melphalan and Leukemia--Promyelocytic--Acute

The incidence of secondary myelodysplasia/acute myeloid leukemia (AML) was retrospectively assessed in an international joint study in 305 node-positive breast cancer patients, who received mitoxantrone-based high-dose chemotherapy (HDCT) followed by autologous stem cell support as adjuvant therapy. The median age of the patients was 57 years (range 22-67). In all, 268 patients received peripheral blood stem cells, and 47 patients received autologous bone marrow. After a median follow-up of 57 months (range 10-125), three cases of secondary AML (sAML) were observed, resulting in a cumulative incidence of 0.94%. One case of sAML developed 18 months after HDCT (FAB M3) The karyotype was translocation 15;17 and, after induction therapy, the patient underwent autologous stem cell transplantation, and is in complete remission (CR) of both breast cancer and AML. The second patient developed AML (FAB M4eo with inversion 16) 5 months after HDCT. This patient achieved CR after induction therapy, but died of infectious complication. A third patient developed AML (FAB M4) 6 months after HDCT. She achieved CR after induction therapy, but relapsed and expired 28 months after diagnosis of AML. sAML after mitoxantrone-based HDCT is a possible, but rare complication in breast cancer patients.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Epirubicin; Female; Humans; Incidence; Leukemia, Myeloid; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Leukemia, Radiation-Induced; Lymphatic Metastasis; Melphalan; Middle Aged; Mitoxantrone; Neoplasms, Second Primary; Paclitaxel; Peripheral Blood Stem Cell Transplantation; Radiotherapy, Adjuvant; Thiotepa; Transplantation Conditioning; Transplantation, Autologous

The nuclear arrangement of promyelocytic leukaemia nuclear bodies (PML NBs) was studied in vitro after the cell treatment by clinically used agents such as all-trans retinoic acid (RA) in human leukaemia and cytostatics or gamma radiation in multiple myeloma cells. In addition, the influence of phorbol ester (PMA) on PML NBs formation was analyzed. A reduced number of PML bodies, which led to relocation of PML NBs closer to the nuclear interior, mostly accompanied RA- and PMA-induced differentiation. Centrally located PML NBs were associated with transcriptional protein RNAP II and SC35 regions, which support importance of PML NBs in RNA processing that mostly proceeds within the nuclear interior. Conversely, the quantity of PML NBs was increased after cytostatic treatment, which caused re-distribution of PML NBs closer to the nuclear envelope. Here we showed correlations between the number of PML NBs and average Centre-to-PML distances. Moreover, a number of cells in S phase, especially during differentiation, influenced number of PML NBs. Studying the proteins involved in PML compartment, such as c-MYC, cell-type specific association of c-MYC and the PML NBs was observed in selected leukaemic cells undergoing differentiation, which was accompanied by c-MYC down-regulation.

Topics: Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Flow Cytometry; Gamma Rays; HL-60 Cells; Humans; Intranuclear Inclusion Bodies; K562 Cells; Leukemia, Promyelocytic, Acute; Melphalan; Multiple Myeloma; Tetradecanoylphorbol Acetate; Tretinoin; U937 Cells

The association of leukemia and multiple myeloma is well described usually as a complication of chemotherapy but also in the absence of chemotherapy or at diagnosis. Such leukemias are typically acute myeloid leukemia (AML), particularly myelomonocytic subtype, and cases of acute promyelocytic leuke (APL) are rarely reported. Controversy exists as to whether myeloma and AML originate from a single haematopoietic progenitor or arise from different cell lineages. We report a case of a 58 year old female who developed APL 10 months following diagnosis of nonsecretory light chain (kappa) myeloma which had been treated with local spinal irradiation and low dose oral melphalan and prednisone. Clonality had originally been demonstrated by light chain restriction (kappa) of her bone marrow plasma cells whilst immunoglobulin heavy chain and T cell receptor genes were germ line. At development of APL cytogenetics revealed t(15;17) and PML-RAR fusion gene was detected by RT-PCR. The patient was treated with all-trans retinoic acid (ATRA) and received 2 cycles of consolidation chemotherapy with Idarubicin. Following this therapy the t(15;17) and PML-RAR were both undetectable whilst the clonal population of kappa staining plasma cells persisted. This particular patient represents a rare case of APL complicating multiple myeloma with persistence of the myeloma clone but disappearance of PML-RAR alpha RNA following therapy. This case study appears to support the argument that the APL and myeloma originated from distinct cell lineages.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Lineage; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Clone Cells; Combined Modality Therapy; Diphosphonates; Embryonal Carcinoma Stem Cells; Female; Gene Rearrangement, B-Lymphocyte, Light Chain; Humans; Idarubicin; Immunoglobulin kappa-Chains; Leukemia, Promyelocytic, Acute; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Neoplasm Proteins; Neoplasms, Multiple Primary; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Osteolysis; Pamidronate; Prednisone; Remission Induction; Translocation, Genetic; Tretinoin

Acute myeloid leukemia (AML) comprises 15%-20% of childhood acute leukemia cases. The long-term disease free survival (DFS) in childhood AML is poor with standard chemotherapy alone. Early intensive chemotherapy is generally regarded to be necessary for achieving high complete remission (CR) rates. Recent experience has shown that incorporation of early intensification with high-dose melphalan conditioning and autologous bone marrow transplantation (BMT) during the first remission significantly improves long-term DFS in children with AML. In this article, we report the use of autologous BMT for treatment of a three-and-half year old child with acute promyelocytic leukemia (APL or M3) in second remission. The patient was conditioned with high-dose melphalan of 180 mg/kg prior to bone marrow reinfusion. A total of 4.0 x 10(7)/kg mononuclear cells and 1.07 x 10(5)/kg granulomonocytic colony forming units (CFU-GM) were infused. Haematopoietic stem cells were enriched by almost 20-fold after the separation and cryopreservation procedures. Haematological recovery was achieved four-and-a-half weeks post-BMT. She has remained in complete remission 18 months after transplantation. Our experience in this patient indicates that this procedure can be used in second remission and it may provide a better alternative for the management of childhood AML in Singapore.

Topics: Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Disease-Free Survival; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Melphalan; Remission Induction; Transplantation, Autologous

A 33-year-old man who had received previous chemotherapy with cytarabine, daunorubicin and mitoxantrone followed by an autologous marrow transplant after conditioning with busulfan, melphalan and cyclophosphamide, fathered sex-mismatched fraternal twins approximately 6 years post-transplant. HLA and DNA analyses showed the probability of paternity to be in excess of 99% for each twin. To our knowledge this represents the first documented case of paternity following conditioning with this combination of marrow ablative agents and the first report of twin paternity following autologous marrow transplantation.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Cyclophosphamide; Humans; Leukemia, Promyelocytic, Acute; Male; Melphalan; Paternity; Transplantation, Autologous; Twins, Dizygotic

To explore more effective and less toxic conditioning regimen without total body irradiation for autologous bone marrow transplantation (ABMT) for acute leukemia (AL).. Twenty patients with AL were treated with ABMT, including 13 cases of acute myelocytic leukemia (AML) and 7 cases of acute lymphocytic leukemia (ALL). A median of 1.06 (range, 0.69-1.75) x 10(8) nucleated BM cells/kg was harvested and stored in normal salt solution containing heparin at 4 degrees C. The conditioning regimen (MAC) consisted of high-dose melphalan (M, 140-160 mg/m2), cyclophosphamide (CY, 120 mg/kg) and cytosine arabinoside (Ara-C, 2.0 g/m2). These 3 drugs were administered within 25 hours and the unpurged autologous marrow infusion began after another 24-hour interval.. MAC regimen could result in myeloblastic efficacy in a week. All marrow cells were reinfused within 56 hours after the harvest so that hemopoietic reconstitutions could occur in all the patients. The median time to reach a neutrophil count of > 1.0 x 10(9)/L and a platelet count of > 50 x 10(9)/L was 20 and 26 days respectively. With a median observation period of 25 months, the median duration on continuous complete remission in our patients was 22 months, and the longest reached 56 months. The median survival was 33 months, and the longest was over 6 years. The event-free survival at 2 years had reached 72%. In seven patients with leukemic relapse, six (86%) relapsed within 8 months after ABMT. The relapse rate and mortality in AML patients were significantly lower than those in ALL patients. In 7 patients with M3, relapse had not yet been observed. The nonhematologic toxic effects of MAC conditioning regimen occurred mainly in the gastrointestinal tract.. The preliminary results indicated that the ABMT using MAC conditioning regimen had some advantages in stronger antileukemic efficacy, less extrahematologic toxicity and earlier recovery of platelet and could greatly prolong the duration of remission and survival in some patients with AL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Cyclophosphamide; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Melphalan; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma