Publications (23)74.56 Total impact
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Article: Microarray Demonstrates Different Gene Expression Profiling Signatures Between Waldenström Macroglobulinemia and IgM Monoclonal Gammopathy of Undetermined Significance.
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ABSTRACT: Waldenström macroglobulinemia (WM) (symptomatic and indolent) and immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgMMGUS) can be identified based on the bone marrow (BM) infiltration and the existence of symptoms. The purpose of this study was to investigate the biological and genetic characteristics of both disorders comparing the molecular signature of WM versus IgMMGUS using microarray analysis. We investigated BM CD19+ cells isolated from 21 WM patients and 10 IgMMGUS cases, and CD138+ BM cells isolated from all of the WM patients and 4 of the IgMMGUS cases. Gene expression profiling of WM versus IgMMGUS CD19+ cells highlighted 151 differently expressed genes and the comparison with CD138+ cells demonstrated 43 differently expressed genes in WM versus IgMMGUS. Regulation of transcription, Janus kinase/signal transducer and activator of transcription, PI3K/Akt/mammalian target of rapamycin, mitogen-activated protein kinase signaling pathways are the relevant gene ontology biological processes occurring in CD19+ cells, and immune response, cell activation, and signaling processes developing in CD138+ cells mainly distinguish WM and IgMMGUS.Clinical lymphoma, myeloma & leukemia 03/2013; -
Article: Fludarabine, Cyclophosphamide, and Rituximab in Salvage Therapy of Waldenström's Macroglobulinemia.
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ABSTRACT: The combination FCR (fludarabine, cyclophosphamide, and rituximab) proved to be active in Waldenström's macroglobulinemia in a mixed population of untreated and previously treated patients. Prolonged myelosuppression and concerns about purine analogue treatment led to the conclusion that this regimen should be avoided in younger patients in first-line treatment. In this retrospective study on 40 patients we observed a response rate of 80% (32) after FCR salvage treatment with 32.5% (13) of patients reaching at least a very good partial remission. None of the prognostic variables had a significant effect on response or good quality of response achievement. Median event-free survival was reached at 77 months; median progression-free survival was not reached after a median follow-up of 51 months with any difference when categorizing patients according to quality of response. The results of this study suggest that the FCR regimen might overcome poor prognostic features and should be taken into account as salvage treatment. Tardive immunosuppression and myelosuppression warrant accurate patient follow-up.Clinical lymphoma, myeloma & leukemia 03/2013; -
Article: An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia.
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ABSTRACT: Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m² per day, oral cyclophosphamide 250 mg/m² per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.Blood 07/2011; 118(15):4079-85. · 9.90 Impact Factor -
Article: Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease.
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ABSTRACT: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM). Forty-three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m(2) intravenously on day 1 and fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses. The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow-up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the β2-microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long-lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow-up. The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good-quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration.Cancer 07/2011; 118(2):434-43. · 4.77 Impact Factor -
Article: Relationship between pharmacokinetic profile of subcutaneously administered alemtuzumab and clinical response in patients with chronic lymphocytic leukemia.
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ABSTRACT: Alemtuzumab serum levels and clinical response after subcutaneous administration (10 mg 3 times/week for six weeks) have been explored in 29 chronic lymphocytic leukemia patients receiving the monoclonal antibody as consolidation. Serum concentrations after each administration gradually increased during the first week and more markedly during weeks 2 and 3, approaching the steady-state at week 6. Absorption continued slowly through the tissues for about 2-3 weeks after the last administration, starting to decrease thereafter. Difference between Responders and Non-responders was statistically significant: maximal concentration (Cmax) was 1.69 μg/mL vs. 0.44 μg/mL; concentration before subcutaneous administration (Cpre-dose) on day 15 was 0.7 vs. 0.21 μg/mL, area under curve (AUC0-12h) was 11.09 vs. 2.26 μgxh/mL for Responders and Non-responders, respectively. Higher systemic exposure to alemtuzumab correlated with a better clinical response and minimal residual disease. Results suggest that an adjusted schedule according to serum level could improve clinical outcome of patients receiving subcutaneous alemtuzumab.Haematologica 02/2011; 96(6):932-6. · 6.42 Impact Factor -
Article: Factors predicting transformation of asymptomatic IgM monoclonal gammopathy.
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ABSTRACT: We evaluated the risk of transformation of asymptomatic immunoglobulin (Ig) M monoclonal gammopathy (aIgM MG) into symptomatic lymphoproliferative disease in 287 patients all analyzed for bone marrow histopathology and immunophenotyping. This series included 201 patients with IgM MG of undetermined significance (IgM MGUS) and 86 with smoldering Waldenström's macroglobulinemia (sWM). After a median of 50 months (range, 12-322 months), 32 cases of aIgM-MG (11.1%) evolved into symptomatic malignant lymphoproliferative disease, as follows: symptomatic WM (n=26), non-Hodgkin lymphoma (n=6). The cumulative transformation percentage at 5 and 10 years was 8% and 19.5%, respectively. The parameters significantly correlated with evolution were, at univariate analysis, BM lymphoplasmacytic infiltration, high erythrocyte sedimentation rate, serum MC, serum IgM size, and serum IgA size. Among patients with aIgM-MG, those at high risk of evolution were patients with sWM, a distinct entity with serum IgM monoclonal protein≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration.Clinical lymphoma, myeloma & leukemia 02/2011; 11(1):77-9. -
Article: Therapy-Related Myeloid Neoplasms in Chronic Lymphocytic Leukemia and Waldenstrom's Macroglobulinemia.
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ABSTRACT: Secondary myelodysplasia (MDS) and acute myeloid leukemia (AML) are frequent long term complications in Chronic Lymphocytic Leukemia (CLL) and Waldenström Macroglobulinemia (WM) patients. Although disease-related immune-suppression plays a crucial role in leukemogenesis there is great concern that therapy may further increase the risk of developing these devastating complications.Nucleoside analogs (NA) and alkylating agents are considered appropriate agents in the treatment of both CLL and WM patients. Prolonged immunosuppression related to NA therapy and the incorporation of these agents or their metabolites into DNA, with potentially mutagenic action, leads to speculation that their therapeutic use might be responsible for an increased incidence of second cancer especially when combined with other DNA damaging agents like alkylating agents.In this review the published studies considering the occurrence of secondary MDS and AML in CLL and WM patients are reported and the potential role of chemotherapeutic agents in leukemogenesis is discussed.Mediterranean Journal of Hematology and Infectious Diseases 01/2011; 3(1):e2011031. -
Article: Gene expression profiling identifies ARSD as a new marker of disease progression and the sphingolipid metabolism as a potential novel metabolism in chronic lymphocytic leukemia.
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ABSTRACT: Several studies demonstrated IGVH mutational status and ZAP70 expression as the most relevant prognostic markers in Chronic Lymphocytic Leukemia (CLL), suggesting the separation of two patient subgroups: with good mutated ZAP70 negative (MTZAP70(-) and poor unmutated ZAP70 positive (UMZAP70(+)) prognosis. We determined the gene expression of B cells in 112 CLL patients divided into three classes: class 1 with MTZAP70(-), class 2 with UMZAP70(+), and class 3 included both UMZAP70(-) and MTZAP70(+). We found LPL, AGPAT2, MBOAT1, CHPT1, AGPAT4, PLD1 genes encoding enzymes involved in lipid metabolism overexpressed in UMZAP70(+). In addition, this study identified ARSD, a gene belonging to the sphingolipid metabolism, as a new gene significantly overexpressed in UMZAP70(+) compared to MTZAP70(-). Western blots confirmed that ARSD protein levels were significantly different between the 3 classes of patients and normal controls. Statistical analysis identified a significant correlation between ARSD and IGVH; however, both ARSD protein level and IGVH were independently associated with the need for therapy of CLL patients. ARSD is a novel prognostic factor as the time to start therapy is shorter in patients with high levels of ARSD protein and sphingolipid metabolism could represent a new biological mechanism in CLL.Cancer biomarkers: section A of Disease markers 01/2011; 11(1):15-28. · 1.08 Impact Factor -
Article: Bendamustine: new perspective for an old drug in lymphoproliferative disorders.
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ABSTRACT: Bendamustine is an old bifunctional alkylating agent that also has potential antimetabolite properties, and only partial cross-resistance with other alkylators. Although it was synthesized in 1963 only few validated study results exist from this early period. More recently, its peculiar mechanism of action has reawakened interest in this drug that has been extensively studied in indolent non-Hodgkin lymphoma (NHL) and in chronic lymphocytic leukemia (CLL). Experience has also been reported in high-grade NHL and Hodgkin disease. Based on its unique structure, various strategies can be used for mechanism-based combination chemotherapeutic regimens with bendamustine. Moreover, data indicates that bendamustine when combined with rituximab is a valid therapeutic choice for patients with CLL or low-grade NHL demonstrating refractoriness to standard chemotherapy regimens. Furthermore, its documented favorable toxicity profile makes it a particularly useful treatment option for elderly patients.Expert Review of Hematology 04/2010; 3(2):131-48. · 1.16 Impact Factor -
Article: The spectrum of use of rituximab in chronic lymphocytic leukemia.
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ABSTRACT: The monoclonal chimeric anti-CD20 antibody, rituximab, has considerably improved therapeutic outcome in B-cell chronic lymphocytic leukemia. Rituximab has limited clinical activity when used as a single agent. The combination of the monoclonal antibody with fludarabine-based regimens clearly demonstrated, in Phase II and randomized trials, an increase in clinical efficacy in previously untreated and pretreated patients. Furthermore the addition of rituximab enabled the eradication of minimal residual disease, which is correlated with the prognosis in a high proportion of patients. Although the combination of rituximab with fludarabine-based regimens increased myelosuppression and immunosuppression, incidence of infections did not increase. The benefit of adding rituximab to other purine analogs or other chemotherapeutic combination regimens has also been explored. Moreover there could be a role for achieving better quality of responses with the combination of different monoclonal antibodies, considering that they target different antigens and exert different mechanism of action. Although the role of rituximab as maintenance therapy in low grade non-Hodgkin's lymphomas has been determined, the benefit and optimal schedule in chronic lymphocytic leukemia are still under investigation. This review brings together knowledge of the pharmacokinetics, mechanism of action and clinical use of rituximab in chronic lymphocytic leukemia.OncoTargets and Therapy 01/2010; 3:227-46. · 1.26 Impact Factor -
Article: ZAP-70, IgVh, and cytogenetics for assessing prognosis in chronic lymphocytic leukemia.
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ABSTRACT: New prognostic factors such as IgVh mutational status, ZAP-70 protein expression and cytogenetic abnormalities have shown to offer important prognostic information for patients with chronic lymphocytic leukemia (CLL). Our aim was to evaluate the optimal cut-off for IgVh mutational status, ZAP-70 expression and cytogenetic abnormalities in association with disease progression defined as the need for treatment within 3~years from diagnosis in 170 patients with B-CLL. Receiver operating characteristics (ROC) analysis and multivariate general linear models (GLMs) were used to investigate the most significant cut-off values of these biomarkers and their prognostic impact. Our findings estimated that the optimal cut-off for IgVh mutation status and for ZAP-70 protein expression was 97% and 16.5% respectively and a high concordance between the two was demonstrated. We identified 30% as being the best-cut-off for 17p-, 11q- and 6q-. In univariate analysis 17p- was found to be a significant predictor of the event only for the whole population. Multivariate analysis including all biological parameters, identified 11q deletion as the only significant regressor. We assessed that IgVh mutational status, ZAP-70 protein and 6q- are powerful prognostic markers. Analyses of all these factors revealed that 11q deletion was the strongest predictor of disease progression in B-CLL.Cancer biomarkers: section A of Disease markers 01/2010; 6(1):1-9. · 1.08 Impact Factor -
Article: Fludarabine-based combination therapies for Waldenström's macroglobulinemia.
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ABSTRACT: In Waldenström's macroglobulinemia, treatment is currently reserved for symptomatic patients. For many years, conventional treatment consisted of alkylating agents with or without steroids. In the past decade, fludarabine has proved to be effective in untreated and previously treated patients, even in those who experience primary treatment failure with alkylating agents. Based on in vitro evidence of synergistic effects and on the promising results obtained in other lymphoproliferative disorders, attempts have been made to combine alkylating agents with purine analogues. Encouraging results with high responses have been observed with the association of fludarabine and cyclophosphamide. The addition of an effective and nonmyelosuppressive therapeutic agent such as rituximab to fludarabine-based therapy ameliorates the quality and the response rates. Despite the lack of randomized trials, the recent consensus report indicates that combination therapy either with nucleoside analogues and alkylating agents or with nucleoside analogues and rituximab are reasonable choices for primary therapy.Clinical Lymphoma & Myeloma 03/2009; 9(1):67-70. · 1.13 Impact Factor -
Article: Fludarabine in the treatment of chronic lymphocytic leukemia: a review.
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ABSTRACT: Fludarabine (FAMP) is the most effective and most extensively studied purine analog in indolent B-cell malignancies. Its use is indicated for first-and second-line treatment of B-cell chronic lymphocytic leukemia (B-CLL). FAMP as a single agent has produced superior response rates and progression-free survival than standard therapy with chlorambucil and alkylator-based regimen. Efficacy of FAMP may be increased by combining this purine analog with other chemotherapeutic and non-chemotherapeutic agents. FAMP and cyclophosphamide combination (FC) has shown promising results with higher overall response and complete response rates than FAMP in monotherapy, although no difference has been detected in survival. Quality of response and eradication of minimal residual disease (MRD) have been reported to be associated with prolonged survival. Eradication of MRD has been achieved by combining FC with mitoxantrone or monoclonal antibody including alemtuzumab or rituximab or both. FAMP has been widely used in non-myeloablative conditioning regimens, often combined with a variety of other cytotoxic agents, with the aim of inducing enough immunosuppression to allow successful engraftment and to exert some pretransplant anti-tumor activity. The current paper provides an overview of use of FAMP as a single agent or as a cornerstone of different therapeutic strategies for treatment of B-CLL patients.Therapeutics and Clinical Risk Management 03/2009; 5(1):187-207. -
Article: Twice daily fludarabine/Ara-C associated to idarubicin, G-CSF and ATRA is an effective salvage regimen in non-promyelocytic acute myeloid leukemia.
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ABSTRACT: Preclinical data suggest that all-trans retinoic acid (ATRA) synergizing with granulocyte colony stimulating factor (G-CSF), can improve the effectiveness of chemotherapy in acute myeloid leukemia (AML). Fludarabine 15 mg/m(2) is the minimum dose able to optimize intensification with fludarabine-arabinosylcytosine regimen. In this study 52 patients with relapsed/refractory AML obtained a complete remission (CR) rate of 69.2% after FLAIRG regimen (Fludarabine and arabinosylcytosine twice daily, idarubicin, G-CSF, ATRA). This schedule resulted effective and tolerable enabling 53% of the responding patients to receive transplant procedure. FLAIRG regimen could be proposed as a "bridge" to transplant treatment in this poor risk setting.Leukemia research 02/2009; 33(8):1072-8. · 2.36 Impact Factor -
Article: Prospective monocentric study of non-tunnelled central venous catheter-related complications in hematological patients.
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ABSTRACT: Indwelling central venous catheters (CVCs) are used in the management of hematologic patients. However, insertion and maintenance of CVCs are susceptible to complications. Study design and methods data concerning 388 consecutive catheterisations, performed in oncohematologic patients between April 2003 and December 2004, were prospectively collected. At insertion thrombocytopenia was present in 109 cases (28.1%) and neutropenia in 67 (17.3%). Hemorrhage after CVC insertion occurred in five thrombocytopenic patients (1.3%). The median duration of catheterisation was 18.8 days (range 1-89), longer in the 7-French CVCs utilised in leukemic patients (24.3 days) and shorter in 12-French CVCs (11 days), used for PBSC harvesting. Deep venous thrombosis was diagnosed in 13 cases (3.3%). Ninety-two catheterisations (12.6/1000 days-catheter) were complicated by infections: 19 local infections (4.8%) and 73 (18.8%) bacteraemias of which 45 (11.6%) were catheter-related, mainly due to Gram positive germs (32/45, 71.1%). The frequency of catheter-related bacteraemia was 7.2 events/1000 days-catheter. Thirteen CVCs were removed due to thrombosis, 15 due to infections, 20 due to malfunction, the remaining 333 at patients discharge. At univariate analysis high-dose chemotherapy (p = 0.013), 7-Fr lumen (p = 0.023), acute myeloid leukemia (AML) (p = 0.001), duration of neutropenia >10 days and length of catheterisation were significantly correlated to infection. Multivariate analysis confirmed the duration of catheterisation, AML and high-dose chemotherapy as risk factors. Even though hematological in-patients are at increased risk for bleeding and infections, non-tunnelled CVCs offer a safe venous access also in patients affected by severe thrombocytopenia and prolonged neutropenia.Leukemia & lymphoma 12/2008; 49(11):2148-55. · 2.40 Impact Factor -
Article: Outcome of hyperleukocytic adult acute myeloid leukaemia: a single-center retrospective study and review of literature.
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ABSTRACT: Hyperleukocytic acute myeloid leukaemia is considered to have a poor prognosis due to high early death rate secondary to leukostasis. Supportive treatments do not seem to have reduced early exitus in this subset of patients. Prognostic impact of hyperleukocytosis on outcome has been the object of few studies. Clinical characteristics and outcome of 45 consecutive adult patients with newly diagnosed acute myeloid leukaemia presenting to our institution with a white cell count (WBC) above 100 x 10(9)L(-1) were reviewed. The outcome of this subset of patients was compared with 200 patients with a leukocyte count lower than 100 x 10(9)L(-1) similarly treated in the same period. Eight hyperleukocytic patients (17%) died of intracranial haemorrhage or pulmonary failure due to leukostasis within the first 7 days of treatment. A significant association was found between complete response (CR) and absence of hyperleukocytosis, but if early deaths were removed from analysis the difference was no longer significant. Hyperleukocytosis also significantly reduces the overall survival (OS) but does not significantly influence the disease-free survival (DFS). We reviewed in literature studies in which the outcome of series of at least 10 patients with hyperleukocytosis were compared with that of patients with a leukocyte count lower than 100 x 10(9)L(-1). Our data were consistent with those of the literature regarding the rate of early mortality and causes of death. In most of the reviewed series hyperleukocytosis does not seem to influence the outcome of patients. Avoiding early death seems to be an important step in this subset of patients. New data about pathophysiology of leukostasis are needed.Leukemia Research 09/2008; 32(8):1221-7. · 2.92 Impact Factor -
Article: Alemtuzumab in the treatment of fludarabine refractory B-cell chronic lymphocytic leukemia (CLL).
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ABSTRACT: The introduction of immunotherapeutic agents has provided renewed hope for Chronic lymphocytic leukemia fludarabine-refractory patients. Several clinical trials have shown that alemtuzumab is a more effective option compared to combination chemotherapy for treatment of patients who have relapsed or who are refractory to fludarabine, including those with poor prognostic factors. Although there are significant potential toxicities associated with alemtuzumab, such as infusional reactions and the risk of cytomegalovirus (CMV) reactivation, most are manageable. Pre-treatment anti-pyretics and anti-histamines are recommended to prevent or mitigate the acute infusional reactions associated with intravenous infusion. Recent use of alemtuzumab via the subcutaneous route has been shown to be well tolerated and has yielded similar response rates to the infusional method of administration. Prophylaxis with thrimethoprim/sulphamethoxazole (TMP/SMZ) as well as valacyclovir or a similar anti-viral can prevent many of the opportunistic infections seen in early trials. Reactivation of CMV infection can be effectively managed with monitoring and early treatment. Chemo-immunotherapy combination with alemtuzumab has been tested and demonstrated unprecedented clinical results in relapsed and refractory patients. The use of this agent earlier in the algorithm of patients with these characteristics should be considered. Future areas of research will include the use of alemtuzumab in combination with other monoclonal antibodies and other targeted therapies.Targets & therapy 04/2008; 2(1):41-52. -
Article: Intense reversal of bone marrow angiogenesis after sequential fludarabine-induction and alemtuzumab-consolidation therapy in advanced chronic lymphocytic leukemia.
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ABSTRACT: Increased bone marrow (BM) angiogenesis has been demonstrated in several hematologic malignancies. BM angiogenesis is significantly decreased in patients with chronic lymphocytic leukemia (CLL) treated with fludarabine. The anti-angiogenic potential of alemtuzumab in CLL has not yet been investigated. We, therefore, evaluated BM angiogenesis in CLL patients treated sequentially with fludarabine and low doses of alemtuzumab. BM microvessel area was sequentially evaluated in 20 patients with advanced B-cell CLL who received, after a clinical response obtained with fludarabine-induction therapy, alemtuzumab, three times weekly for 6 weeks at a dose of 10 mg. The complete response rate improved from 45% after fludarabine induction to 90% after alemtuzumab consolidation. The extent of BM angiogenesis decreased continuously after either fludarabine or alemtuzumab (p=0.0002; Kruskal-Wallis test). Thirteen out of 20 (65%) patients changed from having a monoclonal to a polyclonal pattern of IgH sequences after alemtuzumab consolidation. A separate evaluation carried out in patients who achieved molecularly undetectable disease, as defined by polymerase chain reaction negativity, and in patients who remained with minimal residual disease after therapy with alemtuzumab showed a significant reduction of BM microvessel area only in the former (p=0.0002). Finally, molecular responses and a significant reduction of BM angiogenesis were more common in patients who received the cumulative planned dose of alemtuzumab (i.e.,180 mg) than in patients who received reduced doses (p=0.007 and p=0.0001, respectively). Overall, these data demonstrate a decrease in BM vascularity that characterized CLL patients who received low doses of subcutaneous alemtuzumab consolidation therapy after a clinical response to fludarabine induction therapy. Such a finding reflects, at least in part, the molecular response and cumulative dose of alemtuzumab.Haematologica 11/2007; 92(10):1367-74. · 6.42 Impact Factor -
Article: Role of fludarabine in hematological malignancies.
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ABSTRACT: Fludarabine is a prodrug that is converted to the free nucleoside 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A), which enters cells and accumulates mainly as the 5'-triphosphate, F-ara-ATP. F-ara-ATP has multiple mechanisms of action, which are mostly directed toward DNA. Collectively, these actions affect DNA synthesis, which is the major mechanism of F-ara-A-induced cytotoxicity. Secondarily, incorporation into RNA and inhibition of transcription has been shown in cell lines. As a single agent, fludarabine has been effective for indolent leukemia. Biochemical modulation strategies resulted in enhanced accumulation of cytarabine triphosphate and led to the use of fludarabine for the treatment of acute leukemia. The combination of fludarabine with DNA-damaging agents to inhibit DNA repair processes has been highly effective for indolent leukemia and lymphomas. Other strategies have incorporated fludarabine into preparative regimens for nonmyeloablative stem-cell transplantation.Expert Review of Anti-infective Therapy 10/2006; 6(9):1141-61. · 2.65 Impact Factor -
Article: Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia.
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ABSTRACT: Treatment with alemtuzumab has resulted in negative responses for minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL). In a prior analysis we demonstrated that it is possible to achieved MRD negativity, as assessed by polyclonality of immunoglobulin heavy chain after consolidation with alemtuzumab. This phase II study evaluated 34 patients with CLL who received alemtuzumab consolidation in an effort to improve the quality of their response to fludarabine-based induction. Subsequent peripheral blood stem-cell (PBSC) collection and transplantation, tolerability, and pharmacokinetics also were assessed. Thirty-four patients younger than 65 years who had a clinical response to fludarabine-based induction therapy received alemtuzumab 10 mg subcutaneously three times per week for 6 weeks. PBSCs were collected after mobilization with cytarabine and granulocyte colony-stimulating factor. Blood samples for pharmacokinetics study were taken between days 1 and 31. The complete response rate improved from 35% after fludarabine induction to 79.4% after alemtuzumab consolidation, including 19 patients (56%) who achieved MRD negativity. The most common adverse events were injection-site reactions and fever. Cytomegalovirus reactivation occurred in 18 patients, all of whom were successfully treated with oral ganciclovir. PBSC collection was successful in 24 (92%) of 26 patients, and 18 patients underwent autologous PBSC transplantation. Alemtuzumab plasma concentrations increased gradually during the first 2 weeks and accumulated more rapidly thereafter. Subcutaneously administered alemtuzumab was effective, safe, and well tolerated as consolidation therapy in patients with CLL who responded to fludarabine induction therapy. Subsequent PBSCT was feasible thereafter.Journal of Clinical Oncology 06/2006; 24(15):2337-42. · 18.37 Impact Factor
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2004–2013
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Azienda Ospedaliera Niguarda Ca' Granda
- Department of Hematology
Milano, Lombardy, Italy
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