6. ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
- Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1)]
- Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2)]
- Myelosuppression [see Warnings and Precautions (5.3)]
- Infusion related reactions [see Warnings and Precautions (5.4)]
- QT interval prolongation [see Warnings and Precautions (5.5)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The adverse reactions described in this section reflect exposure to BESPONSA in 164 patients with relapsed or refractory ALL who participated in a randomized clinical study of BESPONSA versus Investigator's choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (INO-VATE ALL Trial [NCT01564784]) [see Clinical Studies (14)].
Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18–78 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black.
In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range: 0.1–26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1–15.6 weeks), with a median of 1 treatment cycle started in each patient.
In patients who received BESPONSA, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.
In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue.
In patients who received BESPONSA, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).
VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1)].
Table 6 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.
| Body System Adverse Reaction | BESPONSA (N=164) | FLAG, MXN/Ara-C, or HIDAC (N=143†) | ||
|---|---|---|---|---|
| All Grades | ≥ Grade 3 | All Grades | ≥ Grade 3 | |
| % | % | % | % | |
| Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the last dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT). Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. Severity grade of adverse reactions were according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events. | ||||
| ||||
| Infections | ||||
| Infection‡ | 48 | 28 | 76 | 54 |
| Blood and lymphatic system disorders | ||||
| Thrombocytopenia§ | 51 | 42 | 61 | 59 |
| Neutropenia¶ | 49 | 48 | 45 | 43 |
| Anemia# | 36 | 24 | 59 | 47 |
| LeukopeniaÞ | 35 | 33 | 43 | 42 |
| Febrile neutropenia | 26 | 26 | 53 | 53 |
| Lymphopeniaß | 18 | 16 | 27 | 26 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 12 | 1 | 13 | 2 |
| Nervous system disorders | ||||
| Headacheà | 28 | 2 | 27 | 1 |
| Vascular disorders | ||||
| Hemorrhageè | 33 | 5 | 28 | 5 |
| Gastrointestinal disorders | ||||
| Nausea | 31 | 2 | 46 | 0 |
| Abdominal painð | 23 | 3 | 23 | 1 |
| Diarrhea | 17 | 1 | 38 | 1 |
| Constipation | 16 | 0 | 24 | 0 |
| Vomiting | 15 | 1 | 24 | 0 |
| Stomatitisø | 13 | 2 | 26 | 3 |
| Hepatobiliary disorders | ||||
| Hyperbilirubinemia | 21 | 5 | 17 | 6 |
| General disorders and administration site conditions | ||||
| Fatigueý | 35 | 5 | 25 | 3 |
| Pyrexia | 32 | 3 | 42 | 6 |
| Chills | 11 | 0 | 11 | 0 |
| Investigations | ||||
| Transaminases increased£ | 26 | 7 | 13 | 5 |
| Gamma-glutamyltransferase increased | 21 | 10 | 8 | 4 |
| Alkaline phosphatase increased | 13 | 2 | 7 | 0 |
Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%).
Table 7 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.
| BESPONSA | FLAG, MXN/Ara-C, or HIDAC | |||||
|---|---|---|---|---|---|---|
| All Grades | Grade 3/4 | All Grades | Grade 3/4 | |||
| Laboratory Abnormality* | N | % | % | N | % | % |
| Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events. | ||||||
| ||||||
| Hematology | ||||||
| Platelet count decreased | 161 | 98 | 76 | 142 | 100 | 99 |
| Hemoglobin decreased | 161 | 94 | 40 | 142 | 100 | 70 |
| Leukocytes decreased | 161 | 95 | 82 | 142 | 99 | 98 |
| Neutrophil count decreased | 160 | 94 | 86 | 130 | 93 | 88 |
| Lymphocytes (absolute) decreased | 160 | 93 | 71 | 127 | 97 | 91 |
| Chemistry | ||||||
| GGT increased | 148 | 67 | 18 | 111 | 68 | 17 |
| AST increased | 160 | 71 | 4 | 134 | 38 | 4 |
| ALP increased | 158 | 57 | 1 | 133 | 52 | 3 |
| ALT increased | 161 | 49 | 4 | 137 | 46 | 4 |
| Blood bilirubin increased | 161 | 36 | 5 | 138 | 35 | 6 |
| Lipase increased | 139 | 32 | 13 | 90 | 20 | 2 |
| Hyperuricemia | 158 | 16 | 3 | 122 | 11 | 0 |
| Amylase increased | 143 | 15 | 2 | 102 | 9 | 1 |
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to inotuzumab ozogamicin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
In clinical studies of BESPONSA in patients with relapsed or refractory ALL, the immunogenicity of BESPONSA was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay was performed to detect neutralizing antibodies.
In clinical studies of BESPONSA in patients with relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment.