melphalan and Demyelinating-Diseases

Crow-Fukase syndrome, also called POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, is a rare cause of demyelinating and axonal mixed neuropathy with multiorgan involvement. The pathogenesis of Crow-Fukase syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF), probably mediated by monoclonal proliferation of plasma cells, is likely to be responsible for most of the characteristic symptoms. There is no established treatment regimen. In appropriate candidates, high-dose chemotherapies with autologous peripheral blood stem cell transplantation is highly recommended, because this treatment could result in obvious improvement in neuropathy as well as other symptoms, with a significant decrease in serum VEGF levels. Indication of this treatment has not yet been established, and long-term prognosis is unclear at present. Thalidomide should be considered for patients who are not indicated for transplantation therapy. Treatments that should be considered as future therapy include lenalidomide, bortezomib, and anti-VEGF monoclonal antibody (bevacizumab).

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Bevacizumab; Boronic Acids; Bortezomib; Combined Modality Therapy; Demyelinating Diseases; Humans; Lenalidomide; Melphalan; Peripheral Blood Stem Cell Transplantation; POEMS Syndrome; Pyrazines; Thalidomide; Transplantation, Autologous; Vascular Endothelial Growth Factor A

Toxicity associated with immunosuppression and conditioning regimens represents a common cause of neurological complications after allogeneic stem cell transplantation.. We present a 56-year-old female patient with refractory acute lymphoblastic leukemia undergoing reduced-intensity conditioning with fludarabine, BCNU and melphalan followed by matched-sibling allogeneic stem cell transplantation. Under immunosuppressive treatment with cyclosporine A (CSA) the patient developed early-onset (day +33) and ultimately fatal leukoencephalopathy.. As fludarabine and CSA represent two key substances of today's reduced-intensity conditioning regimens we raise the question of whether CSA, fludarabine or a combination of both led to this outcome and discuss differential diagnoses.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclosporine; Demyelinating Diseases; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Assessment; Stem Cell Transplantation; Vidarabine

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Blood Transfusion, Autologous; Bone and Bones; Castleman Disease; Charcot-Marie-Tooth Disease; Demyelinating Diseases; Diagnosis, Differential; DNA Mutational Analysis; Genetic Testing; Genotype; Humans; Inheritance Patterns; Male; Melphalan; Middle Aged; Myeloablative Agonists; Pedigree; Peripheral Nerves; Peripheral Nervous System Diseases; POEMS Syndrome; Treatment Outcome; Vascular Endothelial Growth Factor A

We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 x 10(5) or 5 x 10(6) TE-671 human rhabdomyosarcoma cells or 5 x 10(6) D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mM solution, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mM intrathecal melphalan produced an increase in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphalan with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mM, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concentrations. Comparison of a single dose of 1 mM melphalan with multiple doses of 0.25 mM melphalan in the treatment of D-54 MG revealed an increase in median survival of 475+% for each of the regimens. Intrathecal melphalan may be an important new addition in the treatment of neoplastic meningitis and is currently being evaluated clinically in a Phase 1 trial.

Topics: Animals; Brain Neoplasms; Demyelinating Diseases; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Glioma; Humans; Injections, Spinal; Melphalan; Meningitis; Rats; Rats, Nude; Rhabdomyosarcoma; Subarachnoid Space; Transplantation, Heterologous; Tumor Cells, Cultured

A pathogenic role of the M protein in monoclonal IgM neuropathy has been suggested. This is based among other things on a close relation between immunosuppressive treatment, lowered concentration of M protein, and clinical effect. We studied five patients with monoclonal IgM and antibodies to peripheral nerve myelin. The immunosuppressive treatment was beneficial in three of the patients. In three patients there was a relationship between antibody concentration and clinical effect (in one there was no change in antibody concentrations and correspondingly no change in clinical status, and in two patients clinical improvement corresponded to decreased antibody concentrations). In two patients, however, there was no clear correlation, since one patient improved despite increasing antibody concentrations and one patient did not improve despite a lowered antibody concentration. It is therefore possible that other mechanisms may contribute to the effect of treatment.

Topics: Adult; Aged; Blood Proteins; Chlorambucil; Demyelinating Diseases; Drug Therapy, Combination; Female; Humans; Immunoglobulin M; Immunoglobulins; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Myelin Proteins; Myelin-Associated Glycoprotein; Neurologic Examination; Peripheral Nerves; Polyradiculoneuropathy; Prednisolone; Synaptic Transmission