Therapy-related acute myeloid leukemia after single-agent treatment with fludarabine for chronic lymphocytic leukemia

A 70-year-old man with B-cell chronic lymphocytic leukemia (CLL) received single-agent treatment with the purine analogue fludarabine, which led to complete remission. After 8 years, he presented with pancytopenia. Marrow examination showed acute myeloid leukemia (AML) with trilineage myelodysplasia (MDS). Cytogenetic analysis showed an unbalanced der(1;7)(p10;q10) that resulted effectively in deletion 7q; confirming the diagnosis of therapy-related AML (t-AML). No residual CLL was present. Together with previous reports of secondary cancers after fludarabine treatment and the association of monosomy 7/7q- with another purine analogue azathioprine, results suggest that t-AML might develop after fludarabine therapy.     

Identical reconstitution after bone marrow transplantation in twins who received fresh and cryopreserved grafts harvested at the same time from their older brother

We report here the reconstitution after bone marrow transplantation (BMT) in identical infant twins with acute myelogenous leukemia (AML). They were diagnosed at 8 and 9 months of age. Complete remission was induced after two courses of chemotherapy. After four and five courses of chemotherapy, respectively, they received BMT at 2-month interval from the same HLA-identical older brother. The total dose of marrow nucleated cells (NC) harvested was 77.7 x 10(8). The first patient was transplanted with half of the total dose of NC. The remaining cells were cryopreserved without the use of a programmed freezer and transplanted into the second patient 2 months later. The number of days for neutrophil (>0.5 x 10(9)/L), platelet (>50 x 10(9)/L), and reticulocyte (>1%) recovery were, respectively, 15, 21, and 14 in the first case and 12, 21, and 15 in the second case. The clinical courses after BMT were uneventful in both cases, except for mild acute GVHD, and complete remission has been maintained >4 yr with full recovery of immune and marrow function. Based on the results in these cases, we confirmed that marrow cells that have been cryopreserved without the use of a programmed freezer could reconstitute immune and marrow function as well as non-cryopreserved cells.     

Drastic effect of cell density on the cytotoxicity of daunorubicin and cytosine arabinoside

White blood cell count (WBC) is generally accepted as a prognostic risk factor in acute myeloid leukemia (AML) outcome and displays a marked interindividual variation. The dose regimen currently used ignores the size of the tumor burden and the standardization of the dose is generally based on body surface area. In this study we have investigated the effect of cell density on the cytotoxic activity of daunorubicin (DNR) and cytosine arabinoside (AraC) towards HL60 cells and leukemic cells isolated from patients with AML. We demonstrate that drug cytotoxicity decreased with cell density and that apoptosis induction by DNR in isolated leukemic cells was greatly reduced at higher cell density. A marked reduction of the uptake of DNR and AraC in HL60 parental and mitoxantrone resistant cells was observed with increasing cell density. Such a drug depleting effect by cells at high density has been previously described for vincristine, doxorubicin and paclitaxel. By extrapolating the in vitro results to the in vivo situation, one could hypothesize that a high WBC can lower the plasma concentration through high uptake in the tumor burden, leading to a shortage of drug in leukemic blasts. Patients with high WBC might therefore benefit from a dose increase of DNR and/or AraC.     

Induction of anti-leukemic cytotoxic T lymphocytes by fusion of patient-derived dendritic cells with autologous myeloblasts

Presentation of AML antigens by dendritic cells (DC) could potentially induce a T cell-mediated anti-leukemic immune response. In the present study, we generated DC from adherent (AD-DC) and non-adherent (NAD-DC) myeloblasts obtained from bone marrows of AML patients. Both cell populations displayed morphological, phenotypic and functional properties of DC. The functions of NAD-DC were compared to AD-DC that had been fused with autologous AML blasts (FC/AML). The FC/AML induced greater T cell proliferation and CTL activity against autologous AML blasts (9/10 cases) as compared to NAD-DC. FC/AML may thus represent a promising strategy for DC-based immunotherapy of patients with AML.     

Cytogenetic and hematological spontaneous remission in a case of acute myelogenous leukemia

Several cases of spontaneous remission (SR) interrupting the invariably progressive course of untreated acute myeloblastic leukemia (AML) have been reported so far. We shall add to this series the hematological and cytogenetic SR occurring in a 72-yr-old man affected by AML following myelodysplastic syndrome. At diagnosis cytogenetic analysis showed the 48, xy, del (6) (p22-pter), +13, +14 karyotype. Owing to a lobar pneumonia, the chemotherapy was deferred and a broad spectrum antibiotic therapy was established. Supportive care included red cells and platelet transfusions and low-dose corticosteroid. Two months later, after the pneumonia had completely disappeared, a complete remission, lasting about 5 months, was documented on bone marrow morphological and cytogenetical examination, although some degree of myeloid dysplasia persisted. Possible mechanisms of the various SRs described during the course of AML are discussed with a review of the literature.     

Chromosomal rearrangement in Down syndrome with acute myeloid leukemia

The incidence of acute leukemia in children with Down syndrome (DS) is high as compared to general population. Recent findings have demonstrated that DS children with acute myeloid leukemia (AML) have the highest event free survival rates with high dose cytosine arabinoside (Ara-C). We present 3 year-old DS female child with AML-M5, whose chromosomal analysis revealed constitutional t(21;21) alongwith del(5)(q31q33) and a unique translocation t(16;20)(q13;q12). After chemotherapy, child achieved complete clinical remission. Karyotype analysis of remission marrow showed disappearance of abnormal clone of der(20) t(16;20)(q13;q12), del(5q) indicating cytogenetic remission too. This case alongwith supportive literature indicate that pediatric DS-AML is a distinct biologic sub-group differs from that of non-DS-AML with respect to chemosensitivity.     

Unusual presentation of central nervous system relapse with oculomotor nerve palsy in a case of CD56-positive acute myeloid leukemia following allogeneic stem cell transplantation

Allogeneic stem cell transplantation (allo-SCT) plays an important role in the treatment of infants and children with acute myelogenous leukemia (AML). Leukemic relapse after allo-SCT is responsible for a high rate of treatment failure. Extra-medullary relapse (EMR), without involvement of bone marrow, is rare compared to medullary relapse. CD56, the neural cell adhesion molecule, may contribute to the higher frequency of CNS relapse in CD56-positive AML. We observed an isolated EMR on the oculomotor nerve of a 17-month-old girl 12 weeks after cord blood transplantation (CBT), who was transplanted because of CD56-positive AML. Diagnosis of relapse was suspected clinically and confirmed by magnetic resonance imaging (MRI), and fluorescence-activated cell sorter (FACS) and chimerism analysis of cerebrospinal fluid (CSF). Therapy consisted of intra-thecal chemotherapy, CNS irradiation, and systemic immunomodulation by cyclosporin A (CsA) and basiliximab withdrawal. Twenty-one months after relapse, the patient shows full remission of symptoms and previously described oculomotor nerve infiltration.