Except for some understanding of the mechanism of cellular toxicity, no other information is available on the metabolism of cladribine injection in humans. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a five-day continuous intravenous infusion of 3.5 to 8.1 mg/m 2/day of cladribine injection. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.
Two single-center open label studies of cladribine injection have been conducted in patients with Hairy Cell Leukemia with evidence of active disease requiring therapy. In the study conducted at the Scripps Clinic and Research Foundation (Study A), 89 patients were treated with a single course of cladribine injection given by continuous intravenous infusion for seven days at a dose of 0.09 mg/kg/day. In the study conducted at the M.D. Anderson Cancer Center (Study B), 35 patients were treated with a seven-day continuous intravenous infusion of cladribine injection at a comparable dose of 3.6 mg/m 2/day. A complete response (CR) required clearing of the peripheral blood and bone marrow of hairy cells and recovery of the hemoglobin to 12 g/dL, platelet count to 100 x 10 9/L, and absolute neutrophil count to 1,500 x 10 6/L. A good partial response (GPR) required the same hematologic parameters as a complete response, and that fewer than 5% hairy cells remain in the bone marrow. A partial response (PR) required that hairy cells in the bone marrow be decreased by at least 50% from baseline and the same response for hematologic parameters as for complete response. A pathologic relapse was defined as an increase in bone marrow hairy cells to 25% of pretreatment levels. A clinical relapse was defined as the recurrence of cytopenias, specifically, decreases in hemoglobin ≥ 2 g/dL, ANC ≥ 25% or platelet counts ≥ 50,000. Patients who met the criteria for a complete response but subsequently were found to have evidence of bone marrow hairy cells (< 25% of pretreatment levels) were reclassified as partial responses and were not considered to be complete responses with relapse.
Among patients evaluable for efficacy (N=106), using the hematologic and bone marrow response criteria described above, the complete response rates in patients treated with cladribine injection were 65% and 68% for Study A and Study B, respectively, yielding a combined complete response rate of 66%. Overall response rates (i.e., Complete plus Good Partial plus Partial Responses) were 89% and 86% in Study A and Study B, respectively, for a combined overall response rate of 88% in evaluable patients treated with cladribine injection.
Using an intent-to-treat analysis (N=123) and further requiring no evidence of splenomegaly as a criterion for CR (i.e., no palpable spleen on physical examination and ≤ 13 cm on CT scan), the complete response rates for Study A and Study B were 54% and 53%, respectively, giving a combined CR rate of 54%. The overall response rates (CR + GPR + PR) were 90% and 85%, for Studies A and B, respectively, yielding a combined overall response rate of 89%.
RESPONSE RATES TO CLADRIBINE INJECTION TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA
In these studies, 60% of the patients had not received prior chemotherapy for Hairy Cell Leukemia or had undergone splenectomy as the only prior treatment and were receiving cladribine injection as a first-line treatment. The remaining 40% of the patients received cladribine injection as a second-line treatment, having been treated previously with other agents, including α-interferon and/or deoxycoformycin. The overall response rate for patients without prior chemotherapy was 92%, compared with 84% for previously treated patients. Cladribine injection is active in previously treated patients; however, retrospective analysis suggests that the overall response rate is decreased in patients previously treated with splenectomy or deoxycoformycin and in patients refractory to α-interferon.
OVERALL RESPONSE RATES (CR + GPR + PR) TO CLADRIBINE INJECTION TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA
After a reversible decline, normalization of peripheral blood counts (Hemoglobin >12 g/dL, Platelets >100 x 10 9/L, Absolute Neutrophil Count (ANC) >1,500 x 10 6/L) was achieved by 92% of evaluable patients. The median time to normalization of peripheral counts was nine weeks from the start of treatment (Range: 2 to 72). The median time to normalization of Platelet Count was two weeks, the median time to normalization of ANC was five weeks and the median time to normalization of Hemoglobin was eight weeks. With normalization of Platelet Count and Hemoglobin, requirements for platelet and RBC transfusions were abolished after Months 1 and 2, respectively, in those patients with complete response. Platelet recovery may be delayed in a minority of patients with severe baseline thrombocytopenia. Corresponding to normalization of ANC, a trend toward a reduced incidence of infection was seen after the third month, when compared to the months immediately preceding cladribine injection therapy (see also WARNINGS, PRECAUTIONS and ADVERSE REACTIONS).
CLADRIBINE INJECTION TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA TIME TO NORMALIZATION OF PERIPHERAL BLOOD COUNTS
*Day 1 = First day of infusion
For patients achieving a complete response, the median time to response (i.e., absence of hairy cells in bone marrow and peripheral blood together with normalization of peripheral blood parameters), measured from treatment start, was approximately four months. Since bone marrow aspiration and biopsy were frequently not performed at the time of peripheral blood normalization, the median time to complete response may actually be shorter than that which was recorded. At the time of data cut-off, the median duration of complete response was greater than eight months and ranged to 25+ months. Among 93 responding patients, seven had shown evidence of disease progression at the time of the data cut-off. In four of these patients, disease was limited to the bone marrow without peripheral blood abnormalities (pathologic progression), while in three patients there were also peripheral blood abnormalities (clinical progression). Seven patients who did not respond to a first course of cladribine injection received a second course of therapy. In the five patients who had adequate follow-up, additional courses did not appear to improve their overall response.