On Location
Breakthroughs in Blood Disorders
The 26th European Hematology Association Annual Congress , known as EHA2021 Virtual , was held June 9-17 , offering international hematologists a platform to access recorded oral abstract sessions and view live plenary presentations . As part of the program , presenters shared the latest results from clinical and translational research in hematologic disorders remotely . Here , ASH Clinical News presents highlights from the virtual meeting , including new treatments for hereditary hemorrhagic telangiectasia and evidence supporting the FLAVIDA regimen in acute myeloid leukemia .
PDE9 Inhibitor Shows Promise as Monotherapy and With Hydroxyurea in Sickle Cell Disease
Data from two new studies indicated that daily dosing of the oral phosphodiesterase type 9 ( PDE9 ) inhibitor IMR-687 , at doses up to 200 mg , was safe and well-tolerated as a monotherapy or in combination with hydroxyurea in patients with sickle cell disease ( SCD ). Biree Andemariam , MD , of the University of Connecticut Health Center , presented results of the phase IIa study at EHA2021 Virtual .
In preclinical studies , IMR-687 has been shown to increase intracellular cyclic guanosine monophosphate ( cGMP ) levels by activating the nitric oxidecGMP pathway , increasing fetal hemoglobin expression , and reducing hemolysis and sickling of red blood cells , Dr . Andemariam explained .
“ The data point to a clinically relevant improvement in key outcome measures with IMR-687 treatment .”
— Biree Andemariam , MD
Ninety-three patients with SCD were randomized to receive placebo or IMR-687 ( at a 50 mg dose escalated to 100 mg , or a 100 mg dose escalated to 200 mg ) once daily for four to six months . In an open-label expansion study , 24 patients received IMR-687 200 mg once daily with or without hydroxyurea ( n = 7 and n = 14 patients , respectively ).
There were no treatment-related serious adverse events ( AEs ) or treatmentrelated grade 3 or higher AEs . There were also no clinically relevant changes in laboratory safety data , ECG results , or vital signs . “ Importantly , there were no cases of neutropenia ,” Dr . Andemariam added . “ Overall , IMR-687 was generally welltolerated as a monotherapy as well as in combination with hydroxyurea .”
AEs leading to treatment discontinuation occurred in 10 % of patients on placebo and 8 % of patients on IMR-687 . Common AEs included headache , nausea , and abdominal pain .
Treatment with IMR-687 reduced the average annualized rate of vaso-occlusive crises ( VOCs ) by 40 % compared with placebo . The median annualized rate of VOCs was 0 for the pooled IMR-687 group compared with 1.87 per year for the placebo group ( p = 0.048 ), while the mean annualized rate of VOC-related hospitalizations was 0.84 among patients who received IMR-687 and 1.36 among those who received placebo .
The time to first VOC was almost twice as long with IMR-687 compared with placebo ( median = 169 vs . 87 days ; p = 0.029 ). The researchers also looked at characterization of pain from VOC episodes , finding that IMR-687 at doses of 100 mg / 200 mg showed a significant reduction in pain episode severity . In the open-label expansion study , there was a low VOC rate that was maintained in patients who remained on IMR-687 long term , as well as in patients who switched to IMR-687 after placebo .
“ The data point to a clinically relevant improvement in key outcome measures with IMR-687 treatment ,” Dr . Andemariam concluded .
Pharmacokinetic and pharmacodynamic data showed increases in F cells correlated with hemoglobin F and with IMR-687 exposure . More than onethird of patients ( 36 %) increased their hemoglobin F by more than 3 % at month eight with minimal change in total hemoglobin .
Dr . Andemariam added that higher doses of IMR- 687 up to 400 mg are being investigated in ongoing phase IIb studies .
Study authors report relationships with Imara , which sponsored this trial .
Reference Andemariam B , Bronte L , Gordeuk V , et al . The safety , pharmacokinetics & pharmacodynamic effects of IMR-687 , a highly-selective PDE9 inhibitor , in adults with sickle cell disease : Phase-2A placebo-controlled & open-label extension studies . Abstract # S263 . Presented at the EHA 2021 Virtual Congress , June 9-17 , 2021 .
Venetoclax Added to Intensive Chemotherapy Is Safe , Effective in Relapsed / Refractory AML
In a study presented at EHA2021 Virtual , adding short-term venetoclax to an intensive FLA-IDA chemotherapy regimen proved safe and led to high rates of overall response ( ORRs ) and measurable residual disease ( MRD ) negativity in patients with relapsed / refractory acute myeloid leukemia ( AML ). The findings were shared by Rabia Shahswar , MD , of Hannover Medical School in Germany .
Noting the limited treatment options for patients in this setting , Dr . Shahswar and researchers conducted a retrospective controlled study to evaluate the FLAVIDA combination ( the BCL2 inhibitor venetoclax plus fludarabine , cytarabine , and idarubicin ) in patients with relapsed / refractory AML .
Thirty patients ( median age = 54 years ) were included in the analysis . One-third of patients had secondary or therapy-related AML , and most patients ( 57 %) had intermediate-risk disease . Patients received a seven-day course of venetoclax 100 mg , along with standard intensive FLA-IDA chemotherapy . Patients received a maximum of one course FLAVIDA .
The ORR was 73 % ( n = 22 / 30 ), which included 18 patients ( 60 %) who achieved a complete response ( CR ) or CR with incomplete hematologic recovery ( CRi ). Responses were seen across patients with different disease risk levels ( 75 % for favorable , 71 % for intermediate , and 78 % for adverse ). Four patients underwent
34 ASH Clinical News August 2021