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Marco Montillo

Publications and source records attributed to Marco Montillo.

15 recordsLinked to original sources
PubMed2006

Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia.

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2006

Role of fludarabine in hematological malignancies.

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.

Animals↗
PubMed2005

Imatinib mesylate in the treatment of Core Binding Factor leukemias with KIT mutations. A report of three cases.

Aim of this study is to investigate the capability of Imatinib to induce an anti-leukemic effect in Core Binding Factor (CBF)-leukemia patients presenting either with extracellular juxtamembrane or kinase KIT mutations. On the basis of a screening analysis for KIT mutations, two patients with a kinase mutation and one with extracellular juxtamembrane mutation, in first or subsequent leukemic relapse, received 400mg Imatinib twice daily for 30 days. After Imatinib discontinuation, bone marrow cells were re-tested to assess the KIT mutational status and the chromosomal set. In our experience, none of the treated patients had a response by standard criteria; in particular, we did not observe any activity against acute myeloid leukemia (AML) associated with KIT kinase mutations. However, in the patient with extracellular juxtamembrane mutation, Imatinib seems to have some clinical beneficial effect and, most important, is able to abrogate the leukemic subclone carrying the mutation. Whether Imatinib, in combination with other agents, may play a role in the treatment of AML with more sensitive extracellular juxtamembrane KIT mutation remains to be determined.

Antineoplastic Agents↗
PubMed2005

Eradication of minimal residual disease with alemtuzumab in B-cell chronic lymphocytic leukemia (B-CLL) patients: the need for a standard method of detection and the potential impact of bone marrow clearance on disease outcome.

The introduction of new therapeutic agents, such as fludarabine phosphate (Fludara) and alemtuzumab (MabCampath, Campath), has made it possible to treat B-cell chronic lymphocytic leukemia (B-CLL) more effectively, compared with alkylating agents. However, although an increasing number of patients are able to achieve complete remission (CR), relapse is almost inevitable, because of the re-emergence of the malignant clone from small numbers of residual malignant cells. This phenomenon has introduced a need for a more sensitive assessment of low-level disease which, in turn, has encouraged the development of therapies aimed at the eradication of all residual disease in CR patients. The eradication of residual disease is associated with improved remission durability and has great potential in offering the possibility of cure. Alemtuzumab is the foundation of many eradication-based treatment approaches because of its ability to achieve clinical remissions and to successfully purge minimal residual disease (MRD) from both blood and bone marrow in B-CLL patients. This article describes and compares polymerase chain reaction (PCR) and flow cytometric methodologies for the assessment of MRD, and presents data demonstrating that alemtuzumab can eliminate residual malignant cells from blood and bone marrow (whether assessed by PCR or flow cytometry) at the highest levels of sensitivity currently available. The ability to clear MRD from bone marrow in patients achieving clinical CR using alemtuzumab is a significant step forward in the treatment of B-CLL, and supports treatment strategies in which alemtuzumab is used in combination with other agents. Purging of MRD from both blood and bone marrow also enables patients to proceed to autologous hematopoietic stem cell transplantation, a strategy that is able to achieve long-term remission.

Alemtuzumab↗
PubMed2005

Chronic lymphocytic leukemia: novel prognostic factors and their relevance for risk-adapted therapeutic strategies.

BACKGROUND AND OBJECTIVES: Many years ago it was established that prompt treatment of early stage chronic lymphocytic leukemia (CLL), the stage at which almost two-thirds of CLL patients present, has no benefit over a management of watching and waiting, then treating progression. However, this fact was based on series treated ineffectually with chlorambucil, which were not stratified according to prognostic markers. DESIGN AND METHODS: The prognosis and clinical course of CLL are heterogeneous. While some patients may have a normal life expectancy without requiring treatment, others die of drug-resistant disease as early as within two years of presentation. However, unlike the situation in non-Hodgkin's lymphoma, there is no standard Prognostic Index that can be used to group patients with CLL according to likely outcome or to guide treatment. RESULTS: A number of clinical and biological factors of prognostic relevance, which may add to the classical assessment provided by the staging systems, have been identified. These include clinical characteristics, such as age, gender and performance status, and laboratory parameters reflecting the tumor burden or disease activity, such as lymphocyte count, lactate dehydrogenase (LDH) increase, bone marrow infiltration pattern or lymphocyte doubling time. Recently more informative prognostic parameters have been identified: serum markers such as soluble CD23, b2-microglobulin or thymidine kinase and genetic markers of tumor cells, such as genomic aberrations, gene abnormalities (p53, ATM), the mutation status of the variable segments of the immunoglobulin heavy chain genes (IGVH) or surrogate markers for these factors, such as CD38 and ZAP-70. INTERPRETATION AND CONCLUSIONS: From the clinician's perspective the importance of this new knowledge is how it affects treatment. It is now possible to produce molecular remissions even in advanced disease using combinations of purine analogs and monoclonal antibodies. Moreover, potentially curative therapeutic modalities such as autologous and allogeneic stem cell transplantation are becoming safer. Clinical trials of effective treatment stratified by more reliable prognostic markers are surely now warranted.

Biomarkers↗
PubMed2005

Multiple lines of chemotherapy are the main risk factor for severe infections in patients with chronic lymphocytic leukemia with febrile episodes.

We report on febrile episodes occurring among 379 patients affected by chronic lymphocytic leukemia, observed from 1984 to 2002. One hundred and twenty eight patients (33.7%) developed 341 febrile episodes, of which 251 were documented infections (82 severe and 169 moderate). Among various risk factors, only previous treatment with multiple regimens of chemotherapy was associated with severity of infection (p=0.0005).

Adult↗
PubMed2003

Phase II study of cladribine and cyclophosphamide in patients with chronic lymphocytic leukemia and prolymphocytic leukemia.

BACKGROUND: One of the mechanisms of action of cladribine is the inhibition of DNA repair of damage caused by radiation, alkylating agents, or other drugs. To determine its antitumor activity in combination with cyclophosphamide, we initiated a Phase II trial of the two agents in patients with advanced chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL). METHODS: Twenty-nine patients with refractory or recurrent CLL or PLL received cladribine 4 mg/m(2)/day and cyclophosphamide 350 mg/m(2)/day (both administered intravenously) for 3 days every 4 weeks. RESULTS: Eleven patients (38%), nine with CLL and two with PLL, had a response. The median duration of response was 12 months. Severe extrahematologic toxicity (National Cancer Institute Grade 3-4) occurred in two patients, consisting of skin rash in one patient and progressive multifocal leukoencephalopathy in the other. The most common form of hematologic toxicity was severe neutropenia, which developed after 25% of the 84 courses was administered. Severe thrombocytopenia and anemia developed after 12% and 7% of the courses, respectively, and five episodes of anemia were immunomediated. In addition, three major infections resulted in the death of one patient. CONCLUSIONS: Although inferior to the combination fludarabine plus cyclophosphamide, this regimen showed interesting activity in patients with advanced CLL or PLL. Myelosuppression was the major dose-limiting toxic effect.

Adult↗
PubMed2003

Interphase fluorescence in situ hybridization analysis of del(11)(q23) and del(17)(p13) in chronic lymphocytic leukemia. a study of 40 early-onset patients.

Although B-cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in Western countries, little is known about its underlying molecular abnormalities and their prognostic significance, particularly for use in early therapeutic interventions in young patients. As TP53 tumor suppressor gene abnormalities and 11q23 deletions are reported to be prognostically adverse in hematologic malignancies, we used interphase fluorescence in situ hybridization to analyze their incidence and prognostic significance in young B-CLL patients. Bone marrow samples from 40 untreated B-CLL patients at diagnosis were studied using five yeast artificial chromosome clones from the 11q23.1 approximately q23.3 chromosomal region and a probe specific for the 17p13.1 locus. Twenty-three patients (58%) carried 11q deletions. Interestingly, 16 of 17 patients (94%) who showed early disease progression exhibited this chromosomal abnormality, suggesting that 11q deletions may help to identify more aggressive disease in early stage patients. In contrast, monoallelic TP53 deletions were found in all of the patients. The TP53 and 11q deletions were only present in a proportion of the clonal B-cells, which suggests that they are secondary events in B-CLL.

Adult↗
PubMed2003

Utility of percutaneous lung biopsy for diagnosing filamentous fungal infections in hematologic malignancies.

BACKGROUND AND OBJECTIVES: The incidence of invasive filamentous fungal infections in hematologic patients is increasing as a consequence of high dose chemotherapy and bone marrow transplant procedures. Mortality is usually very high. The diagnosis is often difficult and yet a fast, accurate diagnosis is of fundamental importance for treating the infection and planning subsequent management of the hematologic disease. We evaluated the sensitivity of computed tomography (CT)-guided percutaneous biopsy in diagnosing pulmonary fungal infections. DESIGN AND METHODS: Between 1997 and 2002 we performed 17 CT-guided percutaneous transthoracic lung biopsies in 17 hematologic patients with suspected filamentous fungi infection with negative BAL, to obtain a certain diagnosis and to know what species of fungi was responsible for infection. In all cases suspected mycosis began during the post-chemotherapy aplastic period. Patients were receiving antifungal therapy at the time of all biopsies. When the platelet count rose above 50 x 10(9)/L, CT-guided percutaneous lung biopsy with fine-needle aspiration for cytology was performed. RESULTS: Twelve of 17 patients had histologic confirmation of the fungal infection (70.5%), 8 with Aspergillus spp. 4 with Mucorales spp. Biopsies provided non-specific results in 4 cases; in 2 of these cases, clinical course and response to therapy confirmed the diagnosis of mycosis; in the last case bronchoalveolar carcinoma was found as a new diagnosis. Cultures were positive in only 6 cases, all for Aspergillus spp. The sensitivity of CT-guided percutaneous lung biopsy was 70.6% and its positive predictive value (PPV) was 100%. This procedure provided an immediate diagnosis and only one side-effect (1 pneumothorax, without complications). INTERPRETATION AND CONCLUSIONS: Histologic discrimination between aspergillosis and mucormycosis is very important for deciding secondary prophylaxis during transplant procedures, because Mucor is usually resistant to azoles.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2002

The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease.

BACKGROUND: CD23 antigen is a cell surface protein considered important in the differentiation of chronic lymphocytic leukemia (CLL) from other lymphoid leukemias. METHODS: To better clarify CD23 role as a diagnostic tool, the authors retrospectively evaluated clinical and laboratory features of 372 patients who were referred to M.D. Anderson Cancer Center with a diagnosis of CLL or B-cell chronic lymphoproliferative disease. RESULTS: Most of the patients (91%) were CD19+/CD5+. Only 6% of these CD19+/CD5+ patients were CD23-. Overall, CD23- patients had the worse prognostic features compared with CD23+ cases, including anemia (P = 0.03), massive splenomegaly (P = 0.000), high lactate dehydrogenase (P = 0.007), high beta2-microglobulin (P = 0.006), older age (P = 0.001), and male gender (P = 0.02). Surface immunoglobulin expression was moderate/strong in 19 (82%) patients, and FMC-7 was positive in 22 (96%) patients. None of the 13 patients tested for CD10 expressed the antigen. Based on morphology, of the CD23, 16 (70%) were diagnosed with mantle cell leukemia (MCL) was diagnosed in 16 (70%) CD23- patients, 3 (13%) with splenic marginal-zone leukemia, 3 (13%) with prolymphocytic leukemia (PLL) or PLL/CLL, and 1 (4%) with CLL. No cyclin D1 protein expression was noted by Western blot analysis in the one case that showed typical CLL morphology, and this patient did not require therapy. On the whole, the survival rate of CD23- patients was significantly worse than that of patients with CD23+. In contrast, 15 of 32 (49%) CD19+/CD5- patients were CD23-. CD23 negativity in this group was not associated with distinct clinical features or outcome. Eleven (73%) of these patients were classified as having splenic marginal-zone lymphoma and 4 as having follicular lymphoma. CONCLUSIONS: These data indicate that CD23 negativity is rare in typical B-cell CLL, and CD23 negativity in patients with CD19+/CD5+ is suggestive of mantle cell leukemia a more aggressive disease with poor response to conventional therapy in which newer chemotherapy regimens such as hyper-CVAD may be more effective.

Adult↗
PubMed2002

Post-transplant lymphoproliferative disorders: improved outcome after clinico-pathologically tailored treatment.

BACKGROUND AND OBJECTIVES: Clinical and pathologic variability of post-transplant lymphoproliferative disorders (PTLDs), their aggressive behavior and the recognized therapy-related toxicity make management of patients with these disorders difficult. Assessment of first-line treatment and identification of prognostic factors need to be better defined. DESIGN AND METHODS: Data on 40 PTLDs which developed in adult solid organ recipients were analyzed in order to evaluate clinical and pathologic features, response to treatment and prognostic factors. Data were collected retrospectively between 1989 and 1996; since 1997 a prospective study has been activated. RESULTS: The median time from transplant to PTLD was 56 months. Regarding histologic features, plasmacytic hyperplasia was diagnosed in 5 patients (12.5%), polymorphic lymphoproliferative disorders in 3 (7.5%), malignant lymphoma in 32 (80%). The diagnosis was made at autopsy in eight patients (20%). Late-onset PTLDs (>12 months from transplant) occurred in 33 patients (83%), EBV-negative forms in 12 (31%). Relevant differences have been observed between EBV-positive and EBV-negative forms. Twenty-nine patients completed their scheduled treatment and are evaluable for outcome. The cumulative probability of survival at 1 year is 57% (CI 37.6-73.4) and the median survival time of the entire group has not been reached at 54 months. Clinical stage, performance status, lactate dehydrogenase and number of sites are predictive factors for survival. The International Prognostic Index and the PTLD index are able to identify different risk groups. INTERPRETATION AND CONCLUSIONS: Although rare, PTLDs are a significant cause of mortality in allograft recipients. Therapy tailored on histologic and clinical features of PTLD is feasible and is able to give long-lasting complete responses.

Adult↗
PubMed2002

Safety and efficacy of subcutaneous Campath-1H for treating residual disease in patients with chronic lymphocytic leukemia responding to fludarabine.

BACKGROUND AND OBJECTIVES: Recent observations suggested that targeted monoclonal antibodies might be best employed in lymphoid malignancies under conditions of minimal residual disease. This prompted us to investigate the role of Campath-1H as treatment for patients with chronic lymphocytic leukemia (CLL) in whom fludarabine (FAMP) had produced a marked disease debulking with persistence of bone marrow (BM) infiltration or a complete remission (CR) without the disappearance of the molecular aberration (IgH monoclonal expression). As intravenous Campath-1H is almost invariably associated with reactions, sometimes of WHO grade 3-4, we adopted the subcutaneous route of administration, which proved to induce rare and mild adverse reactions but had comparable efficacy. DESIGN AND METHODS. Nine patients (7 males, 2 females) with a median age of 55 years (range 41-61) who responded to FAMP (1 had a CR, 5 a nodular partial remission [PRN], and 3 a partial remission [PR]), according to NCI Working Group Criteria, received subcutaneous Campath-1H, three times a week for 6 weeks in escalating doses up to 10 mg. Monoclonal rearrangement of IgH was present in all patients before immunotherapy. Patients received acyclovir and cotrimoxazole as infection prophylaxis. Granulocyte colony-stimulating factor (G-CSF), at the dosage of 5-10 microg/kg/die, or intermediate-dose Ara-C (800 mg/m(2)/q 12h x 6 doses), was administered to obtain peripheral blood stem cell (PBSC) mobilization. RESULTS: All patients were evaluable for response. Five patients, 2 in PR and 3 in PRN after FAMP treatment, reached a CR. Three patients, one in PR, one in PRN and one in CR, converted to a molecular remission. In four out of seven patients PBSC harvesting was successful; more than 2.5 x 10(6) cells/kg were collected from all these patients. Collection was polyclonal for IgH gene rearrangement in three cases. One patient has been transplanted after cyclophosphamide and total body irradiation as conditioning regimen, without complications and with rapid hemopoietic engraftment. All patients were evaluable for toxicity. A WHO grade 1-2 skin reaction was observed in 5 patients at the site of injection. No infectious episodes were recorded. Two out of three patients presenting cytomegalovirus reactivation, without pneumonia, were successfully treated with oral gancyclovir. INTERPRETATION AND CONCLUSIONS: Subcutaneous Campath-1H administered to CLL patients with residual BM disease after FAMP proved to be safe and effective. Of nine patients, three obtained a molecular CR and five converted into a morphologic and immunophenotypic CR. In four of seven patients submitted to PBSC mobilization, this treatment also allowed a harvest uncontaminated by CD5/CD19 double-positive CLL cells, which was polyclonal for IgH gene rearrangement in three cases.

Adult↗
PubMed2002

Hepatitis C virus infection in a hematology ward: evidence for nosocomial transmission and impact on hematologic disease outcome.

BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) infection is frequent among patients with hematologic malignancies and unapparent routes of infection may be important in this setting. Moreover, the impact of this infection on the outcome of the hematologic disease needs to be better defined. DESIGN AND METHODS: To define sources and clinical courses of HCV infection, an epidemiologic study was performed on 13 patients newly admitted over one year who showed transaminase elevation and anti-HCV seroconversion. The investigation, started in August 1998, included laboratory tests and molecular analysis of virus isolates, and was extended to staff and blood donors. Clinical, hematologic and serologic surveillance of all infected patients were part of the subsequent follow-up study which started in September 1998 and was completed in December 2001. RESULTS: Anti-HCV seroconversion was observed in 13 of 294 patients (4.4%), admitted to the unit from August 1997 and August 1998; 11 of the seroconverted cases had central catheters, 12 received transfusions. Transmission via blood derivatives and staff was ruled out. All patients were infected by genotype 1b and 11 harbored the same viral variant. HCV infection did not influence the course of the underlying disease or the use of specific therapies. Forty months after the outbreak, five patients are alive (one after autologous and one after allogeneic stem cell transplantation), while eight have died, seven of hematologic disease, and one of cardiac failure. None died of liver disease. INTERPRETATION AND CONCLUSIONS: The molecular data suggest a patient-to-patient nosocomial HCV transmission. After having analyzed all the possible routes of transmission, a series of preventive measures were adopted: search for HCV RNA in newly admitted patients, protection of mucosae and isolation of patients during neutropenic phases, and avoidance of multidose vials. As regards the impact of HCV infection on the outcome of the hematologic diseases, changes in the scheduled therapy, including stem cell transplantation, were not required.

Adolescent↗