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2017 – a Landmark Year for Food and Drug Administration Approvals for Haematological Malignancies

Authors: Katrina Mountfort, Senior Medical Writer, Touch Medical Media, Reading, UK
Tim Sheldrick, Group Director and Advisory Editor, Touch Medical Media, Reading, UK

The 2017 American Society of Hematology (ASH) 59th Annual Meeting was held on 9–12 December 2017 at the Georgia World Congress Center, Atlanta, GA, USA and featured nearly 5,000 scientific abstract presentations in malignant and non-malignant blood diseases. At the meeting, Richard Pazdur, Director of the Food and Drug Administration’s (FDA) Oncology Center of Excellence, reviewed what he described as a “phenomenal” year for drug approvals in haematological malignancies.

2017 marked the approval of the first two chimeric antigen receptor (CAR) T-cell immunotherapies for the treatment of advanced haematologic malignancies. Approval for tisagenlecleucel (Kymriah®, Novartis) for paediatric precursor B-cell acute lymphoblastic leukaemia (ALL) was based on the findings of the JULIET study, a phase II, single-cohort, global study of tisagenlecleucel in 75 paediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The overall remission rate within 3 months was 81%, event-free survival 73% and overall survival 90% at 6 months, and 50% and 76% respectively at 12 months.1 Transient high-grade toxic events including cytokine release syndrome occurred in over 70% of participants. Tocilizumab (Actemra/RoActemra®, Roche) was concurrently approved for the treatment of CAR T cell-induced cytokine release syndrome. An interim analysis presented at the ASH meeting showed that, for 46 patients with at least 6 months of follow-up, the overall response rate was 37%, with 30% achieving a complete response and 7% achieving a partial response.2

The other approved CAR-T therapy is axicabtagene ciloleucel (Yescarta®, Kite Pharma) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. In the phase I-II multi-centre study evaluating axicabtagene ciloleucel in subjects with refractory aggressive non-Hodgkin lymphoma (ZUMA-1; NCT02348216), which involved 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma who had refractory disease despite prior therapy, the objective response rate in patients treated with axicabtagene ciloleucel was 82%, the complete response rate was 54% and the overall rate of survival at 18 months was 52%. Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients respectively.3 Long-term follow-up data presented at ASH 2017 suggest that these responses are durable, with remissions maintained at 24 months. No new treatment-related cytokine-release syndrome, neurologic events nor grade 5 adverse events have been reported.4

On March 15, 2017, the FDA granted accelerated approval to pembrolizumab (Keytruda®, Merck), an anti-programmed cell death protein-1 (PD-1) monoclonal antibody for adults and children with classic Hodgkin lymphoma that is refractory to treatment or has relapsed after three or more prior lines of therapy. Approval was based on data from the study of pembrolizumab (MK-3475) in participants with relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-087; NCT02453594), which involved 201 patients. At a median follow-up of 9.4 months, the overall response rate was 69%, with complete remission in 22% and partial remission in 47%. The median duration of response was 11.1 months (range=0.0–11.1 months).5

This was also an exceptional year for the treatment of patients with acute myeloid leukaemia (AML), In April 2017, midostaurin (Rydapt®, Novartis) was approved for the treatment of adults with newly diagnosed FLT3-positive AML in combination with standard intensive induction consolidation chemotherapy. Approval was based on the findings of the daunorubicin, cytarabine, and midostaurin in treating patients with newly diagnosted acute myeloid leukemia (RATIFY) study (NCT00651261), which involved 717 patients with AML and a FLT3 mutation. The addition of midostaurin to standard chemotherapy significantly prolonged overall survival (hazard ratio for death, 0.78; p=0.009) and event-free survival (hazard ratio for event or death, 0.78; one-sided p=0.002).6

In August 2017, the FDA approved another molecular targeted therapy: enasidenib (Idhifa®, Celgene) for the treatment of adults with relapsed/refractory AML and an isocitrate dehydrogenase-2 (IDH2) mutation. Nearly 10% of AML patients have a neomorphic mutation in IDH2, and enasidenib – a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes – represents a novel therapeutic approach. Approval was based on an open-label, single-arm, multicentre, clinical trial involving 199 adults with relapsed or refractory AML and IDH2 mutation. A median complete response of 8.2 months was reported in 19% of patients, and a median partial hematologic recovery of 9.6 months in 4%. Of the 157 patients who needed transfusions at the trial’s start, 34% no longer required them during at least one 56-day time period while receiving enasidenib.7 The FDA concurrently approved a companion diagnostic, the RealTime IDH2 Assay, for detecting the IDH2 mutation.

Also in August 2017, daunorubicin plus cytarabine (Vyxeos®, Jazz Pharmaceuticals) – a liposome-encapsulated combination of cytarabine and daunorubicin – was approved for the treatment of adults 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 with myelodysplasia-related changes. Approval followed a phase III study evaluating the efficacy and safety of the liposomal formulation compared to standard cytarabine and daunorubicin induction in 309 patients aged 60–75 years with newly diagnosed t-AML or AML-MRC and demonstrated an improvement in overall survival in this difficult-to-treat cohort.8

In September 2017, gemtuzumab ozogamicin (Mylotarg®, Pfizer) also received FDA approval for the treatment of adults with newly diagnosed CD33-positive AML, as well as the treatment of patients aged ≥2 years with relapsed or refractory CD33-positive AML. The drug had originally received accelerated approval in May 2000 for older patients with CD33-positive AML who relapsed but was withdrawn from the market after subsequent trials did not show a clinical benefit and raised safety concerns, including early death. The current approval is for a lower dose and schedule than previously. Approval of gemtuzumab in combination with chemotherapy was based on a phase III study of 280 patients aged 50–70 years with newly diagnosed AML and found that the use of fractionated lower doses of gemtuzumab ozogamicin allowed the safe delivery of higher cumulative doses.9 Approval as a single agent was based on a randomised phase III study comparing two schedules of low dose gemtuzumab in 56 older patients unfit for intensive chemotherapy,10 and a phase II single-arm study of 57 AML patients in first relapse.11

The approval of four new products for AML represents phenomenal progress considering that the previous four decades saw only two approvals — cytaribine plus daunorubicin in 1973 and in 2000, gemtuzumab ozogamicin. A number of molecular-targeted therapies are also in advanced clinical development. Furthermore, several of these molecular alterations, including mutations in FLT3 and IDH2, are found in myelodysplastic syndromes and other myeloid leukaemias related to AML, raising hopes that the new therapies will be beneficial in these conditions.

In collaboration with the FDA, ASH has produced a series of webinars featuring unbiased discussions of newly approved drugs and their uses —


1. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

2. Schuster S, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large b-cell lymphoma. Presented at: the 59th ASH Annual Meeting, Atlanta, GA, 11 December, 2017. Abstract 577.

3. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large b-cell lymphoma. N Engl J Med. 2017;377:2531–44.

4. Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: A pivotal trial of axicabtagene ciloleucel in patients with refractory aggressive non-Hodgkin lymphoma. Presented at: the 59th ASH Annual Meeting, Atlanta, GA, 11 December, 2017. Abstract 578.

5. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35:2125–32.

6. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–64.

7. FDA. Idhifa (enasidenib) tablets prescribing information. 2017. Available at: (accessed 4 May 2018).

8. Makris M, Van Veen JJ, Tait CR, et al. Guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol. 2013;160:35–46.

9. Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379:1508–16.

10. Amadori S, Suciu S, Selleslag D, et al. Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19). Br J Haematol. 2010;149:376–82.

11. Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia. 2007;21:66–71.

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