The Year in FDA Approvals

In the past year, the U.S. Food and Drug Administration (FDA) approved several therapies for the treatment of myeloid malignancies, including drugs approved for multiple indications. We review the regulatory approvals since our last “Focus on Myeloid Malignancies” special edition published in May 2017. Midostaurin was approved for FLT3-mutated acute myeloid leukemia (AML) and aggressive systemic mastocytosis in April 2017.


On August 1, 2017, the FDA approved enasidenib for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation. The drug is approved for use with the RealTime IDH2 Assay, a companion diagnostic that can detect specific mutations in the IDH2 gene in this patient population.

The approval was based on the results of the single-arm, phase I/II AG221-C-001 study that included 199 patients (median age = 68 years; range = 19-100 years) with relapsed/refractory IDH2-mutated AML that was detected by the RealTime IDH2 Assay. Patients had received a median of two prior therapies (range = 1-6 therapies).

After a minimum of six months of treatment, 19.3 percent of patients (95% CI 13.8-25.9) who received enasidenib experienced a complete remission (CR) for a median of 8.2 months, and 4 percent of patients experienced a CR with partial hematologic recovery for a median of 9.6 months. Of the 157 patients who required blood or platelet transfusions at baseline, 34 percent no longer required transfusions after receiving enasidenib.

The most common adverse events (AEs) associated with enasidenib included nausea, vomiting, diarrhea, increased bilirubin levels, and decreased appetite.

The drug carries a boxed warning that differentiation syndrome can occur and can be fatal if left untreated. Differentiation syndrome is associated with fever; dyspnea; acute respiratory distress; radiographic pulmonary infiltrates; pleural or pericardial effusions; rapid weight gain; peripheral edema; or hepatic, renal, or multi-organ dysfunction.


On August 3, 2017, the FDA approved CPX-351, a fixed combination of cytarabine and daunorubicin, for the treatment of adult patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC – both of which are considered high-risk leukemia subtypes.

Approval was based on results from the CLTR0310-301 study, in which 309 patients with newly diagnosed t-AML or AML-MRC were randomized to receive daunorubicin and cytarabine either in the liposomal, fixed-combination formulation (CPX-351) or as separate treatments (standard 7+3 regimen). Patients who received CPX-351 had a longer median overall survival (OS), compared with those who received separate treatments (9.56 months vs. 5.95 months).

Common AEs associated with CPX-351 included hemorrhage, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, and fatigue – frequent adverse events with other cytarabine/anthracycline induction chemotherapy regiments for AML, including the 7+3 regimen. Blood count recovery is slower with CPX-351 than with 7+3, but 60-day induction mortality was lower.

Patients who have a history of serious hypersensitivity to daunorubicin, cytarabine, or any component of the formulation should not use the drug. The prescribing information also includes a boxed warning not to interchange CPX-351 with other daunorubicin- or cytarabine-containing products, in part because the dose of CPX-351 is different from that of other approved products.

Gemtuzumab Ozogamicin

On September 1, 2017, the FDA approved gemtuzumab ozogamicin (GO) for two patient populations: adults with newly diagnosed CD33-positive AML and children (≥2 years) with relapsed or refractory CD33-positive AML. GO may be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML or as a stand-alone treatment for certain adult and pediatric patients.

GO originally received accelerated approval in May 2000 as monotherapy for older patients with relapsed CD33-positive AML. In June 2010, the drug was voluntarily withdrawn from the market after subsequent confirmatory trials such as the Southwest Oncology Group (SWOG) S0106 study failed to verify clinical benefit and demonstrated safety concerns, including early deaths.

This recent approval includes a lower recommended dose (3 mg/m2 (up to a cap of one 4.5 mg vial) on days 1, 4 and 7 of induction) compared to the initial 2000 approval (9 mg/m2 in 2 doses separated by 2 weeks), as well as new patient populations. “We are approving [GO] after a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

The approval was based on outcomes from three clinical trials – one pivotal trial investigated GO in combination with chemotherapy (ALFA-0701) and two other trials investigated GO as a single agent. In the combination study, adult patients treated with daunorubicin and cytarabine with GO had longer median event-free survival than those treated with daunorubicin and cytarabine without GO (17.3 months vs. 9.5 months; p value not reported).

In the first monotherapy study (EORTC-GIMEMA AML-19), patients with newly diagnosed AML who could not tolerate or chose not to receive intensive chemotherapy were randomized to receive GO or best supportive care. The median OS was 4.9 months in those receiving GO, compared with 3.6 months in those receiving best supportive care (p value not reported). In the second monotherapy trial (MyloFrance-1), which was a single-arm study of 57 patients with relapsed CD33-positive AML, 26 percent of patients achieved a CR that lasted a median of 11.6 months (range not reported) after receiving a single course of GO.

The most common AEs associated with GO included pyrexia, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, and neutropenia. Severe AEs included leukopenia, infection, liver damage, hepatic veno-occlusive disease (VOD), infusion-related reactions, and hemorrhage.

GO previously received orphan-drug designation and carries a boxed warning that severe or fatal hepatotoxicity (including VOD and sinusoidal obstruction syndrome) has occurred in some patients.


On November 9, 2017, the FDA expanded the indication of the tyrosine kinase inhibitor (TKI) dasatinib to include pediatric patients with Philadelphia chromosome–positive (Ph+) chronic-phase chronic myeloid leukemia (CP-CML). The drug was previously approved to treat adults with Ph+ CP-CML.

The decision was based on the results of two studies (one open-label, non-randomized, dose-ranging trial and one open-label, non-randomized, single-arm trial) of 97 pediatric patients with Ph+ CP-CML. Fifty-one patients (from the single-arm trial) were newly diagnosed with CP-CML, and 46 patients (17 from the dose-ranging trial and 29 from the single-arm trial) were imatinib resistant or intolerant. Ninety-one participants were treated with dasatinib 60 mg/m2 once-daily. After approximately five years of follow-up across both trials, the median duration of response (including the efficacy endpoints complete cytogenetic response [CCyR], major cytogenetic response [MCyR], and major molecular response [MMR]) could not be estimated.

Among the newly diagnosed cohort, the response duration ranged from 2.5 to 66.5 months for CCyR, 1.4 to 66.5 months for MCyR, 5.4 to 72.5 months for patients who achieved MMR by month 24, and 0.03 to 72.5 months for those who achieved MMR at any time. Among the imatinib-resistant or -intolerant group, durations of response ranged from 2.4 to 86.9 months for CCyR, 2.4 to 86.9 months for MCyR, and 2.6 to 73.6 months for MMR.

AEs were reported in 14.4 percent of patients, the most common (occurring in >15% of patients) of which included myelosuppression, headache, nausea, diarrhea, skin rash, and pain in the abdomen and extremities.


On December 19, 2017, the FDA granted accelerated approval to the oral TKI bosutinib for the treatment of adult patients with newly diagnosed Ph+ CP-CML. Bosutinib was first approved in September 2012 for the treatment of adult patients with relapsed or refractory chronic-, accelerated-, or blast-phase Ph+ CML.

The decision was based on results of the multinational, open-label, randomized, phase III BFORE (Bosutinib trial in First Line Chronic Myelogenous Leukemia Treatment) study, which included 536 patients with Ph+ CP-CML who were randomized 1:1 to receive bosutinib 400 mg or imatinib 400 mg.

At 12 months, a higher percentage of patients receiving bosutinib achieved MMR (47.2% vs. 36.9%; p=0.02). People treated with bosutinib also had a significantly higher rate of CCyR at 12 months (77.2% vs. 66.4%; p=0.008).

The most common AEs associated with bosutinib included diarrhea (70%), nausea (35%), thrombocytopenia (35%), rash (34%), increased alanine aminotransferase (ALT; 31%), abdominal pain (25%), and increased aspartate aminotransferase (AST; 23%).


On March 22, 2018, the FDA approved nilotinib for the treatment of pediatric patients (≥1 year) with Ph+ CP-CML that is newly diagnosed or resistant or intolerant to prior TKI therapy. On December 22, 2017, the product label for nilotinib was also updated to include information on nilotinib discontinuation, post-discontinuation monitoring criteria, and guidance for treatment re-initiation in patients taking nilotinib for Ph+ CML who have achieved a sustained molecular response.

The March approval was based on results from two open-label, single-arm, multicenter trials: The CAMN107A2120 trial enrolled pediatric patients with Ph+ CP-CML that was resistant or intolerant to imatinib or dasatinib, while the CAMN107A2203 trial included pediatric patients with Ph+ CP-CML resistant or intolerant to imatinib or dasatinib, and newly diagnosed Ph+ CP-CML.

At cycle 12, the MMR was 40.9 percent in patients with resistant or intolerant Ph+ CP-CML and 60.0 percent in those with newly diagnosed Ph+ CP-CML. The cumulative MMR rates were 47.7 percent and 64.0 percent, respectively.

The common AEs (occurring in >20% of patients) were hyperbilirubinemia, thrombocytopenia, rash, neutropenia, lymphopenia, increased ALT, headache, anemia, pyrexia, nausea, upper respiratory tract infection, increased AST, and vomiting; the most common grade 3/4 AEs were increased ALT and hyperbilirubinemia.

The drug carries a boxed warning for risk of QT prolongation and sudden death.