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Inflammatory cytokines released by activated lymphocytes and innate cells in the context of cellular therapy can cause fever, vasodilatation and end organ damage, so-called cytokine release syndrome (CRS). CRS can occur after allogeneic blood or marrow transplantation, but especially after HLA-haploidentical (haplo) peripheral blood transplantation (PBT). We reviewed charts of all patients who underwent haplo PBT between October 1, 2013 and September 1, 2017 and graded CRS. A total of 146 consecutive related haplo PBTs were analyzed. CRS occurred in 130 (89%) of the patients, but most was of mild (Grades 0–2) severity. Severe CRS (Grades 3–5) occurred in 25 patients (17% of PB haploPBT). In this group with severe CRS, 13 had encephalopathy; 12 required hemodialysis, and 11 were intubated. Death from the immediate complications of CRS occurred in 6 patients (24% of the severe CRS group and 4% of the entire haplo PBT cohort). The cumulative probability of non-relapse mortality (NRM) for patients with severe CRS was 38% at 6 months; it was 8% in the 121 out of 146 patients without severe CRS. In conclusion, CRS occurs in nearly 90% of haploidentical peripheral blood stem cell transplants. Older recipients (OR 2.4, 95% CI 0.83–6.75, p=0.11) of haploidentical PBT and those with a history of XRT (OR=3.85, 95% CI 1.32–11.24, p=0.01) have a higher risk of developing severe CRS. Most recipients of haplo PBT develop CRS, but less than 20% experience severe complications. The development of severe CRS significantly increases NRM.

Background & Methods Post-transplantation cyclophosphamide (PTCy)-based HCT has been associated with an increased frequency of hemorrhagic cystitis (HC), dominantly associated with BK viruria. We prospectively evaluated the incidence of BK viruria and HC in 115 patients [(median age 20 years, 2-65), malignant(87) and non-malignant(28)], undergoing PTCy-based haploidentical HCT with CTLA4Ig (n=71) or without (n=44). Conditioning was predominantly myeloablative (74%). As prophylaxis for HC, continuous infusion of Mesna was used from 30 minutes prior to PTCy at 50% of the daily dose of Cy every 8 hourly for 72 hours. Development of HC before day+15 was termed as ‘early HC’ and later was referred to as ‘HC’. Results The overall incidence of BK viruria was 65.7%. None with BK viruria Overall BK viruria was significantly lower in those receiving CTLA4Ig (54.1% vs 89.4% in those without CTLA4Ig, p=0.001, Figure 2A). The incidences of both high BK viruria (4.3% with vs 11.9% without CTLA4Ig, p=0.08) and HC (2.9% with vs 9.5% without CTLA4Ig p=0.09, Figure 2B) tended to be lower in those receiving CTLA4Ig-based protocols. A higher NRM was observed in those with BK viruria ≥ 104 copies/ml, related to GVHD and its complications (41.7% vs 12.6%, p=0.04). Conclusions In conclusion, our study demonstrates that extended infusion of Mesna, along with reduction in alloreactivity with the use of CTLA4Ig were probably responsible for a much lower incidence of BK viruria and resultant HC, than previously reported following PTCy-based haploidentical HCT.

Background Colonization with CRGNB and the duration of neutropenia are the strongest risk factors for further bacteremia and extremely high mortality (mjhid 2018). Methods We studied the outcome of 102 patients (age 2-65 years), colonized with CRGNB undergoing a PTCy based Haploidentical HSCT. All patients underwent surveillance for CRGNB colonization with weekly rectal swabs. The initial 33 patients received only antimicrobials directed towards CRGNB at the onset of neutropenic fever (non-PGI group). The subsequent 69 patients received infusion of apheresed granulocytes from within the first 48 hours of neutropenic fever (PGI-group). The infusions were continued daily until engraftment. Results All patients (83-malignant, 19-non-malignant) developed neutropenic fever at a median of 9 days (range -2 to 12). Both the groups were comparable in terms of patients and donor characteristics. The median time to neutrophil engraftment was 15 days (range 9-20) and was similar for both groups. The median dose of granulocytes infused was 5 × 1010 (range,1-30) granulocytes/infusion and median number of granulocyte infusion was 2 (range,1-7). The median increment in ANC 24 hours following PGI was 0.2 × 109/ml (range 0.1-0.9). The overall incidence of CRGNB bacteremia was 21.2% in non-PGI group (7/33) and 17.5% (12/69), in the PGI group (p = 0.8). The median time to CRGNB bacteremia was 16 days (12-92 days) in the non-PGI group and 12 days (range, 9-15) in the PGI group. However, the CRGNB related mortality was 100% (7/7) in non-PGI group vs 16.6% (2/12) in the PGI group (p = 0.001, Fig 1). All deaths were attributed to CRGNB which were responsible for colonization. The median time from onset of CRGNB bacteremia to death was 4 days (range 1-9). Two- year non-relapse mortality (NRM) was 28.1% (9/33) in the non-PGI group and 6% (4/69) in the PGI group (p = 0.002, Fig 2). CRGNB was the major cause for NRM in the non-PGI group (7/9) compared to 2/4 in the PGI group. The day 100 NRM was significantly higher in the non-PGI group (18.9 vs 2.9 in PGI group, p = 0.007). The overall survival at 2 years was 75.6% in the PGI group vs 21.2% in the non-PGI group (p = 0.0001) which was attributable to both reduction in CRE related deaths and reduction in disease progression with no increase in alloreactivity with our current protocols. Conclusions CRGNB colonization in patients undergoing HSCT is associated with very high mortality. We have demonstrated that pre-emptive granulocyte infusion can markedly reduce early mortality associated with CRGNB in the colonized patients undergoing PTCy based Haploidentical HSCT.

Topic Significance & Study Purpose/Background/Rationale Long term maintenance of Hickman catheter [HC] following allogeneic transplantation is a nursing challenge particularly in those colonized with Methicillin Resistant Staphylococcus Aureus [MRSA] or Coagulase Negative Staphylococcus [MRCoNS]. We prospectively analyzed the feasibility of long-term maintenance of HC after haploidentical family donor transplantation in 67 patients colonized with MRSA or MRCoNS employing Chlorhexidine impregnated patch [CIP,BIOPATCH 44150]. Methods, Intervention, & Analysis Patients undergoing haploidentical transplantation were screened for MRSA/MRCoNS with weekly nasal & skin swabs before transplantation & weekly thereafter for four weeks. Colonized patients were initiated on eradication protocol with Mupirocin ointment & Chlorhexidine bath. The patients were nursed in a class 1000 room with 1:1 nursing. HC dressing was carried out every 5 th day as inpatient & weekly thereafter with CIP and transparent dressing. Planned removal of HC was carried out at 180 days. HC which were retained beyond this period were taken care of by the caregivers who was intensively trained for the same. We analysed the incidence of catheter related bloodstream infections (CRBSI) or Hickman Catheter associated soft tissue Infections [HCASTI] following transplantation until the removal of HC. Findings & Interpretation 67 patients [males: 43, females: 24; malignant ds: 50, non-malignant ds: 17] who were colonized with MRSA [N=42] & MRCoNS [N=25] underwent PTCy based Haploidentical transplantation. The median age of the cohort was 32 years (range 2-65); 26 of those were Discussion & Implications Our study shows that with meticulous nursing coupled with intensive education of the patients & caregivers, long term maintenance of HC is possible without CRBSI or HCASTI. Employment of rigorous eradication program and application of Chlorhexidine based approach in HC dressing helped in minimizing the adverse impact of MRSA colonization on transplantation outcome with long term use of HC.

CMV related morbidity and mortality remains a major limiting factor in Haploidentical HSCT. We have developed a novel approach to Haploidentical PBSCT combining T cell Costimulation Blockade (T-COSB) with PTCy and Cyclosporine or Sirolimus (BBMT 2018). We studied the pattern of CMV reactivation (CMV-R) and its progression in 60 patients undergoing Haploidentical HSCT in this protocol in relation to the kinetics of Immune Reconstitution (IR) and pattern of leukemia relapse. PCR based CMV monitoring was carried out until 180 days with preemptive anti-CMV therapy. All patients and donors were CMV seropositive. CMV-R was 54.2% with median onset at 32 days (14-75) in the study group [compared to 52.5% in 42 who had received PTCy alone (p=0.8)]. The median peak viral load was 5.7 × 103/ml (1.8-25.8). The median duration of anti-CMV therapy was 16 days (7-60 days). There was no recurrence noted before100 days and only 2/32 (6.2%) beyond 100 days with no CMV disease. CMV-R was higher in those transplanted for malignant diseases compared to non-malignant diseases (62.5% vs 8.2%, p=0.01). Analysis of IR in relation to CMV-R showed no difference in CD3 or CD4+T cell reconstitution. However, CD56dimCD16+ NK cells at D+60 were significantly higher in patients without CMV-R (median 95 vs 45 cells/µl, p=0.02) and the same population of cells were associated with lower peak of viral load (p=0.04). In those with a lower viral peak and lower duration of viral replication, CD56dimCD16+ NK cells had a higher KIR repertoire with lower NKG2A expression. In those with CMV-R, a subsequent surge in absolute NK cells was observed (median 188 vs 112 cells/µl, p=0.01). This was primarily contributed by massive expansion of CD56dimNKG2AnegNKG2Cbright NK cells (median 7.8% [5-14.6%] at day +30 to 35% [28-65%] at day +90, p=0.01, Fig 1). This phenomenon was not witnessed in patients treated with PTCy alone. Peak viral load inversely correlated with NKG2C+ NK cells and CD45RO+CD8+ T cells at day +90 (p=0.03). The incidence of aGVHD (10.2%), cGVHD (18%), NRM (9.5%), and overall survival (75.8%) were not influenced by CMV-R. Incidence of relapse was 23.5 % at 28-144 days (median 85 days). However, none of the patients who relapsed before 100 days had proliferation of NKG2C+ NK cells and only 1/38 patients with proliferation and persistence of this subpopulation beyond 100 days experienced leukemia relapse at a median follow-up of 18 months (p=0.01). The kinetics of NK cell reconstitution in relation to the pattern of viral replication suggests that an early surge of CD56dimNKG2Alow NK cells with cytotoxic potential is responsible for the initial containment of viral replication followed by late surge and persistence of memory type NKG2C+NK cells preventing late recurrence as well as leukemia relapse. This unique synaptic response was possibly responsible for improved outcome with this novel approach of T-COSB based haploidentical HSCT.

s / Biol Blood Marrow Transplant 19 (2013) S257eS278 S264 Results: One hundred and thirty-four patients were analyzed (59 for allograft and 75 for autograft). Thirty-eight bacterial isolates from blood of 34 patients (25.3%; 20 patients for allograft and 14 for autograft) were reported. Patients with allogenic HSCT had more frequent BSI (odds ratio 2.23, p 1⁄4 0.047) compared to those with autologous HSCT. BSI of autologous HSCT were reported earlier compared to those of allogenic HSCT (mean 12.1 3.4 vs. 26.5 18.5 days, p 1⁄4 0.007). HSCT in patients with AML (p 1⁄4 0.029), no use of antibiotics from conditioning (p 180 days after diagnosis (p 1⁄4 0.035), elevated CRP (p 1⁄4 0.018), lower serum albumin (p1⁄4 0.033), and acute GVHD G2 (p1⁄4 0.015) showed relation to BSI in multivariate analysis. As for 75 patients with autologous HCT, only no antibiotics use (p 1⁄4 0.007) and elevated CRP (p 1⁄4 0.031) were independent risk factors of BSI. BSIs after allograft was more fatal: 7 of 20 patients with allograft (35%) died of BSI whereas only 1 of 14 patients who underwent autologous HSCT expired. Conclusion: Except pre-transplant serum CRP elevation, allogenic and autologous HSCT have different risk factors. BSI with autologous HSCT occurred earlier and showed better clinical outcomes compared to BSI with allograft. Distinctive natures of bacterial infection after HSCT between allogenic and autologous HST should be considered to establish the best defense strategy against BSI.