Allo-hematopoietic Stem Cell Transplantation Research Articles

Sexual Dysfunction and Abnormal Androgen Level after Hematopoietic Stem Cell Transplantation

Introduction: Hematopoietic stem cell transplantation (HSCT) is a potentially curative or consolidative therapy for a large number of hematological diseases. Sexual dysfunction (SD) and abnormal level of the sexual hormone are common in patients after HSCT, which are usually caused by intensive myeloablative conditioning. The change of sexual hormone level and SD resulted in the poor quality of life in this population after transplantation. The current aims of this study were to determine: (i) the incidence rate of SD and the association with androgen post both autologous (auto) and allogeneic (allo) HSCT; (ii) multi-factors analysis between SD and clinical characteristics, primary diease, donor type, cGVHD, etc; (iii) the association of androgen with cGVHD and glucocorticoid (GC) therapy. Methods: From April 2010 to February 2019, a total of 126 (74 males and 52 females) patients with hematological diseases undergoing HSCT were enrolled in our study. The reason for the small sample of patients was that only 126 patients completed our Sexual Function Questionnaire. Controls were 108 healthy, age and gender matched persons came from Medical Examiniation Center of our hospital. Assessment indexes included clinical characteristics, donor type, GVHD incidence, sex hormone levels, and Sexual Functioning Questionnaire (SFQ). The SFQ was implemented by the team members of our research group through a telephone interview, email, paper letter, and WeChat. All of the information and privacy of each patient was strictly conserved. Results: 1. Clinical characteristics of the 126 patients who underwent HSCT were shown in Table 1. The median age of the patients was 38 years old (range 16-66) and the follow up after HSCT was from 6 months to 7 years. The predominant disease spectra were multiple myeloma (MM) and acute leukemia in auto- and allo-HSCT group, respectively. Our results showed a significant difference in gender (P<0.004), donor type (P<0.004), and GVHD development (P<0.0001), indicating a higher incidence of SD when we included these indicators into our analysis. There was no singficant difference of SD development in age, education background, annual family income, primary disease, time post HSCT, and phycological state. 2. Figure 1 showed a higher incidence of SD in both female and male patients after HSCT compared to the healthy controls (P<0.001). Most of them complained that they had trouble in normal sex life and sexual function had not yet recovered to the pre-transplantation level. Moreover, female patients exhibited much significantly decline in overall sexual function (OSD) than the male group (P<0.004). As depicted in the figure 2a and 2b, 54% female and 44% of male developed at least one physical sexual problem. Almost all of the female patients of childbearing age were infertility, and only a small number of young (< 30 years) male patients post transplantation could store fertility (data not shown). 3. From the foregoing data analysis, we confirmed that patients after allo-HSCT with or without GVHD usually acompanied with a higher incidence of SD compared to auto-HSCT group (Table 2). Female patients undergoing allo-HSCT who developed SD had a significantly lower level of androgen (P = 0.02, Table 3a), and that of the male patients was lower compared to healthy control with no significance (Table 3b). Female patients diagnosed with cGVHD had much lower adrongen level, especially in those received GC therapy (Table 4). 4. Although some young female patients had been given regular leuprolide injection every 28 days during their chemotherapy period or pre-transplantation, no significant difference was observed both in SD incidence and androgen level (P > 0.05, due to a small sample, data not shown here). Conclusions: Our results here indicated SD remained a major obstacle for patients to have a better quality of life after HSCT. We should pay more attention to the female patients because they might be at a higher risk to develop SD, especially in those underwent cGVHD and received GC therapy. To improve the sexual function for this population, more intervention methods including optimization of conditioning, better controlling of cGVHD, and reproductive function reservation might be helpful to reduce the incidence of SD. Finally, our study suggested that low androgen levels may contribute to SD and androgen replacement therapy might be a promising choice to improve OSD for patients undergoing HSCT. Disclosures No relevant conflicts of interest to declare.

Preemptive Administration of Ruxolitinib Rapidly Ameliorate Gvhd after Allo-Hematopoietic Stem Cell Transplantation: A Single-Center Retrospective Study

Objective: Clinical benefit with ruxolitinib as a salvage therapeutic agent in steroid-refractory acute graft-versus-host disease (aGVHD) has been reported. The purpose of this study is to explore the efficacy and safety profile of preemptive administration of ruxolitinib for patients with GVHD after hematopoietic stem cell transplantation (HSCT), and to determine the optimal timing of start of ruxolitinib treatment. Methods: We conducted a single-center retrospective study to analyze the overall response rate at day 28 and the amelioration of GVHD after preemptive treatment of ruxolitinib in patients with GVHD post-HSCT. A total of 35 patients (26 males/ 9 females) with GVHD (30 aGVHD/ 5 cGVHD) treated at Fujian Medical University Union Hospital (Fuzhou, China) from July 2016 to April 2019 were enrolled. All patients received conditioning regimens including ATG, cyclosporine A, methylprednisolone, methotrexate mycophenolate mofetil w/o basiliximab for prevention of GVHD. Ruxolitinib was administered orally at 10 mg twice daily for patients ≥ 40 kg or 5 mg twice daily if <40 kg. The patients were divided into 3 groups according to the starting time of GVHD treatment with the preemptive ruxolitinib: shorter than 3 days (≤3 day,13, 37.1%), between days 3-7 (3-7 days,10, 28.6%) and more than 7 days(>7 days,12, 34.3%). Treatment responses of ruxolitinib and the safety are compared among groups. Results: These three groups were well matched demographically. There were no significant differences in conditioning regimens, donor types, CD34+ cells infusion, GVHD prophylaxis regimens and primary treatment among 3 groups. The median time to response of ≤3 days group, 3-7 days group and >7 days group was 20.5 (6-43) , 19.5 (2-107) and 20.5 (9-60) days, respectively. The ≤3 d group showed a best overall response rate (ORR) and complete remission rate (CRR) at day 28 after treatment than 3-7 d group and >7 d group (ORR: 92.3% vs 90.0% vs 83.3%, P=0.361; CRR: 46.2% vs 40.0% vs 25.0%, P=0.512 ). The cumulative complete remission rates among 3 groups were 58.5% (≤3 d group), 86.7% (3-7 d group) and 25% (>7 d group), respectively (P=0.096). The severity of GVHD were significantly ameliorated at day 28 in ≤3 d group than the other 2 groups ( 92.3% vs 70.0% vs 50.0%, P=0.064), and moreover, the clinical GVHD scores dropped significantly in ≤3 d group than >7 d group (-1.54 grade vs -0.75 grade, P=0.041) at day 28 after treatment. Incidence and severity of adverse reactions did not differ significantly between groups (P>0.05). Conclusion: When preemptive administration ruxolitinib is initiated rapidly, remarkable efficacy on amelioration of GVHD can be achieved without significant adverse effects. Larger randomized trials are needed to confirm efficacy. Disclosures No relevant conflicts of interest to declare.

Perspectives on the Use of a Medium-Dose Etoposide, Cyclophosphamide, and Total Body Irradiation Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation: The Japanese Experience from 1993 to Present.

The outcome for adults with acute lymphoblastic leukemia (ALL) treated with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) is poor. Therefore, allogeneic HSCT (allo HSCT) for adults aged less than 50 years with ALL is performed with myeloablative conditioning (MAC) regimens. Among the several MAC regimens, a conditioning regimen of 120 mg/kg (60mg/kg for two days) cyclophosphamide (CY) and 12 gray fractionated (12 gray in six fractions for three days) total body irradiation (TBI) is commonly used, resulting in a long term survival rate of approximately 50% when transplanted at the first complete remission. The addition of 30 mg/kg (15 mg/kg for two days) etoposide (ETP) to the CY/TBI regimen revealed an excellent outcome (a long-term survival rate of approximately 80%) in adults with ALL, showing lower relapse and non-relapse mortality rates. It is preferable to perform allo HSCT with a medium-dose ETP/CY/TBI conditioning regimen at the first complete remission in high-risk ALL patients and at the second complete remission (in addition to the first complete remission) in standard-risk ALL patients. The ETP dose and administration schedule are important factors for reducing the relapse and non-relapse mortality rates, preserving a better outcome. The pharmacological study suggests that the prolonged administration of ETP at a reduced dose is a promising treatment.

Gut resistome plasticity in pediatric patients undergoing hematopoietic stem cell transplantation

The gut microbiome of pediatric patients undergoing allo-hematopoietic stem cell transplantation (HSCT) has recently been considered as a potential reservoir of antimicrobial resistance, with important implications in terms of patient mortality rate. By means of shotgun metagenomics, here we explored the dynamics of the gut resistome – i.e. the pattern of antibiotic resistance genes provided by the gut microbiome – in eight pediatric patients undergoing HSCT, half of whom developed acute Graft-versus-Host Disease (aGvHD). According to our findings, the patients developing aGvHD are characterized by post-HSCT expansion of their gut resistome, involving the acquisition of new resistances, as well as the consolidation of those already present before HSCT. Interestingly, the aGvHD-associated bloom in resistome diversity is not limited to genes coding for resistance to the antibiotics administered along the therapeutic course, but rather involves a broad pattern of different resistance classes, including multidrug resistance, as well as resistance to macrolides, aminoglycosides, tetracyclines and beta-lactams. Our data stress the relevance of mapping the gut resistome in HSCT pediatric patients to define the most appropriate anti-infective treatment post HSCT.

A good response of refractory mantel cell lymphoma to haploidentical CAR T cell therapy after failure of autologous CAR T cell therapy

BackgroundThe aggressive form of Mantle cell non-hodgkin B cell lymphoma (MCL) has a dismal prognosis. Dual targeting BTK and BCL2 with ibrutinib and venetoclax has improved outcomes in MCL patients who were predicted not to respond to conventional therapy, but it is unlikely to be curative. Chimeric antigen receptor-modified T (CAR T) cells exhibit very effective function in elimination of relapsed/refractory B-cell lymphoid malignancies, we investigated their use in a patient with relapsed MCL.Case presentationHere, we report a case of a refractory MCL in a patient who had relapsed after conventional chemotherapy and autologous CAR T cell therapy. The patient received multiple molecularly targeted therapies, including targeting BTK and BCL2, and haplo-identical CAR T (haplo-CAR T) cells from her daughter without previous allo-hematopoietic stem cell transplantation. Haplo-CAR T cells could effectively proliferate in vivo and had a clinically significant antitumor activity without serious side effects. The patient achieved a partial remission, with minimal residual disease.ConclusionsThis case suggests that haplo-CAR T cell therapy can be effective in controlling lymphoma that failed to respond to autologous CAR T cell therapy and overcome limitation of autologous CAR T cells, thus may be one possible regimen before the era of off-the-shelf “universal” CAR T cell therapy.Trial registrationChiCTR-OPN-16008526. http://www.chictr.org.cn/showproj.aspx?proj=13798; ChiCTR1800019385. http://www.chictr.org.cn/showproj.aspx?proj=32805; ChiCTR1800019449. http://www.chictr.org.cn/showproj.aspx?proj=32778.

Survival after Post-Hematopoietic Stem Cell Transplantation AML Relapse: A Single Center Experience

Introduction Post-allogeneic hematopoietic stem cell transplantation (HSCT) acute myeloid leukemia (AML) relapse has a dismal prognosis and no standard of care treatment. Current common treatment options for (re)inducing a graft versus leukemia effect (GvL) are cessation of immunosuppressive therapy, administering hypomethylating agents or high dose chemotherapy. After reinduction of remission is achieved, the effect can be consolidated with a donor lymphocyte infusion (DLI) or a second allogeneic HSCT. In this study we analyzed outcomes of patients with post-allogeneic HSCT AML relapse in our institute. Objectives To evaluate outcome of patients with post-allogeneic HSCT AML relapse, who received different types of reinduction therapy regimens and of whom a subgroup underwent immunological consolidation therapy. Methods Data was collected from the medical history of all 83 adult patients that had received an allogeneic stem cell transplantation for AML or high-risk myelodysplastic syndrome (MDS) at the Amsterdam University Medical Centers between January 1st 2010 and 31st December 2016 and who relapsed before December 31st 2017. In this retrospective analysis, patients were divided into a curative intent treatment group and a palliative care group. Statistical analysis was done with IBM SPSS version 24.0.0.1 using Mann-Whitney U, Chi-square testing, Pearson's R for ordinal variables and Kaplan Meier survival analysis with log rank testing. Results 50 (60%) of the 83 patients were treated with the intent to cure and the other 33 (40%) received palliative care. Of the patients treated with curative intent, 13 (26%) survived. The patients in the palliative care group were older than the patients in the curative intent group (median age 58 vs 53 year, P=0.043). They also had a higher bone marrow blasts count (median 37.5% vs 20.5%, P=0.025), and shorter time between allo HSCT and relapse (median 21 weeks with IQR of 6-28 vs median of 21 weeks with IQR 14-47.25, P=0.047). Within the curative intent group these variables did not differ significantly between survivors and deceased. Of the patients in the curative intent group 44% reached CR and of these patients 50% survived. The majority of the survivors received high dose cytarabine treatment (69%) and immunologic consolidation therapy (69%). A relapse ≤ 12 weeks after allogeneic HSCT but not relapse Conclusion This retrospective analysis of a real-life, non-preselected patient group with post-allogeneic HSCT AML or MDS relapse demonstrated that patients who were fit enough to receive high-dose reinduction therapy, followed by a immunologic consolidation with DLI or a second allogeneic HSCT had the best chance to obtain durable remissions, in particular when immunologic consolidation was performed when the patient had obtained complete remission.

The Effectiveness of the Neutropenic Diet in Pediatric Bone Marrow Transplant Patients

Background Opportunistic infections are a significant cause of morbidity and mortality in children treated with chemotherapy. Historically, the neutropenic diet has been utilized to limit the incidence of infections by reducing exposure to potential pathogens. The neutropenic diet is utilized at our center for all allogeneic(allo) hematopoietic stem cell transplant (HSCT) patients at admission and restricts uncooked vegetables, fruits without thick peels, undercooked meats/seafood, and any restaurant food. Autologous (auto) HSCT patients follow a regular diet with food safety education according to Center for Disease Control (CDC) and Food and Drug Administration (FDA). The neutropenic diet is not endorsed by the CDC and FDA due to lack of evidence to support it. We hypothesize the neutropenic diet offers limited advantage over the FDA and CDC food safety guidelines in respect to rates of neutropenic fever or infection. Methods We performed a retrospective descriptive review of consecutive pediatric patients >1 year of age that underwent HSCT between June 2016 and February 2017 to assess fever and infectious complications occurring before engraftment. All patients were placed on prophylactic antibiotic therapy (cipro and pen VK) on admission until fever or engraftment. Results A total of 72 HSCT procedures were conducted on our inpatient unit (Auto, 24 and Allo 48). Median age at HSCT was 6 years (Range 1-24 years). Of 72 total transplants, 56 (78%) had at least one fever episode from the start of conditioning until engraftment. The median day of fever was day -2. 6 of 57 episodes of fever were due to blood steam infection (3 allogeneic; 3 autologous), Organisms included Bacillus species, Enterobacter cloacae, acid fast bacilli, Streptococcus oralis and Staph epidermidis. Twenty-eight patients had diarrhea, five had identified stool pathogens to include C.difficile (n=2), Adenovirus (n=3), Norovirus (n=1), E.coli (N=1), of note 2 patients had 2 concurrent infections present. Sixty seven(89%) patients received TPN for a median of 41 days (ranging from 9-233 days) for allogeneic and median of 20 days (ranging from 6-170 days) for autologous recipients. Thirty seven (49%) patients had clinically documented mucositis (see Table 1). Discussion Fevers were commonly chemotherapy related and infectious causes were rare for both auto HSCT on a regular diet and allo HSCT on a neutropenic diet. Antibiotic practices may contribute to outcomes. Further investigation evaluating the safety of the FDA diet during the neutropenic period of HSCT is warranted to improve overall nutrition and quality of life.

Risk factors for decreased pulmonary function after allo-hematopoietic stem cell transplantation

Risk factors for decreased pulmonary function after allo-hematopoietic stem cell transplantation

The 8p11 myeloproliferative syndrome: a review of recent literature

The 8p11 myeloproliferative syndrome (EMS) is a relatively rare hematological malignancy defined by the presence of chromosomal abnormalities associated with fibroblast growth factor-1 gene, located in the 8p11-12.1 chromosomal locus. To date, only around a hundred cases have been reported in the literature. Patients with EMS present with various forms of myeloid/lymphoid malignancies, such as myeloproliferative neoplasms, acute myeloid leukemia, and T- or B-linage lymphoblastic lymphoma, which are frequently associated with eosinophilia. Prognosis of EMS is poor and a standard treatment strategy has not yet been established. In contrast to myeloid/lymphoid neoplasms associated with PDGFR-A or PDGFR-B rearrangement, the tyrosine kinase inhibitor (TKI) imatinib is not an effective therapeutic option for EMS patients. Other types of TKI, i.e., PKC412, sorafenib, ponatinib, dasatinib, and dovitinib, show growth-inhibitory effects against the cells harboring several types of FGFR-1 fusion genes in in vitro studies; however, the usefulness of either drug has not been confirmed by clinical trials. Therefore, at present, allo-hematopoietic stem cell transplantation is the only curative methods for EMS. Very recently, a phase-2 study with pemigatinib, an inhibitor for FGFR1, showed clinical benefits for EMS patients, including major cytogenetic response, suggesting a new therapeutic option for EMS.

Clinical Efficacy of Therapies for Transfusion-Dependent Non-Severe Aplastic Anemia: A Retrospective Cohort Study in Multiple Hospitals

BACKGROUND: This study aims to evaluate the clinical efficacy and prognosis of currently popular treatments for patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA).METHODS: Medical records of patients with TD-NSAA were collected from three hospitals and divided into four groups based on their treatment. Treatment efficacy was evaluated at 6 months after treatment, with subgroup analysis based on patients' disease courses. Adverse events and 3-year survival status were also reviewed.RESULTS: A total of 175 patients' records were collected in this study. The analysis of treatment efficacy indicated that the most effective treatment was allo-hematopoietic stem cell transplant (HSCT) with the response rate of 84.62%, which was followed by Anti thymocyte globulin and ciclosporin A (ATG + CsA) (68.52%), CsA + androgen (26.92%), and androgen (0%), respectively. The subgroup analysis showed that for patients with less than 6-month disease courses, ATG + CsA treatment could achieve similar response rate as allo-HSCT (84.00%). Besides, ATG + CsA showed better efficacy than CsA + androgen in all stratified arms (P<0.05). Three-year event-free survival rates were higher in patients treated with ATG + CsA (83.3%) than with CsA + androgen (64.4%) (P=0.013).CONCLUSIONS: Therefore, we concluded that ATG+ CsA could achieve better efficacy to treat TS-NSAA than did CsA+ androgen. DisclosuresNo relevant conflicts of interest to declare.

A Novel Unifrac-Based Analytical Method for Determining Sequential Changes in Gut Microbiota after Hematopoietic Stem Cell Transplantation

The human gut harbors various microorganisms, which are important for maintenance of systemic health, including metabolism and immune system homeostasis. Recent studies demonstrated the association of intestinal flora with various diseases such as inflammatory bowel disease and rheumatoid arthritis. In addition, studies on patients with hematopoietic stem cell transplantation (HSCT) showed that the variation in intestinal bacterial flora after transplantation is related to prognosis, frequency of infection, sensitivity to antimicrobial agents, and severity of graft versus host disease. Nonetheless, most studies showing less diversity of intestinal flora evaluated patients' feces a certain period after HSCT. In order to determine the relationship between the alterations in intestinal flora composition and the clinical course post-HSCT, we used metagenomic analysis to evaluate the time-dependent changes in intestinal bacterial flora in patients undergoing allogeneic (allo) HSCT, and compared them with those of healthy controls (HC) or recipients of autologous (auto) peripheral blood HSCT.Patients who received autologous or allogeneic HSCT at the Osaka University Hospital were enrolled after obtaining informed consent. We collected 613 feces samples from 24 patients from August 2016 to May 2017 before and after transplantation. Samples were collected in sterile centrifuge tubes and 16S rRNA deep sequencing was performed using MiSeq (Illumina). In total, 543 specimens were available for analysis.First, we evaluated the diversity of the microbiota in pre-transplantation specimens using Simpson's and Shannon-Wiener index. However, neither method revealed any significant difference between auto/allo-patients and HC despite intensive treatment history of the patients, but showed that the major phyla of gut microbiota contained Bacteroides, Firmicutes, and Fusobacteria in all three groups. Next, we utilized ‘uniFrac distance’ to evaluate both the diversity in community structure and members. Indeed, this method was useful for evaluating both weighted (quantitative) and unweighted (qualitative) variations of numerous organisms. Using this method, we were able to accurately estimate the abundance of gut microbiota. Interestingly, weighted uniFrac distance, which describes distances in community structure, was significantly wider between allo vs HC and HC vs HC (p < 0.001) and auto vs HC and HC vs HC (p < 0.001). Furthermore, unweighted uniFrac, which describes the distance between community members, was significantly wider between allo vs HC and HC vs HC (p < 0.001), but not between auto vs HC and HC vs HC (p = 0.69).Next, we analyzed the structural components of microbiota using pre-treatment samples. Results showed that the population of beneficial bacteria such as butyric acid-producing bacteria, Coprococcus, Faecalibacterium, and Lachnospiraceae, were significantly reduced in the microflora of pre-transplantation patient samples compared to HC. In addition, sequential chronological analyses revealed that dynamic fluctuation in the intestinal flora was induced in patients by use of antibiotics. We also observed inter-patient variation in the extent of fluctuation; > 50% patients lost flora diversity after transplantation, whereas some patients retained it despite administration of broad spectrum antibiotics.Next, we analyzed whether alteration in flora composition and/or the loss of diversity affected patient survival. Among 24 patients, 16 showed altered flora composition, whereas 8 retained the flora characteristics. Among these 16 cases, the 2-year mortality of patients who had lost flora diversity was 63.6 %, whereas it was 25.0 % for patients who retained the diversity (p < 0.001). In contrast, all 8 patients who retained original flora composition were alive. Hence, we concluded that both alteration in flora composition and loss of diversity are strongly associated with patient survival.In conclusion, commonly used diversity indexes do not completely describe the differences within genera of gut microbiota, and uniFrac analysis is a powerful tool for evaluating gut microbiota in patients with HSCT, as it analyzes community composition/structure in detail. This method can also be used to simultaneously evaluate alterations in flora composition and loss of diversity, both of which affect survival post-HSCT. DisclosuresYokota:Pfizer Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; MSD K.K.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Shibayama:Ono Pharmaceutical Co.,LTD: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding; Bristol-Meyer Squibb K.K: Honoraria, Research Funding; Mundipharma K.K.: Honoraria, Research Funding; Fujimoto Pharmaceutical: Honoraria, Research Funding; Jansen Pharmaceutical K.K: Honoraria; Novartis Pharma K.K.: Honoraria, Research Funding; Takeda Pharmaceutical Co.,LTD.: Honoraria, Research Funding. Kanakura:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Association of CD117 and HLA-DR expression with shorter overall survival and/or progression-free survival in patients with multiple myeloma treated with bortezomib and thalidomide combination treatment without transplantation.

Certain immunophenotypes in multiple myeloma (MM), including CD56 and CD117, have been reported to be associated with overall survival (OS). However, previous reports have ignored the impact of different treatment regimens and the long-term prognostic value of immunophenotyping in MM when treated with novel agents, including thalidomide and bortezomib, in the absence of transplantation for autologous stem cell transplantation and allo-hematopoietic stem cell transplantation. To further understand the long-term prognostic value of immunophenotyping in MM, when treated with bortezomib combined with thalidomide-based regimens without transplantation, 80 patients who were newly diagnosed between January 2007 and December 2015, were analyzed retrospectively. In contrast to previous studies, no significant survival time difference was observed between CD56+/CD117+ and CD56-/CD117- groups. Multivariate analysis suggested that human leukocyte antigen-antigen D-related (HLA-DR)+ was independently associated with shorter OS and progression-free survival (PFS), while CD117+ was an independent prognostic factor for decreased PFS. In addition, the myeloma prognostic index (MPI), defined by HLA-DR+, age ≥65 years and international staging system stage III, was suitable for risk stratification of patients treated with novel agents for OS and PFS. The results of the current study suggested that HLA-DR+ patients had a shorter OS and PFS and CD117+ patients had shorter PFS. HLA-DR+ or CD117+ was sufficient to affect survival. Evaluating these markers may reveal valuable prognostic factors for MM in patients receiving bortezomib combined with thalidomide-based regimens without autologous stem cell transplantation and allo-hematopoietic stem cell transplantation). MPI may describe an accessible tool to predict the prognosis of patients with MM.

Safety and Efficacy of VDMP Re-induction Regimen in Chinese Children with Relapsed Acute Lymphoblastic Leukemia-A Report from Jiangsu Childhood Hematology Group

To evaluate the therapeutic safety and efficacy of VDMP re-induction regimen in Chinese children with relapsed acute lymphoblastic leukemia (ALL). Forty-one patients with relapsed ALL were prospectively enrolled in this study. All the patients were distributed in 3 children's hospitals and treated with VDMP regimen as the first re-induction chemotherapy. Therapeutic efficacy and side-effects were analyzed. The ratio of male to female was 27:14. The median age was 7.9 (2.2-15.4) years old. Patients relapsed at very early, early, and late stage were 7 cases, 11 cases, and 23 cases, respectively.The immunophenotype analysis showed that 38 cases were B-ALL, and 3 cases were T-ALL. All patients suffered from grade 4 of neutropenia and forty(97.6%) cases got infection, of them one case died. Thirty-nine(95.1%) cases had nonhematologic adverse event at least one organ involved grade 3 in 38 out of 41 cases, the VDMP therapy was completed, 34(89.5%) cases achieved a complete remission (CR), 1 case achieved partial remission(PR), and 3 cases didn't get remission. Follow-up data of 38 cases with completing VDMP chemotherapy were obtained, only one case was lost. Among 37 cases available for evaluation, 16 cases received allo-hematopoietic stem cell transplantation(allo-HSCT) after chemotherapy, and 13 patients survived, while 21 cases did not receive allo-HSCT(treated with chemotherapy only), and 8 patients survived.The overall survival rate of allo-HSCT group was significantly higher than that of those treated with chemotherapy only(P<0.05). VDMP re-induction regimen is effective and well tolerable for pafients in the treated children with relapsed ALL. After remission, allo-HSCT is recommended with the aim of long survival.

Villous atrophy in the terminal ileum is a specific endoscopic finding correlated with histological evidence and poor prognosis in acute graft-versus-host disease after allo-hematopoietic stem cell transplantation

BackgroundGraft-versus-host disease (GVHD) is a common complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Endoscopic biopsy can provide a definitive diagnosis, but the optimal endoscopic approach for diagnosis remains uncertain. This study evaluated whether ileocolonoscopic imaging can predict acute GVHD severity after allo-HSCT.MethodsConsecutive patients who underwent allo-HSCT were referred to our institution, and those diagnosed with acute GVHD by pathology were included in this retrospective study.ResultsFifty-one of 261 patients who underwent ileocolonoscopy were suspected to have acute intestinal GVHD. We performed univariate and multivariate conditional logistic regression with stepwise variable selection; villous atrophy in the terminal ileum remained a statistically significant predictor of GVHD severity (odds ratio, 4.69; 95% confidence interval, 1.07–20.60, P = 0.04). Patients were classified into three groups based on ileal endoscopic findings in the terminal ileum: group S, GVHD with severe villous atrophy; group M, mild atrophy; and group N, no atrophy. Compared with patients in groups M and N, those in group S had significant clinical GVHD at diagnosis (P = 0.03). In group S, three of four, compared with five of 13 patients in groups M and N, required the addition of second-line agents (P = 0.02).ConclusionsThis study showed that severe atrophy of the terminal ileum predicts severe clinical GVHD that is likely to be refractory to steroid treatment. Thus, the severity of terminal ileum atrophy may serve as a tool in predicting clinically severe GVHD.Trial registrationTrial Registration Number UMIN 000022805, Registration date July 1, 2016.

Role of Regulatory T Cells in Tumor-Bearing Mice Treated with Allo-Hematopoietic Stem Cell Transplantation Plus Thymus Transplantation.

We recently developed a new allogeneic hematopoietic stem cell transplantation method (allo-HSCT) combined with thymus transplantation (TT) from the same donor (allo-HSCT + TT). This method induces elevated T cell function with mild graft-versus-host disease (GVHD) in comparison to conventional HSCT alone and HSCT + donor lymphocyte infusion (DLI). This new method is effective against several intractable diseases, including malignant tumors, for which conventional treatments are ineffective. Regulatory T (Treg) cells play an important role in the enhanced graft-versus-tumor (GVT) effect and reduction of GVHD, thus leading to longer survival. Replacement and reduction of elevated Treg cells by donor-derived allo-Treg cells from the transplanted thymus may play one of crucial roles in the effect. This review discusses the role of Treg cells in a tumor-bearing mouse model treated with allo-HSCT + TT.

Effects of IFN-γ on Pulmonary GVHD after Allo-Hematopoietic Stem Cell Transplantation

To explore the effects of IFN-γ on pulmonary GVHD after hematopoietic stem cell transplantation (HSCT). The mouse GVHD models were established by using C57BL/6J, B6D2F1 mice and different HSCT. According to HSCT modes, the mice were divided into 3 groups: syngeneic HSCT group(C57BL/6J→C57BL/6J), allogeneic HSCT group (C57BL/6J→B6D2F1) and IFN-γ -/- allogeneic HSCT group (IFN-γ -/-→C57BL/6J→B6D2F1). The survival time, GVHD clinical seore, pulmonary pathologic changes in 3 groups were compared and analyzed, and the total cell count in BALF and IFN-γ level in serum were detected in 3 groups after transplantation. The mice in syngeneic HSCT group all survived at day 42 after transplantation without GVHD symptoms in lung, the GVHD clinical score was low. The mice in allogeneic HSCT group survived at day 24 after transplantation (survial rate >50%), the GVHD clinical score was higher than that in syngeneic HSCT group, the pathologic changes in lung did not serious, though the GVHD presentation was observed, but the olveola bleeding and lymphocyte infiltration in lung tissue were observed at day 28 after transplantation. The mice in IFN-γ -/- allogeneic HSCT group all died of lethal GVHD within 14 days after transplantation, the GVHD clinical score reached to 6.7± 0.83 at 1st week after tansplantation, which was significantly higher than that in syngeneic and allogeneic HSCT groups. At 1st week after transplantation, the serious GVHD pathological changes occured in lung tissue, total cell count in BALF significanty increased, compared with syngeneic and allogeneic HSCT groups, but IFN-γ level in serum was significantly lower than that in syngeneic and allogeneic HSCT groups (P<0.05). Donor-derived IFN-γ plays an important immunoprotective role for lung tissue after HSCT.

Co-existence of isodicentric Ph chromosomes and the three-way Ph chromosome variant t(3;9;22)(p21;q34;q11) in a rare case of chronic myeloid leukemia.

More than 90% of patients with chronic myeloid leukemia (CML) have the chromosomal translocation t(9;22)(q34;q11), while 5-8% of patients have complex variant translocations that have previously been thought not to affect the efficacy of imatinib therapy. The present study reports a patient with CML in B-lymphoid blast crisis who had a rare three-way Philadelphia (Ph) variant t(3;9;22)(p21;q34;q11), in addition to isodicentric Ph chromosomes. The patient was initially treated with imatinib for >2 months with a very poor response. When no T315I or F317L mutations in the ABL proto-oncogene 1 region were detected, the patient received dasatinib treatment (140 mg daily) and achieved a complete hematologic response. Following allo-hematopoietic stem cell transplantation, the patient displayed clinical, hematological and cytogenetic remission, with complete molecular response and complete donor chimerism, and stopped taking dasatinib at the last follow-up. The present data suggest that BCR-ABL gene amplification may be associated with imatinib resistance, which can be overcome with dasatinib. The present analysis suggests an alternative therapy strategy for CML involving isodicentric Ph chromosomes.

The Impact of a Humanized CCR4 Antibody (Mogamulizumab) on Patients with Aggressive-Type Adult T-Cell Leukemia-Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation.

Although a humanized CCR4 antibody (mogamulizumab) was reported to be effective for refractory adult T-cell leukemia-lymphoma (ATL), several reports regarding the use of mogamulizumab before allo-hematopoietic stem cell transplantation (HSCT) strongly indicated a high incidence of severe acute graft-versus-host-disease (GVHD) and treatment-related mortality (TRM). We retrospectively analyzed nine aggressive-type ATL patients who underwent allo-HSCT at a single institution in Miyazaki from 2006.1.1 to 2015.7.31. Among nine ATL patients, three had used mogamulizumab before treatment with allo-HSCT because of the poor control of refractory ATL. All three patients were treated with four to eight cycles of mogamulizumab. The interval from last administration of mogamulizumab to allo-HSCT was two to five months. All three patients with prior mogamulizumab treatment developed mild-moderate acute GVHD (grade 2) 28, 34, or 40 days after allo-HSCT. Acute GVHD was controlled by prednisolone treatment. Two patients in complete remission before allo-HSCT exhibited relatively prolonged survival (survival rate, 66%). Moreover, one patient developed human T-cell leukemia virus type 1-associated myelopathy-mimicking myelitis at five months after allo-HSCT. In contrast, two of six ATL patients without a history of mogamulizumab use survived (survival rate 33%). Thus, in cases of mogamulizumab use before treatment with allo-HSCT for refractory ATL, an appropriately long interval from the last administration of mogamulizumab to allo-HSCT may be one of factors to reduce TRM by acute GVHD, and to subsequently enhance graft-versus-tumor effects in ATL cases. Furthermore, caution is needed when administering mogamulizumab before allo-HSCT for severe GVHD and TRM.

急性GVHDとリコンビナント トロンボモジュリン

Hematopoietic stem cell transplantation (HSCT) involves the potential for certain serious transplant-related complications such as graft-versus-host disease (GVHD), and recovery from such complications is vital for a successful HSCT outcome. Acute GVHD (aGVHD) occurs in the early period after transplantation and is initiated by alloreactive donor T cells. The mechanisms whereby immune responses trigger this post-transplantation condition remain unclear, but endothelial cell function might play a role in this. Authors investigated the expression of endothelial cell activation markers such as sE-selectin, sVCAM-1, PAI-1 and microparticle (MP) in patients undergoing allogeneic HSCT. Additionally, authors studied the effects of recombinant soluble thrombomodulin (rTM) on the expression of these markers. This study cohort included 312 patients who underwent allo HSCT at 25 institutions in Japan. In the 143 patients who developed aGVHD, levels of endothelial cell activation markers were significantly higher compared to patients who did not develop aGVHD. Moreover, patients who received rTM exhibited a significantly lower frequency of aGVHD and reduced levels of endothelial cell activation markers. These findings suggest that endothelial cell activation might be linked to aGVHD, and that rTM might at least in part act to prevent aGVHD by its effect on endothelial cells.

A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD.Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03.Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation.Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. DisclosuresSchroeder:Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.