Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several... more Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several new agents, the prognosis of acute lymphoid leukemia (ALL) patients relapsing after stem-cell transplantation (SCT) remains poor. Monoclonal-antibodies (moAb) could provide a useful tool in this setting. In particular, anti-CD52 moAb is useful in lymphoid malignancies. We thus treated as compassionate with campath-1H 3 ALL patients relapsed after SCT. In 2 cases we observed a reduction of peripheral blood and/or bone marrow blasts. In 1 case a GVHD grade reduction was observed. Larger trials are required in order to define the role of campath-1H in ALL.
The (1;19)(q23;p13) translocation, leading to the production of the E2A/PBX1 fusion transcript, i... more The (1;19)(q23;p13) translocation, leading to the production of the E2A/PBX1 fusion transcript, is one of the most common translocations in pediatric B-lineage acute lymphoblastic leukemia (ALL). It was assumed to be associated with a poor clinical outcome, although intensive therapy and bone marrow transplantation have been shown to be able to overcome the negative prognostic impact. Only few data are available concerning t(1;19)(q23;p13) in adult ALL. In particular, the prognostic significance of this genetic aberration is not yet clear. We describe three cases of adult ALL carrying the t(1;19)(q23;p13), who were all characterized by an aggressive clinical course and short survival, and discuss the molecular features of the disease as recently identified by gene expression profiling.
other than (or in addition to) the F317L might have intervened, nor can we exclude the possibilit... more other than (or in addition to) the F317L might have intervened, nor can we exclude the possibility that the concomitant M351T or L387M mutations in the third and fifth patients might have contributed to resistance. However, our experience suggests that the F317L mutation might be problematic at least in some advanced-phase patients treated with second-line dasatinib.
The aim of the study is to evaluate clinical features, treatments and outcome of patients with sy... more The aim of the study is to evaluate clinical features, treatments and outcome of patients with systemic mast cell disease (MCD) who arrived to the attention of hematologists. A retrospective study was conducted over 1995-2006 in patients admitted in 18 Italian hematological divisions. Twenty-four cases of advanced MCD were collected: 12 aggressive SM (50%), 8 mast cell leukemia (33%), 4 SM with associated clonal non-mast cell-lineage hematologic disease (17%). Spleen and liver were the principal extramedullary organ involved. The c-kit point mutation D816V was found in 13/18 patients in which molecular biology studies were performed (72%). Treatments were very heterogeneous: on the whole Imatinib was administered in 17 patients, a-Interferon in 8, 2-CdA in 3; 2 patients underwent allogeneic hematopoietic stem cell transplantation. The overall response rate to Imatinib, the most frequently employed drugs, was of 29%, registering one complete remission and four partial remission; all responsive patients did not present D816V c-kit mutation. Overall three patients (12%) died for progression of disease. We conclude that MCD is characterized by severe mediator-related symptoms but with a moderate mortality rate.
Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, pers... more Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, persistent hypereosinophilia associated with multiple organ dysfunctions. The cause of HES is unknown and shows clinical heterogeneity. FIP1L1-PDGFRA fusion is a clonal marker for the diagnosis and treatment of HES. We prospectively studied 78 patients with chronic eosinophilia. In all cases, the most salient clinical and biological characteristics as well as the response to the therapy were analyzed. In addition, we performed conventional cytogenetics and fluorescent in situ hybridization (FISH) with three BACs covering the FIP1-like-1 (FIP1L1)/platelet-derived growth factor receptor-α gene (PDGFRA) fusion. Nineteen of 78 patients (24 %) presented criteria of HES. The majority of patients were male (18) with median age of 49 years (range 19-84 years). FIP1L1-PDGFRA fusion was found in eight patients. Patients with FIP1L1-PDGFRA fusion presented with more bone marrow eosinophils and peripheral blood eosinophilia as well as anemia, leukocytosis and thrombocytopenia. Using of low-dose imatinib mesylate (100 mg/day) a hematological and molecular remission in all patients displaying the FIP1L1-PDGFRA fusion gene was observed. Therefore, imatinib may be effective for use in the treatment of chronic eosinophilic leukemia, and patients should be treated before tissue damage.
The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelp... more The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.
The treatment of hematologic malignancies has been based for many years on chemotherapy and possi... more The treatment of hematologic malignancies has been based for many years on chemotherapy and possibly, for the more aggressive forms, stem cell transplantation. In 2001, the signal transduction inhibitor 571 (STI571, imatinib mesylate) was reported to have striking effects in chronic myeloid leukaemia patients. Since then, imatinib became the first molecular-targeted agent approved for the treatment of human cancer and was later on demonstrated to be effective in other malignancies, such as Philadelphia positive acute lymphoid leukemia, hypereosinophilic syndromes, gastrointestinal stromal tumours and more recently, systemic mastocytosis and other myeloprolipherative disease-carrying platelet-derived growth factor receptor abnormalities. In this article, the authors review the evidence which led to imatinib approval in the treatment of several of the above mentioned diseases.
Background: fms-related tyrosine kinase 3 (Flt3) is the most commonly mutated gene in human acute... more Background: fms-related tyrosine kinase 3 (Flt3) is the most commonly mutated gene in human acute myeloid leukemia (AML) and has been implicated in its pathogenesis. Because screening of Flt3 in AML patients by PCR followed by gel electrophoresis is time-consuming and fails to detect some very small internal tandem duplications (ITDs), we developed a method for screening of FLT3 receptor mutations with PCR plus denaturing HPLC (D-HPLC).
Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several... more Despite aggressive approaches, including second transplant, donor lymphocyte infusion and several new agents, the prognosis of acute lymphoid leukemia (ALL) patients relapsing after stem-cell transplantation (SCT) remains poor. Monoclonal-antibodies (moAb) could provide a useful tool in this setting. In particular, anti-CD52 moAb is useful in lymphoid malignancies. We thus treated as compassionate with campath-1H 3 ALL patients relapsed after SCT. In 2 cases we observed a reduction of peripheral blood and/or bone marrow blasts. In 1 case a GVHD grade reduction was observed. Larger trials are required in order to define the role of campath-1H in ALL.
The (1;19)(q23;p13) translocation, leading to the production of the E2A/PBX1 fusion transcript, i... more The (1;19)(q23;p13) translocation, leading to the production of the E2A/PBX1 fusion transcript, is one of the most common translocations in pediatric B-lineage acute lymphoblastic leukemia (ALL). It was assumed to be associated with a poor clinical outcome, although intensive therapy and bone marrow transplantation have been shown to be able to overcome the negative prognostic impact. Only few data are available concerning t(1;19)(q23;p13) in adult ALL. In particular, the prognostic significance of this genetic aberration is not yet clear. We describe three cases of adult ALL carrying the t(1;19)(q23;p13), who were all characterized by an aggressive clinical course and short survival, and discuss the molecular features of the disease as recently identified by gene expression profiling.
other than (or in addition to) the F317L might have intervened, nor can we exclude the possibilit... more other than (or in addition to) the F317L might have intervened, nor can we exclude the possibility that the concomitant M351T or L387M mutations in the third and fifth patients might have contributed to resistance. However, our experience suggests that the F317L mutation might be problematic at least in some advanced-phase patients treated with second-line dasatinib.
The aim of the study is to evaluate clinical features, treatments and outcome of patients with sy... more The aim of the study is to evaluate clinical features, treatments and outcome of patients with systemic mast cell disease (MCD) who arrived to the attention of hematologists. A retrospective study was conducted over 1995-2006 in patients admitted in 18 Italian hematological divisions. Twenty-four cases of advanced MCD were collected: 12 aggressive SM (50%), 8 mast cell leukemia (33%), 4 SM with associated clonal non-mast cell-lineage hematologic disease (17%). Spleen and liver were the principal extramedullary organ involved. The c-kit point mutation D816V was found in 13/18 patients in which molecular biology studies were performed (72%). Treatments were very heterogeneous: on the whole Imatinib was administered in 17 patients, a-Interferon in 8, 2-CdA in 3; 2 patients underwent allogeneic hematopoietic stem cell transplantation. The overall response rate to Imatinib, the most frequently employed drugs, was of 29%, registering one complete remission and four partial remission; all responsive patients did not present D816V c-kit mutation. Overall three patients (12%) died for progression of disease. We conclude that MCD is characterized by severe mediator-related symptoms but with a moderate mortality rate.
Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, pers... more Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by unexplained, persistent hypereosinophilia associated with multiple organ dysfunctions. The cause of HES is unknown and shows clinical heterogeneity. FIP1L1-PDGFRA fusion is a clonal marker for the diagnosis and treatment of HES. We prospectively studied 78 patients with chronic eosinophilia. In all cases, the most salient clinical and biological characteristics as well as the response to the therapy were analyzed. In addition, we performed conventional cytogenetics and fluorescent in situ hybridization (FISH) with three BACs covering the FIP1-like-1 (FIP1L1)/platelet-derived growth factor receptor-α gene (PDGFRA) fusion. Nineteen of 78 patients (24 %) presented criteria of HES. The majority of patients were male (18) with median age of 49 years (range 19-84 years). FIP1L1-PDGFRA fusion was found in eight patients. Patients with FIP1L1-PDGFRA fusion presented with more bone marrow eosinophils and peripheral blood eosinophilia as well as anemia, leukocytosis and thrombocytopenia. Using of low-dose imatinib mesylate (100 mg/day) a hematological and molecular remission in all patients displaying the FIP1L1-PDGFRA fusion gene was observed. Therefore, imatinib may be effective for use in the treatment of chronic eosinophilic leukemia, and patients should be treated before tissue damage.
The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelp... more The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.
The treatment of hematologic malignancies has been based for many years on chemotherapy and possi... more The treatment of hematologic malignancies has been based for many years on chemotherapy and possibly, for the more aggressive forms, stem cell transplantation. In 2001, the signal transduction inhibitor 571 (STI571, imatinib mesylate) was reported to have striking effects in chronic myeloid leukaemia patients. Since then, imatinib became the first molecular-targeted agent approved for the treatment of human cancer and was later on demonstrated to be effective in other malignancies, such as Philadelphia positive acute lymphoid leukemia, hypereosinophilic syndromes, gastrointestinal stromal tumours and more recently, systemic mastocytosis and other myeloprolipherative disease-carrying platelet-derived growth factor receptor abnormalities. In this article, the authors review the evidence which led to imatinib approval in the treatment of several of the above mentioned diseases.
Background: fms-related tyrosine kinase 3 (Flt3) is the most commonly mutated gene in human acute... more Background: fms-related tyrosine kinase 3 (Flt3) is the most commonly mutated gene in human acute myeloid leukemia (AML) and has been implicated in its pathogenesis. Because screening of Flt3 in AML patients by PCR followed by gel electrophoresis is time-consuming and fails to detect some very small internal tandem duplications (ITDs), we developed a method for screening of FLT3 receptor mutations with PCR plus denaturing HPLC (D-HPLC).
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Papers by M. Rondoni