Safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff. In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Other adverse experiences reported frequently during the first 14 days after initiating treatment included: fatigue (45%), nausea (28%), rash (27%), headache (22%) and injection site reactions (19%). Most non-hematologic adverse experiences were mild to moderate in severity.
Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 500 × 106/L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 × 109/L) developed in 12% of patients, compared to 4% in whom it was noted initially.
During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding LEUSTATIN therapy.
During the first month, 11% of patients experienced severe fever (i.e., ≥104°F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics. (see WARNINGS and PRECAUTIONS)
Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/µL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/µL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/µL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.
Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts.
The vast majority of rashes were mild and occurred in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause rash.
Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.
Adverse reactions reported during the first 2 weeks following treatment initiation (regardless of relationship to drug) by > 5% of patients included:
Body as a Whole: fever (69%), fatigue (45%), chills (9%), asthenia (9%), diaphoresis (9%), malaise (7%), trunk pain (6%)
Gastrointestinal: nausea (28%), decreased appetite (17%), vomiting (13%), diarrhea (10%), constipation (9%), abdominal pain (6%)
Hemic/Lymphatic: purpura (10%), petechiae (8%), epistaxis (5%)
Nervous System: headache (22%), dizziness (9%), insomnia (7%)
Cardiovascular System: edema (6%), tachycardia (6%)
Respiratory System: abnormal breath sounds (11%), cough (10%), abnormal chest sounds (9%), shortness of breath (7%)
Skin/Subcutaneous Tissue: rash (27%), injection site reactions (19%), pruritis (6%), pain (6%), erythema (6%)
Musculoskeletal System: myalgia (7%), arthralgia (5%)
Adverse experiences related to intravenous administration included: injection site reactions (9%) (i.e., redness, swelling, pain), thrombosis (2%), phlebitis (2%) and a broken catheter (1%). These appear to be related to the infusion procedure and/or indwelling catheter, rather than the medication or the vehicle. From Day 15 to the last follow-up visit, the only events reported by > 5% of patients were: fatigue (11%), rash (10%), headache (7%), cough (7%), and malaise (5%).
For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see WARNINGS.
The following additional adverse events have been reported since the drug became commercially available. These adverse events have been reported primarily in patients who received multiple courses of LEUSTATIN Injection:
Hematologic: bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia, which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported.
Hepatic: reversible, generally mild increases in bilirubin and transaminases.
Nervous System: Neurological toxicity; however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens.
Respiratory System: pulmonary interstitial infiltrates; in most cases, an infectious etiology was identified.
Skin/Subcutaneous: urticaria, hypereosinophilia. In isolated cases Stevens-Johnson and toxic epidermal necrolysis have been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.
Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by LEUSTATIN Injection.