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EfficacyEfficacyKey Take AwaysHospitalisation DataSafetySafetyAdverse Event Management: VOD/SOSSelected Adverse ReactionsDosingDosing and Dose ModificationsAdministrationSupport and ResourcesPublications
EfficacyINO-VATE ALL: The pivotal phase 3 registration study for BESPONSA, was an open-label, randomised study in adults with R/R CD-22 + 
B-cell ALL1-41.8 mg/m2 was given in 3 divided doses: 0.8 mg/m2 on Day 1, 0.5mg/m2 on Days 8 and 15 of a 21 day cycle for cycle 1. Subsequent cycles lasted 28 days. BESPONSA dose was reduced to 1.5 mg/m2/cycle once the patient achieved CR/CRi. 1.5 mg/m2 was given as 3 divided doses of 0.5 mg/m2 on Days 1, 8, and 151ALL=acute lymphoblastic leukemia; AraC=cytarabine; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; DoR=duration of remission; FLAG=fludarabine + AraC + granulocyte colony-stimulating factor; HiDAC=high-dose cytarabine; HSCT=hematopoietic stem cell transplantation; MRD=measurable residual disease; MXN=mitoxantrone; OS=overall survival; PFS=progression-free survival; Ph-=Philadelphia chromosome-negative; Ph+=Philadelphia chromosome-positive; PRO=patient‑reported outcome; R/R=relapsed/refractory.
Kantarjian HM, et al. N Engl J Med. 2016;375(8):740-753.Besponsa Summary of Product CharacteristicsKantarjian HM, et al. Cancer. 2018;124(10):2151-2160.Kantarjian HM et al. Cancer 2019;125(14):2474–2487. 
INO-VATE ALL: CR/CRi and OS were the two primary endpoints1
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BESPONSA SC
CR/CRi1 80.7% (n=88/109)
(95% CI, 72.1-87.7)		 29.4% (n=32/109)
(95% CI, 21.0-38.8)

2-sided P < 0.001
OS: Not met
mOS1		 7.7 months (n-164)
(95% Cl, 6.0-9.2)		 6.7 months (n-162)
(95% Cl, 4.9-8.3)

HR 0.77 (97.5% Cl, 0.58-1.03); 2-sided P = 0.04
ITT218 Oct 2, 2014
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  BESPONSA SC
CR/CRi2 73.8% (n = 121/164) 30.9% (n=50/162)
  1-sided P < 0.001
OS: Not met
mOS2,3		 7.7 months (n-164)
(95% Cl, 6.0-9.2)		 6.2 months (n-162)
(95% Cl, 4.7-8.3)
  HR 0.75 (97.5% Cl, 0.57-0.99); 1-sided P = 0.0105;
HR = 0.751 (95% Cl, 0.588-0.959); 2-sided P=0.0210
2-year
survival2		 22.8%
(95% Cl, 16.7-29.6)		 10.0%
(95% Cl, 5.7-15.5)
3-year
survival2		 20.3%
(95% Cl, 14.4-27.0)		 6.5%
(95% Cl, 2.9-12.3)
ITT326 Long-term follow-up Jan 4, 2017
ALL=acute lymphoblastic leukemia; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; HR=hazard ratio; ITT=intention-to-treat; mOS=median overall survival; OS=overall survival; SC=standard chemotherapy.Kantarjian HM, et al. N Engl J Med. 2016;375(8):740-753.Kantarjian HM, et al. Cancer. 2019;125(14):2474-2487.Besponsa Summary of Product Characteristics
Response Rates by Bone Marrow Blast Count

Disease burden post-hoc analysis

Rates of CR/CRi and MRD Negativity in BESPONSA-treated Patients Were Higher Than With SC, Irrespective of Bone Marrow Blast Count1

Note: Due to the small sample size, results should be interpreted with caution.  
BMB data was not available for three of the 326 patients in INO-VATE ALL.
 Lighter-colored grey and pink bar segments represent patients that achieved CR/CRi but did not achieve MRD negativity.

BMB=bone marrow blast; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; MRD=measurable residual disease; SC=standard chemotherapy.1

1.DeAngelo DJ, et al. Blood Cancer J. 2020;10(8):81.

For Patients With EMD/LBL, Outcomes Appeared Improved With BESPONSA vs SC; However, Sample Sizes Were Very Small1Note: Due to the small sample size, results should be interpreted with caution. The study was not powered to look at these subsets.BMB=bone marrow blast; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; EMD=extramedullary disease; HR=hazard ratio; LBL=lymphoblastic lymphoma; mo=months; mPFS=median progression-free survival; MRD=measurable residual disease; SC=standard chemotherapy.1

1.DeAngelo DJ, et al. Blood Cancer J. 2020;10(8):81.Response Rates by Salvage Lines

Salvage line post-hoc analysis

Rates of CR/CRi and MRD Negativity in BESPONSA-treated Patients Were Greater in First Salvage1

 
Note: Due to the small sample size, results should be interpreted with caution.  
BMB data was not available for three of the 326 patients in INO-VATE ALL. 
 
Lighter-colored grey and pink bar segments represent patients that achieved CR/CRi but did not achieve MRD negativity.

​​​​​​​BMB=bone marrow blast; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; MRD=measurable residual disease; SC=standard chemotherapy.
DeAngelo DJ, et al. Blood Cancer J. 2020;10(8):81.Optional footnote area for disclaimers etc.

Note: The increased CR/CRi rates for SC in S2 vs S1 was not expected and may be due to the limited sample size or differences in baseline characteristics.

Salvage treatment line was according to the clinical report form. Lighter-colored grey and pink bar segments represent patients who achieved CR/CRi but did not achieve MRD negativity.CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; MRD=measurable residual disease; S1=salvage 1; S2=salvage 2; SC=standard chemotherapy.

1.Jabbour E, et al. Leuk Lymphoma. 2020;61(8):2012-2015.Outcomes by MRD Status

MRD post-hoc analysis

​​​​​​​Median OS was 19.2 Months in MRD-negative Patients Treated With BESPONSA Who Underwent HSCT1

The primary endpoint of OS was not met in INO-VATE ALL2,3Note: Due to the small sample size, results should be interpreted with caution.

In the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared with the investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.4
Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD.4

ALL=acute lymphoblastic leukemia; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; HR=hazard ratio; HSCT=hematopoietic stem cell transplantation; mo=months; mOS=median overall survival; MRD=measurable residual disease; OS=overall survival; VOD=veno-occlusive disease.
Jabbour E, et al. Leuk Res. 2020;88:106283.Kantarjian HM, et al. N Engl J Med. 2016;375(8):740-753.Kantarjian HM, et al. Cancer. 2019;125(14):2474-2487.Besponsa Summary of Product CharacteristicsThe primary endpoint of OS was not met in INO-VATE ALL2,3

mOS was 15.6 months in MRD-negative patients in first salvage compared with 6.9 months in patients who were MRD-positive1

ALL=acute lymphoblastic leukemia; CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery of peripheral blood counts; mo=months; mOS=median overall survival; MRD=measurable residual disease; MRD–/MRD+=measurable residual disease-negative/-positive; OS=overall survival; S1=salvage 1; S2=salvage 2.Jabbour E, et al. Leuk Res. 2020;88:106283.Kantarjian HM, et al. N Engl J Med. 2016;375(8):740-753.Kantarjian HM, et al. Cancer. 2019;125(14):2474-2487.Follow-up HSCT & Survival

ITT326, Long-term follow-up Jan 4, 2017

​​​​​​​​​​​​​​Improvements in Long-term Survival Were More Pronounced In Patients Treated With BESPONSA in First Salvage1

The primary endpoint of OS was not met in INO-VATE ALL2,3
In this post-hoc analysis, 24-month OS with BESPONSA was 25.9% in S1 vs. 16.8% in S21Note: Due to the small sample size, results should be interpreted with caution.
In the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared with the investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.4
Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD.4

Hashmarks on Kaplan–Meier graphs correspond to patients censored.
Salvage treatment line by clinical report form; ITT population.1
ALL=acute lymphoblastic leukemia; CI=confidence interval; HSCT=hematopoietic stem cell transplantation; ITT=intention-to-treat; OS=overall survival; S1=first salvage; S2=second salvage; SC=standard chemotherapy;
VOD=veno-occlusive disease.
Jabbour E, et al. Leuk Lymphoma 2020;61(8):2012-2015.Kantarjian HM, et al. N Engl J Med. 2016;375(8):740-753.Kantarjian HM, et al. Cancer. 2019;125(14):2474-2487.BESPONSA Summary of Product CharacteristicsMore Patients Proceeded to Transplant With BESPONSA When Treated in First Salvage1A greater proportion of patients proceeded to post-treatment HSCT with BESPONSA when treated in first salvage1
(52.3% in S1 vs. 39.2% in S2)1,aIn the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared with the investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.2
Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD.2

a There was an increased risk of VOD in BESPONSA-treated patients proceeding to HSCT in INO-VATE ALL.2,3 

Salvage treatment line by clinical report form, ITT population.1

ALL=acute lymphoblastic leukemia; CI=confidence interval; HSCT=hematopoietic stem cell transplantation; ITT=intention-to-treat; S1=salvage 1; S2=salvage 2; SC=standard chemotherapy; VOD=veno-occlusive disease.
Jabbour E, et al. Leuk Lymphoma 2020;61(8):2012-2015.BESPONSA Summary of Product CharacteristicsKantarjian HM, et al. Cancer. 2019;125(14):2474-2487.Post-transplant Survival Achieved in Patients Proceeding Directly to Their First Transplant in CR – 51% Survival at 2 Years1,a

Adapted from Marks DI, et al. Biol Blood Marrow Transplant. 2019;25(9):1720-1729

The primary endpoint of OS was not met in INO-VATE ALL2,3

Results from pooled data from INO-VATE ALL and the earlier phase 1/2 study 1010 of patients who proceeded to HSCT after treatment (n=101 for BESPONSA)1

  • The objective of the analysis was to assess post-HSCT outcomes, identify predictors of outcomes, and describe any unique drug-related toxicity potentially exacerbated by HSCT1
  • Of 236 BESPONSA-treated patients, 43% proceeded to HSCT and were included in this analysis1
  • The majority of patients received BESPONSA in first salvage (62%); 85% had no previous HSCT1
In the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared with the investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.4
Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD.4

There was an increased risk of VOD in BESPONSA-treated patients proceeding to HSCT in INO-VATE ALL.3,4 

a Without intervening or additional treatment.1

ALL=acute lymphoblastic leukemia; CI=confidence interval; CR=complete remission; HSCT=hematopoietic stem cell transplantation; OS=overall survival; VOD=veno-occlusive disease.

1. Marks DI, et al. Biol Blood Marrow Transplant. 2019;25(9):1720-1729.
2. Kantarjian HM, et al. N Engl J Med. 2016;375(8):740-753.
3. Kantarjian HM, et al. Cancer. 2019;125(14):2474-2487.
4. BESPONSA Summary of Product Characteristics.INO-VATE Patient CharacteristicsPatient Characteristics From INO-VATE ALL1
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    BESPONSA
(n = 164)		 SC
(n = 162)
Over two-thirds (68.1%) of patients had a high bone marrow blast count (BMB ≥ 50%)
BMB, n (%)    
< 50% 53 (32.3) 48 (29.6)
≥ 50% 109 (66.5) 113 (69.8)
Missing 2 (1.2) 1 (0.6)
The majority of patients (65.3%) were treated in first relapse
Salvage status, n (%)    
1 111 (67.7) 102 (63.0)
2 51 (31.1) 59 (36.4)
Missing 2 (1.2) 1 (0.6)
18.7% of patients had received a prior HSCT
Prior HSCT, n (%)    
Yes 29 (17.7) 32 (19.8)
Most patients (62%) had a short duration of first remission (< 12 months) Duration of  first remission, n(%)    
< 12 months 96 (58.5) 106 (65.4)
The median age of patients was 46.5 years and 47.5 years in the BESPONSA and SC arms, respectively Age    
Median (range), years 46.5
(18-78)		 47.5 (18-79)
< 55 years, n (%) 104 (63.4) 103 (63.6)
≥ 55 years, n (%) 60 (36.6) 59 (36.4)
15% of patients were Ph+ Baseline cytogenetics, n (%)     
Ph+ 22 (13.4) 27 (16.7)
ITT326, Long-term follow-up Jan 4, 2017

ALL=acute lymphoblastic leukemia; BMB=bone marrow blast; HSCT=hematopoietic stem cell transplantation; 
Ph+=Philadelphia chromosome-positive; SC=standard chemotherapy.Kantarjian HM, et al. Cancer. 2019;125(14):2474-2487.

Potential Factors Impacting Outcomes in R/R B-Cell ALL

  • High disease burden/BMB count1,2
    • Some trials define a high blast count as BMB ≥ 50%1,3,4
    • Determination of BMB percentage is a mandatory test for ALL diagnosis and is used as a measure of disease burden1,2
  • Later salvage lines5
  • Previous HSCT5
  • Duration of first remission5
  • Age2,5,6
  • Ph status6
ALL=acute lymphoblastic leukemia; BMB=bone marrow blast; HSCT=hematopoietic stem cell transplantation; 
ITT=intention-to-treat; Ph=Philadelphia chromosome; R/R=relapsed/refractory.DeAngelo DJ, et al. Blood Cancer J. 2020;10(8):81.Hoelzer D, et al. Ann Oncol. 2016;27(5):v69-v82.Topp MS, et al. Lancet Oncol. 2015;16(1):57-66.Kantarjian HM, et al. N Engl J Med. 2016;375(8):740-753.Gökbuget N, et al. Haematologica 2016;101(12):1524-1533.NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia v1 2021.Kantarjian HM, et al. Cancer. 2019;125(14):2474-2487.
ALL=acute lymphoblastic leukemia; HSCT=hematopoietic stem cell transplantation; MRD=measurable residual disease; SmPC=Summary of Product Characteristics.
Efficacy Safety VisitLoading Besponsa Prescribing Information VisitLoading INO-VATE ALL Analyses Timeline 

Please click here to view the INO-VATE ALL analyses timeline and data cuts

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