ABMT for children AML: Italian experience. GITMO-AIEOP Groups.

We report data from an Italian survey on ABMT in 93 AML children less than 14 years in 1st or 2nd remission performed in 15 Centers. Different conditioning regimens have been employed: BAVC, an original schedule of chemotherapy; TBI plus Cy and/or other drugs (TBI + CHT); other high dose chemotherapy schedules (HD CHT). 62 patients have been transplanted in 1st CR; 38 have been conditioned with BAVC, 16 with TBI + CHT and 8 with HD CHT. Relapses were 21 in the BAVC group (DFS = 35% at 66 months), 5 in the TBI group (DFS = 61% at 48 months) and 5 in the HD CHT group; overall DFS is 39% at 66 months. 31 patients have been transplanted in 2nd CR; 14 were conditioned with BAVC and 16 with TBI + CHT; 6 patients relapsed in the first group, DFS is 56% at 50 months; in the second group 2 early deaths and 3 relapses occurred, DFS is 65% at 65 months. 1 patient in 2nd CR, conditioned with HD CHT, died during aplasia. Overall DFS is 59% at 65 months. Although no final conclusions concerning ABMT in AML children may be drawn from this retrospective study because of heterogeneity of population and methods, results obtained in 2nd CR are clearly better to those obtained with standard chemotherapy alone, confirming the role of ABMT in this high risk category of patients.

Characterization of a new case of trisomy 8 in acute lymphoblastic leukemia.

Trisomy 8 is a relatively common finding in acute nonlymphoblastic leukemia (ANLL). In childhood acute lymphoblastic leukemia (ALL) it apparently is much more rare. Although Human Gene Mapping 11 included trisomy 8 as a marker for a subgroup of ALL, morphologic and immunologic characteristics of this entity have not been defined. We describe a case of early T-cell ALL (T-ALL) in a pediatric patient in whom this abnormality was the sole chromosome aberration. In situ hybridization with a chromosome 8-specific alpha-satellite DNA probe was performed. Our data are discussed and compared with pertinent literature.

Autologous blood stem cell transplantation in malignant lymphomas: an Italian Cooperative Study.

Twenty-three patients with malignant lymphoma, (7 Hodgkin's, and 16 non-Hodgkin's) in different phases of disease were autografted in 4 Italian Haematology institutions using only chemotherapy-mobilized blood stem cells (BSC) collected by apheresis. Clinical and laboratory data were analysed centrally and showed mean collection yields of 8.1 x 10(8) kg mononuclear cells (MNC) (SE 0.5; range 2.6-13.8) and 24.1 x 10(4) kg CFU-GM (SE 7.4; range 1.4-162.9). The mean times required to attain 0.5 x 10(9)/l neutrophils and 50 x 10(9)/l platelets after marrow-ablative high-dose chemo+radiotherapy and BSC reinfusion were 14.9 days (SE 1.5; range 7-38) and 18.6 days (SE 2.6; range 6-49) respectively. The incidence of early deaths was < 5% and the requirement for support with blood product transfusion was moderate. The progression free survival (PFS) is > 50% at 3 years with a median follow-up of 17.3 months. Results were significantly better for patients autografted in remission. These results suggest that autologous blood stem cell transplantation (ABSCT) may be proposed for the primary treatment of poor prognosis malignant lymphomas. However, ABSCT needs to be compared with autologous bone marrow transplantation (ABMT) followed by infusion of growth factors to accelerate recovery.

Prognostic factors in autologous stem cell transplantation for multiple myeloma: an EBMT Registry Study. European Group for Bone Marrow Transplantation.

Autologous bone marrow- and blood progenitor cell transplantation was performed in 130 patients with multiple myeloma in 16 European centers between 1986 and 1993. At the time of follow-up, 77 patients were alive and 53 were dead. Complete remission after transplantation was obtained in 47% of all patients. The actuarial survival at 65 months was 28%. The median duration of relapse-free survival among patients who were in complete remission after transplantation was 29 months. The following factors were predictive for longer survival and freedom of progression in a univariate analysis: Male sex, age less than 45 years, a low serum-beta-2-microglobulin value at diagnosis, prior administration of only one treatment regimen, response on conventional chemotherapy immediately pretransplant and the use of a preparative regimen including melphalan. The last factor, in addition to stage I disease at diagnosis, male sex and responsive disease immediately pretransplant, were also demonstrated as independent predictive variables for longer survival in a multivariate analysis. Progression-free survival was significantly better for patients who were in complete remission after transplantation, as compared to those with persisting signs of disease. We conclude that high-dose chemo-radiotherapy with autologous stem cell transplantation can induce long-term responses, primarily in younger, male patients with chemotherapy-responsive early disease. High-dose melphalan, as single drug or in combination, appeared to be superior to other regimens. The chance of being persistently disease-free seemed to be greatest for patients being in complete remission already before the transplantation.

Therapy of 'high risk' myelodysplastic syndromes with an association of low-dose Ara-C, retinoic acid and 1,25-dihydroxyvitamin D3.

Forty-four patients with high risk primary myelodysplastic syndromes and an excess of marrow blasts were treated with a combination of low-dose Ara-C, retinoic acid and vitamin D3. Morphological subtypes were refractory anemia with excess of blasts (RAEB) in 16, RAEB in transformation (RAEB-T) in 20 and chronic myelomonocytic leukemia (CMML) in eight patients. The therapy was continued in responders until relapse or death. The results were compared to those of a matched control of 44 patients given a supportive therapy only. In the treated group the overall response rate was 50% (75% in RAEB, 50% in RAEB-T and 0% in CMML) and the survival was significantly better than in the control group (P < 0.025). Comparing separately each FAB subgroup gave statistical evidence that the treatment prolonged the survival in the RAEB-T subgroup only (P < 0.002). The median duration of response was 15 months and the survival in responders was statistically better than in non-responders (P < 0.0001). Myelosuppression has been the most important side effect, however, no death related to the treatment was observed. Our study suggests that patients with RAEB-T, who are not suitable candidates for aggressive chemotherapy, could benefit from our treatment schedule. The long duration of therapy seems to be of value for patients achieving a response in order to prolong the survival. The toxicity is acceptable and the therapy can be given on an outpatient basis.

Plasma cell leukemia: a report on three patients.

Three patients with plasma cell leukemia are reported. Two of them has a previous history of myeloma; the third one started with a plasma cell leukemia. Diagnosis was made from the required presence of 20% plasma cells in the peripheral blood. In all 3 cases, bone marrow aspiration and peripheral blood showed plasma cells strongly positive for acid phosphatase and alpha-naphthyl acetate esterase, and negative for periodic acid-Schiff. The first patient was treated with a polychemotherapy regimen that included vincristine, cyclophosphamide, chlorambucil and prednisone, and the second patient with melphalan and prednisone; the third one, who started with plasma cell leukemia, received total body irradiation at the dose of 600 rad. The results of the therapy and survival time, which was never more than 3 months, are in accord with other reports in the literature.

Progenitor cells purging: negative selection.

Disease relapse after autologous bone marrow transplantation (ABMT) may arise from residual tumor in the recipient and/or from cancer cells that are reinfused. The aim of purging by negative selection is to remove tumor cells from the marrow without adversely affecting the engraftment potential of the normal cell. We report the results of a study on fifty-six patients (pts) with non Hodgkin's lymphoma or acute leukemia submitted to ABMT after immunomagnetobead (IMB) purging (11 pts), Maphosphamide purging (31 pts) and no purging (14 pts). The IBM procedure involved one incubation of 3 monoclonal antibodies (CD10, CD19 and CD22) and two incubations with magnetic beads (Dynabeads M-450). The median recovery of mononuclear cells and CFU-GM was 40% and 45% after IMB purging and 84% and 5% after Maphosphamide purging respectively. The rate of leukocyte, neutrophils and platelets recovery following ABMT was similar in the three groups of pts, although platelet recovery was slow in patients received graft purged with Maphosphamide. Our study confirms the clinical feasibility of the IMB procedure, but only randomized studies will be able to definitely address the question of the clinical utility of purging.

Autologous blood stem cell collection after chemotherapy in patients with sensitive and refractory malignancies: a multicenter retrospective study.

A retrospective study was undertaken to assess the factors affecting the yield of peripheral blood stem cell (PBSC) collections after chemotherapy. Fifty-five patients with malignancies, observed in 4 Italian Institutions from January 1987 to June 1991 were eligible for evaluation. This series included 19 non-Hodgkin lymphoma, 11 multiple myeloma, 9 ovarian cancer, 7 Hodgkin disease, 7 acute non-lymphocytic leukemia, 1 acute lymphoblastic leukemia, 1 neuroblastoma. Five hundred and twenty two PBSC collections were performed on 55 patients after a median of 18 days after the start of chemotherapy. The yields of PBSC collections were related to the dose of cytoreductive chemotherapy exploited for PBSC mobilization and to the number of circulating white blood cells, colony forming unit granulocyte/macrophage (CFU-GM) and the percentage of monocytes at the time of collection. Forty-eight patients out of 55 transplanted (87%) had rapid, complete and sustained engraftment. Three patients (5%) died of transplant related complications.

Survival after PBSC transplantation and comparison of engraftment speed with autologous and allogeneic marrow transplantation: results of a multicenter study.

We have analyzed the results of a multicenter study on peripheral blood stem cell transplantation (PBSCT) performed on 55 patients suffering from various neoplastic diseases. After myeloablative therapy, they received a median of 6.8 x 10(8)/kg MNC and 11.4 x 10(4)/kg CFU-GM harvested by a median of 9 apheresis after mobilization with chemotherapy alone. As of date, 34 of the 55 patients are alive and 28 of them are in continuous complete remission after a follow-up of 30 months. The probability of survival was related to the disease status at transplant, CR/PR vs. PD (p = 0.0001) and the bone marrow involvement, BM-vs. BM+ (P = 0.009). Furthermore, a comparative study on speed of engraftment and clinical management was conducted on the 55 PBSCT patients as well as on 41 autoBMT and 52 alloBMT patients. Days to reach WBC > 1.0 x 10(9)/L, PMN > 0.5 x 10(9)/L and PLT > 50 x 10(9)/L was 12/14/33 for PBSCT, 17/20/23 for ABMT and 15/16.5/18 for BMT, respectively. Days with fever > 38 degrees C, systemic antibiotic therapy and length of hospitalization was 3/12/36 for PBSCT, 5/18.5/42 for ABMT and 9/25/46 for BMT respectively.

Empiric antibiotic and antifungal therapy for granulocytopenic patients with acute leukemia.

A prospective study was undertaken to determine the effectiveness of an empiric antibiotic treatment employing the combination of a beta-lactam and an aminoglycoside followed in non responders by vancomycin and amphotericin B after 48 and 96 hours respectively. We have evaluated 180 febrile episodes in 102 granulocytopenic leukemic patients. Febrile episodes (44%) were microbiologically documented; 29% were only clinically documented and 27% were possible. In the 180 evaluable episodes treated with a beta-lactam and an aminoglycoside the overall response rate was 61%. In non responders the addition of vancomycin increased the response rate to 83% and the subsequent addition of amphotericin B moved the total responders to 96%. Antibiotic related side effects were minimal. These data suggest the importance of an empiric strategy for treatment of bacterial infections arising in granulocytopenic patients. An early empiric antifungal therapy also appears necessary to control clinically undetected fungal invasion.

Amphotericin B prophylaxis against invasive fungal infections in neutropenic patients: a single center experience from 1980 to 1995.

Fungal infections are a common complication in hematological and oncological patients. In the study the results of a retrospective analysis of the onset of fungal infections among 383 patients admitted at the hematology unit of San Camillo Hospital, Rome, from 1980 to 1995 are reported. In the eleven years prior to 1991 only four cases of fungal infection were detected in high risk patients (1.8% of the high risk patients). From 1991 to 1993 there was a dramatic increase of fungal infections (Candida and Aspergillus). Thirteen cases of infections were observed during this period, eight of which were due to Aspergillus (12% of the high risk patients). For this reason it was decided to introduce a different prophylactic treatment for all high risk patients consisting of combined conventional intravenous (i.v.) amphotericin B, oral amphotericin B and nebulized amphotericin B, starting from the first day of hospitalization. Since the introduction of this new prophylactic regimen no cases of invasive fungal infections were observed in the 48 high risk patients examined. The prophylactic treatment was well tolerated by all patients. The results suggest that the combined use of oral, nebulized and i.v. amphotericin B is very effective in preventing invasive fungal infections in high risk patients.

Hereditary factor VII deficiency: report of a case of intracranial hemorrhage.

A case of factor VII deficiency in a 52-year-old woman who developed central nervous system hemorrhage is here reported. Screening coagulation tests were all normal except for prothrombin time, normotest and thrombotest. Specific assays of vitamin K-dependent factors revealed that factor VII activity was reduced (11 U/dl). The studies of the family demonstrated that 2 sisters out of 4 were heterozygous for the defect. The activity of factor VII in the offspring, classified as obligatory carriers, ranged between 62 and 78 U/dl, the antigen between 55 and 75 U/dl. The wide variability of factor VII in normal people and the possible compensative effect of normal alleles in carriers do not allow to define the variant, namely if the patient is a CRMR homozygote or a CRMR/CRM-double heterozygote.

Glucose-6-phosphate dehydrogenase Velletri.

A new variant of red cell glucose-6-phosphate dehydrogenase (G6PD) has been found in a Caucasian man with congenital non-spherocytic haemolytic anaemia. This variant has reduced activity, increased thermolability, increased Michaelis constants for glucose-6-phosphate and NADP, slightly increased electrophoretic mobility, and a biphasic pH-activity profile. The red cell adenine compounds and ATP, are in normal limits. The increased activity of red cell NADP-glutathione reductase is probably the expression of a mechanism of compensation for the decrease of G6PD and a consequence of the decrease of NADPH.

High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with high-grade non-Hodgkin's lymphoma: the EBMT experience. Lymphoma Working Party of the European Group for Bone Marrow Transplantation.

One hundred and eighteen patients presenting with high-grade non-Hodgkin's lymphoma, undergoing autologous bone marrow transplantation (ABMT) in first complete remission (CR), have been reported to the European Group for Bone Marrow Transplantation (EBMT). Of these, 102 were eligible for inclusion in this study following review of registration forms. Patients with lymphoblastic lymphoma were excluded. Remission induction and high-dose regimens varied between contributing centres. A maintained CR was observed in 90% of patients. Early relapse was observed in 6%, and 4% suffered toxic deaths. With a median follow-up of 45 months (3-112 months), the 5-year actuarial overall and progression-free survivals are both 70%. Nineteen (18%) patients relapsed at a median of 3.5 months (0.25-52 months) after ABMT, only 1 achieving a further durable CR. The only factor with prognostic significance was histological subtype, with diffuse small noncleaved-cell lymphoma having a significantly worse outcome. High-dose therapy and ABMT has produced effective consolidation of first remission in this group of patients, even in those with poor prognostic features at presentation.

Blood stem cells autografts in patients with high risk multiple myeloma.

Five patients with high risk multiple myeloma not responsive to standard chemotherapy were treated by high-dose chemotherapy (Melphalan, Cyclophosphamide) (HDC) and total body irradiation (TBI) followed by autografting with blood stem cells. These cells were previously collected by leukaphereses from eight to twelve occasions during hematopoietic recovery following profound aplasia induced by each course of intensive chemotherapy (Vincristine, Adriamycin, Cyclosphosphamide, Prednisone) when the patient reached a neutrophil count of 1,000/microliters and a platelet count of 100,000/microliters. No patients had evidence of tumor plasmacells in leukaphereses products using cytology, immunocytochemistry and immunofluorescence. At this time the patient 5 is not evaluable because of the short follow-up. One died at day 30 from heart failure. All living patients achieved a complete remission which persisted at a follow-up of 300, 261 and 136 days. Autologous blood derived hematopoietic stem cells induced successful and sustained engraftment in all living patients. Our results indicate the feasibility of this therapeutic approach over allogenic or autologous bone marrow transplantation in selected patients with high tumour mass multiple myeloma.