melphalan and Liver-Diseases

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

The purpose of this study was to determine the incidence of veno-occlusive disease (VOD) after a high-dose regimen of busulfan, melphalan, and thiotepa and the risk factors for a more severe outcome. We followed 253 consecutive patients with malignant disorders who received autologous transplants after stem cell harvest followed by 12 mg/kg busulfan, 100 mg/m2 melphalan, and 500 mg/m2 thiotepa. Diagnosis of VOD was based on weight gain, hepatomegaly, and jaundice. Risk factors for moderate or severe VOD were identified using logistic regression models. VOD occurred in 70 of 253 patients (28%), of whom 31 (12%) had moderate and 11 (4%) severe VOD. The median day of onset of hyperbilirubinemia was day 9, significantly later than the onset of jaundice after our cyclophosphamide-based regimens (p < 0.001). Resolution of weight gain and jaundice, followed by their reappearance several weeks later, occurred in 23 of 70 patients with VOD and was an adverse prognostic sign. Risk factors for moderate or severe VOD were a diagnosis of lymphoma or myeloma (odds ratio [OR] 2.65 compared with breast cancer), tumor involvement in the liver (OR 3.95), fever in the month before transplant (OR 3.32), and prior radiation therapy (OR 2.70). We conclude that VOD after busulfan, melphalan, and thiotepa was less frequent and less severe and developed later than VOD after our historical cyclophosphamide-based regimens. Significant risk factors included a diagnosis other than breast cancer, hepatic metastases, persistent fever, and prior radiation therapy. This study suggests that alkylating agents of comparable overall toxicity differ in their liver toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Busulfan; Child; Child, Preschool; Cyclophosphamide; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Liver Diseases; Male; Melphalan; Middle Aged; Multiple Organ Failure; Multivariate Analysis; Radiotherapy; Risk Factors; Survival Rate; Thiotepa; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

High-dose melphalan and autologous stem cell transplantation (HDM) is an effective treatment for systemic amyloid light chain (AL) amyloidosis but the eligibility criteria exclude many patients with this disorder. The aim of this study was to determine appropriate treatment strategies for systemic AL amyloidosis according to each patient's clinical condition in Japan.. Historical cohort study. Fifty-three patients with systemic AL amyloidosis (those with malignancies were excluded) were treated in our hospital with HDM (15 patients), melphalan + prednisolone (MP) (17 patients), vincristine + adriamycin + dexamethasone (VAD) (11 patients), or supportive treatment (no chemotherapy, 10 patients). We compared the survival rates among these treatment groups.. Mean survival was significantly longer in the HDM group than in the other three groups (P < 0.01, log-rank test). This trend remained the same when patients were divided into those with and without cardiac amyloid involvement. Furthermore, in patients with heart involvement, survival in the VAD therapy group was significantly inferior to that in the MP therapy group (P < 0.01 by log-rank test). Significant factors related to the survival rate included the presence or absence of heart involvement and treatment modality.. HDM should be considered the treatment of choice in eligible patients with systemic AL amyloidosis even in the presence of cardiac amyloidosis. If HDM is not eligible, indications for VAD therapy should be carefully evaluated in patients with cardiac amyloidosis.

Topics: Adult; Aged; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Combined Modality Therapy; Dexamethasone; Doxorubicin; Female; Heart Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Liver Diseases; Male; Melphalan; Middle Aged; Prognosis; Survival Rate; Vincristine

The prognosis in amyloid light chain (AL)-amyloidosis and multiorgan involvement is poor, with a high-treatment-related mortality after high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Some patients, however, might benefit from the therapy. We report a case of cardiac AL-amyloidosis with multiorgan involvement where the progressive cardiomyopathy was halted after successful treatment with HDM/SCT in 2001. The patient is in an excellent cardiac condition with a good quality of life, receiving treatment with angiotensinogen receptor blockers and a flexible diuretics regimen at follow-up after 10 years.

Topics: Amyloidosis; Female; Follow-Up Studies; Gastrointestinal Diseases; Heart Diseases; Humans; Immunoglobulin Light Chains; Liver Diseases; Melphalan; Middle Aged; Myeloablative Agonists; Myocardium; Stem Cell Transplantation

High-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation has been shown to result in durable hematologic response and prolonged overall survival in systemic AL amyloidosis. In this retrospective study, we evaluated clinical and hematologic responses in 69 patients with predominant liver involvement who were treated with high-dose intravenous melphalan and autologous stem cell transplantation from 1998 to 2006. Nine patients (13%) died from treatment-related mortality, similar to patients without hepatic involvement. The overall survival was 81% at one year and 61% at five years, by Kaplan-Meier estimates. A hematologic complete response was achieved by 53% (31/58) of patients at one year. A hepatic response occurred in 57% (33/58) at one year after high-dose intravenous melphalan and autologous stem cell transplantation and 63% (19/30) at two years after high-dose intravenous melphalan and autologous stem cell transplantation. In conclusion, hepatic disease improves in almost 2/3 patients treated with high-dose intravenous melphalan and autologous stem cell transplantation who have a complete or partial hematologic response to treatment.

Topics: Adult; Aged; Amyloidosis; Female; Humans; Liver; Liver Diseases; Male; Melphalan; Middle Aged; Myeloablative Agonists; Retrospective Studies; Stem Cell Transplantation; Treatment Outcome

A 55-year-old woman with primary Immunoglobulin light chain (AL) systemic amyloidosis died due to spontaneous rupture of her liver following treatment with high-dose melphalan and autologous stem cell transplant (HDM/SCT). She was first diagnosed after developing nephrotic-range proteinuria. Spontaneous rupture of her liver occurred 10 days after treatment with HDM/SCT and was complicated by septic shock. She was not eligible for surgical intervention and died shortly after. Amyloid fibrils were extracted from the autopsied liver sample (05-135L) and the biochemical nature of the fibrils was analyzed using electrophoretic and immunohistochemical techniques. Our testing showed that the fibrils were composed of immunoglobulin lambda light chains that were not glycosylated. While the liver is often involved in AL amyloidosis, this is the first documented case of a spontaneous hepatic rupture in a patient during treatment with HDM/SCT. A literature review of spontaneous liver rupture in patients with amyloidosis is presented.

Topics: Amyloid; Amyloidosis; Electrophoresis, Polyacrylamide Gel; Fatal Outcome; Female; Humans; Immunohistochemistry; Liver Diseases; Melphalan; Middle Aged; Rupture, Spontaneous; Stem Cell Transplantation; Transplantation Conditioning

Topics: Abdomen; Aged; Amyloidosis; Anti-Inflammatory Agents; Biopsy; Glucocorticoids; Hepatomegaly; Humans; Liver; Liver Diseases; Male; Melphalan; Myeloablative Agonists; Prednisone; Prognosis; Radiography, Abdominal; Radiography, Thoracic; Tomography, X-Ray Computed; Ultrasonography

We describe the results of a clinical trial to evaluate the feasibility and toxicity of autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with progressive multiple sclerosis (MS). Fifteen patients (all patients with secondary progressive MS) were enrolled. The median expanded disability status scale (EDSS) score at baseline was 6.0 (range, 4.5-7.5). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. In 9 patients, CD34+ cell selection was performed with a CliniMACS cell selection system, and 6 patients accepted infusion of unmodified peripheral blood stem cells. The modified BEAM (carmustine, teniposide, cytarabine, and melphalan) was the sole conditioning regimen used. The adverse effects included infections, mucositis, transient hepatotoxicity, and diarrhea. Three patients had flares of neurologic deterioration during mobilization, 8 patients had the same manifestation during transplantation, and 2 patients had similar flares within 3 months of transplantation. Six patients experienced continuous neurologic improvement after transplantation, 5 patients experienced neurologic progression, and 4 patients had stabilization of their disease. The confirmed progression-free rate was 63.8% at 49 months. The results of lymphocyte purging were no better than for no purging. Auto-HSCT proved to be safe and beneficial for some MS patients. Further studies are needed to establish the merit of this procedure for MS patients.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Diarrhea; Disease-Free Survival; Female; Hematopoietic Stem Cell Mobilization; Humans; Liver Diseases; Lymphocyte Depletion; Male; Melphalan; Middle Aged; Mucositis; Multiple Sclerosis; Peripheral Blood Stem Cell Transplantation; Podophyllotoxin; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Busulfan; Chemical and Drug Induced Liver Injury; Cholangitis; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Incidence; Infant, Newborn; Liver Diseases; Liver Function Tests; Male; Melphalan; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Isolated hepatic perfusion of nonresectable liver cancer using the combination of TNF and melphalan can be associated with a treatment-related hepatotoxicity. We investigated whether, apart from TNF, also melphalan is cytotoxic in primary murine liver cells in vitro and investigated mediators, mode of cell death, and cell types involved. Melphalan induced a caspase-dependent apoptosis in hepatocytes, which was not seen in liver cell preparations depleted of Kupffer cells. Neutralization of TNF prevented melphalan-induced apoptosis and liver cells derived from mice genetically deficient in either TNFR 1 or 2, but not from lpr mice lacking a functional CD95 receptor, were completely resistant. Cell-cell contact between hepatocytes and Kupffer cells was required for apoptosis to occur. Melphalan increased membrane-bound but not secreted TNF in Kupffer cells and inhibited recombinant TNF-alpha converting enzyme in vitro. Melphalan induced also severe hepatotoxicity in the isolated recirculating perfused mouse liver from wild-type mice but not from TNFR 1 or 2 knockout mice. In conclusion, this study shows that melphalan elicits membrane TNF on Kupffer cells due to inhibition of TNF processing and thereby initiates apoptosis of hepatocytes via obligatory activation of both TNFRs. The identification of this novel mechanism allows a causal understanding of melphalan-induced hepatotoxicity.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Apoptosis; Caspases; Cell Communication; Cells, Cultured; Chemical and Drug Induced Liver Injury; Hepatocytes; Kupffer Cells; Liver Diseases; Male; Melphalan; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Tumor Necrosis Factor-alpha

A 65-year-old male patient presented with right upper-quadrant abdominal pain. Ultrasonography revealed hypoechoic lesion in the perihepatic and intraparenchymal area. Computed tomography (CT) showed hypodense lesion in the same localization. A fine needle biopsy specimen of the perihepatic lesion was hemorrhagic. On abdominal CT, the liver showed enhancement, but the spleen did not enhance. The spleen could not be detected by scintigraphic imaging using Tc99m sulfur dioxide. A diagnosis of primary amyloidosis was made by renal biopsy. Melphalan 10 mg/day for 4 days/month was started. The clinical and radiological follow up demonstrated a resorption of the hematoma. The patient is still alive at the eighth month of therapy.

Topics: Abdominal Pain; Aged; Amyloidosis; Biopsy, Needle; Diagnosis, Differential; Follow-Up Studies; Hematoma; Humans; Immunohistochemistry; Liver Diseases; Male; Melphalan; Radionuclide Imaging; Risk Assessment; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography, Doppler

Isolated limb perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan is well tolerated and highly effective in irresectable sarcoma and melanoma. No data are available on isolated hepatic perfusion (IHP) with these drugs for irresectable hepatic malignancies. This study was undertaken to assess the feasibility of such an approach by analysing hepatic and systemic toxicity of IHP with TNF-alpha with and without melphalan in pigs. Ten healthy pigs underwent IHP. After vascular isolation of the liver, inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter was placed in the inferior vena cava (IVC). An extracorporeal veno-venous bypass was used to shunt blood from the lower body and intestines to the heart. The liver was perfused for 60 min with (1) 50 microg kg(-1) TNF-alpha (n = 5), (2) 50 microg kg(-1) TNF-alpha plus 1 mg kg(-1) melphalan (n = 3) or (3) no drugs (n = 2). The liver was washed with macrodex before restoring vascular continuity. All but one pigs tolerated the procedure well. Stable perfusion was achieved in all animals with median perfusate TNF-alpha levels of 5.1 +/- 0.78 x 10(6) pg ml(-1) (+/- s.e.m). Systemic leakage of TNF-alpha from the perfusate was consistently < 0.02%. Following IHP, a transient elevation of systemic TNF-alpha levels was observed in groups 1 and 2 with a median peak level of 23 +/- 3 x 10(3) pg ml(-1) at 10 min after washout, which normalized within 6 h. No significant systemic toxicity was observed. Mild transient hepatotoxicity was seen to a similar extent in all animals, including controls. IHP with TNF-alpha with(out) melphalan in pigs is technically feasible, results in minimal systemic drug exposure and causes minor transient disturbances of liver biochemistry and histology.

Topics: Alanine Transaminase; Animals; Antineoplastic Agents, Alkylating; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; L-Lactate Dehydrogenase; Liver; Liver Diseases; Melphalan; Perfusion; Swine; Tumor Necrosis Factor-alpha

This study reports a large cooperative experience in myeloablative therapy and bone marrow rescue undertaken to define better the outcome of children with disseminated neuroblastoma after megatherapy. Between 1984 and 1993, 135 children underwent myeloablative therapy with bone marrow transplantation (BMT) in nine Italian Centres. One hundred and seventeen children received unpurged autologous BMT, five allogeneic BMT and 13 peripheral blood progenitor cells as rescue. Of these 135 children, 57 were in 1st CR, 11 in 2nd or subsequent CR, 42 in 1st PR, and 25 had more advanced disease. Twelve children (9%) died of toxicity, 86 relapsed or progressed at 1-68 months (median 7 months) and 80 of these subsequently died of progressive disease. Forty-three children are still alive with 37 in continuous remission at a median of 65 months (30-123 months) after BMT. Overall and disease-free survival at 8 years are 28.5% (s.e. 4.3) and 26% (s.e. 4), respectively. Disease-free survival is 34.6% (s.e. 6.7) for the patients grafted in 1st complete remission, 23.6% (s.e. 6.6) for patients grafted in 1st partial remission, 36.4% (s.e. 14.5) for patients grafted in 2nd or subsequent CR, and 8% (5.4) for patients with advanced disease. We conclude these data confirm that early toxicity of myeloablative therapy is manageable and that myeloablative therapy with bone marrow rescue may contribute to an improved long-term survival of children with disseminated neuroblastoma but the objective of cure of all patients remains distant.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Infant; Infant, Newborn; Infections; Italy; Liver Diseases; Male; Melphalan; Neuroblastoma; Registries; Survival Analysis; Survival Rate; Transplantation Conditioning; Treatment Outcome; Vincristine; Whole-Body Irradiation

Topics: Acute Disease; Amyloidosis; Cardiomyopathies; Cholangitis; Cholestasis; Female; Humans; Liver Diseases; Melphalan; Middle Aged

Topics: Amyloidosis; Bone Diseases, Metabolic; Bone Marrow; Colchicine; Drug Therapy, Combination; Female; Humans; Liver Diseases; Melphalan; Middle Aged; Prednisone; Remission Induction

We report the first case of biopsy-proven primary hepatic amyloidosis in which histologic regression was demonstrated after therapy with melphalan and prednisone. On the basis of the cumulative reported experience regarding the treatment of this rare plasma cell dyscrasia, we recommend a trial of cytotoxic therapy for patients with primary hepatic amyloidosis.

Topics: Adult; Amyloidosis; Female; Humans; Liver Diseases; Male; Melphalan; Middle Aged; Prednisone

Topics: Adult; Humans; Lichen Planus; Liver Diseases; Male; Melphalan

A 37-year-old woman with amyloidosis derived from light chain immunoglobulin had hepatosplenomegaly, elevated serum alkaline phosphatase values, and progressively destructive bony lesions. A 44-month intermittent course of chemotherapy with melphalan and prednisone resulted in regression, confirming the occasional efficacy of cytotoxic chemotherapy in this disease.

Topics: Adult; Amyloidosis; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Liver Diseases; Melphalan; Prednisone; Splenic Diseases

Topics: Adult; Alkaline Phosphatase; Bone Diseases; Chemistry, Clinical; Chloramphenicol; Fenclonine; Humans; Liver Diseases; Melphalan; Neoplasms; Phenylalanine; Phenylketonurias; Stereoisomerism

Topics: Clofibrate; Humans; Lipid Metabolism; Liver Diseases; Male; Melphalan; Middle Aged; Multiple Myeloma; Skin Neoplasms; Xanthomatosis