6 ADVERSE REACTIONS

The following clinically-significant adverse reactions are discussed in greater detail in other sections of the label:
• Neurologic [see Boxed Warning, Warnings and Precautions (5.1)]
• Hematologic [see Warnings and Precautions (5.2)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
• Effects on Ability to Drive and Use Machines [see Warnings and Precautions (5.6)]

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 T-ALL and T-LBL
Nelarabine was studied in 459 patients in Phase I and Phase II clinical trials.
Adult Patient: The safety profile of nelarabine is based on data from 103 adult patients treated with the recommended dose and schedule in 2 studies: an adult T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) trial and an adult chronic lymphocytic leukemia trial.
The most common adverse reactions in adults, were fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia.
The most common adverse reactions in adults by Body System, including severe or life-threatening adverse reactions (NCI CTCAE Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 1.

Table 1. Most Commonly Reported (≥5% Overall) Adverse Reactions in Adult Patients Treated with 1,500 mg/m2 of Nelarabine Administered Intravenously over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

Body System Adverse Reaction	Percentage of Patients (N = 103)
Toxicity Grade
Grade 3 %	Grades 4 and 5**a** ****%	All Grades %
Blood and Lymphatic System Disorders
Anemia	20	14	99
Thrombocytopenia	37	22	86
Neutropenia	14	49	81
Febrile neutropenia	9	1	12
Cardiac Disorders
Sinus tachycardia	1	0	8
Gastrointestinal Disorders
Nausea	0	0	41
Diarrhea	1	0	22
Vomiting	1	0	22
Constipation	1	0	21
Abdominal pain	1	0	9
Stomatitis	1	0	8
Abdominal distension	0	0	6
General Disorders and Administration Site Conditions
Fatigue	10	2	50
Pyrexia	5	0	23
Asthenia	0	1	17
Edema, peripheral	0	0	15
Edema	0	0	11
Pain	3	0	11
Rigors	0	0	8
Gait, abnormal	0	0	6
Chest pain	0	0	5
Noncardiac chest pain	0	1	5
Infections
Infection	2	1	9
Pneumonia	4	1	8
Sinusitis	1	0	7
Hepatobiliary Disorders
AST increased	1	1	6
Metabolism and Nutrition Disorders
Anorexia	0	0	9
Dehydration	3	1	7
Hyperglycemia	1	0	6
Musculoskeletal and Connective Tissue Disorders
Myalgia	1	0	13
Arthralgia	1	0	9
Back pain	0	0	8
Muscular weakness	5	0	8
Pain in extremity	1	0	7
Nervous System Disorders (see Table 2)
Psychiatric Disorders
Confusional state	2	0	8
Insomnia	0	0	7
Depression	1	0	6
Respiratory, Thoracic, and Mediastinal Disorders
Cough	0	0	25
Dyspnea	4	2	20
Pleural effusion	5	1	10
Epistaxis	0	0	8
Dyspnea, exertional	0	0	7
Wheezing	0	0	5
Vascular Disorders
Petechiae	2	0	12
Hypotension	1	1	8

Abbreviation: AST, aspartate transaminase.
aFive patients had a fatal adverse reaction. Fatal adverse reactions included hypotension (n = 1), respiratory arrest (n = 1), pleural effusion/pneumothorax (n = 1), pneumonia (n = 1), and cerebral hemorrhage/coma/leukoencephalopathy (n = 1).

Other Adverse Reactions: Blurred vision was also reported in 4% of adult patients.

There was a single report of biopsy-confirmed progressive multifocal leukoencephalopathy in the adult patient population.

Neurologic Adverse Reactions: Nervous system adverse reactions, were reported for 76% of adult patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥ 2%) in adult patients, including all grades (NCI CTCAE) are shown in Table 2.

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Table 2. Neurologic Adverse Reactions (≥ 2%) in Adult Patients Treated With 1,500 mg/m2 of Nelarabine Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

Nervous System Disorders	Percentage of Patients (N =103)
Grade 1 %	Grade 2 %	Grade 3 %	Grade 4 %	All Grades %
Adverse Reaction
Somnolence	20	3	0	0	23
Dizziness	14	8	0	0	21
Peripheral neurologic disorders, any adverse reaction	8	12	2	0	21
Neuropathy	0	4	0	0	4
Peripheral neuropathy	2	2	1	0	5
Peripheral motor neuropathy	3	3	1	0	7
Peripheral sensory neuropathy	7	6	0	0	13
Hypoesthesia	5	10	2	0	17
Headache	11	3	1	0	15
Paresthesia	11	4	0	0	15
Ataxia	1	6	2	0	9
Depressed level of consciousness	4	1	0	1	6
Tremor	2	3	0	0	5
Amnesia	2	1	0	0	3
Dysgeusia	2	1	0	0	3
Balance disorder	1	1	0	0	2
Sensory loss	0	2	0	0	2

One patient had a fatal neurologic adverse reaction, cerebral hemorrhage/coma/leukoencephalopathy.

Most nervous system adverse reactions in the adult patients were evaluated as Grade 1 or 2. The additional Grade 3 adverse reactions in adult patients, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional Grade 4 adverse reactions were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).

The other neurologic adverse reactions reported as Grade 1, 2, or unknown in adult patients were abnormal coordination, burning sensation, disturbance in attention, dysarthria, hyporeflexia, neuropathic pain, nystagmus, peroneal nerve palsy, sciatica, sensory disturbance, sinus headache, and speech disorder, each reported in one patient (1%).

Pediatric Patient: The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-ALL/T-LBL treatment trial.

The most common adverse reactions in pediatric patients were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the non- hematologic adverse reactions in pediatric patients, the most frequent adverse reactions reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.

The most common adverse reactions in pediatric patients by System Organ Class, including severe or life threatening adverse reactions (NCI CTCAE Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 3.

Table 3. Most Commonly Reported (≥ 5% Overall) Adverse Reactions in Pediatric Patients Treated With 650 mg/m2 of Nelarabine Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days

Body System	Percentage of Patients (N = 84)
Toxicity Grade
Adverse Reaction	Grade 3 %	Grade 4 and 5****a %	All Grades %
Blood and Lymphatic System Disorders
Anemia	45	10	95
Neutropenia	17	62	94
Thrombocytopenia	27	32	88
Leukopenia	14	7	38
Hepatobiliary Disorders
Transaminases increased	4	0	12
Blood albumin decreased	5	1	10
Blood bilirubin increased	7	2	10
Metabolic/Laboratory
Blood potassium decreased	4	2	11
Blood calcium decreased	1	1	8
Blood creatinine increased	0	0	6
Blood glucose decreased	4	0	6
Blood magnesium decreased	2	0	6
Nervous System Disorders (see Table 4)
Gastrointestinal Disorders
Vomiting	0	0	10
General Disorders & Administration Site Conditions
Asthenia	1	0	6
Infections & Infestations
Infection	2	1	5

aThree patients had a fatal adverse reaction. Fatal adverse reactions included neutropenia and pyrexia (n = 1), status epilepticus/seizure (n = 1), and fungal pneumonia (n = 1).

Neurologic Adverse Reactions: Nervous system adverse reactions were reported for 42% of pediatric patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥ 2%) in pediatric patients including all grades (NCI CTCAE) are shown in Table 4.

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Table 4. Neurologic Adverse Reactions (≥ 2%) in Pediatric Patients Treated With 650 mg/m2 of Nelarabine Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days

** Nervous System Disorders**	Percentage of Patients (N = 84)
Grade 1 %	Grade 2 %	Grade 3 %	Grade 4 and5a**** %	All Grades %
Adverse Reaction
Headache	8	2	4	2	17
Peripheral neurologic disorders, any adverse reaction	1	4	7	0	12
Peripheral neuropathy	0	4	2	0	6
Peripheral motor neuropathy	1	0	2	0	4
Peripheral sensory neuropathy	0	0	6	0	6
Somnolence	1	4	1	1	7
Hypoesthesia	1	1	4	0	6
Seizures	0	0	0	6	6
Convulsions	0	0	0	3	4
Grand mal convulsions	0	0	0	1	1
Status epilepticus	0	0	0	1	1
Motor dysfunction	1	1	1	0	4
Nervous system disorder	1	2	0	0	4
Paresthesia	0	2	1	0	4
Tremor	1	2	0	0	4
Ataxia	1	0	1	0	2

aOne (1) patient had a fatal neurologic adverse reaction, status epilepticus.

The other Grade 3 neurologic adverse reaction in pediatric patients was hypertonia reported in 1 patient (1%). The additional Grade 4 neurologic adverse reactions, were 3rd nerve paralysis, and 6th nerve paralysis, each reported in 1 patient (1%).

The other neurologic adverse reactions reported as Grade 1, 2, or unknown in pediatric patients were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, lethargy, mental impairment, paralysis, and sensory loss, each reported in 1 patient (1%).

Nelarabine in Combination with Multi-Agent Chemotherapy in T-ALL and T-LBL

Nelarabine was studied in combination with multi-agent chemotherapy in a randomized clinical trial [NCT00408005]. The safety population in this trial included 804 patients with newly-diagnosed T-ALL (85%) or T-LBL (15%) treated with (n = 411) or without (n =393) nelarabine in combination with the augmented Berlin-Frankfurt-Münster chemotherapy regimen (aBFM) after initial induction therapy. Patients assigned to nelarabine received 650 mg/m2 intravenously over 1 hour daily for 5 consecutive days, during consolidation days 1 to 5 and 43 to 47, delayed intensification days 29 to 33, and during the initial 3 courses of maintenance days 29 to 33. The median age on enrollment was 9.5 years (range, 1-29), the majority of patients were male (73%) and white (69%). Sixty-five percent of patients assigned to the nelarabine arms received at least 85% of the planned dose through the third course of maintenance therapy compared to 79% of patients on the control arms who received 3 courses of maintenance therapy.

There was one fatal neurological adverse reaction in the nelarabine arm. The incidence of the following grades 3 and 4 adverse reactions were higher in the nelarabine treated arms compared to the control arms: abnormal transaminases, motor and sensory neuropathy, nausea and vomiting, and dehydration. The incidence of seizures of any grade was 3% (14 of 411). Rhabdomyolysis was diagnosed in 2% (7 of 411) of nelarabine treated patients and occurred after the first course of nelarabine during the consolidation phase of therapy.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of nelarabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Infections and Infestations: Fatal opportunistic infections.
Metabolism and Nutrition Disorders: Tumor lysis syndrome.
Nervous System Disorders: Demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
Musculoskeletal and Connective Disorders: Rhabdomyolysis, blood creatine phosphokinase increased.

14 CLINICAL STUDIES

14.1 Adult Clinical Trial in Relapsed or Refractory T-ALL and T-LBL

The safety and efficacy of nelarabine in adult patients were studied in a clinical trial which included 39 treated patients, 28 who had T-ALL or T-LBL that had relapsed following or was refractory to at least two prior induction regimens. A 1,500-mg/m2 dose of nelarabine was administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with nelarabine. Seventeen patients had a diagnosis of T-ALL and 11 had a diagnosis of T-LBL. For patients with ≥ 2 prior inductions, the age range was 16 to 65 years (mean: 34 years) and most patients were male (82%) and Caucasian (61%). Patients with central nervous system (CNS) disease were not eligible.

Complete response (CR) in this trial was defined as bone marrow blast counts ≤ 5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without complete hematologic recovery (CR*) was also assessed. The results of the trial for patients who had received ≥ 2 prior inductions are shown in Table 5.

Table 5. Efficacy Results in Adult Patients With ≥ 2 Prior Inductions Treated With 1,500 mg/m2 of Nelarabine Administered Intravenously Over 2 Hours on Days 1, 3, and 5 Repeated Every 21 Days

	N = 28
CR plus CR* % (n) [95% CI]	21% (6) [8%, 41%]
CR % (n) [95% CI]	18% (5) [6%, 37%]
CR* % (n) [95% CI]	4% (1) [0%, 18%]
Duration of CR plus CR* (range in weeks)a	4 to 195+
Median overall survival (weeks) [95% CI]	20.6 weeks [10.4, 36.4]

Abbreviations: CR, complete response; CI, confidence interval; CR*, Complete response without hematologic recovery.
a Does not include 1 patient who was transplanted (duration of response was 156+ weeks).

The mean number of days on therapy was 56 days (range of 10 to 136 days). Time to CR plus CR* ranged from 2.9 to 11.7 weeks.

14.2 Pediatric Clinical Trial in Relapsed or Refractory T-ALL and T-LBL

The safety and efficacy of nelarabine in pediatric patients were studied in a clinical trial which included patients aged 21 years and younger, who had relapsed or refractory T-ALL or T-LBL. Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens, were treated with
650 mg/m2/day of nelarabine administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (see Table 6). Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with nelarabine.

Table 6. Pediatric Clinical Trial - Patient Allocation

Patient Population	N
Patients treated at 650 mg/m2/day x 5 days, every 21 days.	84
Patients with T-ALL or T-LBL with two or more prior induction treated at 650 mg/m2/day x 5 days, every 21 days.	39
Patients with T-ALL or T-LBL with one prior induction treated at 650 mg/m2/day x 5 days, every 21 days.	31

Abbreviations: T-ALL, T-cell acute lymphoblastic leukemia; T-LBL, T-cell lymphoblastic lymphoma.

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The 84 patients ranged in age from 2.5 to 21.7 years (overall mean: 11.9 years), 52% were 3 to 12 years of age and most were male (74%) and Caucasian (62%). The majority (77%) of patients had a diagnosis of T-ALL.

Complete response (CR) in this trial was defined as bone marrow blast counts ≤ 5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without full hematologic recovery (CR*) was also assessed as a meaningful outcome in this trial. Duration of response is reported from date of response to date of relapse, and may include subsequent stem cell transplant. Efficacy results are presented in Table 7.

Table 7. Efficacy Results in Patients Age 21 Years and Younger at Diagnosis With ≥ 2 Prior Inductions Treated With 650 mg/m2 of Nelarabine Administered Intravenously Over 1 Hour Daily for 5 Consecutive Days Repeated Every 21 Days

	N = 39
CR plus CR* % (n) [95% CI]	23% (9) [11%, 39%]
CR % (n) [95% CI]	13% (5) [4%, 27%]
CR* % (n) [95% CI]	10% (4) [3%, 24%]
Duration of CR plus CR* (range in weeks)a	3.3 to 9.3
Median overall survival (weeks) [95% CI]	13.1 [8.7, 17.4]

Abbreviations: CR, complete response; CI, confidence interval; CR*, complete response without hematologic recovery

a Does not include 5 patients who were transplanted or had subsequent systemic chemotherapy (duration of response in these 5 patients was 4.7 to 42.1 weeks).

The mean number of days on therapy was 46 days (range: 7 to 129 days). Median time to CR plus CR* was 3.4 weeks (95% CI: 3.0, 3.7).