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M Baccarani

Publications and source records attributed to M Baccarani.

At least 37 records · Page 2Linked to original sources
PubMed2003

Prognosis and prognostic factors for patients with chronic myeloid leukemia: nontransplant therapy.

Reliable knowledge about an individual's prognosis is needed to select the appropriate treatment for patients with chronic myeloid leukemia (CML). The New CML score using age, spleen size, blast cell count, eosinophil count, basophil count, and platelet count shows good discrimination for survival (96, 65, or 42 months, P </=.0001) and has been thoroughly validated. Careful analyses indicate that the New CML score is considerably more precise in identifying high-risk patients than the Sokal score. Achievement of complete hematologic response (CHR) up to 9 months shows a distinct impact on survival, which, however, depends on the baseline prognosis. Ten-year survival probabilities for low- and intermediate-risk patients with a CHR were 0.51 (95% confidence interval [CI], 0.42 to 0.60) and 0.23 (95% CI, 0.15 to 0.31) and without a CHR were 0.26 (95% CI, 0.16 to 0.37) and 0.12 (95% CI, 0.04 to 0.20). In high-risk patients CHR had no impact on prognosis. Therapeutic options were widened by the approval of imatinib for the treatment of CML. However, it will still take 2 or more years to know whether the high rates of CHR and cytogenetic complete remission (CCR) achieved with imatinib translate into a clinically relevant survival advantage for all patients.

Humans↗
PubMed2003

CD34+-selected versus unmanipulated autologous stem cell transplantation in multiple myeloma: impact on dendritic and immune recovery and on complications due to infection.

BACKGROUND: Large-scale CD34+ enrichment has been demonstrated a safe method in autologous transplantation for multiple myeloma. However, the high CD34+ enrichment and the consequent plasma cell purging result in concomitant T-cell and dendritic-cell (DC) depletion, theoretically increasing the risk of life-threatening infections. PATIENTS AND METHODS: We evaluated immunological and dendritic reconstitution in 72 myeloma patients who had undergone CD34+-selected (n = 45) and unmanipulated (n = 27) stem cell transplant, and its correlation with infections. RESULTS: Haematological recovery occurred promptly in all patients. Only a slight delay in platelet recovery to >50 x 10(9)/l was observed in patients receiving CD34+-enriched graft. Natural killer (NK) cell count recovered in all patients within 2 months and B-cell count had recovered by 6 months post-transplant in both groups. CD3 cells remained lower than normal in both groups. CD8 cells increased above the normal level, reaching a peak at day 90, and lowered to normal level within 1 year post-transplant. CD4 lymphocytes remained <50% of normal, especially in selected patients. In both groups, both DC1 and DC2 counts were already significantly lower than in normal individuals before conditioning therapy. Pre-conditioning levels of DC1 were reached in unmanipulated patients at day 30 and became normal at 6 months. In selected patients, DC1 pre-transplant level was observed at day 60 and was maintained thereafter. DC2 recovery showed a similar trend. In unselected patients, DC2 count increased to pre-conditioning level at haematological recovery and was normal after 1 year. In selected transplants, DC2 increased more slowly than DC1 in the same patients: pre-transplant level was detected at day 90 but was still significantly lower than normal 1 year after transplant. The incidence of infection was similar in both groups. Sepsis had Gram+ aetiology in the majority of cases. After engraftment only viral infections were recorded, mostly due to herpes reactivation, with no difference between groups. DISCUSSION: In spite of a delay in immune recovery, CD34 enrichment is not associated with a significant increase of complications due to infection. Relatively fast NK cell recovery to pre-transplant levels and the presence of functionally efficient DCs can justify the low incidence of infections.

Adult↗
PubMed2002

Liposomal daunorubicin (DaunoXome) for treatment of poor-risk acute leukemia.

Toxicity limits the use of anthracyclines in elderly sick patients and in heavily pretreated patients. Since the liposomal preparation of daunorubicin (DNR) (DaunoXome, or DNX) is expected to be less toxic than conventional DNR, we tested DNX combined with high-dose arabinosyl cytosine (HDAC) in 42 adult poor-risk acute leukemia patients. Thirty-one patients had acute non-lymphocytic leukemia (ANLL). Of these, 12 patients were newly diagnosed but were not eligible for standard induction treatment, 13 were in first relapse, and 6 were in second or subsequent relapse. Eleven patients had acute lymphocytic leukemia (ALL), in first (eight cases) or second (three cases) relapse. DNX was given i.v. in three doses of 80 or 100 mg/m(2) each (days 1-3) by a 60-min infusion in glucose 5%, followed by a 4-h infusion of HDAC 2 g/m(2) (days 1-5). Among 31 ANLL patients there were 16 (51%) complete remissions (CR), 5 deaths during induction, and 10 failures. Among 11 ALL patients there were 10 CRs and 1 failure. The response rate was not affected by the overexpression of MDR-related proteins (PgP, MRP-1, and LRP). Non-hemopoietic toxicity was negligible, with no intestinal toxicity and only one case of gram-negative bacteremia. We conclude that DNX, in combination with HDAC, is an effective treatment for poor-risk adult AL. Because of the low non-hematologic toxicity, it can be used to reinduce remission in poor-risk patients who are candidates for allogeneic bone marrow transplantation. The high CR rate observed in ALL requires confirmation.

Adult↗
PubMed2002

Use of anti-BDCA-2 antibody for detection of dendritic cells type-2 (DC2) in allogeneic hematopoietic stem cell transplantation.

TH2-inducing dendritic cells (DC2) are commonly identified as negative for lineage markers and positive for HLA-DR and CD123 expression. More recently, normal blood DC2 were shown also to be positive for BDCA-2 and BDCA-4 antigens. The aim of this study was to evaluate whether BDCA-2 expression on DC2 is impaired in patients undergoing an allogeneic hematopoietic stem cell transplantation (HSCT) and in healthy donors treated with G-CSF for HSC mobilization. Flow cytometry assays for DC2 detection using either a triple staining with anti-HLA-DR PerCP, anti-Lin(+) anti-CD34 FITC and anti-CD123 PE monoclonal antibodies (mAbs), or a double staining with anti-HLA-DR PE and anti-BDCA-2 FITC mAbs were compared in blood samples from patients who underwent an allogeneic HSCT (n = 30) or from healthy donors before (n = 11) and after (n = 8) G-CSF mobilization, as well as in healthy donors' leukapheresis products (n = 12) or bone marrow (n = 4). Staining of BDCA-2(+) cells with other markers such as anti-CD38, anti-CD54 and anti-CD58 were also performed. Median values of CD123(+) DC2 and BDCA-2(+) DC2 were not statistically different in the blood of patients previously treated with chemotherapy, nor in the blood or bone marrow of heathy donors. Also, a 5 day G-CSF treatment did not affect BDCA-2 or adhesion molecule expression on healthy donors' blood DC2 significantly. A correlation between all the results (n = 65) obtained with the two assays was demonstrated in a linear regression curve (r = 0.914) (P = 0.00001). BDCA-2 is a marker highly specific for DC2 that is not downregulated by chemotherapy or G-CSF treatment. Therefore, the anti-BDCA-2 mAb can be efficiently combined with other mAbs and used in studies addressing the role of DC2 in the allogeneic HSCT setting.

Antibodies, Monoclonal↗
PubMed2002

Dendritic cell recovery after autologous stem cell transplantation.

There is persistent immunosuppression not only in allogeneic but also in autologous stem cell transplantation because humoral and cellular immunity may take a year or more to return to normal, with increased risk of infectious complications. This immune defect may also involve antigen presentation, in particular dendritic cell (DC) function. We evaluated DC subset reconstitution in 58 patients who underwent bone marrow (BM) or peripheral blood (PB) autologous haematopoietic stem cell transplantation (HSCT). In all patients DC type 1 (DC1) and DC type 2 (DC2) were already significantly lower than in normal individuals before conditioning therapy (DC1/microl 3.1 +/- 1.0, DC2/microl 3.0 +/- 1.1). On day 0 and day +7 the mean DC1 and DC2 numbers were very low in both groups. Patients who received unmanipulated marrow or peripheral blood stem cells reached pre-conditioning levels of DC1 and DC2 cells on day +20. In patients receiving selected CD34 cells, DC increased slowly and pre-transplant counts were observed only on day +60. Nearly 'normal' levels of DC1 and DC2 could be observed in the first group from day +180, and were maintained thereafter; in CD34(+) selected patients DC1 and DC2 counts remained lower than normal. Our data emphasise that circulating antigen presenting cells (APC) recover quickly. It remains to be determined if DC frequency in PB reflects their tissue function. The relatively low incidence of infections in patients undergoing autologous transplantation, despite defective lymphocyte reconstitution, could be related to functionally efficient DC.

Adolescent↗
PubMed2002

Clinical efficacy and antiangiogenic activity of thalidomide in myelofibrosis with myeloid metaplasia. A pilot study.

Increased neoangiogenesis has been reported in myelofibrosis with myeloid metaplasia (MMM). Thus we studied the effects of thalidomide, an antiangiogenic drug, in 12 MMM patients. Before treatment, all the cases showed a significantly increased micro-vessel density (MVD); in all eight tested cases bFGF and VEGF plasma levels were higher than controls. All patients presented disease progression in the last 3 months with standard therapy, regarding splenomegaly, anemia and/or thrombocytopenia and/or hyperleukocytosis. Thalidomide was administered at daily doses increasing from 100 to 600 mg. Eleven out of 12 patients were evaluable. No progression of disease was seen during the treatment in any case. In particular, spleen size decreased in 7/11 patients, anemia improved in 3/4 (two are now transfusion independent), thrombocytopenia in 2/2 and hyperleukocytosis in 2/5 patients. Side-effects were frequent, although not severe. After treatment, VEGF and bFGF plasma levels varied widely and in selected cases decreased. In particular, VEGF and/or bFGF decreased in 4/5 responders and in 1/3 non-responders. Moreover, MVD significantly decreased in all the responders evaluated after treatment. We conclude that thalidomide is a feasible therapy in MMM patients and looks promising at least to control the growth progression of disease.

Adult↗
PubMed2002

Nuclear factor-erythroid 2 (NF-E2) expression in normal and malignant megakaryocytopoiesis.

Although the transcription factor nuclear factor-erythroid 2 (NF-E2) is known to be functionally linked to the megakaryocytic lineage, little is known about its role in malignant megakaryocytes. We used real-time RT-PCR and Western blotting to investigate expression of NF-E2 and its partner, MafG, in CD34-derived normal (five cases) and malignant megakaryocytes from essential thrombocythemia (ET) patients (eight cases) and in megakaryoblastic cell lines. We also quantitated the mRNA of the thromboxane synthase (TXS) gene, which is directly regulated by NF-E2. Although real-time RT-PCR showed that both a and f NF-E2 isoforms were significantly reduced with respect to the normal counterpart both in ET megakaryocytes and in cell lines (P < or = 0.01), western blotting revealed decreased NF-E2 protein expression only in the latter. However, both the NF-E2a/MafG mRNA ratio (P < or = 0.01) and TXS (P< or = 0.01) mRNA expression were significantly reduced in megakaryocytes from ET patients and cell lines with respect to healthy subjects. These two findings provide strong indirect evidence of altered activity of the a isoform of NF-E2 in malignant megakaryocytes, raising the possibility that NF-E2 could play a role in megakaryocyte transformation.

Adult↗
PubMed2002

Advantages of positron emission tomography (PET) with respect to computed tomography in the follow-up of lymphoma patients with abdominal presentation.

For abdominal lymphoma patients, fluorine-18 fluorodeoxyglucose positron emission tomography (PET) provides unique information on the presence of residual active disease. We provide an update on the largest reported cohort of patients whose management following induction therapy was based on routine PET and computed tomography (CT) restaging. Fifty-nine patients with Hodgkin's disease or aggressive non-Hodgkin's lymphoma presenting abdominal involvement (35% with bulky disease) were studied with both PET and CT following combined chemotherapy/radiation treatment. After treatment, 3/3 (100%) patients who were PET+/CT- relapsed, compared with 0/7 patients in the PET-/CT- subset. Among the 49 patients who were CT+, six of the 10 (60%) who were PET+ relapsed, as compared with only two of the 39 (5%) who were PET-. The actuarial relapse-free survival (RFS) rates were 0 and 100% in the PET+/CT- and PET-/CT- subsets, respectively. In the PET+/CT+ subset, RFS was 94% at 5 years. PET restaging is very valuable for the identification of patients who would need appropriate second-line therapy because of the presence of residual active abdominal disease and should be made widely available in combination with CT.

Abdominal Neoplasms↗
PubMed2002

Randomized trial of 8-week versus 12-week VNCOP-B plus G-CSF regimens as front-line treatment in elderly aggressive non-Hodgkin's lymphoma patients.

BACKGROUND: Among the third-generation chemotherapy regimens specifically adapted in the last decade for elderly aggressive non-Hodgkin's lymphoma (NHL) patients, we designed an 8-week cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) plus granulocyte colony-stimulating factor (G-CSF) regimen which, in a national multicenter trial, induced good complete response (CR) and relapse-free survival rates with only moderate toxic effects. Here we report a prospective, multicenter, randomized trial comparing the efficacy and toxicity of 8- and 12-week regimens of VNCOP-B plus G-CSF. PATIENTS AND METHODS: From February 1996 to June 2001, 306 consecutive previously untreated stage II-IV aggressive NHL patients > or =60 years of age were enrolled from 12 Italian cooperative institutions. Of the 297 evaluable patients, 149 and 148 received 8- and 12-week regimens, respectively, of VNCOP-B. RESULTS: The CR rates were 63% and 56% in the 8- and 12-week groups; at a median of 32 months (range 3-62 months), relapse-free survival rates were 59% and 55%, respectively. Hematological and non-hematological toxicities were similar in both treatment groups. CONCLUSIONS: Our data show that extending induction treatment with the VNCOP-B plus G-CSF regimen from 8 to 12 weeks does not raise the CR rate or provide a more durable remission.

Aged↗
PubMed2001

Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders.

Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-alpha), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-alpha alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-alpha treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.

Adult↗
PubMed2001

Pulsed ATRA as single therapy restores long-term remission in PML-RARalpha-positive acute promyelocytic leukemia patients: real time quantification of minimal residual disease. A pilot study.

All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a 'negligible quantity' of PML-RARalpha fusion transcript (ratio PML-RARalpha/ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.

Adult↗
PubMed2001

Long-lasting complete remission of hepatitis C virus (HCV) infection and HCV-associated immunocytoma with alpha-interferon treatment.

Several epidemiological data suggest the involvement of hepatitis C virus (HCV) in the pathogenesis of some histotypes of B-cell non-Hodgkin's lymphomas, in particular immunocytoma. We report a patient with HCV-associated immunocytoma, first treated with six courses of fludarabine. A partial response was achieved and subsequent therapy with alpha-interferon resulted in the clearance of the virus and a long-lasting complete clinical and histological remission of the lymphoproliferative disease.

Adult↗
PubMed2001

Chronic myelogenous leukemia.

The treatment recommendations for chronic myelogenous leukemia (CML) are evolving rapidly. In the past year, pegylated interferon and STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, have become commercially available and non-myeloablative stem cell transplants continue to be refined. Clinicians and patients face a bewildering array of treatment options for CML. In this article Dr. Sawyer reviews the clinical results with STI571 and ongoing investigations into mechanisms of resistance to STI571. Given the newness of STI571, a practical overview on the administration of STI571 is presented by Drs. Druker and Ford, focusing on aspects such as optimal dose, management of common side effects, and potential drug interactions. The most recent data on interferon-based regimens are reviewed by Dr. Baccarani in the third section. In the last section Dr. Goldman presents recent results of allogeneic stem cell transplants, including the reduced intensity conditioning regimens. Lastly, the proposed place of each of these treatments in the management of CML patients is addressed to assist in deciding amongst treatment options for CML patients.

Antineoplastic Agents↗
PubMed2001

Fludarabine, arabinosyl cytosine and idarubicin (FLAI) for remission induction in poor-risk acute myeloid leukemia.

Progress in treatment of acute myeloid leukemia (AML) is slow and treatment intensification alone has limited effects, particularly in poor-risk cases. Poor-risk cases, that are identified mainly by prior history, leukemic cell mass and cytogenetic abnormalities, share multiple mechanisms of drug resistance that are responsible for treatment failure. Since Pgp-mediated resistance to anthracycline can be reduced with Idarubicin (IDA) and resistance to arabinosyl cytosine (AC) can be reduced with Fludarabine (FLUDA), we tested a combination of high dose AC (2000 mg/sqm, 5 doses), FLUDA (30 mg/sqm, 5 doses) and IDA (12 mg/sqm, 3 doses) for remission induction and consolidation in 45 consecutive cases of poor-risk AML. The complete remission (CR) rate was 71% after the first course and 82% overall, with a projected 2-year survival and relapse-free survival of 44% and 50% respectively. Non-hematologic toxicity was very mild, that is very important in elderly patients, but hemopoietic toxicity was substantial, with a time to hematologic recovery of 3 to 4 weeks and two cases of death in CR. Peripheral blood stem cells (PBSC) could be mobilized and collected successfully only in 11 cases. This three-drug combination is effective and has a limited non-hematologic toxicity, but FLUDA may increase the difficulty of obtaining PBSC early after remission induction.

Acute Disease↗
PubMed2001

Real-time quantification of different types of bcr-abl transcript in chronic myeloid leukemia.

BACKGROUND AND OBJECTIVES: The most common translocation in chronic myeloid leukemia (CML) t(9;22) (q34;q22) produces the BCR/ABL fusion gene. We set up and evaluated a rapid and reliable real-time reverse-transcription-polymerase chain reaction (RT-PCR) approach using TaqMan technology for detection and quantification of bcr-abl transcripts in CML patients at diagnosis and during therapy. DESIGN AND METHODS: A pair of primers and probe complementary to ABL exon 2 were designed, enabling detection of the most frequent bcr-abl transcripts, and also of the normal ABL-Ia transcript as an internal control. Conditions were established to amplify less than 1(-10) target molecules/reaction and detect one CML cell in 10(6) cells from healthy donors. To determine the utility of the assay, we quantified the bcr-abl/ABL-Ia ratio in 59 bone marrow samples (45 samples with evidence of different Ph+ chromosome percentages and 14 samples in complete cytogenetic remission) from 48 CML patients, 34 of them at diagnosis and 14 in clinical remission (CR). In 14 cases, this ratio was compared with results obtained by a competitive-quantitative RT-PCR/capillary electrophoresis method from contemporary specimens. RESULTS: By real-time RT-PCR, the median value of bcr-abl/ABL-Ia ratio at diagnosis was 15.334 (range 3.3-28.81) and fell to 0.9 (range 0.003-26.1) in CR. The median value of bcr-abl/ABL-Ia ratio at cytogenetic remission was 0.7 (range 0.003-2.83). The real-time bcr-abl/ABL-Ia ratios correlated with those obtained by competitive RT-PCR (p < 0.0001) and the percentage of Ph+ metaphases (p < 0.0001). The high sensitivity and specificity of the real-time RT-PCR procedure was confirmed in all 14 patients with minimal residual disease. INTERPRETATION AND CONCLUSIONS. We conclude that this real-time RT-PCR procedure is a reliable and sensitive method of monitoring CML patients after therapy, and that the bcr-abl/ABL-Ia ratio correlates strongly with cytogenetic analysis.

Bone Marrow↗