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The rapidly changing face of new agents entering practice: Will FLT3 inhibitors make the grade in AML?…and more on our final best of ASH summary

The May 17th historic FDA approval (accelerated) of the anti-PD-1 antibody nivolumab for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous stem cell transplantation and post-transplant brentuximab vedotin is a vivid reminder of just how far we have come in moving new options for patients into practice. Nivo’s endorsement was predicated on an evaluation of efficacy in just 95 patients, but because the drug as monotherapy produced useful responses in approximately two thirds of individuals with limited treatment options, the FDA’s decision is great news to oncologists, and it could be that pembrolizumab, which also has strong but similarly limited supporting data, could soon follow.

However, while it is comforting to see new therapies that are clearly effective become rapidly available, in reality many of the “steps forward” in clinical research continue to come as a result of large randomized trials evaluating standard systemic regimens alone or in combination with novel agents, many of which demonstrate marginal but clearly statistically significant advantages. What makes these kinds of findings and subsequent regulatory approvals so challenging is that they often come in diseases with dismal outcomes and few options for treatment, and usually the drug in question has limited single-agent activity and, most significantly, the benefit provided is far from a home run.

These factors create an environment of constant debate about the relevance of a therapy and how it fits into the risk/benefit/value equation. Recent examples in the hem/onc world include in multiple myeloma the use of panobinostat as an add-on to bortezomib/​dexamethasone and the incorporation of elotuzumab with lenalidomide/dexamethasone. The same issue arises in chronic lymphocytic leukemia with the addition of obinutuzumab (as opposed to rituximab) to chlorambucil and in follicular lymphoma to bendamustine.

This is precisely the scenario that is emerging in the world of acute myeloid leukemia (AML) related to the combination of multikinase tyrosine kinase inhibitors (TKIs) with induction chemotherapy and maintenance for the approximately 35% of patients with AML who have FLT3 genomic alterations — long known to be associated with a particularly adverse prognosis, which has led to the current common practice of following induction treatment with allogeneic stem cell transplantation.

The FLT3 AML debate began during a 2014 ASH plenary presentation of a large German study that demonstrated a progression-free survival advantage with the addition of the multikinase TKI sorafenib to induction chemotherapy and its continuation for a year as maintenance. A key and very provocative finding (and to this point pretty much unexplained) was that the benefit was observed in patients with and without FLT3 abnormalities.

At the ASH 2015 meeting another plenary talk focused on this strategy — specifically the presentation by Dana-Farber’s Dr Richard Stone of the international Phase III RATIFY trial led by the CALGB that blindly randomly assigned 717 patients with 1 of the 3 FLT3 alterations, including tyrosine kinase domain mutations and both low and high internal tandem duplication allele burdens, to another multikinase TKI, midostaurin, which, like other similar compounds, has limited single-agent activity but can be safely combined with intensive chemotherapy.

The study added midostaurin to daunorubicin/cytarabine induction and high-dose ara-C consolidation and then administered it as maintenance therapy in patients age 18 to 60 and met its primary endpoint of improving overall survival, although the 23% relative reduction in risk of death translates to a somewhat modest improvement in 4-year survival from 44.2% to 51%. Of great interest is that the benefit was observed regardless of whether allotransplant occurred or which of the 3 major predetermined FLT3 subtypes were present, which caused some in the audience to wonder if, as with the sorafenib trial, the benefit might accrue to a larger segment of patients.

I met with Dr Stone for his take on these data, what they mean to patient care and whether this is the beginning of the end of an era in AML lasting more than a decade in which the only regulatory action has been in the wrong direction (withdrawal of approval of gemtuzumab ozogamicin).

To make a long story short, the key message from our conversation is that although some caveats exist, Dr Stone believes that these findings are meaningful and the drug should be incorporated into practice. This sentiment appears to be echoed by the FDA, which recently granted midostaurin a breakthrough therapy designation, but we shall see whether it will become another in the recent unprecedented flurry of novel agents entering practice.

Either way, a host of other new small molecules with anti-FLT3 activity such as gilteritinib (formerly ASP2215) are marching on in the research development process with the hope of greater specificity resulting in increased efficacy and more favorable tolerability.

Of course, midostaurin was definitely not the only relevant news coming out of ASH. For that reason and to keep you up to date on what happened, we have created the following 26 slide sets across a number of diseases (AML, myelodysplastic syndromes, acute lymphocytic leukemia, myeloproliferative neoplasms and chronic myeloid leukemia), which review highlights from the data and provide Dr Stone’s insights into their relevance and meaning.

Acute myeloid leukemia (AML)/chronic myelomonocytic leukemia (CMML)/myelodysplastic syndromes (MDS) 
(PLENARY) Up-front use of the multikinase inhibitor midostaurin with a “7 plus 3” chemotherapy regimen in FLT3-mutated AML
Sorafenib with chemotherapy improves the overall survival of older adults with FLT3-ITD-mutated AML
Antileukemic activity and tolerability of the multikinase inhibitor gilteritinib in FLT3-mutated AML
Up-front treatment with venetoclax and decitabine or azacitidine for older patients with AML
Pracinostat with azacitidine in elderly patients with AML; oral azacitidine monotherapy in AML
Allogeneic stem cell transplantation after high- versus reduced-intensity conditioning in MDS and AML
Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 in advanced hematologic cancers
Azacitidine with lenalidomide or vorinostat versus azacitidine monotherapy in MDS and CMML
Eltrombopag for the treatment of thrombocytopenia of low and intermediate-1 IPSS risk MDS; luspatercept in low or intermediate-1 risk MDS
 Acute lymphoblastic leukemia (ALL) 
(PLENARY) Rituximab and chemotherapy in adults with CD20-positive, Philadelphia chromosome-negative, B-cell precursor ALL
Dose-intensified pegylated asparaginase pediatric regimen in adults with untreated ALL
Blinatumomab in adult patients with relapsed/refractory Philadelphia chromosome-positive ALL
Front-line inotuzumab ozogamicin combination with low-intensity chemotherapy for older patients with ALL
 Chronic myeloid leukemia (CML) 
Long-term follow-up of the French 1 Stop Imatinib study in CML
Personalized daily doses of imatinib by therapeutic drug monitoring in CML
Clinical significance of early imatinib-induced ABCB1 overexpression in CML
Dose-optimized nilotinib in newly diagnosed CML
Impact of age on efficacy and toxicity of nilotinib in patients with CML
Dasatinib and peginterferon alpha-2b as up-front treatment for CML
Ponatinib versus allogeneic stem cell transplant in patients with CML/acute lymphoblastic leukemia and the T315I mutation
Next-generation sequencing versus conventional sequencing to detect BCR-ABL mutations in CML
 Myeloproliferative neoplasms (MPN) 
Long-term efficacy and safety of ruxolitinib (RUX) in myelofibrosis (MF)
Pacritinib in MF
The antifibrotic agent PRM-151 in MF
5-azacytidine with RUX in MDS/MPN; sonidegib with RUX in patients with MF; RUX with pomalidomide in MF; RUX and buparlisib in MF
Interferon alpha-2 with a JAK1/2 inhibitor in Philadelphia chromosome-negative MPN

Neil Love, MD
Research To Practice
Miami, Florida