An enterococcal phage-derived enzyme suppresses graft-versus-host disease.

Changes in the gut microbiome have pivotal roles in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogenic haematopoietic cell transplantation (allo-HCT)1-6. However, effective methods for safely resolving gut dysbiosis have not yet been established. An expansion of the pathogen Enterococcus faecalis in the intestine, associated with dysbiosis, has been shown to be a risk factor for aGVHD7-10. Here we analyse the intestinal microbiome of patients with allo-HCT, and find that E. faecalis escapes elimination and proliferates in the intestine by forming biofilms, rather than by acquiring drug-resistance genes. We isolated cytolysin-positive highly pathogenic E. faecalis from faecal samples and identified an anti-E. faecalis enzyme derived from E. faecalis-specific bacteriophages by analysing bacterial whole-genome sequencing data. The antibacterial enzyme had lytic activity against the biofilm of E. faecalis in vitro and in vivo. Furthermore, in aGVHD-induced gnotobiotic mice that were colonized with E. faecalis or with patient faecal samples characterized by the domination of Enterococcus, levels of intestinal cytolysin-positive E. faecalis were decreased and survival was significantly increased in the group that was treated with the E. faecalis-specific enzyme, compared with controls. Thus, administration of a phage-derived antibacterial enzyme that is specific to biofilm-forming pathogenic E. faecalis-which is difficult to eliminate with existing antibiotics-might provide an approach to protect against aGVHD.

Systemic inflammatory autoimmune disease before allogeneic hematopoietic stem cell transplantation is a risk factor for death in patients with myelodysplastic syndrome or chronic myelomonocytic leukemia.

Myelodysplastic syndrome (MDS) is well known to be complicated by systemic inflammatory autoimmune disease (SIADs). However, it remains unclear how the prognosis after allogenic hematopoietic stem cell transplantation (allo-HSCT) in patients with MDS is impacted by SIADs that occur before allo-HSCT. Therefore, we hypothesized that SIADs before allo-HSCT may be a risk factor for negative outcomes after allo-HSCT in patients with MDS. We conducted a single-center, retrospective, observational study of sixty-nine patients with MDS or chronic myelomonocytic leukemia who underwent their first allo-HCT. Fourteen of the patients had SIADs before allo-HSCT. In multivariate analysis, the presence of SIADs before allo-HSCT was an independent risk factor for overall survival (HR, 3.36, 95% confidence interval: 1.34-8.42, p = 0.009). Endothelial dysfunction syndrome was identified in five of 14 patients with SIADs who required immunosuppressive therapy or intensive chemotherapy, and notably, all patients with uncontrollable SIADs at allo-HSCT developed serious endothelial dysfunction syndrome and died in the early phase after allo-HSCT. The development of SIADs in the context of MDS is thought to reflect the degree of dysfunction of hematopoietic cells in MDS and suggests a higher risk of disease progression. In addition, MDS patients with SIADs before allo-HSCT are considered to be at higher risk of endothelial dysfunction syndrome because of preexisting vascular endothelial dysfunction due to SIADs. In conclusion, SIADs before allo-HSCT constitute an independent risk factor for death in MDS patients undergoing allo-HSCT.

Autotaxin is a potential predictive marker for the development of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT), and stratification of the high-risk group before transplantation is significant. Serum autotaxin (ATX) levels have been reported to increase in patients with liver fibrosis caused by metabolic inhibition from liver sinusoidal endothelial cells. Considering that the pathophysiology of VOD/SOS begins with liver sinusoidal endothelial cell injury, an increase in serum ATX levels may precede the onset of VOD/SOS. A retrospective study with 252 patients, including 12 patients with VOD/SOS, who had received allo-HCT was performed. The cumulative incidence of VOD/SOS was higher in the group with serum ATX levels before conditioning (baseline ATX) above the upper reference limit (high ATX group, p < 0.001), and 1-year cumulative incidences were 22.7% (95% confidence interval [95%CI], 3.1-42.4%) and 3.5% (95%CI, 1.1-5.8%), respectively. In the multivariate analysis, elevated baseline ATX was identified as an independent risk factor for VOD/SOS development and showed an additive effect on the predictive ability of known risk factors. Furthermore, the incidence of VOD/SOS-related mortality was greater in the high ATX group (16.7% vs. 1.3%; p = 0.005). Serum ATX is a potential predictive marker for the development of VOD/SOS.

Predictive significance of high neutrophil ratio for thrombosis in myeloproliferative neoplasms: JSH-MPN-R18 subanalysis.

Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch's T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted.

Posttransplantation cyclophosphamide mediates effective reconstitution of memory B cells after allogeneic hematopoietic cell transplantation.

OBJECTIVES: Impaired B-cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT) contributes to the pathogenesis of chronic graft-versus-host disease (cGVHD). Therefore, methods to consistently achieve effective B cell lymphogenesis are required. We assessed the long-term effects of posttransplantation cyclophosphamide (PTCy) use on immune reconstitution in clinical settings, an emerging strategy to suppress allogeneic immunological inflammation early after allo-HCT and prevent subsequent GVHD. METHODS: We comprehensively analyzed peripheral immune cell subsets and measured serum immunoglobulin G (IgG) or cytokine levels in 39 patients who survived for >1 year after allo-HCT. RESULTS: The absolute counts of B1 and IgM memory B cells were significantly lower in patients with severe cGVHD than in those without. The absolute count and percentage (among total CD19+ B cells) of switched memory B cells and serum IgG levels were significantly higher in patients transplanted with PTCy than in those transplanted with conventional GVHD prophylaxis. Interestingly, increased percentages of switched memory B cells and serum IgG levels were observed only in patients transplanted with PTCy and not in those transplanted with umbilical cord blood. CONCLUSIONS: PTCy administration can mediate favorable memory B-cell reconstitution long after allo-HCT and may therefore suppress cGVHD.

Impacts of Posttransplant Cyclophosphamide Dose on Graft-versus-leukemia Effects via HLA-B Leader in HLA-haploidentical Peripheral Blood Stem Cell Transplantation.

INTRODUCTION: The graft-versus-leukemia effect of HLA-B leader dimorphism, i.e. methionine (M) or threonine (T) at position -21 of the leader sequence, has been observed in HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo). However, the biological mechanism has been unclear, and the contributions of HLA-B leader genotype to risk reduction of relapse might be dependent on posttransplant cyclophosphamide (PTCy) doses. METHODS: To investigate whether the effect of HLA-B leader dimorphism was modified by the PTCy dose, we retrospectively analyzed 99 patients who received PTCy-haplo. RESULTS: In the low-dose PTCy group, the patient M+ HLA-B leader genotype did not significantly affect the cumulative incidence of relapse (CIR) but negatively impacted the overall survival (OS) compared to the M- genotype. In contrast, in the high-dose PTCy group, patients with the M+ genotype had a decreased CIR, but no significant difference in the OS was observed between patients with the M+ and M- genotypes. Regardless of PTCy doses, the patient M+ genotype had detrimental effects on nonrelapse mortality. CONCLUSION: Our findings suggest that the effect of the patient HLA-B leader genotype is modified by the PTCy dose, providing immunological insight into the PTCy dosage and supporting further studies to investigate the underlying mechanisms.

Invasive fungal infection caused by Blastobotrys mokoenaii in an immunocompromised patient with acute myeloid leukemia: A case report.

Blastobotrys is a genus of rare yeast that is increasingly recognized as a cause of fungal infections in humans. However, there have been no reports of fungal infections in humans caused by Blastobotrys mokoenaii. We describe a case of invasive fungal infection (IFI) caused by B. mokoenaii in an immunocompromised patient with acute myeloid leukemia (AML). A 46-year-old man with relapsed/refractory AML underwent a second allogeneic peripheral blood hematopoietic stem cell transplantation (allo-PBSCT) during remission. The patient had prolonged neutropenia and received systemic steroid therapy for graft-versus-host disease before the second allo-PBSCT. Uncommon yeast was isolated from the blood cultures obtained on day 4. We initially suspected that the uncommon yeast was Trichosporon spp. based on its morphology. However, unlike Trichosporon spp., in vitro antifungal susceptibility tests showed that this yeast isolate was resistant to micafungin, caspofungin, voriconazole, itraconazole, and fluconazole. We performed DNA sequencing and identified it as B. mokoenaii. B. mokoenaii was persistently isolated from blood cultures taken during combination therapy with liposomal amphotericin B and voriconazole. The patient died of multiorgan failure on day 24. B. mokoenaii can cause severe IFI in immunocompromised patients; however, it may not be correctly identified by routine clinical microbiology testing in a hospital laboratory and DNA sequencing is useful for diagnosis.

[Usefulness of web-based application for health surveys before and after peripheral blood stem cell harvest from healthy donors].

Health surveys to assess adverse events after peripheral blood stem cell harvest (PBSCH) have conventionally been conducted by phone, but phone calls are suboptimal for conducting frequent surveys. We developed a web-based application (donor app) that enables donors to inform healthcare professionals (HCPs) of their health status as an electronic patient-reported outcome (ePRO). In this prospective observational study, we compared the usefulness of this donor app to phone calls for conducting health surveys. App users reported ePRO daily, and patients called by HCPs reported their health status at least once a week when called. The observation period was from the first administration of granulocyte colony-stimulating factor to the first follow-up visit after PBSCH, excluding the hospitalization period. Each group consisted of eight donors with a median age of 32 years (range: 19-58). Nine (56.3%) were female. There were eight related donors in the phone call group and four in the donor app group. During the observation period, HCPs obtained health status reports more frequently from app users than from phone call recipients (mean proportion of days with reports made during the observation period, 27.0% vs 53.5%; p<0.05). Average time spent by the HCPs for one follow-up and total follow-ups were both significantly shorter when the donor app was used. There were no differences in donor burden or satisfaction with donation. Our study suggests that use of a donor app could provide more detailed health survey data without increasing the burden on donors and HCPs.

Sinusoidal obstruction syndrome associated with disseminated toxoplasmosis involving the liver after allogeneic hematopoietic stem cell transplantation: A case report.

Sinusoidal obstruction syndrome (SOS) is a fatal complication after hematopoietic stem cell transplantation (HSCT). Only a few complications after HSCT have been reported as risk factors for SOS, including sepsis. Here, we report the case of a 35-year-old male diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent peripheral blood HSCT from a human leukocyte antigen-matched unrelated female donor in remission. Graft-versus-host disease prophylaxis contained tacrolimus, methotrexate, and low-dose anti-thymoglobulin. The patient was treated with methylprednisolone for engraftment syndrome from day 22. On day 53, he presented worsening fatigue, breathlessness, and abdominal pain in the right upper quadrant that had persisted for 4 days. Laboratory tests showed severe inflammation, liver dysfunction, and positive for Toxoplasma gondii PCR. He died on day 55. An autopsy showed SOS and disseminated toxoplasmosis. Hepatic infection with T. gondii was identified in zone 3 of the liver, which overlapped with the pathological features of SOS. In addition, the timing of the exacerbation of hepatic dysfunction coincided with the onset of systemic inflammatory symptoms and T. gondii reactivation. This rare case of toxoplasmosis is the first to suggest that hepatic infection with T. gondii is strongly associated with SOS after HSCT.

Immunomodulatory and direct activities of ropeginterferon alfa-2b on cancer cells in mouse models of leukemia.

Although ropeginterferon alfa-2b has recently been clinically applied to myeloproliferative neoplasms with promising results, its antitumor mechanism has not been thoroughly investigated. Using a leukemia model developed in immunocompetent mice, we evaluated the direct cytotoxic effects and indirect effects induced by ropeginterferon alfa-2b in tumor cells. Ropeginterferon alfa-2b therapy significantly prolonged the survival of mice bearing leukemia cells and led to long-term remission in some mice. Alternatively, conventional interferon-alpha treatment slightly extended the survival and all mice died. When ropeginterferon alfa-2b was administered to interferon-alpha receptor 1-knockout mice after the development of leukemia to verify the direct effect on the tumor, the survival of these mice was slightly prolonged; nevertheless, all of them died. In vivo CD4+ or CD8+ T-cell depletion resulted in a significant loss of therapeutic efficacy in mice. These results indicate that the host adoptive immunostimulatory effect of ropeginterferon alfa-2b is the dominant mechanism through which tumor cells are suppressed. Moreover, mice in long-term remission did not develop leukemia, even after tumor rechallenge. Rejection of rechallenge tumors was canceled only when both CD4+ and CD8+ T cells were removed in vivo, which indicates that each T-cell group functions independently in immunological memory. We show that ropeginterferon alfa-2b induces excellent antitumor immunomodulation in hosts. Our finding serves in devising therapeutic strategies with ropeginterferon alfa-2b.

[Warm autoimmune hemolytic anemia and IgM-monoclonal gammopathy following BNT162b2 COVID-19 vaccine in a patient with splenic marginal zone lymphoma].

There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient's symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient's serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.

Association of serum autotaxin levels with liver fibrosis in patients pretreatment and posttreatment with chronic hepatitis C.

BACKGROUND AND AIM: The evaluation of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection is important as it is a risk factor for hepatocellular carcinoma. In the recent years, autotaxin (ATX) has been established as a new noninvasive biomarker to predict liver fibrosis. However, antiviral treatment has been reported to decrease serum ATX, but it is unclear whether posttreatment ATX levels reflect liver fibrosis. In the present study, the correlation between ATX and liver fibrosis in pretreatment and posttreatment patients with HCV infection was analyzed. METHODS: A total of 199 samples from 136 patients with HCV infection who had undergone hepatic biopsy before and/or after antiviral treatment at Osaka City University Hospital were used. Posttreatment patients included 38 interferon-treated patients and 80 interferon-free direct-acting antiviral-treated patients; all patients achieved a sustained virological response (SVR). Serum ATX levels were determined by enzyme immunoassay with an AIA-2000 analyzer. RESULTS: Serum ATX levels were largely correlated with liver fibrosis stage in patients with HCV infection before and after antiviral treatment. The measured values decreased even in similar liver fibrosis stages after treatment. The area under the receiver operating characteristic curve for the ability of ATX to diagnose above F2 stage before treatment was 0.81 (both male and female) and that after achieving SVR, it was 0.71 (male) and 0.72 (female). CONCLUSIONS: Serum ATX levels were correlated with histological liver fibrosis stage after achieving SVR. However, separate cutoff values before and after antiviral therapy should be established.

Donor KIR2DS1-Mediated Decreased Relapse and Improved Survival Depending on Remission Status at HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.

HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) is becoming the standard of care for patients without an HLA-matched related or unrelated donor. PT/Cy-haplo can give more patients the opportunity to undergo allo-HCT, because most patients have multiple available HLA-haploidentical related donor candidates. The optimal donor selection algorithm in the PT/Cy-haplo setting has not yet been established, however. To contribute to the establishment of a donor selection formula based on disease status and killer-cell immunoglobulin-like receptor (KIR) genotype, we retrospectively analyzed 91 patients who underwent PT/Cy-haplo at our institution. In both patients and donors, HLA allele genotyping was performed for HLA-A, -B, -C, and -DRB1, and 16 KIR genes were genotyped. Patients in complete remission (CR) who underwent PT/Cy-haplo from a KIR2DS1-positive donor had a significantly lower cumulative incidence of relapse (CIR) than those who underwent PT/Cy-haplo from a KIR2DS1-negative donor (1-year CIR: 0% versus 32.6%, P = .037; 2-year CIR: 9.2% versus 42%, P = .037). Moreover, PT/Cy-haplo from a KIR2DS1-positive donor was significantly associated with improved overall survival (OS) (1-year OS: 91.7% versus 58.7%, P = .010; 2-year OS: 83% versus 34%, P = .010). In contrast, in non-CR individuals, PT/Cy-haplo from KIR2DS1-positive donors did not significantly improve CIR or OS (1-year CIR: 56.5% versus 64.7%, P = .973; 2-year CIR: not reached versus 64.7%, Pnot evaluable; 1-year OS: 25.4% versus 20.6%, P = .418; 2-year OS: 5.1% versus 20.6%, P = .418). In addition, lower infused CD34+ cell dose, female-to-male transplantation, and acute myelogenous leukemia were significantly associated with increased risk of relapse and mortality. This study demonstrates that graft-versus-leukemia/tumor effects were exerted through donor KIR2DS1 at PT/Cy-haplo when patients have low tumor burdens. It would be worth examining the inclusion of donor KIR genotyping and disease status assessment in establishing optimal donor selection criteria for PT/Cy-haplo.

Pretransplant serum beta-2 microglobulin level is a potential novel prognostic marker of overall survival after allogeneic hematopoietic cell transplantation - a retrospective observational study.

Although elevated serum beta-2 microglobulin (BMG) has been reported as a poor prognostic marker for various hematological malignancies, no study has assessed its prognostic significance in allogenec hematopoietic cell transplantation (allo-HCT). Therefore, we conducted this retrospective observational study in 227 consecutive patients with available pretransplant serum BMG levels between April 2010 and September 2017 at our institute. We also collected and retrospectively analyzed various pretransplant variables likely related to transplant outcomes. Multivariable analysis, including major prognostic variables, such as the disease risk index and the hematopoietic cell transplant-comorbidity index, showed a significant association between higher serum BMG levels and poorer overall survival (OS) in all three adjusted models [hazard ratio (HR) per its standard deviation (SD) (SD = 1.094): 1.67 (1.35-2.03; P < 0.001), HR per SD: 1.46 (1.14-1.86; P = 0.002), HR per SD: 2.03 (1.62-2.55; P < 0.001)], respectively, due to the significant association between higher serum BMG levels and relapse/progression [HR 1.52 (1.20-1.94; P < 0.001)] instead of nonrelapse mortality [HR 1.06 (0.70-1.60; P = 0.780)]. Moreover, DRI and serum BMG had statistically significantly higher c-statistic estimates for OS compared with DRI alone (c-index 0.74 and 0.68, respectively; P < 0.001). In conclusion, pretransplant serum BMG level may serve as a useful prognostic marker and help clinical decision in allo-HCT.

Post-Treatment M2BPGi Level and the Rate of Autotaxin Reduction are Predictive of Hepatocellular Carcinoma Development after Antiviral Therapy in Patients with Chronic Hepatitis C.

Patients with chronic hepatitis C virus (HCV) develop hepatocellular carcinoma (HCC) regardless of achieving a sustained viral response (SVR). Because advanced liver fibrosis is a powerful risk factor for HCC, we analyzed the association between autotaxin (ATX), a liver fibrosis marker, and post-SVR HCC development within 3 years after antiviral treatment. We included 670 patients with HCV who received direct-acting antivirals, achieved SVR and were followed up for at least 6 months (270 of them were followed up for 3 years or more). We measured serum ATX levels before treatment and 12/24 weeks after treatment. The diagnosis of HCC was based on imaging modalities, such as dynamic computed tomography and dynamic magnetic resonance imaging and/or liver biopsy. The present study revealed that high levels of serum ATX predicted post-SVR HCC development (area under the receiver operating characteristic: 0.70-0.76). However, Wisteria floribunda agglutinin positive Mac-2 binding protein (M2BPGi), another liver fibrosis marker, was a more useful predictive marker especially post-treatment according to a multivariate analysis. Patients with a high rate of ATX reduction before and after antiviral treatment did not develop HCC regardless of high pretreatment ATX levels. In conclusion, post-treatment M2BPGi level and the combination of pretreatment ATX levels and rate of ATX reduction were useful predictive markers for post-SVR HCC development in patients with chronic HCV infection.

[Erythrocytosis following allogeneic hematopoietic stem cell transplantation].

Post-transplant erythrocytosis (PTE) following allogeneic hematopoietic stem cell transplantation (alloHSCT) is rare, and the clinical characteristics of this condition remain unknown. In this study, we examined the clinical characteristics of three PTE cases among 321 patients who received allo HSCT from January 1992 to December 2011 at our institution. All three patients exhibited normal levels of white blood cell and platelet counts when their hemoglobin levels reached their peak. Two patients exhibited normal levels of erythropoietin. No thrombosis or hemorrhage was observed in any of the three patients without cytoreductive therapy or an antiplatelet agent. All three patients tested negative for JAK2V617F mutations. Two patients had high levels of IL-13, an upstream signal for the JAK/STAT pathway. JAK2 is known to significantly contribute to the pathology of polycythemia vera; however, this pathology may differ from that of PTE. We believe that it is necessary to construct a more appropriate management structure for PTE by analyzing more case data in the future.

[High-dose polyclonal intravenous immunoglobulin therapy for refractory viral infections including viremia after allogeneic hematopoietic cell transplantation].

Refractory viremia/viral disease is a major life-threatening complication that may arise among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to clarify the therapeutic effect of high-dose polyclonal intravenous immunoglobulin (IVIG) against viremia/viral diseases after allo-HCT. We conducted a pilot study to investigate the therapeutic effect of 400 mg/kg of IVIG given for 5 consecutive days against refractory viremia/viral disease after allo-HCT. Overall, 7 patients were drug-resistant and the other 7 had not previously received any drug for their viremia/viral disease. All patients completed the 5-day therapy regimen of IVIG. A complete response at Day 56 was observed for 8 of 14 patients (57.1%). Additionally, 10 of 14 patients (71.4%) were alive at Day 56, although only one death occurred due to the viremia/viral disease. Remarkably, all 3 cases who developed exogenous viremia/viral diseases including respiratory syncytial virus pneumonia/bronchitis and human parvovirus B19 viremia achieved a complete response, suggesting that high-dose polyclonal IVIG may be more effective against exogenous viruses rather than endogenous ones. Congestive heart failure was observed in 1 patient. High-dose polyclonal IVIG could be an effective and feasible therapy for refractory viremia/viral disease after allo-HCT.

Clinical Impacts of Using Serum IL-6 Level as an Indicator of Cytokine Release Syndrome after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.

HLA-haploidentical allogeneic hematopoietic cell transplantation with post-transplantation cyclophosphamide (PT/Cy-haplo) is widely used because of such advantages as low procedure cost, high probability of finding a suitable donor, and donor availability at short notice. Cytokine release syndrome (CRS), resulting from bidirectional alloreaction between host and donor, occurs frequently in recipients of PT/Cy-haplo, especially when peripheral blood is used. Severe and life-threatening instances of CRS have been reported. The clinical significance of CRS remains unclear, however. Here we used serum IL-6 level as a surrogate marker of CRS to evaluate the impact of outcomes in 65 consecutive patients receiving PT/Cy-haplo at our institution. Our results indicate that active disease status, high Hematopoietic Cell Transplantation-Specific Comorbidity Index score, and very severe CRS are significantly related to peak serum IL-6 level. In our cohort, high peak serum IL-6 level and severe CRS were significantly associated with the development of grade III or IV acute graft-versus-host disease (GVHD). High peak serum IL-6 level was identified a significant risk factor for poor 3-year overall survival. Our results suggest that even transient CRS following PT/Cy-haplo may contribute to poor survival owing to an increase in severe acute GVHD.

A prospective observational study of immune reconstitution following transplantation with post-transplant reduced-dose cyclophosphamide from HLA-haploidentical donors.

Allogeneic hematopoietic cell transplantation (HCT) from HLA-haploidentical donors with post-transplantation high-dose cyclophosphamide (PT/Cy-haplo) now predominates worldwide. However, to our knowledge, no prospective study has compared immune reconstitution after PT/Cy-haplo with that after conventional HCT. The mechanism by which chronic graft-versus-host disease (GVHD) is inhibited by PT/Cy-haplo also remains unknown. We prospectively compared immune recovery patterns of lymphocyte subsets among four groups of adult patients with hematological disease who received HCT from either HLA-matched related or HLA-matched unrelated donors, cord blood transplantation, or reduced-dose PT/Cy-haplo. Counts of CD4+ T-cell subsets, CD8+ T-cell subsets, and NK cells on days 30 and 60 were often lower in PT/Cy-haplo than those in HLA-matched related HCT. The immune recovery pace in PT/Cy-haplo subsequently caught up with that of the other grafts. The regulatory T cells (Tregs) to conventional CD4+ T-cell (Tcon) ratio was significantly higher until day 90 in PT/Cy-haplo. In multivariate analysis, a higher Tregs-to-Tcon ratio on day 60 was significantly associated with a lower incidence of chronic GVHD (P < 0.01). The preservation of Tregs by PT/Cy in the early phase might have resulted in a lower incidence of chronic GVHD.