Kinetics of IgG subclasses and their effects on the incidence of infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The impact of the reconstitution of IgG subclasses after allogeneic hematopoietic cell transplantation (allo-HCT) on the outcomes is unclear. METHODS: We investigated the effects of stem cell source on the levels of serum IgG subclasses and their influence on the infection risk and prognosis. The levels of serum IgG, IgG2 and IgG4 were measured chronologically in 100 patients who underwent allo-HCT at our institute. RESULTS: The median levels of serum IgG, IgA and IgM and the number of total B-cells were determined up to one year after allo-HCT. The serum IgG2 levels decreased within one year. A multiple linear regression analysis identified lymphoid malignancy, cord blood, and days after allo-HCT as significant risk factors for low serum IgG2 levels. There were no significant differences in the level of IgG or IgG2 at 90 days after allo-HCT between the late bacterial infection group (≥90 days following allo-HCT) and the control group (P = 0.34 and 0.45, respectively). There was no significant impact of the IgG, IgG2 or IgG4 levels on the survival or non-relapse mortality. CONCLUSION: The results suggest that cord blood transplantation might affect humoral immune reconstitution, including the IgG2 level, after allo-HCT.

Risk Factor and Long-Term Outcome Analyses for Acute Limbic Encephalitis and Calcineurin Inhibitor-Induced Encephalopathy in Adults following Allogeneic Hematopoietic Cell Transplantation.

Post-transplantation acute limbic encephalitis (PALE) is a rare, severe inflammatory disorder in the bilateral limbic system, including the hippocampus. To date, only a few studies have reported details, including risk factors for PALE; however, further clinical evidence of PALE, especially in cerebrospinal fluid human herpesvirus 6-negative cases, is warranted. In addition, data are sparse regarding the risk factors for calcineurin inhibitor (CNI)-induced encephalopathy (CNIE) following allogeneic hematopoietic cell transplantation (allo-HCT) in adults. Therefore, we examined the risk factors for and clinical details of PALE and CNIE. We retrospectively analyzed consecutive patients who underwent allo-HCT between January 2005 and November 2017. A total of 485 patients age 46 years (median) were eligible. In total, 14 PALE cases and 11 CNIE cases were identified. Multivariable analyses identified older age, use of an HLA-mismatched unrelated donor (URD), graft-versus-host disease (GVHD) prophylaxis with CNI and mycophenolate mofetil, and grade II-IV acute GVHD as significantly associated with an increased risk of PALE. In 13 patients who received high-dose methylprednisolone (mPSL) therapy, 6 (46%) responded to mPSL therapy, and 3 (23%) achieved complete remission at day 90 after mPSL administration. Furthermore, myelodysplastic syndrome (MDS), HLA-mismatched URD, and grade II-IV acute GVHD were significantly associated with an increased risk of CNIE. The 5-year nonrelapse mortality rate was 50% in PALE and 63% in CNIE, suggesting a very poor prognosis. In conclusion, this study provides evidence that HLA-mismatched URD and acute GVHD may independently contribute to the development of PALE, possibly in part through HLA-mismatch-derived alloimmune responses. Other than acute GVHD, we have identified MDS and HLA-mismatched URD as novel predictors of CNIE after allo-HCT.

High-grade B-cell lymphoma developed during the treatment of chronic myeloid leukemia with bosutinib.

Tyrosine kinase inhibitor (TKI) can help to increase the survival time in chronic myeloid leukemia (CML) patients; however, the risk of secondary malignancies due to TKIs is a growing concern. Only few reports showed clinical course of patients who developed lymphoma during TKI therapies. Herein, we report a case of high-grade B-cell lymphoma diagnosed in the course of CML treatment with bosutinib. The 75-year-old male patient had been diagnosed with CML 25 years ago. After receiving TKIs (imatinib, nilotinib, and bosutinib), he achieved a major molecular response. Over 3 years after starting bosutinib, he was diagnosed with a high-grade B-cell lymphoma. A total of six courses of DA-EPOCH-R therapy brought complete remission of the lymphoma. Moreover, BCR-ABL1 transcript copies remained undetectable by RT-PCR, 8 months after stopping bosutinib. The risk of secondary malignancy due to TKI has been controversial. It is reported that TKI induces irreversible chromosomal abnormalities or chromosome aberrations and inhibits the proliferation or function of T cells, B cells, and NK cells. These mechanisms of TKI may contribute to the development of secondary malignancy. There remains no consensus on the management of secondary lymphoma during TKI therapies. At present, the only alternative is to observe patients receiving TKI treatment cautiously and to treat secondary lymphoma in the same manner as de novo lymphoma.

Interactive Web Application for Plotting Personalized Prognosis Prediction Curves in Allogeneic Hematopoietic Cell Transplantation Using Machine Learning.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for malignant hematological disorders. Transplant clinicians estimate patient-specific prognosis empirically in clinical practice based on previous studies on similar patients. However, this approach does not provide objective data. The present study primarily aimed to develop a tool capable of providing accurate personalized prognosis prediction after allo-HCT in an objective manner. METHODS: We developed an interactive web application tool with a graphical user interface capable of plotting the personalized survival and cumulative incidence prediction curves after allo-HCT adjusted by 8 patient-specific factors, which are known as prognostic predictors, and assessed their predictive performances. A random survival forest model using the data of patients who underwent allo-HCT at our institution was applied to develop this application. RESULTS: We succeeded in showing the personalized prognosis prediction curves of 1-year overall survival, progression-free survival, relapse/progression, and nonrelapse mortality (NRM) interactively using our web application (https://predicted-os-after-transplantation.shinyapps.io/RSF_model/). To assess its predictive performance, the entire cohort (363 cases) was split into a training cohort (70%) and a test cohort (30%) time-sequentially based on the patients' transplant dates. The areas under the receiver-operating characteristic curves for 1-year overall survival, progression-free survival, relapse/progression, and nonrelapse mortality in test cohort were 0.70, 0.72, 0.73, and 0.77, respectively. CONCLUSIONS: The new web application could allow transplant clinicians to inform a new allo-HCT candidate of the objective personalized prognosis prediction and facilitate decision-making.

Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.

Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.

Acquired Gray Platelet Syndrome Associated with Primary Myelofibrosis.

A 53-year-old man presented with uncontrolled bleeding caused by acquired platelet dysfunction accompanied by calreticulin-mutated primary myelofibrosis. Based on the detection of abnormal platelets, including large gray platelets, under light microscopy and the loss of the second wave of aggregation observed by light transmission aggregometry, the patient was diagnosed with platelet dysfunction accompanied by myeloproliferative neoplasms (MPNs). In addition, the absence of platelet α-granules was confirmed by electron microscopy. Therefore, this condition may be termed "acquired gray platelet syndrome." Acquired platelet dysfunction must be ruled out when abnormal platelets are observed in patients with MPNs.

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.

Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11.

The prognostic impact of KIT mutation on core-binding factor acute myeloid leukemia (CBF-AML) remains controversial. We registered 199 newly diagnosed de novo CBF-AML patients, aged 16 to 64 years, who achieved complete remission. They received 3 courses of high-dose cytarabine therapy and no further treatment until hematological relapse. Mutations in exons 8, 10-11, and 17 of the KIT gene were analyzed. Furthermore, we analyzed mutations in 56 genes that are frequently identified in myeloid malignancies and evaluated minimal residual disease (MRD). The primary end point was relapse-free survival (RFS) according to KIT mutations. The RFS in KIT-mutated patients was inferior to that in unmutated patients (hazard ratio, 1.92; 95% confidence interval, 1.23-3.00; P = .003). Based on subgroup analysis, KIT mutations had a prognostic impact in patients with RUNX1-RUNX1T1, but not in those with CBFB-MYH11, and only exon 17 mutation had a significant prognostic impact. Multivariate Cox regression analysis with stepwise selection revealed that the KIT exon 17 mutation and the presence of extramedullary tumors in patients with RUNX1-RUNX1T1, and loss of chromosome X or Y and NRAS mutation in patients with CBFB-MYH11 were poor prognostic factors for RFS. MRD was evaluated in 112 patients, and it was associated with a poorer RFS in the patients with CBFB-MYH11, but not in those with RUNX1-RUNX1T1. These results suggested that it is necessary to separately evaluate AML with RUNX1-RUNX1T1 or CBFB-MYH11 according to appropriate prognostic factors. This study was registered at www.umin.ac.jp/ctr/ as #UMIN000003434.

Phase I study of graft-versus-host disease prophylaxis including bortezomib for allogeneic hematopoietic cell transplantation from unrelated donors with one or two HLA loci mismatches in Japanese patients.

This phase I study was designed for graft-versus-host disease (GVHD) prophylaxis including bortezomib in allogeneic hematopoietic cell transplantation (allo-HCT) from human leukocyte antigen (HLA)-mismatched unrelated donors in Japanese patients. Patients were administered bortezomib on days 1, 4, and 7, with short-term methotrexate and tacrolimus. Three bortezomib dose levels were prepared (1.0, 1.3, and 1.5 mg/m2). A dose of 1.3 mg/m2 was planned for administration to the initial six patients, and was adjusted if dose-limiting toxicity developed. Five of six patients enrolled for the initial dose had bone marrow donors. Two cases had single-antigen and single-allele mismatches; four had single-antigen mismatch at the A, B, C, and/or DRB1 loci in the GVH direction. All patients achieved neutrophil engraftment and complete donor chimerism. Three patients developed grade II acute GVHD, and none developed grade III-IV GVHD or any dose-limiting toxicity attributable to bortezomib by day 100. Two patients developed late-onset acute GVHD, and two developed chronic GVHD, but all cases were manageable. All patients were alive without relapse after a median follow-up period of 52 months. The optimal dose of bortezomib was determined to be 1.3 mg/m2. Prophylaxis against GVHD using a regimen including bortezomib thus seems feasible for HLA-mismatched unrelated allo-HCT.

An Elderly Woman with Anti-neutrophil Antibody-positive Agranulocytosis Who Responded to High-dose Intravenous Methylprednisolone.

Although anti-neutrophil antibodies (ANAs) often exist and immunoreaction may be involved in agranulocytosis, few reports have so far described ANA-positive cases of agranulocytosis with an unknown etiology. We herein describe the case of a 69-year-old woman who presented with ANA-positive agranulocytosis. In this case, both the withdrawal of the drugs that had possibly caused neutropenia and the use of granulocyte-colony stimulating factor (G-CSF) were ineffective treatment measures. Approximately 2 weeks after the discontinuation of the suspected drugs, we initiated corticosteroid pulse therapy; the neutrophil count recovered by day 19 of steroid therapy. High-dose methylprednisolone therapy should thus be considered for patients demonstrating ANA-positive agranulocytosis with an unknown etiology that is refractory to G-CSF treatment.

Pulmonary Involvement of Acute Myeloid Leukemia Mimicking Transfusion-related Acute Lung Injury.

Transfusion-related acute lung injury (TRALI) is defined as a new episode of acute lung injury (ALI) occurring during transfusion or within 6 hours of transfusion completion. A 66-year-old man suffering from acute myeloid leukemia developed acute respiratory distress syndrome after platelet transfusion. TRALI was diagnosed clinically, but an autopsy showed leukemic cells in diffuse pulmonary edema. Anti-human neutrophil antigen (HNA)-3a antibodies were detected in the donor serum, and the HNA-3 genotype of the patient was identified as a/a. This case was considered to represent pulmonary involvement of acute myeloid leukemia, rather than TRALI. A revision of the definition of TRALI accounting for hematological malignancies should therefore be considered.

Drug interactions and safety profiles with concomitant use of caspofungin and calcineurin inhibitors in allogeneic haematopoietic cell transplantation.

AIM: Small-scale clinical studies have reported on drug interactions between caspofungin (CPFG) and calcineurin inhibitors in healthy subjects; however, little is known about these interactions in allogeneic haematopoietic cell transplantation (allo-HCT) patients. METHODS: We retrospectively assessed the drug interactions and safety profiles in allo-HCT recipients treated concomitantly with CPFG and calcineurin inhibitors. RESULTS: Ninety-one consecutive cases were evaluated. There were no statistically significant differences in the plasma concentration/dose (C/D) ratios of tacrolimus (TAC) in 34 patients before and after co-administration with CPFG (median: 575.6-672.4, P = 0.200). In contrast, the median C/D ratio of cyclosporin A (CsA) in 16 patients was significantly elevated after co-administration with CPFG (median: 62.8-74.9, P = 0.016). There were no serious adverse effects on liver or renal function associated with the therapy. CONCLUSIONS: Our data show that CPFG did not affect the pharmacokinetics of TAC and that it could mildly increase CsA blood concentrations in allo-HCT patients.

Diagnostic value of serum ferritin and the risk factors and cytokine profiles of hemophagocytic syndrome following allogeneic hematopoietic cell transplantation.

To examine the diagnostic value of serum ferritin, the associated risk factors, and cytokine profiles of hemophagocytic syndrome (HPS) following allogeneic hematopoietic cell transplantation (allo-HCT), we retrospectively analyzed data from patients undergoing allo-HCT between 2006 and 2012. Of 223 eligible patients, 18 patients developed HPS. A serum ferritin level above 30,000 µg/l was highly specific for the detection of HPS (specificity, 93%). The one-year survival rate for HPS was significantly lower than that of non-HPS patients (37.5% vs. 72.9%, respectively, Log-rank p < .01). In multivariable Cox models, antigen mismatches in human leukocyte antigen (HLA) in both graft-versus-host (GVH) and host-versus-graft (HVG) directions were significantly associated with the incidence of HPS. We found a significant elevation of Th1 cytokine (IFN-γ), Th2 cytokines (IL-10), and chemokines (MCP-1 and IP-10), at the onset of HPS. Our results suggest that allo-reactivity, derived from HLA-mismatch, and possibly causing a cytokine storm, may be associated with HPS development.

Combinational approach using in situ hybridization targeting 23S ribosomal RNA genes and blood cultures for bacterial identification in patients with neutropenia and fever.

BACKGROUND: A new 23S ribosomal RNA genes-targeted in situ hybridization (ISH) probe to detect global bacterial genomic DNA (59 species from 35 genera; referred to as the GB probe) phagocytized in leukocytes was recently developed. This method provided early and direct evidence of bacterial infection with high sensitivity and specificity in spontaneous bacterial peritonitis ascites. However, the utility of this method in febrile neutropenia (FN) is unknown. METHODS: We prospectively evaluated the utility of the ISH approach using the GB probe and previously reported probes in patients with neutropenia and fever undergoing chemotherapy at our institution between June 2011 and July 2013. Blood samples for culture analysis and ISH tests were collected simultaneously at the onset of fever; the latter were performed repeatedly. RESULTS: Fifty febrile episodes were evaluated. In 24 episodes of fever of unknown origin and 15 episodes of local infection (all negative for blood cultures), ISH tests identified causal bacteria in 21% and 13% of cases, respectively, at the onset of fever. In seven sepsis cases (all positive for blood culture), positive ISH test results at fever onset were achieved in 71%; for two patients with neutrophil counts of 0/µl and 171/µl, respectively, negative results were obtained. CONCLUSIONS: This new ISH approach could prove useful for early detection of bacteria in patients with neutropenia and blood culture-negative, with fever of unknown etiology after chemotherapy. Using this method in combination with blood culture, even in cases with extremely low neutrophil counts, might contribute to better management of FN.

Plasma Kinetics of Th1, Th2 and Th17 Cytokines in Polymyositis Related to Chronic Graft-versus-Host Disease.

We herein describe a case of myelodysplastic syndrome with chronic graft-versus-host disease (cGVHD)-related polymyositis. On approximately day 1,570 post HLA-identical sibling bone marrow transplant, the patient presented with a fever, myalgia and liver dysfunction. A muscle biopsy revealed destruction of the muscle fibers and infiltration of CD20(+) B cells and CD4(+) and CD8(+) T cells, and a liver biopsy confirmed the findings of cGVHD. An analysis of plasma cytokine profiles indicated elevation of not only T-helper (Th)1 and Th2, but also Th17 cytokines. Increases in these cytokines in addition to the invasion of inflammatory cells might be associated with the pathophysiology of cGVHD involving the muscle and liver.

Efficacy and safety of intra-arterial steroid infusions in patients with steroid-resistant gastrointestinal acute graft-versus-host disease.

There is no established second-line treatment for steroid-resistant acute graft-versus-host disease (GVHD). We prospectively assessed the safety and efficacy of intra-arterial steroid infusions (IASIs) for steroid-resistant acute gastrointestinal (GI) GVHD and compared the outcomes with those of historical controls at our institution. Nineteen consecutive, allogeneic hematopoietic stem cell transplantation subjects aged 31-67 years (median 52) were enrolled between October, 2008, and November, 2012. Acute GVHD was confirmed by biopsy in all cases. The enrolled patients were treated with infusions of methylprednisolone into the mesenteric arteries and/or gastroduodenal and left gastric arteries. Fourteen consecutive patients who developed steroid-resistant acute GI GVHD between 2001 and 2008 were used as controls. For the primary endpoint at day 28, the overall and complete responses in the IASI group trended higher (79% vs. 42%, p = 0.066) and were significantly higher (63% vs. 21%, p = 0.033) than those in the control group. Although not statistically significant, owing to the small population, the crude day-180-nonrelapse mortality rate was about 20% lower and the day-180-overall-survival rate tended to be higher than the control (11% vs. 29%, p = 0.222; 79% vs. 50%, p = 0.109, respectively). There were no serious IASI-related complications. Our results suggest that IASI can safely provide excellent efficacy for refractory acute GI GVHD without increasing infection-related complications and may improve prognosis.

[Cold autoimmune hemolytic anemia complicated with relapsed myelodysplastic syndrome after allogeneic hematopoietic cell transplantation].

Myelodysplastic syndrome (MDS) is known to often be complicated by a range of autoimmune diseases. We herein present a case with MDS complicated by cold autoimmune hemolytic anemia (cold AIHA). The patient was a 51-year-old woman. She was diagnosed with MDS (refractory cytopenia with multilineage dysplasia) in May 2009. In January 2010, she underwent unrelated allogeneic bone marrow transplantation but was re-admitted in October 2010 for treatment of relapsed MDS. Despite daily transfusions of red blood cells, her anemia failed to improve. Her laboratory examinations showed a low haptoglobin level and elevation of indirect bilirubin and LDH. The direct Coombs test was positive at a low and at room temperature and cold agglutinin was negative. After confirming the diagnosis of cold AIHA, all transfusion fluids were warmed but her anemia still failed to improve. In addition to the warmed transfusion fluids, we administered corticosteroids, immunosuppressive agents and high-dose intravenous immunoglobulin infusions. This management strategy ameliorated the patient's hemolytic anemia. To our knowledge, MDS cases complicated by cold AIHA are rare. Our patient thus provides a valuable contribution to medical knowledge.

Prognostic value and clinical implication of serum ferritin levels following allogeneic hematopoietic cell transplantation.

Little research has been done on changes in serum ferritin (s-ferritin) levels and clinical implications following allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated the correlation of s-ferritin levels after HCT with survival in 203 patients. The s-ferritin level was significantly elevated, with 75% of the patients showing peak levels 90 days after HCT. The level was >10,000 ng/ml in a total of 43% of the patients, a finding that was associated with febrile neutropenia or infection. The s-ferritin level at day 30 and at 1 year after HCT was significantly associated with prognosis. However, this statistically significant relationship was lost after adjusting for acute-phase reactants. We conclude that hyperferritinemia is very common and the degree of influence of a red blood cell transfusion will vary depending on the phase after HCT. A prospective study is needed to determine if iron load in and of itself contributes to a worse prognosis after HCT.