The 22nd Congress of the European Hematology Association (EHA) took place in sunny Madrid last month. Over four days (June 22-25), more than 10,000 delegates including researchers, clinicians, and industry representatives gathered to discuss the latest data and trends in the treatment of a range of blood disorders. A large part of the congress was dedicated to blood cancers, which broadly includes lymphoma, leukemia, and multiple myeloma. In this piece, we will focus more specifically on a subtype of leukemia that is on the verge of witnessing significant changes in the treatment landscape: acute myeloid leukemia (AML), a niche indication with nearly 30,000 newly diagnosed incident cases across the seven major markets in 2016.1


Principles of current treatment

AML is a heterogeneous group of malignancies of the bone marrow. Over recent years, cytogenetic and molecular analyses have shown that AML is a collection of molecularly distinct subgroups with varying prognoses, and thousands of driver mutations have been described.2 However, the general principles of AML therapy have barely changed for decades and revolve around induction therapy (with the goal to achieve a complete remission) and postremission consolidation therapy (with the goal to maintain remission and prevent disease recurrence).

• Induction. Newly diagnosed patients are assessed to determine their eligibility for intensive induction chemotherapy, based primarily on age, performance status, and comorbidities. For younger and medically fit patients, the mainstay of induction therapy is cytarabine for 7 days in combination with an anthracycline (typically daunorubicin or idarubicin) for 3 days in the so-called “7+3” regimen. Older patients and those unfit for intensive chemotherapy may receive low-intensity chemotherapy, DNA hypomethylating agents (such as Celgene’s Vidaza [azacitidine] and Otsuka/Janssen’s Dacogen [decitabine]), or best supportive care.

• Consolidation. Consolidation therapy is based on chemotherapy agents (typically single-agent cytarabine) and can be complemented by a stem-cell transplantation in eligible patients. While risk stratification based on cytogenetics and molecular testing can help guide treatment choices, there is no consensus on the optimal consolidation strategy.

The prognosis of relapsed/refractory (R/R) patients is poor, and no standard therapy exists for patients who relapse after initial remission or become refractory to agents administered in the first line. Repetition of first-line therapy may be applicable in patients whose disease relapses after at least one year. R/R patients may also be enrolled in clinical trials or receive palliative care only.

In April 2017, the FDA approved Novartis’s FLT3 inhibitor Rydapt (midostaurin) in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation for newly diagnosed AML with FLT3 mutations, which are found in about a third of patients. Importantly, Rydapt is not approved as a single-agent induction therapy for this patient population.3,4 Approval was granted under priority review and with a companion diagnostic test (Invivoscribe Technologies’ LeukoStrat® CDx FLT3 Mutation Assay).5 Full results from the Phase III (RATIFY) trial, published in NEJM on the second day of the 2017 EHA congress, showed that Rydapt plus chemotherapy was associated with a 22% reduction in the risk of death versus control.6 This approval marks the first entry of a targeted therapy in AML and is the first step of a likely pivotal shift in the treatment paradigm, whereby cytogenetics and molecular testing will not only help inform disease classification and prognosis but also the choice of drug treatment.


What’s on the horizon?

Several drug developers are engaged in the race to bring new therapies to the AML market, and the 2017 approval of Rydapt is likely to be the first of a new wave of agents. The pipeline for AML is particularly active and spans several drug classes, including cytotoxic agents, hypomethylating agents, next-generation FLT3 inhibitors, and other targeted agents. Below is a small selection of AML pipeline drugs for which data were presented at the 2017 EHA Congress.

• Enasidenib (planned brand name Idhifa; Celgene/Agios Pharmaceuticals). Enasidenib is an inhibitor of the mutated IDH2 protein that is currently under FDA priority review for R/R AML patients who harbor a IDH2 mutation, which occurs in approximately 12% of cases. The filing is based on data from a single-arm Phase I/II trial (with a PDUFA date of August 30, 2017)7 and a Phase III (IDHENTIFY) trial is ongoing versus conventional therapy in older R/R AML patients with an IDH2 mutation. Updated Phase I/II data presented at the 2017 EHA Congress reported an ORR of 37% (including 20% CR) among 214 patients with R/R AML; the median duration of response for patients achieving a CR was 8.8 months.8

• CPX-351 (planned brand name Vyxeos; Jazz Pharmaceuticals). CPX-351 is a liposomal drug encapsulating cytarabine and daunorubicin at a 5:1 molar ratio. In May 2017, the FDA granted priority review to an NDA based on data from five studies, including a Phase III trial in newly diagnosed secondary AML that demonstrated a 3.6-month improvement in MOS over the standard 7+3 regimen. A subgroup analysis of this Phase III trial presented at the 2017 EHA Congress showed that outcomes in therapy-related AML patients mirrored those reported in the overall population.9

• Venetoclax (Venclexta/Venclyxto; AbbVie/Genentech). Venetoclax is a Bcl-2 inhibitor that is already approved for CLL patients with 17p deletion. Two Phase III trials are ongoing in newly diagnosed AML patients who are ineligible for standard induction therapy, the first in combination with Vidaza and the second in combination with low-dose cytarabine. Updated early phase data were also reported for both combinations at the 2017 EHA congress.10,11

• Vadastuximab talirine (Seattle Genetics). Vadastuximab talirine is a CD33-directed antibody that is conjugated to two molecules of a pyrrolobenzodiazepine (PBD) dimer. A few days before the 2017 EHA Congress, the company announced the discontinuation of a pivotal Phase III (CASCADE) trial of vadastuximab talirine plus a hypomethylating agent (Vidaza or Dacogen) in older patients with newly diagnosed AML, based on a higher rate of deaths in the combination arm.12 Patient enrollment in other ongoing clinical trials is now suspended, and future plans for this antibody drug conjugate are unclear at this stage. Phase I data presented at the Congress reported a CR + CRi rate of 76% for vadastuximab talirine plus a hypomethylating agent.13


The dynamic nature of the drug pipeline makes AML a key indication to watch, and we will be covering this exciting indication in an upcoming Niche & Rare Disease Landscape & Forecast report later this year.

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  1. Decision Resources Group proprietary epidemiology analysis. The seven major markets include the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan
  2. Papaemmanuil E, et al. Genomic classification and prognosis in acute myeloid leukemia. NEJM. 2016;374(23):2209-2221.
  3. FDA, press release, April 28, 2017.
  4. Rydapt U.S. prescribing information, issued April 2017.
  5. Invivoscribe Technologies, press release, April 28, 2017.
  6. Stone RM, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. NEJM. 2017 Jun 23. doi: 10.1056/NEJMoa1614359. [Epub ahead of print]
  7. Celgene and Agios Pharmaceuticals, press release, March 01, 2017.
  8. Agios Pharmaceuticals, press release, June 24, 2017.
  9. Lancet JE, et al. Overall survival with CPX-351 versus 7+3 in older adults with newly diagnosed, therapy-related acute myeloid leukemia: subgroup analysis of a Phase 3 study. Presented at the 22nd EHA Congress. 2017. Abstract P556.
  10. Wei AH, et al. Updated safety and efficacy results of Phase I/II study of venetoclax plus low-dose cytarabine in treatment-naive acute myeloid leukemia patients aged ≥65 years and unfit for standard induction therapy. Presented at the 22nd EHA Congress. 2017. Abstract S473.
  11. Pratz K, et al. Safety and efficacy of venetoclax (Ven) in combination with decitabine or azacitidine in treatment-naive, elderly patients (≥65 years) with acute myeloid leukemia (AML). Presented at the 22nd EHA Congress. 2017. Abstract S472.
  12. Seattle Genetics, press release, June 19, 2017.
  13. Ravandi F, et al. Vadastuximab talirine plus hypomethylating agents (HMA): a well-tolerated regimen with high remission rate in frontline older patients with acute myeloid leukemia (AML). Presented at the 22nd EHA Congress. 2017. Abstract P201.

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