[Show abstract][Hide abstract] ABSTRACT: Background Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. Methods We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. Results After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). Conclusions The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275 .).
Full-text · Article · Jan 2016 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is an uncommon, but frequently fatal, complication after allogeneic hematopoietic stem cell transplant. Prospective post-transplant virological and immunological monitoring allowed to successfully manage a patient who developed both polymorphic and monomorphic, "diffuse large B-cell lymphoma like", as an EBV-PTLD, 65days after allogeneic bone marrow transplant. Early detection of significant increase in EBV DNA level in patient's peripheral blood (peak of viral load equal to 119,039 copies/mL whole blood, +56day after transplant) led to administration of pre-emptive anti-CD20 monoclonal antibody (rituximab) and close clinical monitoring. After one week, physical exam revealed laterocervical adenopathy. Histopathologic features, immunohistochemical characterization and in situ hybridization study allowed to establish a diagnosis of EBV-related PTLD. Immunological monitoring showed no EBV-specific T-cell responses during EBV replication, thus potentially explaining the occurrence of high EBV load with subsequent PTLD development. A total of four doses of anti-CD20 monoclonal antibody were administered and at the end of the treatment, EBV infection was cleared and imaging technique showed complete disease remission. In conclusion, the early use of anti-CD20 monoclonal antibody proved to be a safe and effective treatment strategy for EBV-PTLD. Moreover, combined virological-immunological monitoring of EBV infection may more accurately assess patients at higher risk for EBV-PTLD.
No preview · Article · Dec 2015 · Transplant Immunology
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown. In this retrospective study, 601 patients were included. Patients received allo-SCT in CR1, CR2, CR >2 or in advanced disease in 69%, 15%, 2% and 14% of cases, respectively. With an overall follow-up of 58 months, 523 patients received a TBI-based regimen, whereas 78 patients received a chemotherapy-based regimen including IV busulfan-cyclophosphamide (IV Bu-Cy) (n=46). Unlike patients aged ⩾35 years, patients aged <35 years who received a TBI-based regimen displayed an improved outcome compared with patients who received a chemotherapy-based regimen (5-year leukemia-free survival (LFS) of 50% for TBI versus 18% for chemo-only regimen or IV Bu-Cy regimens, P=10(-5) and 10(-4), respectively). In multivariate analysis, use of TBI was associated with an improved LFS (hazard ratio (HR)=0.55 (0.34-0.86), P=0.01) and overall survival (HR=0.54 (0.34-0.87), P=0.01) in patients aged <35 years. In conclusion, younger adult patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens.Bone Marrow Transplantation advance online publication, 30 November 2015; doi:10.1038/bmt.2015.278.
No preview · Article · Nov 2015 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Background:
In the setting of allogeneic human leukocyte antigen (HLA)-matched bone marrow transplantation, transplanting male patients with grafts from female donors has been associated with a higher incidence of graft-versus-host disease (GVHD) and of nonrelapse mortality (NRM). The aim of the current analysis was to compare transplantation outcomes in male patients given female unrelated cord blood (UCB) versus other gender combinations.
Patients and methods:
Data from 552 consecutive patients with acute myeloid leukemia (AML) given a single UCB transplantation between 2000 and 2014 were included.
In comparison with other gender combination, male patients given female UCB (n = 131) had a trend for a higher incidence of grades II-IV acute GVHD (33 versus 25 %, P = 0.08), a trend for a higher incidence of NRM (41 versus 33 %, P = 0.06), and a lower leukemia-free (LFS, 30 versus 41 %, P = 0.01) and overall survival (OS, 33 versus 45 %, P = 0.008). In multivariate analyses, taking into consideration all patients for which data on HLA-matching and cell dose transplanted were fully available (n = 363), male patients transplanted with a female UCB had a trend for a higher incidence of grade III-IV acute GVHD (hazard ratio (HR) = 2.0, P = 0.06), a trend for a higher NRM (HR = 1.5, P = 0.06), and a worse LFS (HR = 1.4, P = 0.04) and OS (HR = 1.3, P = 0.06).
Our data suggest that male patients transplanted with female UCB might have higher risk of acute GVHD and of NRM leading to worse LFS and OS. These results should be confirmed in other large cohorts of patients before used for determining the choice of an UCB unit.
Full-text · Article · Oct 2015 · Journal of Hematology & Oncology
[Show abstract][Hide abstract] ABSTRACT: Busulfan liver metabolism depends on glutathione, a crucial mediator of cellular and systemic stress. Here we investigated 40 polymorphisms at 27 loci involved in hepatic glutathione homeostasis, with the aim to test their impact on the clinical outcome of 185 busulfan-conditioned allogeneic transplants. GSTA2 S112T serine allele homozygosity is an independent prognostic factor for poorer survival (RR=2.388), for increased any time- and 100-day Transplant Related Mortality (RR=4.912 and RR=5.185, respectively). The genotype also predicts a wider busulfan area under the concentration-time curve (1214.36+570.06 vs 838.10+282.40 μMol*min) and higher post-transplant bilirubin serum levels (3.280+0.422 vs 1.874+0.197 mg/dL). In vitro, busulfan elicits pro-inflammatory activation (increased NF-KappaB activity and interleukin-8 expression) in human hepatoma cells. At the same time, the drug down-regulates a variety of genes involved in bilirubin liver clearance: constitutive androstane receptor, multidrug resistance-associated protein, solute carrier organic anion transporters, and even GSTA2. Worthy of note, is the fact that GSTA2 also acts as an intra-hepatic bilirubin binding protein. These data underline the prognostic value of GSTA2 genetic variability in busulfan-conditioned allotransplants and suggest a patho-physiological model in which busulfan-induced inflammation leads to the impairment of post-transplant bilirubin metabolism.
[Show abstract][Hide abstract] ABSTRACT: Cancer stem cell survival relies on the activation of inflammatory pathways, which is speculatively triggered by cell autonomous mechanisms or by microenvironmental stimuli. Here, we observed that hypoxic bone marrow stroma-derived transforming growth factor-β 1 promotes the growth of human breast cancer stem cells as mammospheres. The ensuing Slug-dependent serine 139 phosphorylation of the DNA damage sensor H2AX in breast cancer stem cells induces tumor necrosis factor-α and IL-8 mRNAs, whose stability is enhanced by cytoplasmic β-catenin. β-Catenin also up-regulates and binds miR-221, reducing the stability of the miR-221 targets Rad51 and ERα mRNAs. Our data show that the Slug/β-catenin-dependent activation of DNA damage signaling triggered by the hypoxic microenvironment sustains the proinflammatory phenotype of breast cancer stem cells.
Full-text · Article · Sep 2013 · American Journal Of Pathology
[Show abstract][Hide abstract] ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Full-text · Article · Jul 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: To evaluate trends in allografting from unrelated donors we conducted a study on 196 consecutive myeloma patients transplanted between 2000 and 2009 in Italy. Twenty-eight %, 37% and 35%, respectively, received a myeloablative, a reduced-intensity and a non-myeloablative conditioning. In these 3 cohorts, one-year and five-year transplant-related mortality were 28.8% and 37.0%; 20.3% and 31.3%; 25.0% and 30.3% respectively (p=0.745); whereas median overall (OS) and event-free survivals (EFS) from transplant were 29 and 10, 11 and 6, 32 and 13 months (p=0.039 and p=0.049). Overall cumulative incidences of acute and chronic graft-versus-host-disease (GVHD) were 46.1% and 51.1%. By Cox multivariate analyses, chronic GVHD was significantly associated with longer OS (HR 0.51; p=0.009), whereas the use of peripheral blood stem cells was borderline significant (HR 0.55; p=0.051). Better response post-transplant was associated with longer EFS (HR 2.13-4.25; p<0.001). Acute GVHD was associated with poorer OS (HR 2.53; p=0.001). This analysis showed a strong association of acute and chronic GVHD, and depth of response post-transplant with clinical outcomes. Long-term disease control remains challenging regardless of the conditioning. In the light of these results, prospective trials may be designed to better define the role of allografting from unrelated donors in myeloma.
No preview · Article · Mar 2013 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Background:
Unrelated cord blood transplantation (UCBT) is associated with delayed hematopoietic recovery. Intrabone injection of cord blood cells (IB-UCBT) and double-UCBT (dUCBT) are designed to circumvent this problem.
In a retrospective registry-based analysis, we compared outcomes of 87 IB-UCBT with 149 dUCBT recipients, after myeloablative conditioning regimen adjusting for the differences between the two groups. Median-infused total nucleated cells were 2.5×10/kg for IB-UCBT and 3.9×10/kg for dUCBT (P<0.001).
At day +30, cumulative incidence (CI) of neutrophil recovery was 76% and 62% (P=0.014) with a median time to engraftment of 23 and 28 days (P=0.001), after IB-UCBT and dUCBT, respectively. At day +180, CI of platelets recovery was 74% after IB-UCBT, and 64%, after dUCBT (P=0.003). In multivariate analysis, IB-UCBT was associated with neutrophil and platelets recovery and lower acute graft versus host disease (II-IV) (P<0.01). At 2 years, CI of nonrelapse mortality and relapse incidence were 30% and 25% after IB-UCBT and 34% and 29% after dUCBT, and disease-free survival was 45% and 37%, respectively. However, after landmark analysis at 4.7 months from transplantation, in multivariate analysis, relapse incidence was reduced (P=0.03), and there was a trend for better disease-free survival after IB-UCBT (P=0.09).
Both approaches expand the possibility of offering UCBT to patients with hematopoietic malignancies; IB-UCBT is associated with faster myeloid and platelet recovery and lower acute graft versus host disease and may reduce the total cost. However, studies on cost effectiveness are needed to compare both strategies.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The monitoring of minimal residual disease (MRD) through low sensitivity real-time (RT) PCR analysis of BCR-ABL transcripts allows early detection of chronic myeloid leukemia(CML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT). The introduction of more sensitive techniques, such as RT quantitative (Q)-PCR, may lead to overestimate the risk of CML relapse. PATIENTS AND METHODS: In this study we reviewed the results of peripheral blood (PB) RT Q-PCR in CML patients who underwent allogeneic HSCT from 1983 to 2007. In our laboratory, RT Q-PCR analysis was routinely performed since 2002. Eighty-seven out of 189 patients had available RT Q-PCR data; 63 patients had at least three RT Q-PCR analyses evaluable. RESULTS: Fifty-two out of 63 patients (83%) had, at least once, detectable transcript levels, but with BCR-ABL/ABL ratio <0.1% defined as <MR3, whereas 11 (17%) had persistent undetectable BCR-ABL transcripts. Six out of 52 patients with <MR3 relapsed, defined as BCR-ABL transcript numbers > 0.1% confirmed by the finding of Ph+ positive cells in bone marrow. No patients with persistent undetectable transcripts relapsed (p=0.19). Relapse did not correlate with the number of occurrences of <MR3, or with the time to the first <MR3 result. Finally, out of 46 patients with detectable transcripts who did not relapse, 35 had undetectable transcripts at last contact. RT Q-PCR analysis had low specificity (19%) and low positive predictive value (12%) in predicting relapse of CML patients after allogeneic HSCT. CONCLUSION: Our data suggest that detectionof low BCR-ABL transcript levelsby RT Q-PCR analysis has a poor accuracy in defining the risk of CML relapse, and it should not be considered as the unique indication to treatment. Fluctuation of BCR-ABL transcripts levels is common as late as ≥10 years after transplant, possibly suggesting the long-term persistence of CML stem cells.
Full-text · Article · Jan 2013 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: center dot Remarkable progress has been made in the treatment of hairy cell leukemia (HCL) in the past 30 years, but often control rather than cure of the disease is obtained. center dot Purine analogues are considered the best treatment, but the optimal strategy is still debated. center dot Allogeneic stem cell transplantation (allo-SCT) is yet an anecdotal therapeutic option for patients who have had multiple relapses of HCL. center dot We describe the case of a young patient with HCL who was treated with several therapeutic approaches without any significant response. center dot Conceivably, this report represents further important evidence of the potential role of allo-SCT in heavily pretreated patients with late-stage HCL.
No preview · Article · May 2012 · Clinical lymphoma, myeloma & leukemia
[Show abstract][Hide abstract] ABSTRACT: An unrelated donor (UD) search was submitted to the Italian Bone Marrow Donor Registry between February 2002 and December 2004, for 326 consecutive patients with hematological malignancies, eligible for a reduced intensity conditioning (RIC) UD transplant. Only two regimens were allowed: melphalan, alemtuzumab, fludarabine and total body irradiation of 200 cGy (regimen A) and thiotepa, cyclophosphamide, anti-thymocyte globulin (regimen B). The outcome of patients receiving an UD transplant (n=121) was compared with patients who did not find a donor (n=205), in a time dependent analysis, correcting for time to transplant. The median follow up from activation of donor search was 6.1 years. UD transplant was associated with a significantly better survival in patients with acute leukemia and non-Hodgkin's lymphoma (NHL) whereas only a favorable trend was documented for Hodgkin's disease. No survival benefit was registered for chronic leukemias. The outcome of the two different conditioning regimens was comparable, in terms of survival, transplant-related mortality and graft versus host disease. In conclusion, finding an UD and undergoing a RIC transplant significantly improves survival of patients with acute leukemia and NHL. The advantage is less clear for HD and chronic leukemias. The role of different conditioning regimens remains to be elucidated by prospective clinical trials.
Full-text · Article · Mar 2012 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: BCR-ABL kinase domain (KD) mutation analysis may be an useful tool for physicians and is being performed in a growing number of laboratories. Recommendations aimed to rationalize the use of mutation testing in chronic myeloid leukemia (CML) have recently (Blood 2011) been compiled by a panel of experts appointed by European LeukemiaNet (ELN) – including specific recommendations as to when mutation analysis should be performed. They came from the expert opinion of the panel members whenever published data were insufficient or contradictory. In order to provide further data to validate or refine these recommendations, we have analyzed the GIMEMA CML WP database recording the results of mutation analyses performed in CML pts (n=1301) receiving imatinib and/or 2nd generation TKIs between January 2004 and July 2011.
At dagnosis, mutation analysis was recognized to be useful in the few pts who present in accelerated phase or blast crisis (BC), while it was not recommended in chronic phase (CP) pts. Interrogating our database, we could retrieve 58 mutation analyses in newly diagnosed pts in CP and 12 in newly diagnosed pts in BC. Imatinib-resistant mutations were detected in 0 and 2 pts, respectively.
In pts receiving 1st-line imatinib, mutation analysis was recommended both in case of failure and in case of suboptimal response. We have analyzed 399 chronic phase (CP) CML pts receiving first-line imatinib because they were found to meet one of the criteria for failure or suboptimal response. Overall, 45/166 (27.1%) failures were found to be positive for one or more BCR-ABL KD mutations. In particular, mutations were detected in 3/16 (18.8%) pts with less than CHR at 3 months, 1/9 (11.1%) pts with no CyR at 6 months, 4/24 (16.7%) pts with less than PCyR at 12 months, 6/36 (16.7%) pts with less than CCyR at 18 months, 15/49 (30.6%) pts who lost CCyR and 16/32 (50%) pts who lost CHR. More interestingly, only 11/233 (4.7%) suboptimal responders we analyzed were positive for mutations. Among ‘cytogenetic' suboptimal responders, mutations were detected in 1/15 (6.7%) pts with no CyR at 3 months, 1/20 (5.0%) pts with less than PCyR at 6 months, 5/51 (8.2%) pts with less than CCyR at 12 months. Among ‘molecular' suboptimal
responders, mutations were detected in 0/52 pts with less than MMR (but having achieved CCyR) at 18 months and in 4/95 (4.2%) pts who lost MMR (but not CCyR).
Which rise in Bcr-Abl transcript level should trigger a mutation analysis was the most difficult issue to provide recommendations upon, given the lack of convincing and reproducible data in the literature. It was finally agreed to recommend mutation analysis only in case of MMR loss. In 159 of the CP pts we
have analyzed, mutation analysis was specifically requested because of a transcript increase at a single RQ-PCR assessment: 29 pts had less than 1-log increase and 41 pts had a 1-log increase or more – but with no loss of MMR. None of these pts was found to have mutations. Another 36 pts had less than
1-log increase and 53 had a 1-log increase or more, leading to loss of MMR. Mutations were detected in 1 (2.8%) and 3 (5.7%) pts, respectively.
In pts receiving dasatinib or nilotinib as 2nd-line agents, mutation analysis was recommended at baseline and then in case of failure according to the provisional definitions proposed by Baccarani et al (J Clin Oncol 2009). Nineteen among the pts we analyzed met these criteria; overall, mutations were detected in 11 (57.8%), including 5/7 pts with no CyR at 3 months, 6/9 pts with minimal CyR at 6 months, 1/4 pts with less than PCyR at 12 months. In addition, newly acquired mutations were detected in 93/131 (71%) pts who lost a previously achieved HR or CyR. We also tested 19 pts who met the provisional definitions for suboptimal response to dasatinib or nilotinib 2nd-line. Mutations were detected in 4/19 pts (21%), including 2/5 pts with minor CyR at 3 months, 1/7 pts with PCyR at 6 months, 1/7 pts with less than MMR at 12 months.
Our data indicate that: a) pts harbouring mutations can more frequently be found among cytogenetic suboptimal responders than among molecular suboptimal responders; b) any Bcr-Abl transcript increase that is not associated with MMR loss shouldn't indeed trigger a mutation analysis; c) although definitions of response to dasatinib or nilotinib 2nd-line are still provisional and might soon be refined, not only failures but also suboptimal responses are frequently associated with mutations.
[Show abstract][Hide abstract] ABSTRACT: Several studies have shown that chronic GVHD (cGVHD) is more frequent in patients receiving transplants from PBSC than in those receiving BM. In the setting of PBSC-unrelated transplants, the addition of anti-T-cell globulin (ATG) has shown a significant decrease in incidence/severity of cGVHD, without an increase in relapses or infections. However, no prospective data are yet available in the sibling setting. We retrospectively analyzed the effects of intensification of standard GVHD prophylaxis (CsA+MTX) by the addition of low-dose ATG in 245 patients receiving a transplant from HLA-identical sibling. From 1996 to 2001, patients received PBSC as the preferred source (group 2), and then ATG was added before transplant (group 3) because of a high cGVHD rate. Patients receiving BM in the same time period were analyzed as a control group (group 1). The incidence of grade III-IV acute GVHD and cGVHD was not significantly different in the three groups, but extensive cGVHD was highest in group 2 (38%) compared with group 3 (21%) or group 1 (28%; P=0.03). OS, TRM and time to relapse/progression were similar in the three groups. Our analysis shows that adding ATG to PBSC sibling allogeneic transplants can lower cGVHD, without an increase of relapse. Further prospective studies are needed to confirm these findings.
Full-text · Article · Nov 2011 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Rescue chemotherapy or autologous stem cell transplantation (autoSCT) gives disappointing results in relapsed peripheral T-cell lymphomas (PTCLs). We have retrospectively evaluated the long-term outcome of 52 patients receiving allogeneic SCT for relapsed disease. Histologies were PTCL-not-otherwise specified (n=23), anaplastic large-cell lymphoma (n=11), angioimmunoblastic T-cell lymphomas (n=9) and rare subtypes (n=9). Patients were allografted from related siblings (n=33, 64%) or alternative donors (n=13 (25%) from unrelated and 6 (11%) from haploidentical family donors), following reduced-intensity conditioning (RIC) regimens including thiotepa, fludarabine and cyclophosphamide. Most of the patients had chemosensitive disease (n=39, 75%) and 27 (52%) failed a previous autoSCT. At a median follow-up of 67 months, 27 of 52 patients were found to be alive (52%) and 25 (48%) were dead (n=19 disease progression, n=6 non-relapse mortality (NRM)). The cumulative incidence (CI) of NRM was 12% at 5 years. Extensive chronic graft-versus-host disease increased the risk of NRM (33% versus 8%, P=0.04). The CI of relapse was 49% at 5 years, influenced by disease status at the time of allografting (P=0.0009) and treatment lines (P=0.007). Five-year overall survival and progression-free survival (PFS) were 50% (95% CI, 36 - 63%) and 40% (95% CI, 27 - 53%), respectively. The current PFS was 44% (95% CI, 30-57%). In all, 8 out of 12 patients (66%) who received donor-lymphocytes infusions for disease progression had a response. At multivariable analysis, refractory disease and age over 45 years were independent adverse prognostic factors. RIC allogeneic SCT is an effective salvage treatment with a better outcome for younger patients with chemosensitive disease.
Full-text · Article · Sep 2011 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K