Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adolescent , Adult , Age Factors , Daunorubicin/administration & dosage , Follow-Up Studies , Hematopoietic Stem Cell Transplantation , Humans , Idarubicin/administration & dosage , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Middle Aged , Remission Induction , Transplantation, Homologous , Treatment Outcome , Young AdultABSTRACT
Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Chromosome Aberrations , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/chemically induced , Adult , Aged , Base Sequence , Boronic Acids/administration & dosage , Bortezomib , Clone Cells , Dexamethasone/administration & dosage , Disease Progression , Evolution, Molecular , Female , Follow-Up Studies , Gene Deletion , Gene Expression Profiling , Humans , Male , Middle Aged , Molecular Sequence Data , Multiple Myeloma/complications , Multiple Myeloma/genetics , Mutation , NF-kappa B/genetics , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/genetics , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide/genetics , Pyrazines/administration & dosage , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Retinoblastoma Protein/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Nucleic Acid , Tumor Suppressor Protein p53/geneticsABSTRACT
A 33-year-old man with an atypical course of hypereosinophilic syndrome including malignant hypercalcemia, osteolytic lesions and evolution into severe myelofibrosis was treated by allogeneic bone marrow transplantation after conditioning with cytoxan and total body irradiation. As the transplant was sex-mismatched, chimerism was studied by means of cytogenetic analysis and Y chromosomal DNA amplification by PCR assay. Long-term complete remission has been assessed by normalization of blood cell counts, magnetic resonance imaging and karyotypic analysis. A relapse was observed 40 months after transplantation. The patient remains alive 44 months post-BMT. This case report is compared with those reported in the literature.
Subject(s)
Bone Marrow Transplantation , Hypereosinophilic Syndrome/therapy , Primary Myelofibrosis/therapy , Adult , Humans , Hypereosinophilic Syndrome/physiopathology , Male , Transplantation, HomologousABSTRACT
We report on two cases of central nervous system (CNS) relapse after high-dose chemotherapy and autologous stem cell transplantation. A 55-year-old man received two courses of vincristin, doxorubicin and dexamethasone (VAD) as an induction treatment for stage IIIB IgG kappa multiple myeloma. Bone marrow stem cell collection was performed after a high-dose melphalan (HDM) course (140 mg/m2). Autologous bone marrow transplantation (ABMT) was performed with this cryo-preserved unpurged bone marrow sample after a second HDM course. Three months after ABMT, the patient presented with signs of central nervous involvement with plasma cells and monoclonal IgG kappa in the cerebral fluid. The patient died despite systemic and intrathecal chemotherapy. A 50-year-old man was initially treated with 3 courses of VAD for a stage IIIA IgD lambda multiple myeloma. Blood stem cell were collected after a course of high-dose etoposide and cyclophosphamide. ABMT was performed after total body irradiation (TBI) and HDM. Three months later, he presented with right leg palsy and a lumbar puncture showed numerous plasma cells and the presence of the IgG lambda. The patient died of neurological complications three months later. Extramedullary occurred prior to medullary relapse in the two cases, suggesting the presence of an extramedullary clone of plasma cells with a high degree of chemo-resistance. Although high-dose chemotherapy appears promising, this therapeutic approach could allow the occurrence of presently unobserved complications. Wether CNS prophylaxis is indicated in this context, as recommended in leukemia, remains an open question.
