Hematology Pipeline Update
Drug Updates from the 2016 ASH Annual Meeting
n 2016 , the U . S . Food and Drug Administration approved several drugs to treat hematologic conditions , including nivolumab for classical Hodgkin lymphoma and the first recombinant agent for bleeding control in patients with von Willebrand disease . In this section , we take a look at these approvals , as well as early-phase research from other hematology drugs that may soon be entering the approval pipeline .
Early Studies Reveal Efficacy , Safety Concerns With Vadastuximab Talirine in Patients With Acute Myeloid Leukemia
Early studies of vadastuximab talirine ( 33A ) in patients with acute myeloid leukemia ( AML ) have shown preliminary efficacy , whether the drug has been used as monotherapy or in combination with other treatments . However , recently reported deaths in several phase I trials , and hepatotoxicity , have prompted the U . S . Food and Drug Administration ( FDA ) to place the trials on clinical hold .
According to Anjali Advani , MD , of the Department of Hematologic Oncology and Blood Disorders at the Taussig Cancer Institute at the Cleveland Clinic in Ohio , who presented results at the 2016 ASH Annual meeting , the appeal of 33A is that it targets CD33 – a cell-surface antigen expressed in approximately 90 percent of patients with AML .
“ Once the drug is internalized into the leukemia cells , the dimer attaches to the DNA within the leukemia cell and basically leads to cell death ,” Dr . Advani told ASH Clinical News . “ This drug may be a little better than some of the other previous drugs because it has this stable linker , [ which suggests that ] it doesn ’ t have much off-target toxicity .”
Dr . Advani presented results from a phase I study of 33A as a monotherapy in older patients with treatment-naïve CD33-positive AML . 1 Twentyseven patients ( median age = 74 years ; range = 67-89 years ) received 33A administered intravenously at 40 mcg / kg ( the recommended dose from the dose-escalation portion of the study ) every three weeks for up to two treatment cycles . If patients achieved complete remission ( CR ) or CR with incomplete blood count recovery ( CRi ), they received low-dose maintenance with 33A . All patients had AML and an Eastern Cooperative Oncology Group performance status of 0-1 , and were either ineligible for or declined conventional treatment with induction and consolidation .
Researchers found that most adverse events ( AEs ) associated with 33A were “ manageable .” The most common grade ≥3 AEs were thrombocytopenia ( 44 %), febrile neutropenia ( 41 %), and anemia ( 33 %).
Of the 26 patients who were evaluable for efficacy , 14 ( 54 %) achieved either CR ( n = 6 ) or CRi ( n = 8 ), while five patients ( 19 %) achieved a morphologic leukemia-free state . However , Dr . Advani noted that the remissions were short-lived . “ I think [ 33A ] is active as a single agent , but to achieve longer relapse-free and overall survival , it probably needs to be combined with [ another ] therapy ,” she told ASH Clinical News . “ We need to sort out the best way to do that .”
Amir T . Fathi , MD , of Massachusetts General Hospital in Boston , and co-authors investigated 33A in combination with hypomethylating agents in a phase I study of patients with previously untreated CD33-positive AML who had declined intensive therapy . 2 Patients ( median age = 75 years ; range = 60-87 years ) received 33A at a dose of 10 mcg / kg every four weeks ; 33A was given on the last day of a five-day regimen of a hypomethylating agent ( HMA ) ( either azacitidine or decitabine ).
The authors concluded that the combination was “ well tolerated with no identified pattern of off-target toxicity .” No dose-limiting toxicities or infusion reactions were reported , and grade ≥3 AEs ( reported in ≥15 % of patients ) included thrombocytopenia ( 55 %), anemia ( 43 %), febrile neutropenia ( 43 %), neutropenia ( 38 %), pneumonia ( 19 %), and leukopenia ( 17 %). No grade 4 or 5 bleeding events were observed . Rates of 30- and 60-day mortality were 2 percent and 8 percent , respectively , with no treatmentrelated deaths reported .
Forty-nine patients were evaluable for efficacy : 36 patients ( 73 %) achieved either CR ( n = 21 ) or CRi ( n = 15 ). Remissions were achieved after a median of two treatment cycles ( range = 1-4 cycles ). Most patients with poor-risk disease achieved remission , including those with antecedent myelodysplasia , adverse cytogenetics , FLT3 / ITD mutation , and age ≥75 years , the authors noted .
“ Activity with the combination appears markedly improved when compared with the historic experience of HMA monotherapy in this patient population ,” the authors concluded . “ The CR / CRi rate of 73 percent in this setting is particularly encouraging .”
REFERENCES
1 . Bixby DL , Stein AS , Fathi AT , et al . Vadastuximab talirine monotherapy in older patients with treatment-naive CD33- positive acute myeloid leukemia ( AML ). Abstract # 590 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , California .
2 . Fathi AT , Erba HP , Lancet JE , et al . Vadastuximab talirine plus hypomethylating agents : a well-tolerated regimen with high remission rate in frontline older patients with acute myeloid leukemia . Abstract # 591 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , California .
26 ASH Clinical News March 2017