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BUSULFAN INJECTION Clinical Studies (busulfan injection)

14 CLINICAL STUDIES

Documentation of the safety and efficacy of busulfan as a component of a conditioning regimen prior to allogeneic hematopoietic progenitor cell reconstitution is derived from two sources:

i) analysis of a prospective clinical trial of Busulfan Injection that involved 61 patients diagnosed with various hematologic malignancies, and

ii) the published reports of randomized, controlled trials that employed high-dose oral busulfan as a component of a conditioning regimen for transplantation, which were identified in a literature review of five established commercial databases.

Prospective Clinical Trial of Busulfan Injection: The prospective trial was a single-arm, open-label study in 61 patients who received Busulfan Injection as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation. The study included patients with acute leukemia past first remission (first or subsequent relapse), with high-risk first remission, or with induction failure; chronic myelogenous leukemia (CML) in chronic phase, accelerated phase, or blast crisis; primary refractory or resistant relapsed Hodgkin's disease or non-Hodgkin's lymphoma; and myelodysplastic syndrome. Forty-eight percent of patients (29/61) were heavily pretreated, defined as having at least one of the following: prior radiation, greater than or equal to 3 prior chemotherapeutic regimens, or prior hematopoietic stem cell transplant. Seventy-five percent of patients (46/61) were transplanted with active disease.

Patients received 16 Busulfan Injection doses of 0.8 mg per kg every 6 hours as a two-hour infusion for 4 days, followed by cyclophosphamide 60 mg per kg once per day for two days (BuCy2 regimen). All patients received 100% of their scheduled Busulfan Injection regimen. No dose adjustments were made. After one rest day, allogeneic hematopoietic progenitor cells were infused. The efficacy parameters in this study were myeloablation (defined as one or more of the following: absolute neutrophil count [ANC] less than 0.5×109/L, absolute lymphocyte count [ALC] less than 0.1×109/L, thrombocytopenia defined as a platelet count less than 20,000/mm3 or a platelet transfusion requirement) and engraftment (ANC greater than or equal to 0.5×109/L).

All patients (61/61) experienced myeloablation. The median time to neutropenia was 4 days. All evaluable patients (60/60) engrafted at a median of 13 days post-transplant (range 9 to 29 days); one patient was considered non-evaluable because he died of a fungal pneumonia 20 days after BMT and before engraftment occurred. All but 13 of the patients were treated with prophylactic G-CSF. Evidence of donor cell engraftment and chimerism was documented in all patients who had a chromosomal sex marker or leukemic marker (43/43), and no patient with chimeric evidence of allogeneic engraftment suffered a later loss of the allogeneic graft. There were no reports of graft failure in the overall study population. The median number of platelet transfusions per patient was 6, and the median number of red blood cell transfusions per patient was 4.

Twenty-three patients (38%) relapsed at a median of 183 days post-transplant (range 36 to 406 days). Sixty-two percent of patients (38/61) were free from disease with a median follow-up of 269 days post-transplant (range 20 to 583 days). Forty-three patients (70%) were alive with a median follow up of 288 days post-transplant (range 51 to 583 days). There were two deaths before BMT Day +28 and six additional patients died by BMT Day +100. Ten patients (16%) died after BMT Day +100, at a median of 199 days post-transplant (range 113 to 275 days).

Oral Busulfan Literature Review: Four publications of randomized, controlled trials that evaluated a high-dose oral busulfan-containing conditioning regimen (busulfan 4 mg/kg/d ×4 days + cyclophosphamide 60 mg/kg/d ×2 days) for allogeneic transplantation in the setting of CML were identified. Two of the studies (Clift and Devergie) had populations confined to CML in chronic phase that were randomized between conditioning with busulfan/cyclophosphamide (BU/CY) and cyclophosphamide/total body irradiation (CY/TBI). A total of 138 patients were treated with BU/CY in these studies. The populations of the two remaining studies (Ringden and Blume) included patients with CML, acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML). In the Nordic BMT Group study published by Ringden, et al., 57 patients had CML, and of those, 30 were treated with BU/CY. Patients with CML in chronic phase, accelerated phase, and blast crisis were eligible for this study. The participants with CML (34/122 patients) in a SWOG study published by Blume, et al., had disease beyond first chronic phase. Twenty of those CML patients were treated with BU/CY, and the TBI comparator arm utilized etoposide instead of cyclophosphamide.

Table 4 summarizes the efficacy analyses reported from these 4 studies.

Table 4: Summary of efficacy analyses from the randomized, controlled trials utilizing a high dose oral busulfan-containing conditioning regimen identified in a literature review.
BU = Busulfan
CY = Cyclophosphamide
TBI = Total Body Irradiation
DFS = Disease Free Survival
ANC = Absolute Neutrophil Count
*
Eto = etoposide. TBI was combined with etoposide in the comparator arm of this study.
Clift, 1994
CML Chronic Phase;
3 year Overall Survival3 year DFS
(p=0.43)
RelapseTime to Engraftment
(ANC greater than or equal to 500)
BU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBI
80%80%71%68%13%13%22.6 days22.3 days
Devergie, 1995
CML Chronic Phase;
5 year Overall Survival
(p=0.5)
5 year DFS (p=0.75)Relapse (Relative Risk analysis BU/CY:CY/TBI)
(p=0.04)
Time to Engraftment
(ANC greater than or equal to 500)
BU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBI
60.6%
±11.7%
65.8%
±12.5%
59.1%
±11.8%
51.0%
±14%
4.10
(95%CI =1.00 to 20.28)
None GivenNone Given
Ringden, 1994
CML, AML, ALL;
3 year Overall Survival
(p<0.03)
3 year Relapse Free Survival
(p=0.065)
Relapse
(p=0.9)
Time to Engraftment
(ANC greater than 500)
BU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBI
62%76%56%67%22%26%20 days20 days
Blume, 1993*
CML, AML, ALL; Relative Risk Analysis BU/CY: Etoposide/TBI
RR of MortalityDFSRR of Relapse
(Relative Risk analysis BU/CY:Eto/TBI)
Time to Engraftment
BU/CYEto/TBIBU/CYEto/TBIBU/CYEto/TBIBU/CYEto/TBI
0.97
(95% CI=0.64 to 1.48)
Not Given1.02
(95% CI=0.56 to 1.86)
Not Given
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