Alessandro Indovina

Haemopoietic reconstitution after autologous blood stem cell transplantation in patients with malignancies: a multicentre retrospective study

A retrospective study was undertaken to evaluate the efficacy of autologous blood stem cell transplantation (ABSCT) in terms of haemopoietic reconstitution after ablative chemotherapy or chemo‐radiotherapy. 55 patients with malignancies, observed in four Italian institutions from January 1987 to June 1991, were eligible for evaluation. This series included 19 non‐Hodgkins lymphoma, 11 multiple myeloma, nine ovarian cancer, seven Hodgkins disease, seven non‐lymphocytic leukaemia, one acute lymphoblastic leukaemia, one neuroblastoma. 522 PBSC collections were performed on 55 patients. Following ABSCT, the rate of engraftment was positively related to the dose of CFU‐GM infused and negatively to the presence of bone marrow involvement at conditioning. 48 patients out of 55 transplanted (87%) had rapid, complete and sustained engraftment. Three patients (5%) died of transplant‐related complications. Considering that 60% of the patients in this series were in partial remission or in progressive disease at the time of ABSCT, we conclude that ABSCT is a safe approach for the use of ablative conditioning therapy in patients with a wide scope of malignancies, provided that a large number of CFU‐GM have been collected after mobilizing treatment.

High Dose Cyclophosphamide: Stem Cell Mobilizing Capacity in 21 Patients

In the present study we assess the antitumor effect and circulating stem cells (CSC) mobilizing capacity of high-dose cyclophosphamide (5 to 7 gr/m2, HDCY). This treatment was given to 21 patients with various hematologic malignancies (8 NHL, 5 MM, 4 HD, 3 CML) excluding 1 with neuroblastoma. All were eligible for later autologous blood stem cell transplantation (ABSCT). To reduce the hematologic toxicity of HDCY, GM CSF was simultaneously administered in 5 patients. HDCY produced a response (as defined by a > 50% reduction of previous tumor mass) in 3 out of 12 HD/NHL and 1 out of 3 MM. Patients with CML were not considered to be evaluable for tumor response. Cell collection yields after HDCY varied widely with a range of 1.5 to 169.9 x 10(4)/Kg (median 13.1) CFU-GM and 1.7 to 18.4 x 10(8)/Kg (median 5.8) MNC collected per patient. Hematologic recovery was rapid and sustained with a median of 16 (12-18) days to PMN > 0.5 x 10(9)/L and 14 (11-18) days to Plt > 100.0 x 10(9)/L. Granulocyte recovery was significantly faster after GM-CSF (13 vs 16 days to PMN > 0.5, p = 0.0008). Non hematologic toxicity consisted mainly of nausea and vomiting, but fatal complications occurred in 2 patients, from pulmonary infection in one and from tumor-lysis syndrome in the other. HDCY represents a useful means of increasing collection of CSC, but toxicity is not irrelevant. Whether a similar anti-tumor effect and mobilizing capacity would be offered by single lower intermediate doses of the drug is still to be ascertained.

TRANSPLANTATION OF UNMANIPULATED ALLOGENEIC PBSC : PRELIMINARY REPORT ON 24 PATIENTS

To explore the feasibility and potential advantages of PBSC in allogeneic transplantation, we grafted 24 patients (age 16-57, median 37) with different hematologic diseases (ALL = 10, AML = 5, MM = 4, NHL = 2, CML = 1, MDS = 1, AA = 1), 23 HLA-identical to their siblings and 1 partially matched. Cells were collected from donors by apheresis after G-CSF 10 to 16 mg/kg/day for 4 to 5 days, and stored at 4 degrees C until infusion. The patients were conditioned with chemotherapy regimens including busulfan and cyclophosphamide in the majority of cases and received GVHD prophylaxis with CSA-MTX in all but two. The graft consisted of PBSC alone, with a median of 143.5 (range 18.1-358.9) x 10(4)/kg CFU-GM, 9.0 (range 3.3-18.0) x 10(6)/kg CD34+ cells and 2.8 (range 1.2 to 8.6) x 10(8)/kg CD3+ and cells. An ANC >0.0.5 x 10(9)/L was recovered on (median) day 13 (range 11-17), and a platelet count >50 x 10(9)/L on (median) day 13 (range 12-55) post graft. There was no correlation between CD34+ cells or CFU-GM number in the inoculum and time to hematologic reconstitution. Acute GVHD (grade II-IV) occurred in 10 out of 22 (45%), chronic GVHD in 10 out of 18 evaluable (55%) patients. We found no relationship between occurrence of acute or chronic GVHD and number of CD3+ cells in the graft. Four patients relapsed and 7 died after transplantation. Fifteen patients are currently alive and disease-free 67 to 710 (median 286) days from the graft. Allogeneic transplantation with unmanipulated PBSC ensures a fast and stable engraftment. Acute GVHD incidence and severity seems comparable to that of bone marrow transplantation, but there may be an increase in chronic GVHD, mainly of the extensive form.

Multidisciplinary approach in pregnancy-associated thrombotic thrombocytopenic purpura: a case report.

Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder first described by Eli Moschowitz almost 90 years ago1,2. TTP is recognised as being an immune-mediated syndrome associated with inhibitory autoantibodies directed against the von Willebrand factor-cleaving metalloprotease, ADAMTS-13. A classical pentad of clinical features were described, consisting of thrombocytopenia, microangiopathic haemolytic anaemia, renal involvement, neurological abnormalities and fever. The last three features are not necessary for the diagnosis and seem to be relatively late events following end-organ damage3. Plasma exchange treatment with steroid administration has dramatically changed the otherwise grim prognosis of TTP. Rituximab and high-doses of corticosteroids are widely used therapeutic options indicated in refractory/relapsing disease. Other immunosuppressive agents have been also considered, such as vincristine, prostacyclin, cyclosporine, and intravenous immunoglobulins. Pregnancy can be considered a precipitating event for the onset of TTP. In fact pregnancy is commonly associated with numerous metabolic, immunological and haemostatic changes which collectively increase thrombotic risk. Procoagulant activity increases during the course of pregnancy, and is associated with decreased fibrinolytic activity4,5. Thrombocytopenia, resulting from a variety of pathological conditions, is also a common finding in pregnancy, with a prevalence at the end of pregnancy of between 6.6 and 11.6%6. Pregnancy-related syndromes such as pre-eclampsia, eclampsia and HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count) share many of the clinical features of pregnancy-associated TTP and the differential diagnosis is sometimes not easy5. Here we report a case of idiopathic pregnancy-associated TTP with a severe episode of acute pulmonary embolism in the immediate post-partum period and haemorrhagic complications following anticoagulant therapy, requiring prolonged plasma exchange treatment before remission, in a patient intolerant to rituximab.

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

Twenty-three patients with malignant lymphoma, (7 Hodgkins, and 16 non-Hodgkins) 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.

Collection and Transplantation of Peripheral Hemopoietic Stem Cells Results in 35 Patients with Hematological and Non-Hematological Malignancies

It is well known that committed progenitor cells circulate in the peripheral blood of animals and human beings [1,2]. The levels of committed myeloid (CFU-GM), erythroid (BFU-E) and multipotent (CFU-GEMM) progenitor cells, found in the peripheral blood of normal subjects and patients suffering from hematological or neoplastic diseases,vary individually, but are generally very low [3,4]. Evidence in animals and in humans indicate that these cells are capable to restore hemopoiesis, both in lethally irradiated animals and in men [5–12] suggesting that also pluripotent hemopoietic stem cells (PHSC) circulate in peripheral blood and thus can be harvested by leukapheresis.