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Chronic graft versus host disease (cGVHD) affects 30–50% of allogeneic hematopoietic stem cell transplantation recipients, with those failing standard therapy including ruxolitinib constituting an important unmet medical need. We retrospectively analyzed the use of the ROCK2 inhibitor belumosudil in moderate to severe cGVHD that had failed ≥ 2 lines of systemic therapies, in order to evaluate its efficacy and safety in routine practice. Eighteen men and thirteen women at a median age of 50 (21–68) years with cGVHD (moderate, N  = 12; severe, N  = 19) that had failed a median of 3 (2–6) lines of systemic therapy were studied. Twenty-eight patients (90%) had failed prior ruxolitinib therapy, with seventeen patients (55%) continuing ruxolitinib despite unsatisfactory response. Among 29 patients evaluable, overall response rate was 52% (complete response:7%; partial response: 45%). Median time to response was 2.1 months (95% confidence interval, CI: 1.6–5.7), and was significantly shorter in patients older than 50 years ( P  = 0.008) and having received < 4 lines of therapy ( P  = 0.007). Median duration of response was 36.8 weeks (95% CI: 16.4 weeks to not reached). Median time to reduction of immunosuppressants by ≥ 50% was 6.7 months (95% CI: 2.3–12.2). Grade ≥ 3 adverse events occurred in 13% (4/31) of patients. Six patients (19%) discontinued treatment. At 12 months, overall survival and failure-free survival were 95% and 55%. Concomitant ruxolitinib significantly increased the probability of immunosuppressant reduction ( P  = 0.007). Belumosudil showed promising efficacy and safety in cGVHD patients in routine practice.

Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is one of the key determinants of outcome in myelofibrosis (MF) and remains an important unmet need. In this retrospective single-centre study, we evaluated 35 consecutive patients with MF receiving allogeneic HSCT. At 30 days post-HSCT, full donor chimerism was achieved in 31 patients (88.6%). The median time to neutrophil engraftment was 16.8 (10–42) days and the median time to platelet engraftment was 26 (12–245) days. Four patients (11.4%) experienced primary graft failure. With a median duration of follow-up of 33 (1–223) months, with the 5-year overall survival (OS) and progression-free survival (PFS) were 51.6% and 46.3%, respectively. Relapse after HSCT (P < 0.001), leucocyte count ≥ 18 × 109/L at HSCT (P = 0.003) and accelerated/blast phase disease at HSCT (P < 0.001) were significantly associated with worse OS. Age at HSCT ≥ 54 years (P = 0.01), mutated ETV6 (P = 0.03), leucocyte count ≥ 18 × 109/L (P = 0.02), accelerated/blast phase MF (P = 0.001), and grade 2–3 bone marrow reticulin fibrosis at 12 months post-HSCT (P = 0.002) were significantly associated with worse PFS. JAK2V617F MRD ≥ 0.047 [sensitivity 85.7%; positive predictive value (PPV) 100%; AUC 0.984; P = 0.001] at 6 months and JAK2V617F MRD ≥ 0.009 (sensitivity 100%; PPV 100%; AUC 1.0; P = 0.001) at 12 months were highly predictive of post-HSCT relapse. Inferior OS and PFS were significantly associated with detectable JAK2V617F MRD at 12 months (P = 0.003 and P = 0.0001, respectively).

Background Various glomerular pathologies have been reported in patients who have undergone haematopoietic stem cell transplantation (HSCT), but the data on clinico-pathological correlations and clinical outcome remain limited. Methods We analysed the clinical and histopathological data of patients who had biopsy-proven de novo glomerular diseases after HSCT since 1999. Results A total of 2204 patients underwent HSCT during the period 1999–2021, and 31 patients (1.4%) developed de novo glomerular diseases after a mean duration of 2.8 ± 2.7 years after HSCT. Fifteen of these patients (48.4%) had graft-versus-host-disease prior to or concomitant with renal abnormalities. Proteinuria and eGFR at the time of kidney biopsy were 4.1 ± 5.3 g/day and 50.8 ± 25.4 mL/min/1.73 m2, respectively. Kidney histopathologic diagnoses included thrombotic microangiopathy (TMA) (38.7%), membranous nephropathy (MN) (25.8%), mesangial proliferative glomerulonephritis (12.9%), minimal change disease (9.7%), focal segmental glomerulosclerosis (9.7%) and membranoproliferative glomerulonephritis (3.2%). Immunosuppressive treatment was given to patients who presented with nephrotic-range proteinuria and/or acute kidney injury, while renin–angiotensin–aldosterone blockade was given to all patients with proteinuria ≥1 g/day, with complete and partial response rates of 54.8% and 19.4%, respectively. One patient with TMA progressed to end-stage kidney disease after 24 weeks, and two patients, one with TMA and one with MN, (6.4%) progressed to chronic kidney disease (CKD) Stage ≥3. Kidney and patient survival rates were 96.6% and 83.5%, respectively, at 5 years. Conclusion De novo glomerular diseases with diverse histopathologic manifestations affect 1.4% of patients after HSCT, and approximately 10% develop progressive CKD. Graphical Abstract Graphical Abstract

Hepatitis B core-related antigen (HBcrAg) is a novel serum marker that correlates with intrahepatic hepatitis B virus (HBV) activity. Its association with HBV reactivation in hepatitis B surface antigen (HBsAg)-negative antibody to hepatitis B core antigen (anti-HBc)-positive patients undergoing high-risk immunosuppressive therapy is undefined. HBcrAg was measured in HBsAg-negative, anti-HBc-positive Asian patients with undetectable HBV DNA, who participated in two prospective studies investigating HBV reactivation during rituximab-containing chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Patients were monitored every 4 weeks for up to 2 years, with entecavir started when HBV reactivation, defined as HBV DNA ≥10 IU ml , developed. One hundred and twenty-four HBsAg-negative, anti-HBc-positive patients (rituximab, N=62; allogeneic HSCT, N=62) with a median follow-up of 64 weeks (range: 4-104 weeks) were studied. HBV reactivation occurred in 31 patients, with a 2-year cumulative reactivation rate of 40.4%. Serum HBcrAg was detected in 43 (34.7%) patients. Baseline HBcrAg positivity was significantly associated with HBV reactivation (P=0.004, hazard ratio (HR): 2.94, 95% confidence interval (95% CI): 1.43-6.07). HBcrAg-positive patients had a significantly higher 2-year HBV reactivation rate than HBcrAg-negative patients (71.8 vs. 31%, P=0.002). In the rituximab cohort, the HRs for positive HBcrAg and negative antibody to HBsAg for HBV reactivation were 3.65 and 2.84, respectively (P=0.011, 95% CI: 1.35-9.86 and P=0.032, 95% CI: 1.10-7.37, respectively). Serum HBcrAg positivity is a significant risk factor of HBV reactivation in HBsAg-negative, anti-HBc-positive patients undergoing high-risk immunosuppressive therapy and can potentially have a role in identifying patients who will best benefit from prophylactic nucleoside analogue treatment.

Graft-versus-host disease (GVHD) is an important complication after allogeneic haematopoietic stem cell transplantation (HSCT). Corticosteroids are the standard first-line treatment. Steroid-resistant/-dependent (SR/D) acute and chronic GVHD (aGVHD, cGVHD) lead to significant morbidity/mortality. The JAK2 inhibitor ruxolitinib has recently been shown in clinical trials to be effective in SR/D aGVHD and cGVHD. We retrospectively analysed the efficacy and safety of ruxolitinib in a cohort of SR/D aGVHD and cGVHD patients treated in a non-trial setting. In the aGVHD cohort, there were 14 men and 12 women, median age at 38 (19–63) years. At day 28 post-ruxolitinib, the overall response rate (ORR) was 86% (complete response, CR, 36%; partial response, PR, 50%). Continued ruxolitinib beyond day 28 resulted in a final CR of 68%. However, 3/15 (20%) of CR patients developed cGVHD. In the cGVHD cohort, there were 16 men and 15 women, median age at 33 (21–64) years. The ORR, CR and PR rates changed with continued ruxolitinib treatment, being 86%, 17% and 69% at 1 month; 79%, 38% and 41% at 3 months; and 83%, 52% and 31% at 6 months. Five patients had overlap GVHD, four of whom achieved CR. Multivariate analysis showed that superior overall survival and failure-free survival were associated with CR at day 28 for aGVHD, and CR at 1 year for cGVHD. Ruxolitinib treatment was efficacious for SR/D aGVHD and cGVHD, and continued treatment for at least 6 months was needed to maximize benefit.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative treatment for multiple hematologic malignancies and non-malignant hematological diseases. However, graft-vs.-host disease (GVHD), one of the main complications after allo-HSCT, remains the major reason for morbidity and non-relapse mortality. Emerging evidence has demonstrated that innate lymphoid cells (ILCs) play a non-redundant role in the pathophysiology of GVHD. In this review, we will summarize previously published data regarding the role of ILCs in the pathogenesis of GVHD.

Chronic graft-versus-host disease (cGVHD) is an important complication after allogeneic hematopoietic stem cell transplantation (HSCT). To define the roles of T-cells and B-cells in cGVHD, a murine minor histocompatibility complex–mismatched HSCT model was used. Depletion of donor splenocyte CD4 + T-cells and B220 + B-cells alleviated cGVHD. Allogeneic recipients had significantly increased splenic germinal centers (GCs), with significant increases in follicular T-helper (Tfh) cells and GC B-cells. There were increased expressions in Tfh cells of inducible T-cell co-stimulator (ICOS), interleukin (IL)-4 and IL-17, and in GC B-cells of B-cell activating factor receptor and ICOS ligand. Depletion of donor splenocyte CD4 + T-cells abrogated aberrant GC formation and suppressed Tfh cells and GC B-cells. Interestingly, depletion of donor splenocyte B200 + B-cells also suppressed Tfh cells in addition to GC B-cells. These results suggested that in cGVHD, both Tfh and GC B-cells were involved, and their developments were mutually dependent. The mammalian target of rapamycin (mTOR) inhibitor everolimus was effective in suppressing cGVHD, Tfh cells, and GC B-cells, either as a prophylaxis or when cGVHD had established. These results implied that therapeutic targeting of both T-cells and B-cells in cGVHD might be effective. Signaling via mTOR may be another useful target in cGVHD.

Background. Polyoma BK virus (BKV) is associated with hemorrhagic cystitis during hematopoietic stem cell transplantation (HSCT). The objective of this study was to test whether standard-dose ciprofloxacin might suppress reactivation of BKV infection during HSCT. Methods. Sixty-eight patients received ciprofloxacin or a cephalosporin as antibiotic prophylaxis after undergoing allogeneic HSCT. Urine samples were collected weekly from day 7 before HSCT to day 50 after HSCT. Laboratory investigations included quantification of BKV load and urinary ciprofloxacin levels and in vitro drug sensitivity of BKV. Results. Twenty-two patients received ciprofloxacin, 21 received cephalosporins, 12 received concomitant corticosteroids and antibiotics (9 received ciprofloxacin, and 3 received cephalosporins), and 13 received interrupted ciprofloxacin therapy. Ciprofloxacin recipients developed a significantly lower peak BKV load, compared with cephalosporin recipients (median, 3 × 105 copies/mL vs. 2.6 × 109 copies/mL; P = .021), irrespective of concomitant receipt of corticosteroid therapy. Fewer ciprofloxacin recipients than cephalosporin recipients (P = .013) developed BKV viruria with a ⩾3-log increase in BKV load during HSCT, which was associated with significantly more cases of hemorrhagic cystitis (8 of 29 patients with a peak increase of ⩾3 log vs. 0 of 39 patients without a peak increase of this level; P < .001). Ciprofloxacin recipients excreted ciprofloxacin in urine at a mean 24-h rate of 71.7 µg/mL (range, 23.0–152.9 µg/mL), which was comparable with the in vitro inhibitory concentration of 125–250 µg/mL of ciprofloxacin found for 3 of 7 BKV isolates. Conclusions. Ciprofloxacin decreased urinary BKV reactivation after HSCT.