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CR/CRi
MRD negativity
Subgroups
HSCT
OS
CR/CRi was a primary endpoint and was analyzed in the first 218 patients randomized (remission analysis population) per the statistical plan.1,2
CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; ITT=intent to treat; MRD=minimal residual disease; SC=standard chemotherapy.
MRD negativity was a secondary endpoint analyzed among responding patients in the first 218 patients randomized.2
These subgroup analyses were exploratory and not powered to detect statistical significance. Small patient numbers and lack of multiplicity adjustments can be a limitation of these analyses. No conclusion about efficacy in subgroups can be drawn from these data.
In a post hoc analysis of the phase 3 INO-VATE trial (N=326), the efficacy of BESPONSA vs SC was examined among patients with bone marrow blasts (BMB; ie, disease burden) at the following cutoffs: low (<50%; n=53 vs 48), moderate (50%-90%; n=79 vs 83), or high (>90%; n=30 vs 30). The primary endpoint of CR/CRi was analyzed in the first 218 patients randomized in the intent-to-treat population; this subgroup analysis was based on the full 326-patient population. Findings reported here, including differences among subgroups in the BESPONSA and SC treatment groups, should be interpreted with caution, given the post hoc nature of these analyses and the modest sample sizes evaluated. Exclusion criteria from the INO-VATE ALL trial (eg, patients with peripheral blasts ≥10,000/µL) affected the enrolled patient population and may impact the generalizability of these results.
In a post hoc analysis of the phase 3 INO-VATE ALL trial (N=326), the efficacy of BESPONSA vs SC was examined among adult patients (≥18 years; median age 47). Patients were stratified based on patient age at randomization (≥55 years or <55 years). CR/CRi was a primary endpoint analyzed in the first 218 patients randomized in the intent-to-treat population. This subgroup analysis was based on the full 326-patient population.1,4
In a post hoc analysis of the phase 3 INO-VATE ALL trial (N=326), the efficacy of BESPONSA vs SC was examined among adult patients (≥18 years; median age 47). Patients were stratified based on salvage setting at randomization (first or second). CR/CRi was a primary endpoint analyzed in the first 218 patients randomized in the intent-to-treat population.1-3
In a post hoc analysis of the phase 3 INO-VATE ALL trial (N=326), the efficacy of BESPONSA vs SC was examined among adult patients (≥18 years; median age 47). Patients were stratified based on duration of first remission at randomization (≥12 months vs <12 months). CR/CRi was a primary endpoint analyzed in the first 218 patients randomized in the intent-to-treat population.1-3
Analysis overview
Key limitations
Methodology
These analyses were exploratory, not prespecified, and not powered to detect statistical significance. Small patient numbers, specifically in later cycles of the control arm, can be limitations of these analyses. Patients in the BESPONSA arm received a median of 3 cycles of study therapy, compared with a median of 1 cycle for the SC arm; patients in the SC arm received up to 4 cycles.
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Reason for hospitalization | Number of patients | Hospitalizations per patient month |
---|---|---|
Scheduled ALL treatment or study related |
45.7% (75/164) of patients in the BESPONSA arm vs 63.6% (91/143) of patients in the SC arm |
4.11 DAYS (vs 10.62 days with SC) |
Treatment toxicities |
28.7% (47/164) of patients in the BESPONSA arm vs 21.0% (30/143) of patients in the SC arm |
1.44 DAYS (vs 2.80 days with SC) |
The analysis of OS did not meet a prespecified boundary for statistical significance of P=0.0104.3
Treatment arm | Clinical factors |
---|---|
BESPONSA (n=123) |
|
SC arm (n=80) |
|
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WARNING: HEPATOTOXICITY, INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE (VOD) (ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME) and INCREASED RISK OF POST–HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) NON-RELAPSE MORTALITY (NRM):
Hepatotoxicity, Including Hepatic VOD: Hepatotoxicity, including fatal and life-threatening VOD, occurred in 23/164 patients (14%) during or following treatment with BESPONSA or following subsequent HSCT. VOD was reported up to 56 days after the last dose during treatment or follow-up without an intervening HSCT. The median time from HSCT to onset of VOD was 15 days.
Patients with prior VOD or serious ongoing liver disease are at an increased risk of worsening liver disease, including development of VOD, following treatment with BESPONSA. Monitor closely for signs and symptoms of VOD; these may include elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. For patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles. A third cycle may be considered for patients who do not achieve a CR or CRi and MRD-negativity after 2 cycles. Monitor liver tests closely during the first month post HSCT, then less frequently thereafter, according to standard medical practice.
Grade 3/4 increases in aspartate aminotransferase, alanine aminotransferase, and total bilirubin occurred in 7/160 (4%), 7/161 (4%), and 8/161 (5%) patients, respectively.
Increased Risk of Post-HSCT Non-Relapse Mortality (NRM): There was a higher post-HSCT NRM rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate. The rate of post-HSCT NRM was 31/79 (39%) with BESPONSA and 8/35 (23%) with investigator’s choice of chemotherapy. In the BESPONSA arm, the most common causes of post-HSCT NRM included VOD and infections. Monitor closely for toxicities post HSCT, including signs and symptoms of infection and VOD.
Myelosuppression: Myelosuppression, and severe, life-threatening, and fatal complications of myelosuppression, including hemorrhagic events and infections, have occurred with BESPONSA. Thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively. Febrile neutropenia was reported in 43/164 patients (26%).
Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment and provide appropriate management. As appropriate, administer prophylactic anti-infectives during and after treatment with BESPONSA. Dose interruption, dose reduction, or permanent discontinuation may be required.
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.