Besponsa

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 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 See full prescribing information for complete boxed warning. • Hepatotoxicity, including fatal and life-threatening VOD occurred in patients who received BESPONSA. ( 5.1 ) • A higher post-HSCT non-relapse mortality rate occurred in patients receiving BESPONSA ( 5.2 ) HEPATOTOXICITY, INCLUDING VOD • Hepatotoxicity, including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia (ALL) who received BESPONSA. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ upper limit of normal (ULN) before HSCT were significantly associated with an increased risk of VOD. • Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles. • Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ]. INCREASED RISK OF POST-HSCT NON-RELAPSE MORTALITY • There was higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate [see Warnings and Precautions (5.2) ] .

5. WARNINGS AND PRECAUTIONS • Myelosuppression: Monitor complete blood counts; for signs and symptoms of infection; bleeding/hemorrhage; or other effects of myelosuppression during treatment; manage appropriately. ( 5.3 ) • Infusion related reactions: Monitor for infusion related reactions during and for at least 1 hour after infusion ends. ( 5.4 ) • QT interval prolongation: Obtain electrocardiograms (ECGs) and electrolytes at baseline and monitor during treatment. Monitor more frequently when using concomitant mediations known to prolong QT interval. ( 5.5 ) • Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome) BESPONSA can cause hepatotoxicity, including VOD. In adult patients in the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD occurred in 23/164 patients (14%) in the BESPONSA arm during or following treatment or following a HSCT after completion of treatment. VOD occurred up to 56 days after the final dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days). In the BESPONSA arm, among the 79 patients who proceeded to a subsequent HSCT, VOD occurred in 18/79 patients (23%), and among all 164 patients treated, VOD occurred in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total bilirubin level greater than or equal to the ULN before HSCT are significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles. Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following treatment with BESPONSA. In Study WI203581 (ITCC-059) VOD occurred in 8/53 (15%) of pediatric patients treated with single agent BESPONSA. Among the 26 pediatric patients who underwent HSCT, VOD occurred in 5 (19%) patients [see Adverse Reactions (6.1) ] . Monitor closely for signs and symptoms of VOD including elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Due to the risk of VOD, for patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles [see Dosage and Administration (2.1) ] . For patients who proceed to HSCT, monitor liver tests at least weekly during the first month post-HSCT, then less frequently thereafter, according to standard medical practice. In adult patients in the INO-VATE ALL trial, increases in liver test abnormalities occurred. Grade 3 or 4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively. In pediatric patients in Study WI203581 (ITCC-059), liver test abnormalities occurred, with Grade 3 or 4 increases in AST, ALT, and blood bilirubin in 11/53 (21%), 11/53 (21%), and 5/53 (9%) of patients, respectively [see Adverse Reactions (6.1) ] . In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. Based on elevations of liver tests withhold, reduce dose, or permanently discontinue BESPONSA [see Dosage and Administration (2.3) ] . 5.2 Increased Risk of Post-Transplant Non-Relapse Mortality In adult patients in the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared to the Investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate. Overall, 79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the Investigator's choice of chemotherapy arm had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 31/79 (39%) and 8/35 (23%) in the BESPONSA arm compared to the Investigator's choice of chemotherapy arm, respectively. In the BESPONSA arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events that occurred post-HSCT were fatal. In the BESPONSA arm, among patients with ongoing VOD at time of death, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection). In pediatric patients in Study WI203581 (ITCC-059), 26/53 patients (49%) had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 7/26 (27%). Monitor for toxicities post-HSCT, including signs and symptoms of infection and VOD [see Warnings and Precautions (5.1 , 5.3) ] . 5.3 Myelosuppression BESPONSA can cause myelosuppression, including thrombocytopenia and neutropenia [see Adverse Reactions (6.1) ] . In adult patients in the INO-VATE ALL trial, thrombocytopenia and neutropenia occurred in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia occurred in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia occurred in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, occurred in 43/164 patients (26%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to > 50,000/mm 3 was later than 45 days after the final dose in 15/164 patients (9%) who received BESPONSA and 3/162 patients (2%) who received Investigator's choice of chemotherapy. Complications associated with myelosuppression (including infections and bleeding/hemorrhage) occurred in patients receiving BESPONSA [see Adverse Reactions (6.1) ] . Infections, including serious infections, some of which were life-threatening or fatal, occurred in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, occurred in 8/164 patients (5%). Bacterial, viral, and fungal infections occurred. Hemorrhage occurred in 54/164 patients (33%). Grade 3 or 4 hemorrhage occurred in 8/164 patients (5%), including a fatality in 1/164 patients (1%) (intra-abdominal hemorrhage). The most common type of hemorrhage was epistaxis which occurred in 24/164 patients (15%). In pediatric patients in Study WI203581 (ITCC-059), Grade 3 or 4 thrombocytopenia occurred in 24/53 (45%) patients. Grade 3 or 4 neutropenia occurred in 21/53 (40%) patients. Infections occurred in 23/53 (43%) patients, and hemorrhage occurred in 22/53 (42%) patients. The most common types of hemorrhage were hematoma in 8/53 (15%), mouth hemorrhage in 6/53 (11%), and epistaxis in 6/53 (11%) patients [see Adverse Reactions (6.1) ] . 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 with BESPONSA. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with BESPONSA. Based on the severity of myelosuppression, reduce dose, temporarily withhold, or permanently discontinue BESPONSA [see Dosage and Administration (2.3) ]. 5.4 Infusion Related Reactions BESPONSA can cause infusion related reactions. In adult patients in the INO-VATE ALL trial, infusion related reactions occurred in patients who received BESPONSA. Infusion related reactions (all Grade 2) occurred in 4/164 patients (2%) [see Adverse Reactions (6.1) ] . Infusion related reactions generally occurred in Cycle 1 shortly after the end of the BESPONSA infusion and resolved spontaneously or with medical management. In pediatric patients in Study WI203581 (ITCC-059), infusion related reactions occurred in 4/53 (8%) patients [see Adverse Reactions (6.1) ] . Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing [see Dosage and Administration (2.2) ] . Monitor patients closely during and for at least 1 hour after the end of infusion for the potential onset of infusion related reactions, including symptoms such as fever, chills, rash, or breathing problems. Interrupt infusion and institute appropriate medical management if an infusion related reaction occurs. Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue BESPONSA [see Dosage and Administration (2.3) ] . 5.5 QT Interval Prolongation BESPONSA can cause QT interval prolongation. In adult patients in the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericia’s formula (QTcF) of ≥ to 60 msec from baseline occurred in 4/162 patients (3%). Grade 2 QT prolongation was reported in 2/164 patients (1%) [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2) ] . In pediatric patients in Study WI203581 (ITCC-059), increases in QTcF of > 60 msec from baseline occurred in 7/49 (14%) patients. 3/52 (6%) of patients had QTcF values > 500 msec [see Adverse Reactions (6.1) ] . Administer BESPONSA with caution in patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval [see Drug Interactions (7) ] , and in patients with electrolyte disturbances [see Drug Interactions (7) ]. Obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment [see Drug Interactions (7) , Clinical Pharmacology (12.2) ] ). 5.6 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. In animal studies, inotuzumab ozogamicin caused embryo-fetal toxicities, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for 8 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose. Advise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with BESPONSA [see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ].

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) ] The most common (≥ 20%) adverse reactions, including laboratory abnormalities, in adult and pediatric patients are thrombocytopenia, pyrexia, neutropenia, infection, anemia, vomiting, leukopenia, hemorrhage, fatigue, nausea, febrile neutropenia, headache, transaminases increased, abdominal pain, and gamma-glutamyltransferase increased, and hyperbilirubinemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Relapsed or Refractory B-cell Precursor ALL Adult Patients The safety of BESPONSA was evaluated in adult patients with relapsed or refractory B-cell precursor ALL in the INO-VATE ALL trial. The study was a randomized clinical study of BESPONSA (n=164) versus Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (n=143) [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 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy. Table 7. Adverse Reactions With ≥ 10% Incidence Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included. in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) Body System Adverse Reaction BESPONSA (N=164) FLAG, MXN/Ara-C, or HIDAC (N=143 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment. ) 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 final 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 Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. 48 28 76 54 Blood and lymphatic system disorders Thrombocytopenia Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia. 51 42 61 59 Neutropenia Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased. 49 48 45 43 Anemia Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased. 36 24 59 47 Leukopenia Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased. 35 33 43 42 Febrile neutropenia 26 26 53 53 Lymphopenia Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia. 18 16 27 26 Metabolism and nutrition disorders Decreased appetite 12 1 13 2 Nervous system disorders Headache Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache. 28 2 27 1 Vascular disorders Hemorrhage Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage. 33 5 28 5 Gastrointestinal disorders Nausea 31 2 46 0 Abdominal pain Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain. 23 3 23 1 Diarrhea 17 1 38 1 Constipation 16 0 24 0 Vomiting 15 1 24 0 Stomatitis Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis. 13 2 26 3 Hepatobiliary disorders Hyperbilirubinemia 21 5 17 6 General disorders and administration site conditions Fatigue Fatigue includes the following reported preferred terms: Asthenia and Fatigue. 35 5 25 3 Pyrexia 32 3 42 6 Chills 11 0 11 0 Investigations Transaminases increased Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia. 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 8 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy. Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) BESPONSA FLAG, MXN/Ara-C, or HIDAC All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy. 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 Pediatric Patients The safety of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL was evaluated in a multicenter, single-arm, open-label study (ITCC-059) [see Clinical Studies (14) ] . Patients (n=53) received the recommended dosage of BESPONSA [see Dosage and Administration (2.1) ] or BESPONSA at an initial dose of 1.4 mg/m 2 /cycle (approximately 0.78 times the recommended initial dosage). Patients received BESPONSA for a median of 2 (range: 1-4) cycles. The median age of patients who received BESPONSA was 9 years (range: 1-17), with 68% male. Serious adverse reactions occurred in 62% of patients who received BESPONSA. Serious adverse reactions in > 2% of patients included infection (21%), febrile neutropenia (17%), VOD (15%), hemorrhage (4%), pyrexia (6%) and multiorgan failure (2%). Fatal adverse reactions occurred in 8% of patients who received BESPONSA, including multiorgan failure, lung infection, sepsis, and encephalopathy. Permanent discontinuation of BESPONSA due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent discontinuation of BESPONSA in 2 or more patients included ALT increased and platelet count decreased. Dosage interruptions of BESPONSA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption of BESPONSA in 6 patients included increased transaminases, febrile neutropenia, and headache. The most common adverse reactions (≥ 20%), including laboratory abnormalities, were thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache. Table 9 summarizes the adverse reactions in ITCC-059. Table 9. Adverse Reactions (≥ 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059) Severity grade of adverse reactions were according to NCI CTCAE version 4.03. Body System Adverse Reaction BESPONSA Monotherapy (N=53) All Grades ≥ Grade 3 % % General disorders and administration site conditions Pyrexia 49 4 Edema Includes other related terms. 19 0 Fatigue 17 0 Pain 15 2 Chills 8 0 Blood and lymphatic system disorders Anemia 45 38 Febrile neutropenia 28 28 Gastrointestinal disorders Vomiting 45 2 Nausea 32 0 Abdominal pain 25 2 Constipation 19 2 Stomatitis 17 6 Diarrhea 11 0 Infections and infestations Infection Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection. 43 23 Vascular disorders Hemorrhage Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage. 42 6 Hypotension 6 4 Nervous system disorders Headache 21 0 Skin and subcutaneous tissue disorders Rash 19 4 Pruritis 9 0 Hyperhidrosis 6 0 Musculoskeletal and connective tissue disorders Pain in extremity 19 2 Back pain 6 0 Neck pain 6 0 Muscular weakness 6 0 Respiratory, thoracic and mediastinal disorders Cough 17 0 Dyspnea 8 2 Hypoxia 8 4 Hepatobiliary disorders Veno-occlusive disease 15 13 Hyperbilirubinemia 9 8 Metabolism and nutrition disorders Decreased appetite 11 4 Tumor lysis syndrome 11 11 Investigations Weight increased 8 2 Injury, poisoning and procedural complications Infusion related reaction Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity. 8 0 Cardiac disorders Sinus tachycardia 6 2 Psychiatric disorders Anxiety 6 0 Table 10 summarizes select laboratory abnormalities in pediatric patients with CD22-positive relapsed/refractory ALL after receiving BESPONSA monotherapy in Study WI203581 (ITCC-059). Table 10. Select Laboratory Abnormalities in Pediatric Patients with CD22-positive Relapsed/Refractory ALL after receiving BESPONSA Monotherapy in Study WI203581 (ITCC-059) Severity grade of laboratory abnormalities according to NCI CTCAE version 4.03. Abbreviations: N= number of subjects with valid post-baseline assessment; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events. Laboratory Abnormality BESPONSA Monotherapy All Grades Grade 3/4 N % % Hematology Platelet count decreased 53 100 85 Neutrophil count decreased 53 98 96 White blood cell decreased 53 98 89 Hemoglobin decreased 53 96 42 Lymphocyte count decreased 52 87 73 Chemistry AST increased 53 87 21 ALT increased 53 83 21 GGT increased 33 79 27 Blood bilirubin increased 53 30 9 ALP increased 53 28 0 Lipase increased 48 23 4 Serum amylase increased 49 14 0

<table ID="_RefID0EH4AE" width="85%"><caption>Table 7. Adverse Reactions With &#x2265; 10% Incidence<footnote ID="_RefID0EL4AE">Only adverse reactions with &#x2265; 10% incidence in the BESPONSA arm are included.</footnote> in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator&apos;s Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)</caption><col width="36%"/><col width="16%"/><col width="16%"/><col width="16%"/><col width="16%"/><thead><tr><th align="left" rowspan="3" styleCode="Rrule Lrule Toprule " valign="bottom"><content styleCode="bold">Body System</content> <content styleCode="bold"> Adverse Reaction</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><content styleCode="bold">BESPONSA</content> <content styleCode="bold">(N=164)</content></th><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><content styleCode="bold">FLAG, MXN/Ara-C, or HIDAC</content> <content styleCode="bold">(N=143</content><footnote ID="_RefID0EY5AE">19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.</footnote><content styleCode="bold">)</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">All Grades</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">&#x2265; Grade 3</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">All Grades</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">&#x2265; Grade 3</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">%</content></th></tr></thead><tfoot><tr><td align="left" colspan="5" valign="top">Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final 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.</td></tr></tfoot><tbody><tr><td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Infections</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection<footnote ID="_RefID0EJAAG">Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>48</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>76</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>54</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and lymphatic system disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Thrombocytopenia<footnote ID="_RefID0E5AAG">Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>51</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>42</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>61</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>59</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Neutropenia<footnote ID="_RefID0EMBAG">Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>48</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>45</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>43</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia<footnote ID="_RefID0E1BAG">Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>36</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>59</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>47</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Leukopenia<footnote ID="_RefID0EICAG">Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased. </footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>35</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>42</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>53</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>53</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Lymphopenia<footnote ID="_RefID0ECDAG">Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and nutrition disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache<footnote ID="_RefID0EKEAG">Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hemorrhage<footnote ID="_RefID0E6EAG">Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>33</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>31</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>46</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal pain<footnote ID="_RefID0EAGAG">Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Stomatitis<footnote ID="_RefID0ESHAG">Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hepatobiliary disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperbilirubinemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General disorders and administration site conditions</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fatigue<footnote ID="_RefID0E1IAG">Fatigue includes the following reported preferred terms: Asthenia and Fatigue.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>35</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pyrexia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>32</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>42</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Chills</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Investigations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Transaminases increased<footnote ID="_RefID0EHKAG">Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Gamma-glutamyltransferase increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Alkaline phosphatase increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

<table ID="_RefID0EKLAG" width="85%"><caption>Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator&apos;s Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) </caption><col width="26%"/><col width="6%"/><col width="14%"/><col width="13%"/><col width="13%"/><col width="14%"/><col width="13%"/><thead><tr><th align="left" styleCode="Rrule Lrule Toprule " valign="top"/><th align="left" styleCode="Rrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">BESPONSA</content></th><th align="left" styleCode="Rrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">FLAG, MXN/Ara-C, or HIDAC </content></th></tr><tr><th align="left" styleCode="Rrule Lrule " valign="top"/><th align="left" styleCode="Rrule " valign="top"/><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">All Grades</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade 3/4</content></th><th align="left" styleCode="Rrule " valign="top"/><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">All Grades</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade 3/4</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="bottom"><content styleCode="bold">Laboratory Abnormality</content><footnote ID="_RefID0EKNAG">Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.</footnote></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">N</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">%</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">%</content></th></tr></thead><tfoot><tr><td align="left" colspan="7" valign="top">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.</td></tr></tfoot><tbody><tr><td colspan="7" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Hematology</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Platelet count decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>161</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>98</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>76</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>142</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>100</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>99</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hemoglobin decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>161</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>94</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>142</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>100</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>70</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Leukocytes decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>161</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>95</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>82</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>142</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>99</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>98</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Neutrophil count decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>160</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>94</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>86</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>130</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>93</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>88</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lymphocytes (absolute) decreased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>160</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>93</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>71</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>127</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>97</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>91</paragraph></td></tr><tr><td colspan="7" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Chemistry</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>GGT increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>148</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>67</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>111</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>68</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>AST increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>160</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>71</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>134</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>ALP increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>158</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>57</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>133</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>52</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>ALT increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>161</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>137</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>46</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Blood bilirubin increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>161</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>36</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>138</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>35</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lipase increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>139</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>32</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>90</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hyperuricemia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>158</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>122</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Amylase increased</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>143</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>102</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>

<table width="85%"><caption>Table 9. Adverse Reactions (&#x2265; 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059)</caption><col width="57%"/><col width="22%"/><col width="19%"/><tfoot><tr><td align="left" colspan="3" valign="top">Severity grade of adverse reactions were according to NCI CTCAE version 4.03.</td></tr></tfoot><tbody><tr><td rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Body System</content></paragraph><paragraph><content styleCode="bold"> Adverse Reaction</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">BESPONSA Monotherapy</content></paragraph><paragraph><content styleCode="bold">(N=53)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Grades</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">&#x2265; Grade 3</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General disorders and administration site conditions</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pyrexia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Edema<footnote ID="_Ref160721137">Includes other related terms.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fatigue<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Chills</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and lymphatic system disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Anemia<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>45</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>38</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>45</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>32</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abdominal pain<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Stomatitis<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infections and infestations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infection<footnote ID="_Ref160721210">Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection. </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>43</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>23</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vascular disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hemorrhage<footnote ID="_Ref160721231">Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>42</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypotension</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>21</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pruritis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperhidrosis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Pain in extremity</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Back pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Neck pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Muscular weakness</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypoxia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Hepatobiliary disorders </content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Veno-occlusive disease<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hyperbilirubinemia<footnoteRef IDREF="_Ref160721137"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and nutrition disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Tumor lysis syndrome</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Investigations</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Weight increased</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Injury, poisoning and procedural complications</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Infusion related reaction<footnote ID="_Ref160721313">Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cardiac disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Sinus tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Psychiatric disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> Anxiety</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>