Consuelo Corti - Academia.edu (original) (raw)

Papers by Consuelo Corti

European Journal of Haematology, 2015

Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell tr... more Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3-ITD-positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off-label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post-transplantation FLT3-ITD-positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand-foot syndrome. None of the patients developed graft-vs.-host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T-cell infusions. Six patients are alive and in remission at the last follow-up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3-ITD-positive post-transplantation relapses, manageable also in combination with other therapeutic strategies.

Biology of Blood and Marrow Transplantation, 2015

Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) gr... more Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/μL of 41 days. Cumulative incidences of grade II to IV and III and IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.

Chronobiologia

No mention is made of any aspect of BP bioperiodicity, among current clinical criteria for diagno... more No mention is made of any aspect of BP bioperiodicity, among current clinical criteria for diagnosing pregnancy-related hypertension. The abnormal BP, based on a single unqualified measurement, is accepted and utilized as a clinical feature to identify pregnancy at risk. Systolic, diastolic and mean arterial blood pressure were measured every 15 min for 24 h in 5 women (2 non pregnant clinically healthy subjects, 1 clinically healthy subject in her third trimester of pregnancy, 1 presenting mild and 1 severe toxiemia, also in their third trimester of pregnancy) by an automated BP recording apparatus (Dynamap). All variables, analyzed by the single cosinor method, exhibited statistically significant circadian rhythms. A high amplitude could nullify the time-unqualified usual range. The change in circadian amplitude precedes an overt mesor hypertension and constitutes a tool for earlier detection of fetal distress.

Methods and findings in experimental and clinical pharmacology, 1984

A new experimental model is presented for determining the optimum dose of 3 different doses (13 m... more A new experimental model is presented for determining the optimum dose of 3 different doses (13 mg, 25 mg, 37 mg per day) of hydrochlorothiazide employed to enhance hypotensive effect of 200 mg/day of metoprolol in human hypertension. The model takes into account the circadian variability of blood pressure as sinusoidal function and wash-out effect as a linear trend so as to compensate for bias due to normal temporal variability.

Haematologica, Jan 6, 2015

Developing an optimal radiation-free central nervous system prophylaxis is a desirable goal in ac... more Developing an optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m2 in Philadelphia-negative B- and T-cell disease, respectively. The comparative assessment of the risk/benefit ratio was the primary study objective, combining the analysis of feasibility, toxicity and efficacy. In liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in triple therapy arm (P=0.0002), the median number of neurotoxicity episodes of any grade was 1 per patient c...

Transfusion, 2015

In allogeneic hematopoietic stem cell (HSC) transplantation, the collection of an appropriate num... more In allogeneic hematopoietic stem cell (HSC) transplantation, the collection of an appropriate number of HSCs while maintaining a high level of safety for healthy donors is fundamental. Inadequate HSC mobilization can be seen with the standard use of granulocyte-colony-stimulating (G-CSF). Plerixafor (PL) is a chemokine receptor CXC Type 4-stromal-derived factor 1 inhibitor; its HSC-mobilizing properties are synergistic with G-CSF in poor mobilizing patients. The use of PL as adjuvant or alternative to G-CSF in healthy donors has shown a good safety profile but is so far off-label. We report 10 healthy HSC donors treated with PL because of insufficient response to G-CSF alone or contraindication to G-CSF. Eight donors did not mobilize enough CD34+ cells with G-CSF alone because poor mobilizers or because insufficient HSCs were harvested according to the clinical need of the patient; in two cases G-CSF administration and marrow harvest were unfeasible or contraindicated in the donor. The use of PL for mobilization increased the number of circulating CD34+ cells by 2.8-fold and the CD34+/kg collection by 3.0-fold. Only mild adverse events were reported (bone pain or discomfort) and not univocally attributable to PL. Rate of engraftment and graft-versus-host disease were similar to those seen in recipients of grafts from G-CSF only-mobilized donors. We exposed 10 allogeneic donors to mobilization with PL. PL was well tolerated in all cases and ensured procurement of an adequate graft for transplantation resulting in a normal hematopoietic engraftment.

Leukemia, 2014

Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of... more Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their 'classical' counterparts (median: 307 vs 88 days, P o0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65-38.92; P = 0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05-0.46; P = 0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after 'classical' and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.

Biology of Blood and Marrow Transplantation, 2014

The management of Hodgkin's lymphoma (HL) recurring after allogeneic stem cell transplantation is... more The management of Hodgkin's lymphoma (HL) recurring after allogeneic stem cell transplantation is challenging. We retrospectively describe 18 adults treated with bendamustine followed by escalated donor lymphocyte infusion. Hematological toxicity was manageable (39% grade III to IV neutropenia and 28% grade III to IV thrombocytopenia). The overall response rate was 55%, with 3 complete and 7 partial responses. Median overall and progression-free survival were 11 (range, 1 to 52) and 6 (range, 1 to 28) months, respectively. One-year overall survival of responders (complete or partial) was 70% (95% confidence interval, 42% to 98%), although it was only 16% for nonresponders (n ¼ 8). Our data show that bendamustine followed by donor lymphocyte infusion is feasible and can be efficacious as salvage treatment in HL relapsing after an allograft.

Hematological Oncology, 2014

Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in t... more Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in the era of new drugs that so far only mitigate symptoms. The choice to proceed to allogeneic transplantation is based on several variables including age, disease phase, degree of splenomegaly, donor availability, comorbidities and iron overload. These factors, along with conditioning regimen and time to transplantation, may influence the outcome of ASCT. We report 14 patients affected by myelofibrosis with a median age of 57 years (range, 41-76) receiving a treosulfan-fludarabine based reduced toxicity conditioning. Patients (pts) received a stem cell transplantation from an HLA identical (n = 10) or matched unrelated donor (n = 4). All pts had a complete myeloablation followed by engraftment and in 12 out of 13 evaluated pts donor chimerism was 100% at 1 month. In most cases a reduction of splenomegaly and a reduction (or resolution) of bone marrow fibrosis was observed. After a median follow-up of 39 months (range, 3-106), the 3-year probability of overall survival and disease free survival was 54 +/- 14% and 46 +/- 14%, respectively. The cumulative incidence of non-relapse mortality at 2 years was 39 +/- 15%. Causes of non-relapse mortality were: infection (n = 2), GvHD (n = 2) and haemorrhage (n = 1). We can conclude that a treosulfan and fludarabine based conditioning has a potent myeloablative and anti-disease activity although non-relapse mortality remains high in this challenging clinical setting. Copyright © 2014 John Wiley & Sons, Ltd.

Bone Marrow Transplantation, 2014

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem a... more Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem after SCT. A retrospective survey (January 2010 to July 2013) involving 52 Italian centers was performed to assess the epidemiology and the prognostic factors of CRKp infections in auto- and allo-SCT. Cases of CRKp infection were reported in 53.4% of centers. CRKp infections were documented in 25 auto-SCTs and 87 allo-SCTs, with an incidence of 0.4% (from 0.1% in 2010 to 0.7% in 2013) and 2% (from 0.4% in 2010 to 2.9% in 2013), respectively. A CRKp colonization documented before or after transplant was followed by an infection in 25.8% of auto-SCT and 39.2% of allo-SCT patients. The infection-related mortality rates were 16% and 64.4%, respectively. A pre-transplant CRKp infection (hazard ratio (HR) 0.33, 95% confidence intervals (CIs) 0.15-0.74; P=0.007) and a not CRKp-targeted first-line treatment (HR 2.67, 95% CI 1.43-4.99; P=0.002) were independent factors associated with an increased mortality in allo-SCT patients who developed a CRKp infection. Our study shows challenging findings of CRKp infections in SCT patients in Italy particularly after allo-SCT. The detection of carriers and the definition of early therapeutic strategies represent critical aspects of the management of CRKp infections after SCT.

New England Journal of Medicine, 2009

Transplantation of hematopoietic stem cells from partially matched family donors is a promising t... more Transplantation of hematopoietic stem cells from partially matched family donors is a promising therapy for patients who have a hematologic cancer and are at high risk for relapse. The donor T-cell infusions associated with such transplantation can promote post-transplantation immune reconstitution and control residual disease. We identified 43 patients who underwent haploidentical transplantation and infusion of donor T cells for acute myeloid leukemia or myelodysplastic syndrome and conducted post-transplantation studies that included morphologic examination of bone marrow, assessment of hematopoietic chimerism with the use of short-tandem-repeat amplification, and HLA typing. The genomic rearrangements in mutant variants of leukemia were studied with the use of genomic HLA typing, microsatellite mapping, and single-nucleotide-polymorphism arrays. The post-transplantation immune responses against the original cells and the mutated leukemic cells were analyzed with the use of mixed lymphocyte cultures. In 5 of 17 patients with leukemia relapse after haploidentical transplantation and infusion of donor T cells, we identified mutant variants of the original leukemic cells. In the mutant leukemic cells, the HLA haplotype that differed from the donor's haplotype had been lost because of acquired uniparental disomy of chromosome 6p. T cells from the donor and the patient after transplantation did not recognize the mutant leukemic cells, whereas the original leukemic cells taken at the time of diagnosis were efficiently recognized and killed. After transplantation of haploidentical hematopoietic stem cells and infusion of donor T cells, leukemic cells can escape from the donor's antileukemic T cells through the loss of the mismatched HLA haplotype. This event leads to relapse.

Human Immunology, 2010

Aim: The antileukemic effect of Hematopoietic Stem Cell Transplantation (HSCT) from family haploi... more Aim: The antileukemic effect of Hematopoietic Stem Cell Transplantation (HSCT) from family haploidentical and unrelated donors (UD) heavily relies on donor T cell alloreactivity, targeting the mismatched HLA molecules. Still, upon in vivo selective pressure by donor T cells, leukemia can undergo genomic loss of the patient-specific HLA, a mechanism which our group demonstrated to be frequently responsible for leukemia relapse (Vago et al., NEJM, 2009).

Hematological Oncology, 1996

The incidence of secondary myelodysplastic syndromes (MDS) are rarely reported in an homogeneous ... more The incidence of secondary myelodysplastic syndromes (MDS) are rarely reported in an homogeneous patient population treated for non-Hodgkin's lymphoma (NHL). Less than 10 per cent of secondary MDS are usually observed in patients treated for Hodgkin's disease and NHL. Data on the incidence of secondary MDS induced by modern chemotherapeutic regimens is needed. Between January 1985 and January 1989, 20 patients with localized gastric non-Hodgkin's lymphomas (stage I to IIE) were prospectively treated at the Institut Gustave-Roussy with PROMACE-MOPP multi-agent chemotherapy and involved-field irradiation. The mean age was 54 years (range 23 to 69 years). Seven patients died while on therapy or relapsed 2 to 28 months after therapy. Thirteen patients were followed up for at least 5 years. Three of the 13 long-term survivors (23 per cent) developed a myelodysplastic syndrome (MDS) 48, 62 and 72 months after the end of therapy. Cytogenetic analysis was performed in two cases and showed-7 and 18q- in one case, t(9;21)(q13;q22), 21q+, i17q in the other case. PROMACE-MOPP plus radiotherapy should not be recommended in patients with localized gastric non-Hodgkin's lymphoma due to the high risk of developing secondary myelodysplastic syndromes.

European Journal of Cancer, 1993

TO UNDERSTAND better the immunological reactions primed by interleukin-2 (IL-2) in cancer patient... more TO UNDERSTAND better the immunological reactions primed by interleukin-2 (IL-2) in cancer patients we have investigated the biological effects of systemic rIL-2 on the circulating lymphocytes of cancer patients [ 1, 21. We report here immunological tests, either functional or phenotypic, in 8 patients with advanced renal cell carcinoma treated with rIL-2 (18 x lo6 U/m*/day) by continuous intravenous administration for 5 consecutive days. Heparinised blood samples were drawn immediately before starting the first treatment cycle, 24 and 96 h after starting the rIL-2 infusion, and 2 days after the end of the infusion (168 h). Mononuclear cells were obtained by centrifugation over Ficoll gradient and resuspended in RPM1 1640 medium (Biochrom, Berlin, FRG). Phenotypic analysis was performed in a direct, doubie-staining, immunofluorescence assay. During lymphopenia, induced by the IL-2 administration, we observed a progressive decrease in the percentage of theCD3+CD4+ T-lymphocytes, while theCD3+CD8+ subset did not change significantly. Small CD4+ and CDS+ T cells are extracted by high endothelial venules with different efficiency (higher for the CD4+ than for the CD8+ subset) {3] and the rIL-2 infusion seems to emphasise this difference. The hypothesis that the decrease of the CD4+ T cells might be due to increased extravasation, is also sustained by concomitant reduced proliferation of the patients' peripheral blood mononuclear cells (PBMC) cultured for 3 days with different concentrations of phytohaemaglutinin (PI-IA) or concavalin A (ConA) (Sigma Chemical Co, St. Louis, Missouri). On stopping the rIL-2 infusion, when a rebound lymphocytosis is observed, the percentage of the CD4+ T-lymphocytes, and the capacity of Correspondence to C. Fortis. The authors are at

European Journal of Cancer, 1993

European Journal of Haematology, 2015

Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell tr... more Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3-ITD-positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off-label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post-transplantation FLT3-ITD-positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand-foot syndrome. None of the patients developed graft-vs.-host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T-cell infusions. Six patients are alive and in remission at the last follow-up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3-ITD-positive post-transplantation relapses, manageable also in combination with other therapeutic strategies.

Biology of Blood and Marrow Transplantation, 2015

Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) gr... more Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/μL of 41 days. Cumulative incidences of grade II to IV and III and IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.

Chronobiologia

No mention is made of any aspect of BP bioperiodicity, among current clinical criteria for diagno... more No mention is made of any aspect of BP bioperiodicity, among current clinical criteria for diagnosing pregnancy-related hypertension. The abnormal BP, based on a single unqualified measurement, is accepted and utilized as a clinical feature to identify pregnancy at risk. Systolic, diastolic and mean arterial blood pressure were measured every 15 min for 24 h in 5 women (2 non pregnant clinically healthy subjects, 1 clinically healthy subject in her third trimester of pregnancy, 1 presenting mild and 1 severe toxiemia, also in their third trimester of pregnancy) by an automated BP recording apparatus (Dynamap). All variables, analyzed by the single cosinor method, exhibited statistically significant circadian rhythms. A high amplitude could nullify the time-unqualified usual range. The change in circadian amplitude precedes an overt mesor hypertension and constitutes a tool for earlier detection of fetal distress.

Methods and findings in experimental and clinical pharmacology, 1984

A new experimental model is presented for determining the optimum dose of 3 different doses (13 m... more A new experimental model is presented for determining the optimum dose of 3 different doses (13 mg, 25 mg, 37 mg per day) of hydrochlorothiazide employed to enhance hypotensive effect of 200 mg/day of metoprolol in human hypertension. The model takes into account the circadian variability of blood pressure as sinusoidal function and wash-out effect as a linear trend so as to compensate for bias due to normal temporal variability.

Haematologica, Jan 6, 2015

Developing an optimal radiation-free central nervous system prophylaxis is a desirable goal in ac... more Developing an optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m2 in Philadelphia-negative B- and T-cell disease, respectively. The comparative assessment of the risk/benefit ratio was the primary study objective, combining the analysis of feasibility, toxicity and efficacy. In liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in triple therapy arm (P=0.0002), the median number of neurotoxicity episodes of any grade was 1 per patient c...

Transfusion, 2015

In allogeneic hematopoietic stem cell (HSC) transplantation, the collection of an appropriate num... more In allogeneic hematopoietic stem cell (HSC) transplantation, the collection of an appropriate number of HSCs while maintaining a high level of safety for healthy donors is fundamental. Inadequate HSC mobilization can be seen with the standard use of granulocyte-colony-stimulating (G-CSF). Plerixafor (PL) is a chemokine receptor CXC Type 4-stromal-derived factor 1 inhibitor; its HSC-mobilizing properties are synergistic with G-CSF in poor mobilizing patients. The use of PL as adjuvant or alternative to G-CSF in healthy donors has shown a good safety profile but is so far off-label. We report 10 healthy HSC donors treated with PL because of insufficient response to G-CSF alone or contraindication to G-CSF. Eight donors did not mobilize enough CD34+ cells with G-CSF alone because poor mobilizers or because insufficient HSCs were harvested according to the clinical need of the patient; in two cases G-CSF administration and marrow harvest were unfeasible or contraindicated in the donor. The use of PL for mobilization increased the number of circulating CD34+ cells by 2.8-fold and the CD34+/kg collection by 3.0-fold. Only mild adverse events were reported (bone pain or discomfort) and not univocally attributable to PL. Rate of engraftment and graft-versus-host disease were similar to those seen in recipients of grafts from G-CSF only-mobilized donors. We exposed 10 allogeneic donors to mobilization with PL. PL was well tolerated in all cases and ensured procurement of an adequate graft for transplantation resulting in a normal hematopoietic engraftment.

Leukemia, 2014

Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of... more Genomic loss of the mismatched human leukocyte antigen (HLA) is a recently described mechanism of leukemia immune escape and relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Here we first evaluated its incidence, risk factors and outcome in 233 consecutive transplants from partially HLA-mismatched related and unrelated donors (MMRD and MMUD, respectively). We documented 84 relapses, 23 of which with HLA loss. All the HLA loss relapses occurred after MMRD HSCT, and 20/23 in patients with acute myeloid leukemia. Upon MMRD HSCT, HLA loss variants accounted for 33% of the relapses (23/69), occurring later than their 'classical' counterparts (median: 307 vs 88 days, P o0.0001). Active disease at HSCT increased the risk of HLA loss (hazard ratio (HR): 10.16; confidence interval (CI): 2.65-38.92; P = 0.001), whereas older patient ages had a protective role (HR: 0.16; CI: 0.05-0.46; P = 0.001). A weaker association with HLA loss was observed for graft T-cell dose and occurrence of chronic graft-versus-host disease. Outcome after 'classical' and HLA loss relapses was similarly poor, and second transplantation from a different donor appeared to provide a slight advantage for survival. In conclusion, HLA loss is a frequent mechanism of evasion from T-cell alloreactivity and relapse in patients with myeloid malignancies transplanted from MMRDs, warranting routine screening in this transplantation setting.

Biology of Blood and Marrow Transplantation, 2014

The management of Hodgkin's lymphoma (HL) recurring after allogeneic stem cell transplantation is... more The management of Hodgkin's lymphoma (HL) recurring after allogeneic stem cell transplantation is challenging. We retrospectively describe 18 adults treated with bendamustine followed by escalated donor lymphocyte infusion. Hematological toxicity was manageable (39% grade III to IV neutropenia and 28% grade III to IV thrombocytopenia). The overall response rate was 55%, with 3 complete and 7 partial responses. Median overall and progression-free survival were 11 (range, 1 to 52) and 6 (range, 1 to 28) months, respectively. One-year overall survival of responders (complete or partial) was 70% (95% confidence interval, 42% to 98%), although it was only 16% for nonresponders (n ¼ 8). Our data show that bendamustine followed by donor lymphocyte infusion is feasible and can be efficacious as salvage treatment in HL relapsing after an allograft.

Hematological Oncology, 2014

Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in t... more Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in the era of new drugs that so far only mitigate symptoms. The choice to proceed to allogeneic transplantation is based on several variables including age, disease phase, degree of splenomegaly, donor availability, comorbidities and iron overload. These factors, along with conditioning regimen and time to transplantation, may influence the outcome of ASCT. We report 14 patients affected by myelofibrosis with a median age of 57 years (range, 41-76) receiving a treosulfan-fludarabine based reduced toxicity conditioning. Patients (pts) received a stem cell transplantation from an HLA identical (n = 10) or matched unrelated donor (n = 4). All pts had a complete myeloablation followed by engraftment and in 12 out of 13 evaluated pts donor chimerism was 100% at 1 month. In most cases a reduction of splenomegaly and a reduction (or resolution) of bone marrow fibrosis was observed. After a median follow-up of 39 months (range, 3-106), the 3-year probability of overall survival and disease free survival was 54 +/- 14% and 46 +/- 14%, respectively. The cumulative incidence of non-relapse mortality at 2 years was 39 +/- 15%. Causes of non-relapse mortality were: infection (n = 2), GvHD (n = 2) and haemorrhage (n = 1). We can conclude that a treosulfan and fludarabine based conditioning has a potent myeloablative and anti-disease activity although non-relapse mortality remains high in this challenging clinical setting. Copyright © 2014 John Wiley & Sons, Ltd.

Bone Marrow Transplantation, 2014

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem a... more Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem after SCT. A retrospective survey (January 2010 to July 2013) involving 52 Italian centers was performed to assess the epidemiology and the prognostic factors of CRKp infections in auto- and allo-SCT. Cases of CRKp infection were reported in 53.4% of centers. CRKp infections were documented in 25 auto-SCTs and 87 allo-SCTs, with an incidence of 0.4% (from 0.1% in 2010 to 0.7% in 2013) and 2% (from 0.4% in 2010 to 2.9% in 2013), respectively. A CRKp colonization documented before or after transplant was followed by an infection in 25.8% of auto-SCT and 39.2% of allo-SCT patients. The infection-related mortality rates were 16% and 64.4%, respectively. A pre-transplant CRKp infection (hazard ratio (HR) 0.33, 95% confidence intervals (CIs) 0.15-0.74; P=0.007) and a not CRKp-targeted first-line treatment (HR 2.67, 95% CI 1.43-4.99; P=0.002) were independent factors associated with an increased mortality in allo-SCT patients who developed a CRKp infection. Our study shows challenging findings of CRKp infections in SCT patients in Italy particularly after allo-SCT. The detection of carriers and the definition of early therapeutic strategies represent critical aspects of the management of CRKp infections after SCT.

New England Journal of Medicine, 2009

Transplantation of hematopoietic stem cells from partially matched family donors is a promising t... more Transplantation of hematopoietic stem cells from partially matched family donors is a promising therapy for patients who have a hematologic cancer and are at high risk for relapse. The donor T-cell infusions associated with such transplantation can promote post-transplantation immune reconstitution and control residual disease. We identified 43 patients who underwent haploidentical transplantation and infusion of donor T cells for acute myeloid leukemia or myelodysplastic syndrome and conducted post-transplantation studies that included morphologic examination of bone marrow, assessment of hematopoietic chimerism with the use of short-tandem-repeat amplification, and HLA typing. The genomic rearrangements in mutant variants of leukemia were studied with the use of genomic HLA typing, microsatellite mapping, and single-nucleotide-polymorphism arrays. The post-transplantation immune responses against the original cells and the mutated leukemic cells were analyzed with the use of mixed lymphocyte cultures. In 5 of 17 patients with leukemia relapse after haploidentical transplantation and infusion of donor T cells, we identified mutant variants of the original leukemic cells. In the mutant leukemic cells, the HLA haplotype that differed from the donor's haplotype had been lost because of acquired uniparental disomy of chromosome 6p. T cells from the donor and the patient after transplantation did not recognize the mutant leukemic cells, whereas the original leukemic cells taken at the time of diagnosis were efficiently recognized and killed. After transplantation of haploidentical hematopoietic stem cells and infusion of donor T cells, leukemic cells can escape from the donor's antileukemic T cells through the loss of the mismatched HLA haplotype. This event leads to relapse.

Human Immunology, 2010

Aim: The antileukemic effect of Hematopoietic Stem Cell Transplantation (HSCT) from family haploi... more Aim: The antileukemic effect of Hematopoietic Stem Cell Transplantation (HSCT) from family haploidentical and unrelated donors (UD) heavily relies on donor T cell alloreactivity, targeting the mismatched HLA molecules. Still, upon in vivo selective pressure by donor T cells, leukemia can undergo genomic loss of the patient-specific HLA, a mechanism which our group demonstrated to be frequently responsible for leukemia relapse (Vago et al., NEJM, 2009).

Hematological Oncology, 1996

The incidence of secondary myelodysplastic syndromes (MDS) are rarely reported in an homogeneous ... more The incidence of secondary myelodysplastic syndromes (MDS) are rarely reported in an homogeneous patient population treated for non-Hodgkin's lymphoma (NHL). Less than 10 per cent of secondary MDS are usually observed in patients treated for Hodgkin's disease and NHL. Data on the incidence of secondary MDS induced by modern chemotherapeutic regimens is needed. Between January 1985 and January 1989, 20 patients with localized gastric non-Hodgkin's lymphomas (stage I to IIE) were prospectively treated at the Institut Gustave-Roussy with PROMACE-MOPP multi-agent chemotherapy and involved-field irradiation. The mean age was 54 years (range 23 to 69 years). Seven patients died while on therapy or relapsed 2 to 28 months after therapy. Thirteen patients were followed up for at least 5 years. Three of the 13 long-term survivors (23 per cent) developed a myelodysplastic syndrome (MDS) 48, 62 and 72 months after the end of therapy. Cytogenetic analysis was performed in two cases and showed-7 and 18q- in one case, t(9;21)(q13;q22), 21q+, i17q in the other case. PROMACE-MOPP plus radiotherapy should not be recommended in patients with localized gastric non-Hodgkin's lymphoma due to the high risk of developing secondary myelodysplastic syndromes.

European Journal of Cancer, 1993

TO UNDERSTAND better the immunological reactions primed by interleukin-2 (IL-2) in cancer patient... more TO UNDERSTAND better the immunological reactions primed by interleukin-2 (IL-2) in cancer patients we have investigated the biological effects of systemic rIL-2 on the circulating lymphocytes of cancer patients [ 1, 21. We report here immunological tests, either functional or phenotypic, in 8 patients with advanced renal cell carcinoma treated with rIL-2 (18 x lo6 U/m*/day) by continuous intravenous administration for 5 consecutive days. Heparinised blood samples were drawn immediately before starting the first treatment cycle, 24 and 96 h after starting the rIL-2 infusion, and 2 days after the end of the infusion (168 h). Mononuclear cells were obtained by centrifugation over Ficoll gradient and resuspended in RPM1 1640 medium (Biochrom, Berlin, FRG). Phenotypic analysis was performed in a direct, doubie-staining, immunofluorescence assay. During lymphopenia, induced by the IL-2 administration, we observed a progressive decrease in the percentage of theCD3+CD4+ T-lymphocytes, while theCD3+CD8+ subset did not change significantly. Small CD4+ and CDS+ T cells are extracted by high endothelial venules with different efficiency (higher for the CD4+ than for the CD8+ subset) {3] and the rIL-2 infusion seems to emphasise this difference. The hypothesis that the decrease of the CD4+ T cells might be due to increased extravasation, is also sustained by concomitant reduced proliferation of the patients' peripheral blood mononuclear cells (PBMC) cultured for 3 days with different concentrations of phytohaemaglutinin (PI-IA) or concavalin A (ConA) (Sigma Chemical Co, St. Louis, Missouri). On stopping the rIL-2 infusion, when a rebound lymphocytosis is observed, the percentage of the CD4+ T-lymphocytes, and the capacity of Correspondence to C. Fortis. The authors are at

European Journal of Cancer, 1993