FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia

Relapsed or refractory adult acute lymphoblastic leukemias (ALL) have poor prognosis. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of the salvage regimen is acceptable. Twenty three patients with relapsed/refractory adult ALL were treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA). Five patients had primary refractory disease, and 18 were in first relapse. Nine (39.1%) patients achieved complete remission (CR) following salvage therapy, whereas 13 (56.5%) patients were refractory, and one patient died in aplasia due to infection. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×10⁹/l and 1×10⁹/l was 20 (range 16–25) and 24 (range 20–28) days from the start of chemotherapy, respectively. Platelet levels of more than 20×10⁹/l and 100×10⁹/l were achieved in a median time of 23 (range 19–25) and 33 (range 28–39) days, respectively. Fever more than 38.5°C was observed in 18 of 23 patients (78.2%), 13 had fever of unknown origin, and 5 had documented infections. Nonhematological side effects, consisting mainly of mucositis (18/23 or 78.2%) and transient liver toxicity increase (10/23 or 43.4%), were generally tolerated. All nine patients who achieved CR received a second course with FLAG-IDA, and seven patients underwent allogeneic stem cell transplantation (four from a matched donor, one from a mismatched donor, and two from an unrelated donor), while two did not reach that stage due to early relapse from CR. The median overall survival (OS) for all 23 patients was 4.5 (range 1–38) months; for the nine responders, the disease-free survival (DFS) and the OS were 6 (range 3–38) and 9 (7–38) months, respectively; the seven patients who received allogeneic stem cell transplantation had a DFS of 10 (range 7–38) months. In our experience, FLAG-IDA is a well-tolerated regimen in relapsed/refractory ALL patients; the toxicity is acceptable, enabling patients who have achieved CR to receive allogeneic transplantation.     

Lymphoid enhancer binding factor-1 (LEF1) expression as a prognostic factor in adult acute promyelocytic leukemia

Lymphoid enhancer-binding factor 1 (LEF1) is a downstream effector of the Wnt/ β-catenin signaling pathway. High LEF1 expression has been reported as a prognostic marker in hematologic malignancies. We evaluated the prognostic significance of LEF1 expression in 78 adult acute promyelocytic leukemia (APL) patients. APL samples were dichotomized at the median value and divided into: LEF1^low and LEF1^high. LEF1^high patients had lower WBC counts at baseline and were less likely to carry a FLT3 -ITD than LEF1^low patients. Early death occurred only in the LEF1^low group. Moreover, LEF1^low expression was associated with a high Sanz score. Survival analysis of 61 APL patients < 60 years revealed that the LEF1^high group had a significantly longer overall survival (OS). Cox analysis for OS confirmed only LEF1 expression as an independent prognostic factor. Of the 17 patients over the age of 60, those in the LEF1^high group showed a higher median survival. In silico analysis identified 9 differentially expressed, up-modulated genes associated with a high expression of LEF1; the majority of these genes is involved in the regulation of apoptosis. Our study provides evidence that LEF1 expression is an independent prognostic factor in APL, and could be used in patients risk stratification.     

FLAG-IDA in the treatment of refractory/relapsed acute myeloid leukemia: single-center experience

We evaluated the efficacy and toxicity profiles of the combination of fludarabine, high-dose cytosine arabinoside (AraC), idarubicin, and granulocyte colony-stimulating factor (G-CSF) in refractory/relapsed acute myeloblastic leukemia (AML) patients. Between October 1998 and February 2002, 46 AML patients were treated with FLAG-IDA (fludarabine 30 mg/m(2), AraC 2 g/m(2) for 5 days, idarubicin 10 mg/m(2) for 3 days, and G-CSF 5 micro g/kg from day +6 until neutrophil recovery). Thirty patients were in relapse after conventional chemotherapy including cytarabine, etoposide, and daunorubicin or mitoxantrone according to the GIMEMA protocols. Four were in relapse after autologous peripheral stem cell transplantation and two after allogeneic bone marrow transplantation. Ten patients had refractory disease (after 10 days of standard doses of cytarabine, 3 days of mitoxantrone or daunorubicin, and 5 days of etoposide). Recovery of neutrophils and platelets required a median of 19 and 22 days from the start of therapy. Complete remission (CR) was obtained in 24 of 46 patients (52.1%) and 3 of 46 (6.6%) died during reinduction therapy: 2 due to cerebral hemorrhage and 1 due to fungemia ( Candida tropicalis). Fever >38.5 degrees C was observed in 40 of 46 patients (86.9%), 27 had fever of unknown origin (FUO) and 13 documented infections; 31 of 46 (67.3%) developed mucositis and 14 of 46 (30.4%) had grade 2 WHO transient liver toxicity. After achieving CR, 11 patients received allogeneic stem cell transplantation, 4 patients received autologous stem cell transplantation, 4 were judged unable to receive any further therapy, and 5 refused other therapy. Ten patients are at present in continuous CR after a median follow-up of 13 months (range: 4-24). In our experience, FLAG-IDA is a well-tolerated and effective regimen in relapsed/refractory AML. The toxicity is acceptable, enabling most patients to receive further treatment, including transplantation procedures.     

Molecular detection of minimal residual disease is associated with early relapse in adult acute lymphoblastic leukemia

Several studies in childhood acute lymphoblastic leukemia (ALL) have documented that molecular detection of minimal residual disease (MRD) based on screening for T-cell receptor and immunoglobulin gene rearrangements can identify patients at a high risk of relapse. In our experience, evaluation of MRD in adult ALL can help to identify high risk patients.     

Non-treatment-related chronic myeloid leukemia as a second malignancy

The characteristics of the very rare non-treatment-related chronic myeloid leukemia (nTr-CML) cases have never before been analyzed. The literature up to December 2002 was screened using the Medline database to identify cases of Tr-CML and nTr-CML. We considered five cases with nTr-CML identified among 270 newly diagnosed CML at our Department. Our report thus considers nine cases with nTr-CML compared to 77 affected by Tr-CML as a secondary neoplasm. The median age at the appearance of the first tumor was higher in nTr-CML patients compared to that of the Tr-CML group (P<0.0001). The median age at CML diagnosis was significantly higher in the nTr-CML than in the Tr-CML group (P<0.0001). The proportion of hematological malignancies as first tumor type was not different in the two groups (44% in nTr-CML versus 56% in Tr-CML). Our study underlines that nTr-CML as a second malignancy is a rare entity associated with elderly age.     

Normal percentage of CD56bright natural killer cells in young patients with a history of repeated unexplained implantation failure after in vitro fertilization cycles

Changes in endometrial leukocyte subpopulations and most of all in the percentage of uterine natural-killer cells (uNK), during the menstrual cycles, may have a pivotal role in the implantation process. An increase of activated NK cells (CD56dim CD16+ CD69+) in the peripheral blood of patients with a reduced rate of embryo implantation in IVF treatment has been reported elsewhere, but we found, by using flow cytometry, normal endometrial lymphocyte subpopulations in young patients with a history of repeated unexplained implantation failure who were undergoing IVF cycles for idiopathic infertility.     

Bone marrow aspirate on the 14th day of induction treatment as a prognostic tool in de novo adult acute myeloid leukemia

BACKGROUND AND OBJECTIVES: In adult acute myeloid leukemia (AML), a variety of clinical and biological parameters have been examined for their potential value in predicting treatment response. Early response to induction therapy could be an important prognostic factor in this disease. DESIGN AND METHODS: We studied the relationship between reduced blasts in bone marrow aspirate on the 14th day (BMA14th) of induction chemotherapy and treatment outcome in 198 adult AML patients of whom 124 were < 60 years old (group A) and 74 > or = 60 years old (group B). Receiver operating characteristic curve analysis was used to assess the prognostic performance of BMA14th. Using the percentages of blasts of < or = 22% and < or = 15% as criteria for predicting treatment outcome gave the highest accuracy in terms of sensitivity and specificity in groups A and B, respectively. RESULTS: In group A, of 97 patients with a BMA14th < or = 22%, 77 (79%) achieved complete remission (CR), whereas of 27 patients with a BMA14th > 22%, 22 (81%) were non-responders (NR) (p < 0.0001). The test sensitivity and specificity were 93.9% and 71.4%, respectively. In group B, of 27 patients with a BMA14th < or = 15%, 18 (67%) achieved CR, whereas of 47 patients with a BMA14th >15%, 38 (81%) were NR (p = 0.0001). The test sensitivity and specificity were 66.7% and 80.9%, respectively. INTERPRETATION AND CONCLUSIONS: Our data suggest that BMA14th may be a predictive test for CR, helping to identify NR patients early in their disease. Further studies are needed to establish the practical implications of the results of our study.     

A novel translocation t(2;9)(q14;p12) in AML-M2 with an uncommon phenotype: myeloperoxidase-positive and myeloid antigen-negative

We report a case of acute myeloid leukemia (AML-M2) expressing myeloperoxidase (MPO) but no myeloid antigens. A few cases with this discordant phenotype have been reported and an association has been suggested between the lack of CD13 and CD33 in MPO positive AML and the presence of t(8;21). Cytogenetic and molecular analyses performed in our case showed 48,XY,+Y,+8,t(2;9)(q14;p12). We believe that combined approaches can contribute to detect particular AL cases like the present one, that confirms the heterogeneity of AML. However, further studies are needed to clarify the relationship between phenotypic aberrations and cytogenetic abnormalities.     

Vascular endothelial growth factor serum levels are elevated in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic angiodysplasia affecting multiple organs. Two genes involved in the transduction of TGF-beta signalling are responsible for HHT. An additional role for vascular endothelial growth factor (VEGF) has been proposed. Serum VEGF, which has been evaluated in several diseases characterized by aberrant angiogenesis, has never been measured in patients with HHT. AIMS: To evaluate VEGF serum levels in HHT patients as compared to normal subjects. MATERIALS AND METHODS: 32 HHT patients (age 47.7 +/- 16.7 years) and a control group of 37 healthy subjects (age 48.2 +/- 15.5 years) were entered in the study. Each patient underwent serum VEGF dosage using a commercial ELISA specific for the human molecule. RESULTS: The serum level of VEGF in HHT patients was 196.3 +/- 103.2 pg/ml, while it was 152.0 +/- 84.1 pg/ml in the control group. Statistical analysis showed that serum VEGF was significantly higher in HHT patients than in the controls (p < 0.031). CONCLUSIONS: According to a study performed in a murine model, persistence of the activation phase of angiogenesis might be responsible for an increased production of several angiogenic factors, in particular VEGF, in HHT. Our work is the first to suggest an increased expression of VEGF in the serum of subjects with HHT in agreement with the stimulation of VEGF synthesis proposed in the murine model.     

LIGHT/TNFSF14 increases osteoclastogenesis and decreases osteoblastogenesis in multiple myeloma-bone disease

LIGHT, a TNF superfamily member, is involved in T-cell homeostasis and erosive bone disease associated with rheumatoid arthritis. Herein, we investigated whether LIGHT has a role in Multiple Myeloma (MM)-bone disease. We found that LIGHT was overproduced by CD14+ monocytes, CD8+ T-cells and neutrophils of peripheral blood and bone marrow (BM) from MM-bone disease patients. We also found that LIGHT induced osteoclastogenesis and inhibited osteoblastogenesis. In cultures from healthy-donors, LIGHT induced osteoclastogenesis in RANKL-dependent and -independent manners. In the presence of a sub-optimal RANKL concentration, LIGHT and RANKL synergically stimulated osteoclast formation, through the phosphorylation of Akt, NFκB and JNK pathways. In cultures of BM samples from patients with bone disease, LIGHT inhibited the formation of CFU-F and CFU-OB as well as the expression of osteoblastic markers including collagen-I, osteocalcin and bone sialoprotein-II. LIGHT indirectly inhibited osteoblastogenesis in part through sclerostin expressed by monocytes. In conclusion, our findings for the first time provide evidence for a role of LIGHT in MM-bone disease development.