Written in Blood
study protocol was amended to require mandatory pneumocystis prophylaxis and herpes simplex virus prophylaxis .
Eleven patients ( 5 %) experienced fatal AEs , eight of which were related to infections .
“ While the study was not designed to detect significant differences between dose levels , there did not appear to be a notable difference in the safety profile of duvelisib by dose ,” the authors reported . In the two largest cohorts ( 25 mg and 75 mg ), the rates of severe AEs were 80 percent and 87 percent , respectively .
The overall response rate ( defined as complete response [ CR ] or partial response [ PR ]) in each disease subtype were :
• 56 % ( n = 31 / 55 ) in relapsed / refractory CLL , including 1 CR
• 83 % ( n = 15 / 18 ) in treatment-naïve CLL , all PR
• 58 % ( n = 18 / 31 ) in indolent NHL , including 6 CRs
• 32 % ( n = 6 / 19 ) in cutaneous T-cell lymphoma , all PRs
• 50 % ( n = 8 / 16 ) in peripheral T-cell lymphoma , including 3 CRs
“ In extensively pretreated patients with relapsed / refractory leukemia or lymphoma and previously untreated CLL , duvelisib monotherapy demonstrated clinically meaningful activity ,” the authors concluded .
Based on the study ’ s findings , the researchers selected a 25 mg dose for future studies . Two ongoing studies are evaluating this dose of duvelisib : DYNAMO , a phase II study , is evaluating the agent in patients with relapsed indolent NHL , and DUO , a phase III study , is evaluating duvelisib in patients with relapsed / refractory CLL .
This early-phase study is limited by its lack of a comparator arm and mixture of previously treated and untreated patients across a variety of cancers .
Infinity Pharmaceuticals and Verastem provided financial support for this study .
The authors report financial relationships with Verastem and Infinity Pharmaceuticals . Acumen Medical Communications and Infinity Pharmaceuticals provided editorial support .
REFERENCE
Flinn IW , O ’ Brien S , Kahl B , et al . Duvelisib , a novel oral dual inhibitor of PI3K-δ , γ , is clinically active in advanced hematologic malignancies . Blood . 2017 November 30 . [ Epub ahead of print ]
Can AMT-060 Gene Therapy FIX Hemophilia B ?
After a single infusion of AMT-060 ( an adeno-associated virus-5 vector [ AAV5 ] carrying a corrected human factor IX [ FIX ] gene ), patients with hemophilia B experienced increases in FIX activity and reductions in spontaneous bleeds , according to results of a phase I / II study published in Blood . Patients achieved these responses without developing detectable inhibitors or a T-cell response against the therapy , noted Wolfgang Miesbach , MD , PhD , of the University Hospital Frankfurt in Germany , and co-authors .
“ Improvement of disease severity was observed in all participants and allowed the majority to discontinue FIX prophylaxis ,” the authors wrote of the findings . These results further support the role of gene therapy in “ correcting ” hemophilia ; at the 2017 ASH Annual Meeting , investigators reported the first successful gene therapy in hemophilia A .
This multinational , open-label , first-in-human , dose-escalation study included 10 adult male patients with either a severe FIX deficiency ( defined as FIX < 1 %) or moderately severe FIX deficiency ( defined as FIX 1-2 %) and a severe bleeding phenotype . Nine participants had severe hemophilia B ( FIX activity of < 1.0 IU / dL ), and one had moderate hemophilia B ( FIX activity of 1.5 IU / dL ). At the time of enrollment , nine patients previously received FIX prophylaxis , and one with severe hemophilia was using on-demand therapy as needed . Dosing cohorts included :
• 5 × 10 12 gc / kg ( low dose ; cohort 1 ; n = 5 ; median age = 69 years ; range = 35-72 years )
• 2 × 10 13 gc / kg ( high dose ; cohort 2 ; n = 5 ; median age = 35 years ; range = 33-46 years )
Participants remained on their prestudy regimen of FIX prophylaxis after AMT-060 until six to 12 weeks post-treatment . If patients achieved FIX activity ≥2.0 IU / dL for at least two consecutive measurements , they were allowed to taper FIX replacement over a two-week period . If this FIX level was maintained , they were encouraged to withhold prophylaxis .
Patients in cohort 1 were generally older , had more severe arthropathy , and – despite prophylactic FIX ( average = 4,000 IU weekly ) – experienced more bleeds in the year prior to study entry , compared with cohort 2 .
Patients prospectively reported bleeding and FIX consumption using an electronic diary . Diaries were reviewed at study visits ( once-weekly in cohort 1 and twice-weekly in cohort 2 for up to 12 weeks , then every two weeks from weeks 12 to 26 , and quarterly between six months and one year ). Quarterly visits will continue until three years post-therapy , followed by twice-annual visits from years three to five . The study is ongoing , with a planned follow-up of five years .
“Improvement of disease severity was observed in all participants and allowed the majority to discontinue FIX prophylaxis .”
— WOLFGANG MIESBACH , MD , PhD
As of November 8 , 2016 ( the planned interim analysis ), three patients in each dosing cohort experienced 14 treatment-related adverse events ( AEs ). Four patients reported increased liver enzymes , three of whom were in cohort 2 . Three serious AEs were reported : mild , asymptomatic elevations in liver enzymes ; short , self-limiting fever in the first 24 hours post-treatment ; and alanine transaminase elevation .
The mean endogenous FIX activity increased to 4.4 IU / dL ( 95 % CI 1.5- 7.3 ) in cohort 1 and to 6.9 IU / dL ( 95 % CI 2.6-11.3 ) in cohort 2 . “ Following a single administration [ of AMT- 060 ], FIX activity increased to levels classified as mild in six [ patients ] and moderate in four participants ,” the authors wrote , “ and remained stable for the duration of follow-up .”
Treatment with AMT-060 reduced the need for FIX use by 81 percent in cohort 1 and by 73 percent in cohort 2 , for an overall reduction of 79 percent .
Patients also experienced a lower mean annualized bleeding rate ( ABR ). In cohort 1 , ABR decreased by 53 percent ( from 9.8 to 4.6 ); in cohort 2 , ABR decreased by 70 percent
( from 3.0 to 0.9 ). The ABR was “ still relatively high post-treatment ” in cohort 1 , the authors noted , which they said may be related to preexisting joint damage . “ It will be of interest in this population whether continuing improvements in arthropathy and decrease of ABR will be observed with longer-term follow up ,” they wrote . Mean annualized rate of traumatic bleeds remained stable in both cohorts .
The improvements in FIX activity and bleed rates allowed most patients who were receiving FIX prophylaxis ( n = 8 / 9 ) to discontinue , leading to “ large reductions in annualized factor consumption from approximately 2.64 million to 563,507 IU ,” the investigators concluded .
The researchers reported that treatment was well tolerated and effective , including in “ those with lowtiter antibodies , suggesting no likely impact of low-titer immunoglobulin ( Ig ) G or IgM on transduction , clinical effectiveness , or cellular immune response following treatment .”
The results are limited by the study ’ s small patient population , restricted range of doses studied , and lack of a comparator arm . In addition , pretreatment data were collected retrospectively and bleeding was patient-reported , which could have introduced bias . Variation in patient characteristics between the two cohorts ( including older age , poorer bleed control , and more extensive joint damage in cohort 1 ) “ makes direct comparison of clinical outcomes between the two [ dosing ] cohorts challenging ,” the researchers added .
Support for the study was provided by uniQure . ●
The corresponding authors report financial support from uniQure , Novo Nordisk , Bayer , Shire , Biotest , Pfizer , Octapharma , LFB , CSL Behring , Sobi , Biogen , BPL , Baxter , Sanquin , Boehringer Ingelheim , Bristol-Myers Squibb , and Aspen . uniQure provided editorial support for the original manuscript .
REFERENCE
Miesbach W , Meijer K , Coppens M , et al . Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B . Blood . 2017 December 15 . [ Epub ahead of print ]
30 ASH Clinical News February 2018