melphalan and Renal-Insufficiency

The availability of novel drugs with different and innovative mechanisms of action such as proteasome inhibitors such as bortezomib and immunomdulatory agents as thalidomide and lenalidomide have changed the landscape of the treatment of patients with newly diagnosed multiple myeloma, allowing the development of several new therapeutic regimens both for transplant-eligible and -ineligible patients. Among these new agents, lenalidomide has become one of the most commonly used in these patients. In this article, we review the current state-of-the-art of different induction and maintenance lenalidomide-containing regimens administered in transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma. We also discuss the safety profile and potential long-term side effects of this drug and analyze its utility in certain subgroups of patients like those with high-risk disease or different degrees of renal impairment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Prednisone; Renal Insufficiency; Risk Factors; Stem Cell Transplantation; Thalidomide

Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.

Topics: Aged; Amyloidosis; Bence Jones Protein; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney; Lenalidomide; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Pyrazines; Renal Insufficiency; Thalidomide

Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.

Topics: Boronic Acids; Bortezomib; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Melphalan; Multiple Myeloma; Prognosis; Pyrazines; Renal Insufficiency; Thalidomide; Transplantation, Autologous

Autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Gene Expression Profiling; History, 20th Century; History, 21st Century; Humans; Immunotherapy; Melphalan; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prognosis; Renal Insufficiency; Salvage Therapy; Thalidomide; Transplantation, Autologous; Transplantation, Homologous

Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal impairment with light-chain deposit disease was diagnosed in a 51-year-old man. Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone) a partial remission was achieved. Peripheral blood stem cells (PBSC) were then collected following mobilization with cyclophosphamide and recombinant human granulocyte colony-stimulating factor and enriched for CD34-positive cells by immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC transplantation his renal function improved, and the patient has been in in continuous complete remission for 1 year. Thus, high-dose chemotherapy can be safely administered to patients with multiple myeloma and severe renal impairment. Our findings confirm previous reports summarized in the current presentation.

Topics: Antineoplastic Agents, Alkylating; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Kidney; Male; Melphalan; Middle Aged; Multiple Myeloma; Renal Insufficiency

We retrospectively reviewed the impact of impaired renal function (eGFR < 45 ml/min/SA) on post-transplant outcomes in patients receiving ASCT for AL amyloidosis. Patients were grouped into two cohorts, those with normal renal function (NRF) eGFR ≥ 45 ml/min (n = 568) and those with impaired renal function (IRF) eGFR < 45 ml/min (n = 87). Patients with IRF had higher renal stage (>Stage 1: 100% IRF vs 37% NRF, p < 0.0001) and the majority received conditioning with melphalan <200 mg/m

Topics: Adult; Aged; Autografts; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Renal Dialysis; Renal Insufficiency; Survival Rate; Transplantation Conditioning

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Creatinine; Dexamethasone; Disease Progression; Drug Administration Schedule; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Renal Insufficiency; Severity of Illness Index; Survival Analysis; Thalidomide; Treatment Outcome

The purpose of this study was to develop a high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) regimen for treatment of patients with ovarian carcinoma that could be administered in an outpatient setting. Fourteen patients with advanced ovarian (n = 9) or breast (n = 5) carcinoma, who had failed conventional chemotherapy, were entered into a dose-escalation trial to determine the maximum tolerated dose (MTD) of carboplatin that could be administered with fixed doses of melphalan (160 mg/m2) and mitoxantrone (50 mg/m2). Twenty-five additional patients were included in a phase II trial at the MTD. Two of two patients had grade 4 severe regimen-related toxicities (RRT), one fatal, at a dose level of 1600 mg/m2. Two of 29 patients (6.9%) treated at the MTD (carboplatin, 1400 mg/m2) died of RRT. All three patients who died of toxicity had a calculated AUC for carboplatin >30 mg/ml/min. Thirty-one patients with ovarian cancer who had failed chemotherapy were treated, 24 at the MTD. Fourteen of 20 patients (70%) with ovarian carcinoma with evaluable disease achieved a CR and seven (35%) are alive disease-free a median of 20 months (range, 7-26). Five of seven patients with ovarian cancer who had failed chemotherapy but were rendered clinically disease-free following surgery survive without progression a median of 13 months (range, 9-19). Eight of 16 (50%) platinum-resistant and 4/12 (33%) platinum-sensitive patients with ovarian cancer survive disease-free.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Breast Neoplasms; Carboplatin; Carcinoma; Cerebral Hemorrhage; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Life Tables; Lung Diseases, Interstitial; Melphalan; Middle Aged; Mitoxantrone; Ovarian Neoplasms; Renal Insufficiency; Salvage Therapy; Treatment Outcome

Autologous stem cell transplant (ASCT) is a feasible treatment option for multiple myeloma (MM) patients with renal insufficiency; however, these patients tend to experience higher rates of drug toxicity and transplant-related mortality (TRM) during ASCT. Recent adoption of bortezomib-based induction regimens and dose reduction of melphalan during conditioning may improve outcomes in this population. In this single center retrospective study, we compared the toxicity and survival outcomes of 96 MM patients with renal insufficiency undergoing ASCT between two eras: 1998-2007 and 2008-2016. The proportion of dialysis dependent patients was similar in both groups (49 and 45%). We found no TRM in those transplanted more recently as compared with 13% in the older era of ASCT. There were significantly more high grade (grades 3-4) toxicities in the older era of ASCT including high grade electrolyte abnormalities, mucositis, delirium, and bleeding. Patients transplanted more recently had significantly higher overall response rate (ORR) as well as deeper responses to ASCT (≥VGPR in 79% vs 39%). Progression-free survival (PFS) was prolonged by 26 months in the more recent era compared with the older era. Overall, improvements in treatment regimens have resulted in reduced TRM and toxicities for patients with renal insufficiency undergoing ASCT.

Topics: Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Renal Insufficiency; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

To assess the safety and efficacy of autologous haematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients with dialysis-dependent renal failure.. During a period from May 2010 to December 2016 fourteen MM patients with dialysis-dependent renal failure aged 48 to 65 years underwent auto-HSCT. After the induction therapy complete response, very good partial response, partial response were documented in 64, 29, 7% of patients, respectively. In no case was a renal response achieved. Haematopoietic stem cell mobilization in most patients (13/14) was performed according to the scheme: G-CSF 10 g/kg. Melphalan in 3 dosages was used as pre-transplant conditioning: 100, 140 and 200 mg/m2; 13 patients underwent a single and in one case underwent a tandem auto-HSCT against the background of hemodialysis. Evaluation of the antitumor and renal response was assessed on the 100th day after auto-HSCT. Subsequently, against the background of programmed hemodialysis and in the setting of high-dosed melphalan (100200 mg/m2), 13 patients underwent a single and one patient underwent a tandem auto-HSCT. At +100 days after auto-HSCT, an antitumor response and renal response were assessed.. The period of agranulocytosis after auto-HSCT was from 5 to 12 days (median 8,5) and was accompanied by infectious complications, cardiac and neurological dysfunctions. At +100 days after auto-HSCT, the complete response was confirmed in 71% patients and very good partial response was confirmed in 29% patients. The minimal renal response was registered in 2 patients (14%), hemodialysis was stopped. The transplant-related mortality was absent. After a median follow-up of 53 months 5-year progression-free survival was 59%, and overall survival was 93%.. Carrying out auto-HSCT in patients with dialysis-dependent renal failure contributed to the achievement of a minimal renal response in 14% of cases, which allowed these patients to stop hemodialysis. Patients whose conditioning regimen was performed using melphalan at a dose of 200 mg/m2showed more frequent complications in the early post-transplant period compared to patients who received a lower dose of melphalan (100140 mg/m2). Auto-HSCT in MM patients with dialysis-dependent renal failure is a feasible and effective treatment method, which in some cases contributes to independence from hemodialysis.. Цель.Оценить безопасность и эффективность трансплантации аутологичных стволовых клеток (ауто-ТГСК) крови больным множественной миеломой (ММ) с диализ-зависимой почечной недостаточностью (ПН). Материалы и методы.В ретроспективное исследование включены 14 больных ММ с диализ-зависимой ПН в возрасте от 48 до 65 лет, которым с мая 2010 по август 2018 г. выполнена ауто-ТГСК. После индукционного этапа лечения полная ремиссия, очень хорошая частичная ремиссия, частичная ремиссия документированы у 64, 29, 7% больных соответственно. Ни в одном случае почечный ответ не достигнут. Мобилизация стволовых кроветворных клеток у большинства больных (13/14) проводилась по схеме Г-КСФ 10 мкг/кг. В качестве предтрансплантационного кондиционирования использовался мелфалан в 3 дозировках: 100, 140 и 200 мг/м2; 13 больным выполнена однократная и в одном случае тандемная ауто-ТГСК на фоне программного гемодиализа. Оценка противоопухолевого и почечного ответа проводилась на 100-й день после ауто-ТГСК. Результаты.Период миелотоксического агранулоцитоза после ауто-ТГСК длился от 5 до 12 сут (медиана 8,5 дня) и сопровождался инфекционными эпизодами, кардиальной и неврологической дисфункциями. На +100-й день ауто-ТГСК полная ремиссия диагностирована в 71% случаев, очень хорошая частичная ремиссия у 29% больных. Почечный ответ зарегистрирован у 2 (14%) больных, программный гемодиализ им отменен и возобновления заместительной почечной терапии не потребовалось в течение 24100 мес после ауто-ТГСК. Летальность, связанная с трансплантацией, отсутствовала. При медиане наблюдения 53 мес 5-летняя выживаемость без прогрессии составила 59%, общая выживаемость 93%. Заключение.Проведение ауто-ТГСК больным с диализ-зависимой ПН способствовало достижению минимального почечного ответа в 14% случаев, что позволило прекратить выполнение гемодиализа этим пациентам. У больных, предтрансплантационное кондиционирование которым проведено с применением мелфалана в дозе 200 мг/м2, отмечены более частые осложнения в раннем посттрансплантационном периоде по сравнению с пациентами, получившими меньшую дозу мелфалана (100140 мг/м2). Ауто-ТГСК является эффективным методом лечения больных ММ с диализ-зависимой ПН, в ряде случаев способствующим достижению независимости от гемодиализа.

Topics: Aged; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Renal Dialysis; Renal Insufficiency; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Autografts; Carmustine; Cytarabine; Humans; Lymphoma, B-Cell; Male; Melphalan; Podophyllotoxin; Renal Insufficiency; Severity of Illness Index; Stem Cell Transplantation; Transplantation Conditioning

Topics: Adult; Aged; Creatinine; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Renal Insufficiency; Survival Analysis

Topics: Antineoplastic Agents, Alkylating; Creatine; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Renal Insufficiency; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

We report a 50-year-old female patient with diffuse and rapidly progressing splenic calcification. She had developed nephrotic syndrome and been diagnosed with renal amyloid light-chain amyloidosis in 2010. Although she had been given melphalan and dexamethasone therapy and high-dose melphalan followed by autologous blood stem-cell transplantation, her renal function worsened and hemodialysis was started in May 2011. Since November 2011, splenic calcification, probably associated with amyloidosis, had progressed, and diffuse calcification was observed throughout the splenic area in September 2012. During the same period, the patient was hospitalized for thrombocytopenia. Although splenic dysfunction due to calcification was suspected to be the cause of thrombocytopenia, the association between the two could not be established. The platelet count rose with an improvement in hepatic congestion due to reinforced fluid removal during dialysis.

Topics: Amyloidosis; Calcinosis; Dexamethasone; Disease Progression; Female; Humans; Melphalan; Middle Aged; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Renal Insufficiency; Splenic Diseases; Thrombocytopenia; Transplantation, Autologous

The role of thalidomide, bortezomib and lenalidomide in multiple myeloma patients presenting with renal impairment was evaluated in 133 consecutive newly diagnosed patients who were treated with a novel agent-based regimen. A significant improvement of renal function (renalPR (renal partial response)) was observed in 77% of patients treated with bortezomib, in 55% with thalidomide and in 43% with lenalidomide (P=0.011). In multivariate analysis, bortezomib-based therapy was independently associated with a higher probability of renal response compared with thalidomide- or lenalidomide-based therapy. Other important variables included eGFR (estimated glomerular filtration rate) ≥30 ml/min, age ≤65 years and myeloma response. Patients treated with bortezomib achieved at least renalPR in a median of 1.34 months vs 2.7 months for thalidomide and >6 months for lenalidomide-treated patients (P=0.028). In multivariate analysis bortezomib-based therapy, higher doses of dexamethasone (≥160 mg during the first month of treatment), an eGFR ≥30 ml/min and age ≤65 years were independently associated with shorter time to renal response. In conclusion, bortezomib-based therapies may be more appropriate for the initial management of patients with myeloma-related renal failure; however, thalidomide and lenalidomide are also associated with significant probability of improvement of their renal function.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Pyrazines; Renal Insufficiency; Survival Rate; Thalidomide; Vincristine

Renal impairment (RI) is a frequent complication with higher incidence of infections and an important prognostic factor for survival. Melphalan clearance is renal function dependent whereas cyclophosphamide is renal function independent. We investigated which combination regimen should be selected between melphalan-combining regimen (MPT) or cyclophosphamide-combining regimen (TCD) in elderly multiple myeloma (MM) patients with RI. Between 2005 and 2009, 157 newly diagnosed MM patients with RI were included comparing MPT with TCD therapy as initial treatment. Seventy-four patients were given MPT regimen, and 83 patients were given TCD regimen. Baseline characteristics were similar between the MPT and TCD groups. Analysis of different cutoff levels between 25% and 75% quartiles using log-rank test determined that glomerular filtration rate (GFR), 40 ml/min/1.73 m(2) as the cutoff point, yielded the highest difference in event-free survival (EFS) and overall survival (OS). The MPT subgroup with low GFR (GFR <40 ml/min/1.73 m(2)) had poorer response rates than others. The incidence of neutropenia and infection with febrile neutropenia were higher in the MPT subgroup with low GFR than the others (p = 0.016, p < 0.001). Furthermore, mortality due to the infection was higher in the MPT subgroup with low GFR than the others (p < 0.001). EFS was lower in the MPT subgroup with low GFR than the others (p < 0.001). OS was lower in the MPT subgroup with low GFR than the others (p < 0.001). In newly diagnosed elderly MM patients with RI, TCD regimen would be an effective and tolerable treatment option due to the combination of cyclophosphamide independent to renal function and dexamethasone effective for RI.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Creatinine; Cyclophosphamide; Disease-Free Survival; Female; Glomerular Filtration Rate; Humans; Male; Melphalan; Multiple Myeloma; Renal Insufficiency; Retrospective Studies; Treatment Outcome

Topics: Age Factors; Aged; Antineoplastic Agents; Boronic Acids; Bortezomib; Dexamethasone; Humans; Melphalan; Multiple Myeloma; Prognosis; Pyrazines; Renal Insufficiency; Risk Factors; Stem Cell Transplantation; Transplantation, Homologous

We report here a 50-years old female with multiple myeloma-associated chronic renal failure who underwent high-dose chemotherapy supported by autologous hematopoietic stem cell transplantation. She developed progressive encephalopathy on day 5 progressing to coma despite hemodialysis and no obvious organ failure. She finally recovered after a single 1-liter plasma exchange. The final diagnosis was metabolic encephalopathy due to hypercytokinemia, particularly high serum TNF levels. We discuss here the pathogenesis and raise an alert for monitoring cytokine levels in patients with renal failure undergoing high-dose chemotherapy.

Topics: Brain Diseases, Metabolic; Coma; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Plasma Exchange; Renal Dialysis; Renal Insufficiency; Treatment Outcome; Tumor Necrosis Factor-alpha

A 52-year-old patient with atypical plasmocytoma presented with a bilateral serous detachment of the retina as well as a huge detachment of the pigment epithelium (PE) in the periphery. Shortly thereafter the PE ruptured. In the left eye this led to substantial central macular fibrosis.. The clinically healthy patient showed a nephrotic syndrome; neither typical monoclonality was detectable nor was erythropoiesis or myelopoiesis reduced.. To avoid further reduction of VA pars plana vitrectomy (ppV) with silicone oil tamponade and laser coagulation was performed. Clinical findings were reduced significantly and VA was stabilized for 2.5 years.. PE detachments and serous retinal detachments in patients with nephrotic syndrome are only mentioned in a few cases. However, a peripheral rupture of the PE to this extent seems to be very rare. Early ppV with silicone oil and laser coagulation may prevent further macular fibrosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Choroidal Neovascularization; Comorbidity; Female; Fluorescein Angiography; Follow-Up Studies; Humans; Kidney Neoplasms; Laser Coagulation; Lenses, Intraocular; Melphalan; Middle Aged; Nephrotic Syndrome; Ophthalmoscopy; Plasmacytoma; Postoperative Complications; Prednisolone; Recurrence; Renal Insufficiency; Reoperation; Retinal Detachment; Retinal Perforations; Silicone Oils; Visual Acuity; Vitrectomy

A 27-year-old man with aplastic anemia and renal insufficiency requiring dialysis underwent allogeneic PBSCT. The preparative regimen consisted of melphalan, ATG and TLI. GVHD prophylaxis consisted of cyclosporine and prednisolone. He was dialyzed prior to administration of melphalan and at 24 and 72 h after it. Otherwise, the dialysis schedule was unchanged, at three times a week. Engraftment was rapid. Regimen-related toxicity was minimal. Pharmacokinetic parameters of melphalan were not significantly altered with its plasma half-life 1.5 h. Patients with renal failure can receive allogeneic HSCT, and a combination of melphalan, ATG and TLI may serve as an alternative to CY and ATG.

Topics: Adult; Anemia, Aplastic; Antineoplastic Combined Chemotherapy Protocols; Cross Infection; Graft Survival; Graft vs Host Disease; Humans; Lymphatic Irradiation; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Renal Dialysis; Renal Insufficiency; Transplantation Conditioning; Transplantation, Homologous

Data are presented on 81 multiple myeloma (MM) patients with renal failure (creatinine > 176.8 micromol/l) at the time of autologous stem cell transplantation (auto-SCT), including 38 patients on dialysis. The median age was 53 years (range: 29-69) and 26% had received more than 12 months of prior chemotherapy. CD34+ cells were mobilized with granulocyte colony-stimulating factor (G-CSF) alone (n = 51) or chemotherapy plus G-CSF (n = 27), yielding medians of 10 and 16 x 106 CD34+ cells/kg respectively (P = 0.003). Sixty patients (27 on dialysis) received melphalan 200 mg/m2 (MEL-200). Because of excessive toxicity, the subsequent 21 patients (11 on dialysis) received MEL 140 mg/m2 (MEL-140). Thirty-one patients (38%) completed tandem auto-SCT, including 11 on dialysis. Treatment-related mortality (TRM) was 6% and 13% after the first and second auto-SCT. Median times to absolute neutrophil count (ANC) > 0.5 x 109/l and to platelets > 50 x 109/l were 11 and 41 d respectively. Non-haematological toxicities included mucositis, pneumonitis, dysrhythmias and encephalopathy. At a median follow up of 31 months, 30 patients have died. Complete remission (CR) was achieved in 21 patients (26%) after first SCT and 31 patients (38%) after tandem SCT. Two patients discontinued dialysis after SCT. Median durations of complete remission (CR) and overall survival (OS) have not been reached; probabilities of event-free survival (EFS) and OS at 3 years were 48% and 55% respectively. Dialysis dependence and MEL dose did not affect EFS or OS. Sensitive disease prior to SCT, normal albumin level and younger age were independent prognostic factors for better OS. In conclusion, renal failure had no impact on the quality of stem cell collections and did not affect engraftment. MEL-140 had an acceptable toxicity and appeared equally effective as MEL-200. In the setting of renal failure, the role of auto-SCT early in the disease course and benefits of tandem SCT require further evaluation.

Topics: Adult; Aged; Antigens, CD34; Antineoplastic Agents, Alkylating; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Renal Dialysis; Renal Insufficiency; Transplantation, Autologous; Treatment Outcome

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Diphosphonates; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Interferons; Melphalan; Multiple Myeloma; Oncology Service, Hospital; Patient Care Planning; Patient Education as Topic; Patient Selection; Prednisolone; Renal Insufficiency

Isolated perfusion of the extremities with high-dose tumour necrosis factor alpha (TNF-alpha) plus melphalan leads to dramatic tumour response in patients with irresectable soft tissue sarcoma or multiple melanoma in transit metastases. We developed in vivo isolated organ perfusion models to determine whether similar tumour responses in solid organ tumours can be obtained with this regimen. Here, we describe the technique of isolated kidney perfusion. We studied the feasibility of a perfusion with TNF-alpha and assessed its anti-tumour effects in tumour models differing in tumour vasculature. The maximal tolerated dose (MTD) proved to be only 1 microg TNF-alpha. Higher doses appeared to induce renal failure and a secondary cytokine release with fatal respiratory and septic shock-like symptoms. In vitro, the combination of TNF-alpha and melphalan did not result in a synergistic growth-inhibiting effect on CC 531 colon adenocarcinoma cells, whereas an additive effect was observed on osteosarcoma ROS-1 cells. In vivo isolated kidney perfusion, with TNF-alpha alone or in combination with melphalan, did not result in a significant anti-tumour response in either tumour model in a subrenal capsule assay. We conclude that, because of the susceptibility of the kidney to perfusion with TNF-alpha, the minimal threshold concentration of TNF-alpha to exert its anti-tumour effects was not reached. The applicability of TNF-alpha in isolated kidney perfusion for human tumours seems, therefore, questionable.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Kidney; Male; Melphalan; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Rats; Renal Insufficiency; Shock, Septic; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

We describe two patients admitted to our hospital because of renal failure. We diagnosed multiple myeloma in both. One patient had high peripheral blood eosinophilia, that normalized during therapy. The patients were treated with melphalan and prednisone, hemodialysis and one patient with recombinant human erythropoietin. Both patients responded to that treatment: after 7 months the number of plasma cell in bone marrow decreased from 65 to 10% in the first patient, and from 38 to 4% in the second patient. They returned to work and were on maintenance hemodialysis 2 times weekly. The patients have been observed for 21 months.

Topics: Aged; Erythropoietin; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Treatment Outcome

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Renal Insufficiency; Transplantation, Autologous