William P. Vaughan

Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: A phase I study

The unpredictable intestinal absorption and erratic bioavailability of oral busulfan (Bu) has limited the drugs use in high-dose pretransplantation conditioning therapy. To standardize drug delivery, we solubilized Bu for parenteral use. This new intravenous (i.v.) Bu formulation was combined with oral Bu and cyclophosphamide (Cy) to evaluate (1) the human acute toxicity of i.v. Bu and its solvent system and (2) the pharmacokinetics of Bu in patients undergoing hematopoietic progenitor cell transplantation (HPCT). One dose of i.v. Bu (escalating from 0.08 to 0.8 mg/kg) was given over 2 hours by pump; 6 hours later, an oral Bu regimen was begun, consisting of 1 mg/kg every 6 hours for 15 doses, followed by Cy, 60 mg/kg daily for 2 days. After 1 day of rest, HPCT was performed. The i.v. Bu dose was well tolerated and did not produce any acute toxicity reaction that could be attributed to the solvent system of dimethylacetamide and polyethylene glycol (PEG)-400. All observed treatment-related toxicity was as would be expected after high-dose oral Bu plus Cy. When the i.v. Bu was used as reference solution, the pharmacokinetic analysis indicated an average bioavailability of oral high-dose Bu of 69%, ranging from <10% to virtually 100%. Further, the 2-hour infusion of i.v. Bu gave a time to maximum plasma concentration following drug administration similar to that of oral Bu (2 hours and 1.8 hours, respectively), and i.v. Bu had a clearance similar to that of oral Bu. Based on the data in this study, we suggest that the optimal (starting) dose of i.v. Bu (in combination with Cy) in our forthcoming phase 2 trial should be on the order of 0.8 mg/kg to target an area under the curve (AUC) of 1100 to 1200 micromol/L per minute. This would secure myeloablation and engraftment but save the vast majority of patients from the increased risk of serious hepatic veno-occlusive disease that has been reported when the AUC level exceeds 1500 micromol/L per minute. Bu administration via the i.v. route will assure complete bioavailability and reliable systemic drug exposure with more predictable blood levels and, therefore, possibly lower the risks for serious/life-threatening toxicity, graft rejection, and recurrent leukemia.

Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study.

IntroductionCyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes.MethodsWe performed a retrospective cohort study of 350 women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial (ECOG-2190/INT-0121). Subjects in this trial received standard-dose cyclophosphamide, doxorubicin and fluorouracil (CAF), followed by either observation or high-dose cyclophosphamide and thiotepa with stem cell rescue. We used bone marrow stem cell-derived genomic DNA from archival specimens to genotype CYP2B6, CYP2C9, CYP2D6, CYP3A4, CYP3A5, GSTM1, GSTT1, and GSTP1. Cox regression models were computed to determine associations between genotypes (individually or in combination) and disease-free survival (DFS) or overall survival (OS), adjusting for confounding clinical variables.ResultsIn the full multivariable analysis, women with at least one CYP3A4 *1B variant allele had significantly worse DFS than those who were wild-type *1A/*1A (multivariate hazard ratio 2.79; 95% CI 1.52, 5.14). CYP2D6 genotype did not impact this association among patients with estrogen receptor (ER) -positive tumors scheduled to receive tamoxifen.ConclusionsThese data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer.

Host Genetic Variants in the Interleukin-6 Promoter Predict Poor Outcome in Patients with Estrogen Receptor-Positive, Node-Positive Breast Cancer

Interleukin-6 modulates immune response, estrogen production, and growth pathways in breast cancer. We evaluated the effect of several common, functional interleukin-6 promoter variants in node-positive breast cancer patients enrolled on a multicenter, cooperative group, adjuvant chemotherapy trial to determine whether these variants were associated with clinical outcome overall and by estrogen receptor tumor phenotype. Genomic DNA and clinical data were collected from a clinical trial of adjuvant anthracycline-based chemotherapy followed by randomization to high-dose cyclophosphamide/thiotepa or observation (Intergroup Trial 0121). Genotyping for -174G>C (rs1800795), -597G>A (rs1800797), and -572G>C (rs1800796) was done by site-specific PCR and PyroSequencing, whereas the -373A(n)T(n) repeat was directly sequenced. Log-rank tests and Cox modeling were used to compare outcomes by genotype/haplotype and other factors. Three hundred forty-six patients (64% of trial) had corresponding genotype/clinical data available and did not differ from overall trial participants. After adjustment, patients with estrogen receptor-positive tumors and genotypes 597 GG or 174 GG had significantly worse disease-free survival [hazard ratio (HR), 1.6; P = 0.02 and HR, 1.71; P = 0.007, respectively], whereas the 373 8A12T repeat appeared to be protective (HR, 0.62; P = 0.02). The presence of at least one copy of the haplotype ([-597G, -572G, -373[10A/11T], -174G]) was associated with worse disease-free survival (HR, 1.46; P = 0.04). Kaplan-Meier plots show that all patients in this group relapsed by 24 months from diagnosis. This poor-risk haplotype was quite common overall (estimated frequency, 0.20) and twice as frequent among Blacks (estimated frequency, 0.41).

Amelioration of oral mucositis pain by NASA near-infrared light-emitting diodes in bone marrow transplant patients.

PurposeThis study seeks to investigate the use of extra-orally applied near-infrared phototherapy for the reduction of oral pain secondary to chemotherapy- and radiation therapy-induced mucositis in adult and pediatric hematopoietic stem cell transplant (HSCT) patients.MethodsEighty HSCT patients were divided into regular (R) and low (L) risk groups, then to experimental (E) and placebo (P) groups, resulting in four groups (ER, EL, PR, PL). Experimental subjects received 670 (±10)u2009nm gallium-aluminum-arsinide light-emitting diode device for 80xa0s at ∼50xa0mW/cm2 energy density and power exposure of 4xa0J/cm2. Placebo patients received the same procedures, but with a placebo phototherapy (identical device but <5xa0mW/cm2 energy density). Patients received their respective light therapy once per day starting on the day of the HSCT (dayxa00) and continued through dayxa0+14. Blinded evaluators examined the patients three times per week and scored their oral tissues and patient-reported pain assessments at each evaluation utilizing the WHO, NCI-CTCAE, and OMAS scales.ResultsAnalysis of the mean scores at each observation demonstrate that the extra-oral application of phototherapy resulted in a significant reduction in patient-reported pain between the ER and PR patients (pu2009<u20090.05) at dayxa0+14 when graded via the WHO criteria. The ER and EL patients were improved in almost all other categories and assessment scales, but the differences were not statistically significant.ConclusionPhototherapy demonstrated a significant reduction in patient-reported pain as measured by the WHO criteria in this patient population included in this study. Improvement trends were noted in most other assessment measurements.

Bone Marrow Transplantation for Non-Hodgkin's Lymphoma:A Review

High dose chemotherapy and stem-cell rescue (bone marrow transplantation) is used increasingly in the treatment of malignant disorder. Numerous trials have demonstrated the effectiveness of bone marrow transplantation in the treatment of non-Hodgkins lymphoma. However, there are many unanswered questions as to the role of high-dose therapy in certain subtypes of lymphoma, the timing of transplant, and even the type of transplant to perform. An attempt will be made to clarify many of these unanswered questions. The utilization of high-dose therapy for non-Hodgkins lymphoma is recommended for most patients who have relapsed after initial therapy. Transplantation in first remission is not recommended routinely. Allogeneic bone marrow transplantation should by reserved for individuals with poorly responding disease or in individuals with bone marrow involvement. The precise roles of purging and transplantation of individuals with low grade lymphoma are being investigated.

Phase I/II study incorporating intravenous hydroxyurea into high-dose chemotherapy for patients with primary refractory or relapsed and refractory intermediate-grade and high-grade malignant lymphoma.

PURPOSEnA phase I/II study was performed to evaluate the incorporation of hydroxyurea (HU) into high-dose chemotherapy of non-Hodgkins lymphoma (NHL).nnnPATIENTS AND METHODSnThirty-eight patients with primary refractory and refractory relapsed NHL were treated with carmustine (BCNU) (300 mg/m2 on day -8), cyclophosphamide (Cy) (2.5 g/m2/d on days -8 and -7), etoposide (E) (150 mg/m2 every 12 hours on days -6, -5, and -4), and HU (BCHE) with autologous hematopoietic stem-cell rescue. Twenty-one patients received HU in a dose escalation of 2 to 12 g/m2 intravenously (IV) by 72-hour continuous infusion. When the IV formulation was not available, 17 patients were given 18 g/m2 of HU orally in divided doses every 6 hours over the same 72-hour period.nnnRESULTSnThe dose-limiting toxicity of 72-hour continuous infusion HU in this regimen was mucositis. Endotracheal intubation was necessary to protect the airway in two thirds of patients treated at 12 g/m2. Six patients (oral BCHE, five of 17; IV BCHE, one of 21) died with nonresponding or progressive disease and, at least in part, from the complications of the high-dose chemotherapy. Seventeen patients (45%) achieved complete remission (CR). More patients treated with IV BCHE achieved CR than patients treated with oral BCHE (12 of 21 v five of 17; P < .1, chi 2 test). Nine patients (two of 17 oral BCHE and seven of 21 IV BCHE) remain disease-free as of January 31, 1994, with a minimum follow-up time of 3 years. The lower mortality and higher response rate with IV BCHE translated into a significantly superior probability of progression-free survival (PFS) (33% at 4 year v 12% for oral BCHE; P = .048, log-rank test).nnnCONCLUSIONnHigh-dose BCHE is effective treatment for primary refractory and refractory relapsed NHL. Continuous IV HU appears to be less toxic and more effective than intermittent oral HU in this regimen.

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80xa0years but was amended due to high early treatment-related mortality (TRM) in patientsxa0>xa065xa0years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (nxa0=xa066) or NHL (nxa0=xa0141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (nxa0=xa0203), patientsxa0>xa065xa0years (nxa0=xa017), and patientsxa0≤xa065xa0years (nxa0=xa0186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large Bxa0cell lymphoma (DLBCL; nxa0=xa063), mantle cell lymphoma (MCL; nxa0=xa029), and follicular lymphoma (FL; nxa0=xa023), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in Bxa0cell NHL patients ≤ 65xa0years but produced worse PFS in HL patients when compared with BEAM.

The Long Road to a Cure for Acute Myelocytic Leukemia: From Intensity to Specificity

Twenty-five years ago, increasing numbers of children with acute lymphocytic leukemia were being cured with prolonged-duration, multiagent chemotherapy programs developed over the previous 20 years in serial clinical investigations conducted principally at the United States National Cancer Institute and in the cooperative group trials. The application of these strategies to acute myelocytic leukemia (AML), however, produced disappointing results in children and adults despite the availability of more effective agents, especially cytarabine and the anthracyclines. With the emergence of improved supportive care in transfusion medicine and infectious disease management, it became feasible to investigate more intensive remission induction regimens and to rethink the role of maintenance therapy. More intensive combination chemotherapy with daunorubicin or doxorubicin plus cytarabine was rapidly becoming the standard for remission induction. To further intensify remission induction therapy with these agents, Philip Burke, MD, in whose laboratory and clinical program we worked, hypothesized that timed sequential chemotherapy could recruit noncycling malignant cells into cell cycle, making them more sensitive to a short infusion of the cell cycle–specific second drug (cytarabine) if given in an optimally timed sequence after an initial infusion of the two drugs together. In a series of studies in the laboratory and in clinical trials, the optimum timing for most efficient cell kill and therapeutic index were worked out, and the role of humoral factors in the recruitment of malignant cells into cycle was explored. In these trials, adults with AML were treated with a timed sequential regimen of daunorubicin and continuous-infusion cytarabine administered on days 1 through 3 followed by another 3 days of cytarabine after a short interval. An early indication of the increased effectiveness of this strategy was the observation that a complete remission rate was achieved for four of seven patients who had AML occurring after exposure to prior chemotherapy or radiation. Previously, these patients were considered to have disease that was completely refractory to induction therapy. This series of patients was treated before the routine use of cytogenetics to determine risk for treatment failure, and, to our knowledge, this regimen has not been studied in high-risk patients so identified, but it seems unlikely that the patients in our series were predominantly good risk. This observation was reported in 1983 in the article reprinted in this silver anniversary edition of Journal of Clinical Oncology. Meanwhile, a clinical trial was being completed in which a second cycle of the same regimen was given as consolidation and no further chemotherapy until relapse. Forty percent of the patients treated with two cycles of timed sequential therapy achieved long-term complete remission. Longer follow-up reported in a later article suggested that they are probably cured. The timed sequential therapy approach has subsequently been evaluated in three randomized clinical trials. The first was a Children’s Cancer Study Group study chaired by Bill Woods, MD, in which children with AML were randomly assigned to receive four courses of intensive multiagent chemotherapy with time for marrow recovery between each course or as two cycles of timed sequential therapy over the same overall time period. The timed sequential therapy arm produced statistically significantly better long-term disease-free survival and was the first report of a greater than 50% long-term survival rate in pediatric AML. Recently, the use of this regimen and schedule was reported by investigators at M.D. Anderson Cancer Center to also be more effective in terms of long-term disease-free survival in adults up to age 50 years. Meanwhile, an intensified version of the original Burke regimen was tested in a large French consortium trial against two other standard induction regimens. Despite substantially greater toxicity, the timed sequential therapy regimen produced a significantly better duration of complete remission for patients younger than 50 years. The disappointing reality is that more than 25 years after the development of this and other aggressive approaches, we are still using the same treatment strategies and the same two agents as the treatment for standardand high-risk AML, with the exception of acute promyelocytic leukemia (APL). The cure rate with anthracyclines and cytarabine chemotherapy in this subset has long been recognized to be high, but with the discovery of the pathogenetic role of the sensitivity to retinoids and the remarkable effectiveness of arsenic trioxide, the cure rate approaches 80%, with much less treatment-related mortality. Building on the APL example and continued improved understanding of the molecular pathogenesis of various other subtypes of AML, investigators are right to move the focus of clinical trials from intensity to specificity in the management of the disease. The case of APL is unique in terms of the specifics related to therapy but may not be the only AML subtype whose stem cells present targets not present in normal cells, especially hematopoietic stem cells. Other so-called good prognosis sub-types such as inv(16) and JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 21 JULY 2