11/432. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. The combined use of retinoic acid and chemotherapy has led to an important improvement of cure rates in acute promyelocytic leukemia. Retinoic acid forces terminal maturation of the malignant cells and this application represents the first generally accepted differentiation-based therapy in leukemia. Unfortunately, similar approaches have failed in other types of hematological malignancies suggesting that the applicability is limited to this specific subgroup of patients. This has been endorsed by the notorious lack of response in acute promyelocytic leukemia bearing the variant t(11;17) translocation. Based on the reported synergistic effects of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF), we studied maturation of t(11;17) positive leukemia cells using several combinations of retinoic acid and growth factors. In cultures with retinoic acid or G-CSF the leukemic cells did not differentiate into mature granulocytes, but striking granulocytic differentiation occurred with the combination of both agents. At relapse, the patient was treated with retinoic acid and G-CSF before reinduction chemotherapy. With retinoic acid and G-CSF treatment alone, complete granulocytic maturation of the leukemic cells occurred in vivo, followed by a complete cytogenetical and hematological remission. Bone marrow and blood became negative in fluorescense in situ hybridization analysis and semi-quantitative polymerase chain reaction showed a profound reduction of promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion transcripts. This shows that t(11;17) positive leukemia cells are not intrinsically resistant to retinoic acid, provided that the proper costimulus is administered. These observations may encourage the investigation of combinations of all-trans retinoic acid and hematopoietic growth factors in other types of leukemia. ( info) |
12/432. Complete atrioventricular block after arsenic trioxide treatment in an acute promyelocytic leukemic patient. AV block after arsenic trioxide (As2O3) treatment for refractory acute promyelocytic leukemia is very rare. In this patient, the block was at A-H level and manifested with complete AV block and Wenckebach second-degree type 3:2 block. The junctional recovery time during complete AV block did not significantly prolong after administration of more arsenic trioxide. The effect of heart block of arsenic trioxide seemed reversible after the discontinuation of arsenic trioxide and was not correlated to the leukemic status as observed in this patient. ( info) |
13/432. Acute promyelocytic leukemia with additional chromosomal abnormalities and absence of Auer rods. We report 4 acute promyelocytic leukemia cases that demonstrated karyotypic abnormalities in addition to the classic t(15;17) translocation and did not contain any Auer rods in leukemic blasts and dysplastic promyelocytes, either in the peripheral blood or in the bone marrow. Morphologically, 2 cases were characterized as the common or hypergranular type, and 2 were otherwise typical of the microgranular variant. Three patients had typical clinical and laboratory signs of disseminated intravascular coagulation. Immunophenotypic analysis of the blasts and dysplastic promyelocytes by dual-color flow cytometry revealed an immunoprofile consistent with acute promyelocytic leukemia. cytogenetic analysis of the bone marrow revealed the following karyotypes: case 1, [47,XY,t(15;17)(q22;q12), 21]; case 2, [47,XY,t(15;17)(q22;q12),-16, 2 mar]; case 3, [47,XX,t(15;17)(q22;q12)ider(17)(q10), 8]; and case 4, [47,XY,der(5)t(5;?9)(p15;q12).t(15;17)(q22;q12]. review of an additional 7 cases with t(15;17) as the sole cytogenetic abnormality revealed Auer rods in all cases. Our findings emphasize the importance of cytogenetics in evaluating acute myeloid leukemias. Acute promyelocytic leukemia without Auer rods, which may be morphologically confused with other types of leukemia (in particular, acute myeloblastic leukemia, type M2 or M5) or agranulocytosis with maturation arrest, appears to be associated with additional chromosomal abnormalities and possibly a poorer prognosis. ( info) |
14/432. Acute neutrophilic dermatosis induced by all-trans-retinoic acid treatment for acute promyelocytic leukemia. All-trans-retinoic acid (ATRA) is considered the recommended induction treatment for acute promyelocytic leukemia (APL). Although the dermatological side effects associated with ATRA treatment are relatively common, acute neutrophilic dermatosis (Sweet's syndrome) has only been rarely reported. We describe such a case who responded to chemotherapy and not to low doses of corticosteroids. ( info) |
15/432. Acute trilineage leukemia with monosomy of chromosome 7 following an acute promyelocytic leukemia. We describe an 8 year old boy who had received chemotherapy for an acute promyelocytic leukemia and developed a secondary leukemia 27 months after the diagnosis of this first malignancy. Blasts cells were positive for cytoplasmic markers CD22, CD3 and myeloperoxidase. Cell surface T and myeloid-associated markers were also detected. Cytogenetic study disclosed monosomy 7. The patient achieved complete remission, but relapsed 15 months later with identical immunophenotypic and cytogenetic findings. Three-lineage commitment is proved by the expression of specific criteria for myeloid, and lymphoid T and B typing. A multipotent immature progenitor must be the target of leukemogenic agents. The prognosis is obviously ominous. ( info) |
16/432. The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Acute promyelocytic leukaemia (APL) exhibits a characteristic t(15;17) translocation that fuses the promyelocytic leukaemia (PML) gene on 15q22 to the retinoic acid receptor alpha (RARA) gene on 17q12-q21.1. In a small subset of acute promyelocytic-like leukaemias (APL-L), RARA is fused to a different partner: the pro-myelocytic leukaemia zinc finger (PLZF) gene on 11q23, the nucleophosmin (NPM) gene on 5q35 or the nuclear mitotic apparatus (NuMA) gene on 11q13. We report on the molecular characterization of a RARA gene re-arrangement in a patient with APL-L and demonstrate that the signal transducer and activator of transcription STAT5b gene is fused with RARA. STAT5b belongs to the janus kinase (JAK)-STAT signalling pathway. Remarkably, the STAT5b component of the chimeric protein is delocalized from the cytoplasm to the nucleus, where it displays a microspeckled pattern. Therefore, unusual features of this APL-L might result from dysregulation of the JAK/STAT5 signal transducing pathways in the patient leukaemic cells. In this study, we identified STAT5b as a new gene fused to RARA in leukaemia; this is the first human tumour bearing a structurally abnormal STAT gene. ( info) |
17/432. Sweet's syndrome followed by retinoic acid syndrome during the treatment of acute promyelocytic leukemia with all-trans retinoic acid. We present here the case of a 49-year-old female with acute promyelocytic leukemia (APL) who, after first developing all-trans retinoic acid (ATRA)-related Sweet's syndrome, was later diagnosed as having retinoic acid (RA) syndrome. Preceding the RA syndrome diagnosis, she developed a fever as well as erythematous nodules on her upper arms. These symptoms were observed on day 18 of treatment with ATRA. Ten days later, she began to develop respiratory distress. There was no indication of infection, and her condition did not improve with empiric therapy. At this time, the diagnosis of RA syndrome was made, resulting in the initiation of steroid pulse therapy, and within 24 hours her elevated fever and respiratory distress improved markedly. In addition, the erythematous nodules gradually began disappearing. A skin biopsy revealed a dense dermal infiltrate consisting of neutrophils. ( info) |
18/432. arsenic and all-trans retinoic acid as induction therapy before autograft in a case of relapsed resistant secondary acute promyelocytic leukemia. arsenic trioxide has recently been reported to be successful in the treatment of promyelocytic leukemia. Several concerns about the use of this toxic agent are currently reducing its potential clinical use even in severely ill patients. In this report we describe the results achieved by As2O3 with all-trans retinoic acid in a patient suffering from secondary, relapsed, resistant promyelocytic leukemia. Several complications, including sepsis and an extensive area of skin necrosis, did not allow us to treat the patient further with chemotherapy. With As2O3 and ATRA therapy, the patient obtained a complete molecular remission without any significant toxicity and, subsequently, it was possible to perform a bone marrow autograft in a state of complete remission. ( info) |
19/432. Successful treatment with arsenic trioxide of a patient with ATRA-resistant relapse of acute promyelocytic leukemia. arsenic trioxide has recently been introduced as a promising new agent to treat refractory acute promyelocytic leukemia (APL). In the present study, arsenic trioxide was given intravenously for 42 days to a 56-year-old female patient suffering from chemotherapy/ATRA-resistant APL, with 43% APL blasts in the bone marrow and elevated D-dimers. During the first days of arsenic trioxide treatment a rapid decrease in the D-dimers was seen (normal values reached until day 7), together with a slight decrease in peripheral blood leukocytes. This initial coagulation response was followed by a second phase of hematological response (starting on days 15-20) characterized by leukocytosis, occurrence of myeloid progenitor cells in the peripheral blood, and a decrease in bone marrow blasts (<1% on days 28 and 36). Finally, the patient entered complete hematological and cytogenetic remission, although the PML-RAR alpha fusion product was still detectable by PCR. These data confirm the therapeutic value of arsenic trioxide in relapsed/resistant APL. ( info) |
20/432. Terminal deletion of the long arm of chromosome 9 in acute promyelocytic leukemia with a cryptic PML/RAR alpha rearrangement. Deletions of the long arm of chromosome 9 (9q-) are rare aberrations specifically found in acute myeloid leukemia (AML). Here we describe the first case of acute promyelocytic leukemia (APL) with a terminal 9q deletion as a sole abnormality. Chromosome analysis of the bone marrow cells showed 46,XX,del(9)(q22) in all 20 metaphases. fluorescence in situ hybridization (FISH) analysis with painting probes of chromosomes 15, 17, and 9 revealed only two normal chromosomes 15 and 17, normal chromosome 9, and del(9)(q22). FISH with cosmid dna probes flanking the breakpoints of t(15;17) did not show the retinoic acid receptor alpha (RAR alpha)/PML fusion signal usually generated on the der(17) t(15;17). However, rearrangement of the RAR alpha gene and expression of the PML/RAR alpha chimeric transcript were identified by Southern blot and reverse transcriptase-polymerase chain reaction analyses, respectively. These results suggested that the PML/RAR alpha fusion gene was generated by submicroscopic interstitial insertion of the RAR alpha gene into the PML gene. Therefore, 9q- was interpreted as a secondary aberration following the PML/RAR alpha rearrangement. The patient died during induction therapy because of intracerebral hemorrhage. Considering other reported cases of APL with 9q-, 9q- may be an adverse prognostic factor in APL as observed in AML with t(8;21). ( info) |