melphalan and Obesity

In September 2016 in Lille, France, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th Allogeneic Stem Cell Transplantation Clinical Practices Harmonization Workshop Series. Our work group focused on chemotherapy drug dose adaptation for hematopoietic stem cell transplantation patients presenting a comorbidity. The purpose of this workshop was to provide recommendations on chemotherapy drug dose adaptation for patient populations receiving hematopoietic stem cell transplantation who also had the following comorbidities: obesity, chronic kidney disease and hepatopathy.

Topics: Adult; Age Factors; Busulfan; Child; Comorbidity; Cyclophosphamide; Etoposide; France; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Liver Diseases; Melphalan; Obesity; Renal Insufficiency, Chronic; Societies, Medical; Surveys and Questionnaires; Thiotepa; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. This article reviews the current published literature on the dosing of pharmacologic agents used for HCT preparative regimens with specific focus on the obese patient population. The review found that dose adjustments for obesity have, to date, been based empirically or extrapolated from published data in the nontransplantation patient population. As a result, the Committee determined that clear standards or dosing guidelines are unable to be made for the obese population because Level I and II evidence are unavailable at this time. Instead, the Committee provides a current published literature review to serve as a platform for conditioning agent dose selection in the setting of obesity. A necessary goal should be to encourage future prospective trials in this patient population because further information is needed to enhance our knowledge of the pharmacokinetics and pharmacodynamics of conditioning agents in the setting of obesity.

Topics: Antilymphocyte Serum; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Cytarabine; Drug Administration Schedule; Drug Dosage Calculations; Etoposide; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Myeloablative Agonists; Obesity; Transplantation Conditioning

Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose melphalan. Despite 30 years of clinical and pharmacokinetic (PK) experience with high-dose melphalan, and its continuing central role as cytoreductive therapy for large numbers of patients with myeloma, the pharmacodynamics and pharmacogenomics of melphalan are still in their infancy. The addition of protectant agents such as amifostine and palifermin allows dose escalation to 280 mg/m(2), but at these doses it is cardiac, rather than gut, toxicity that is dose-limiting. Although combination with additional alkylating agents is feasible, the additional TRM may not be justified when so many post-consolidation therapies are available for myeloma patients. Current research should optimise the delivery of this single-agent chemotherapy. This includes the use of newer formulations and real-time PKs. These strategies may allow a safe and effective platform for adding synergistic novel therapies and provide a window of lymphodepletion for the addition of immunotherapies.

Topics: Amifostine; Antineoplastic Agents, Alkylating; Fibroblast Growth Factor 7; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Neoplasms; Obesity; Reproducibility of Results

Topics: Adult; Aged; Allografts; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Obesity; Podophyllotoxin; Prospective Studies; Transplantation Conditioning

High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing.. Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM.. Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m. The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.

Topics: Adult; Cohort Studies; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Obesity; Transplant Recipients

Topics: Adult; Humans; Melphalan; Multiple Myeloma; Obesity; Transplantation, Autologous

Limited guidance exists for dosing melphalan for autologous stem cell transplantation (ASCT) in the obese patient population, because the current literature reports conflicting clinical outcomes between obese and nonobese patients. In 2014, the American Society for Blood and Marrow Transplantation published conditioning chemotherapy dosing guidelines for obese patients and recommended dosing of melphalan using actual body weight (ABW) in the body surface area calculation. The practice at Barnes-Jewish Hospital has consistently been to dose melphalan using adjusted body weight (AdBW), with a 20% correction when a patient weighs ≥120% of his or her ideal body weight (IBW). The purpose of this study was to compare outcomes of melphalan ASCT in patients with multiple myeloma between obese (≥120% IBW) and nonobese (<120% IBW) populations. This retrospective, single-center study included adult patients with multiple myeloma undergoing first ASCT with melphalan conditioning between January 2009 and December 2012. Patient demographic data, transplantation characteristics, and clinical outcomes were collected. The primary outcome was 3-year event-free survival (EFS). Secondary outcomes included response at 100 days post-transplantation, 3-year overall survival, treatment-related mortality (TRM), time to neutrophil engraftment, and hospital length of stay (LOS). To ensure that melphalan dosage adjustment in the obese population did not impact efficacy, the primary outcome was assessed using a noninferiority design, with a predetermined noninferiority margin of 7%. Assuming a 70% 3-year EFS in the nonobese population, a noninferiority margin of 7%, a power of 80%, and an α value of .05, an analysis of 280 patients was required. A total of 270 patients, including 171 (63%) obese patients and 99 (37%) nonobese patients, met our inclusion criteria. Baseline characteristics were well matched between the 2 cohorts, including high-risk cytogenetics, disease severity at diagnosis, and use of maintenance therapy, with the only detectable differences related to weight itself. The 3-year EFS was 41% for the total cohort, with fewer events occurring in the obese cohort compared with the nonobese cohort (51% versus 40%; P = .0025). The 95% lower confidence limit established noninferiority. High-risk cytogenetics, disease severity at diagnosis, and therapy response pre- and post-ASCT were all associated with significantly shorter EFS. No between-group differences in TRM, time to

Topics: Aged; Autografts; Body Weight; Disease-Free Survival; Female; Humans; Length of Stay; Male; Melphalan; Middle Aged; Multiple Myeloma; Obesity; Retrospective Studies; Stem Cell Transplantation; Survival Rate

After ilioinguinal radical lymph node dissection (RLND), the therapy for lymph fistulas constitutes a challenge. Risk factors for the genesis of lymph fistulas have not been sufficiently evaluated. We investigated possible factors that could influence the development of lymph fistulas in patients suffering from malignant melanoma after iloinguinal RLND.. The analysis was related to patients with intransit and lymphonodal metastasised malignant melanoma of the lower limb, who underwent RLND and isolated limb perfusion (ILP). Prospective data acquisition from patients undergoing ilioinguinal RLND and ILP in a one-step approach was performed. The association of lymph fistulas to risk factors was calculated using chi-squared, linear-by-linear test and ROC curves. As possible risk factors we investigated the presence of prior surgery and diabetes mellitus type II in the medical history, chemotherapeutics, patient age and the body mass index (BMI).. Postoperative lymph fistula occurred in 11 of 108 patients (10.2%). A significant association to lymph fistulas was found in BMI (30.2± 7.0 kg/m (2), p<0.02). Other parameters, such as prior surgery (82% vs. 71%), diabetes mellitus type II (9% vs. 11.7%), chemotherapeutics and patient age (mean 67.8 vs. 62.4 years) showed no influence.. Our results indicate that the incidence of lymph fistulas after RLND and ILP of malignant melanoma of the lower limb was associated with an increased BMI. Thus, for the prevention of lymph fistulae, an initially alternative wound-closure dressing like vacuum assisted closure (V.A.C.) dressing could be of clinical relevance for obese patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Female; Fistula; Humans; Inguinal Canal; Leg; Lymph Node Excision; Lymphatic Diseases; Male; Melanoma; Melphalan; Middle Aged; Negative-Pressure Wound Therapy; Neoplasm Staging; Obesity; Postoperative Complications; Retrospective Studies; Risk Factors; Skin Neoplasms; Tumor Burden; Tumor Necrosis Factor-alpha

Obesity has implications for chemotherapy dosing and selection of patients for therapy. Autologous hematopoietic stem cell transplant (AutoHCT) improves outcomes for patients with multiple myeloma, but optimal chemotherapy dosing for obese patients is poorly defined. We analyzed the outcomes of 1087 recipients of AutoHCT for myeloma reported to the CIBMTR between 1995 and 2003 who received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal, overweight, obese, or severely obese. There was no overall effect of BMI on progression-free survival (PFS), overall survival (OS), progression, or nonrelapse mortality (NRM). In patients receiving melphalan and TBI conditioning, obese and severely obese patients had superior PFS and OS compared with normal and overweight patients, but the clinical significance of this finding is unclear. More obese patients were more likely to receive a reduced dose of melphalan, but there was no evidence that melphalan or TBI dosing variability affected PFS. Therefore, current common strategies of dosing melphalan do not impair outcomes for obese patients, and obesity should not exclude patients from consideration of autologous transplantation. Further research is necessary to optimize dosing of both chemotherapy and radiation in obese patients.

Topics: Body Mass Index; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Obesity; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation