with a CR rate of 28.6% and a CRh rate was 14.3%. The median durations of CR and CR+CRh could not be estimated, with 41.7% of those who achieved CR or CRh remaining on TIBSOVO® treatment as of the data cutoff (treatment duration ranged from 20.3 to 40.9 months). At 12 months after receiving treatment, 58.3% of patients who achieved CR or CRh, remained in remission. For those who achieved a CR or CRh, the median time to best response of CR or CRh was 2.8 months. Among those patients who were dependent on RBC and/or platelet transfusions at baseline, 41.2% achieved transfusion independence lasting at least 8 weeks.

The most common adverse reactions were fatigue, nausea, diarrhea, rash, pyrexia, arthralgia, leukocytosis and QT prolongation. One important side effect of the IDH inhibitors is the induction of differentiation of the malignant cells, and in 10-20% of patients, a clinical syndrome known as the IDH differentiation syndrome can occur. The IDH differentiation syndrome should be promptly managed by dose interruption and treatment with glucocorticoids, oral hydroxyurea, or both.

It was concluded that TIBSOVO® can induce durable responses among newly diagnosed poor risk AML patients with an IDH1 mutation, who are ineligible for intensive chemotherapy, fulfilling an unmet need. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ivosidenib-first-line-treatment-aml-idh1-mutation

TIBSOVO® (Ivosidenib)

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The FDA on May 2, 2019 approved TIBSOVO® for newly diagnosed Acute Myeloid Leukemia (AML), with a susceptible IDH1 mutation, as detected by an FDA-approved test, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. TIBSOVO® was approved in July 2018 for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. TIBSOVO® is a product of Agios Pharmaceuticals, Inc.