Rate Of Veno-occlusive Disease Research Articles

Incidence and risk factors of early onset VOD/SOS differ in younger vs older adults after stem cell transplantation

AbstractVeno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Among patients aged 18 to 25 years, disease risk index (DRI; 31% with high/very high DRI vs 12% low/intermediate DRI; P = .03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1; P = .03) were the strongest predictors of VOD. Incidence of VOD in patients aged >25 years of age consistently ranged between 3% and 5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase, alanine aminotransferase) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared with those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors of VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.

Incidence and Risk Factors of Veno-Occlusive Disease Are Different in Younger Versus Older Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic stem cell transplantation (allo-SCT). Improved transplant techniques and increased awareness of modifiable risk factors have reduced VOD incidence. However, the interaction of historic risk factors in the current era, particularly with the increasing use of calicheamicin-based therapies and post-transplant cyclophosphamide as GVHD prophylaxis, remains unclear. Methods: We conducted a retrospective, single center, chart-based study of consecutive adult patients (age ≥ 18 years) undergoing allo-SCT at MD Anderson Cancer Center between January 1 st, 2017 and December 31 st, 2021. VOD cases were defined using the classic VOD EBMT criteria or if patients received defibrotide treatment for VOD based on clinical judgment of the treating physician. Risk factors for VOD were evaluated in univariate analysis using Fine and Grey regression analysis. Multivariate analysis was performed using Classification and Regression Tree (CART) analysis to validate the findings of univariate analysis and evaluate independent effects accounting for potential interaction effects. Results: A total of 1561 patients were included in our analysis. Median age was 56 years and 60% were male. Patients primarily had acute myeloid leukemia/myelodysplastic syndrome (AML/MDS; 60%), acute lymphoblastic leukemia (ALL; 13%), or myeloproliferative neoplasms (13%). Most patients had matched related (28%) or unrelated donors (48%), and 21% underwent haploidentical transplantation. Forty-nine (3%) patients received inotuzumab ozogamicin (InO) containing regimens prior to allo-SCT, and 30 (2%) were exposed to gemtuzumab ozogamicin (GO). Post-transplant cyclophosphamide (PTCy) was used as GVHD prophylaxis in 72% of patients. Incidence of VOD in the entire study population was 4.8%. There was a significant difference in the median age of patients diagnosed with VOD compared to those without VOD (46 years vs 56 years, respectively, p=0.001). Further examination of the incidence of VOD within different age groups identified a VOD rate of 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those > 25 years (Table 1). Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD (Figure 1). Given these findings, risk factor analysis was stratified according to age. In patients ≤25 years of age, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Within the younger cohort of patients with AML/MDS, 2 of 3 patients (67%) who received gemtuzumab ozogamicin (GO) developed VOD compared to 10% who did not receive GO (p=0.05). In patients aged >25 years, elevated baseline bilirubin, AST, ALT, and GO exposure were associated with increased VOD rates. VOD incidence based on baseline bilirubin levels (WNL, >ULN to 1.5x ULN, and >1.5x ULN) was 3%, 14%, and 16%, respectively (p<0.001). For baseline ALT levels (WNL, >ULN to 2.5x ULN, and >2.5x ULN), VOD rates were 4%, 3%, and 8%, respectively (p=0.02). Similarly, VOD rates with baseline AST levels (WNL, >ULN to 2.5x ULN, and >2.5x ULN) were 3%, 4%, and 27%, respectively (p≤0.001). In patients aged >25 years with AML/MDS, those receiving GO had a higher incidence of VOD compared to AML/MDS patients not exposed to GO (15% vs. 3%; p=0.01). There was no significant difference in VOD rates between those receiving PTCy and those receiving alternate GVHD prophylaxis in either age cohort. Conclusion: In summary, our data highlight that young adults (age 18 - 25 years) represent a distinct adult population with increased rates of VOD compared to their older counterparts, which are exacerbated by disease and treatment related factors (DRI and number lines of therapy). In contrast, patients > 25 years of age had low rates of VOD even in the presence of historical predictors, with only hepatic risk factors identified as increasing baseline VOD risk. There was no observed increased incidence of VOD among those receiving PTCy as GVHD prophylaxis.

Baseline Liver Elastography Does Not Predict Risks of Hepato-Toxicity to Reduced Dose Inotuzumab Therapy Combined with Minihcvd in B-Cell Acute Lymphoblastic Leukemia

Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody drug conjugate that is FDA approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-cell ALL). Liver toxicity, particularly veno-occlusive disease (VOD) was the most important grade 3 toxicity in the Phase III INO-VATE study of InO, driven by the active cytotoxic agent calicheamicin conjugated to InO, especially in pts who underwent subsequent stem cell transplantation (SCT) (Kantarjian et. al, NEJM 2016). However proper assessment of liver function and fibrosis through elastographic measurements might predict the risks of subsequent liver toxicity with InO. Aim: We aimed to study the extent of liver toxicity, including VOD, in pts treated with InO and its correlation to baseline liver elastography. Methods: Pts with B-cell ALL treated with InO containing low intensity combination regimen [miniCVD-InO- blinatumomab-rituximab (previously published; Jabbour et. al. Cancer 2018)] as part of a clinical trial (NCT01371630) underwent baseline liver elastography and were prospectively monitored for any evidence of liver toxicity, including VOD. Elastography was done within 4 weeks prior to the first infusion of InO and liver stiffness was stratified based on the median shear wave velocity (SWV) using the acoustic radiation force impulse (ARFI) technique. Elastographic median SWV >1.7 m/s was considered as evidence of definite liver fibrosis. We captured the patient characteristics, history of known liver disorders, baseline liver function tests, total dose of InO administered and any subsequent liver toxicities including VOD. Any antecedent or subsequent history of SCT was noted; liver toxicity was graded according to the NCI CTCAE, v5. The dose of InO was capped at a cumulative maximum of 2.7mg/m2 of body surface area (administered in fractionated doses) and all pts received concurrent ursodiol prophylaxis with InO. Results: From Jan 2018- April 2022, 50 consecutive pts treated with the above regimen and with baseline elastography reports available as part of the research protocol were analyzed. The median age of the pts was 54.9 years (yrs) (range, 21.7-87.7 yrs) and only 1 pt had a known prior liver ailment of non-alcoholic fatty liver disease (NAFLD). Baseline characteristics are mentioned in Table 1. The median InO dose received by the pts were 1.5 mg/m2 (range, 0.9-2.7 mg/m2) and only 11 pts (22%) received the maximum cumulative InO dose of 2.7 mg/m2. A total of 11 pts (22%) had a baseline maximum SWV >1.7 m/s which radiologically corresponds to possible compensated advanced chronic liver disease (cACLD) and no pts had a SWV >2.1 m/s (corresponds to clinically significant portal hypertension; CSPH). All pts achieved CR/CRi as best response and 14 pts (28%) underwent consolidative SCT. Only one pt developed a VOD of the liver, diagnosed based on clinical and radiological findings, at D+60 post haploidentical-SCT with Flu/Mel140 conditioning and post-transplant cyclophosphamide. This pt had normal baseline liver elastography and had received a cumulative InO dose of 1.5 mg/m2. Another 5-pts (10%) had ≥ grade 3 liver toxicity (1 pt with hyperbilirubinemia and 4 pts with ALT elevation), all of whom had baseline SWV <1.7 m/s on elastography. On regression analysis using age, cumulative InO dose, baseline values of total bilirubin, ALT and INR, and SWV cutoffs as covariates, no factor significantly affected the risks of ≥ grade 3 liver toxicity. After adopting the use of reduced dose fractionated InO administration regimen, routine ursodiol prophylaxis and avoiding peri-transplant azole antifungal prophylaxis in InO exposed B-cell ALL pts at our center, the frequency of liver toxicites including VOD has significantly reduced compared to the 11% rate of VOD described in the INO-VATE study. With these improvisations reducing the overall frequency of InO induced liver toxicity, the positive predictive value of a pre-InO elastography to envisage the risks of subsequent VOD and other liver toxicity in these pts is highly limited. Conclusion: In a prospectively monitored group of pts of B-cell ALL treated with fractionated InO containing combination regimen, baseline liver elastography did not predict the risk of subsequent liver toxicity. Sequential liver elastographies to monitor dynamic changes in SWV needs to be analyzed in future studies to further assess its predictive role for InO induced liver toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Outcomes with Low-Dose Inotuzumab and Mini-Hyper-CVD Followed By Blinatumomab Consolidation in Relapsed-Refractory Acute Lymphoblastic Leukemia: Results of a Phase II Study

Background: Patients (pts) with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) have a poor prognosis. The combination of low-intensity chemotherapy with mini-hyper-CVD (mini-HCVD) and inotuzumab has shown encouraging results. The aim of this study is to evaluate whether the sequential addition of blinatumomab to mini-HCVD-inotuzumab with lower doses of weekly inotuzumab might further improve outcomes. Methods: Pts with Philadelphia chromosome-negative B-cell ALL were included. Odd cycles of mini-HCVD consisted of cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracyclines. Even cycles consisted of cytarabine (0.5 g/m2 given every 12 h on days 2 and 3) and methotrexate (250 mg/m2 on day 1). During the first 4 courses, pts received rituximab when CD20 expression was ≥20%, and intrathecal chemotherapy. Initially, inotuzumab was administered on day 3 of the first 4 cycles at the dose of 1.3-1.8 mg/m2 in course 1, followed by 1.0-1.3 mg/m2 in subsequent courses. Pts received maintenance therapy with POMP, consisting of 1 year of monthly prednisone 50 mg/d for 5 days and vincristine at 2 mg every month, along with 3 years of 6-mercaptopurine 50 mg twice daily and weekly oral methotrexate 10 mg/m2. An amendment to the protocol was made after the inclusion of 67 pts to add 4 cycles of blinatumomab after 4 cycles of the combination mini-HCVD + inotuzumab. Inotuzumab was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 in course 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 in subsequent courses; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. Maintenance therapy was reduced to 12 courses of POMP with 1 course of blinatumomab after each 3 courses of POMP for a total of 4 courses. The decision to undergo allogeneic stem cell transplantation (ASCT) was based on the discretion of the treating physician after discussion with the patient. Results: Between February 2013 and July 2021, 112 pts were treated on study, including 45 pts with mini-HCVD + inotuzumab + blinatumomab. Baseline characteristics and outcomes are summarized in Table 1. The median follow-up is 41 months (range, 3-112). Before the study amendment, 67 pts were treated: 38 (57%) in salvage(S)1, and 29 (43%) in S2+. Nineteen pts (28%) had received prior ASCT. After the amendment, additional 45 pts were treated: 42 (93%) in S1, and 3 (7%) in S2+; 3 (7%) pts had prior ASCT. The overall response rate (ORR) was 83% (CR, 63%) in the entire cohort, 76% (CR, 60%) pre-amendment, and 93% (CR, 67%) post-amendment. Among 91 responders evaluable for measurable residual disease (MRD), 76 pts (82%) achieved MRD negativity by multicolor flow cytometry, with higher rates of MRD negativity in S1 (89%). The rates of MRD negativity before and after the amendment were 82% and 85%, respectively. Overall, 53 (47%) pts underwent ASCT: 29 (43%) pts pre-amendment and 24 (53%) post-amendment. The median overall survival (OS) for the entire cohort was 17 months, with a 3-year OS rate of 41%. After the amendment, the addition of blinatumomab resulted in superior median OS (37 months vs 14 months) and 3-year OS rates (55% versus 34%) (Figure 1). Pts in S1 had better survival compared with those in S2+, with 3-year OS of 51% and 17%, respectively (P=0.001). In a 2-month landmark analysis among pts in S1, the median OS was 57 months in those who received blinatumomab compared with 31 months in those who did not. Overall, pts who achieved MRD negativity had higher 3-year OS rate of 55% compared to 10% in pts who were MRD-positive at best response (P=0.0001). Survival with mini-HCVD + inotuzumab +/- blinatumomab compared favorably to that of inotuzumab monotherapy: 17 months vs 6 months; P<0.0001. A 3-month landmark analysis among responders showed similar 3-year OS rates between pts who underwent subsequent ASCT and those who did not (55% vs 48%, respectively). Veno-occlusive disease (VOD) was observed in 10 of the 112 pts (9%), and its incidence was reduced from 13% with single dose of inotuzumab to 2% with fractionated dose schedule (P=0.056). Conclusion: The addition of blinatumomab to mini-HCVD-inotuzumab, along with a lower weekly dose of inotuzumab, further improves the outcomes of pts with R-R ALL. These adjustments reduced the rate of VOD and improved survival. Long-term survival was similar regardless of subsequent ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Updated Results from a Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia

Reduced-Intensity Chemotherapy with Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: Results from a Phase II Study

Reduced-Intensity Chemotherapy with Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: Results from a Phase II Study

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina) As Salvage Therapy for Patients (Pts) with Acute Lymphoblastic Leukemia (ALL) in First Relapse

Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplant (HSCT). Busulfan has a narrow therapeutic index and its concentration was found to correlate with VOD. Our primary objective was to assess the association between busulfan clearance and VOD in HSCT patients. In this retrospective analysis, we included patients who received their HSCT between 2003 and 2014 and followed at Sultan Qaboos University Hospital. All patientswho received dose-targeted busulfan-containing conditioning were included. Target steady-state concentration (Css) was 800-900ng/ml. VOD was assessed using modified Seattle criteria. The impact of busulfan clearance on VOD was analyzed using univariable logistic regression model. Seventy-three patients were included with a mean age of 15years. Of those, 47% were transplanted for hematological malignancies and 53% for inherited hemoglobinopathies. Target Css was achieved in 85% of patients. The rate of VOD was 17%. There was no significant impact of busulfan clearance (p = 0.919) or area-under-the-concentration-time-curve (p = 0.275) on VOD. Targeting busulfan Css into narrow therapeutic range may have accounted for the findings. The risk of VOD might be related to other factors such as the genetic background, and more studies are required to investigate these factors.

Inotuzumab Ozogamicin Post-Transplant for Acute Lymphoblastic Leukemia

<h3>Background</h3> Allogeneic transplant (alloHCT) is a curative therapy for patients with acute lymphocytic leukemia (ALL). The curative potential of alloHCT is hampered by relapse, which is the major cause of treatment failure. Overall, relapse rates for these patients are in the range of 30% to 50% with the majority of these relapses occurring within the first year after alloHCT. Currently, there is no standard post-transplant therapy for patients with ALL. Inotuzumab ozogamicin (INO) is a CD22 monoclonal antibody bound to calicheamicin which has been shown to have significant activity against relapsed ALL. We hypothesize that low dose post-alloHCT maintenance therapy of INO will be safe and will reduce relapse rates after alloHCT for ALL. <h3>Methods</h3> Eligibility included patients aged 16-75 who have undergone alloHCT for CD22+ALL, have a high risk for relapse, have adequate graft and organ function, are between day 40 and 100 post-transplant, do not have active grade III/IV GVHD or any active GVHD of the liver, and have no history of veno-occlusive disease (VOD). The primary objective of this phase I clinical trial is to define a post alloHCT maximum tolerated dose (MTD) of INO. Secondary objectives include describing the safety profile of INO post-alloHCT, determining the rate of VOD, disease free survival (DFS) and overall survival (OS) at 1 year post alloHCT. The trial design is a 3+3 model. The study treatment consists of a total of four 28 day cycles of INO starting at dose level 0 (0.3mg/m2) given on day 1. Dose limiting toxicities (DLT) include VOD, prolonged cytopenia (more than 28 days), and death. If there are no DLTs experienced in a cohort, patients may be enrolled in the next highest dose level (Table 1). <h3>Results</h3> As of October 1st, 2019, 9 patients have been treated. One patient went off treatment after 1 cycle of INO (patient choice), two went off treatment after 3 cycles of INO (patient choice and physician choice) and one experienced a DLT due to prolonged thrombocytopenia. We have completed 1 year post-transplant follow up on 5 patients. All patients are alive and in CR. No patients experienced VOD. Significant side effects include thrombocytopenia and neutropenia. The percentage of any aGVHD is 62.5% and the rate of grade III/IV aGVHD is 0%. The percentage of any cGVHD is 42.8%. Patient characteristics are described below (Table 2). <h3>Conclusions</h3> In this phase 1 study, INO at doses of 0.3 and 0.4mg/m2 was well tolerated. Thrombocytopenia may be the dose limiting toxicity. The absence of disease recurrence in this small cohort of high risk ALL patients is very promising.

Updated Results of a Phase II Study of Reduced-Intensity Chemotherapy with Mini-Hyper-CVD in Combination with Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Updated Results of a Phase II Study of Reduced-Intensity Chemotherapy with Mini-Hyper-CVD in Combination with Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (Mini-hyper-CVD) with or without Blinatumomab Is Highly Effective in Patients (pts) with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse

Sequential Combination of Inotuzumab Ozogamicin (InO) with Low-Intensity Chemotherapy (Mini-hyper-CVD) with or without Blinatumomab Is Highly Effective in Patients (pts) with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in First Relapse

Treosulfan Based Conditioning Regime for Allogenic HSCT in Resource Poor Setting

Allogenic stem cell transplantation is a curative procedure for many blood disorders including haemtological malignancies. The outcomes are very dependent on the conditioning regime used. Infections from a variety of micro-organisms and graft vs host disease(GVHD) can be the other parameters affecting outcomes. Relapse rate specially in a malignant condition influences the choice of regime as does the prevention of certain conditions like veno occlusive disease- Sinusoidal obstruction syndrome.Busalfan based regimes have been used extensively but shows a high rate of veno occlusive disease (VOD) specially when used with post transplant high dose Cyclophosphamide for GVHD prevention. Also Buslfan drug monitoring is not available in many places making this kind of transplants risky. Once VOD develops, the mortality is very high and it is better prevented. The use of drugs like Defibrotide makes the transplant very expensive also. We developed a conditioning regime using Treosulfan (di hydroxy Busulfan), followed by post transplant Cyclophosphamide and did not see a single patient suffering from VOD in the 15 patients transplanted so far. These were for a variety of malignant conditions including Myelodysplasia, Acute myeloid leukaemia, Acute Lymphoblastic leukaemia, Chronic Myeloid leukaemia, Follicular Lymphoma. The age group varied from 10-58 years(median=35) and there was almost an equal sex distribution. Among the 15 patients transplanted 7 patients were in CR(complete remission)1, 6 in CR2 and 2 in CR3. The graft was a peripheral stem cell graft taken from a mix of Haploidentical donors, Matched unrelated donor and sibling donors. 10 patients are alive so far and are in CR. 2 relapses were seen who ultimately died in agressive acute myeloid leukaemia, 2 died of a secondary infection, 1 transplant related mortality due to microangiopathy was seen. 1 grade 4 GVHD was noted which was treated with steroids. In conclusion, Treosulfan gives an advantage over Busulfan in our results and with the advent of generic Treosulfan the cost of the transplant procedures have gone down also. The avoidance of medicines like Defibrotide and no requirement of drug monitoring make these procedures simple and cheaper and is much suited in a resource poor setting.

Chemoimmunotherapy with Inotuzumab Ozogamicin Combined with Mini-Hyper-CVD, with or without Blinatumomab, for Newly Diagnosed Older Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: Results from a Phase II Study

Chemoimmunotherapy with Inotuzumab Ozogamicin Combined with Mini-Hyper-CVD, with or without Blinatumomab, for Newly Diagnosed Older Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: Results from a Phase II Study

Defibrotide for Treatment of Severe Veno-Occlusive Disease in Pediatrics and Adults: An Exploratory Analysis Using Data from the Center for International Blood and Marrow Transplant Research

Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.

A Novel Protocol Decreased Incidence of Hepatic Veno-Occlusive Disease and Improved Results in Hematopoietic Cell Transplantation for Patients with b-Thalassemia Major

▪Hepatic veno-occlusive disease (VOD) is a common complication of hematopoietic cell transplantation (HCT), especially patients with β-thalassemia major (TM). To estimate whether incidence of VOD recently decreased after using NF-08-TM protocol (NP), 311 TM-HCTs performed from February 2003 to June 2013 were analyzed. 241 patients received NP in or after 2009 and 70 received non-NP before 2009. VOD was diagnosed by Seattle criteria (SC) or Baltimore Criteria (BC). Patients were stratified by Nanfang (NF) criteria. A total of 31(10.0%) and 14 (4.5%) HCTs developed VOD (6 and 5 developed severe VOD) in SC and BC cohorts, respectively. The incidence of VOD was significantly lower in NP versus non-NP groups and in Class 2 versus Class 3 groups. Overall survival was significantly higher in NP versus non-NP cohorts. Rate of VOD in alternative donor transplant (ADT) was similar to that in matched sibling transplant (MST). Requirement of platelet and value of D-dimer significantly increased in the VOD patients. Our study showed the incidence of VOD significantly decreased in our center after using NP. ADT was similar to MST on rate of VOD. NF criteria of stratification can indicate occurrence of VOD. The SC can be more suitable criteria for early diagnosis. DisclosuresNo relevant conflicts of interest to declare.

Defibrotide for Prevention and Treatment of Veno-Occlusive Disease in Adults: Single-Center Experience

Background: Hepatic veno-occlusive disease (VOD) has been reported at a rate up to 50% following intensive conditioning regimens used in allogeneic hematopoietic stem cell transplantation (AHSCT). Studies on the prophylactic effect of defibrotide to prevent hepatic VOD in adults are rare. Purpose: The research presented here aimed to evaluate whether propylactic defibrotide use can reduce incidence and severity of VOD in adults undergoing AHSCT. Also, we aimed to assess the benefit of defibrotide for treatment of VOD. Methods: Study population comprised 86 consecutive AHSCT patients transplanted between January 2005 and December 2009. 17 of the patients at high risk of developing VOD could have access to defibrotide and received defibrotide prophylaxis. Results: Modified Seattle criteria were used for VOD diagnosis. 14 of 86 patients (10 severe, 3 moderate, 1 mild) were diagnosed with VOD (16.2%). VOD incidence was similar between patients transplanted before December 2004 and after January 2005 (9.3% and 16.2%, respectively; p =0.14, HR =1.88, 95% CI 0.82- 4.29). 13 of 14 patients diagnosed with VOD in the study population were treated with defibrotide whereas only 2 of 12 in the control group received defibrotide for treatment (92.8% and 16.6%, respectively; p =0.0002, HR =65 , 95% CI 5.13-823.1). Mortality rate of VOD in the controls was significantly higher than the study population (66.6% and 21.4%, respectively; p =0.044, HR =0.13, 95% CI 0.02-0.78). Conclusions: Mortality rate related to VOD was lower in the defibrotide group. Therefore, we conclude defibrotide might be beneficial for treatment of VOD in adults.

Safety of conditioning agents for allogeneic haematopoietic transplantation

Allogeneic stem cell transplantation (allo-SCT) for haematological malignancies became a safer approach in recent years, for example, owing to improved supportive strategies. However, despite the efficacy of the procedure, morbidity and mortality mainly caused by infections and organ toxicity remain serious problems. Due to the variety of conditioning regimens being applied before allo-SCT, one important aspect is represented by the toxicity profiles of the specific compounds, which are being applied for the reduction of the leukaemia cell load and for immunosuppression. This is being illustrated by the hepatotoxic profile of busulfan with its high rate of veno-occlusive disease. However, recent advances in our understanding of drug metabolism, progress in the measurement of drug concentration, and the invention of some new drugs and therapeutic approaches in the conditioning period are promising steps in achieving more safety for patients undergoing allo-SCT. Reduced-intensity conditioning concepts allow the inclusion of heavily pretreated patients or patients with severe co-morbidities in transplantation concepts. New prophylactic regimens, including poly- or monoclonal antibodies, result in reduced rates of graft-versus-host disease, and some ‘new’ drugs such as treosulfan or clofarabine widen the range of available conditioning regimens for specific situations.

Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation

AbstractSirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression.

All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct to High-Dose Cytarabine-Based Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of AMLSG 05-04 Trial.

Background: Patients with primary refractory acute myeloid leukemia (AML) have a dismal outcome. Only allogeneic stem cell transplantion (SCT) currently offers the chance of cure to these patients. In order to improve outcome after allogeneic SCT, one important prerequisite is to increase response rates prior to SCT.Aims: To evaluate the impact of all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) given as adjunct to high-dose cytarabine-based salvage therapy in younger adult patients with primary refractory AML on achievement of response. Consecutive allogeneic SCT was intended in all patients.Methods: Main inclusion criteria of the AMLSG 05-04 trial (NCT00143975) werei.refractory AML following one cycle of ICE (idarubicin, cytarabine, etoposide); andii.age 18 to 60 years.Dose and schedule of the GO-A-HAM regimen were as follows: GO 3mg/m2, day 1; cytarabine 3g/m2 bid., days 1–3; mitoxantrone 12mg/m2, days 2,3; ATRA 45mg/m2, days 3–5, 15mg/m2 days 6–28. Primary endpoint of the study was CR rate. Safety endpoints comprised early / hypoplastic (ED/HD) death rate, liver toxicity CTC grade 3–5, and rate of veno occlusive disease (VOD) after allogeneic SCT.Results: Between September 2004 and June 2007, 94 patients (median age, 48 yrs; range, 22 to 62) were enrolled. Distribution of cytogenetics was as follows: adverse, n=29 [abn(3q), −5/5q-, −7/7q-, abn(12p), abn(17p), complex]; other n=57 [core binding factor (n=3), cytogenetically normal AML (n=37), various aberrations (n=18)]. FLT3-ITD was present in 18 (22%) of 82 analyzed patients. Response to GO-A-HAM was as follows: CR, n=28 (30%); CRi, n=19 (20%); PR, n=11 (12%); refractory disease (RD), n= 34 (36%); and ED/HD, n=2 (2%). In a logistic regression analysis for achievement of CR, the only significant variable was adverse cytogenetics (OR 0.34, p=0.02). The rate of severe liver toxicity was 0%, the incidence of neutropenic fever was 52%, platelet and neutrophil recovery times from start of treatment were 21 and 22 days, respectively. Following GO-A-HAM, allogeneic SCT was actually performed in 60 patients (64%): matched related (n=14) or unrelated donor (n=42); haploidentical related donor, n=4. All SCT were performed within 3 months after GO-A-HAM, intermediate/severe VOD developed in 5 patients after SCT (9%, 95%-confidence interval (CI) 4–19%), mild VOD in 3 patients. Survival analyses revealed that patients with adverse cytogenetics and/or FLT3-ITD (n=45) had a significantly (p=0.001) inferior overall survival after one year of 38% compared to all other patients (n=39) of 81%. The proportions of patients receiving an allogeneic SCT were similar in both groups (68% and 66%, respectively).Conclusions: The GO-A-HAM regimen is feasible and effective as salvage therapy. However, cytogenetics still remains the most significant variable for achievement of response. Allogeneic SCT after GO-A-HAM was not associated with an increased VOD-rate.

THE PATHOLOGY, DIAGNOSIS, AND TREATMENT OF HEPATIC VENO‐OCCLUSIVE DISEASE: CURRENT STATUS AND NOVEL APPROACHES

THE PATHOLOGY, DIAGNOSIS, AND TREATMENT OF HEPATIC VENO‐OCCLUSIVE DISEASE: CURRENT STATUS AND NOVEL APPROACHES