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Informatics strategies and applications available to stem cell transplant (SCT) programs are diverse and changing rapidly. Although most hospitals have electronic medical records (EMRs), few are equipped with specialized SCT applications. Most EMRs do not contain critical elements to support SCT practice and research. Strategies to optimize information technology resources to support SCT programs are reviewed and technical and workflow support discussed. Guidance and rationale for the use of both SCT applications and EMRs are emphasized. [ABSTRACT FROM AUTHOR]

We conducted a randomized, double blind, placebo-controlled multi-institutional trial to assess the ability of amifostine to protect patients against acute lung injury associated with cyclophosphamide/cisplatin/carmustine (BCNU) (STAMP I), a BCNU-containing high dose chemotherapy regimen used with hematopoietic cell transplantation. Amifostine was administered in a dose of 740 mg/m2 for 2 doses preceding administration of BCNU, the presumed pulmonary-toxic component of the regimen. The trial was stopped after 79 patients were randomized and a planned interim analysis demonstrated that it was unlikely that pulmonary cytoprotection would be detected with further accrual. We conclude that amifostine, used in the dose and schedule we tested, does not reduce the incidence of acute lung injury produced by STAMP I. Further, we suggest that amifostine use with BCNU in other contexts and with clinically achievable doses is unlikely to protect the lung from BCNU-associated acute injury. [Copyright &y& Elsevier]

Submission of transplant center data to CIBMTR commonly involves manual transcription of center data derived from departmental databases, EMR, or other institutional systems to FormsNetR (72%) or vendor/institutional applications (19%). This transcription method is expensive, error prone, and complex to audit. In contrast, if data were transmitted directly from institutional systems to CIBMTR, substantial cost reduction and improved data accuracy would be realized. Only a very limited number of centers have developed this type of solution which requires design complexities. MD Anderson Department of Stem Cell Transplantation and Cellular Therapy developed a direct electronic data transmission method of this type which has been in continuous use since 2009. More than 21,000 forms have been successfully accepted by CIBMTR. This method requires several components. An audited departmental Oracle database was developed with structured data fields and tables containing almost all specialized granular or derived data required to populate CIBMTR forms, as well as a much larger data set required for departmental research and quality purposes. This data was stored using common data elements (CDE) contained in the Cancer Data Standards Repository (caDSR) of the NCI. EMR interfaces were developed to acquire all HL-7 coded data necessary to contribute to the forms, and from specialized sources such as the HL-A Laboratory and centralized LIS systems. An interface engine with business rule functionality was designed to transform granular data to derived as well as to reconfigure "time stamped" elements to conform to the periodic forms (30 day, 100 day, 1 year, etc) structure used by the CIBMTR. This method has resulted in substantial reductions in data management effort and has served as a stimulus for CIBMTR to consider newer IT methods in the future. Schematic representations for these systems will be displayed on the full poster. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine whether single nucleotide polymorphisms (SNPs) in genes involved in gemcitabine metabolism, DNA damage repair, multidrug resistance, and alkylator detoxification influence the clinical outcome of patients with refractory/relapsed lymphoid malignancies receiving high-dose gemcitabine/busulfan/melphalan (Gem/Bu/Mel) with autologous stem cell support. We evaluated 21 germline SNPs of the gemcitabine metabolism genes CDA , deoxycytidine kinase, and hCNT3 ; DNA damage repair genes RECQL , X-ray repair complementing 1, RAD54L , ATM , ATR , MLH1 , MSH2 , MSH3 , TREX1 , EXO1 , and TP73 ; and multidrug-resistance genes MRP2 and MRP5 ; as well as glutathione-S-transferase GSTP1 in 153 patients with relapsed or refractory lymphoma or myeloma receiving Gem/Bu/Mel. We studied the association of genotypes with overall survival (OS), progression-free survival (PFS), and nonhematological grade 3 or 4 toxicity. CDA C111T and TREX1 Ex14-460C>T genotypes had a significant effect on OS ( P = .007 and P = .005, respectively), and CDA C111T, ATR C340T, and EXO1 P757L genotypes were significant predictors for severe toxicity ( P = .037, P = .024, and P = .025, respectively) in multivariable models that adjusted for clinical variables. The multi-SNP risk score analysis identified the combined genotypes of TREX1 Ex14-460 TT and hCNT3 Ex5 +25A>G AA as significant predictors for OS and the combination of MRP2 Ex10 + 40GG/GA and MLH1 IVS12-169 TT as significant predictor for PFS. Polymorphic variants of certain genes involved in gemcitabine metabolism and DNA damage repair pathways may be potential biomarkers for clinical outcome in patients with refractory/relapsed lymphoid tumors receiving Gem/Bu/Mel. [ABSTRACT FROM AUTHOR]

We prospectively evaluated the prognostic significance of occult tumor cells (OTCs) contaminating the peripheral blood progenitor cell apheresis products of patients with advanced breast cancer receiving high-dose chemotherapy. Immunocytochemistry of peripheral blood progenitor cells was performed in 242 patients with high-risk primary breast cancer (HRPBC) and in 111 patients with metastatic breast cancer (MBC). OTCs were detected in 6.6% of HRPBC patients and in 16.2% of MBC patients (P = .005). In HRPBC, OTCs correlated with worse prognostic scores and larger tumor sizes, but not with axillary nodal status, hormone receptors, or HER2. In the MBC group, OTCs correlated with bone marrow involvement and with disease status at transplantation. The number of apheresis procedures was not associated with the risk of contamination. In HRPBC patients, at a median follow-up of 7 years (range, 1.5–11 years), the presence of OTCs correlated with worse event-free survival (P = .007) and overall survival (P = .002). In the MBC group, OTCs correlated with worse event-free survival (P = .04), but not overall survival (P = .2). In multivariate analyses, the presence of OTCs had an independent adverse effect on outcome in HRPBC, but not MBC. Our observations imply a direct role of OTCs in posttransplantation relapse in HRPBC. [Copyright &y& Elsevier]

We conducted a prospective phase 2 trial of gemcitabine, busulfan and melphalan (Gem/Bu/Mel) with autologous stem cell transplantation (ASCT) in patients with primary refractory or poor-risk relapsed Hodgkin lymphoma (HL) (ie, extranodal relapse or within 1 year of frontline therapy). The trial was powered to detect an improvement in 2-year progression-free survival (PFS) from a historical 50% using a BEAM regimen (carmustine/etoposide/cytarabine/melphalan) to 65%. We compared the study population with all other concurrent patients who were eligible for the trial but instead received the BEAM regimen at our center. No patient received post-ASCT maintenance therapy. The Gem/Bu/Mel trial enrolled 80 patients with a median age of 31 years, 41% with primary refractory HL and 59% with relapsed HL (36% extranodal relapses), and 30% with positron emission tomography (PET)-positive lesions at ASCT. The concurrent BEAM (n = 45) and Gem/Bu/Mel cohorts were well balanced except for higher rates of bulky relapse and PET-positive tumors in the Gem/Bu/Mel cohort. There were no transplantation-related deaths in either cohort. At a median follow-up of 34.5 months (range, 26 to 72 months), Gem/Bu/Mel was associated with better 2-year PFS (65% versus 51%; P  = .008) and overall survival (89% versus 73%; P  = .0003). In conclusion, our data show that Gem/Bu/Mel is safe, in this nonrandomized comparison yielding improved outcomes compared with a concurrently treated and prognostically matched cohort of patients with primary refractory or poor-risk relapsed HL receiving BEAM. [ABSTRACT FROM AUTHOR]

Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu. In a preliminary report, we previously showed the safety and efficacy of Clo ± Flu with i.v. Bu in 51 patients with high-risk AML, CML, and MDS. The study has now been completed, and we present long-term follow-up data on the entire 70-patient population, which included 49 (70%), 8 (11%), and 13 (19%) patients with AML, MDS, and CML, respectively. Thirteen patients (19%) were in complete remission, and 41 patients (59%) received matched unrelated donor grafts. Engraftment was achieved in all patients. Sixty-three patients (90%) achieved complete remission. There were no deaths reported at day +30, and the 100-day nonrelapse mortality rate was 4% (n = 3). Thirty-one percent of patients (n = 22) developed grades II to IV acute graft-versus-host disease, and the median overall survival and progression-free survival times were 2.4 years and .9 years, respectively. Our results confirm the safety and overall and progression-free survival advantage of the arms with higher Clo doses and lower Flu doses, which was most prominent in the AML/MDS group. [ABSTRACT FROM AUTHOR]

More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days −8 to −3). Gemcitabine was infused continuously at 10 mg/m 2 /minute over 4.5 hours (days −8 and −3). Busulfan dosing targeted 4000 μM-minute/day (days −8 to −5). Melphalan was infused at 60 mg/m 2 /day (days −3 and −2). Patients with CD20 + tumors received rituximab (375 mg/m 2 , days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography–positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation. [ABSTRACT FROM AUTHOR]

Donor chimerism after allogeneic stem cell transplantation (allo-SCT) is commonly used to predict overall survival (OS) and disease-free survival (DFS). Because chimerism is observed at 1 or more times after allo-SCT and not at baseline, if chimerism is in fact associated with OS or DFS, then the occurrence of either disease progression or death informatively censors (terminates) the observed chimerism process. This violates the assumptions underlying standard statistical regression methods for survival analysis, which may lead to biased conclusions. To assess the association between the longitudinal post-allo-SCT donor chimerism process and OS or DFS, we analyzed data from 195 patients with acute myelogenous leukemia (n = 157) or myelodysplastic syndrome (n = 38) who achieved complete remission after allo-SCT following a reduced-toxicity conditioning regimen of fludarabine/intravenous busulfan. Median follow-up was 31 months (range, 1.1 to 105 months). Fitted joint longitudinal-survival time models showed that a binary indicator of complete (100%) donor chimerism and increasing percent of donor T cells were significantly associated with longer OS, whereas decreasing percent of donor T cells was highly significantly associated with shorter OS. Our analyses illustrate the usefulness of modeling repeated post-allo-SCT chimerism measurements as individual longitudinal processes jointly with OS and DFS to estimate their relationships. [ABSTRACT FROM AUTHOR]

Abstract: For patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993 and 2011. First-line salvage included second HSCT (n = 19), donor lymphocyte infusion with or without prior chemotherapy (n = 11), radiation therapy (n = 6), cytoreductive chemotherapy (n = 30), mild chemotherapy (n = 27), or palliative care (n = 23), with median postrelapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission rate of 38% after first-line salvage in the treated patients, the OS rate remained limited with 1- and 2- year OS rates of 17% (95% confidence interval, 13 to 29) and 10% (95% confidence interval, 6 to 20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (<6 months). There was no difference in the 6-month survival postrelapse in patients with isolated extramedullary relapse (44%) compared with combined extramedullary and bone marrow relapse (29%) or those with isolated bone marrow relapse (34%) (P = .8). Our data provide more insight into the disease behavior and treatment outcomes of ALL at relapse after HSCT against which future trials may be compared. [Copyright &y& Elsevier]

Abstract: More active high-dose chemotherapy (HDC) regimens are needed for refractory Hodgkin''s lymphoma (HL). We report a cohort analysis of 180 consecutive patients with primary refractory or poor-risk relapsed HL treated with busulfan-melphalan (Bu-Mel) (n = 39), gemcitabine-busulfan-melphalan (Gem-Bu-Mel) (n = 84), or BEAM (BCNU, etoposide, ara-C, melphalan; n = 57) between 2005 and 2010. Their pre-HDC positron emission tomography (PET) scans were interpreted prospectively. Despite more prevalent poor-risk features in the Gem-Bu-Mel cohort, such as PET-positive tumors at HDC, tumors growing at HDC, extranodal disease, or bulky tumors at prior relapse, this cohort had improved outcomes compared with the Bu-Mel and BEAM cohorts, with event-free survival (EFS) rates of 57%, 33%, and 39%, respectively (P = .01), at median follow-up of the whole population of 36 months (range, 3 to 72). Their respective overall survival (OS) rates were, respectively, 82%, 52%, and 59% (P = .04). Secondary acute myelogenous leukemia was seen in 5 patients after BEAM but was not seen in Gem-Bu-Mel and Bu-Mel cohorts (P = .004). Multivariate analyses showed independent adverse effects of an HDC regimen different from Gem-Bu-Mel (hazard ratio [HR] for EFS = 2.3, P = .0008; HR for OS = 2.7, P = .0005), positive PET at HDC (HR for EFS = 2.2, P = .004, HR for OS = 3.1, P = .0001), and >1 previous salvage line (HR for EFS = 1.9, P = .008, HR for OS = 1.8, P = .07). Gem-Bu-Mel improved outcomes in this cohort analysis of patients with refractory/poor-risk relapsed HL and merits evaluation in randomized phase III trials. [Copyright &y& Elsevier]

Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen’s antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I–Clo:Flu 10:30 mg/m2, Arm II—20:20 mg/m2, Arm III—30:10 mg/m2, and Arm IV–single-agent Clo at 40 mg/m2. The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (Thymoglobulin™). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher-dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell)-derived DNA. There has been no secondary graft failure. In the first 100 days, 1 patient died of pneumonia, and 1 of liver GVHD. We conclude that (1) Clo ± Flu with i.v. Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients; (2) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia; and (3) the median OS of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo ± Flu with i.v. Bu as pretransplant conditioning therapy are warranted. [Copyright &y& Elsevier]

We investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with advanced lymphoid malignancies undergoing autologous stem cell transplantation. Bu 130 mg/m2 was infused daily for 4 days, either as a fixed dose per body surface area (BSA), or to target an average daily area under the curve of 5000 μmol-min, determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high-dose regimen, followed by a rest day, followed by 2 daily doses of Mel at 70 mg/m2. Stem cells were infused the following day. Eighty patients had i.v. Bu delivered per test dose guidance. The median daily systemic Bu exposure was 4867 μmol-min. One hundred two patients (Hodgkin lymphoma n = 49, non-Hodgkin lymphoma n = 12, multiple myeloma = 41) with a median age of 44 years (range: 19-65 years) were treated. The 2-year overall survival and progression-free survival rates were 85% and 57%, respectively, for patients with Hodgkin lymphoma, 67% and 64%, respectively, for patients with non-Hodgkin lymphoma, and 82% and 42%, respectively, for patients with multiple myeloma. The regimen was very well tolerated with treatment-related mortality at 100 days, 1 year, and 2 years of 1%, 3%, and 3%, respectively. Intravenous Bu-Mel was well tolerated. Disease control wa encouraging, and should be explored in larger phase II studies. [Copyright &y& Elsevier]

Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of follicular non-Hodgkin lymphoma in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations reached unanimously by a panel of follicular lymphoma experts are: (1) autologous SCT is recommended as salvage therapy based on pre-rituximab data, with a significant improvement in overall survival (OS) and progression-free (PFS) survival; (2) autologous SCT is not recommended as first-line treatment for most patients because of no significant improvement in OS; (3) autologous SCT is recommended for transformed follicular lymphoma patients; (4) reduced intensity conditioning before allogeneic SCT appears to be an acceptable alternative to myeloablative regimens; (5) an HLA-matched unrelated donor appears to be as effective an HLA-matched related donor for reduced intensity conditioning allogeneic SCT. There are insufficient data to make a recommendation on the use of autologous SCT after rituximab-based salvage therapy. Eleven areas of needed research in the treatment of follicular lymphoma with SCT were identified and are presented in the review. [Copyright &y& Elsevier]

Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of myelodysplastic syndromes (MDS) in adults is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in , and were reached unanimously by a panel of MDS experts. The identified priority areas of needed future research in MDS include: (1) the benefit of using alternative donor sources (eg, cord blood; haploidentical family donors) for patients without matched sibling or unrelated donors; (2) the role and appropriate timing of allogeneic SCT in combination with hypomethylating and immunomodulatory treatment regimens; (3) randomized trials comparing the safety and efficacy of various novel agents for treating MDS; and (4) the influence of the various MDS treatment modalities on patient-reported quality-of-life outcomes. [Copyright &y& Elsevier]

Abstract: Arsenic trioxide (ATO) is synergistic with ascorbic acid (AA) and melphalan against myeloma both in vitro and in vivo. The aim of this randomized phase II trial was to determine the safety and efficacy of a combination of ATO, melphalan, and AA as preparative regimen in 48 patients undergoing autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). Forty-eight patients received melphalan 200 mg/m2 i.v. over 2 days and AA 1000 mg i.v. over 7 days in 3 treatment arms: no ATO (arm 1), ATO 0.15 mg/kg i.v. × 7 days (arm 2), and ATO 0.25 mg/kg i.v. × 7 days (arm 3). No dose-limiting toxicity, engraftment failure, or nonrelapse mortality (NRM) was seen in the first 100 days post-ASCT. Complete responses (CR) were seen in 12 of 48 patients (25%), with an overall response rate (ORR = CR + PR) of 85%. Median progression-free survival (PFS) was 25 months; median overall survival (OS) has not yet been reached. There was no significant difference in CR, PFS, or OS among the 3 treatment arms, and no adverse effect of ATO on melphalan pharmacokinetics. Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for MM. [Copyright &y& Elsevier]

Abstract: We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with i.v. busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. Sixty-seven patients received BuCy2, and subsequently, 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these nonrandomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 versus 39 years, P < .01), more often had unrelated donors (47.3% versus 20.9%, P < .0003), and had shorter median follow-up (39.7 versus 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 acute myelogenous leukemia (AML) patients receiving Melphalan-Flu (MF), treated in parallel during this time (1997-2004) were used to estimate the period effect. The MF patients'' outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in the first complete remission (CR1) had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, whereas CR1 patients younger than age 41 had a 3-year EFS of 83%. These results support replacing BuCy ± ATG with Bu-Flu ± rabbit-antithymocyte globulin (ATG), and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1. [Copyright &y& Elsevier]

Abstract: In pretransplantation therapy busulfan is typically given every 6 hours. We infused busulfan once daily at 130 mg/m2 for 4 days, performing pharmacokinetic analyses on plasma concentration-time data (n = 60 patients) on days 1, 3, and/or 4. Mean (percent coefficient of variation) maximum concentration, volume of distribution, half-life, and clearance were 3.6 μg/mL (13.8%), 22.6 L/m2 (20.2%), 2.73 hours (27.5%), and 109 mL/min/m2 (26%), respectively. The mean (percent coefficient of variation) and median daily areas under the curve were 4873 (21.8%) and 4871 μM × minute. Intrapatient variability in day-to-day estimated clearance was <20%, without day-to-day drug accumulation. The pharmokinetic parameters were compared with those from 47 patients given intravenous busulfan at ∼0.8 mg/kg (∼32 mg/m2) every 6 hours. We conclude that there is (1) a dose proportionality based on mean and median areas under the curve, (2) unchanged estimated clearance with a 4-fold increase in dose and a 2.5-fold difference in dosing rate, (3) negligible variability in dose-to-dose pharmacokinetics and negligible interdose accumulation with once-daily administration, and (4) no change in pharmokinetic parameter(s) with concomitant use of imidazole antifungals, oral contraceptives, or phenytoin. In summary, intravenous busulfan has highly predictable, linear pharmacokinetics from 32 mg/m2 (∼0.8 mg/kg) to 130 mg/m2 (∼3.2 mg/kg). Further, once-daily intravenous busulfan dosing is convenient, favoring its more widespread application. [Copyright &y& Elsevier]

Abstract: We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m2, day −4 to day −2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control. [Copyright &y& Elsevier]

Abstract: We conducted this study to determine event-free and overall survival among women with hormone-insensitive or hormone-resistant metastatic breast cancer receiving consolidation with high-dose chemotherapy (HDC) and hematopoietic support versus no further chemotherapy after intensive induction chemotherapy. Eligible patients received induction doxorubicin, 5-fluorouracil, and methotrexate (AFM) for 2 to 4 cycles. Women in complete remission were randomized to immediate HDC with cyclophosphamide, cisplatin, and carmustine followed by autologous hematopoietic support or to no further therapy. Patients on the observation arm of therapy were offered salvage HDC at the time of relapse. Partial responders to AFM were offered immediate HDC. A total of 425 patients were enrolled onto the study. The median event-free survival for women randomized to induction therapy alone was 3.8 months, compared with 9.7 months for women who completed HDC (P < .006). Of the patients randomized to observation, 5 (10%) of 51 remain event free, compared with 13 (26%) of 49 patients who underwent immediate HDC (P = .03). Of women converted to a complete response by salvage HDC after a partial response to AFM, overall survival was similar to that in women randomized to immediate HDC. Follow-up is now in excess of 5 years. The 5-year event-free survival is 15% (95% confidence interval, 12%-18%), and the 5-year overall survival is 20% (95% confidence interval, 17%-25%). Immediate HDC after a complete response to AFM produced some durable long-term responses in hormone-insensitive/-resistant metastatic breast cancer. Salvage HDC converted 30% of partial responders to complete responders with similar survivals. The addition of novel targeted therapies to intensive-dose chemotherapy regimens may further improve survival in metastatic breast cancer. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150–550 mg/m2 infused over 2 hours on day −6), melphalan (150–165 mg/m2 infused over 15 minutes from day −5 to −3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day −5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m2, combined with melphalan (150 mg/m2) and carboplatin (1000 mg/m2). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150–550 mg/m2). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7–72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation. [Copyright &y& Elsevier]

Clinical research published since the 2001 evidence-based review on the role of hematopoietic stem cell transplantation (SCT) in the treatment of diffuse large B cell lymphoma (DLBCL) in adults is presented and critically evaluated in this update. Treatment recommendations that remain unchanged from the original review include: (1) autologous SCT as salvage therapy is recommended for patients with chemosensitive relapsed DLBCL; and (2) autologous SCT is not recommended for patients who achieve a partial response to an abbreviated induction regimen. New treatment recommendations based on new published data include: (1) autologous SCT as first-line therapy is not recommended for any IPI group; (2) planned tandem or multiple sequential autologous SCT is not recommended; (3) peripheral blood is the standard stem cell source for autologous SCT; (4) age is not a contraindication for autologous SCT, although outcomes in older adults are not as good as in younger adults. There are insufficient data to make recommendations on the routine use of rituximab maintenance after autologous SCT, autologous versus allogeneic SCT, fewer versus more cycles of induction therapy prior to autologous SCT, or the use of reduced intensity versus myeloablative conditioning regimens. Areas of needed research in the treatment of DLBCL with SCT were identified and are presented in the review. [ABSTRACT FROM AUTHOR]