Increase In Non-relapse Mortality Research Articles

Allogeneic Stem Cell Transplantation for Relapsed and/or Refractory Hodgkin Lymphoma: A Multicenter Real World Experience

Allogeneic Stem Cell Transplantation for Relapsed and/or Refractory Hodgkin Lymphoma: A Multicenter Real World Experience Introduction Relapsed and/or refractory (R/R) Hodgkin Lymphoma (HL) after autologous stem cell transplant (SCT) is associated with poor outcomes and nearly 50% of patients will ultimately relapse. Novel therapeutic agents such as checkpoint inhibitors (CPIs) (nivolumab, pembrolizumab) and brentuximab vedotin (BV) have both shown considerable activity in this patient population, but allogeneic SCT (alloSCT) maintains its curative potential also in the era of new drugs. Herein we report on our multicenter experience with alloSCT for R/R HL. Methods Seventy patients with R/R classic HL who underwent alloSCT between 2004 and 2021 in three transplant centers were included. Patients were included between 2004-2010 (era1) in one centre, 2011-2021 (era2) in all centers. Disease response was evaluated according to Lugano classification. Primary end point was post transplant (tx) overall response rate (ORR). Secondary endpoints were overall survival (OS), progression free survival (PFS), non relapse mortality (NRM) and response rates according to parameters especially tx years, and pre/post tx CPIs and/or BV usage. Results Patient characteristics are summarized in the Table. Median follow up time after alloSCT was 64 months (range, 40.7-87.3). Post tx disease relapse or progression occurred in 23 patients (33%). The median time to disease relapse was 6.3 months (range, 1-24.5). Twenty nine patients were alive at the analytic date (41%); 23 in complete response (CR) (79%), 4 partial response (PR) (14%), 2 stabl disease (SD) (7%). The 3-year OS, PFS were 39% (95% CI 27.2-50.8) and 28% (95% CI 16.2-39.8), respectively; the day 100 and 1-year NRM rates were 26% (95% 16.2-35.8) and 37% (95% CI 25.2- 48.8), respectively. According to the tx year, the pre tx response rates were not statistically different between the two eras (p=0.46) but post tx CR rates were significantly higher in era2 (p=0.01). The survival (OS, PFS) analysis and NRM rates demonstrated no difference between both eras, but the PFS was significantly longer in 2016 and after (p=0.03). Patients who received alloSCT between era 1 and era 2 in one and only centre; the survival rates, and NRM were similar across the two eras. The patients with chemosensitive disease (CR, PR) at the time of alloSCT had more common pre tx BV usage (p=0.03), RIC conditioning regimen (p=0.002), and were with high HCT CI score (p=0.02), while the low proportion of ATG usage (p=0.02). Achievement of a CR at pre tx associated with better OS, PFS, and NRM. Patients in CR at the time of the post tx was associated with significantly improved OS and PFS (p<0.05). Patients who received BV and CPIs at any point pre and post tx had better OS, PFS and the NRM was low, but not statistically significant. There was a lower NRM rates in the post tx BV (p=0.06) and CPIs (p=0.08) usage. Regarding to post tx cyclophosphamide (cy) versus ATG usage; patients who received ATG had signicantly shorter OS (p=0.04), an increase in NRM (p=0.01), but similar PFS (p=0.28) compared with those who did not. Patients who received post tx cy had signicantly better OS (p=0.04) and PFS (p=0.05) but similar NRM (p=0.19) compared with those who did not. There was no statistically significant difference in OS, PFS and NRM with regard to the conditioning regimens (RIC and MAC) (p>0.05). Regarding donor type; the use of pre tx CPIs, TBI in conditioning regimen, and post cy were common for haploidentical (haplo) tx (p<0.05). ATG was used more commonly for matched/mismatched unrelated donor (MUD/MMUD) when compared with matched related donor (MRD) (p<0.001). The incidence of acute graft versus host disease (GVHD) (p=0.09) and chronic GVHD (p=0.002) were higher in patients who received MRD grafts when compared with MUD/MMUD and haplo. Haplo donors had significant better OS (p=0.015) and PFS (p=0.03) compared with MUD/MMUD and MRD. There was a significantly higher NRM in the MUD/MMUD compared with others (p<0.05). Conclusions Our results suggest that alloSCT continues to play an important therapeutic role for patients with R/R cHL. The improved outcomes of alloSCT in HL over time, probably due to general improvements in supportive care, a better selection of patients and the arrival of novel therapeutic therapies. The efficacy of alloSCT can be determined by multicenter prospective studies in selected patient groups.

Continuously Improving Outcome over Time after Second Allogeneic Stem Cell Transplantation in Relapsed Acute Myeloid Leukemia - a Retrospective Analysis of 1540 Patients on Behalf of the Acute Leukemia Working Party of EBMT

Second allogeneic stem cell transplantation (alloSCT2) is an increasingly used treatment for acute myeloid leukemia relapsing after first alloSCT. The scope of this study was to analyze trends in patient characteristics, transplant settings and outcome over time to identify factors associated with improved results after alloSCT2. In this retrospective registry-based analysis, 1540 patients receiving a second alloSCT after hematologic relapse between 2000 and 2019 were included, excluding alloSCT2 given for graft failure. Patients were grouped by period of transplant in 5-year intervals, median follow-up from alloSCT2 was 4.9 years. Over time, the number of patients reported to have received an alloSCT2 in EBMT centers increased from 144 in the period 2000-2004 to 619 in 2015-2019, with remarkable changes with respect to patient characteristic and transplant setting: In recent time periods, patients were of older age (median age 43.4 years between 2000-2004 and 48.6 years between 2015-2019, p=0.012) and had a better performance status before alloSCT2 (2000-2004: Karnofsky index ≥90% in 25.5% patients, 2015-2019: increase to 58.5%, p<0.001). Beyond, the interval between relapse after alloSCT1 and alloSCT2 increased from 2.5 to 3.5 months (p<0.001). In the more recent time periods, a different donor for second alloSCT and especially unrelated [increase from 30.6% (2000-2004) to 61.7% (2015-2019)] and haploidentical [increase from 0.7% (2000-2004) to 22.9% (2015-2019)] donors were used more frequently (p<0.0001 each). Finally, over time more myeloablative conditioning (MAC) (p=0.045), more in vivo T cell depletion (p<0.001), post-transplant cyclophosphamide (p<0.001) and ciclosporin A/MMF for graft versus host disease (GVHD) prophylaxis (p<0.001) were used in alloSCT2. Concerning clinical results after alloSCT2, cumulative relapse incidence (RI) after alloSCT2 decreased over time, whereas outcome improved (Figure 1). Between 2000 and 2019, two-year overall survival (OS) increased from 22.5% to 35%, leukemia free survival (LFS) increased from 14.5% to 24.5%. Whereas no clear trend was observed for incidence of GVHD and non-relapse mortality (NRM), RI decreased from 64% to 50.7%. In multivariate analysis, a later period of alloSCT2 was closely associated with improved OS and LFS (2015-2019: HR 0.47, p<0.001 for OS, HR 0.53, p=0.01 for LFS). Beyond, disease status at alloSCT2 had significant effects on OS, LFS, RI and NRM (HR for active disease at alloSCT2 1.59, p<0.001 for OS; HR 1.63, p<0.001 for LFS; HR 1.91, p<0.001 for RI; HR 1.35, p=0.04 for NRM). Similarly, longer remission duration after alloSCT1 was associated with better OS and LFS, lower RI and higher rates of NRM and acute GVHD (HR for lower remission duration 1.83, p<0.001 for OS; HR 1.72, p<0.001 for LFS; HR 1.86, p<0.001 for RI; HR 1.46, p=0.01 for NRM, HR 1.32, p=0.02 for acute GVHD). AlloSCT2 from haploidentical or unrelated donor, and older patient age were associated with higher NRM (HR 1.88, p=0.01 for haploidentical donor, HR 2.14, p<0.001 for unrelated donor, HR 1.1, p<0.001 for increasing age by 5-year intervals) and therefore inferior OS (HR 1.34, p=0.02 for haploidentical donor, HR 1.32, p=0.02 for unrelated donor, HR 1.05, p=0.002 for age). Further, MAC was associated with decreased RI without increase in NRM, leading to increased OS and LFS (HR 0.7, p<0.001 for RI, HR 1.1, p=0.47 for NRM, HR 0.82, p=0.02 for OS, HR 0.79, p=0.002 for LFS). LFS and OS were positively affected by a better Karnofsky index (HR 0.84, p=0.02 for LFS, HR 0.74, p<0.001 for OS). In vivo T-cell depletion was associated with lower NRM and lower rates of GVHD (HR 0.7, p=0.02 for NRM, HR 0.52, p<0.001 for acute GVHD II-IV, HR 0.64, p=0.003 for chronic GVHD). In conclusion, according to this large registry analysis on >1500 patients, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. In particular, decreased relapse incidence that did not come at cost of increased toxicity could be observed. This might be a result of better disease control and improved performance score at time of alloSCT2, as well as an increasing use of MAC, in vivo T-cell depletion and eventually post-transplant cyclophosphamide in alloSCT2 over time. These data encourage to perform alloSCT2 in relapsed AML and may help to define future strategies. Figure Legend Figure 1: Outcome after alloSCT2 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adult patients with Ph+ ALL benefit from conditioning regimen of medium-dose VP16 plus CY/TBI.

The medium-dose etoposide (VP16) added on cyclophosphamide (CY)/total body irradiation (TBI) is one of the intensified myeloablative conditioning regimens used in allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL). However, the patient subgroups who can actually benefit from VP16/CY/TBI compared to CY/TBI have not been precisely defined. Therefore, we conducted a multi-center retrospective study using the Japanese nationwide registry database to elucidate the efficacy of VP16/CY/TBI on post-transplant prognosis. Biological and clinical distinct subtypes (i.e., Philadelphia chromosome-positive (Ph+) and -negative (Ph-) ALL) were evaluated separately, which included 820 Ph+ and 1463 patients with Ph- ALL, respectively. Compared with the CY/TBI group, the VP16/CY/TBI group showed superior progression-free survival (PFS) in patients with Ph+ALL (65% vs. 57% at 3years after HSCT; adjusted hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.55-0.98; p=0.03), along with significantly reduced incidence of relapse (adjusted HR, 0.58; 95% CI, 0.37-0.90; p=0.02) without the increase of non-relapse mortality (NRM). By contrast, in patients with Ph- ALL, VP16/CY/TBI did not improve PFS nor incidence of relapse; addition of VP16 reduced relapse (HR, 0.65; p=0.06) in patients with Ph- ALL transplanted at CR1, while improved PFS was not observed (HR, 0.90; p=0.52) due to increased NRM. This study demonstrated that VP16/CY/TBI is a more effective and well-tolerated regimen in comparison with CY/TBI in patients with myeloablative allo-HSCT for adult Ph+ALL. Our findings can provide a novel algorithm for conditioning regimen selection in patients with adult ALL.

Real-world analysis of safety and efficacy of CAR T-cell therapy in patients with lymphoma with decreased renal function.

7536 Background: Chimeric antigen receptor T-cell therapy (CART) is approved for treatment of relapsed and refractory large B cell lymphoma (r/r LBCL), however eligibility for patients (pts) treated on clinical trials included normal kidney function (NKF). There is a gap in knowledge regarding the safety and efficacy of CART in pts with reduced kidney function (RKF), despite the prevalence of chronic kidney disease in lymphoma pts. Methods: This is a single-center retrospective analysis of adult pts with r/r LBCL who received CART between 2017-2021. RKF was defined as estimated glomerular filtration rate (GFR) of &lt; 60 ml/min and NKF defined as GFR ≥ 60 ml/min, at time of lymphodepletion chemotherapy (LDC). Increased length of ICU stay define as &gt; 3 days. Kaplan-Meier method used to estimate the time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: We identified 210 pts who received CART, of those 169 (80.5%) had NKF and 41(19.5%) had RKF (15-59 ml/min, 27% &lt; 45). Median age of pts was 60 and 63% of RKF pts were older than 60 vs 45% in NKF group (p = 0.03). Median Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score of pts with RKF was higher than NKF (3 vs. 1, P = 0.004). Pts with RKF had significantly longer ICU length of stay (29.3% vs. 13.6%; p = 0.01). There was no difference in grade 3 hematological toxicity (82.9% vs. 84.5%, p = 0.80) or infection within 30 days of CART (51.2% vs. 37.9%, p = 0.11) between RKF and NKF pts, respectively. CART specific toxicity including grade and frequency of cytokine release syndrome and neurotoxicity was also not related to renal function. After a median follow-up of 22.9 months (95% CI: 21.1-25.6 months), there was no significant difference in PFS and OS when comparing pts with RKF vs. NKF; PFS at 1 year of 31% (19-50%) vs. 33% (26-41%), p = 0.97, and OS at 1 year was 47% (34-67%) vs. 44% (37-57%), p = 0.45, and respectively. However, pts with RKF had a significant increase in non-relapse mortality (NRM) at 3 months (19.5% vs. 8.3%, p = 0.03), and at 6 months (22% vs. 9.5%, p = 0.02), respectively. Conclusions: In this retrospective single center study we observed reassuring durable remission rates in pts with r/r LBCL and RKF who received CART, without significantly different PFS or OS. Interestingly our analysis found that increased ICU length of stay and higher rates of NRM early after CART were associated with RKF. While our data shows RKF does not preclude pts from receiving CART for r/r LBCL, it does suggest that patients with RKF may need closer monitoring and multidisciplinary management.

Improved Therapeutic Approaches are Needed to Manage Graft-versus-Host Disease.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) offers a potentially curative therapy for patients suffering from diseases of the haematopoietic system but requires a high level of expertise and is both resource intensive and expensive. A frequent and life-threatening complication is graft-versus-host disease (GvHD). Acute GvHD (aGvHD) generally causes skin, gastrointestinal and liver symptoms, but chronic GvHD (cGvHD) has a different pathophysiology and may affect nearly every organ or tissue of the body. In Europe, GvHD prophylaxis is generally a calcineurin inhibitor in combination with methotrexate, with high-dose systemic steroids used for advanced GvHD treatment. Between 39% and 59% of alloHSCT patients will develop aGvHD and around 36–37% will develop cGvHD. Steroid response decreases with increasing disease severity, which in turn leads to an increase in non-relapse mortality. GvHD imposes a financial burden on healthcare systems, significantly increasing post-alloHSCT costs. Increased GvHD disease severity magnifies this. Balancing immunosuppression to control the GvHD whilst maintaining a degree of immunocompetence against infection is critical. European GvHD guidelines acknowledge the lack of evidence to support a standard second-line therapy, and improved long-term outcomes and quality-of-life (QoL) remain an unmet need. Evidence generation for potential treatments is challenging. Issues to overcome include choice of comparator (extensive off-label usage); blinding; selection of relevant patient-reported outcome measures (PROMs); and rarity of the condition, which may infeasibly increase timescales to achieve clinical and statistical relevance.

The Simplified Comorbidity Index: a new tool for prediction of nonrelapse mortality in allo-HCT

AbstractIndividual comorbidities have distinct contributions to nonrelapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT). We studied the impact of comorbidities individually and in combination in a single-center cohort of 573 adult patients who underwent CD34-selected allo-HCT following myeloablative conditioning. Pulmonary disease, moderate to severe hepatic comorbidity, cardiac disease of any type, and renal dysfunction were associated with increased NRM in multivariable Cox regression models. A Simplified Comorbidity Index (SCI) composed of the 4 comorbidities predictive of NRM, as well as age >60 years, stratified patients into 5 groups with a stepwise increase in NRM. NRM rates ranged from 11.4% to 49.9% by stratum, with adjusted hazard ratios of 1.84, 2.59, 3.57, and 5.38. The SCI was also applicable in an external cohort of 230 patients who underwent allo-HCT with unmanipulated grafts following intermediate-intensity conditioning. The area under the receiver operating characteristic curve (AUC) of the SCI for 1-year NRM was 70.3 and 72.0 over the development and external-validation cohorts, respectively; corresponding AUCs of the Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) were 61.7 and 65.7. In summary, a small set of comorbidities, aggregated into the SCI, is highly predictive of NRM. The new index stratifies patients into distinct risk groups, was validated in an external cohort, and provides higher discrimination than does the HCT-CI.

Planned Granulocyte Colony-Stimulating Factor Adversely Impacts Survival after Allogeneic Hematopoietic Cell Transplantation Performed with Thymoglobulin for Myeloid Malignancy

The in vivo depletion of recipient and donor T lymphocytes using antithymocyte globulin (ATG; Thymoglobulin) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce the incidence of both graft failure and graft-versus-host disease (GVHD). However, excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising antitumor effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lymphotoxicity. This study aimed to investigate the effect of an interaction between ATG and post-transplantation granulocyte colony-stimulating factor (G-CSF) on allogeneic HCT outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. We studied patients age ≥18 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who received Thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT between 2010 and 2018. The effect of planned G-CSF that was started between pretransplantation day 3 and post-transplantation day 12 was studied in comparison with transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes at 1 year after transplantation. A total of 874 patients met the study eligibility criteria, of whom 459 (53%) received planned G-CSF. HCT with planned G-CSF was associated with a significantly increased risk for nonrelapse mortality (NRM) (hazard ratio [HR] 2.03; P <.0001; 21% versus 12%) compared to HCT without G-CSF. The 6-month incidence of viral infection was higher with G-CSF (56% versus 47%; P=.007), with a particular increase in Epstein-Barr virus infections (19% versus 11%; P=.002). The observed higher NRM with planned G-CSF led to lower overall survival (HR, 1.52; P=.0005; 61% versus 72%). There was no difference in GVHD risk between the treatment groups. We performed 2 subgroup analyses showing that our findings held true in patients age ≥50 years and in centers where G-CSF was used in some, but not all, patients. In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplantation resulted in a 2-fold increase in NRM and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplantation period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks.

Elevation of Early Plasma Biomarkers in Patients with Clinical Risk Factors Predicts Increased Nonrelapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation

Early prediction of nonrelapse mortality (NRM) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) based on the results of laboratory tests is challenging. Thus, there is a need to evaluate biomarkers for prediction of NRM, a major problem that offsets the advantages of allo-HSCT. We tested the validity and efficacy of 2 plasma biomarkers, ST2 and Reg3α, based on the Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm, for early prediction of NRM in Japanese patients who underwent allo-HSCT. We conducted a multicenter retrospective study to analyze the clinical data of 112 patients with hematopoietic malignancies who underwent allo-HSCT. Patient blood samples on day 7 after allo-HSCT were obtained from 6 hospitals. The plasma concentrations of ST2 and Reg3α were used to calculate a 6-month NRM risk score. Based on the scores determined in this study, we identified 64 low-risk patients and 48 high-risk patients for the 6-month NRM. The cumulative incidence of 6-month NRM was 29.2% in the high-risk group and 10.9% in the low-risk group (P < .05). The cumulative incidence of relapse mortality was similar in the high-risk and low-risk patients. The biomarker score was predictive in patients with an unrelated donor, an HLA-mismatched donor, high/very high Disease Risk Index, and Hematopoietic Cell Transplantation Comorbidity Index ≥1. Multivariate analysis identified high biomarker probability as a significant predictor of NRM. The MAGIC algorithm based on blood samples obtained at 7 days after allo-HSCT can identify individuals at high risk for NRM among patients with clinical risk factors for NRM in a Japanese cohort.

Hb-adjusted DLCO with GLI reference predicts long-term survival after HSCT in children.

This study aimed to evaluate the pretransplant diffusing capacity as a predictor of outcomes in pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT). Retrospective cohort study of 176 children followed outcomes for 5 years after allo-HSCT. We conducted an analysis of PFTs include spirometry, body plethysmography, and diffusing capacity prior to allo-HSCT. We analyzed the probabilities of overall survival (OS), disease-related mortality (DRM), and non-relapse mortality (NRM). Of all carbon monoxide diffusing capacity (DLCO) parameters obtained using the Global Lung Function Initiative (GLI)-2017, univariate analysis showed that the grade 3, 4 of DLCOadj and Category III, IV of LFS significantly increase NRM (p = 0.003 and p = 0.008). Multivariate analysis indicated that a significant increase in the risk of NRM is associated with grades 3, 4 DLCOadj (hazard ratio [HR] = 4.90, p = 0.020). Kaplan-Meier analyses showed that a significant stepwise increase in NRM was observed with both worse pretransplant DLCOadj grades and LFS categories (p < 0.001 and p = 0.003). A compromised pretransplant diffusing capacity and a high LFS significantly increase the risk of NRM. Especially, DLCOadj before transplantation can be used as an important predictor of NRM after allo-HSCT in children with malignancy.

Favorable Outcomes after Single Cord Blood Transplantation for Patients with High-Risk Hematologic Diseases: A Single-Institute Retrospective Analysis

The donor selection algorithm for cord blood (CB) with regards to matched related and unrelated donors has not been fully investigated. To assess the potential of CB transplantation (CBT) in patients with hematologic malignancies, especially for high-risk patients, we performed a single-institute retrospective analysis and compared the clinical outcomes of CBT with those of HLA-matched sibling and unrelated donor transplantation. We included 394 patients aged 16 years and older with hematologic diseases who received their first allogeneic hematopoietic cell transplantation between 1990 and 2018 at Kyoto University Hospital. These included 394 recipients of single unrelated cord blood units (UCB, n=108), HLA-matched sibling donors (MSDs, n=143), or HLA-matched unrelated donors (MUDs, n=143). There was no significant difference in relapse-free survival (RFS) between UCB, MSD, and MUD recipients (P=.975). However, we found a significant interaction between transplant year and CBT outcomes (P=.010), with significantly better outcomes observed in the more recent years. Furthermore, we found that CBT showed better RFS than matched donor transplantation (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30 to 0.84). This impact was more prominent in high-risk patients (HR, 0.35; 95% CI, 0.16 to 0.77), with lower relapse rates (HR, 0.25; 95% CI, 0.11 to 0.54), and comparable non-relapse mortality (NRM) compared to matched donor transplantation. Extensive chronic graft-versus-host disease was less frequently observed in CBT (HR, 0.58; 95% CI, 0.26 to 1.28). CBT associated with favorable outcomes, particularly in high-risk patients, with good RFS and low relapse rates without an increase in NRM in the single-institute study. Although the findings should be externally validated, CBT might serve as a reasonable donor choice, particularly in high-risk patients.

Fractionated busulfan myeloablative conditioning improves survival in older patients with acute myeloid leukemia and myelodysplastic syndrome.

A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown. Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival. Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01). A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.

Cytomegalovirus (CMV) management in allogeneic hematopoietic cell transplantation: Pre-transplant predictors of survival, reactivation, and spontaneous clearance.

Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplant (alloHCT). We analyzed 159 alloHCT recipients with 4409 quantitative CMV viral loads to determine pre-transplant predictors of CMV reactivation, clinically significant CMV infection (cs-CMVi, defined as CMV viral load >1000IU/mL), CMV disease, kinetics of spontaneous clearance of CMV, and survival using a standardized pre-emptive therapy approach to identify at-risk groups to target prevention strategies. Cs-CMVi was most common in D-/R+ unrelated donor transplants (URD). Spontaneous CMV clearance occurred in 26% of patients who reached a viral load of 56-137IU/mL, 6% at 138-250IU/mL and in one patient >250IU/mL. Median time between the first CMV reactivation (>56IU/mL) and a viral load >250IU/mL was 13days, whereas the time from the first viral load >250IU/mL to reach a vial load >1000IU/mL was 4days. Cs-CMVi was associated with a significant increase in non-relapse mortality (NRM) on multivariate analysis. Overall, this study indicates that D-/R+ URD recipients are at high-risk for cs-CMVi- and CMV-related mortality, and are potential candidates for targeted CMV prophylaxis. Spontaneous clearance of CMV beyond a viral load of 250IU/mL is uncommon, suggesting that this could be used as an appropriate threshold to initiate pre-emptive therapy.

Comparison of Outcomes of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Older Versus Younger Patients

Introduction: Previous studies have demonstrated that allogeneic haploidentical (haplo) peripheral blood stem cell transplantation (PBSCT) with post-transplant cyclophosphamide (PTCy) yields improved progression free survival (PFS) when compared to haplo bone marrow transplant (BMT) with PTCy, attributable to lower relapse without an increase in non-relapse mortality (NRM) (Bashey, et al. JCO. 2017). However, haplo PBSCT results in higher rates of graft-versus-host disease (GVHD) which may negate these benefits in older patients who are more susceptible to transplant related toxicity. Thus, evaluation of the outcomes of haplo PBSCT with PTCy in older patients is warranted. Methods: We retrospectively evaluated 121 adult patients with hematologic malignancies treated at the Moffitt Cancer Center with allogeneic T-cell replete PBSCT from a haplo donor followed by PTCy-based GVHD prophylaxis. Data were extracted from the Moffitt BMT Research &amp; Analysis Information Network (BRAIN) database. Myeloablative (n=70, 58%) and reduced intensity (n=51, 42%) conditioning regimens were included. Transplant related outcomes were compared between two age groups: &amp;lt;60 years (n=66) versus &amp;gt;60 years (n=55). Associations with transplant related survival outcomes were assessed using univariate and multivariate Cox proportional hazard survival models. Fine and Gray regression models were used to assess associations of transplant related endpoints with competing risks. Kaplan-Meier curves and cumulative incidence function curves were also plotted. Results: The median age at the time of transplant was 42 years (range: 20-59) for the younger group and 66 years (range: 61-75) for the older group. The median follow-up was 17 months (range: 2-53) for the entire cohort. Younger patients were more likely to receive myeloablative conditioning (83% versus 27%, p&amp;lt;0.001). Baseline characteristics were otherwise similar. Neutrophil engraftment (&amp;gt;500/uL) by day 30 did not differ significantly between the younger and older group (98% versus 93%, p=0.26). However, the median time to neutrophil engraftment was faster in the younger group versus the older group (16 versus 21 days, p&amp;lt;0.001). Platelet engraftment (&amp;gt;20,000/uL) by day 90 was achieved in 92% in the younger group versus 76% in the older group (p=0.03). The time to platelet engraftment was faster in the younger group: 28 days versus 36 days (p=0.006). At day 100, the cumulative incidence (CuI) of grade II-IV acute GVHD in younger patients was 42% (95% CI 29-61%) and for older patients was 35% (95% CI 22-55%, p=0.82). The CuI for grade III-IV acute GVHD for the younger and the older groups were 8% (95% CI 4-25%) and 15% (95% CI 7-38%, p=0.23), respectively. At 2 years, the CuI of chronic GVHD was 67% (95% CI 55-82%) for younger patients versus 56% (95% CI 38-82%) for older patients (p=0.20). NRM for the younger group and the older group, respectively, was 6% (95% CI 2-16%) versus 19% (95% CI 11-34%) at 100 days and 14% (95% CI 6-30%) versus 22% (95% CI 13-37%) at 2 years (p=0.17). The CuI of relapse at 2 years was not significantly different between the two age groups, with the younger recipients having a CuI of 42% (95% CI 20-60%) and the older group 31% (95% CI 17-56%, p=0.70). The 2-year DFS was similar between the younger and older group, respectively: 51% (95% CI 36-66%) and 53% (95% CI 37-70%, p=0.72). Similarly 2-year overall survival (OS) for the younger group was 59% (95% CI 44-74%), while the older group was 66% (95% CI 52-80%, p=0.92). In multivariate analysis, NRM was superior in the younger group (HR=0.31, 95% 0.12-0.82, p=0.02). Otherwise, age was not associated with engraftment, risk of acute or chronic GVHD, relapse, DFS, or OS. Conclusion: Our results demonstrate that outcomes following allogeneic haplo PBSCT with PTCy in patients &amp;gt;60 years approximate outcomes in patients &amp;lt;60 years. While NRM was inferior in the older patient group, this difference did not result in significant differences in long term OS or DFS. Instead, other variables such as the hematopoietic comorbidity index and the disease risk index were better indicators of survival outcomes. Additionally, these survival outcomes with haplo PBSCT with PTCy appear to be similar to prior published data with haplo BMT with PTCy in older patients (Kasamon, et al. JCO. 2015). Based on this study, haplo PBSCT with PTCy is an appropriate transplant platform for elderly patients. Disclosures Khimani: Bristol Myers Squibb-Moffitt-Alliance: Research Funding. Nishihori:Novartis: Other: Research support to institution; Karyopharm: Other: Research support to institution. Pidala:Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

Significant EBV Reactivation Is Associated with Poorer Overall Survival Due to Increased NRM Post Myeloablative/Reduced Intensity, T-Cell Deplete Allogeneic Stem Cell Transplant for MDS or Acute Leukaemia

Introduction EBV reactivation post allogeneic stem cell transplantation (alloSCT) occurs due to profound suppression of T-cell number or function and subsequent reactivation of latent host or recipient EBV infection through loss of immune-surveillance. The relationship of EBV reactivation to patient outcomes has not been reported in patients who have received T-cell depletion (TCD) with Thymoglobulin. This analysis assessed the outcomes in patients who had previously received an alloSCT with TCD using Thymoglobulin and who developed EBV reactivation that either required treatment (EBV Treatment) vs those who did not require treatment (EBV No Treatment) vs those who had no evidence of EBV reactivation (No EBV). Methods This was a retrospective review of all patients who received TCD with Thymoglobulin prior to alloSCT at the Royal Melbourne Hospital between 2006-2017. Eligible patients received reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) for acute leukemia (AL) or myelodysplastic syndrome (MDS). EBV was monitored weekly via semi-quantitative PCR . Preemptive rituximab was given based on peak viral loads, rate of rise in viral loads or biopsy proven post-transplant lymphoproliferative disorder (PTLD). Categorical and continuous baseline characteristics of the cohorts were compared using chi-squared and Kruskal-Wallis tests respectively. EBV Treatment was treated as a time-dependent variable and evaluated for its relationship to overall survival (OS) using Cox proportional modelling, adjusted for age and high or very high Disease Risk Index (DRI) and grade III-IV acute GVHD. Survival estimates were performed by Kaplan-Meier product-limit method. Cumulative incidence (CI) of relapse and non-relapse mortality (NRM) were calculated by the Fine-Gray method. Results Of 165 eligible patients, 101 (61%) had an episode of EBV reactivation at a median of 46 days post-transplant (range 10-221 days). 24 received therapy for EBV. Of these, 4 had biopsy-proven PTLD, and 23 received rituximab alone with 1 receiving R-CHOP for PTLD. An undetectable EBV viral load was achieved in 20 out of 24. The baseline characteristics of the subgroups are presented in Table 1. The median survival of the whole cohort was 79 months with an estimated 2-year OS of 60% (95%CI 56-68) and a median follow up of time of 81 months in survivors. The median survival of the EBV Treatment group was 14 months, compared with 121 months and 81.1 months in the EBV No Treatment and No EBV cohorts respectively (Figure 1). Table 2 lists causes of death per group with relapse and complications of poor graft function (PGF) being the leading causes of death in the EBV Treatment group. The incidence of grade III-IV acute GVHD at 100 days was similar between groups as was the incidence of any chronic GVHD at 6 and 12 months. EBV Treatment was significantly associated with poorer OS even when adjusting for age, high/very high DRI and presence of acute GVHD (HR 2.47 CI 1.46-4.17; p=0.0007). The EBV Treatment group had a significantly higher 2 year CI of NRM compared to the EBV Treatment and No EBV groups (38% vs 11% vs 18% p=0.006) but similar incidence of relapse (Figure 2) . Conclusion In this cohort of AL/MDS patients undergoing TCD alloSCT, those who required treatment for EBV reactivation experienced poorer survival due to increased NRM. This increase in NRM may reflect impaired immune reconstitution of which significant EBV reactivation is a manifestation. Further studies to understand the underlying immune defects post alloSCT that predispose patients to significant EBV reactivation and associated complications is warranted to identify immune recovery strategies that may be employed in this poor prognosis group. Disclosures No relevant conflicts of interest to declare.

Class II HLA mismatch improves outcomes following haploidentical transplantation with posttransplant cyclophosphamide

AbstractHLA disparity is the major predictor of outcome following unrelated donor (UD) transplantation, where a single mismatch (mm) at the HLA-A, HLA-B, HLA-C, or HLA-DRB1 locus leads to increased mortality, and mismatching at multiple loci compounds this effect. In contrast, HLA disparity has not been shown to increase mortality in the context of haploidentical transplant using posttransplant cyclophosphamide (PTCy). To better define the consequences of loci-specific HLA mm, we analyzed 208 consecutive patients undergoing haploidentical transplantation for hematologic malignancy using PTCy at our institution (median age, 52 years [range, 19-75 years]; peripheral blood stem cell, 66%; reduced-intensity conditioning, 59%). Median follow-up was 65.4 months (range, 34.3-157.2 months). In univariate analysis, a single class II HLA mm at HLA-DR, HLA-DQ or a nonpermissive (np) HLA-DP mm had a protective effect on disease-free and overall survival (OS), primarily a result of reduced relapse risk. Furthermore, this survival effect was cumulative, so that patients with 3 class II mm (HLA-DR, HLA-DQ, and np HLA-DP) had the best OS. In multivariate analysis, HLA-DR mm and np HLA-DP mm were both independently associated with improved OS (hazard ratio [HR], 0.43; P =.001; and HR, 0.47; P =.011, respectively). In contrast, single or multiple mm at HLA-A, HLA-B, or HLA-C loci had no effect on acute graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, or survival, although the presence of an HLA-A mm was associated with increased chronic GVHD incidence. The association of class II mm with lower relapse occurred without a corresponding increase in NRM or acute or chronic GVHD. These findings will require validation in larger registry studies.

Impact of patient: donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT.

Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.

Chains of Iron in Umbilical Cord Blood Hematopoietic Stem Cell Transplantation: Comment on "Iron Overload Is Associated with Delayed Engraftment and Increased Nonrelapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation" by Al Malki et al, 2020.

Abstract Comment on “Iron Overload is Associated with Delayed Engraftment and Increased Non-Relapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation” by Al Malki et al. 2020

Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes.

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2×108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98×103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P=.009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

Iron Overload Is Associated with Delayed Engraftment and Increased Nonrelapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation.

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR)=2.26 (95% CI, 1.28 to 4.00, P=.005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR=2.18 (95% CI, 1.10 to 4.31, P=.025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR=0.58 (95% CI, 0.35 to 0.96, P=.034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR=0.48 (95% CI, 0.23 to 0.98, P=.044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.

Clinical outcomes of persistent colonization with multidrug-resistant Gram-negative rods in adult patients undergoing single cord blood transplantation.

Severe bacterial infections are a serious problem after cord blood transplantation (CBT). Colonization with multidrug-resistant Gram-negative rods (MRGNR) is associated with increased morbidity and mortality after allogeneic hematopoietic cell transplantation. However, its impact on outcomes after CBT is unclear. We aim to explore the impact of colonization with MRGNRs in adult patients undergoing CBT. We retrospectively analyzed 145 adult patients who received single-unit CBT in our institute. As a standard practice in our institute, all patients were screened for colonization with MRGNR by oral cavity swabs, urine, and stool specimens between the day of admission for CBT and the day of discharge or day 100 after CBT. There were 62 incidents of colonization with MRGNR in 52 patients, of which 25 involved Stenotrophomonas maltophilia, 19 multidrug-resistant Pseudomonas spp., and 18 extended-spectrum beta-lactamase-producing Enterobacteriaceae. On multivariate analysis, MRGNR persistence significantly affected increase in non-relapse mortality (NRM) (hazard ratio [HR], 8.96; 95% CI 1.85-43.46; P = 0.006) and the subsequent development of bloodstream infection due to MRGNR (HR 11.82; 95% CI 2.15-64.87; P = 0.004), but not MRGNR clearance, compared with non-colonized patients. These data suggest that persistent colonization with MRGNR is significantly associated with higher NRM in CBT for adults.