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In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to “best non-HCT” therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy. [ABSTRACT FROM AUTHOR]

Cord blood transplant (CBT) extends allograft access but is associated with a significant risk for cytomegalovirus (CMV) infection. We analyzed CMV infection in 157 CBT recipients transplanted for hematological malignancies. As compared with antigenemia testing, routine polymerase chain reaction (PCR) monitoring was associated with increased and earlier CMV infection detection (1-year incidence if seropositive 67% [median onset 41 days] vs. 100% at an earlier 33-day median [ p < 0.001]) and decreased gastrointestinal disease. One-year CMV-related transplant-related mortality was 11% in CMV+ patients with 7/9 deaths associated with initial infection. Disease-free survival was lower in seropositive compared with seronegative patients (1-year: 55% vs. 73%, p = 0.02). However, in multivariate analysis adjusting for age, treatment failure risk in CMV+ patients was not significant (hazard ratio 1.52, p = 0.11). CMV infection is a major challenge in seropositive CBT recipients. While PCR surveillance permits early detection of viremia, new prophylaxis and therapeutic strategies are needed. [ABSTRACT FROM AUTHOR]

Summary. The small number of progenitor cells is the major limitation to the use of umbilical cord blood (UCB) for the transplantation of adults. We tested the hypothesis that two units transplanted simultaneously could each contribute to haematopoietic reconstitution. A patient with advanced acute lymphocytic leukaemia received a mismatched, unrelated UCB transplant using units from two donors after conditioning. The recipient achieved a complete remission without graft-versus-host disease. Double chimaerism was documented in several leucocyte subpopulations; both units contributed to haematopoiesis until relapse. Triple chimaerism was present from relapse until death due to leukaemia. This approach may potentially improve UCB transplantation outcome for adults lacking a histocompatible donor. [ABSTRACT FROM AUTHOR]

• Day 100 grade 2 to 3 acute kidney injury (AKI) incidence is high after adult cord blood transplantation. • Grade 1 to 2 AKI can be present with a normal creatinine. • A higher pretransplant serum albumin protects against AKI. • Critical illness and nephrotoxic drugs increase AKI risk. • Early post-transplant AKI increases 2-year chronic kidney disease risk. Although cord blood transplantation (CBT) extends allograft access, patient comorbidities, chemoradiation, and nephrotoxic medications all contribute to acute kidney injury (AKI) risk. We analyzed AKI in adult myeloablative CBT recipients who underwent transplantation from 2006 to 2017 for hematologic malignancies using cyclosporine A (CSA)/mycophenolate mofetil immunosuppression. Maximum grades of AKI were calculated using Kidney Disease: Improving Global Outcomes (grade 1, 1.5 to <2-fold; grade 2, 2 to <3-fold; or grade 3, ≥3-fold over baseline) definitions. In total, 153 patients (median 51 years [range, 23-65], 114/153 [75%] acute leukemia, 27/153 [18%] African, 88/153 [58%] cytomegalovirus seropositive, median age-adjusted hematopoietic cell comorbidity index 3 [range, 0-9], median pretransplant albumin 4.0 g/dL [range, 2.6-5.2]) underwent transplantation. The day 100 cumulative incidence of grade 1-3 AKI was 83% (95% confidence interval [CI], 77%-89%) (predominantly grade 2, median onset 40 days, range 0 to 96), and grade 2-3 AKI incidence was 54% (95% CI, 46%-62%) (median onset 43 days, range 0 to 96). Mean CSA level preceding AKI onset was high (360 ng/mL, target range 300-350). In multivariate analysis, African ancestry, addition of haploidentical CD34+ cells, low day –7 albumin, critical illness/intensive care admission, and nephrotoxic drug exposure (predominantly CSA and/or foscarnet) were associated with AKI. In a day 100 landmark analysis, 6% of patients with no prior AKI had chronic kidney disease (CKD) at 2 years versus 43% with prior grade 1 and 38% with prior grade 2-3 AKI (overall P =.02). Adult CBT recipients are at significant AKI risk, and AKI is associated with increased risk of CKD. Prevention strategies, early recognition, and prompt intervention are critical to mitigate kidney injury. [ABSTRACT FROM AUTHOR]

The availability of cord blood (CB) and haploidentical (haplo) donors in all patient populations is not established. We have investigated the addition of haplo-CD34 + cells to CB grafts (haplo-CBT) to speed myeloid engraftment. Thus, we have prospectively assessed CB and haplo donor availability in adult patients without 8/8 HLA-allele matched unrelated donors (URDs). Analysis of 89 patients eligible for haplo-CBT revealed 4 distinct patient groups. First, 6 patients (7% of total, 33% non-European) underwent CBT only as they had no suitable family members to type. In group 2, 49 patients (45% non-European) received haplo-CBT using the first haplo donor chosen. Group 3 (n = 21, 76% non-European) underwent CBT with/without haplo. In this group, the first haplo donor chosen failed clearance in 20 patients and transplantation was too urgent to permit donor evaluation in 1. Fifty-three haplo donors were evaluated (2 to 6 per patient) for 21 group 3 patients, and 43 of 53 (81%) haplos failed clearance for predominantly medical and/or psychosocial reasons. Group 4, (n = 13, 85% non-European with a high median weight of 96 kilograms) had no CB grafts with/without no haplo donors. Overall, African patients had the worst donor availability with only 65% having a suitable CB graft and only 44% having a suitable haplo donor. Additionally, in non-European patients, a greater number of haplos required evaluation/patient to secure a suitable haplo graft. Although these data should be confirmed in a larger study, it suggests that there are barriers to the availability of both CB and haplo grafts in adult patients without 8/8 URDs, especially in those with African ancestry, and has multiple practical implications for patient management. [ABSTRACT FROM AUTHOR]

Because cord blood (CB) lacks memory T and B cells and recent decreases in herd immunity to vaccine-preventable diseases in many developed countries have been documented, vaccine responses in CB transplantation (CBT) survivors are of great interest. We analyzed vaccine responses in double-unit CBT recipients transplanted for hematologic malignancies. In 103 vaccine-eligible patients, graft-versus-host disease (GVHD) most commonly precluded vaccination. Sixty-five patients (63%; engrafting units median HLA-allele match 5/8; range, 2 to 7/8) received protein conjugated vaccines, and 63 patients (median age, 34 years; range, .9 to 64) were evaluated for responses. Median vaccination time was 17 months (range, 7 to 45) post-CBT. GVHD (n = 42) and prior rituximab (n = 13) delayed vaccination. Responses to Prevnar 7 and/or 13 vaccines (serotypes 14, 19F, 23F) were seen in children and adults (60% versus 49%, P = .555). Responses to tetanus, diphtheria, pertussis, Haemophilus influenzae , and polio were observed in children (86% to 100%) and adults (53% to 89%) even if patients had prior GVHD or rituximab. CD4 + CD45RA + and CD19 + cell recovery significantly influenced tetanus and polio responses. In a smaller cohort responses were seen to measles (65%), mumps (50%), and rubella (100%) vaccines. No vaccine side effects were identified, and all vaccinated patients survived (median follow-up, 57 months). Although GVHD and rituximab can delay vaccination, CBT recipients (including adults and those with prior GVHD) have similar vaccine response rates to adult donor allograft recipients supporting vaccination in CBT recipients. [ABSTRACT FROM AUTHOR]

Double-unit cord blood (DCB) grafts are a rapidly available stem cell source for adults with high-risk leukemias. However, how disease-free survival (DFS) after DCB transplantation (DCBT) compares to that of unrelated donor transplantation (URDT) is not fully established. We analyzed 166 allograft recipients (66 8/8 HLA–matched URDT, 45 7/8 HLA–matched URDT, and 55 DCBT) ages 16 to 60 years with high-risk acute leukemia or chronic myelogenous leukemia (CML). URDT and DCBT recipients were similar except DCBT recipients were more likely to have lower weight and non-European ancestry and to receive intermediate-intensity conditioning. All URDT recipients received a CD34 + cell–selected (T cell–depleted) graft. Overall, differences between the 3-year transplantation-related mortality were not significant (8/8 URDT, 18%; 7/8 URDT, 39%; and DCBT, 24%; P = .108), whereas the 3-year relapse risk was decreased after DCBT (8/8 URDT, 23%; 7/8 URDT, 20%; and DCBT 9%, P = .037). Three-year DFS was 57% in 8/8 URDT, 41% in 7/8 URDT, and 68% in DCBT recipients ( P = .068), and the 3-year DFS in DCBT recipients was higher than that of 7/8 URDT recipients ( P = .021). In multivariate analysis in acute leukemia patients, factors adversely associated with DFS were female gender (hazard ratio [HR], 1.68; P = .031), diagnosis of acute lymphoblastic leukemia (HR, 2.09; P = .004), and 7/8 T cell–depleted URDT (HR, 1.91; P = .037). High DFS can be achieved in adults with acute leukemia and CML with low relapse rates after DCBT. Our findings support performing DCBT in adults in preference to HLA-mismatched T cell–depleted URDT and suggest DCBT is a readily available alternative to T cell–depleted 8/8 URDT, especially in patients requiring urgent transplantation. [ABSTRACT FROM AUTHOR]

Sustained hematopoiesis after double-unit cord blood transplantation (dCBT) is mediated by 1 unit in nearly all patients. To investigate the associations between nondominant unit characteristics and neutrophil engraftment, we studied 129 consecutive myeloablative dCBT recipients. Ninety-five percent (95% confidence interval, 90 to 98) of patients engrafted. Detection of the nondominant unit 21 to 28 days after dCBT was not associated with improved neutrophil engraftment. In univariate analyses, nondominant unit characteristics (infused total nucleated cell [TNC] and viable CD3 + cell doses) were significantly associated with speed and success of neutrophil engraftment as were dominant unit characteristics (infused TNC; viable CD34 + , viable CD3 + , and viable CD3-56 + 16 + cell doses; and post-thaw CD34 + cell viability). In multivariate analysis, higher infused TNC dose of the nondominant unit was independently associated with improved neutrophil engraftment, even when this unit did not contribute to donor hematopoiesis. In further subgroup analysis, this association was only evident when the infused viable CD34 + cell dose of the dominant unit was low (<1.20 × 10 5 /kg). These findings suggest nondominant units mediate a dose-dependent facilitation of engraftment in myeloablative dCBT and support continued investigation of dCBT biology and the clinical practice of dCBT in adults in whom low cell dose grafts are common. [ABSTRACT FROM AUTHOR]

Although mycophenolate mofetil (MMF) has replaced corticosteroids as immunosuppression in cord blood transplantation (CBT), optimal MMF dosing has yet to be established. We intensified MMF dosing from every 12 to every 8 hours to augment graft-versus-host disease (GVHD) prophylaxis in double-unit cord blood transplantation (dCBT) and evaluated outcomes according to the total daily MMF dose/kg in 174 dCBT recipients (median age, 39 years; range, 1 to 71) who underwent transplantation for hematologic malignancies. Recipients of an MMF dose ≤ the median (36 mg/kg/day) had an increased day 100 grade III and IV acute GVHD (aGVHD) incidence compared with patients who received >36 mg/kg/day (24% versus 8%, P = .008). Recipients of ≤ the median dose who had highly HLA allele (1 to 3 of 6) mismatched dominant units had the highest day 100 grade III and IV aGVHD incidence of 37% ( P = .009). This finding was confirmed in multivariate analysis ( P = .053). In 83 patients evaluated for mycophenolic acid (MPA) troughs, those with a mean week 1 and 2 trough < .5 μg/mL had an increased day 100 grade III and IV aGVHD of 26% versus 9% ( P = .063), and those who received a low total daily MMF dose and had a low mean week 1 and 2 MPA trough had a 40% incidence ( P = .008). Higher MMF dosing or MPA troughs had no impact on engraftment after myeloablation. This analysis supports intensified MMF dosing in milligram per kilogram per day and MPA trough level monitoring early after transplantation in dCBT recipients. [ABSTRACT FROM AUTHOR]

While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades ll-IV and lll-IV aGVHD and TRM. Day 180 grade lll-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [Cl], 18-43) vs 13% (95% Cl, 5-23) in patients with low levels (P = .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% Cl, 13-35) vs 5% (95% Cl, 1-13) if levels were low (P = .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating islet-derived protein 3-a were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT. [ABSTRACT FROM AUTHOR]

We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether thc3C could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34+ cell dose was the only characteristic independently associated with engraftment (hazard ratio, 1.43; P = .002). When postthaw characteristics were also included, only dominant unit infused viable CD34 cell dose independently predicted engraftment (hazard ratio, 1.95; P < .001). We then examined the determinants of infused viable CD34+ cell dose (precryopreservation count, postthaw recovery, and postthaw viability) in 402 units thawed at our center. This revealed close correlation between precryopreservation and postthaw CD34+ cell counts (r2 = 0.73). Median CD34+ cell recovery was 101%, although it ranged from 12% to 1480%. Notably, units from non-Netcord Foundation for the Accreditation of Cellular Therapy (Netcord-FACT)-accredited banks were more likely to have low recovery (P< .001). Furthermore, although median postthaw CD34+ cell viability was 92%, 33 (8%) units had <75% viable CD34+ cells. Units from non-Netcord-FACT-accredited banks and units with cryovolumes other than 24.5 to 26.0 mL were more likely to have poor postthaw viability. Precryopreservation CD34+ cell dose and banking practices should be incorporated into CB unit selection. [ABSTRACT FROM AUTHOR]

Abstract: Cord blood transplantation (CBT) is a known risk factor for human herpesvirus-6 (HHV-6) infection. We analyzed the nature of HHV-6 infections in 125 double-unit CBT recipients (median age, 42 years) transplanted for hematologic malignancies with calcineurin inhibitor/mycophenolate mofetil prophylaxis and no antithymocyte globulin. One hundred seventeen patients (94%) reactivated HHV-6 by quantitative plasma PCR (median peak, 7600 copies/mL; range, 100 to 160,000) at a median of 20 days (range, 10 to 59) after transplantation. HHV-6 encephalitis occurred in 2 patients (1.6%), of whom 1 died and 1 recovered with therapy. No association was found between high-level HHV-6 viremia (≥10,000 or ≥25,000 copies/mL) and age, diagnosis, conditioning intensity, or dominant unit characteristics or between high-level viremia and transplant outcomes (engraftment, cytomegalovirus reactivation, day 100 grades II to IV acute graft-versus-host disease, day 100 transplant-related mortality, or 1-year disease-free survival). HHV-6 therapy delayed the onset of cytomegalovirus reactivation. Interestingly, HHV-6 resolution was observed in untreated patients, and resolution of viremia correlated with absolute lymphocyte count recovery. We observed a low incidence of encephalitis and no association with CBT outcomes. Our data suggest therapy in uncomplicated viremia may not be warranted. However, further investigation of the risk-to-benefit of HHV-6 viremia treatment and standardization of PCR testing is required. [Copyright &y& Elsevier]

Abstract: The impact of human leukocyte antigen (HLA) donor-specific antibodies (DSA) on cord blood (CB) engraftment is controversial. We evaluated the influence of pre-existing HLA-antibodies (HLA-Abs) on engraftment in 82 double-unit CB recipients (median age, 48 years) who underwent transplantation for hematologic malignancies. Of 28 patients (34%) with HLA-Abs, 12 had DSA (median mean fluorescence intensity 5255; range, 1057 to 9453). DSA patients had acute leukemia (n = 11) or myelodysplasia (n = 1) and all received either high-dose or reduced-intensity (but myeloablative) conditioning. After myeloablative CB transplantation (CBT) (n = 67), sustained donor engraftment was observed in 95% without HLA-Abs (median, 23 days), 100% with nonspecific HLA-Abs (median, 23 days), and 92% with DSA (median, 31 days, P = .48). Of 6 patients with HLA-Abs to 1 unit, 3 engrafted with that unit and 3 with the other. Of 6 patients with HLA-Abs against both units, 1 had graft failure despite being 100% donor, and 5 engrafted with 1 unit. Successful donor engraftment is possible in patients with DSA after myeloablative double-unit CBT. Our data suggest potential deleterious effects of DSA can be abrogated in patients with hematologic malignancies. [Copyright &y& Elsevier]

Abstract: Washing cord blood (CB) grafts involves product manipulation and may result in cell loss. We investigated double-unit CB transplantation (CBT) using red blood cell (RBC)–depleted units diluted with albumin-dextran in patients with hematologic malignancies. One-hundred thirty-six patients (median age, 43 years; range, 4 to 71; median weight, 69 kilograms (kg); range, 24 to 111) underwent transplantation with a 4/6 to 6/6 HLA-matched graft. Patients ≤ 20 kg were excluded, as they only received washed units. Units were diluted a median of 8 fold to a median volume of 200 mL/unit. The median infused total nucleated cell doses were 2.7 (larger unit) and 2.0 (smaller unit) x 107/kg, respectively, and the median post-thaw recovery was 86%. Units were infused consecutively (median, 45 minutes/unit). While only 17 patients (13%) had no infusion reactions, reactions in the remaining 119 patients were almost exclusively mild-moderate (by CTCAE v4 criteria 12 grade 1, 43 grade 2, 63 grade 3) with only 1 patient (< 1%) having a severe (grade 4) reaction. Moreover, most were easily treated. Grade 2 to 3 hypertension was the most common in 101 (74%) patients. The cumulative incidence of sustained donor-derived neutrophil engraftment was high: 95% in myeloablative and 94% in nonmyeloablative CBT recipients. With appropriate supportive care, double-unit CBT with RBC-depleted grafts infused after albumin-dextran dilution is safe with high rates of engraftment in patients > 20 kg. [Copyright &y& Elsevier]

Abstract: A preparative regimen of reduced intensity that can reliably engraft cord blood (CB) and can be used as an alternative to either high-dose myeloablative or nonmyeloablative conditioning is needed. We evaluated double-unit CB transplantation in 30 patients (median age, 56 years; range, 18 to 69) with acute leukemia or myelodysplasia using a regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, and 400 cGy total body irradiation with cyclosporine-A/mycophenolate mofetil immunosuppression. Ninety-seven percent of patients engrafted at a median of 26 days (range, 13 to 43), and 93% of patients had recovered platelets by day 180. Grades II to IV acute graft-versus-host disease (GVHD) incidence was 67% at day 180, and chronic GVHD was 10% at 1 year. Transplant-related mortality was 20% at day 180, and relapse was 11% at 2 years. Overall, 2-year disease-free survival (DFS) was 60% at 2 years. A hierarchy in DFS was seen according to the Sorror comorbidity score: 11 patients (median age, 55 years) with a score of 1 had a 2-year DFS of 82% compared with 62% in 9 patients (median age, 51 years) with a score of 2 to 3 and 40% in 11 patients (median age, 58 years) with a score of 4 to 5 (P = .13). This reduced-intensity regimen combined with double-unit CB transplantation reliably facilitates sustained donor engraftment without antithymocyte globulin. Although other approaches are needed in patients with high comorbidity scores, this regimen is highly effective in patients ≥50 years old who are otherwise reasonably fit. It also represents a promising alternative to high-dose conditioning in younger patients. [Copyright &y& Elsevier]

The inability to obtain additional stem cells is a disadvantage of unrelated donor cord blood transplantation (CBT). Moreover, in the event of problems with unit shipment, compromised unit quality, thaw mishaps, or graft failure, the time to secure a back-up graft could be unacceptable. Emergent shipment of 1 to 2 back-up units that have been previously typed and reserved could overcome this limitation. However, the advantages of this approach are not established. Therefore, we present our use of back-up units over a 5.5-year period. Six of 121 CBT recipients (5%) required back-up unit infusion. Indications included shipment mishaps (n = 2), poor unit viability (n = 2), significant infusion reaction (n = 1), and graft failure (n = 1). Lack of back-up units would have caused transplantation delay or infusion of inferior-quality units. Five of the 6 patients achieved sustained donor engraftment. We demonstrate that back-up units are emergently required in a significant minority of patients, supporting the incorporation of at least 1 back-up unit in cord blood (CB) selection algorithms to enhance CBT safety. [ABSTRACT FROM AUTHOR]

Factors contributing to infection risk after cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. In the present study, we investigated the potential of double-unit CBT without ATG to reduce the risk of infection and evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients underwent CBT for hematologic malignancies; of these, 52 patients received myeloablative conditioning, and 20 received nonmyeloablative conditioning. The peak incidences of bacterial infections (32%), fungal infections (14%), and bacterial/fungal pneumonias (10%) occurred in the first 30 days posttransplantation. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days posttransplantation, affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections occurring before day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections occurring after day 120 (n = 5), along with all cases of Epstein-Barr virus viremia (n = 5) and adenoviral enteritis (n = 2), occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death, and 3 contributed to death. Patients exhibited steady immune recovery, achieving a median CD3+4+ T cell count >200 cells/μL by day 120 post-CBT, and no infection-related deaths occurred after day 120. Our results suggest that double-unit CBT without ATG is associated with prompt T cell recovery, and, unlike in CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD, and serious infections remain a challenge, especially in the setting of GVHD. New strategies are needed to further reduce infectious complications after CBT; these will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T cell depletion associated with ATG therapy. [Copyright &y& Elsevier]

Cord blood transplantation (CB-T) is increasingly used as a treatment alternative for hematologic malignancies. However, how CB-T compares to related (RD-T) and unrelated donor transplantation (URD-T) is not established. We compared survival of 75 double-unit CB-T, 108 RD-T, and 184 URD-T recipients who received transplants over the same period for the treatment of hematologic malignancies. Patients had similar ages and disease risk, and a similar percentage had acute leukemia. The incidence of day 180 transplant-related mortality (TRM) of 21% (95% confidence interval [CI]: 12-31) after CB-T was higher than that of RD-T recipients. However, this was compensated for by a low risk of TRM after day 180, and a relatively low incidence of relapse. Hence, the 2-year progression-free survival (PFS) of 55% (95% CI: 45-68) after CB-T was similar to that after RD-T or URD-T (P = .573). In multivariate analysis, donor source had no influence on PFS, with the only significant factors being recipient age and disease risk. In a subanalysis of 201 patients with acute leukemia, CB-T, RD-T, and URD-T recipients also had similar 2-year disease-free survival (P = .482). These data provide strong support for the further investigation of double-unit CB grafts as an alternative hematopoietic stem cell source. [ABSTRACT FROM AUTHOR]

Introduction While adult double unit CBT (dCBT) has disease-free survival comparable to that of HLA-matched adult donor allografts, frequent patient (pt) comorbidities combined with chemotherapy/TBI & cyclosporine-A (CSA) contribute to AKI risk. Using KDIGO criteria, we analyzed renal injury incidence & risk factors in adults undergoing dCBT. Methods Adult dCBT pts transplanted 2006-2016 for hematologic malignancies using Cy/ Flu/ Thio/ TBI 400 cGy & CSA (therapeutic range 250-450)/ MMF were analyzed. Using day 0 - 100 creatinines, maximum grade (gr.) AKI [gr. 1 (1.5 - < 2-fold baseline), gr. 2 (2 - < 3-fold baseline) or gr. 3 (> 3-fold baseline)] was calculated. If pts had multiple episodes, the highest grade was analyzed. The 2-yr CKD incidence (> 90 days of GFR < 60 & persisting until 2 years post-transplant) was calculated according to max. grade day 0-100 AKI. Results 153 pts [median 51 years (range 23-65), 114/153 (75%) acute leukemia, 27/153 (18%) African, 88/153 (58%) CMV seropositive] were transplanted. No patient had chronic kidney disease pre-dCBT; 32/153 (21%) had hypertension & 12/153 (8%) were diabetic. Median aaHCT-CI was 3 (range 0-9) with 92/153 (60%) pts having a score > 3. 34 (22%) pts had High-Very High rDRI diagnoses. Median pre-dCBT albumin was 4 (range 2.6 - 5.2). 96% of pts engrafted, 76% had grade II-IV acute GVHD by day 100 & 90% were alive & disease-free at day 100 (11 TRM, 3 relapse). 127 pts had AKI (45 gr. 1, 60 gr. 2, & 22 gr. 3) for a day 100 grade 1-3 AKI cumulative incidence of 83% (95%CI: 77-89) (median onset 40 days, range 0-96) & 54% (95%CI: 46-62) for gr. 2-3 AKI (median onset 43 days, range 0-96) (Figure 1). The mean of the 3-day mean CSA level preceding AKI onset was high at 360 ng/ml. African ancestry, CMV seropositivity & low day -7 albumin level & post-dCBT variables of ICU admission, nephrotoxic drug exposure & bacteremia were associated with gr. 1-3 AKI (Table 1A). In multivariate analysis, low day -7 albumin, ICU admission & nephrotoxic drugs were significant (Table 1B). With a median 40 months (range 12-125) survivor follow-up, 34/109 (31%) evaluable pts had CKD at 2-yrs with 1 pt requiring long-term dialysis. Grade 2-3 AKI prior to day 100 was associated with a higher likelihood of having CKD at 2-yrs: 38% vs 25% (Figure 2). Conclusion dCBT recipients are at significant risk for AKI which increases the likelihood of long-term CKD. Early recognition of impending AKI & prompt intervention is critical to mitigate severe kidney injury & long-term impairment. Prevention strategies include adequate hydration, tight CSA level control & substitution of non-nephrotoxic medications (e.g. Letermovir CMV prophylaxis instead of pre-emptive foscarnet, non-aminoglycosides antibiotics, azoles rather than amphotericin, PO cidofovir instead of IV). Investigation of novel GVHD prophylaxis that could permit lower CSA dosing & early AKI detection using biomarkers should also be investigated. [ABSTRACT FROM AUTHOR]

Introduction PES is common after dCBT. Manifestations have been described but severity & risk factors are not fully established. Methods We analyzed the incidence, manifestations, severity & risk factors of PES in adult dCBT recipients transplanted 8/2012-12/2017 for hematologic malignancies/ severe aplastic anemia with Cy 50/ Flu 150/ Thio 5-10/ TBI 400 & CSA/ MMF. Standard PES therapy was IV methylprednisolone (IV MP) 1 mg/kg/day x 3 days. Results 133 1st allograft dCBT recipients (median 49 years, range 21-65) were analyzed. Patients (pts) most commonly had acute leukemia (n = 98, 74%). The median TNC cell doses were 2.4 × 107/kg/unit (range 1.2-6.0). The median unit-recipient HLA-match was 5/8 (range 3-7); the median unit-unit HLA-match was 4/8 (range 0-8). 71 (53%) pts also received haploidentical CD34+ cells. 96% of pts engrafted with CB. Overall, 98 pts developed non-infectious sustained fevers ≥ 38.5°C consistent with PES for a cumulative incidence of 74% (95%CI: 65-80) by 21 days post-dCBT (Table). The median onset was 10 days (range 6-21) post-dCBT with a median temperature at onset of 38.9°C degrees (range 38-39.8). Nearly all (94, 95%) of PES pts required IV MP therapy. PES associated rash within the 1st 72 hrs only occurred in a minority of pts (incidence 24%; 95%CI: 17-32). Weight gain > 5% from the baseline 24 hrs prior to PES onset (incidence 18%; 95%CI: 12-25) was correlated with the development of hypoxia requiring oxygen (incidence 20%; 95%CI: 14-28). Incidence of PES associated renal impairment (gr 2-3 AKI) was low overall at 2% (95%CI: 0-8). No pt had hypotension. Concurrent bacteremias were treated in 2 pts but clinical manifestations/ therapy response was consistent with PES. Median time to MP therapy was 1 day (range 0-12). Therapy response was rapid (median 1 day, range 1-9). The median MP duration was 3 days (range 3-14). 7/94 (7%) PES pts [7/133, 5% of entire cohort) required ICU care; this correlated with delayed therapy [median MP start 4 days (range 0-5)]. 30 (32%) pts required a 2nd MP course. Addition of haploidentical cells was associated with a higher PES incidence & severity as measured by weight gain & hypoxia (Table). There was no association with age, disease (acute leukemia vs other), dominant unit-recipient or unit-unit HLA-match or total TNC infused dose (split at median). Conclusions PES is common after dCBT. It should be promptly treated with IV MP without waiting for results of infectious work-up as delay can be associated with severe capillary leak syndrome & multi-organ failure. The worse manifestations in haplo-dCBT recipients supports PES being mediated by GVG/ GVH reactions & an associated cytokine storm. This is highly relevant to CBT platforms that involve infusion of multiple donors including 3rd-party products. We are now investigating day -1 tocilizumab 8 mg/kg in dCBT recipients with the aim to abrogate PES & acute GVHD (Politikos et al , ASBMT 2019). [ABSTRACT FROM AUTHOR]

Background The less stringent CB HLA-match requirement extends allograft access. The extent to which HLA-mismatch can adversely affect CBT outcomes & the maximum permitted HLA-mismatch, however, are not established. Methods We analyzed TRM, relapse & PFS after cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI dCBT in adults with hematologic malignancies. Eligible patients (pts) were 1st allograft recipients ≤ 65 years transplanted 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection. Results 102 pts [51 (50%) non-European, median 50 years (range 21-65), median 80 kg (range 36-137), 71 acute leukemias & 17 CML/ MPD/ MDS (all ≤ 10% blasts pre-CBT), 14 NHLs] received double unit grafts. The majority of units [181 (89%)] were 4/6 matched. At high resolution the unit-recipient 8-allele HLA-match was a median of 5/8 (range 3-7). The median infused viable CD34+ dose was 1.3 × 105/kg/unit (range 0.2-8.6). 48 (47%) pts also received haplo-identical CD34+ cells as a myeloid bridge. 97% (95%CI 90-99) engrafted with CB. All pts had a dominant unit (1 early death excluded). Day 180 grade II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Day 180 TRM was 9% (95%CI 4-15) & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), 2-yr OS is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts [6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown] & relapse in 4 pts. By 2-yrs, engrafting unit-recipient HLA-allele match had no association with TRM or PFS (Figure). Analysis of the association between recipient/ graft variables & TRM/ relapse/ PFS are shown (Table). Pts < 50 yrs & those with aaHCT-CI 0-3 had low 2-yr TRM of 5% & 10%, respectively, whereas neither engrafting unit-recipient HLA-match nor CD34+ dose were associated with TRM. No variable was associated with relapse. The 66 pts with a low 0-3 aaHCT-CI had high 2-yr PFS of 82% (95%CI 73-92) whereas engrafting unit-recipient 8-allele HLA-match & CD34+ cell dose had no effect. In multivariate analysis, aaHCT-CI was associated with worse PFS [HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p = 0.01]; neither rDRI [HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p = 0.64] nor engrafting unit-recipient HLA-match [HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p = 0.09] were significant. Conclusions dCBT with mismatched units facilitates allograft access extension & has a high PFS. While further investigation of the CD34+ dose – HLA-mismatch interaction is required, this supports unit selection prioritizing quality & dose in adults to optimize engraftment. Finally, this data supports CBT in younger pts, those with low 0-3 aaHCT-CI, or high rDRI given the high 2-yr PFS in such pts. [ABSTRACT FROM AUTHOR]

Introduction Optimal CB unit selection incorporates TNC & CD34+ cell dose & 8-allele donor-recipient HLA-match. How graft characteristics for these parameters vary by patient (pt) race/ ethnicity, however, is unknown. Methods We analyzed cryopreserved TNC & CD34+ cell content, the cell dose incorporating pt weight, & HLA-match of infused & backup (reserved but not shipped) units by pt ancestry in CB transplant (CBT) recipients transplanted 7/2013-6/2018. Units were chosen based on banking practices, TNC & CD34+ dose & 4-6/6 & 8-allele HLA-match. Patient (pt) racial/ ethnic origins were prospectively obtained & grouped per Barker J. et al , BBMT 2010. Results The characteristics of 544 units chosen for 144 diverse CBT recipients by pt ancestry are shown ( Table 1 ). 286 units were infused (142 doubles, 2 singles) & pts had a total of 258 backup units (0-2/pt). The median TNC content of units for Europeans was higher than for Non-Europeans (216 vs 197, p = 0.002). Units for NW Europeans had the highest median TNC content with lowest in units for Africans & White Hispanics. Units chosen for Europeans also had a higher median CD34+ cell content than Non-Europeans (160 vs 132, p = 0.007). Units for NW Europeans had the highest & units for Africans the lowest median CD34+ content. Median TNC/kg was similar in units for European & Non-European pts (2.7 vs 2.5, p = 0.11) & differences between groups were not marked. However, there was a trend for units for Europeans having a higher median CD34+ dose than units for Non-Europeans (1.9 vs 1.7, p = 0.057) with disparity between groups. Although the median 8 allele HLA-match was 5/8 for units chosen for both European & Non-European pts, units identified for non-Europeans were more mismatched (p = 0.017). When the 286 transplanted units (considered the best) were analyzed, the median TNC & CD34+ contents of units were higher for Europeans than non-Europeans (232 vs 216, p = 0.022, & 181 vs 152, p = 0.009). As shown in Table 2 , while there were no overall differences in the median TNC & CD34+ doses of units for Europeans & non-Europeans, differences in cell content combined with differences in weights resulted in TNC & CD34+ dose disparities within ancestry groups. For example, NW Europeans (high weight, high CD34+ content) had the highest CD34+ doses; lower content in Asian pts was partially compensated for by low weight; African pts (high weight, low content) had the lowest doses. Finally, there was marked differences in HLA-match distribution by ancestry group: eg only 23% of units for NW Europeans were 3-4/8 vs 40% for S. Europeans, 46% for white Hispanics & 51% for Africans. Conclusions CB extends transplant access to minorities but differences in cellular content translates to many ancestry groups pts having access to only lower dosed units. There are also marked racial/ ethnic disparities in HLA-match. This data supports continued funding of banks to further increase the CB inventory. [ABSTRACT FROM AUTHOR]

Background While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery is frequent. Methods We investigated the addition of CD34+ selected haplo-identical PBSC to double unit CB grafts (haplo-dCBT) in patients (pts) undergoing ablative dCBT with the aim to provide a myeloid bridge prior to CB engraftment. ATG was not used due to its adverse effects on immune recovery & potential to increase relapse risk. Results 78 adult pts [median 48.5 years (range 21-68), median 82 kgs (range 48-138), 3 with prior allografts, 54 (69%) acute leukemias or 10 (13%) MDS/ MPN (all 4/8 haplo-recipient HLA-match & ≥ 3/8 winning unit-haplo HLA-match were associated with higher likelihood of bridging (Table 2). Haplo CD34+ dose & winning unit-haplo HLA-match remained significant in multivariate analysis. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs others [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388], optimal bridge pts had earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)]. Conclusions ATG-free haplo-dCBT can speed neutrophil recovery but this benefit is highly variable, and a successful myeloid bridge is not guaranteed due to early haplo rejection. For these reasons our data does not support pursuit of haplo-dCBT. It is likely that similar limitations will also apply to ATG-free single CB unit-haplo transplants. Our findings also have significance for strategies that combine unmanipulated CB with third-party or ex vivo expanded T-cell depleted products given higher CD34+ cell dose & better HLA-match to the unmanipulated CB unit could improve successful bridging. [ABSTRACT FROM AUTHOR]

Introduction Acute graft-versus-host disease (aGVHD) remains a substantial cause of morbidity and mortality after unmodified and ex-vivo CD34+ selected/T-cell depleted (TCD) allogeneic hematopoietic stem cell transplantation (alloHSCT). We identified a cluster of patients who developed severe cutaneous aGVHD and expressed MHC class I HLA-A*0101. Objective To investigate if HLA-A*0101 expression correlates with an increased risk of severe cutaneous aGVHD after alloHSCT. Methods We evaluated 831 patients who received unmodified or TCD allograft at a single institution between 03/2010 and 02/2017. Patients who received cord blood transplants or <8/8 HLA-matched grafts were excluded. For patients with cutaneous aGVHD, we assessed donor-recipient HLA-typing, time of onset, grade at onset, and highest overall grade of cutaneous aGVHD. Results HLA-A*0101 was expressed in 206 (25%) patients (98 TCD, 108 unmodified). These patients had similar demographics to those lacking HLA-A*0101 (Table). At day 180, patients expressing HLA-A*0101 had higher incidence of grade III-IV cutaneous aGVHD compared with patients lacking HLA-A*0101 expression in both the TCD (8% vs. 3%, p =0.027) and unmodified (11% vs. 4%, p =0.01) cohorts (Fig 1). In a multivariate cause-specific Cox model, the presence of HLA-A*0101 in the TCD alloHSCT cohort correlated with increased risk of grade III-IV cutaneous aGVHD [HR=2.79 (95% CI: 1.07-7.28), p =0.036] after adjusting for related status of donor. In the unmodified alloHSCT cohort, presence of HLA-A*0101 allele correlated with increased risk of grade III-IV cutaneous aGVHD [HR=2.68 (95% CI: 1.24-5.79), p = 0.012)] after adjusting for myeloablative v non-myeloablative conditioning and donor relationship status. There were no statistically significant differences in OS or TRM between HLA-A*0101 expressing vs non-expressing patients in the cohorts. Conclusions In this group, donor/recipient expression of HLA-A*0101 correlated with an increased incidence and severity of cutaneous aGVHD after TCD and unmodified alloHSCT. If confirmed in a larger cohort, these findings have potential practical implications in the development of prophylaxis or early therapeutic strategies targeting the skin in this high-risk population. [ABSTRACT FROM AUTHOR]

Background Adult dCBT recipients are at significant risk for aGVHD especially involving the GI tract. Investigation of augmented prophylaxis is indicated. Methods Based on adult donor allograft data (Kennedy et al, Lancet 2015; Drobyski et al Haematologica 2018), we are investigating the addition of a single dose of tocilizumab 8 mg/kg (cap 800mg) on day -1 to standard cyclosporine/ MMF starting day -3 in adult patients (pts) with hematologic malignancies undergoing intermediate intensity Cy 50/ Flu 150/ Thio 10/ TBI 400 dCBT. We report an interim analysis of the first 16 pts of a 27 pt phase II trial (NCT03434730). All pts received standard bacterial/ fungal prophylaxis & Letermovir if CMV seropositive. Results 16 pts [median 50 years (range 27-59), median 85 kg (range 59-125), 6 AML, 5 ALL, 2 MPAL, 2 MDS, 1 CML, median aaHCT-CI of 3 (range 0-6)] received double-unit CB grafts with a median CD34+ cell dose of 1.33 × 105/kg/unit (range 0.24-3.83) & median unit-recipient 8-allele HLA-match of 5/8 (range 3-6). Pt outcomes are shown (Table). All (100%) pts engrafted with a median neutrophil recovery of 26 days (range 19-40). 94% of pts engrafted platelets (median 44 days, range 32-59). All pts had single unit dominance (median day 28 blood winning unit chimerism 100% (range 58-100). Prior to engraftment, 11/16 (69%) had no neutropenic fever, 3/16 (19%) pts had fever with bacteremia, 1 pt (6%) had febrile neutropenia (duration 2 days) responding to antibiotics, & 1 pt (6%) had initial fever due to bacteremia followed by fever/ rash attributed to pre-engraftment syndrome (PES). An additional 2 pts developed rash without fever prior to engraftment attributed to PES. Thus, a total of 3/16 (19%) pts had PES (onset ranging 12-14 days). Ten pts developed grade II aGVHD (median onset 45 days, range 26-81) for a cumulative incidence of 63% (95%CI: 33-82). This was limited primarily to skin &/or the upper gut with one pt having stage I lower GI. No pt has developed grade III-IV aGVHD & no pt has had stage II-IV lower GI aGVHD to date (Figure). With a median follow-up of 147 days (range 74-214), 15 pts are alive & disease-free (1 death due to HHV-6 pneumonitis). Conclusions Preliminary data suggests tocilizumab is safe with no adverse effects upon engraftment or unit dominance. Tocilizumab mitigates PES (expected incidence 65% in dCBT controls, Bhatt et al, ASBMT 2019). Expected days of febrile neutropenia were also reduced especially given the prolonged neutrophil recovery. Notably, lower gut aGVHD appears markedly reduced with no cases of grade III-IV aGVHD or aGVHD mortality to date. Our findings appear consistent with the published adult donor data. Overall, one tocilizumab dose has improved the early post-dCBT morbidity & investigation of this promising & potentially cost-effective approach is ongoing. [ABSTRACT FROM AUTHOR]

Background Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (allo-HCT) patients (pts). Cumulative incidence of CMV infection in high-risk patients such as CD34-selected or haploidentical HCT have been reported as high as 61.8-84.5% and 53-81%, respectively. Letermovir (LTV) was approved in 11/2017 for prophylaxis (ppx) in CMV-seropositive recipients (R+) of allo-HCT. Since 12/2017, LTV ppx was implemented at our center for both primary and secondary ppx. We report our real-world experience. Methods Adult CMV R+ allo-HCT pts who initiated LTV as primary or secondary prophylaxis were identified between 1/1/2018 and 6/30/18. Cord blood transplants were excluded. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Pts were followed through 9/2018. Results 53 pts initiated LTV. 69.8% pts were at high risk for CMV reactivation and disease (primarily ex vivo T-cell depleted HCT [n = 18; 34%] or haploidentical T-replete HCT [n = 12; 22.6%]). Baseline characteristics are summarized in Table 1. 39 pts (73.5%) received LTV as primary ppx after HCT, with a median day of LTV initiation of D+7 (range D+7 D+40). At LTV initiation, 34 pts had an undetectable CMV DNA, and 4 had CMV <137 IU/mL. Clinically significant CMV infection requiring preemptive treatment occurred in 2 of 39 pts (5.1%). One patient was treated with valganciclovir (VGV) for persistent CMV < 137 IU/mL. LTV was then used as secondary ppx. A 2nd patient, developed persistently detectable CMV (<137 IU/mL) and breakthrough CMV viremia with a mutation in UL56 at site C325YLTV successfully treated with VGV. The median duration of primary LTV ppx was 116 days (54-221), with primary ppx continuing beyond 14 weeks post HCT in 29 pts. If LTV was discontinued the median additional follow-up was 40 days (0-154), without clinically significant CMV infection to date. An additional 15 pts* (26.4%) received LTV as secondary ppx after CMV pre-emptive therapy. The median duration of secondary LTV ppx was 127 days (18-270), with no reactivation. LTV was not discontinued due to toxicity or intolerance in any patient. CMV outcomes are summarized in figure 1. All-cause mortality for the 53 pts over the observational period was 11.3%. Conclusion Primary LTV ppx significantly reduced CMV reactivation, and high-risk patients may benefit from extended prophylaxis. In patients who received preemptive therapy for CMV, use of secondary ppx showed no recurrent CMV reactivation. LTV is well tolerated. Additional studies are needed to determine optimal ppx duration and to clarify role of secondary CMV ppx in high-risk allo-HCT. The future standard of care will likely include extended primary ppx and secondary ppx and result in decreased morbidity and mortality associated with CMV. [ABSTRACT FROM AUTHOR]

Background CMV seropositive CBT recipients have a high risk of CMV infection. Early pre-emptive therapy is required to avoid CMV disease but is associated with significant toxicities. Methods This analysis compares the day +100 incidence & severity of clinically significant CMV infection (viremia leading to pre-emptive treatment or disease) in CMV seropositive CBT adult patients (pts) who received letermovir prophylaxis transplanted 12/2017-6/2018 vs historic controls transplanted 3/2013-12/2017. Control pts received ganciclovir prophylaxis days -7 to -2 then standard dose acyclovir. Letermovir pts received standard dose acyclovir & started letermovir IV or PO on day +7 & continued beyond day +100. All pts received uniform intermediate intensity Cy 50 mg/kg / Flu 150 mg/m2/ Thio 5-10 mg/kg / TBI 400 cGy conditioning with CSA/ MMF. Pts were monitored by qPCR twice weekly from approximately day +14-60 & then 1-2 x/weekly days +60-100. Results 62 [median age 51 years (range 23-66), 46 leukemia, 7 MDS/ MPD, 9 NHL/ HL] historic control pts received double unit grafts with a median unit-recipient HLA-allele match of 5/8 (range 2-7). By day +100, 51 pts developed clinically significant CMV infection for a day +100 cumulative incidence of 82% (95%CI: 70-90). The median viremia onset was 34 days (range 5-74) & 5 pts developed CMV disease by day +100 (3 pulmonary, 2 GI). Initial therapy was with foscarnet in 28 pts & ganciclovir/ valganciclovir in 23. Clinically significant therapy toxicities (renal &/or myelosuppression) were observed in 38/51 (75%) pts (Table 1). By day +100, CMV caused or contributed to 3 pulmonary deaths. 10 pts [median age 48 years (range 24-59), 9 leukemia, 1 MDS/ MPD, median 5/8 (range 3-6) unit-recipient HLA-match] received letermovir prophylaxis (8 IV, 2 PO) (Table 2). All pts engrafted. The day +100 cumulative incidence of clinically significant CMV infection was 0% (p < 0.001 vs controls) (Figure). After letermovir was started, 3 pts had a brief low level CMV viremia that spontaneously resolved without CMV-specific therapy. Prophylaxis was well tolerated & there were no drug toxicities attributed to letermovir. By day +100, one letermovir pt died due to HHV-6 infection. Conclusions This analysis suggests letermovir prophylaxis is highly effective at mitigating CMV disease, CMV-related mortality, & the need for toxic CMV therapies. Moreover, it has been well tolerated in CBT recipients. While further detailed investigation in a larger population is required, this data is very promising & the extent of the benefit suggests that letermovir could be a cost-effective new standard of care in adult CBT. The duration of needed prophylaxis beyond day +100 in CBT recipients also requires investigation. [ABSTRACT FROM AUTHOR]

Anti-thymocyte globulin-free dCBT is associated with high rates of acute GVHD (aGVHD) especially involving the GI tract. Investigation of augmented aGVHD prophylaxis is indicated. We are investigating the addition of a single dose of tocilizumab 8 mg/kg (day -1) to CSA/ MMF (starting day -3) aGVHD prophylaxis in adult patients (pts) with hematologic malignancies undergoing dCBT with intermediate intensity Cy 50/ Flu 150/ Thio 10/ TBI 400 conditioning (NCT03434730). Outcomes of the first 26 patients (with survivor follow-up of at least 100 days) were analyzed & compared to 54 dCBT historic controls transplanted with identical conditioning & only CSA/ MMF. All patients received letermovir if CMV seropositive. 26 pts [median age 47 years (range 26-60), median weight 82 kg (range 59-125), 11 AML, 8 ALL, 2 MPAL, 3 MDS/ CML, 2 NHL, median age-adjusted HCT-CI 2.5 (range 0-6)] received dCB grafts with a median CD34+ cell dose of 1.5 × 105/kg/unit (range 0.23-5.94) & median unit-recipient 8-allele HLA-match of 5/8 (range 3-6). One patient had graft failure in the setting of low graft viability/ disseminated adenovirus & a second pt had early transplant-related mortality (TRM) with incomplete count recovery. The remaining 24 patients engrafted at a median of 24 days (range 18-40) for a cumulative incidence of 92% (95%CI:67-98). 88% (95%CI:59-97) of pts engrafted platelets at a median of 43 days (range 32-78). Of evaluable pts, 68% & 83% had 100% single-unit donor chimerism in the blood at days 30 & 100, respectively; single-unit dominance was observed in the remaining cases. Six of 26 pts (23%) developed pre-engraftment syndrome (PES) at a median of 12.5 days, & only 3 of these (12%) required systemic corticosteroids. Additionally, 16 pts (62%) had no neutropenic fever prior to engraftment. The day 100 cumulative incidence of grade II-III & grade III aGVHD was 62% (95%CI:39-78) & 4% (95%CI:<1-17), respectively (Figure). While 16 pts developed upper GI aGVHD, 6 had stage 0+ (stool volume < 500 cc) lower GI aGVHD & the incidence of more severe lower GI involvement was very low [stage 1 (n = 2), stage 3 (n = 1) & no stage 4]. With a median survivor follow-up of 314 days, 1-year overall survival (OS) is 77% (95%:61-98). Five of 26 patients have died to date (1 graft failure, 2 organ failure, 2 infection) with no GVHD-associated TRM. Comparison with historic controls (Table) showed tocilizumab-based dCBT is associated with similar engraftment, reduced PES, reduced severe aGVHD & similar OS to CSA/ MMF alone dCBT. Tocilizumab-based dCBT appears safe with reduced PES & grade III-IV aGVHD. While many pts developed upper GI aGVHD, the marked reduction in lower GI aGVHD supports preferential reduction of T-cell homing to the lower gut. Investigation of this approach including aGVHD treatment responses, immune recovery & correlative biomarker/ microbiota studies are ongoing. [ABSTRACT FROM AUTHOR]

Background Letermovir (LET) is approved for the prophylaxis of cytomegalovirus (CMV) in allogeneic hematopoietic cell transplantation (allo-HCT) patients. LET is a weak-moderate CYP3A4 inhibitor, which may impact calcineurin inhibitor (CNI) levels. In the phase 1 trial, LET caused an increase in maximum plasma concentrations (C max) of CSA and tacrolimus by 37% and 70%, respectively. There are no data to correlate how the C max increase in the presence of LET may affect CNI trough levels. Methods A retrospective review was conducted to evaluate the effect of LET on CNI trough levels and determine if empiric dose adjustments are needed. Patients ≥ 18 years were included if they received an allo-HCT with a CNI from February to June 2018 and received LET 480 mg daily or 240mg daily for tacrolimus- or CSA-based GVHD prophylaxis, respectively. The primary endpoint was percent change in concentration to dose (C/D) ratio over the 7-day period after initiation of LET. The C/D ratio allows for an analysis of the effect on trough levels at any given dose, which we would expect to rise upon initiation of LET due to CYP inhibition. LET reaches steady state in 36-60 hours; therefore, C/D percent changes were evaluated both from baseline to 4 days post-LET and from day 4 to day 7. Results Thirty-four patients (median age 53, range 24-75) were included in the analysis, with 24 (70.6%) patients receiving a tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and 10 (29.4%) patients receiving CSA-based GVHD prophylaxis. There were 8 (24%) umbilical cord blood transplants, 10 (29%) haploidentical HCTs, and 16 (47%) conventional HCTs, with 14 patients (41%) receiving myeloablative conditioning. LET was initiated on a median of day 7 (range 6-30) post-HCT, and 23 patients (68%) received the drug orally. In the 10 patients who received CSA, there was an average of 3.8 (range 1-6) dose changes over 7 days. From baseline to 4 days post-LET, the mean percent change in C/D ratio was +15.9%, with a subsequent -10.0% change in C/D ratio from day 4 to day 7. In the 24 patients who received tacrolimus, there was an average of 2.2 (range 0-5) dose changes over 7 days. From baseline to 4 days post-LET, the mean percent change in C/D ratio was +20.4%, with a subsequent -18.9% change in C/D ratio from day 4 to day 7. Days 0 to 7 trough levels for all patients are displayed in Figures 1 and 2. Conclusion An empiric dose reduction in CNIs upon initiation of LET does not appear to be warranted based on this pilot study. An increase in trough levels is seen within 4 days after initiation of LET; however, the increase seems marginal and is compensated for by adjusting doses based on levels, which is the standard of care. Larger studies are needed to assess additional factors that may affect this drug-drug interaction. [ABSTRACT FROM AUTHOR]