The introduction of high-dose therapy in the 1990s as well as the development of drugs such as th... more The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based ...
Background Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated ... more Background Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated graft and post-transplantation cyclophosphamide (PT-Cy) is growing. Haploidentical transplantation with PT-Cy showed a major activity in Hodgkin lymphoma (HL), reducing the relapse incidence. The most important predictive factor of survival and toxicity was disease status before transplantation, which was better in patients with well controlled disease. Methods We included 198 HL in complete (CR) or partial remission (PR) before transplantation. Sixty-five patients were transplanted from haploidentical donor and 133 from a HLA identical donor (both sibling and unrelated donors). Survival analysis was defined according to the EBMT criteria. Survival curves were generated by using Kaplan-Meier method and differences between groups were compared by the log rank test or by the log rank test for trend when appropriated. Results The PFS, OS, and RI were significantly better in patients in CR c...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018
We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploide... more We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17-74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for <60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the on...
Predicting mobilization failure before it starts may enable patient-tailored strategies. Although... more Predicting mobilization failure before it starts may enable patient-tailored strategies. Although consensus criteria for predicted PM (pPM) are available, their predictive performance has never been measured on real data. We retrospectively collected and analyzed 1318 mobilization procedures performed for MM and lymphoma patients in the plerixafor era. In our sample, 180/1318 (13.7%) were PM. The score resulting from published pPM criteria had sufficient performance for predicting PM, as measured by AUC (0.67, 95%CI: 0.63-0.72). We developed a new prediction model from multivariate analysis whose score (pPM-score) resulted in better AUC (0.80, 95%CI: 0.76-0.84, p < 0001). pPM-score included as risk factors: increasing age, diagnosis of NHL, positive bone marrow biopsy or cytopenias before mobilization, previous mobilization failure, priming strategy with G-CSF alone, or without upfront plerixafor. A simplified version of pPM-score was categorized using a cut-off to maximize posit...
We here report final results of a phase II/III prospective study that evaluated in Multiple Myelo... more We here report final results of a phase II/III prospective study that evaluated in Multiple Myeloma the use of on-demand plerixafor (PLX) added to mobilizing chemotherapy for patients showing predictive signs of mobilization failure. A total of 111 patients with MM were registered, all received cyclophosphamide 4 g/m(2) and granulocyte colony-stimulating factor (G-CSF). Overall, a successful CD34+ cell mobilization was achieved in 97.2% (108/111) of patients. Minimum harvest (≥2.0 × 10(6) CD34+ cells/kg) was achieved in 97.2% (108/111) and optimal harvest success (≥4.0 × 10(6) CD34+ cells/kg) was achieved in 84.6% (94/111). Multivariate analysis showed that patients who received on-demand PLX treatment had significantly higher likelihoods of successfully achieving both the minimal (p = .006) and optimal harvest (p = .05) in respect to a historical control group mobilized without any PLX. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a suc...
Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transpl... more Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβpathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a f...
The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (... more The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (auto-HPCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. Administration of high-dose melphalan (HDM) is considered the standard conditioning regimen. Nevertheless, several attempts have recently been made to improve the conditioning phase of the HDC procedure. We reviewed all the reported experiences and illustrated current knowledge in the field of conditioning regimens. For fit MM patients, HDC followed by auto-HPCT remains the standard of care. The available data confirm that melphalan (MEL) 200 mg/m(2) should continue to be considered the gold standard conditioning regimen, with dose reduction based on age and renal function. Targeting exposure to MEL by using area under the curve is a particularly appealing approach that could be explored to maximize efficacy and minimize toxicity of this drug. Other strategies are currently being evaluated in different trials, and the most interesting areas of research involve the incorporation of newer agents like bortezomib (BOR) into conditioning regimens. Moreover, intravenous busulfan has become available and this formulation may reduce toxicity and result in greater efficacy in association with MEL-based conditioning.
The introduction of high-dose therapy in the 1990s as well as the development of drugs such as th... more The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based ...
Background Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated ... more Background Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated graft and post-transplantation cyclophosphamide (PT-Cy) is growing. Haploidentical transplantation with PT-Cy showed a major activity in Hodgkin lymphoma (HL), reducing the relapse incidence. The most important predictive factor of survival and toxicity was disease status before transplantation, which was better in patients with well controlled disease. Methods We included 198 HL in complete (CR) or partial remission (PR) before transplantation. Sixty-five patients were transplanted from haploidentical donor and 133 from a HLA identical donor (both sibling and unrelated donors). Survival analysis was defined according to the EBMT criteria. Survival curves were generated by using Kaplan-Meier method and differences between groups were compared by the log rank test or by the log rank test for trend when appropriated. Results The PFS, OS, and RI were significantly better in patients in CR c...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018
We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploide... more We report a modified post-transplant cyclophosphamide (PT-CY) regimen, for unmanipulated haploidentical marrow transplants, in 150 patients with acute myeloid leukemia (AML). All patients received a myeloablative regimen, cyclosporine A (CsA) on day 0, mycophenolate on day +1, and PT-CY 50 mg/kg on days +3 and +5. The median age was 51 (range, 17-74) years, 51 (34%) patients had active disease at transplant, and the median follow-up of surviving patients 903 (range, 150-1955) days. The cumulative incidence (CI) of engraftment, acute graft-versus-host disease (GVHD) grade II to IV, and moderate/severe chronic GVHD was 92%, 17%, and 15%, respectively. The 4-year CI of transplant-related mortality (TRM) and relapse was 20% and 24%, respectively. Four-year survival for remission patients was 72% (74% versus 67% for <60 or ≥60 years of age) and 26% for advanced patients (17% versus 41% for <60 or ≥60 years of age). In a multivariate analysis, active disease at transplant was the on...
Predicting mobilization failure before it starts may enable patient-tailored strategies. Although... more Predicting mobilization failure before it starts may enable patient-tailored strategies. Although consensus criteria for predicted PM (pPM) are available, their predictive performance has never been measured on real data. We retrospectively collected and analyzed 1318 mobilization procedures performed for MM and lymphoma patients in the plerixafor era. In our sample, 180/1318 (13.7%) were PM. The score resulting from published pPM criteria had sufficient performance for predicting PM, as measured by AUC (0.67, 95%CI: 0.63-0.72). We developed a new prediction model from multivariate analysis whose score (pPM-score) resulted in better AUC (0.80, 95%CI: 0.76-0.84, p < 0001). pPM-score included as risk factors: increasing age, diagnosis of NHL, positive bone marrow biopsy or cytopenias before mobilization, previous mobilization failure, priming strategy with G-CSF alone, or without upfront plerixafor. A simplified version of pPM-score was categorized using a cut-off to maximize posit...
We here report final results of a phase II/III prospective study that evaluated in Multiple Myelo... more We here report final results of a phase II/III prospective study that evaluated in Multiple Myeloma the use of on-demand plerixafor (PLX) added to mobilizing chemotherapy for patients showing predictive signs of mobilization failure. A total of 111 patients with MM were registered, all received cyclophosphamide 4 g/m(2) and granulocyte colony-stimulating factor (G-CSF). Overall, a successful CD34+ cell mobilization was achieved in 97.2% (108/111) of patients. Minimum harvest (≥2.0 × 10(6) CD34+ cells/kg) was achieved in 97.2% (108/111) and optimal harvest success (≥4.0 × 10(6) CD34+ cells/kg) was achieved in 84.6% (94/111). Multivariate analysis showed that patients who received on-demand PLX treatment had significantly higher likelihoods of successfully achieving both the minimal (p = .006) and optimal harvest (p = .05) in respect to a historical control group mobilized without any PLX. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a suc...
Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transpl... more Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβpathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a f...
The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (... more The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (auto-HPCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. Administration of high-dose melphalan (HDM) is considered the standard conditioning regimen. Nevertheless, several attempts have recently been made to improve the conditioning phase of the HDC procedure. We reviewed all the reported experiences and illustrated current knowledge in the field of conditioning regimens. For fit MM patients, HDC followed by auto-HPCT remains the standard of care. The available data confirm that melphalan (MEL) 200 mg/m(2) should continue to be considered the gold standard conditioning regimen, with dose reduction based on age and renal function. Targeting exposure to MEL by using area under the curve is a particularly appealing approach that could be explored to maximize efficacy and minimize toxicity of this drug. Other strategies are currently being evaluated in different trials, and the most interesting areas of research involve the incorporation of newer agents like bortezomib (BOR) into conditioning regimens. Moreover, intravenous busulfan has become available and this formulation may reduce toxicity and result in greater efficacy in association with MEL-based conditioning.
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