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PubMed2001

Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation.

Published data suggest that the average concentration of busulfan at steady state (Bu Css) is critical for successful engraftment in children receiving busulfan as a conditioning agent for bone marrow transplantation (BMT). We previously found in children that a Bu Css <600 ng/ml correlated with autologous recovery/mixed chimerism; there was no correlation between Bu Css and regimen-related toxicity (RRT). In a cohort continuous with the previous trial, we prospectively evaluated targeted busulfan concentrations in 32 pediatric patients (age 0.6-18.5 years) with AML (n = 6), CML (n = 6) and non-malignant disorders (n = 20) receiving HLA-closely matched donor grafts. In this trial, individual busulfan pharmacokinetics were performed prior to admission. Busulfan doses were then adjusted to achieve a Bu Css target range of 600-900 ng/ml +/- 10% depending on donor source and disease. A repeat study was done following dose 1 of the conditioning regimen. Thirty of thirty-two (94%) patients achieved target concentrations. Total busulfan doses ranged from 10.9 to 29 mg/kg. Thirty of thirty-two patients (94%) have durably engrafted. Grade 3/4 RRT occurred in seven patients (21%). Targeting Bu Css ranges of 600-900 ng/ml significantly improved our rate of successful engraftment from 74% to 94% (P = 0.043). These results indicate that targeted busulfan dosing optimizes allogeneic engraftment in children.

Administration, Oral↗
PubMed2002

Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation.

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.

Adolescent↗
PubMed2001

The pharmacodynamic effect of busulfan in the P39 myeloid cell line in vitro.

Busulfan is an alkylating agent currently used in the myeloablative conditioning regimen before stem cell transplantation. Its mechanism of action is not fully understood, nor the reason for its narrow therapeutic window. We studied the pharmacodynamics of busulfan in an in vitro cell line model, allowing us to evaluate the effects of various doses and exposure times on clonogeneic capacity, proliferation and apoptosis. Cells were incubated with busulfan in concentrations ranging from 10 to 100 microg/ml for 2, 4 or 8 h, then washed and cultured in busulfan-free medium for 72 h. Area under the concentration-time curve (AUC) was estimated by using the trapezoidal rule from different concentrations and times of incubation. In all assays busulfan affected the cells in an AUC-dependent manner. Induced changes in the biological parameters studied appeared at different time points after exposure to busulfan stopped. Thus, the decrease in proliferation and clonogenic capacity preceded cell cycle arrest in G2 phase and development of apoptosis, implying that apoptosis is a secondary event to interruption of vital metabolic processes. Biochemically, apoptotic changes were typical for chemotherapy-induced apoptosis with caspase activation, cleavage of Bcl-2 and PARP proteins, while cleavage of actin was not observed. Cells were rescued from apoptosis with a general caspase inhibitor ZVAD-fmk, but not with granulocyte colony-stimulating factor (G-CSF). Our results add new information about busulfan pharmacodynamics and mechanisms underlying the cytotoxic effect of the drug.

Antineoplastic Agents, Alkylating↗
PubMed1978

Spontaneous regression of syngeneic transplanted tumors in rats pretreated with the antileukemia drug busulfan.

Lethal growth of a syngeneic transplanted tumor (KMT-17) was inhibited in WKA rats pretreated with the antileukemia drug busulfan. The effect of busulfan was short-lasting, and administration of the drug after tumor challenge had little effect on the lethal growth of the tumor. After spontaneous regression of the tumor in rats pretreated with busulfan, specific transplantation resistance to identical tumor was acquired. Busulfan did not exhibit its effect in rats irradiated before tumor challenge. As shown by the Winn test, spleen cells from rats immunized with inactivated tumor cells after busulfan treatment inhibited growth of admixed tumor cells more strongly than did spleen cells from rats immunized without busulfan treatment. Enhancement of immune response to tumor cells rather than tumoricidal activity by busulfan was suggested.

Animals↗
PubMed1988

Recipient preparation for bone marrow transplantation. I. Efficacy of total-body irradiation and busulfan.

The efficacy of total body irradiation and busulfan were studied in recipient preparation for bone marrow transplantation. Male C57BL/6 (B6) mice were prepared for BMT with fractionated TBI or busulfan given in 4 equal doses over 3 days. Both TBI and busulfan are potent stem-cell killers. Both agents resulted in an exponential decrease in CFUs survival with increasing dose down to a 1 x 10(-4) CFUs survival. There appeared to be no break in the curve for either agent. Extrapolated fractional CFUs survival, as related to equivalent donor marrow engraftment or to equivalent 30-day survival without marrow transplantation, appeared lower for TBI as compared to busulfan. This may be due to the effect of busulfan and TBI on different stem-cell populations. Erythroid engraftment was tested after transplanting H-2 compatible LP marrow cells into treated B6 recipients. Greater than 80% of animals demonstrated complete engraftment with 3.4 mg busulfan or 1640 cGy TBI. At these 2 doses, the rate of recovery of donor marrow cellularity and CFUs content in treated recipients were identical for both preparative agents such that a selective effect on the host hematopoietic microenvironment harmful to engraftment was not seen. Complete engraftment in 100% of busulfan-prepared animals could not be achieved as such doses resulted in severe and fatal pulmonary vascular injury at 7-12 weeks posttransplant.

Animals↗
PubMed2004

Intraindividual variability in busulfan pharmacokinetics in patients undergoing a bone marrow transplant: assessment of a test dose and first dose strategy.

Busulfan systemic exposure correlates with regimen-related toxicity, engraftment and relapse in select patients receiving high-dose oral busulfan (HD-BU) (1 mg/kg dose or 40 mg/m dose every 6 h for 16 doses) as part of a preparative regimen for bone marrow transplantation. Therapeutic drug monitoring is frequently conducted after the first HD-BU dose in order to determine necessary dose adjustments. Limitations with this method include the need for rapid determination of busulfan plasma concentration and difficulties with estimating apparent oral clearance in patients who exhibit delayed absorption of HD-BU. This pharmacokinetic study was conducted to evaluate the ability of the apparent oral clearance obtained after administering a lower (0.25 mg/kg) test dose and the traditional (1 mg/kg) first dose to predict the dose required to achieve a desired area under the concentration-time curve (AUC) at steady-state (13th dose). In addition, the pharmacokinetic parameters of test, first and 13th dose were compared to assess intrasubject variability. Twenty-nine patients received a test dose of oral busulfan (0.25 mg/kg) the day immediately prior to initiation of HD-BU. Busulfan serum concentrations were measured following the test, first and 13th doses using gas chromatography with electron capture detection. The AUC and apparent oral clearance were calculated using non-compartmental analysis. Therapeutic drug monitoring following the first dose of HD-BU was conducted for clinical purposes in six patients, and dose adjustment between the first and 13th dose occurred in only two patients. The dose-corrected test dose and first dose AUC and apparent oral clearance were not bioequivalent (two one-sided t-tests, +/-20%). The first dose and 13th dose AUC and apparent oral clearance were also not bioequivalent. Six of the 29 patients receiving HD-BU dose based on weight (1 mg/kg) would have achieved a steady-state AUC of 3600-5400 ng x h/ml, a frequently used target AUC, as compared to eight and 13 patients if their dose was based on the apparent oral clearance following the test dose and first dose HD-BU, respectively. Monitoring busulfan concentrations after a test dose or a first dose provides a better estimate of the dose needed to achieve the target steady-state AUC as compared to traditional weight-based dosing. However, significant intraindividual variability exists in the apparent oral clearance of busulfan and follow-up therapeutic drug monitoring is recommended particularly if the desired target AUC range is narrow.

Administration, Oral↗
PubMed2006

Cytotoxicity of treosulfan and busulfan on pediatric tumor cell lines.

High-dose chemotherapy of solid tumors aims at eliminating residual or metastatic tumor cells, which remained after conventional treatment. Thus, anticancer drugs used for high-dose chemotherapy should display significant cytotoxicity against the respective tumors. As little data are available about the in-vitro toxicity of busulfan and treosulfan especially on pediatric tumor cell lines, we compared the cytotoxicity of treosulfan and busulfan on four Ewing tumor, four neuroblastoma, two osteosarcoma and two leukemia cell lines in vitro. Growth inhibition of tumor cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide test after 24, 48, 72 and 96 h. Treosulfan and busulfan reduced the growth of all tumor cell lines in a time-dependent and dose-dependent manner. In vitro treosulfan was consistently more cytotoxic than busulfan. Fifty percent growth inhibitions of 608-0.73 micromol/l were determined for treosulfan and of above 5,000-2.81 micromol/l for busulfan. Both drugs exhibited similar cytotoxicity profiles. Busulfan-sensitive/resistant cell lines were also sensitive/resistant to treosulfan. Overall, the leukemia cell lines were most sensitive to busulfan and treosulfan. The Ewing tumor cell lines were the second most sensitive followed by the neuroblastoma cell lines. The osteosarcoma cell lines were the most resistant cell lines. Although the in-vitro stability of both drugs makes direct comparison of their in-vitro toxicity difficult and does not allow any estimation of dosages needed clinically, the in-vitro results indicate substantial cytotoxicity of both drugs on leukemias, Ewing tumors and neuroblastomas. These data suggest further evaluation of treosulfan for high-dose chemotherapy of advanced Ewing tumors, neuroblastomas and high-risk leukemias.

Antineoplastic Agents, Alkylating↗
PubMed1999

Cataract induced by short-term administration of large doses of busulfan: a case report.

Busulfan is a carcinostatic which is used for myelocytic leukemia. A 42-year-old Japanese woman given high doses of busulfan for a short time was referred to us because of decreased visual acuity and blurred vision in both eyes. She received 212 mg/day of busulfan for only 4 days. Ophthalmoscopic examination demonstrated a posterior polar subcapsular opacity of the lens in both eyes. Although the occurrence of cataract due to busulfan has been reported after long-term administration of busulfan, this is the first clinical case of cataract caused by high doses of busulfan for a short period. It is necessary to pay more attention to busulfan cataract.

Adult↗
PubMed2001

Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation.

Busulfan, at a dose of 16 mg/kg, is widely used in combination with cyclophosphamide as a conditioning regimen for patients undergoing bone marrow transplantation. Wide interindividual variation in busulfan kinetics and rapid clearance of the drug have been reported, especially in children. Some of the factors contributing to interpatient variability have been identified. They include circadian rhythms, age, disease, drug interaction, changes in hepatic function, and busulfan bioavailability. In this study, we demonstrate that hepatic glutathione S-transferase (GST) activity correlates negatively with busulfan maximum and minimum concentrations (Pearson's correlation r = -0.74 and -0.77, respectively) and positively with busulfan clearance (Pearson's correlation r = 0.728) in children with thalassemia major in the age range of 2 to 15 years. We also found that plasma alpha GST levels were 5 to 10 times higher in patients with thalassemia than in normal controls and age-matched leukemic patients, either reflecting extensive liver damage, elevated expression of the enzyme, or both in thalassemic patients. Plasma alpha GST concentrations showed a similar correlation with busulfan kinetic parameters to that observed for hepatic GST. The status of hepatic GST activity accounts, at least in part, for the observed interindividual variation in busulfan kinetics, while the observed association with plasma alpha GST is difficult to explain at present.

Adolescent↗
PubMed2001

[High-dose busulfan--monitoring plasma levels and dosage adjustments in adults].

Bone marrow and peripheral blood stem cell transplantations, despite their curative potential, still carry significant risks for patients. Toxicity of high-dose chemotherapy is one of the leading causes of peritransplant mortality. Busulfan is a frequently used chemotherapeutic agent in conditioning regimens prior to transplantations. The choice of the optimal busulfan dose and prediction of its clinical effect may be very difficult. Absorption of busulfan from gastrointestinal tract and its metabolism can vary considerably. Several studies published recently showed that the busulfan plasma concentrations correlate better with the clinical effect and extramedullary toxicity caused by this drug than with the actual dose administered to the patient. Approximate target plasma concentrations of busulfan, which meet the optimal balance between the clinical effect and the risk of severe side effects of chemotherapy, were proposed. Almost twenty chromatographic methods were published, which make the quantitative measurement of busulfan possible. The maintenance of certain busulfan plasma concentration during its whole administration with the help of the repeated adjustments of its dosage can reduce the toxicity caused by this agent and improve the results of bone marrow or peripheral blood stem cell transplantations. This method is easily applicable, has low financial and personal demands, and technical appliances, which it requires are usually accessible in most transplant center laboratories.

Adult↗
PubMed1989

Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation.

In a phase I study 28 patients with lymphohematopoietic malignancies were treated with escalating doses of etoposide combined with cyclophosphamide 120 mg/kg and either fractionated total body irradiation (TBI) 1320 cGy in 11 fractions (n = 17) or busulfan 16 mg/kg (n = 11). Twenty transplants were allogeneic, seven autologous and one syngeneic. The maximally tolerated dose of etoposide in combination with TBI and cyclophosphamide was 60 mg/kg; at etoposide doses of 65 mg/kg three patients developed life-threatening or fatal mucosal toxicity. In combination with busulfan, the maximally tolerated dose of etoposide was 30 mg/kg. At an etoposide dose of 40 mg/kg two patients developed life-threatening or fatal toxicity (one mucosal, one hepatic). Mucositis requiring narcotic analgesics, hepatotoxicity, hematologic toxicity and interstitial pneumonitis were otherwise similar in TBI and busulfan-treated patients. Skin toxicity was observed significantly more often in the busulfan group. Five deaths occurred before day +30, two in the TBI group and three in the busulfan group. Eleven patients are surviving, ten in continuous complete remission, at a median of 9 (range 3-23) months following transplantation. Etoposide in combination with TBI and cyclophosphamide or busulfan and cyclophosphamide is associated with significant but acceptable toxicities. The maximally tolerated dose of etoposide is higher when combined with TBI than with busulfan. Promising response rates in this high risk group of hematologic malignancies warrant further evaluation of these etoposide containing conditioning regimens.

Adolescent↗
PubMed1985

Busulfan-induced suppression of natural killer cell activity.

The effect of repeated injections of busulfan, an alkylating agent, on immune response of CAF1 mice was studied. A single injection of busulfan or acetone (vehicle to solubilize busulfan) acutely suppressed mitogenic and allogenic responses that normalized at two weeks. Repeated injections of busulfan (four injections), on the other hand, showed a transient suppression of the mitogenic responses. Natural killer (NK) activity during the first ten days after busulfan or acetone injections remained normal. NK activity diminished significantly after two injections of busulfan, remained low after four injections, and did not recover within four months of rest. Prolonged suppression of NK activity may be implicated as playing a role in the emergence of T-cell lymphomas in mice injected with busulfan.

Animals↗
PubMed1983

In vitro busulfan sensitivity of granulocyte-macrophage and erythroid progenitor cells in patients with chronic myelogenous leukemia.

As part of an attempt to develop and test potential in vitro measures of busulfan sensitivity of patients with chronic myelogenous leukemia (CML) in chronic phase, we compared the busulfan sensitivity of granulocyte-macrophage (CFU-C) and early erythroid progenitor cells (BFU-E) in the bone marrow (BM) and peripheral blood (PB) specimens obtained from ten normal individuals and from 13 patients with CML. CFU-C in the normal BM and in both the BM and PB of CML patients showed comparable degrees of sensitivity to busulfan. BFU-E, regardless of source, showed similar degrees of sensitivity to busulfan, except that normal PB BFU-E were less sensitive than were PB BFU-E of CML patients. CFU-C were more resistant to busulfan than BFU-E. The sensitivity of BM CFU-C and BFU-E of CML patients reflected that of PB CFU-C and BFU-E, respectively, and the sensitivity of BM and PB CFU-C of CML patients reflected that of BM and PB BFU-E, respectively. When the CML patients were ranked according to sensitivity to busulfan, the order of sensitivity of BM CFU-C and BFU-E paralleled that of PB CFU-C and BFU-E, respectively, and the order of sensitivity of BM and PB CFU-C paralleled that of BM and PB BFU-E, respectively. These results suggest that any of the four progenitor cells, BM CFU-C, BM BFU-E, PB CFU-C, and PB BFU-E, can be used to investigate the relative busulfan sensitivity of the hemopoietic progenitor cells of different CML patients.

Busulfan↗
PubMed1994

Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group.

As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.

Adolescent↗
PubMed1993

[Cataracts in a patient treated with busulfan (Mablin powder) for eight years].

Busulfan (Mablin powder) has been used in the treatment of chronic myelogenous leukemia for a long time. Although cataract is known to be an ocular side effect of prolonged Busulfan therapy, it has rarely been reported, especially in Japan. This report describes mature cataracts in a 59-year-old woman with chronic myelogenous leukemia, who had received a total dose of 2,249.7 mg Busulfan over eight years. In our department, the average age at the time of senile cataract operation was 72 years in men and 73.4 years in women during the past five years, so this patient was younger than the average senile cataract patient. A review of case reports, including the present one, suggests that Busulfan cataract characteristically develops rapidly in both eyes of young patients treated with a total dose of over 2,000 mg of Busulfan for more than four years. Busulfan cataracts have rarely been reported probably because cataract is regarded as senile and patients treated with Busulfan usually die before cataract appears.

Busulfan↗
PubMed1996

Association of busulfan area under the curve with veno-occlusive disease following BMT.

Busulfan pharmacokinetics, specifically area under the concentration curve (AUC), have been correlated with the occurrence of veno-occlusive disease (VOD) following BMT. To evaluate the risk of VOD, we studied 66 patients who received pharmacotherapeutically monitored busulfan regimens in combination with CY, etoposide (VP16) and/or Ara-C in preparation for BMT. These patients received a total of 16 doses of busulfan dosed as 1 mg/kg/dose q 6 h beginning at 09.00 (n = 39), 18.00 (n = 2), 21.00 (n = 1) or 24.00 (n = 24) h. With the first dose, blood samples were obtained at baseline, every 15-30 min for 2 h, then every 1-2 h for 4 h. Blood was analyzed for busulfan concentration by high performance liquid chromatography and AUC calculated by the trapezoidal rule. Seventeen patients (25.8%) were not evaluable for AUC calculation due to slow absorption and/or elimination: 13 of 27 (48.1%) received the first dose between 18.00-24.00 vs four of 39 (10.2%) patients who received the first dose at 09.00 (P < 0.001). Eighteen of 51 (35.3%) evaluable patients had an AUC > 1500 mumol x min/l; 10 of whom received doses reduced proportionally to achieve an AUC = 1200 mumol x min/l starting with the 10th to 15th dose. Six of 18 (33.3%) patients with an initial AUC > 1500 mumol x min/l developed VOD vs one of 33 (3.0%) patients with an initial AUC < 1500 mumol x min/l (relative risk = 11.1; P = 0.0056). Other pharmacokinetic parameters, age, gender, type of BMT, previous therapy or pre-transplant liver function tests were not predictive of VOD. A higher incidence of VOD occurred in patients receiving BUCY (4 of 10) compared to those receiving BUCYAra-C (1 of 18) or BUCYVP16 (7 of 38), which could not be attributed to increased busulfan exposure in the BUCY patients. Routine pharmacotherapeutic monitoring of busulfan is recommended with further study to evaluate the impact of earlier and greater overall dose reduction in patients with high initial busulfan exposures.

Adolescent↗
PubMed1997

Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan.

Busulfan, a bifunctional alkylating agent, is a mainstay of myeloablative preparative regimens before hematopoietic stem cell transplantation. The apparent oral clearance of busulfan expressed relative to body surface area is 2-3-fold higher in children 1-4 years old than it is in adults. The first step in busulfan elimination is the formation of a tetrahydrothiophenium ion (THT+) in a glutathione S-transferase-catalyzed reaction. We present computer simulations that demonstrate that the ratio of the AUC of THT+ to that of busulfan over 6 h [(AUC(THT+)/AUC(BU))(0-->6)] is highly correlated (r2 = 0.805) with the determinants of THT+ formation and is virtually independent of the determinants of its elimination (r2 = 0.0201). We compared (AUC(THT+)/AUC(BU))(0-->6) determined in 14 children (0.5-4 years) to that of 11 adults (12-54 years) and found a 1.5-fold elevation in the area ratio (P = 0.0098) and a similarly significant increase in busulfan apparent oral clearance expressed relative to body surface area (P = 0.042). The only common explanation for the elevated busulfan apparent oral clearance and (AUC(THT+)/AUC(BU))(0-->6) is an enhanced ability of children to metabolize busulfan through glutathione conjugation.

Absorption↗
PubMed1985

Lack of relationship between in vitro cell measurements and response to busulfan in chronic myelocytic leukemia.

Twenty-three patients with chronic-phase CML have been treated with intermittent courses of busulfan to determine if the duration of unmaintained remission becomes progressively shorter with successive courses of therapy and to determine whether there was a relationship between cluster and colony formation, suicide index of CFUc, labeling index, percentage of cells in S-phase (as determined by cytofluorographic DNA histogram analysis), in vitro sensitivity of the CFUc to busulfan, and response to busulfan therapy. Serial studies in individual patients and the group as a whole revealed no relationship between changes in the cellular parameters described above and response to busulfan. The white blood cell (WBC) doubling time with serial courses of busulfan in individual patients did not always progressively decrease as has been previously reported. In vitro studies of CFUc in chronic-phase CML appear to be of no value in predicting response to busulfan.

Adolescent↗