Home » Drug Information » FDA Approved Drugs » 1999
Medical Areas: Hematology | Oncology
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Company: Orphan Medical
Approval Status: Approved February 1999
Treatment Area: Oncology/Hematology
Busulflex has been approved for use in combination with
cyclophosphamide as a conditioning regimen prior to allogeneic
hematopoietic progenitor cell transplantation for chronic
The prospective trial was a single-arm, open-label study in 61
patients who received BUSULFEX 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, > 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 BUSULFEX doses of 0.8 mg/kg every 6 hours
as a two-hour infusion for 4 days, followed by cyclophosphamide 60
mg/kg once per day for two days (BuCy2 regimen). All patients
received 100% of their scheduled BUSULFEX 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 0.5x10 9/L, absolute
lymphocyte count [ALC] less than 0.1x10 9/L, thrombocytopenia
defined as a platelet count less than 20,000/mm 3 or a platelet
transfusion requirement) and engraftment (ANC³0.5x10 9/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).
Treatment with BUSULFEX at the recommended dose and schedule
will result in profound myelosuppression in 100% of patients,
including granulocytopenia, thrombocytopenia, anemia, or a combined
loss of formed elements of the blood.
Mechanism of Action
Busulfan is a bifunctional alkylating agent in which two labile
methanesulfonate groups are attached to opposite ends of a four
carbon alkyl chain. In aqueous media, busulfan hydrolyzes to
release the methanesulfonate groups. This produces reactive
carbonium ions that can alkylate DNA. DNA damage is thought to be
responsible for much of the cytotoxicity of busulfan.