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Biomedical subjects

F Frassoni

Publications and source records attributed to F Frassoni.

At least 37 records · Page 2Linked to original sources
PubMed1997

Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells early in chronic myelogenous leukemia.

PURPOSE: Mobilization of Philadelphia (Ph) chromosome-negative progenitors is now possible in many Ph1-positive chronic myelogenous leukemia (CML) patients who had received interferon alfa (IFN-alpha) with no cytogenetic response. In this pilot study, we used this approach in patients without prior IFN-alpha therapy to determine if the number and quality of mobilized progenitors would be increased and to evaluate the potential effect of these cells as autografts. PATIENTS AND METHODS: Twenty-two untreated patients were mobilized within 12 months of diagnosis. The treatment regimen consisted of the mini-ICE protocol. Beginning on day +8, granulocyte colony-stimulating factor (G-CSF) was used in all patients. Leukophoresis was performed as the patients were recovering from aplasia, when WBC count exceeded 0.8 x 10(9)/L. RESULTS: In 14 patients, (63%) the leukophoresis product was entirely Ph1-negative and in four patients the Ph1-positive cell rate was < or = 7%. Significant numbers of long-term culture-initiating cells (LTC-IC) and CD34+ Thy1+Lin- cells were found in most of the Ph1-negative collections that were tested. Twelve patients underwent autografting with their mobilized peripheral-blood progenitor cells (PBPC) (Ph1-negative collections, 10 patients; major cytogenetic response, two patients). All patients engrafted and are alive; six have Ph1-negative marrow 7 to 15 months after autografting. Posttransplant treatment was IFN-alpha combined with interleukin (IL)-2 because of the recent demonstration of synergistic activity in augmenting cytolytic activity. CONCLUSION: Intensive chemotherapy given in early chronic phase of CML is well tolerated and results in high numbers of circulating Ph1-negative precursor cells.

Adult↗
PubMed1996

Splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia. Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

A total of 229 patients with chronic myeloid leukaemia (CML) in chronic phase were randomized between 1986 and 1990 to receive or not receive additional splenic irradiation as part of their conditioning prior to bone marrow transplantation (BMT). Both groups, 115 patients with and 114 patients without splenic irradiation, were very similar regarding distribution of age, sex, donor/recipient sex combination, conditioning, graft-versus-host disease (GvHD) prevention method and blood counts at diagnosis or prior to transplant. 135 patients (59%) are alive as of October 1995 with a minimum follow-up of 5 years. 52 patients have relapsed (23%), 26 patients in the irradiated, 26 patients in the non-irradiated group (n.s.) with a relapse incidence at 6 years of 28%. The main risk factor for relapse was T-cell depletion as the method for GvHD prevention, and an elevated basophil count in the peripheral blood prior to transplant. Relapse incidence between patients with or without splenic irradiation was no different in patients at high risk for relapse, e.g. patients transplanted with T-cell-depleted marrows (P = n.s.) and in patients with low risk for relapse, e.g. patients transplanted with non-T-cell-depleted transplants and basophil counts < 3% prior to transplant (P = n.s.). However, relapse incidence differed significantly in patients with non-T-cell-depleted transplants and high basophil counts (> 3% basophils in peripheral blood). In this patient group, relapse incidence was 11% at 6 years with splenic irradiation but 32% in the non-irradiated group (P = 0.05). Transplant-related mortality was similar whether patients received splenic irradiation or not. This study suggests an advantage in splenic irradiation prior to transplantation for CML in this subgroup of patients and illustrates the need for tailored therapy.

Adolescent↗
PubMed1996

Twelve years experience with high-dose therapy and autologous stem cell transplantation for high-risk Hodgkin's disease patients in first remission after MOPP/ABVD chemotherapy.

High-dose therapy followed by autografting can cure patients with aggressive Hodgkin's disease (HD) refractory or with early relapse to first-line combination chemotherapy. On the other hand, the eradication of the disease is rarely achieved in heavily pretreated patients. It has been suggested that patients with HD with very high risk characteristics at diagnosis, often relapse despite appropriate therapy with 7-8 drugs combination. Thus it seems to us that such patients are potential candidates for early autografting during first remission. Twelve years ago, we initiated a pilot study to investigate whether patients with very high risk characteristics, would benefit from early autografting. The application of early autografting was compared with our historical group of patients in complete remission after receiving MOPP/ABVD, who had the same negative prognostic characteristics, refused autografting and who did not receive other treatment after achieving complete remission. Among the 22 consecutive patients entered into the pilot study and autografted, 18 are alive and 17 (77%) remain alive in unmaintained remission at a median of 86 months. One patient (4%) died of interstitial pneumonitis in the transplantation group. Only 8/24 (33%) patients, who did not receive an autograft, are currently alive and disease free at a median of 89 months. In conclusion, the early application of autografting appears to improve the outcome in patients with very high risk HD who achieved remission with MOPP/ABVD.

Adolescent↗
PubMed1996

High-dose chemo-radiotherapy followed by autologous Philadelphia chromosome-negative blood progenitor cell transplantation in patients with chronic myelogenous leukemia.

Twenty-three patients with chronic myelogenous leukemia in early chronic phase (ECP) and not previously treated with alpha-interferon (IFN-alpha) (10 patients), in ECP but pretreated with IFN-alpha (<12 months) (seven patients) and in late chronic phase (LCP) pretreated with IFN-alpha (>12 months) (six patients) underwent autografting with Philadelphia (Ph) chromosome-negative blood progenitor cells (BPCs) (20 patients), or partially/totally Ph-positive BPCs (three patients), previously mobilized during the early phase of recovery after aplasia induced by intensive chemotherapy. The conditioning regimen consisted of high-dose chemotherapy alone or followed by total body irradiation (TBI). Recombinant G-CSF was given after BPCs infusion on day +8. All patients in ECP not pretreated with IFN-alpha are alive and five of them are Ph-negative in the marrow after autografting. Six of seven patients autografted with Ph-negative BPCs in the group of ECP pretreated with IFN-alpha (<12 months) are alive and two of them are still Ph-negative in the marrow. In the same group, the only patient transplanted with partially Ph-positive BPCs, died of blastic transformation 2 months after reinfusion. Three patients (two patients autografted with Ph-negative BPCs and one patient with Ph-positive BPC) in the group of LCP pretreated with IFN-alpha >12 months are alive but Ph-positive after autografting. The other three patients of the same group died of procedure-related toxicity (two patients) and blastic transformation (one patient). Seventeen patients (10/10 ECP not pretreated with IFN-alpha; 5/7 ECP pretreated with IFN-alpha and 2/6 LCP pretreated with IFN-alpha) of 23 autografted patients were treated with IFN-alpha +/- IL-2. Toxicities after autografting were mostly related to myelosuppression, particularly thrombocytopenia. All patients of the two groups pretreated with IFN-alpha developed febrile episodes during the aplastic phase following BPCs reinfusion. No patient autografted in ECP and those not pretreated with IFN-alpha developed febrile episodes. This is also probably due to the use of i.v. antibiotic and antimicotic prophylaxis when neutrophils were < or = 1 x 10(9)/l after autografting. Greater toxicity was observed in patients pretreated with IFN-alpha, being lethal in two cases in LCF. In conclusion, the "in vivo' manipulation approach employed in our institution is a safe procedure and it results in a high collection of Ph-negative cells in the blood if the cells are harvested: (1) in early chronic phase; (2) in early phase of recovery after chemotherapy-inducing aplasia; (3) in patients not extensively pretreated with IFN-alpha. The data presented here have shown encouraging trends in chronic phase of CML and offer new perspective for patients without an HLA-identical donor or for patients who do not respond to IFN-alpha.

Adult↗
PubMed1996

Collection, analysis and transplantation of Ph-negative blood precursor cells in chronic myeloid leukemia.

This work represents an update of our experience on mobilization and transplantation of peripheral blood progenitor cells (PBPC) collected during the early recovery phase after chemotherapy in patients with chronic myelogenous leukemia. The collection of Ph-negative precursor cells occurred in 13/19 (68%) patients mobilized within the first year from diagnosis and not previously treated with interferon alpha (IFN-alpha). Fourteen out of 42 patients (33%) achieved Ph-negative precursors beyond 1 year from diagnosis. Eleven patients mobilized early after diagnosis were subsequently autografted with Ph-negative precursor cells. All patients are alive in hematologic remission and five of them maintain Ph-negativity in the marrow 7-15 months post-autograft. Four patients showed recurrence of Ph-positive cells (5 to 40%) within 4 to 8 months after autografting. Two patients became progressively Ph-positive after 6 months and are now 100% Ph-positive and in stable chronic phase. In the early stage of the disease the mobilization/transplantation procedure is safe and associated with very good compliance. However, occasional restoration of Ph-negative hematopoiesis could occur up to 45 months after autograft in patients undergoing the procedure beyond 1 year from diagnosis, and highly pretreated with IFN-alpha, but most patients revert to Ph-positive hematopoiesis. In an attempt to control the Ph-negative status and to prevent cytogeneic relapse, we are currently treating autografted patients with low doses of IFN-alpha and interleukin-2 (IL-2). Whether and for how long Ph-negative status can be maintained is a matter for future observation and effort.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Results of allogeneic bone marrow transplantation for acute leukemia have improved in Europe with time--a report of the acute leukemia working party of the European group for blood and marrow transplantation (EBMT).

To evaluate whether the results of bone marrow transplantation have improved in Europe with time, we analyzed the outcome for 2195 patients with acute leukemia. 1405 had acute myeloid leukemia (AML) and 790 had acute lymphoblastic leukemia (ALL), and were allografted in first complete remission between September 1979 and December 1991 with marrow from an HLA-identical sibling donor. We found a continuing improvement more evident since 1987 for AML and since 1986 for ALL. A substantial reduction in the 3 years transplant related mortality (TRM): 26 vs 39% for AML (P = 10(-4)), and 25 vs 39% for ALL (P = 10(-4)), has resulted in an increase of the 5-year actuarial leukemia-free survival (LFS). 57 vs 45% for AML (P < 10(-4)) and 54 vs 45% (P = 10(-4)) for ALL. Four important changes have occurred. (1) Graft-versus-host disease (GVHD) prevention has involved an increased use of cyclosporin A (CsA) alone and subsequently its use in combination with methotrexate: this was associated with lower TRM both in AML and ALL; (2) Use of total body irradiation as pretransplant regimen has decreased; (3) a shorter interval from remission to BMT is more common; (4) an older population of patients has undergone BMT. Multivariate analyses were performed separately in AML and ALL. In AML four variables significantly influenced TRM favorably: year of BMT (P = 10(-4)), younger age at BMT (P = 10(-4)), prevention of GVHD including CsA (P = 0.008), sex match other than female donor to male recipient (P = 0.002). The relapse incidence (RI) was lower in patients with FAB M1-2-3 vs M4-5 (P = 0.0004). The LFS improved by year of BMT (P = 0.0004), younger age at BMT (P = 10(-4)), prevention of GVHD including CsA (P = 0.01), FAB M1-2-3 (P = 0.03). In ALL, three variables were associated with a lower TRM: year of BMT (P = 10(-4)), younger age at BMT (P = 10(-4)), sex combination other than female to male (P = 0.008). The LFS was better after 1986 (P = 0.0004) and in younger patients (P = 10(-4)). However a better outcome after 1986/87 was observed in patients receiving the same GVHD prophylaxis: therefore, other unidentified factors resulting in better patient care have also contributed to this. The improved results of allogeneic BMT are entirely related to a reduction in TRM without loss of the antileukemic effect since relapse incidence has not changed over the years.

Adolescent↗
PubMed1996

Autografting Ph-negative blood precursor cells in chronic myeloid leukaemia.

The study was devised to evaluate whether it was possible to collect Philadelphia-negative precursor cells in patients with chronic myeloid leukaemia. The approach was based on previous experience showing that complete remission (Ph-negative bone marrow cells) is rarely achieved after chemotherapy and is very short-lasting. We decided to explore whether it was possible to collect Ph-negative precursor cells in peripheral blood during the early phase of haemopoietic recovery. These data show that: the collection of Ph-negative precursor cells occurred in 12/16 (75%) patients mobilized within one year of diagnosis (group A) versus 12/33 (36%) in patients with a history of more than one year of disease (group B). Furthermore the numbers of Ph-negative precursor cells were significantly much higher at diagnosis. Ten patients mobilized at diagnosis were subsequently autografted with such Ph-negative precursor cells. Five of them remain Ph-negative from 4 to 12 months while the other five have percentages of Ph-positive cells in their marrow ranging from 20% to 70%. In this stage of the disease the procedure is safe and associated with a very good compliance. Occasional restoration of Ph-negative haemopoiesis could be observed up to 40 months after autograft, in patients of group B, but most of patients revert to Ph-positive haemopoiesis. in conclusion these data suggest that it is possible to restore Ph-negative haemopoiesis in 70% of patients mobilized at diagnosis. This percentage represent the highest one can obtain without allogeneic BMT, and this includes patients who never would have been cytogenetic responders to IFN-alpha. Whether and how long for Ph-negative status can be maintained is a matter for future observation and study.

Adult↗
PubMed1996

Retrospective evaluation of autologous bone marrow transplantation vs allogeneic bone marrow transplantation from an HLA identical related donor in acute myelocytic leukemia. A study of the European Cooperative Group for Blood and Marrow Transplantation (EBMT).

We analyzed retrospectively data from 1696 patients with AML transplanted in Europe from January 1987 to December 1992 and reported to the acute leukemia EBMT registry. Groups of patients were analyzed according to age (adults and children) and status at transplant (first remission = CR1; second remission = CR2). (1) 1114 adult patients were transplanted in CR1; 516 received an allograft; 598 received an autograft. Following alloBMT, the transplant-related mortality (TRM) was significantly higher (27 vs 13%, P < 10(-4)), the relapse incidence (RI) lower (25 vs 52%, P < 10(-4)) and the leukemia-free survival (LFS) better (55 vs 42%, P = 0.006). Favorable prognostic factors for alloBMT were a FAB type other than M4-M5, a donor-recipient combination excluding a female donor to a male recipient, and a younger age. Favorable prognostic factors for ABMT were a younger age of the patients at time of transplant, the AML3 FAB type, and a longer interval from CR1 to ABMT. (2) 288 adult patients were transplanted in CR2: 98 received an allograft; 190 received an autograft. The TRM was higher following allogeneic BMT (32 vs 20%, P = 0.02) and the RI lower (42 vs 63%, P = 0.001). The LFS was not significantly different (alloBMT: 39%; ABMT: 30%, P = 0.22). (3) 242 children were transplanted in CR1; 129 received an allograft; 113 received an autograft. Following alloBMT, the RI was lower (25 + 5 vs 48 + 6%, P < 10(-4)), and the LFS better (68 vs 47%, P = 0.002). The use of TBI was a favorable prognostic factor in allografted patients with a lower RI and a better LFS. (4) The number of children transplanted in CR2 was too small for a comparative analysis. These results confirm that both allogeneic and autologous BMT are suitable curative approaches for AML. They favor the use of an HLA identical related allogeneic transplant when available, especially in younger patients, over ABMT with unpurged marrow. The role of purging in ABMT could not be addressed in this study.

Acute Disease↗
PubMed1996

In vivo mobilization of karyotypically normal peripheral blood progenitor cells in high-risk MDS, secondary or therapy-related acute myelogenous leukaemia.

We have previously reported that mobilization of Philadelphia (Ph) chromosome-negative progenitors is possible in a significant number of Ph1-positive acute lymphoblastic leukaemia (ALL) and chronic myelogenous leukaemia (CML) patients. In this pilot study we employed the same approach for patients with RAEB-t, secondary AML (sAML) and therapy-related AML (t-AML). All patients except one had double or complex cytogenetic abnormalities in marrow cells before mobilization therapy. All patients received an idarubicin-containing regimen (mini-ICE protocol) followed by rh-G-CSF and the first leukapheresis was performed as they were recovering from aplasia. In six out of nine patients the leukapheresis product was entirely karyotypically normal, combined with a significant number of CFU-GM. CD34+ cells and LTC-IC. Recovery time from mobilization therapy was short and no patient died as a result of the procedure. To date, three patients have undergone autografting using their karyotypically normal collections, of which two (sAML) are alive with karyotypically normal marrow a few months after autografting.

Adult↗
PubMed1996

Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporin A combined with methotrexate as prophylaxis. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

A total of 1634 recipients of HLA-identical sibling bone marrow with acute leukemia were treated with the combination of cyclosporin A (CsA) and methotrexate as prophylaxis against graft-versus-host disease (GVHD). The probability of relapse decreased with an increasing grade of acute GVHD, especially in patients grafted in first remission (CR-1): P < 0.01 and P < 0.001 for acute lymphoblastic leukemia and acute myeloid leukemia, respectively. Among patients surviving at least 3 months without a relapse, chronic GVHD was associated with a decreased incidence of relapse in CR-1 (P < 0.0001 for both diagnoses), and a better LFS. Among patients in CR-1, the probability of relapse was the same in those with limited or with extensive chronic GVHD. However, in patients with intermediate stage of the disease (> or = 2nd remission or 1st relapse) with previous acute GVHD, those with extensive chronic GVHD had a reduced probability of relapse (P = 0.05). The graft-versus-leukemia effect of acute and especially chronic GVHD was confirmed by multivariate analyses. Overall, the highest LFS was seen in patients with chronic GVHD and no or grades I-II acute GVHD. The lowest LFS was seen in patients having acute GVHD grades III-IV without chronic GVHD.

Adolescent↗
PubMed1995

Philadelphia-chromosome-negative peripheral blood stem cells can be mobilized in the early phase of recovery after a myelosuppressive chemotherapy in Philadelphia-chromosome-positive acute lymphoblastic leukaemia.

Ten patients in first or second relapse with Philadelphia chromosome acute lymphoblastic leukaemia, ineligible for allogeneic sibling marrow transplantation, were treated with an intensive chemotherapy regimen including idarubicin, intermediate-dose arabinosylcytosine, etoposide and G-CSF. Peripheral blood stem cells were collected by leukapheresis during initial early WBC recovery from chemotherapy-induced aplasia. In 5/10 patients all metaphases in leukapheresis products were found to be Philadelphia-chromosome-negative and they have been used as autotransplants after conditioning with TBI/etoposide/cyclophosphamide (or idarubicin) and G-CSF. All five patients showed sustained engraftment and one of them is alive and well Philadelphia-chromosome-negative 18 months after transplant. These preliminary results suggest that it is possible to recover Philadelphia-chromosome-negative blood stem cells after intensive chemotherapy, even in advanced patients, and to perform autografting with these cells.

Adolescent↗
PubMed1995

CMV-antigenemia after allogeneic bone marrow transplantation: correlation of CMV-antigen positive cell numbers with transplant-related mortality.

One hundred and thirty-four consecutive patients undergoing HLA-identical BMT were prospectively followed on a weekly basis for the development of CMV antigenemia (CMVAg-emia). End-points of the study were (1) incidence, (2) risk factors, and (3) predictive effect on transplant-related mortality (TRM). Fifty-six patients developed CMVAg-emia between day 8-366 (median 40) with an overall actuarial risk of 43%. The median number of positive cells a diagnosis was 4 (range 1-48) the median maximum number was 6.5 (range 1-435). Positive cells are expressed as number/2.5 x 10(5) cells. In multivariate analysis, T cell depletion (TCD) (RR 2.9, P = 0.0009) and acute graft-versus-host disease (RR 2.1, P = 0.01) were the two risk factors predictive for CMVAg-emia. The risk of developing CMV-IP was significantly higher in patients with, as compared to patients without, CMVAg-emia (P = 0.0005) and occurred mostly in patients who received TCD marrow (P = 0.0009) despite treatment with gancyclovir or foscarnet at the time of CMVAg-emia. TRM was 24% in patients not developing CMVAg-emia; it was 21 and 47% in patients with "4" positive cells at diagnosis of CMV (P = 0.008), and 12 vs 54% for patients with "6" positive cells during infection (P = 0.0003). Both were predictive of TRM in multivariate analysis (P = 0.04 and P = 0.002). In conclusion, the risk of developing CMVAg-emia post-allo BMT is influenced by the marrow T cell content and by the occurrence of acute GVHD. High numbers of CMV antigen positive cells are associated with considerable transplant-related mortality, and may therefore identify patients eligible for early aggressive therapy.

Adolescent↗
PubMed1995

Autografting in chronic myelogenous leukemia: new questions.

In the 1970s, when autografting was started, it was hard to imagine that this procedure would have an application in hematological malignancies. Autografting in patients with CML has been difficult to pursue because their bone marrow is often contaminated by Philadelphia-chromosome positive cells. In recent years, renewed interest has come from this procedure and various in vivo or in vitro techniques of manipulation of Ph-positive cells, such as collection of blood progenitor cells in the early phase of recovery after intensive conventional chemotherapy in untreated or pretreated patients, long-term bone marrow culture and chemical purging of marrow cells. Despite all these interesting trials, we do not have enough data to address the question of whether autografting in CML increases the duration of the chronic phase.

Animals↗
PubMed1995

Very primitive hemopoietic cells (LTC-IC) are present in Philadelphia negative cytaphereses collected during early recovery after chemotherapy for chronic myeloid leukemia (CML).

We have previously demonstrated that Philadelphia negative (Ph-ve) hemopoietic cells can be collected by leukaphereses after an acute leukemia-like chemotherapy during the early hemopoietic recovery in patients with chronic myeloid leukemia (CML). In this study we have evaluated whether these collections contain very primitive hemopoietic cells defined as 'long-term culture initiating cells' (LTC-IC) and whether these cells belong to the Ph-positive or Ph-negative population. Twenty-eight out of 76 cytaphereses collected in 15 patients with CML proved to contain Ph-ve cells only (six patients), 21 showed only Ph+ve cells (five patients), and 27 a mixture of Ph+ve and Ph-ve cells (four patients). In cytaphereses containing Ph-ve cells only, we found variable numbers of LTC-ICs, more consistently when we mobilized patients in the first 3 months from diagnosis. In three cases cytogenetic analysis on LTC-ICs and CFU-GM confirmed results obtained on fresh samples. Ph-positive collections were devoid of LTC-ICs except for 2/21 samples. However, their cytogenetic analysis revealed a small number of Ph-negative progenitors. LTC-ICs were randomly detected in mixed (Ph+ve and Ph-ve) collections. In conclusion these data indicate that, in a consistent proportion of chronic myeloid leukemia patients, intensive chemotherapy is able to recruit Ph-ve LTC-ICs in to the peripheral blood. Moreover these data provide the biological basis for developing autografting programs with Ph-negative cells.

Cytapheresis↗
PubMed1995

bcr/abl chimeric transcript in patients in remission after marrow transplantation for chronic myeloid leukemia: higher frequency of detection and slower clearance in patients grafted in advanced disease as compared to patients grafted in chronic phase.

The polymerase chain reaction (PCR) was used to amplify the bcr/abl transcript as a marker of minimal residual disease (MRD) in 76 patients with chronic myeloid leukemia (CML) subjected to allogeneic BMT and in complete hematological remission. We examined 56 patients transplanted in chronic phase (CP) and 20 in advanced phase (AD), including 16 in accelerated phase and four in blastic transformation. A total of 135 samples collected between 4 and 105 months from BMT were analyzed and the PCR analysis was positive in 33 (24%) samples from 20 patients. The bcr/abl chimeric transcript was detected in 7/13 (54%) patients analyzed within 1 year and in 21/88 (23%) beyond 1 year from BMT. Fluctuation of the residual disease at the molecular level in individual patients was recorded. The results have been correlated with a number of clinical parameters obtained before and after BMT; among the tested variables only the phase of the disease at BMT was associated with higher frequency of PCR positivity after BMT. The probability of finding persisting disease 1 year beyond BMT was significantly higher (P = 0.00005) in patients allografted in AD (14/26, 54%) as compared to patients grafted in CP (7/62, 11%). At any interval from BMT the difference between the two groups remained statistically significant: the bcr/abl transcript was present in 5/31 patients transplanted in CP compared to 9/15 patients transplanted in AD (P = 0.003) between 12 and 36 months from BMT, and in 2/31 CP vs 5/11 AD patients (P = 0.008) beyond 36 months from BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗