Age-Adjusted Recipient Pre-Transplant Telomere Length and Treatment Related Mortality After Hematopoietic Stem Cell Transplantation

Abstract Abstract 490 Telomeres are highly conserved protective terminal chromosomal structures consisting of hundreds of repeated TTAGGG hexamers and associated shelterin proteins. Telomeres shorten with every cell cycle, and telomere attrition has a fundamental role in cell senescence. Telomeres of leukocytes are shorter in transplant recipients than in their donors. Dyskeratosis congenita, a congenital aplastic anemia caused by mutations in the telomerase complex genes, is associated with treatment related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). We hypothesized that age-adjusted pre-transplant telomere length might generally predict TRM after HSCT. Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donor after myeloablative conditioning regimen (including TBI in 57 patients), mainly for hematological malignancies (n= 153) in our center. The stem cell source was bone marrow (BM) in 128 cases and peripheral blood (PB) in 50 cases. Median age at transplant was 32 years (range 3–65). Graft-versus-host disease (GvHD) prophylaxis mostly consisted of cyclosporine and methotrexate (n=149, 84%). Before HSCT, blood lymphocytes were obtained from each of the donor-recipient pair. Telomere length was assessed by real time quantitative PCR. We first determined the normal age distribution of telomere length using a group of 173 healthy French hematopoietic stem cell donors (f=-0.00833*age+1.522) as a control group. We then calculated the pre-transplant recipient age-adjusted telomere length in comparison to controls. After age adjustment, we categorized the population in quartiles (shortest telomeres for quartile 1) and analyzed the outcome post HSCT using competing risk in univariate and multivariate analyses (Fine and Gray). The mean telomere length in transplant recipients (1.05) was shorter than in the control group (1.23, p= 0.0001). After age-adjustment, patients' distribution was similar among all four quartiles except for disease severity (more high risk disease was present among patients with the shortest telomeres). The median follow-up was 51 months (range, 1 – 121 months). All patients engrafted. The median time to achieve absolute neutrophils count >500/ul was 18 days (range 4–45) and median time to platelet count >20.000/ul was 17 days (range 7–58). Cumulative incidence (CI) of acute GvHD grade II-IV was 45% (95% confidence interval [95CI] 37%–53%) and of chronic GvHD was 41% at 36 months (95CI 33%–49%). Thirty-four patients relapsed: CI: 22% at 5 years (95CI 16%–28%). There was no correlation between telomere length and engraftment, acute or chronic GvHD or relapse. The overall survival was 62% at 5 years (95CI 54%–70%). During the study, 37 patients died due to TRM. TRM rate inversely correlated with telomere length. In the first quartile, the 5-year CI of TRM was 33% (95CI 2%–22%), 20% (95CI, 8%–32%) in the second quartile; 20% (95CI, 8%–32%) in the third quartile; and 12% in the fourth quartile (95CI, 2%–22%) (p=0.06). When quartiles 2, 3 and 4 were pooled, the increased TRM in first quartile was statistically significant (p = 0.017) (Figure 1). In multivariate analysis using competing risk regression, (including age-adjusted telomeres length, disease stage, age, TBI and source of stem cells), age of the recipients (HR: 1.1, 95% CI [.0–1.1, p=0.0001] and age-adjusted telomeres [HR: 0.4, 95% CI [0.2–0.8, p=0.01]) were independently associated with TRM. The same two factors remained significant in subset analysis of patients with malignant diseases (n=154) (p= 0.0004, HR: 1.1 and p=0.018, HR: 0.43, respectively). No association was found between donor telomere length and outcome post HSCT. In conclusion, age-adjusted recipient pre-transplant telomere length is an independent biological marker of TRM after HSCT from related donors using a myeloablative conditioning regimen and cyclosporine-based GvHD prophylaxis. Disclosures: Peffault de Latour: Alexion: Consultancy, Research Funding.

Download Full-text

Hematopoietic Stem Cell Therapy In Eight Patients with Metachromatic Leukodystrophy – Relevance of Post-Transplant Medication.

Blood ◽

10.1182/blood.v116.21.3727.3727 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3727-3727

Author(s):

Judith Böhringer ◽

Birgit Kustermann-Kuhn ◽

Friederike Gieseke ◽

Annika Erbacher ◽

Michaela Döring ◽

...

Keyword(s):

Gene Therapy ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Metachromatic Leukodystrophy ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Post Transplant ◽

Gvhd Prophylaxis

Abstract Abstract 3727 The lysosomal storage disease metachromatic leukodystrophy (MLD) is caused by mutations in the arylsulfatase A (ASA) gene leading to demyelination in the central nervous system (CNS). Children often present impaired motor skills and progress to an inability to walk, paresis and cognitive deterioration. Therapeutic options are limited and currently focus on enzyme replacement, gene therapy and hematopoietic stem cell transplantation (HSCT). Both, gene therapy and HSCT aim to establish a continuous endogenous supply of ASA, which can be taken up by somatic cells of the recipient to correct their own lysosomal metabolism. We analyzed 8 patients with MLD, who underwent HSCT between 7 months and 15 years of age, regarding toxicity of a reduced intensity condition regimen and GvHD prophylaxis. The mean follow up was 2.8 years (range 8 months to 9.5 years). All patients received conditioning with treosulfan (3 × 14 g/m2), fludarabin (4 × 40 mg/m2) and thiotepa (10 mg/kg). Six patients received bone marrow from a 10/10 matched unrelated donor, one patient from her brother and one patient with late infantile MLD was transplanted from her haploidentical mother. Patients received a mean dose of 7.74 × 106 CD34+ cells/kg BW and engrafted at day 12 (range d11 to d22) with permanent full donor chimerism. Organ toxicity reached mucositis grade III and skin grade I. Three patients developed transient acute graft-versus-host disease (GvHD) of the skin grade II, which responded well to steroids. There was no case of transplant-related mortality and no chronic GvHD. The relative ASA activity in peripheral blood mononuclear cells (PBMCs) pre-transplantation was between 0 and 0.11 A514nm/106 cells and after transplantation between 0.52 and 2.24 A514nm/106 cells. Patients who were asymptomatic prior to transplantation stayed asymptomatic, but those who presented with neurological symptoms showed various degrees of progression. As the conditioning regimen showed no immediate neurotoxicity, we asked if other drugs may account for the disease progression early after transplantation. Cyclosporine A (CsA) is commonly used as post-transplant GvHD prophylaxis and is known for neurotoxic side effects. Thus, we analyzed effects of CsA on the activity of ASA in comparison to tacrolimus or mycophenolic acid (MPA). PBMCs were cultured with and without 75 or 150 ng/ml CsA (pharmacological level) for 8 days. During this time period, the ASA activity decreased to 70% of the activity of PBMC without CsA treatment. By contrast, the ASA activity of PBMCs did not decrease under treatment with pharmacological levels of tacrolimus (7,5 or 15 ng/ml) and MPA (3 or 7,5 μg/ml). Cell viability and metabolic activity were comparable in the presence of CsA and tacrolismus as assessed by MTS assays. This implies that the decrease of the ASA activity was not due to direct cell toxicity of CsA. Taken together, the conditioning regimen was well tolerated with low toxicity and good engraftment. HSCT is an option for treatment of asymptomatic MLD patients, whereas further studies are needed to identify symptomatic patients who may still benefit from the procedure. Here, the choice of GvHD prophylaxis may be an important factor. In vitro data suggested that CsA should be reconsidered with regimens including tacrolimus or mycophenolate mofetil as an alternative. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Drop of Butyrylcholinesterase Activity after Cyclophosphamide Conditioning as a Predictive Marker of Liver Transplant-Related Complications and Its Correlation with Transplant-Related Mortality in Pediatric Hematopoietic Stem Cell Recipients

Journal of Clinical Medicine ◽

10.3390/jcm8060825 ◽

2019 ◽

Vol 8 (6) ◽

pp. 825

Author(s):

Natalia Maximova ◽

Giulia Caddeo ◽

Davide Zanon ◽

Alessandra Maestro ◽

Roberto Simeone

Keyword(s):

Stem Cell ◽

Liver Transplant ◽

Hematopoietic Stem Cell ◽

Conditioning Regimen ◽

Specific Marker ◽

Severe Liver ◽

Hematopoietic Stem ◽

Clinical Issue ◽

Bche Activity ◽

Related Mortality

Transplant-related liver complications are a potentially fatal condition of hematopoietic stem cell transplantation (HSCT) in pediatric patients, actually representing one of the main factors involved in transplant-related mortality (TRM). The search for a specific marker capable of predicting the development of this condition is a relevant clinical issue. We have observed a variable reduction in serum butyrylcholinesterase (BChE) activity after a cyclophosphamide-containing conditioning regimen. This study aims to determine the cutoff of BChE activity reduction that might be a specific prognostic marker for liver complications after HSCT. Our results show that the reduction of BChE values below 2000 U/L the day before the transplantation is an indicator strongly associated with the transplant-related liver complications (p < 0.0001). The incidence of overall survival at 1 year was significantly higher in the BChE > 2000 U/L group compared to the BChE < 2000 U/L group (84.7% versus 58.5%, p < 0.001), while the TRM rate was significantly lower (8.1% versus 23.1%, p < 0.05). None of the patients undergoing prophylaxis with defibrotide developed severe liver complications. Starting defibrotide treatment at the first signs of hepatic dysfunction in patients with particularly low BChE activity levels reduces severe liver transplant-related complications.

Download Full-text

Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan

Blood ◽

10.1182/blood-2012-04-423822 ◽

2012 ◽

Vol 120 (2) ◽

pp. 473-476 ◽

Cited By ~ 110

Author(s):

Maria Ester Bernardo ◽

Eugenia Piras ◽

Adriana Vacca ◽

Giovanna Giorgiani ◽

Marco Zecca ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Hematopoietic Stem

Abstract Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

Download Full-text

Hemorrhagic Cystitis in Haploidentical Hematopoietic STEM CELL Trasplant: Retrospective Study and Comparison with a NON-Haploidentical DONOR Transplant Group

Blood ◽

10.1182/blood.v128.22.3418.3418 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3418-3418 ◽

Cited By ~ 1

Author(s):

Nerea Arratibel ◽

Monica Cabrero ◽

Estefania Perez ◽

Oriana Lopez ◽

Lucia Lopez ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Viral Infections ◽

Hemorrhagic Cystitis ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Haplo Group ◽

Grade Iii ◽

Donor Transplant

Abstract Introduction HLA-haploidentical hematopoietic stem cell transplant (Haplo HSCT) is a potentially curative strategy for patients lacking a HLA matched donor or a suitable unrelated donor. The use of post-transplant Cyclophosphamide (Cy) for GVHD prophylaxis and the particular characteristics of Haplo-HSCT can be linked to a higher risk of hemorrhagic cystitis (HC) and viral infections. In this context, our aim was to analyze HC in both haploidentical and conventional donor transplants in our center. Material and Methods We retrospective analyzed of 237 patients who received an HSCT in our center, between August-2012 and January-2016. We analyze the incidence of HC in the early post-HSCT period (6 months) and its characteristics in those patients receiving Haplo (n=36, 15%) and we compared it with a non-haploidentical donor transplant group from the same period (n=201, 85%). Results Patients' characteristics are summarized in table 1. Both groups are balanced, except for diagnosis due to the high proportion of Hodgkin lymphoma in Haplo group, conditioning regimen, and GVHD grade III-IV with a lower incidence in Haplo. Conditioning regimen in Haplo consisted of Fludarabine (30mg/m2x or 50mg/kg x 4days in RIC or MA regimen) and Busulfan (3.2 mg/kg x 2 in RIC or 3 days in MA). Post-HSCT Cy was used for GVHD prophylaxis in 94%. Median of days to reach more than 500x10^9 granulocytes and more than 20x10^9 platelets in Haplo group were 18 (13-30) and 23 (0-103) respectively. Hemorrhagic cystitis: Incidence of HC was 33% vs. 13% in conventional HSCT (p=0.03). Infectious etiology was documented in 84% of the Haplo recipients and 89% in conventional HSCT (p=0.87). In Haplo, HC was caused by BK/JC polyomavirus in 67% and adenovirus in 17%. Among conventional HSCT recipients, BK/JC was documented in 75% and adenovirus in 14% of HC. Viral infection was diagnosed by positive PCR in urine. HC appeared at a median of 65 days post-HSCT (5-557), without differences between Haplo and non-Haplo: 61 (5-423) vs. 67 (8-557). Treatment of HC consisted of hyper-hydration and spasmolytic drugs in 19 patients. Intravesical cidofovir was used in 7 and intravenous cidofovir was needed in 2 cases. Receiving an Haplo HSCT was associated with a higher risk of developing HC [OR 3.5 (95% CI 1.56-7.91); p=0.002]. We did not observed association between HC and conditioning regimen (p=0.18), receiving ATG (p=0.45) or presence of acute GVHD grade I-II (p=0.75) or grade III-IV (p=0.46). Haplo donor was the only variable with significant impact in multivariate analysis. Conclusions Incidence of HC is higher in Haplo HSCT, being viral infections and not Cy toxicity, the main cause (polyomavirus BK/JC as the first cause). Table 1 Table 1. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria.

Download Full-text

Treatment of AML in First Remission (CR1) with Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Using Unrelated Donors (UD).

Blood ◽

10.1182/blood.v112.11.976.976 ◽

2008 ◽

Vol 112 (11) ◽

pp. 976-976

Author(s):

Leandro de Padua Silva ◽

Borje S. Andersson ◽

Uday Popat ◽

Lori Griffin ◽

Michele Alvarez ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hla Typing ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Unrelated Donors ◽

Engraftment Failure

Abstract Introduction/Methods: A key component of improving the success rate of allogeneic HSCT for AML in CR1 is to reduce non-relapse mortality (NRM), which, if excessive, will deny the benefit of the graft-versus-leukemia effect. UD HSCT has traditionally been associated with high NRM rates. We reported previously on the significant reduction of NRM using the conditioning regimen of fludarabine 40mg/m2, IV busulfan 130 mg/m2 for 4 days and thymoglobulin. Here we analyze the outcomes of all patients (n=37) with AML in CR1 treated with this regimen and UD HSCT in our institution from January 2002 to December 2007. High-resolution allele level HLA typing was performed for all donorrecipient pairs for HLA-A, -B, -C, DRB1 and DQB1; up to one mismatch was allowed (9/10). Median follow up is 30 months (range, 9–72). Results: Median age was 48 years (range, 13–68); 30% (n=11) were older than 54 years and 51% (n=19) were male. Eleven patients (30%) had secondary AML. Prognostic cytogenetics classification was poor and intermediate in 53% and 47% of the cases, respectively. Stem cell source was bone marrow (BM) in 68% (n=25) and peripheral blood (PB) in 32% (n=12). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methotrexate with and without pentostatin (1 or 1.5 mg/m2 on days 8, 15, 22 and 30) in 46% (n=17) and 54% of the cases (n=20), respectively. Donor-recipient HLA match was 9/10 and 10/10 in 14% and 86% of the cases. Median infused total nucleated and CD34+ cells was 3.72 x 108 (range, 0.57 – 11.78) and 3.77 x 106 (range, 0.45 – 12.4), respectively. Median time to neutrophil and platelet engraftment was 12 days (range, 8–18) and 14 days (range, 8–101), respectively. All but one patient engrafted. Grade II–IV acute (a) GVHD rate was 13% (n=2) and 50% (n=10) for patients that received and not received pentostatin-based prophylaxis. Grade III–IV aGVHD rate was 0% versus 15% (n=3) for patients receiving and not receiving pentostatin. Chronic GVHD was diagnosed in 55% (n=18) of all patients (extensive in 10). 100-day and 3-year NRM rate was 11% (n=4) and 20% (n=4), respectively, and was due to engraftment failure (n=1) and aGVHD (n=3). Eight patients (22%) have relapsed, and 8 (22%) have died (4 of relapse, and 4 of NRM causes). Relapse rate was 18% (3/17) and 25% (5/20) for patients that received and not received pentostatin as part of GVHD prophylaxis. Actuarial 3-year event-free and overall survival (figure) is 68% and 78%, respectively. Actuarial 3-year overall survival for patients receiving BM and PB is 80% and 75%, respectively. Conclusion: Long-term disease control can be achieved in a significant fraction of high-risk AML patients undergoing UD transplants as described in this abstract. Use of pentostatin in this context deserves further prospective evaluation. Figure Figure

Download Full-text

Age-adjusted recipient pretransplantation telomere length and treatment-related mortality after hematopoietic stem cell transplantation

Blood ◽

10.1182/blood-2012-01-403337 ◽

2012 ◽

Vol 120 (16) ◽

pp. 3353-3359 ◽

Cited By ~ 19

Author(s):

Régis Peffault de Latour ◽

Rodrigo T. Calado ◽

Marc Busson ◽

Jeffrey Abrams ◽

Nadir Adoui ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Telomere Length ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Hazard Ratio ◽

Hematopoietic Stem ◽

Treatment Related Mortality ◽

Related Mortality

Abstract Telomere attrition induces cell senescence and apoptosis. We hypothesized that age-adjusted pretransplantation telomere length might predict treatment-related mortality (TRM) after hematopoietic stem cell transplantation (HSCT). Between 2000 and 2005, 178 consecutive patients underwent HSCT from HLA-identical sibling donors after myeloablative conditioning regimens, mainly for hematologic malignancies (n = 153). Blood lymphocytes' telomere length was measured by real-time quantitative PCR before HSCT. Age-adjusted pretransplantation telomere lengths were analyzed for correlation with clinical outcomes. After age adjustment, patients' telomere-length distribution was similar among all 4 quartiles except for disease stage. There was no correlation between telomere length and engraftment, GVHD, or relapse. The overall survival was 62% at 5 years (95% confidence interval [CI], 54-70). After a median follow-up of 51 months (range, 1-121 months), 43 patients died because of TRM. The TRM rate inversely correlated with telomere length. TRM in patients in the first (lowest telomere length) quartile was significantly higher than in patients with longer telomeres (P = .017). In multivariate analysis, recipients' age (hazard ratio, 1.1; 95% CI, .0-1.1; P = .0001) and age-adjusted telomere length (hazard ratio, 0.4; 95% CI; 0.2-0.8; P = .01) were independently associated with TRM. In conclusion, age-adjusted recipients' telomere length is an independent biologic marker of TRM after HSCT.

Download Full-text

Impact of Modifying Conditioning and Immunosuppressive Strategies in Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-122988 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5714-5714

Author(s):

Nawar Dakhallah ◽

Mylène Beauchemin ◽

Johanne Richer ◽

Sonia Cellot ◽

Pierre Teira ◽

...

Keyword(s):

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Acute Gvhd ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Current Approach ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis

Background:Hematopoietic stem cell transplants (HSCT) is indicated for some very high-risk childhood acute lymphoblastic leukemia (ALL) patients in complete remission 1 (CR1) and for patients in >CR2. Relapse remains the most frequent complication after transplant. In 2012, in order to decrease the relapse rate, we modified our conditioning and GVHD prophylaxis regimen. Total body irradiation doses were increased, etoposide removed and fludarabine introduced. Anti-thymocyte globulin (ATG) was removed of GVHD prophylaxis regimen and mycophenolate mofetil was added for unrelated marrow grafts. The aim of this study was to compare outcome between previous (PS) and new strategies (NS) prior and after 2012. Methods: This retrospective study included all 47 patients aged 0 to 18 years old who underwent a first HSCT for ALL at Sainte-Justine University Health Center from 2007 to 2017. Our primary endpoint was 2-year event-free survival (EFS) between PS (n=22) and NS (n=25) groups. Secondary endpoints included overall survival (OS), relapse, GVHD, immunological recovery and infection rates. Results: Demographic parameters and leukemia characteristics were not significantly different between groups. In the PS group, median age was 6.1 years [2.7;13.5] and 41% of patients were female. In the NS group, median age was 7.1 years [2.4;11.4] and 44% of patients were female. B-cell and T-cell lineage leukemias were present in respectively 82% and 18% of PS and 76% and 24% in NS. Fourteen percent of patients were transplanted in CR1 in the PS versus 40 % in the NS group. EFS at 2 and 5 years were respectively 46% and 36% with the PS compared to 60% and 53% with the NS (p=0.170). OS at 5 years was significantly higher with the NS (46% vs 75%, p=0.05). Morphologic relapse rates at 5 years of PS and NS were 55% and 30% (p=0.14). Acute GVHD rate at 6 months was superior with the NS (41% vs 80%, p=0.002). Chronic GVHD rate at 5 years was similar between groups. At least one proven infection at 100 days was documented in 96% compared to 88% of patients with the PS and NS respectively (p=0.08). Neutrophil recovery at 60 days and platelets recovery at 180 days were not significantly different. T-cell Immune recovery at 6 months was superior in the NS. Median (min;max) CD3 counts in PS and NS were respectively 339 (132;1152) versus 946 (284;1944) (p=0.009), CD4 counts were 221 (65;612) versus 594 (238;920) (p=0.046) and CD8 counts were 55 (34;414) versus 320 (210;1104) (p<0.001). Conclusion: Compared to the PS, the NS of conditioning regimen and GVHD prophylaxis shows a significant improvement in OS and a tendency towards decreased relapse and increased EFS. However, we found a significant increase in acute GVHD with this regimen, which is explained by the removal of ATG from the regimen. These results highlight the necessity to adjust our strategy with HSCT ALL with the aim of maintaining graft versus leukemia effect without increasing GVHD. Emerging immunotherapy (such as antibody-based and chimeric antigen receptor T cell therapies) might shift the management of refractory and relapsed ALL and our current approach to HSCT. Disclosures Bittencourt: Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Travel, accommodations expenses.

Download Full-text

Masp-2 Levels Following Allogeneic Hematopoietic Stem Cell Transplantation in Adults: Correlation with Development of a Thrombotic Microangiopathy and Implications for Therapy with Anti-Complement Agents

Blood ◽

10.1182/blood-2019-130919 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3305-3305

Author(s):

Jeffrey Laurence ◽

Koen Van Besien ◽

Jasimuddin Ahamed ◽

Sonia Elhadad

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Complement Activation ◽

Thrombotic Microangiopathy ◽

Conditioning Regimen ◽

Clinical Manifestations ◽

Hematopoietic Stem ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

The Impact

Introduction: 8500 adult allogeneic hematopoietic stem cell transplants (alloHSCT) are performed annually in the U.S. and 17,000 in Europe. HSCT-associated thrombotic microangiopathy (TMA), defined by thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction in the absence of disseminated intravascular coagulation, complicates some 20% of these procedures. About half of post-alloHSCT TMAs may resolve when GvHD immunoprophylaxis is modified, but three year survival rates for those with severe HSCT-TMAs are a dismal 11%. Clinical manifestations are similar to other TMAs, but their pathophysiology may be distinct. Damage to vascular endothelium, independent of loss of ADAMTS13 activity, is thought to be critical. Fibrin-rich microthrombi, often accompanied by C4d and C5b-9 (membrane attack complex) deposition, occur in the microvasculature of multiple organs (Clin Adv Hematol Oncol 2014;12:565-573; Transplantation. 2013;96:217-223). This supports a role for complement activation in HSCT-TMA, but the importance of the various complement activation pathways is unclear. Recently, narsoplimab (OMS721), a monoclonal antibody inhibitor of MBL-associated serine protease-2 (MASP-2), a principal component of lectin-dependent complement activation, received Breakthrough Therapy Designation for HSCT-TMA, based on improved survival compared to historical controls in a phase 2 study. A phase 3 program is ongoing. Chemotherapy in association with autologous HSCT is linked to a marked increase in serum MASP-2 levels, persisting for about 4 weeks post-transplant (Front Immunol 2018;9:2153). However, TMAs are rare in autologous transplants, and circulating levels of MASP-2 following alloHSCT, and the impact of TMA development on those levels, are unknown. Methods: All individuals >18 years of age scheduled to undergo alloHSCT for hematologic malignancy at New York Presbyterian Hospital-Cornell were approached to participate in this study (NCT02604420). 100 of the first 101 subjects, age 58.3 +14 yrs, were enrolled and followed for >1.5 years post-transplant. This interval is consistent with the median time to HSCT-TMA diagnosis in adults of 90 days (range 32-733 days). Plasma was obtained at baseline (defined as between the time of consent and beginning of conditioning regimen), and at each regularly scheduled visit post-transplant-day 28 +5 days; day 100 +28 days; day 180 +28 days; and day 365 +28 days-as well as at the time of TMA diagnosis, based on the Consensus Criteria of Cho et al. (Transplantation 2010;90:918-926). A commercial ELISA (MyBioSource) was used to assess MASP-2 concentrations. Results: 20 subjects met study criteria for a HSCT-TMA diagnosis, occurring a median of 69 days (range 33-289) post-transplant. Three resolved following discontinuation of GvHD prophylaxis (mTOR or calcineurin inhibitor) and switch to mycophenolate and increased corticosteroid doses, and 7 had an intercurrent infection, 6 of whom expired with ongoing severe TMA despite a change in GvHD prophylaxis (Figure). TMAs persisted in the remaining 10 subjects. Median MASP-2 levels were significantly elevated in all subjects post-transplant, assessed at the time of TMA development or, in those not developing a TMA, at day 100 + 28 days post-transplant vs. controls (n=36, 86.2ng/ml (23.3-210.9): persistent TMA (n=9 (one plasma unavailable), 154ng/ml (range 82-209)); alloHSCT subjects who did not experience a TMA (n=40 evaluated to date, 113.5ng/ml (56-430.3)). (Figure). Lack of a significant rise in MASP-2 levels in patients with persistent TMAs vs. those who did not develop a TMA, combined with a significant decrease in variance of MASP-2 levels in the former group (p=0.005), may reflect consumption of product at sites of disease activity, i.e., the microvasculature. Conclusions: There is a significant increase in MASP-2 levels, with a wide variance, in post-alloHSCT patients evaluated at a time post-transplant typical of HSCT-TMA development. At time of development of a HSCT-TMA that persists despite withdrawal of GvHD prophylaxis, MASP-2 levels remain elevated over controls, but with a significantly lower variance vs. those not developing TMA. A study of additional samples, including longitudinal specimens, from this cohort is underway to determine if a change in MASP-2 levels correlates with HSCT-TMA development post-alloHSCT. Disclosures Van Besien: Miltenyi Biotec: Research Funding.

Download Full-text

Post-Transplant High-Dose Cyclophosphamide Overcomes the Detrimental Effect of a Single-Locus HLA Mismatched in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-112985 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4576-4576

Author(s):

Patricia Ferraz ◽

Arturo Pereira ◽

María Suárez-Lledó ◽

Gonzalo Gutiérrez-García ◽

Francesc Fernández-Avilés ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Detrimental Effect ◽

Chronic Gvhd ◽

Unrelated Donor ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis

Abstract Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) from unrelated donors mismatched (MMUD) at a single HLA-A, -B, -C, or -DRB1 locus (7/8) were previously reported to be associated with lower overall survival (OS) and disease-free survival (DFS), higher treatment-related mortality (TRM), and more acute graft-versus-host disease (GVHD) compared to 8/8 matched unrelated (MUD) allografts. Despite these risks, 7/8 MMUD grafts remain a viable option for alloSCT, particularly in patients who lack suitable donors or in those with aggressive hematologic malignancies for whom the risks of disease progression due to delays in identifying optimal donors is offset in part by the benefits of earlier transplantation with a 7/8 MMUD alloHCT. According to the published experience of post-transplant cyclophophamide (PTCy) in the context of haploidentical alloSCT, this GVHD prophylaxis strategy could potentialy overcome the detrimental effect of a single-locus HLA MMUD. Methods: We retrospectively analyzed 72 consecutive adult patients (median age 53y, range 18-69) who received 7/8 MMUD (n=44) or 8/8 MUD (N=28) alloSCT with PTCy in our institution. Unrelated donor selection was performed according to standard criteria, including high resolution typing for alleles at HLA-A, -B, -Cw, DRB1 and DQB1. For those patients in whom an 8/8 HLA-matched related or unrelated donor was not available, a search was performed based on a single HLA-mismatch. Results: Acute myeloid or lymphoblastic leukemia accounted for 51% of all hematologic diseases, myelodisplastic syndrome for 17%, chronic lymphoproliferative or myeloproliferative disorders for 28%, and severe aplastic anemia for 4%. Disease Risk Index (DRI) was intermediate in 51%, high 16% and very high 6%. Forty-four percent of patients had a HCT-CI ≥3. All patients, except 6 have received peripheral blood stem cells (PBSC). Fludarabine-based conditioning regimens were used in all patients (fludarabine-busulphan in 61%); of them, myeloablative (MAC) in 34 patients (47%) and RIC in 38 (53%). GVHD prophylaxis consisted on PTCy 50mg/kg IV on days 3 and 4 after transplant followed by one (tacrolimus or mycophenolate mofetil, MMF) (n=62, 86%) or 2 (n=10, 14%) immunossuppresor drugs. All but two patients engrafted and the median time to neutrophil (>500/mL) and platelet (>20,000/mL) recovery were 18 days (range 11-30) and 18 days (10-47), respectively. Thirteen patients (18%) developed an invasive pulmonary Aspergillosis, 20 (27%) had severe bacterial infection, 40 (56%) CMV reactivation, 5 (7%) cytomegalic disease and 3 EBV reactivation. The cumulative incidences of 1-year TRM, 100-days acute grade II-IV, 100-days grade III-IV GHVD, and 1-year moderate-severe chronic GHVD were 19%, 24%, 13%, and 11%, respectively. The cumulative incidence of relapse at 1-year was 16%. After a median follow-up for surviving patients of 12 months (2-60), 2-year OS, DFS, and survival free of moderate/severe chronic GVHD and relapse (cGRFS) were 64%, 61%, and 49%, respectively. Univariate analysis of variables that could influence OS, PFS, and cGRFS, including age, donor/patient sex, comorbidity, DRI, conditioning type, 1 vs. 2 immunosuppressors, and HLA 7/8 vs. 8/8 did not show any statistical differences. At 6 and 12 months after alloSCT, 42% and 73% of patients alive and without relapse were free of immunosuppressor drugs and prednisone. Conclusions: This study suggests that PTCy after unrelated PBSC alloSCT results in a low incidence of acute and chronic GVHD with encouraging survival outcomes even in the context of 7/8 HLA-mismatched transplant. An immunosuppressive schema of intermediate intensity such as PTCy followed by single-agent tacrolimus may provide an adequate GVHD prophylaxis and could be a good alternative to ATG in both MMUD and MUD transplants. Confirmatory and comparative studies are warranted to examine the effect of this approach on alloSCT outcomes. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Martinez:BMS: Research Funding; Takeda: Consultancy.

Download Full-text

Haploidentical Hematopoietic Stem Cell Transplantation for Malignant Infantile Osteopetrosis and Intermediate Osteopetrosis:A Retrospective Analysis of a Single-Center

10.21203/rs.3.rs-195831/v1 ◽

2021 ◽

Author(s):

Guanghua Zhu ◽

Ang Wei ◽

Bin Wang ◽

Jun Yang ◽

Yan Yan ◽

...

Keyword(s):

Stem Cell ◽

Survival Rate ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

High Survival ◽

Hematopoietic Stem

Abstract ObjectiveTo evaluate the clinical efficacy of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for treatment of malignant infantile osteopetrosis (MIOP) and intermediate osteopetrosis.MethodsChildren with MIOP and IOP who underwent haplo-HSCT in Beijing Children’s Hospital, Capital Medical University, from January 2010 to May 2018 were retrospectively analyzed. Data relating to the clinical manifestations, engraftment, and prognosis of the children were extracted from medical records. ResultsTwenty-seven patients, including 18 males and 9 females, with an onset age of 12 (0.04-72) months, were enrolled in this study. The median time from diagnosis to transplantation was 4 (1-23) months. All patients received haplo-HSCT with myeloablative conditioning regimen (including fludarabine, busulfan, and cyclophosphamide). The graft versus host disease (GVHD) prophylaxis was based on anti-human T lymphocyte porcine immunoglobulin /anti-human thymus globulin, methotrexate, and mycophenolate mofetil. The median observation time was 55.2 (0.3-126.2) months. By the end of follow-up, twenty patients survived and seven patients died. The five years overall survival rate was 73.9%. Acute GVHD degree I-II was observed in 20 patients, degree III in 1 patient and without degree IV. Chronic GVHD was observed in 11 patients (40.7%). It was controlled by anti-GVHD therapy.ConclusionHaplo-HSCT was effective for MIOP and IOP, with high survival rate and significantly improved of clinical symptoms. For the patients with vision impairment before HSCT, the improvement was slow after transplantation. The incidence of GVHD was high but mild, and could be effectively controlled after appropriate treatment. These data provided that haplo-HSCT was feasible in the treatment of MIOP and IOP.

Download Full-text