CLINICAL NEWS
Gene therapy may be an alternative treatment option for people ineligible for transplant . patients with other genotypes . The investigators obtained mobilized , autologous CD34-positive cells from participants and transduced the cells ex vivo with Lenti- Globin BB305 vector , which encodes adult hemoglobin ( HbA ) with a T87Q amino-acid substitution ( HbAT87Q ). After undergoing conditioning with single-agent , intravenous busulfan , modified cells were then re-infused at median doses of :
• 11.0 million CD34-positive cells / kg ( range = 6.1 million to 18.1 million cells / kg ) in people with a β0 / β0 genotype
• 7.1 million CD34-positive cells / kg ( range = 5.2 million to 13.0 million cells / kg ) in those with other genotypes
Participants started receiving transfusions at an early age ( median = 3.5 years in HGB-204 and 1.8 years in HGB-205 [ range = 0-26 years
In the INO-VATE ALL study , more patients achieved MRD-negative complete remission and proceeded to HSCT after CD22-directed treatment with BESPONSA 1 , 2
Median OS in patients treated with BESPONSA was 7.7 months ( 95 % CI , 6.0-9.2 ) vs 6.2 months ( 95 % CI , 4.7-8.3 ) in patients treated with SC ( HR = 0.75 ; P = 0.0105 ). b The analysis of OS did not meet a prespecified boundary for statistical significance of P = 0.0104 . 1 , 2
The most common ( ≥2 %) serious adverse events were infection ( 23 %), febrile neutropenia ( 11 %), hemorrhage ( 5 %), abdominal pain ( 3 %), pyrexia ( 3 %), VOD ( 2 %), and fatigue ( 2 %) 1 , 2
Study design : INO-VATE ALL was a Phase 3 , open-label , randomized ( 1:1 ) study of BESPONSA vs investigator ’ s choice of SC in 326 adult patients with relapsed or refractory B-cell precursor ALL . SC included FLAG , HiDAC , or Ara-C + MXN . All patients were required to have ≥5 % bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL . Patients with Ph + B-cell precursor ALL were required to have failed treatment with ≥1 TKI and SC . Single-agent BESPONSA was given by 1-hour IV infusion in 3 fractionated doses at 1.8 mg / m 2 each 3- to 4-week cycle , reduced to 3 fractionated doses at 1.5 mg / m 2 per cycle after achieving CR / CRi , for up to 6 cycles . For patients proceeding to HSCT , the recommended treatment duration with BESPONSA is 2 cycles . Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment . 1 , 3
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Ara-C + MXN = cytarabine + mitoxantrone ; CI = confidence interval ; CR = complete remission ; CRi = CR with incomplete hematologic recovery ; FLAG = fludarabine , Ara-C , and granulocyte colony-stimulating factor ; HiDAC = high-dose cytarabine ; HR = hazard ratio ; HSCT = hematopoietic stem cell transplant ; MRD = minimal residual disease ; OS = overall survival ; Ph += Philadelphia chromosome – positive ; SC = standard chemotherapy ; TKI = tyrosine kinase inhibitor ; VOD = hepatic veno-occlusive disease . Response assessments were performed in the first 218 patients randomized , and survival analyses were completed in the full study population of 326 patients . a
1-sided P value using chi-square test . b
1-sided P value using log-rank test .
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Infusion-Related Reactions : Infusion-related reactions ( all Grade 2 ) were reported in 4 / 164 patients ( 2 %). Premedicate with a corticosteroid , antipyretic , and antihistamine prior to dosing . Monitor patients closely during and for at least 1 hour after the end of the infusion for the potential onset of infusion-related reactions including symptoms such as fever , chills , rash , or breathing problems . Interrupt the infusion and institute appropriate medical management if an infusion-related reaction occurs . Depending on the severity , consider discontinuation of the infusion or administration of steroids and antihistamines . For severe or life-threatening infusion reactions , permanently discontinue BESPONSA .
QT Interval Prolongation : Increases in QT interval corrected for heart rate using Fridericia ’ s formula of ≥60 msec from baseline were measured in 4 / 162 patients ( 3 %). Administer BESPONSA with caution in patients who have a history of or predisposition to QTc prolongation , who are taking medicinal products that are known to prolong QT interval , and in patients with electrolyte disturbances . Obtain electrocardiograms and electrolytes prior to treatment and after initiation of any drug known to prolong QTc , and periodically monitor as clinically indicated during treatment .
Embryo-Fetal Toxicity : BESPONSA can cause embryo-fetal harm . Apprise pregnant women of the potential risk to the fetus . Advise males and females of reproductive potential to use effective contraception during BESPONSA treatment and for at least 5 and 8 months after the last dose , respectively . Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with BESPONSA .
Adverse Reactions : The most common ( ≥20 %) adverse reactions observed with BESPONSA were thrombocytopenia , neutropenia , infection , anemia , leukopenia , fatigue , hemorrhage , pyrexia , nausea , headache , febrile neutropenia , transaminases increased , abdominal pain , gamma-glutamyltransferase increased , and hyperbilirubinemia . The most common ( ≥2 %) serious adverse reactions were infection , febrile neutropenia , hemorrhage , abdominal pain , pyrexia , VOD , and fatigue .
Nursing Mothers : Advise women against breastfeeding while receiving BESPONSA and for 2 months after the last dose .
INDICATION
BESPONSA is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia ( ALL ).
Please see brief summary of full Prescribing Information , including BOXED WARNING , on adjacent pages .
References : 1 . BESPONSA Prescribing Information . New York , NY : Pfizer Inc . 2 . Data on file . Pfizer Inc , New York , NY . 3 . Kantarjian HM , DeAngelo DJ , Stelljes M , et al . Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia . N Engl J Med . 2016 ; 375 ( 8 ): 740-753 .
PP-INO-USA-0183-03 © 2018 Pfizer Inc . All rights reserved . April 2018