Addition of aerosolized deoxycholate amphotericin B to systemic prophylaxis to prevent airways invasive fungal infections in allogeneic hematopoietic SCT: a single-center retrospective study.

Invasive fungal infections (IFIs) still pose major challenges in allogeneic hematopoietic SCT (HSCT), and effective antifungal prophylaxis remains a matter of debate. The aim of this retrospective study was to evaluate the toxicity and the impact of aerosolized deoxycholate amphotericin B (aero-d-AmB) on respiratory tract IFIs (airways IFIs) in a homogeneous cohort of allogeneic HSCT patients, transplanted at one institution. Since 1999, 102 consecutive patients were transplanted from matched related (N = 71) or unrelated donor (MUD). Aero-d-AmB was administered for a median time of 16 days (range 2-45), in addition to systemic antifungal prophylaxis. Prolonged administration was neither associated with increased severe bacterial infections, nor with severe adverse events. In 16 patients in whom aero-d-AmB was delivered for less than 8 days, due to worsened clinical conditions or poor compliance, proven or probable airways IFIs were diagnosed in three cases (one mucormycosis and one fusariosis and one probable aspergillosis), whereas in 84 patients receiving aero-d-AmB for ≥ 8 days, one possible and one probable aspergillosis were diagnosed. A shortened administration (< 8 days) of aero-d-AmB was therefore associated with an increased risk of both total airways IFIs (P = 0.027) and proven/probable IFIs (P = 0.012). At multivariate analysis prolonged aero-d-AmB administration retained an independent protective effect on airways IFIs (P = 0.026) whereas a MUD transplant was associated with a borderline increase of IFIs risk (P=0.052). Overall, 95.1% of patients did not experience airways IFIs and no patient died due to IFIs. In this cohort of patients, prolonged aero-d-AmB seems to have a role in preventing respiratory tract IFIs, but a randomized controlled trial is recommended to verify the impact of this prophylaxis in the setting of allogeneic HSCT.

Prolonged survival and low incidence of late toxic sequelae in advanced follicular lymphoma treated with a TBI-free autografting program: updated results of the multicenter consecutive GITMO trial.

This study provides an updated report of the consecutive multicenter Gruppo Italiano Trapianto Midollo Osseo trial employing an intensified, purging-free, total body irradiation-free, high-dose sequential chemotherapy schedule with peripheral blood stem cell autograft (i-HDS) in advanced-stage follicular lymphoma (FL). Special interest has been devoted to late toxicities and outcome in terms of molecular status. Ninety-two untreated FL patients aged

Secondary acute myeloid leukaemia: results of conventional treatments. Experience of GIMEMA trials.

BACKGROUND: The aim of the study was to evaluate the outcome of acute myeloid leukaemia (AML) in patients with a previous malignancy (sAML) treated with chemo- and/or radiotherapy, enrolled in conventional trials. PATIENTS AND METHODS: In a multicentre setting, a prospective non-concurrent analysis was performed on 2513 new AML patients, aged 12-78 years, consecutively enrolled in EORTC-GIMEMA trials between 1987 and 2001. Thirty-eight patients with sAML were identified and compared with a group of 114 de novo AML patients matched according to age, French-American-British criteria, white blood cell count at diagnosis, trial and time of diagnosis of AML. Induction treatment response, disease-free survival (DFS), duration and overall survival (OS) were evaluated in the two groups. RESULTS: Comparing the complete remission (CR) rate between 38 sAML patients and 114 de novo AML patients, selected according to the previously reported criteria, we observed no difference in the CR rates [25/38 (66%) versus 66/114 (58%); Pearson chi(2) 0.7393, P=0.390] as well as no differences while comparing the DFS and the OS between the two groups. CONCLUSION: The results of this study suggest that sAML patients are characterised by a good performance status permitting their recruitment in conventional trials without a previous myelodysplastic phase. Similar to de novo AML patients, sAML patients show good response to treatment and the possibility of cure.

Transient myeloproliferative disorder with a CD7+ and CD56+ myeloid/natural killer cell precursor phenotype in a newborn.

Anewborn with a transient myeloproliferative disorder and a myeloid/natural killer cell leukemia phenotype is described. The blasts expressed CD7, CD33, CD34, CD56, and CD117 but did not react with cytoplasmic myeloperoxidase and were negative for cy CD22, HLA-DR, and CD90 expression. No megakaryoblastic surface markers were identified. The blast population disappeared from the peripheral blood and bone marrow within 2 months, but hepatomegaly and recurrent respiratory insufficiency persisted. The patient died of unilateral pneumonia in the third month of life. Neither extramedullary infiltration nor other hematologic signs of disease progression were found.

Treatment of Kasabach-Merritt syndrome by embolisation of a giant liver hemangioma.

We report the case of a 14-month-old child with Kasabach-Merritt Syndrome, due to a giant liver hemangioma. The therapeutic approach consisted of peripheral transcatheter embolisation of the right hepatic artery with Ivalon microspheres without the addition of thrombogenic material. This procedure brought to a sensible permanent reduction of the size of the liver hemangioma with normalisation of the previous altered coagulation parameters after 6 years of follow-up.

Risk-oriented postremission strategies in adult acute lymphoblastic leukemia: prospective confirmation of anthracycline activity in standard-risk class and role of hematopoietic stem cell transplants in high-risk groups.

INTRODUCTION: Although definite risk classes are well known, risk-adapted modulation of first-line therapy is seldom attempted in adult ALL. So, a prospective validation of the therapeutic efficacy of a protocol (or a component thereof) in specific risk groups is uncommon. MATERIALS AND METHODS: From 1996-1999 a risk-oriented program (08/96) was evaluated in 102/121 unselected patients (median age 35 years, blast count 0-450 x 10(9)/l, 100 B(lin) (lineage), 21 T(lin)) responsive to induction therapy. The standard risk (SR) class was B(lin) CD10+ Ph- with blasts < 10 x 10(9)/l (prior studies: disease-free survival (DFS) rate 52% at five years with dose-intensive anthracycline-containing programs). The SR protocol was therefore anthracycline-rich (early consolidation cycles with total idarubicin 96 mg/m2), and comprised long-term maintenance. High-risk (HR) patients were eligible to the following three options: allogeneic hematopoietic stem cell transplantation (HSCT) from related family donor; short sequence with high-dose cyclophosphamide-cytarabine-methotrexate followed by melphalan/total body irradiation with autologous HSCT; or T(lin) ALL chemotherapy regimen inclusive of high-dose cytarabine and methotrexate. RESULTS: Treatment realization and three-year DFS rates according to risk class, HR subset and postremission treatment intensity were the following. SR group (n = 28): realization rate 93%, DFS 68.5%. HR group (n = 74): realization rate 80%, DFS 39% (P = 0.052 vs SR category). In HR group, three-year DFS rates by disease subtype were the following. B(lin) Ph- (n = 35) 43%; Ph+ (n = 19) 13% at 2.7 years (P = 0.006 vs other HR subtypes); T(lin) (n = 18) 59.5%. And DFS rates by treatment intensity were: allograft (n = 21) 40%; autograft (n = 28) 27%; shift to SR protocol (n = 13) 52% (P = ns vs allograft/autograft); T(lin) program (n = 10) 57%. Matched analyses of treatment protocols and disease subtypes suggested a possible therapeutic role of the autograft regimen in B(lin) Ph- ALL with a blast count < 25 x 10(9)/l, and of T(lin) protocol for T(lin) ALL. Comparisons with retrospective control cohorts were confirmatory of anthracycline activity in SR subclass. CONCLUSION: The intended strategy was applicable to the majority of study patients, confirming the value of anthracyclines in SR class and, preliminarily, the usefulness a T(lin)-specific treatment. Apart from the case of Ph+ ALL, the indications for high-dose procedures with HSCT remains largely undetermined in this study.

Cemp, a mitoxantrone containing combination, in the treatment of intermediate and high grade non-hodgkin's lymphoma: an effective and non toxic therapeutic alternative for adult and elderly patients.

Here we report the results of a randomised multicenter phase III clinical trial which assesses the therapeutic efficacy and tolerability of a chemotherapy protocol CEMP (cyclophosphamide, etoposide, mitoxantrone and prednisone) in adult and elderly patients with advanced intermediate and high-grade NHL. Between October 1991 and October 1995, 139 patients, aged 55 to 79 years, with diffuse intermediate and high-grade lymphoma, were enrolled. A considerable percentage of patients had clinically aggressive disease: 32.4% had systemic symptoms, 79% had stage III or IV disease, 33.8% had bone marrow involvement, 46% had splenic involvement and 42.5% had increased values of serum lactate dehydrogenate. Complete remission was achieved in 70 of the 139 patients (51.9%) and PR in 12 (16.6%) with an overall response of 68.5%. The overall response survival rate at 6 years was 39%, whereas DFS rate was 48.7% and PFS rate was 28.5%. At four years 49% of the patients were still in CR. Dividing the patients in two groups, under and over 65 years of age, we obtained the same results as far as overall response is concerned. No toxic deaths occurred, neither cardiac, renal nor liver complications happened. CEMP regimen is an effective and safe protocol with good results in elderly people, well comparable to those achieved in younger ones.

Peripheral blood monoclonal B-cells predict the event free survival in multiple myeloma.

Reinfusion of myeloma progenitor cells may contribute to relapse of multiple myeloma after autologous stem cell transplantation. The aim of our study was to investigate whether monoclonal B-cells are present in the apheresis product and to evaluate the clinical relevance of these cells. Leukapheresis products of 55 patients were purged with anti-B-cell-Monoclonal antibodies (MoAbs) and immunobeads. Monoclonal B-cells were found in 85% of patients within the B-cell population. In one third of all myeloma patients, the majority of B-cells was represented by monoclonal myeloma progenitor B-cells, whereas in two thirds of patients monoclonal cells only represented a small part of the entire B-cell population. As shown by sequence analysis, monoclonal precursor B-cells and malignant plasma cells had the identical genetic CDR III sequence. The purging efficacy, using a negative selection system, was a median of 3 logs (range 1,5-3,5). No statistical difference in the purging efficacy was found when 3, 4 or 5 MoAbs against B-cells antigens were used. However, a tumor specific signal could be detected in the purged harvest of all patients, when the highly sensitive ASO-PCR approach was used. Furthermore, we found a direct correlation between the amount of remaining monoclonal cells after negative selection and the event free survival of myeloma patients. 10/15 patients with a median of 20 x 10(3) monoclonal cells in the purged product relapsed at a median of 1,4 years, whereas only 6/24 patients with an oligoclonal pattern including a low number of remaining monoclonal cells relapsed at a median of 2,2 years. The event free survival (EFS) was statistically different between the two groups (p = 0,014).

Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia.

Between July 1992 and June 1996, 3934 new cases of acute leukaemia were registered in the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Archive of Adult Acute Leukaemia. Two hundred cases (5.1%) presented with a history of primary malignancy (PM), 179 of which were acute myeloid leukaemia (AML). The median age of these cases was significantly higher than that of other primitive AML (63 years vs. 57 years; P < 0.001). The number of men was significantly lower than the number of women [74/1544 (4.8%) vs. 105/1420 (7.4%); odds ratio (OR) 0.63, 95% confidence interval (CI) 0.46-0.87; P < 0.002], as was the number of patients aged <65 years [104/1963 (5.3%) vs. 75/1001 (7.5%); OR 0.69, 95% CI 0.50-0.95; P < 0.01]. An increased incidence of cancer was observed among first-degree relatives of patients with AML occurring after a PM (secondary AML; sAML) [66/179 (36.9%) sAML vs. 757/2785 (27.2%) de novo AML, age adjusted; OR 2.62, 95% CI 1.07-6.42; P < 0.005]. Prevalent types of PM were breast cancer, lymphoma and Hodgkin's disease. sAML occurred after a median latency of 52 months (range 2-379). Of the 122 patients who received chemotherapy for sAML, 67 patients (55%) achieved a complete remission (CR), three a partial remission, 15 (12%) died in induction and 37 (30%) were unresponsive. The median duration of CR was 30 weeks (range 4-250). The median overall survival was 7 months (range 1-196). Comparing acute promyelocytic leukaemia with all other French-American-British (FAB) groups, a significant increase in CR achievement was observed [14/18 (77.7%) vs. 53/101 (52.4%), P < 0.046] as well as in median CR duration (55 vs. 24 months, P < 0.02). The analysis of our data suggests that not only previous chemotherapy but also genetic predisposition could play a role in the pathogenesis of sAML.

A validated real-time quantitative PCR approach shows a correlation between tumor burden and successful ex vivo purging in follicular lymphoma patients.

OBJECTIVE: Purging procedures are increasingly used to provide stem cell collections devoid of contaminating tumor cells. In follicle center lymphoma (FCL), most approaches eradicate polymerase chain reaction (PCR);-detectable disease in only a fraction of harvests undergoing ex vivo manipulation. In this study we evaluated whether there is a relationship between tumor burden of stem cell harvests and successful clearance of PCR-detectable disease following ex vivo manipulation. MATERIALS AND METHODS: To address this issue, we developed a real-time PCR approach for quantitative measurement of tumor contamination using the bcl-2 rearrangement. Real-time PCR was used to evaluate the relationship between tumor burden of stem-cell harvests and purging effectiveness in PCR(+) samples derived from 10 FCL patients. Ex vivo purging was performed using the MaxSep cell separator (Baxter Immunotherapy, Deerfield, IL, USA). RESULTS: Our real-time PCR method proved effective, sensitive, accurate, and reproducible. Four collections were successfully cleared of minimal residual disease (MRD) whereas six remained PCR(+). Real-time PCR showed that the four collections successfully cleared of MRD had a prepurging tumor burden significantly lower than those remaining PCR(+) (p = 0.04). CONCLUSION: This study provides the first evidence that evaluation of tumor burden in stem-cell harvests by real-time PCR can predict the effectiveness of therapeutic intervention in non-Hodgkin's lymphoma. Based on these findings, we foresee a more widespread use of this technique to evaluate the impact of different therapeutic approaches in FCL.

Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO).

One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P =.001) and 88% versus 87% for patients aged less than versus more than 16 years (P =.8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF. (Blood. 2000;95:1931-1934)

VACOP-B, high-dose cyclophosphamide and high-dose therapy with peripheral blood progenitor cell rescue for aggressive non-Hodgkin's lymphoma with bone marrow involvement: a study by the non-Hodgkin's Lymphoma Co-operative Study Group.

BACKGROUND AND OBJECTIVE: Sequential treatment with the addition of high-dose therapy (HDT) and peripheral blood progenitor cell (PBPC) rescue has been reported to be active as front-line therapy in aggressive non-Hodgkin's lymphoma (NHL) with bone marrow (BM) involvement. We designed an intensive sequential therapy as front-line therapy in this subset of patients and conducted a phase II study. DESIGN AND METHODS: Patients with aggressive non-Hodgkin's lymphoma and BM involvement at diagnosis received 8 weeks of VACOP-B chemotherapy as induction therapy. The second phase included high-dose cyclophosphamide (HDCY) (7 g/m(2)) with granulocyte colony-stimulating factor (G-CSF) followed by leukaphereses. The third phase included HDT according to the BEAM protocol or melphalan (140 mg/m(2)) plus total body irradiation (8 Gy in a single dose). RESULTS: Forty patients were included in the study. According to the intention-to-treat, after VACOP-B, 11 (27.5%) and 22 (55%) patients achieved complete remission (CR) and partial remission (PR), respectively. Thirty-four received HDCY. After HDCY, 18 patients (45%) were in CR and 13 (32.5%) in PR. Twenty-nine underwent HDT plus peripheral blood cell rescue (PBPC) rescue. At the completion of treatment 29 patients (72.5%) were in CR, and 3 patients (7.5%) in PR. The actuarial 3-year overall survival, disease free survival and failure free survival are 48%, 55% and 40%, respectively. Overall severe toxicity was 7.5%. INTERPRETATION AND CONCLUSIONS: This phase II study suggests that the intensified treatment described is feasible and active in aggressive NHL with BM involvement. A randomized trial is now underway to test this approach.

Fractionated cyclophosphamide added to the IVAP regimen (idarubicin-vincristine-L-asparaginase-prednisone) could lower the risk of primary refractory disease in T-lineage but not B-lineage acute lymphoblastic leukemia: first results from a phase II clinical study.

BACKGROUND AND OBJECTIVE: In a prior study, primary resistant acute lymphoblastic leukemia (RES-ALL) was observed in 11 of 176 (6%) adult patients treated with a four drug regimen (IVAP), its incidence being higher in T-cell or Philadelphia (Ph) chromosome/BCR-ABL rearrangement positive ALL cases with a blast cell count >25x10(9)/L (RES-ALL rate 19%, p=0.04). Aiming to minimize this percentage of resistant disease, fractionated cyclophosphamide (f-CY) was then added to the IVAP regimen. DESIGN AND METHODS: Study 08-96 was a prospective, collaborative phase II trial carried out at eight general hospital centers specialized in the care of hematologic malignancies. Historical IVAP-treated patients served as a retrospective control group. All consecutive, untreated patients (>15 years) with a diagnosis of ALL or advanced-stage lymphoblastic lymphoma (LBL) were eligible. RES-ALL was defined as the persistence of >5% ALL cells in the bone marrow 28-40 days after the start of the IVAP regimen (idarubicin 10 mg/m(2)/d on days 1 and 2; vincristine 2 mg on days 1, 8 and 15; L-asparaginase 6,000 U/m(2) on alternate days 3 6 from day 8; prednisone 60 mg/m(2)/d on days 1-21). In the new study, two f-CY schedules were sequentially adopted: CY 150 or 75 mg/m(2)/bd, given for 4 consecutive days before IVAP (f-CY 1200 or 600, expressing total CY dose in mg/m(2)). RESULTS: Eighty-eight patients were evaluable (age range 15-74 years, blast count 0-240x10(9)/L, 14 T-lineage, 74 B-lineage, 13 Ph/BCR-ABL+). The first 39 patients received the f-CY 1200 schedule, 22 patients received f-CY 600, and the last 27 patients were not given any f-CY. These changes were dictated by the results of interim analyses of the f-CY groups (RES-ALL rate not reduced, myelotoxicity increased). Altogether, compared with the historical IVAP and no f-CY groups, the incidence of RES-ALL was not decreased by the addition of f-CY 1200/600 in B-lineage ALL, regardless of Ph/BCR-ABL expression and blast count. However, none of 14 T-ALL cases in the new study had RES-ALL (8 in f-CY groups, 5 of whom with >25x10(9)/L blast cells), compared to 5/39 (13%, overall) or 4/21 (19%, with >25x10(9)/L blast cells) among the control cases. Owing to small sample size, this difference was not statistically significant. INTERPRETATION AND CONCLUSIONS: This preliminary experience suggests that T-ALL may be more sensitive than B-lineage ALL to an early therapy including f-CY. The hypothesis could be tested in a larger clinical trial.

The relationship between monoclonal myeloma precursor B cells in the peripheral blood stem cell harvests and the clinical response of multiple myeloma patients.

The aim of this study was to determine the presence of monoclonal myeloma precursor B cells in peripheral blood stem cell harvests and to investigate their role in the clinical outcome of multiple myeloma patients. A total of 39 multiple myeloma patients were treated with a sequential therapy including double high-dose melphalan therapy followed by a double transplant procedure. The apheresis products for the second transplant were purged using a panel of four or five different mouse monoclonal antibodies against B-cell antigens (CD10, CD19, CD20, CD22 and CD37). In 19/39 patients a tumour-specific CDR III signal was identified in the diagnostic bone marrow. Gene scan analysis after CDR III PCR of the magnetic bead isolated B-cell fraction from the apheresis products in these 19 patients revealed three different patterns: 32% of patients had a predominantly monoclonal B-cell population; 63% of patients had an identifiable monoclonal signal within an oligoclonal B-cell population. In only 1/19 patients were no monoclonal B cells identified in the B-cell population of the apheresis product. A correlation between the clonal pattern and the clinical response after sequential chemotherapy was found. Patients with a predominance of monoclonal myeloma or myeloma precursor B cells had an early relapse or achieved a minimal response or a partial remission. Patients with an oligo- and/or polyclonal pattern achieved a high percentage of partial as well as complete remissions.

Autologous transplantation in multiple myeloma: a GITMO retrospective analysis on 290 patients. Gruppo Italiano Trapianti di Midollo Osseo.

BACKGROUND AND OBJECTIVE: Autologous transplantation is a better treatment for multiple myeloma (MM) than chemotherapy, but uncertainty remains about patient selection, optimal timing of autograft, conditioning regimen, need for a second autograft, and role of maintenance. To provide partial answers to these questions we assessed the results of autologous transplantation in a large cohort of patients whose data were reported to the GITMO registry. DESIGN AND METHODS: We retrospectively analyzed data from 290 patients with MM (M = 150; F = 140; median age 52 years, range 19-70; stage I = 34, stage II = 75, stage III = 167) reported to the GITMO. At the time of autograft, 20% were in CR, 66% in PR, while the remaining had non-responsive or progressive disease. Median time between diagnosis and transplant was 16 months (1-90). Seventy-two patients (26%) had been planned to receive a double autograft, but this was actually done in only 35 (12%). The conditioning was chemotherapy in 90%. Peripheral blood was the only source of stem cells in 94%, and purging was applied in 10% of cases. For statistical analysis of data, differences between patient subsets were analyzed using the chi-square test, while the Kaplan-Meier method was used to estimate event-free survival (EFS) and survival (OS) probabilities. The Cox model was used for multivariate analysis. RESULTS: Following the autograft, 116 patients (40%) were in CR, 144 (50%) in PR, 24 (8%) did not respond or progressed and 6 (2%) died before response evaluation. Transplant-related mortality occurred in 3%. At a median follow-up of 23 months, 223 (77%) patients are alive, 71 (24%) of them in CR, and 67 (23%) patients have died at a median time of 20 months (0-70). OS and EFS at 6 years are 47% and 28%, respectively, but the EFS curve shows no plateau. In multivariate analysis, age, beta2-microglobulin level and status at transplant emerged as significant prognostic factors for both OS and EFS, while time from diagnosis to transplant showed borderline significance. INTERPRETATION AND CONCLUSIONS: Based on the prognostic factors identified in multivariate analysis, we were able to assess the weight of a single prognostic factor or their combinations on transplant outcome. We also calculated the probability of OS and EFS by the number of factors at the time of autograft. Autologous transplantation is a safe and effective procedure, not only in sensitive patients, but also in resistant cases, provided they are <55 years of age and have low beta2-microglobulin. It should be applied early after the diagnosis of multiple myeloma, following the delivery of brief primary chemotherapy.