DailyMed Label: Busulfan

DailyMed Label: Busulfan

2007

DailyMed Prescription

Busulfan

Busulfan

ESP Pharma, Inc.

NDC: 67286-0054

Busulfan is a bifunctional alkylating agent known chemically as 1,4- butanediol, dimethanesulfonate. BUSULFEX ® (busulfan) Injection is intended for intravenous administration. It is supplied as a clear, colorless, sterile, solution in 10 mL single use vials. Each vial of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a white crystalline powder with a molecular formula of CH 3 SO 2 O(CH 2 ) 4 OSO 2 CH 3 and a molecular weight of 246 g/mole. Busulfan is dissolved in N,N-dimethylacetamide (DMA) 33% vol/vol and Polyethylene Glycol 400, 67% vol/vol. The solubility of busulfan in water is 0.1 g/L and the pH of BUSULFEX diluted to approximately 0.5 mg/mL busulfan in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects the pH of the diluent used and ranges from 3.4 to 3.9. BUSULFEX is intended for dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to intravenous infusion.

BUSULFEX ® (busulfan) Injection is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.

When BUSULFEX (busulfan) Injection is administered as a component of the BuCy conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement, the recommended doses are as follows: Adults (BuCy2): The usual adult dose is 0.8 mg/kg of ideal body weight or actual body weight, whichever is lower, administered every six hours for four days (a total of 16 doses). For obese, or severely obese patients, BUSULFEX should be administered based on adjusted ideal body weight. Ideal body weight (IBW) should be calculated as follows (height in cm, and weight in kg): IBW (kg; men)= 50 + 0.91x (height in cm -152); IBW (kg; women)= 45 + 0.91x (height in cm - 152). Adjusted ideal body weight (AIBW) should be calculated as follows: AIBW= IBW + 0.25x (actual weight -IBW). Cyclophosphamide is given on each of two days as a one-hour infusion at a dose of 60 mg/kg beginning on BMT day –3, no sooner than six hours following the 16 th dose of BUSULFEX. BUSULFEX clearance is best predicted when the BUSULFEX dose is administered based on adjusted ideal body weight. Dosing BUSULFEX based on actual body weight, ideal body weight or other factors can produce significant differences in BUSULFEX (busulfan) Injection clearance among lean, normal and obese patients. BUSULFEX should be administered intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses. All patients should be premedicated with phenytoin as busulfan is known to cross the blood brain barrier and induce seizures. Phenytoin reduces busulfan plasma AUC by 15%. Use of other anticonvulsants may result in higher busulfan plasma AUCs, and an increased risk of VOD or seizures. In cases where other anticonvulsants must be used, plasma busulfan exposure should be monitored (See DRUG INTERACTIONS). Antiemetics should be administered prior to the first dose of BUSULFEX and continued on a fixed schedule through administration of BUSULFEX. Where available, pharmacokinetic monitoring may be considered to further optimize therapeutic targeting. Pediatrics: The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients. For additional information see Special Populations -Pediatric section. An administration set with minimal residual hold-up volume (2-5 cc) should be used for product administration. As with other cytotoxic compounds, caution should be exercised in handling and preparing the solution of BUSULFEX. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If BUSULFEX or diluted BUSULFEX solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water. BUSULFEX is a clear, colorless solution. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever the solution and container permit. If particulate matter is seen in the BUSULFEX ampoule the drug should not be used. BUSULFEX must be diluted prior to use with either 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D 5 W). The diluent quantity should be 10 times the volume of BUSULFEX, so that the final concentration of busulfan is approximately 0.5 mg/mL. Calculation of the dose for a 70 kg patient, would be performed as follows: (70kg patient) x (0.8 mg/kg) ÷ (6 mg/mL) = 9.3 mL BUSULFEX (56 mg total dose). To prepare the final solution for infusion, add 9.3 mL of BUSULFEX to 93 mL of diluent (normal saline or D 5 W) as calculated below: (9.3 mL BUSULFEX)x(10)=93 mL of either diluent plus the 9.3 mL of BUSULFEX to yield a final concentration of busulfan of 0.54 mg/mL (9.3 mL x 6 mg/mL ÷ 102.3 mL = 0.54 mg/mL). All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing. DO NOT put the BUSULFEX into an intravenous bag or large-volume syringe that does not contain normal saline or D 5 W. Always add the BUSULFEX to the diluent, not the diluent to the BUSULFEX. Mix thoroughly by inverting several times. DO NOT USE POLYCARBONATE SYRINGES OR POLYCARBONATE FILTER NEEDLES WITH BUSULFEX. Infusion pumps should be used to administer the diluted BUSULFEX solution. Set the flow rate of the pump to deliver the entire prescribed BUSULFEX dose over two hours. Prior to and following each infusion, flush the indwelling catheter line with approximately 5mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. WARNING: RAPID INFUSION OF BUSULFEX HAS NOT BEEN TESTED AND IS NOT RECOMMENDED. STABILITY Unopened vials of BUSULFEX are stable until the date indicated on the package when stored under refrigeration at 2°-8°C (36°-46°F). BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within that time. BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2°-8°C) for up to 12 hours but the infusion must be completed within that time.

BUSULFEX is contraindicated in patients with a history of hypersensitivity to any of its components.

At the recommended dosage of BUSULFEX (busulfan) Injection, profound myelosuppression is universal, and can manifest as neutropenia, thrombocytopenia, anemia, or a combination thereof. Patients should be monitored for signs of local or systemic infection or bleeding. Their hematologic status should be evaluated frequently. The increased risk of a second malignancy should be explained to the patient. Patients receiving BUSULFEX should be monitored daily with a complete blood count, including differential count and quantitative platelet count, until engraftment has been demonstrated. To detect hepatotoxicity, which may herald the onset of hepatic venoocclusive disease, serum transaminases, alkaline phosphatase, and bilirubin should be evaluated daily through BMT Day +28. Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC > 1500 µM•min in some patients. Fluconazole, and the 5-HT3 antiemetics odansetron (Zofran®) and granisetron (Kytril®) have all been used with BUSULFEX. Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin, the clearance of BUSULFEX at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin. Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (<72 hours) or concurrent with BUSULFEX may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues. Pregnancy Category D. See WARNINGS . It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorgenicity shown for busulfan in human and animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric: The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of BUSULFEX in 24 pediatric patients receiving BUSULFEX as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic (N=15) or non-malignant diseases (N=9). Patients ranged in age from 5 months to 16 years (median 3 years). BUSULFEX dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900-1350 µM•min with an initial dose of 0.8 mg/kg or 1.0 mg/kg (based on ABW) if the patient was >4 or ≤4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1. Patients received BUSULFEX doses every six hours as a two-hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg/kg once daily for four days. After one rest day, hematopoietic progenitor cells were infused. All patients received phenytoin as seizure prophylaxis. The target AUC (900-1350 ± 5% µM•min) for BUSULFEX was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. BUSULFEX levels were within the target range for 21 of 23 evaluable patients. All 24 patients experienced neutropenia (absolute neutrophil count <0.5 x 10 9 /L) and thrombocytopenia (platelet transfusions or platelet count <20,000/mm 3 ). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count <0.1 x 10 9 ). In 23 patients, the ANC recovered to >0.5 x 10 9 /L (median time to recovery = BMT day +13; range = BMT day +9 to +22). One patient who died on day +20 had not recovered to an ANC > 0.5 x 10 9 /L. Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure. Adverse events were reported in all 24 patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), hepatic veno-occlusive disease (HVOD) (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%). Based on the results of this 24-patient clinical trial, a suggested dosing regimen of BUSULFEX in pediatric patients is shown in the following dosing nomogram: BUSULFEX Dosing Nomogram Patient’s Actual BUSULFEX Body Weight (ABW) Dosage ≤12 kgs 1.1 (mg/kg) >12 kgs 0.8 (mg/kg) Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target BUSULFEX exposure (AUC) between 900 to 1350 µM•min with the first dose of BUSULFEX using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of BUSULFEX is recommended. Dose Adjustment Based on Therapeutic Drug Monitoring Instructions for measuring the AUC of busulfan at dose 1 (see Blood Sample Collection for AUC Determination ), and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 µM•min), are provided below. Adjusted dose (mg) = Actual Dose (mg) x Target AUC (µM•min)/Actual AUC (µM•min) For example, if a patient received a dose of 11 mg busulfan and if the corresponding AUC measured was 800 µM•min, for a target AUC of 1125 µM•min, the target mg dose would be: Mg dose = 11 mg x 1125 µM•min / 800 µM•min = 15.5 mg Busulfex dose adjustment may be made using this formula and instructions below. Blood Sample Collection for AUC Determination: Calculate the AUC (µM•min) based on blood samples collected at the following time points: For dose 1: 2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled BUSULFEX administration). Actual sampling times should be recorded. For doses other than dose 1: Pre-infusion (baseline), 2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled BUSULFEX administration). AUC calculations based on fewer than the three specified samples may result in inaccurate AUC determinations. For each scheduled blood sample, collect one to three mL of blood into heparinized (Na or Li heparin) Vacutainer® tubes. The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4°C) within one hour. The plasma, harvested into appropriate cryovial storage tubes, is to be frozen immediately at -20°C. All plasma samples are to be sent in a frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations. Calculation of AUC: BUSULFEX AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula: Dose 1 AUC infinity Calculation: AUC infinity = AUC 0-6hr + AUC extrapolated , where AUC 0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour 6 and the terminal elimination rate constant, z. The z must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. A “0” pre-dose busulfan concentration should be assumed, and used in the calculation of AUC. If the AUC is assessed subsequent to Dose 1, steady-state AUC ss (AUC 0-6hr ) is to be estimated from the trough, 2 hr, 4 hr and 6 hr concentrations using the linear trapezoidal rule. Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug Monitoring: An administration set with minimal residual hold up (priming) volume (1-3 mL) should be used for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for therapeutic drug monitoring and dose adjustment. Prime the administration set tubing with drug solution to allow accurate documentation of the start time of BUSULFEX infusion. Collect the blood sample from a peripheral IV line to avoid contamination with infusing drug. If the blood sample is taken directly from the existing central venous catheter (CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSING to ensure that the end of infusion sample is not contaminated with any residual drug. At the end of infusion (2 hr), disconnect the administration tubing and flush the CVC line with 5 cc of normal saline prior to the collection of the end of infusion sample from the CVC port. Collect the blood samples from a different port than that used for the BUSULFEX infusion. When recording the BUSULFEX infusion stop time, do not include the time required to flush the indwelling catheter line. Discard the administration tubing at the end of the two-hour infusion. See Preparation for Intravenous Administration section for detailed instructions on drug preparation. Geriatric: Five of sixty-one patients treated in the BUSULFEX clinical trial were over the age of 55 (range 57-64). All achieved myeloablation and engraftment. Gender, Race: Adjusting BUSULFEX dosage based on gender or race has not been adequately studied. Renal Insufficiency: BUSULFEX has not been studied in patients with renal impairment. Hepatic Insufficiency: BUSULFEX has not been administered to patients with hepatic insufficiency. Other: Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix.

Dimethylacetamide (DMA), the solvent used in the BUSULFEX formulation, was studied in 1962 as a potential cancer chemotherapy drug. In a Phase 1 trial, the maximum tolerated dose (MTD) was 14.8 g/m

Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC > 1500 µM•min in some patients. Fluconazole, and the 5-HT3 antiemetics odansetron (Zofran®) and granisetron (Kytril®) have all been used with BUSULFEX. Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin, the clearance of BUSULFEX at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin. Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (<72 hours) or concurrent with BUSULFEX may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.

BUSULFEX is supplied as a sterile solution in 10 mL single-use clear glass vials each containing 60 mg of busulfan at a concentration of 6 mg/mL for intravenous use. NDC 67286-0054-2            10mL (6mg/mL) in packages of eight vials. Unopened vials of BUSULFEX must be stored under refrigerated conditions between 2°-8°C (36°-46°F). HANDLING AND DISPOSAL Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1,2,3,4,5,6 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Marketed by: PDL BioPharma, Inc. Redwood City, CA 94063 Manufactured by: Ben Venue Labs, Inc. Bedford OH 44146 United States Patent numbers are 5,430,057 and 5,559,148. Canadian Patent number is CA2171738. European Union Patent number is EP 0 725 637 B1. Part No. 131401 Rev Date: April 2007

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. The pharmacokinetics of BUSULFEX were studied in 59 patients participating in a prospective trial of a BUSULFEX-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg BUSULFEX every six hours, for a total of 16 doses over four days. Fifty-five of fifty-nine patients (93%) administered BUSULFEX maintained AUC values below the target value (<1500 µM•min). Table 1: Steady State Pharmacokinetic Parameters Following Busulfex ® (busulfan) Infusion (0.8 mg/kg; N=59) Mean CV (%) Range * Clearance normalized to actual body weight for all patients. Cmax (ng/mL) 1222 18 496-1684 AUC (μM•min) 1167 20 556-1673 CL (ml/min/kg)* 2.52 25 1.49-4.31 BUSULFEX pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by reproducibility of steady state Cmax and a low coefficient of variation for this parameter. In a pharmacokinetic study of BUSULFEX in 24 pediatric patients, the population pharmacokinetic (PPK) estimates of BUSULFEX for clearance (CL) and volume of distribution (V) were determined. For actual body weight, PPK estimates of CL and V were 4.04 L/hr/20 kg (3.37 ml/min/kg; interpatient variability 23%); and 12.8 L/20 kg (0.64 L/kg; interpatient variability 11%). Distribution, Metabolism, Excretion: Studies of distribution, metabolism, and elimination of BUSULFEX have not been done; however, the literature on oral busulfan is relevant. Additionally, for modulating effects on pharmacodynamic parameters see Drug Interactions . Distribution: Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in plasma. Irreversible binding to plasma elements, primarily albumin, has been estimated to be 32.4 ± 2.2% which is consistent with the reactive electrophilic properties of busulfan. Metabolism: Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate undergoes further extensive oxidative metabolism in the liver. Excretion: Following administration of 14 C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. The incomplete recovery of radioactivity may be due to the formation of long-lived metabolites or due to nonspecific alkylation of macromolecules.

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 BUSULFEX 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. 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/mm3 or a platelet transfusion requirement) and engraftment (ANC≥0.5x10 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). 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 x 4 days + cyclophosphamide 60 mg/kg/d x 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 2 below summarizes the efficacy analyses reported from these 4 studies. Table 2: Summary of efficacy analyses from the randomized, controlled trials utilizing a high dose oral busulfan-containing conditioning regimen identified in a literature review. *Eto = etoposide. TBI was combined with etoposide in the comparator arm of this study. BU = Busulfan CY = Cyclophosphamide TBI = Total Body Irradiation DFS = Disease Free Survival ANC = Absolute Neutrophil Count Clift, 1994 CML Chronic Phase; 3 year Overall 3 year DFS Relapse Time to Engraftment Survival (p=0.43) (ANC ≥ 500) BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI 80% 80% 71% 68% 13% 13% 22.6 days 22.3 days   Devergie, 1995 CML Chronic Phase; 5 year Overall Survival 5 year DFS (p=0.75) Relapse (Relative Risk analysis Time to Engraftment (ANC ≥ 500) (p=0.5) BU/CY:CY/TBI) (p=0.04) BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI 60.6% 65.8% 59.1% 51.0% 4.10 None None ±11.7% ±12.5% ±11.8% ±14% (95%CI =1.00-20.28) Given Given   Ringden, 1994 CML, AML, ALL; 3 year Overall 3 year Relapse Free Relapse Time to Engraftment Survival Survival (p=0.9) (ANC >500) (p<0.03) (p=0.065) BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI 62% 76% 56% 67% 22% 26% 20 days 20 days   Blume, 1993* CML, AML, ALL; Relative Risk Analysis BU/CY: Etoposide/TBI RR of Mortality DFS RR of Relapse Time to Engraftment (Relative Risk analysis BU/CY:Eto/TBI) BU/CY Eto/TBI BU/CY Eto/TBI BU/CY Eto/TBI BU/CY Eto/TBI 0.97 Not Given 1.02 Not Given (95% CI=0.64-1.48) (95% CI=0.56-1.86)