Marcello Rotta - Academia.edu (original) (raw)

Papers by Marcello Rotta

Research paper thumbnail of Long-term Outcome of Patients with Multiple Myeloma after Autologous Hematopoietic Cell Transplantation and Nonmyeloablative Allografting Running title: Auto-Allotransplant in Multiple Myeloma

Research paper thumbnail of Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting

Autologous hematopoietic cell transplanta- tion (HCT) followed by nonmyeloablative allogeneic HCT... more Autologous hematopoietic cell transplanta- tion (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cy- toreduction and graft-versus-myeloma ef- fects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft fol- lowed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT

Research paper thumbnail of Association between Calcineurin Inhibitor Blood Concentrations and Outcomes after Allogeneic Hematopoietic Cell Transplantation

Biology of Blood and Marrow Transplantation, 2000

To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month afte... more To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month after allogeneic hematopoietic cell transplantation (HCT) correlated with the incidence of graft-versushost disease (GVHD) and other outcomes, we retrospectively analyzed data from 1181 patients with hematologic malignancies who had HCT from HLA-matched related (n=634) or unrelated (n=547) donors at a single institution between 2001 and 2009. After myeloablative HCT (n=774), higher CNI concentrations were not associated with lower risks of acute or chronic GVHD. After nonmyeloablative HCT (n=407), higher cyclosporine concentrations were associated with decreased risks of grade 2-4 and 3-4 acute GVHD (hazard ratio [HR] per 100 ng/ml change in cyclosporine concentrations, 0.7; 95% confidence interval [CI], 0.6-0.82; and HR, 0.66, 95%CI, 0.49-0.9, respectively), non-relapse mortality (HR, 0.6, 95% CI, 0.41-0.88), and overall mortality (HR, 0.83, 95%CI, 0.71-0.99). Cyclosporine concentrations were not associated with risks of chronic GVHD and recurrent malignancy after nonmyeloablative HCT. Among patients given tacrolimus after nonmyeloablative HCT, a similar trend of CNI-associated GVHD-protection was observed. Higher CNI concentrations were not associated with apparent renal toxicity. We conclude that higher cyclosporine concentrations relatively early after nonmyeloablative HCT confer protection against acute GVHD that translates into reduced risks of non-relapse and overall mortality.

Research paper thumbnail of Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2010

We retrospectively analyzed outcomes among 1206 patients with hematologic malignancies who had he... more We retrospectively analyzed outcomes among 1206 patients with hematologic malignancies who had hematopoietic cell transplantation (HCT) from HLA-identical siblings (n = 630) or HLA-matched unrelated donors (n = 576) at a single institution between 2001 and 2007 for a correlation between recipient statin use and risk of graft-versus-host disease (GVHD). Among recipients with cyclosporine-based postgrafting immunosuppression (n = 821), statin use at the time of transplant (6%) was associated with a decreased risk of extensive chronic GVHD (cGVHD) (multivariate hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.4-1.0; P = .05) and an increased risk of recurrent malignancy (HR, 1.75; 95% CI, 1.0-3.0; P = .04). Recipient statin use, however, had no apparent impact on the risks of cGVHD and recurrent malignancy among recipients given tacrolimus-based immunosuppression (n = 385; 8% statin treated). Risks of acute GVHD, nonrelapse mortality, and overall mortality were not significantl...

Research paper thumbnail of A Comparison of Allografting with Autografting for Newly Diagnosed Myeloma

New England Journal of Medicine, 2007

In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that e... more In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that entailed a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling with a protocol of tandem autografts. We enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least one sibling. All patients were initially treated with vincristine, doxorubicin, and dexamethasone, followed by melphalan and autologous stem-cell rescue. Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem cells from the sibling. Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan, each of which was followed by autologous stem-cell rescue. The primary end points were overall survival and event-free survival. After a median follow-up of 45 months (range, 21 to 90), the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months vs. 54 months, P=0.01; and 35 months vs. 29 months, P=0.02, respectively). Among patients who completed their assigned treatment protocols, treatment-related mortality did not differ significantly between the double-autologous-transplant group (46 patients) and the autograft-allograft group (58 patients, P=0.09), but disease-related mortality was significantly higher in the double-autologous-transplant group (43% vs. 7%, P<0.001). The cumulative incidence rates of grades II, III, and IV graft-versus-host disease (GVHD) combined and of grade IV GVHD in the autograft-allograft group were 43% and 4%, respectively. Overall, 21 of 58 patients (36%) were in complete remission after a median follow-up of 38 months (range, 10 to 72) after allografting. Of the 46 patients who received two autografts, 25 (54%) died. Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].).

Research paper thumbnail of Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside

Leukemia, 2005

Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis ha... more Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis have identified signaling pathways that have become potential therapeutic targets. It has clearly been established that intracellular regulatory proteins and interactions between malignant plasma cells and the bone marrow microenvironment play an important role in their survival and drug resistance. Several new agents associated with molecular targets are currently being investigated to design new treatment strategies aimed at prolonging survival and improving quality of life. This review illustrates their mechanisms of action and the possible future clinical applications.

Research paper thumbnail of New drugs for treatment of multiple myeloma

The Lancet Oncology, 2004

Multiple myeloma (MM) is a disease of plasma cells that has fatal consequences. New insights into... more Multiple myeloma (MM) is a disease of plasma cells that has fatal consequences. New insights into the biology of MM have identified molecular mechanisms that hold promise as therapeutic targets. Laboratory and preclinical studies have shown that intracellular regulatory proteins and functional interactions between MM cells and the bone-marrow microenvironment have a pivotal role in the growth, survival, drug resistance, and malignant progression of MM cells. New agents associated with molecular targets have prompted clinical investigators to design new treatment strategies initially for advanced MM and later for newly diagnosed MM, with encouraging preliminary results. Here, we discuss the mechanisms of action of these new rational drugs and the preliminary clinical outcomes of a new treatment regimen for MM.

Research paper thumbnail of Unrelated donor haematopoietic cell transplantation after non-myeloablative conditioning for patients with high-risk multiple myeloma

Allografting induces long-term molecular remissions and possibly cure in myeloma patients. The de... more Allografting induces long-term molecular remissions and possibly cure in myeloma patients. The development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high-dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pretreated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning consisted of fludarabine 90 mg/m(2) and 2 Gy total body irradiation. Graft-vs.-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. All patients except two (91%) readily engrafted. After a median follow-up of 20 (10-30) months, incidences of grade II-IV acute and extensive chronic GVHD were 50% and 61%. Overall response (OR) was 55%, with four (20%) complete and seven (35%) partial remissions. However, in patients allografted up-front OR was 89% whereas in the heavily pretreated group OR was 27% (P = 0.01). Two-year overall and event-free survivals were both 79% in the group transplanted up-front and 27% and 25% among relapsed patients (P = 0.025 and P = 0.006, respectively). Overall, six patients died of TRM and three of disease progression. Unrelated donor non-myeloablative allografting is feasible in myeloma. Disease control appears more pronounced when patients are treated soon after diagnosis.

Research paper thumbnail of Kaposi's sarcoma triggered by endogenous HHV-8 reactivation after non-myeloablative allogeneic haematopoietic transplantation

European Journal of Haematology, 2006

Research paper thumbnail of Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo

Research paper thumbnail of Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting

Blood, 2009

Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (... more Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cytoreduction and graft-versus-myeloma effects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft followed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT from human leukocyte antigen-identical siblings. Postgrafting immunosuppressive agent was cyclosporine or tacrolimus and mycophenolate mofetil. Forty-two percent of patients developed grade 2 to 4 acute graft-versushost disease (GVHD) and 74% extensive chronic GVHD. Five-year nonrelapse mortality after allografting was 18%, 95% related to GVHD or infections. Among 95 patients with detectable disease, 59 achieved complete remissions.

Research paper thumbnail of Donor statin treatment protects against severe acute graft-versus-host disease after related allogeneic hematopoietic cell transplantation

Research paper thumbnail of Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma

Blood, 2011

Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myel... more Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.

Research paper thumbnail of Bortezomib after Allografting in Multiple Myeloma: Association between Neurotoxicity and Cyclosporine Treatment

Biology of Blood and Marrow Transplantation, 2007

cases was low. Acute grade II-IV GVHD developed in 17.8% of the patients, most cases of chronic G... more cases was low. Acute grade II-IV GVHD developed in 17.8% of the patients, most cases of chronic GVHD were limited, and the 4 patients with extensive chronic GVHD (17.4% of the patients surviving to day 100) were not severe, did not require prolonged treatment and never developed serious infections. Other groups have demonstrated the beneficial effect of THY in reducing the incidence of acute and chronic GVHD after unrelated SCT [2][3][4][5]7]. With a median follow-up similar to our study, the GITMO group showed a 39% incidence of extensive chronic GVHD in recipients of unrelated SCT after the administration of 7.5 or 15 mg/kg THY, with the last dose infused on day Ϫ3 or Ϫ2 [7]. The patients receiving 15 mg/kg THY also had the lowest incidence of severe acute GVHD, not translating into a survival benefit because of a high rate of fatal infections [7].

Research paper thumbnail of Delaying DLA-Haploidentical Hematopoietic Cell Transplantation after Total Body Irradiation

Biology of Blood and Marrow Transplantation, 2009

Exposure to accidental or deliberate radiation poses a threat to public health, proving lethal at... more Exposure to accidental or deliberate radiation poses a threat to public health, proving lethal at higher doses in large part due to deleterious effects on marrow. In those cases, allogeneic hematopoietic cell transplantation (HCT) might be required to restore marrow function. Most radiation accident victims will have HLA-haploidentical relatives who could serve as HCT donors. Here, we assessed in a canine HCT model the total body irradiation (TBI) doses after which transplants might be required and successful engraftment would be possible. In an attempt at mimicking the logistical problems likely to exist after radiation accidents, 4-, 8-or 10-day intervals were placed between TBI and HCT. In order to keep the experimental readout simple, no graft-vs-host disease (GVHD) prevention was administered. All dogs transplanted after a 4-day delay following 700 or 920 cGy TBI successfully engrafted while virtually all those given 450 or 600 cGy rejected their grafts. Transplant delays of 8 and 10 days following 920 cGy TBI also resulted in successful engraftment in most dogs, while a delay of 8 days after 700 cGy resulted in virtually uniform graft failure. The time courses of acute GVHD and rates of granulocyte recovery in engrafting dogs were comparable among dogs regardless of the lengths of delay. In other studies, we showed that most dogs not given HCT survived 700 cGy TBI with intensive supportive care while those given 800 cGy TBI and higher died with marrow aplasia. Thus, DLA-haploidentical HCT was successful even when carried out 4, 8 or 10 days after TBI at or above radiation exposures where dogs survived with intensive care alone.

Research paper thumbnail of 170: Long-Term Outcome of Nonmyeloalative Allografting from HLA-Identical Sibling for Multiple Myeloma (MM)

Biology of Blood and Marrow Transplantation, 2008

Research paper thumbnail of Association Between Calcineurin Inhibitor Blood Concentrations and Outcomes After Allogeneic Hematopoietic Cell Transplantation

Biology of Blood and Marrow Transplantation, 2011

To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month afte... more To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month after allogeneic hematopoietic cell transplantation (HCT) correlated with the incidence of graft-versushost disease (GVHD) and other outcomes, we retrospectively analyzed data from 1181 patients with hematologic malignancies who had HCT from HLA-matched related (n=634) or unrelated (n=547) donors at a single institution between 2001 and 2009. After myeloablative HCT (n=774), higher CNI concentrations were not associated with lower risks of acute or chronic GVHD. After nonmyeloablative HCT (n=407), higher cyclosporine concentrations were associated with decreased risks of grade 2-4 and 3-4 acute GVHD (hazard ratio [HR] per 100 ng/ml change in cyclosporine concentrations, 0.7; 95% confidence interval [CI], 0.6-0.82; and HR, 0.66, 95%CI, 0.49-0.9, respectively), non-relapse mortality (HR, 0.6, 95% CI, 0.41-0.88), and overall mortality (HR, 0.83, 95%CI, 0.71-0.99). Cyclosporine concentrations were not associated with risks of chronic GVHD and recurrent malignancy after nonmyeloablative HCT. Among patients given tacrolimus after nonmyeloablative HCT, a similar trend of CNI-associated GVHD-protection was observed. Higher CNI concentrations were not associated with apparent renal toxicity. We conclude that higher cyclosporine concentrations relatively early after nonmyeloablative HCT confer protection against acute GVHD that translates into reduced risks of non-relapse and overall mortality.

Research paper thumbnail of Statins Synergize With Cyclosporine in Inhibiting Mitochondrial Function in Activated T Cells

Biology of Blood and Marrow Transplantation, 2011

Research paper thumbnail of 602 Is There a Role for Allografting in Myeloma in the Era of New Drugs?: Long-Term Follow-Up of a Comparative Study

Clinical Lymphoma Myeloma and Leukemia, 2011

... Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ,; Francesca Patriarca: ... Divisio... more ... Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ,; Francesca Patriarca: ... Division of Hematology, AOU San Giovanni Battista, Torino, Italy. ,; Sara Bringhen: ... Email Abstract; Add to My Reading List; Rights/Permissions; Request Reprints; Related Articles Related Articles ...

Research paper thumbnail of Long-term Outcome of Patients with Multiple Myeloma after Autologous Hematopoietic Cell Transplantation and Nonmyeloablative Allografting Running title: Auto-Allotransplant in Multiple Myeloma

Research paper thumbnail of Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting

Autologous hematopoietic cell transplanta- tion (HCT) followed by nonmyeloablative allogeneic HCT... more Autologous hematopoietic cell transplanta- tion (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cy- toreduction and graft-versus-myeloma ef- fects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft fol- lowed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT

Research paper thumbnail of Association between Calcineurin Inhibitor Blood Concentrations and Outcomes after Allogeneic Hematopoietic Cell Transplantation

Biology of Blood and Marrow Transplantation, 2000

To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month afte... more To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month after allogeneic hematopoietic cell transplantation (HCT) correlated with the incidence of graft-versushost disease (GVHD) and other outcomes, we retrospectively analyzed data from 1181 patients with hematologic malignancies who had HCT from HLA-matched related (n=634) or unrelated (n=547) donors at a single institution between 2001 and 2009. After myeloablative HCT (n=774), higher CNI concentrations were not associated with lower risks of acute or chronic GVHD. After nonmyeloablative HCT (n=407), higher cyclosporine concentrations were associated with decreased risks of grade 2-4 and 3-4 acute GVHD (hazard ratio [HR] per 100 ng/ml change in cyclosporine concentrations, 0.7; 95% confidence interval [CI], 0.6-0.82; and HR, 0.66, 95%CI, 0.49-0.9, respectively), non-relapse mortality (HR, 0.6, 95% CI, 0.41-0.88), and overall mortality (HR, 0.83, 95%CI, 0.71-0.99). Cyclosporine concentrations were not associated with risks of chronic GVHD and recurrent malignancy after nonmyeloablative HCT. Among patients given tacrolimus after nonmyeloablative HCT, a similar trend of CNI-associated GVHD-protection was observed. Higher CNI concentrations were not associated with apparent renal toxicity. We conclude that higher cyclosporine concentrations relatively early after nonmyeloablative HCT confer protection against acute GVHD that translates into reduced risks of non-relapse and overall mortality.

Research paper thumbnail of Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2010

We retrospectively analyzed outcomes among 1206 patients with hematologic malignancies who had he... more We retrospectively analyzed outcomes among 1206 patients with hematologic malignancies who had hematopoietic cell transplantation (HCT) from HLA-identical siblings (n = 630) or HLA-matched unrelated donors (n = 576) at a single institution between 2001 and 2007 for a correlation between recipient statin use and risk of graft-versus-host disease (GVHD). Among recipients with cyclosporine-based postgrafting immunosuppression (n = 821), statin use at the time of transplant (6%) was associated with a decreased risk of extensive chronic GVHD (cGVHD) (multivariate hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.4-1.0; P = .05) and an increased risk of recurrent malignancy (HR, 1.75; 95% CI, 1.0-3.0; P = .04). Recipient statin use, however, had no apparent impact on the risks of cGVHD and recurrent malignancy among recipients given tacrolimus-based immunosuppression (n = 385; 8% statin treated). Risks of acute GVHD, nonrelapse mortality, and overall mortality were not significantl...

Research paper thumbnail of A Comparison of Allografting with Autografting for Newly Diagnosed Myeloma

New England Journal of Medicine, 2007

In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that e... more In this trial of the treatment of newly diagnosed multiple myeloma, we compared a protocol that entailed a hematopoietic stem-cell autograft followed by an allograft from an HLA-identical sibling with a protocol of tandem autografts. We enrolled 162 consecutive patients with newly diagnosed myeloma who were 65 years of age or younger and who had at least one sibling. All patients were initially treated with vincristine, doxorubicin, and dexamethasone, followed by melphalan and autologous stem-cell rescue. Patients with an HLA-identical sibling then received nonmyeloablative total-body irradiation and stem cells from the sibling. Patients without an HLA-identical sibling received two consecutive myeloablative doses of melphalan, each of which was followed by autologous stem-cell rescue. The primary end points were overall survival and event-free survival. After a median follow-up of 45 months (range, 21 to 90), the median overall survival and event-free survival were longer in the 80 patients with HLA-identical siblings than in the 82 patients without HLA-identical siblings (80 months vs. 54 months, P=0.01; and 35 months vs. 29 months, P=0.02, respectively). Among patients who completed their assigned treatment protocols, treatment-related mortality did not differ significantly between the double-autologous-transplant group (46 patients) and the autograft-allograft group (58 patients, P=0.09), but disease-related mortality was significantly higher in the double-autologous-transplant group (43% vs. 7%, P<0.001). The cumulative incidence rates of grades II, III, and IV graft-versus-host disease (GVHD) combined and of grade IV GVHD in the autograft-allograft group were 43% and 4%, respectively. Overall, 21 of 58 patients (36%) were in complete remission after a median follow-up of 38 months (range, 10 to 72) after allografting. Of the 46 patients who received two autografts, 25 (54%) died. Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. (ClinicalTrials.gov number, NCT00415987 [ClinicalTrials.gov].).

Research paper thumbnail of Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside

Leukemia, 2005

Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis ha... more Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis have identified signaling pathways that have become potential therapeutic targets. It has clearly been established that intracellular regulatory proteins and interactions between malignant plasma cells and the bone marrow microenvironment play an important role in their survival and drug resistance. Several new agents associated with molecular targets are currently being investigated to design new treatment strategies aimed at prolonging survival and improving quality of life. This review illustrates their mechanisms of action and the possible future clinical applications.

Research paper thumbnail of New drugs for treatment of multiple myeloma

The Lancet Oncology, 2004

Multiple myeloma (MM) is a disease of plasma cells that has fatal consequences. New insights into... more Multiple myeloma (MM) is a disease of plasma cells that has fatal consequences. New insights into the biology of MM have identified molecular mechanisms that hold promise as therapeutic targets. Laboratory and preclinical studies have shown that intracellular regulatory proteins and functional interactions between MM cells and the bone-marrow microenvironment have a pivotal role in the growth, survival, drug resistance, and malignant progression of MM cells. New agents associated with molecular targets have prompted clinical investigators to design new treatment strategies initially for advanced MM and later for newly diagnosed MM, with encouraging preliminary results. Here, we discuss the mechanisms of action of these new rational drugs and the preliminary clinical outcomes of a new treatment regimen for MM.

Research paper thumbnail of Unrelated donor haematopoietic cell transplantation after non-myeloablative conditioning for patients with high-risk multiple myeloma

Allografting induces long-term molecular remissions and possibly cure in myeloma patients. The de... more Allografting induces long-term molecular remissions and possibly cure in myeloma patients. The development of non-myeloablative conditionings has reduced the transplant-related mortality (TRM) associated with myeloablation and extended the eligible age for transplantation. Moreover, high response rates are reported especially when allografting is preceded by cytoreductive high-dose chemotherapy. We investigated the feasibility of unrelated donor non-myeloablative transplantation as either part of the initial treatment plan or as salvage treatment in heavily pretreated patients. Twenty-two patients underwent non-myeloablative allografting, 10 as part of their initial treatment and 12 at relapse. Donors were matched for HLA-A, B, C, DRB1 and DQB1 by high-resolution typing. Only one single class I allele disparity was allowed. Conditioning consisted of fludarabine 90 mg/m(2) and 2 Gy total body irradiation. Graft-vs.-host disease (GVHD) prophylaxis included cyclosporin and mycophenolate mofetil. All patients except two (91%) readily engrafted. After a median follow-up of 20 (10-30) months, incidences of grade II-IV acute and extensive chronic GVHD were 50% and 61%. Overall response (OR) was 55%, with four (20%) complete and seven (35%) partial remissions. However, in patients allografted up-front OR was 89% whereas in the heavily pretreated group OR was 27% (P = 0.01). Two-year overall and event-free survivals were both 79% in the group transplanted up-front and 27% and 25% among relapsed patients (P = 0.025 and P = 0.006, respectively). Overall, six patients died of TRM and three of disease progression. Unrelated donor non-myeloablative allografting is feasible in myeloma. Disease control appears more pronounced when patients are treated soon after diagnosis.

Research paper thumbnail of Kaposi's sarcoma triggered by endogenous HHV-8 reactivation after non-myeloablative allogeneic haematopoietic transplantation

European Journal of Haematology, 2006

Research paper thumbnail of Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo

Research paper thumbnail of Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting

Blood, 2009

Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (... more Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cytoreduction and graft-versus-myeloma effects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft followed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT from human leukocyte antigen-identical siblings. Postgrafting immunosuppressive agent was cyclosporine or tacrolimus and mycophenolate mofetil. Forty-two percent of patients developed grade 2 to 4 acute graft-versushost disease (GVHD) and 74% extensive chronic GVHD. Five-year nonrelapse mortality after allografting was 18%, 95% related to GVHD or infections. Among 95 patients with detectable disease, 59 achieved complete remissions.

Research paper thumbnail of Donor statin treatment protects against severe acute graft-versus-host disease after related allogeneic hematopoietic cell transplantation

Research paper thumbnail of Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma

Blood, 2011

Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myel... more Before the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with "new drugs," median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.

Research paper thumbnail of Bortezomib after Allografting in Multiple Myeloma: Association between Neurotoxicity and Cyclosporine Treatment

Biology of Blood and Marrow Transplantation, 2007

cases was low. Acute grade II-IV GVHD developed in 17.8% of the patients, most cases of chronic G... more cases was low. Acute grade II-IV GVHD developed in 17.8% of the patients, most cases of chronic GVHD were limited, and the 4 patients with extensive chronic GVHD (17.4% of the patients surviving to day 100) were not severe, did not require prolonged treatment and never developed serious infections. Other groups have demonstrated the beneficial effect of THY in reducing the incidence of acute and chronic GVHD after unrelated SCT [2][3][4][5]7]. With a median follow-up similar to our study, the GITMO group showed a 39% incidence of extensive chronic GVHD in recipients of unrelated SCT after the administration of 7.5 or 15 mg/kg THY, with the last dose infused on day Ϫ3 or Ϫ2 [7]. The patients receiving 15 mg/kg THY also had the lowest incidence of severe acute GVHD, not translating into a survival benefit because of a high rate of fatal infections [7].

Research paper thumbnail of Delaying DLA-Haploidentical Hematopoietic Cell Transplantation after Total Body Irradiation

Biology of Blood and Marrow Transplantation, 2009

Exposure to accidental or deliberate radiation poses a threat to public health, proving lethal at... more Exposure to accidental or deliberate radiation poses a threat to public health, proving lethal at higher doses in large part due to deleterious effects on marrow. In those cases, allogeneic hematopoietic cell transplantation (HCT) might be required to restore marrow function. Most radiation accident victims will have HLA-haploidentical relatives who could serve as HCT donors. Here, we assessed in a canine HCT model the total body irradiation (TBI) doses after which transplants might be required and successful engraftment would be possible. In an attempt at mimicking the logistical problems likely to exist after radiation accidents, 4-, 8-or 10-day intervals were placed between TBI and HCT. In order to keep the experimental readout simple, no graft-vs-host disease (GVHD) prevention was administered. All dogs transplanted after a 4-day delay following 700 or 920 cGy TBI successfully engrafted while virtually all those given 450 or 600 cGy rejected their grafts. Transplant delays of 8 and 10 days following 920 cGy TBI also resulted in successful engraftment in most dogs, while a delay of 8 days after 700 cGy resulted in virtually uniform graft failure. The time courses of acute GVHD and rates of granulocyte recovery in engrafting dogs were comparable among dogs regardless of the lengths of delay. In other studies, we showed that most dogs not given HCT survived 700 cGy TBI with intensive supportive care while those given 800 cGy TBI and higher died with marrow aplasia. Thus, DLA-haploidentical HCT was successful even when carried out 4, 8 or 10 days after TBI at or above radiation exposures where dogs survived with intensive care alone.

Research paper thumbnail of 170: Long-Term Outcome of Nonmyeloalative Allografting from HLA-Identical Sibling for Multiple Myeloma (MM)

Biology of Blood and Marrow Transplantation, 2008

Research paper thumbnail of Association Between Calcineurin Inhibitor Blood Concentrations and Outcomes After Allogeneic Hematopoietic Cell Transplantation

Biology of Blood and Marrow Transplantation, 2011

To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month afte... more To determine whether calcineurin inhibitor (CNI) blood concentrations within the first month after allogeneic hematopoietic cell transplantation (HCT) correlated with the incidence of graft-versushost disease (GVHD) and other outcomes, we retrospectively analyzed data from 1181 patients with hematologic malignancies who had HCT from HLA-matched related (n=634) or unrelated (n=547) donors at a single institution between 2001 and 2009. After myeloablative HCT (n=774), higher CNI concentrations were not associated with lower risks of acute or chronic GVHD. After nonmyeloablative HCT (n=407), higher cyclosporine concentrations were associated with decreased risks of grade 2-4 and 3-4 acute GVHD (hazard ratio [HR] per 100 ng/ml change in cyclosporine concentrations, 0.7; 95% confidence interval [CI], 0.6-0.82; and HR, 0.66, 95%CI, 0.49-0.9, respectively), non-relapse mortality (HR, 0.6, 95% CI, 0.41-0.88), and overall mortality (HR, 0.83, 95%CI, 0.71-0.99). Cyclosporine concentrations were not associated with risks of chronic GVHD and recurrent malignancy after nonmyeloablative HCT. Among patients given tacrolimus after nonmyeloablative HCT, a similar trend of CNI-associated GVHD-protection was observed. Higher CNI concentrations were not associated with apparent renal toxicity. We conclude that higher cyclosporine concentrations relatively early after nonmyeloablative HCT confer protection against acute GVHD that translates into reduced risks of non-relapse and overall mortality.

Research paper thumbnail of Statins Synergize With Cyclosporine in Inhibiting Mitochondrial Function in Activated T Cells

Biology of Blood and Marrow Transplantation, 2011

Research paper thumbnail of 602 Is There a Role for Allografting in Myeloma in the Era of New Drugs?: Long-Term Follow-Up of a Comparative Study

Clinical Lymphoma Myeloma and Leukemia, 2011

... Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ,; Francesca Patriarca: ... Divisio... more ... Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ,; Francesca Patriarca: ... Division of Hematology, AOU San Giovanni Battista, Torino, Italy. ,; Sara Bringhen: ... Email Abstract; Add to My Reading List; Rights/Permissions; Request Reprints; Related Articles Related Articles ...