Patients Receiving Stem Cell Transplantation Research Articles

Tandem CD19/CD22 Dual Targets CAR-T Cells Therapy Acquires Superior CR Rate Than CD19 CAR-T Cells: A Case Controlled Study

Background: CD19 chimeric antigen receptor (CAR) T-cells therapy has shown unprecedented success in relapsed/refractory (r/r) ALL. Now it is recommended for the treatment of patients up to 25 years with r/r precursor B-ALL. Despite its high response rate, approximately 50% of r/r ALL patients relapsed after CD19 CAR T-cell therapy, which was mainly due to CD19 antigen loss or short persistence of CAR T-cells in vivo. CD19 and CD22 dual target CAR T-cells have demonstrated to reduce relapse post CD19 CAR T-cell therapy in limited cases. This study was designed to investigate the efficacy and safety of CD19/CD22 dual targets CAR-T cells and the correlation between that and CD19 CAR-T cells. Methods: A novel tandem CD19/CD22 CAR-T construct with CD28 and OX40 co-stimulatory domains were administered. All patients received FC (fludarabine, 30 mg/m2, days 1-3 and cyclophosphamide, 300 mg/m2, days 1-3) based regimen chemotherapy pre-infusion. Median infusion dose of CAR-T cells was 1(0.5-2.5) *107 cells/kg. All the patients accepted the bone marrow examination 28 days post CAR-T infusion. We conducted a retrospective, case controlled study analysis at the First Hospital of Soochow University. Every patient with active disease treated with CD19/CD22 CAR-T cells therapy was paired with one control subject who received CD19 CAR-T cells from January 2017 to September 2019. We matched the control group to prevent bias according to: (1) bone marrow blast before CAR-T infusion; (2) extramedullary involvement; (3) cytogenetic risk groups according to NCCN guideline; (4) transplantation status pre-infusion. Results: From 2017 Oct to 2020 Jul, 36 patients were enrolled into the clinical trial (NCT: 03614858). Patients who accepted more than 4 previous treatments account for 58.3% and 8 patients received stem cell transplantation pre-infusion. Bone marrow blasts 40.75 (0~94.5)%. After tandem CD19/CD22 CAR-T infusion, all patients achieved completely remission (CR) and minimal residual disease negative (MRD-) CR rate is 77.8%. The 6-month OS rate is 88.36% and 12-month OS rate is 70.6%. The 6-month LFS rate is 88.072% and the 12-month LFS rate is 69.216%. CAR-T bridging HSCT (25/36) obviously improves the 1-year LFS rate compared with non-transplantation group (11/36) (82.309% vs 31.169%, p=0.0135). All the side effects were mild and can be relieved through support treatments. 8 out of 36 patients developed with grade 3~4 CRS. 2 patients had HLH but soon relieved through low dose steroids. 28 out of 36 patients who accepted dual targets CAR-T cells didn't get complete remission before infusion. Therefore, 28 patients were enrolled in the CD19 CAR-T group. There are no significant differences between two groups at baseline. The CR rate was higher in CD19/CD22 group than that in CD19 group(100% vs 53.57%, p=0.000), so was MRD-CR rate(71.43% vs 42.86%,p=0.000). In survival analysis, 6 month overall survival rate of CD19/CD22 group was 69.276% while CD19 group was 53.571%. Of 28 patients who received dual target treatment, 7 patents relapsed while 4 relapsed out of 15 CR patients in CD19 group. Conclusions:The tandem CD19/22 dual CAR-T cell therapy is a safe and high efficacy treatment for R/R ALL patients. Our study demonstrated that dual targets CAR-T cells acquires higher CR rate than CD19 CAR-T cells. It is possible that multi-targeted CAR-T cell therapy may overcome this resistance mechanism and improve clinical outcomes. Disclosures No relevant conflicts of interest to declare.

Assessing the Role of Radiation Therapy for Primary Mediastinal Large B-Cell Lymphoma in the Setting of PET Avid Disease after Chemotherapy

Most patients with primary mediastinal large B-cell lymphoma (PMBCL) are treated with dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) without consolidative radiation therapy (RT), and the value of RT is poorly understood. We sought to evaluate the efficacy of RT administered to PMBCL patients with positron emission tomography–computed tomography (PET-CT) positive findings at the time of RT. We conducted a retrospective review of 22 consecutive PMBCL patients who received RT between 2008 and 2018 with residual metabolically active tumor (defined as five-point score [5PS] of 4-5) at the time of RT. Progression-free survival (PFS) and overall survival (OS) were defined from the last day of RT. The median age at diagnosis was 32 years; 68% (n = 15) were female. Frontline DA-R-EPOCH was administered to 86% (n = 19). End of frontline therapy PET-CT revealed 5PS of 4 in 32% (n = 7) and 5PS of 5 in 68% (n = 15). Biopsy was performed in 64% (n = 14), and was positive in 11 (79%) of the patients. RT was given after 1 line of systemic therapy in 59% (n = 13) and after ≥2 lines of therapy in 41% (n = 9). At the time of RT, 23% had a 5PS of 4 (n = 5) and 77% had a 5PS of 5 (n = 17). RT was delivered using a sequential or simultaneous boost to areas of PET-avid disease in 86% of cases (n = 19), with a median dose of 46.7 Gy (R 36-49.8). At a median follow-up of 6.2 years (95% CI 3.0 – 9.5), the 5-year PFS and OS were 54.5% and 76.4%, respectively. The median PFS and OS were not reached. RT resulted in a complete response (CR) rate of 64%; disease progression after RT occurred in 46% (n = 10), all in patients with 5PS of 5, with a median time of 3.0 months (range 0.8 – 6.8). Failures were in-field (n = 2), out-of-field (n = 3), or both (n = 5). PFS was significantly worse for patients with SUVmax>11.6 at the time of RT (p = 0.001), though not affected by RT dose ≥45 Gy (p = 0.47). Patients with a 5PS of 5 had significantly worse PFS compared to patients with a 5PS of 4 at the time of RT (41% vs. 100%, p = 0.04). For these patients with 5PS of 5, the median PFS was 5.3 months (95% CI 1.2 – 9.5), and a pre-RT SUVmax>11.6 was associated with inferior PFS (p = 0.02). In total, 11 patients received stem cell transplant (SCT); in 3 cases RT was given as salvage following SCT relapse. In 8 cases RT was given pre-SCT, with CR achieved due to RT before SCT in 4 patients. Overall, RT was well-tolerated with two cases (9%) of grade 3 toxicity (1 pneumonitis, 1 esophagitis). No cardiac toxicity or secondary malignancies were noted. PMBCL patients with PET avid disease after frontline immunochemotherapy pose a therapeutic challenge. RT achieved a CR in 50% of patients with PET-positive disease, but was less effective for patients with 5PS of 5. Residual SUVmax data may appropriately guide patient selection as higher activity is associated with inferior outcomes.

Management of patients with acute lymphoblastic leukemia in routine clinical practice: Minimal residual disease testing, treatment patterns and clinical outcomes in Belgium, Greece and Switzerland

ObjectivesTo describe real-world management and clinical and economic outcomes of patients with B-cell precursor acute lymphoblastic leukemia (ALL) in Belgium, Greece and Switzerland. MethodsThis descriptive, retrospective medical chart review collected patient-level data in 2018 from adults with ≥1 minimal residual disease (MRD) test during front-line ALL treatment. Data were stratified by MRD status. ResultsEighty-two patients were included (median age 44 years, 23 % Philadelphia chromosome-positive; MRD-positive: n = 17, MRD-negative: n = 50, MRD result unknown: n = 15). HyperCVAD (32 %) and HOVON (26 %) were the most frequently used front-line treatment protocols; 22 % of patients received stem cell transplantation. Overall, 76 % of ALL patients were hospitalized (mean 1.1 hospitalization/month). Complete hematological response (CRh) occurred in 66/82 patients (80 %). Median relapse-free survival from CRh was 32.7 months (MRD-positive: 11.7 months; MRD-negative: 33.3 months). Median overall survival from diagnosis was 28.9 months (MRD-positive: 15.3 months; MRD-negative: not reached). Most patients (88 %) were MRD tested during induction; testing rates considerably decreased thereafter (39 % during consolidation). ConclusionsB-cell precursor ALL represents a clinical burden and impacts healthcare resources; MRD-positive patients have worse prognosis than MRD-negative patients. Efforts should be made to adhere to recommendations for MRD testing in clinical guidelines.

Frontline Treatment with Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX Is Extremely Potent and Safe in Patients (age ≤ 65 years) with Mantle Cell Lymphoma (MCL) - Results of Phase-II Window-1 Clinical Trial

Frontline Treatment with Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX Is Extremely Potent and Safe in Patients (age ≤ 65 years) with Mantle Cell Lymphoma (MCL) - Results of Phase-II Window-1 Clinical Trial

PCN514 REAL WORLD TREATMENT PATHWAYS OF DIFFUSE LARGE B-CELL LYMPHOMA IN GERMAN CLAIMS DATA

Real world sick funds data in Germany were used to reveal the treatment patterns for Diffuse Large B-cell Lymphoma (DLBCL) and to identify unmet medical needs. In two independent cohorts of German claims data 819 and 189 DLBCL patients were identified and diagnoses, hospitalization, medication and health costs were analyzed for at least two consecutive years between 2013 and 2016. In the first [second] cohort, mean age of DLBCL patients was 60.3 [66.5] years, with two peaks at 50-54 and 70-74 years. Total annual health care costs for DLBCL patients ranged from 25,000 to 60,000 EUR versus 1,259 EUR in healthy insured. Per year, mean 3.2 [3.5] hospitalizations with an average of 31.5 [34.5] hospital days were observed. During the observation period less than half of the DLBCL patients received oncological treatment and only few patients received stem cell transplantation or radiation. Most frequent pharmacological first line treatments were Rituximab (RTX) + CHOP (57%, [56%]) and RTX in combination with Bendamustine (8%, [7%]). In both analyses consistently 84% of patients did not receive further therapies after a first line DLBCL treatment during the limited observation period. Despite limitations in sick fund claims analyses, these databases are a reasonable source for real world evidence (RWE) of rare diseases. Both cohorts were well in agreement and revealed standard treatment pathways consistent with the German treatment guidelines. All DLBCL patients frequently required hospitalization and generated significant costs. A high unmet medical need exists for treatments other than palliative care, especially for a tolerable and effective outpatient therapy in elderly relapsed / refractory DLBCL patients.

Treatment Journeys of Patients With Newly Diagnosed Multiple Myeloma (NDMM): Results From The Connect MM Registry

Sankey plots were generated to illustrate the heterogeneity of treatment sequences and transitions over time in real-world patients from the Connect Multiple Myeloma (MM) Registry. Plots identified immunomodulatory agents and proteasome inhibitors as the mainstays of treatment for patients who did or did not receive stem cell transplant. More patients received stem cell transplant (shown above) and continued to second-line treatment, which highlights the need to choose optimal first-line regimens – particularly for patients without a transplant intent.

Clinically significant delay in engraftment with day -1 melphalan prior to stem cell infusion in myeloma patients receiving stem cell transplant.

Although single agent melphalan is considered the standard conditioning regimen for autologous transplant in myeloma, the timing of melphalan administration is less standardized with limited evidence on optimal timing of infusion.

Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China.

Although many studies have investigated Mendelian susceptibility to mycobacterial disease (MSMD) worldwide, there is no report of the long-term clinical management and prognosis for MSMD in China. This is a cohort study from January 2000 to June 2018. Three hundred and twenty-four patients with bacillus Calmette-Guérin (BCG) infection were diagnosed during this period, and those with MSMD diagnosed by genetic and functional experiments were enrolled in the study. The clinical and genetic characteristics and management of these MSMD patients were summarized. Thirty patients diagnosed with MSMD were followed up. The age at the follow-up end point ranged from 5 to 173months. Among the patients, IL12RB1 mutations were identified in 22, IFNGR1 mutations in 5, STAT1 mutations in 2, and IFNGR2 mutation in 1. The medium age at onset was 3months. BCG infection involved multiple organs, including regional infection (8/30; 26.7%) or distant or disseminated infection (22/30; 73.3%). Ten percent (30/324) of patients with BCG infection had a confirmed MSMD diagnosis. Protein expression of IL12RB1 or IFNGR1 was decreased in all patients with IL12RB1 or IFNGR1 mutation, respectively, as indicated by flow cytometry. In addition, 77.8% of patients received rhIFN-γ treatment, which can improve the prognosis of patients with IL12RB1 deficiency. Two patients received stem cell transplantation. Twenty-five patients remained alive at the time of publication. MSMD is an important cause of BCG infection. Flow cytometric detection of IL12RB1 and IFNGR1 expression is very useful for rapid MSMD diagnosis. rhIFN-γ therapy is effective in patients with MSMD, particularly improving prognosis in those with IL12RB1 deficiency.

Racial and Socioeconomic Disparities in Mantle Cell Lymphoma

BackgroundAlthough race and socioeconomic factors are associated with outcome in many malignancies, few studies have examined the effect of race and socioeconomic status on patients with mantle cell lymphoma (MCL). Patients and MethodsWe used the National Cancer Database to identify patients with MCL diagnosed between 2004 and 2013. We used χ2 and analysis of variance to assess associations of covariates with race/ethnicity. For univariate and multivariable analyses of overall survival (OS) we used Cox proportional hazards models. OS from the time of diagnosis was the primary end point. ResultsOf 18,120 MCL patients, 14,984 (83%) were white non-Hispanic (NH), 709 (4%) black NH, and 1096 (6%) Hispanic. Of these patients, 6798 (39%) had private insurance, 9520 (55%) Medicare, and 635 (4%) Medicaid. Compared with white NH race, black race was associated with treatment at an academic/research program (347 of 681 patients [51%] vs. 5577 of 14,851 [38%]), B symptoms (196 patients [28%] vs. 3 [25%]), Medicaid/uninsured status (101 patients [15%] vs. 642 [5%]), and residence in regions with lower average education and income (all P < .001). Compared with NH black and Hispanic patients, more white NH patients received stem cell transplantation (73 patients [10%] vs. 114 [10%] vs. 1891 [13%]; P < .001). In multivariable analysis, Hispanic ethnicity, private insurance, and treatment at an academic center were associated with better OS (5-year OS 55.8%, 66.2%, and 56.6%, respectively), whereas black race was associated with inferior OS (5-year OS 46.8%). ConclusionWe identified disparities according to race and ethnicity in OS, independent of insurance and socioeconomic status. Further assessment of treatment patterns might elucidate new targets for improving access to care and health outcomes for rare cancers.

Survival of Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) Patients Receiving Stem Cell Transplantation (SCT)

Background The prognosis of patients with R/R AML is poor. The aim of salvage therapy in R/R AML patients is to bring patients to complete response (CR) and subsequently proceed to SCT. CR rate is generally low among R/R AML patients, particularly after 2nd salvage therapy, which can be as low as 13% according to a recent large-scale retrospective analysis (Kantarjian HM et al, Cancer 2018;124(12):2534-2540). Objective To evaluate the survival of R/R AML patients receiving SCT, we systematically reviewed survival outcomes of R/R AML patients who underwent SCT after salvage therapy and compared with outcomes of R/R AML patients who didn't undergo SCT after salvage therapy. Evidence Acquisition A systematic review was conducted in PubMed, Embase, Cochrane and grey literature. Studies in R/R AML patients reporting survival of both patients receiving SCT and not receiving SCT after salvage therapy were included. Results Twenty-four studies were included. Median CR rate after salvage chemotherapy, among the included studies, was 30% (range: 3.3% - 75%). The highest value corresponds to a population with translocation (t)(8;21) (classified within the favourable prognosis group). Eligibility for proceeding to SCT varied among studies. Median SCT rate, among the included studies, was 26.6% (range: 5% - 76.3%). Median time from salvage chemotherapy to SCT ranged from 2.1 to 4.8 months. Survival of SCT and non-SCT population was compared in a non-randomized setting in all the included studies. Median OS for patients who proceeded to SCT ranged from 6.5 to 39 months, whereas for patients who were not able to proceed to SCT median OS ranged from 1.5 to 11.9 months. Significantly lower hazard ratio (HR) for SCT compared to non-SCT was also reported, with HRs ranging from 0.25 - 0.58. Additionally, 1 thru 5-year OS rate favored SCT in all studies. Furthermore, four studies evaluated OS of SCT recipients after CR or no-CR. Median OS of SCT after CR and no-CR ranged from 11.7 to 60 months and 4 to 15 months respectively. Age, blast counts, and performance status were among the significant prognostic factors of survival after salvage chemotherapy. While in some studies blast counts and white blood cell count were also significant predictors of, respectively, OS and DFS after SCT, not all studies provided information on whether patients had active disease. Conclusion R/R AML patients who have managed to receive SCT demonstrated better survival compared to those who did not. A limitation of this review was that no randomized controlled trials comparing SCT with chemotherapies were found and patient characteristics between the SCT and non-SCT populations differed in the included studies. Novel targeted conditioning with anti-leukemia therapies may make SCT achievable, with a reduced time to transplant, and may improve outcomes in R/R AML patients.

VP46 German Claims Data In Rare Disease HTA: Diffuse Large B-cell Lymphoma

IntroductionIn rare disease areas representative data are scarce. Routine sick fund claims data provide a meaningful and reliable base for the in- and outpatient treatment landscape. This real-world data (RWE) from Germany was used to describe treatment patterns for Diffuse Large B-cell Lymphoma (DLBCL), the most frequent and aggressive non-Hodgkin lymphoma type in adults.MethodsClaims data from several sick funds of 4.8 Million insured were analyzed. Diagnosis of non-follicular Lymphoma (C83) was confirmed in 2.178 patients, DLBCL (C83.3) in 819 patients. The analysis was age- and gender-adjusted, observational period was 2014 and 2015. Treatments were analyzed for hospitalization and medication based on ATC-Code, Pharma Central Number and coded diagnoses (per ICD).ResultsMean age of DLBCL patients was 60.3 years, with two peaks at 50-54 and 70-74 years. Total costs for patients with DLBCL averaged 25.048 EUR versus 1.259 EUR in healthy insured. Charlson comorbidity index (CCI) of 4.58 indicates clinical relevance and severity. Comorbidities included several psychiatric diagnoses such as depression in every fifth patient. Mean 3.2 hospitalizations with average 31.5 hospital days were observed in DLBCL patients. Forty-seven percent of patients during observational time-frame did not receive oncological treatment, including relapsed / refractory patients. Only few patients received stem cell transplantation (2.6 percent) or radiation (3.9 percent). Most pharmacological treatments were Rituximab (RTX) + CHOP (57 percent), followed by RTX mono therapy (25 percent) or RTX in combination with Bendamustine (8 percent).ConclusionsDespite limitations in sick fund claims analyses, these provide a reasonable database for rare diseases. They allow standard treatment pathway- and longitudinal analyses. All DLBCL patients frequently required hospitalization and generated significant costs. A high unmet medical need exists for treatments other than palliative care, especially for a tolerable and effective outpatient therapy in elderly relapsed / refractory DLBCL.

Risk Factors for Invasive Fungal Infection in Children and Adolescents With Hematologic and Malignant Diseases: A 10-year Analysis in a Single Institute in Japan.

Infection, especially invasive fungal infection (IFI), is an important complication of chemotherapy and stem cell transplantation. It is also a well-known risk factor in pediatric hematologic malignancy, acute myelogenous leukemia, recurrent disease and allogeneic stem cell transplantation. We previously revealed that a diagnosis of acute myelogenous leukemia, recurrent disease and >10 years of age were risk factors for IFI in patients with pediatric hematologic malignancies. We examined and compared the incidence, risk factors and mortality rate from IFI between 276 patients from 2007 to 2016 and patients in our past report. The cumulative incidence of IFI was 10.5%; this comprised cases of probable and possible IFI at rates of 5.1% and 5.4%, respectively. Univariate analysis showed that age >9 years at admission, recurrent disease and acute myelogenous leukemia diagnosis were risk factors for IFI. Similar to the results of the previous study, multivariate analysis showed that each of these 3 variables was an independent predictor of IFI. The survival rate was lower in patients with IFI than in those without IFI (38.8% versus 69.9%; P < 0.001). However, IFI was a direct cause of death in only 2 patients. Although 11 patients received stem cell transplantation after IFI treatment, only 2 patients have survived, and the other 9 patients died of other complications.

Treatment, HSCT Patterns, and Survival of Elderly Diffuse Large B-Cell Lymphoma Patients in the SEER-Medicare Linked Database

Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive, sometimes fatal hematologic malignancy and is the most common subtype of Non-Hodgkin's Lymphoma. DLBCL has been readily treated with long, durable remissions with the introduction of rituximab to standard chemotherapy in 1997. The most common front line therapy used to treat DLBCL patients is R-CHOP (Rituximab + Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone). Since DLBCL is primarily a disease of the elderly, the Surveillance, Epidemiology, and End Results program linked with Medicare (SEER-Medicare) database was queried for adult patients (66 years and older) to describe the characteristics of elderly DLBCL patients, current treatment patterns and regimen changes over time, receipt of any type of hematopoietic stem cell transplantation (HSCT), and overall survival.Methods: This retrospective cohort study included adult patients aged 66 years and older newly-diagnosed with DLBCL from 2001 - 2013 and with continuous enrollment in Medicare parts A and B one year prior to diagnosis. Outcomes of interest included most common treatment regimens, overall survival, and receipt of stem cell transplantation. Descriptive statistics and various subgroup analyses were conducted. Kaplan-Meier overall survival proportions and HSCT proportions were estimated.Results: The cohort included 18,058 patients with a median age of 78 at DLBCL diagnosis. About 19% of patients were 66-70, 22% were 71-75, 23% were 76-80, and 36% were 81 or older. There were slightly more females than males (53% vs. 47%), 88% of patients with non-missing race were Caucasian, 4% Asian, 4% Black, and 2% Hispanic. Among the 69% of patients who received treatment after diagnosis of DLBCL, R-CHOP was the most common front line therapy, followed by rituximab in combination with other chemotherapy agents, and rituximab mono-therapy (Table 1). Approximately 30% of patients survived until the end of follow-up. Overall survival of DLBCL patients improved the more recently they were diagnosed. Median survival of patients diagnosed in the most recent years (2010 - 2013) was nearly twice as long as those diagnosed in the earliest years (2001 - 2003) at approximately 922 days (~2.5 years) compared to 484 days (~1.3 years) (Figure 1). At five years post-diagnosis, estimated survival probabilities by year of diagnosis were 0.32 (2001 - 2003), 0.34 (2004 - 2006), 0.36 (2007 - 2009), and 0.39 (2010 - 2013). Approximately 20% of patients received stem cell transplantation during follow-up. In the first six months following diagnosis, HSCT occurred in <1% diagnosed from 2001 - 2003; 16% of those diagnosed from 2004 - 2006; 26% of those diagnosed from 2007 - 2009; and 31% of those diagnosed from 2010 - 2013. On average, HSCT patients differed from non-HSCT patients significantly (p<0.001) by later year of diagnosis (Figure 2), younger age, and less comorbidity burden.Conclusion: The large sample size and recent data are advantageous in describing temporal changes in treatment strategies and overall survival of DLBCL patients. Over time, the use of CHOP as a front line therapy without rituximab nearly diminished. Overall survival estimates indicate that survival rates have steadily improved in more recent years; however, 5-year survival is still less than 40%, suggesting the need for improved treatment options. Stem cell transplants became increasingly more common for the more recently diagnosed patients, and usually occurred within the first six months after DLBCL diagnosis. HSCT recipients were also more likely to be younger and have less comorbidity burden. These data provide insight into current treatment strategies of DLBCL, the types of patients receiving stem cell transplants, and changes that have occurred over time. [Display omitted] DisclosuresKim:Amgen: Employment, Equity Ownership.

Epidemiology of Visceral Mycoses in Patients with Acute Leukemia and Myelodysplastic Syndrome: Analyzing the National Autopsy Database in Japan

【Introduction】Visceral mycoses (VM) are deadly infection and commonly occur in the severely immunocompromised hosts such as in patients with acute leukemia and myelodysplastic syndrome (MDS). To investigate the prevalence of visceral mycoses, we retrospectively analyze the data reported to the “Annual Report of Autopsy Cases in Japan” that includes nationwide autopsy cases published yearly by the Japanese Society of Pathology.【Method】We analyzed all the autopsy data from patients with acute leukemia and MDS included adult T-cell leukemia (ATL) reported in the “Annual Report of Autopsy Cases in Japan” between 1989 to 2015. These data also include patients received hematopoietic stem cell transplantation (SCT). Cases involved stillborn babies or inconclusive in diagnoses are excluded in current analysis. Severe cases were defined as follows: (1) direct cause of death, (2) severe pulmonary infection involving both lobes of the lung, (3) severe visceral infections of 2 or more organ systems, including those involving the central nervous system, (4) multiorgan systemic infection of 3 or more, or (5) a case described as fungemia.【Result】There are total of 175,615 autopsy cases in the data bank and about 7183 cases (4.1%) are acute leukemia and MDS patients. While visceral mycoses were only found in 7756 cases (4.4%) in total cases, there are 1,562 cases (21.7 %) in acute leukemia and MDS, nearly 6-fold higher in prevalence compared with none acute leukemia and MDS cases.Among cases confirmed by single infected pathogen, Aspergillus spp. is the most predominant causative agent (45.0%), while Candida spp. is the second (22.7%). The prevalence of Aspergillus spp. was increased and peaked around 54.0% between 2001 and 2005, then gradually decreased since with more significantly in recent years. Candida spp. was also steadily decreased yearly and bottomed out in 2013. Overall, prevalence is half in Candida spp. and doubled in Mucor spp. compare with 30years ago.Complicated infections cases were founded in 6.5% of patients with acute leukemia and MDS. The most frequent combination is Candida spp. plus Aspergillus spp. (59.8%), while next Mucor spp. plus another spp. (27.0%) and such combination has a trend of gradually increasing since 1997.Most of the severe cases are patients with acute leukemia and MDS presented as visceral mycoses (62.2%). Among them the frequency was 55-67% in Aspergillus spp., Candida spp. and Cryptococcus spp. in severe cases. Otherwise, it was 70-75% in Mucor spp. and complicated cases. After reached the peak of incidence in 2005, the prevalence of Aspergillus spp. has been decreased since 2009.Moreover, we also analyzed the 1098 autopsy cases on patients received stem cell transplantation. 294 cases are found to have visceral mycoses (26.8%). It was 378 cases with GVHD, and visceral mycoses were 23.3% with GVHD group. Prevalence is not decrease in total of SCT cases. Otherwise, it has been decreased in GVHD cases. Aspergillus spp. is the most common (51.6%) and Candida spp.was 19.4% in SCT cases. Interestingly, Candida spp.was more popular than before and the same frequency as Aspergillus spp. with GVHD cases in 2015.【Discussion】A limitation of this study is a retrospective epidemiology from the national archived autopsied cases that may bias towards the severely fatal fungal infection spectrum. Nonetheless, we believe this epidemiological analysis of the autopsied cases with fungal infection provides a strong evidence and incentive to intensify efforts in diagnosing and treating visceral mycosis. Comprehensive prophylaxis or pre-emetic treatment for visceral mycoses may be necessary for selective patients who are undergoing long-term immunosuppressive agent for acute or chronic GVHD, especially the emergence of the non-Candidaalbicans spp. recently as a breakthrough infection that is due to decades of widely use of fluconazole in these patient populations.【Conclusion】Our study is a long-term nationwide study of endemics of visceral mycoses among significant immunosuppressive patients. More recently frequent agents were Mucor spp. in leukemia and MDS, and especially Candida spp. with GVHD. Our data provide valuable evidence that antifungal treatment is one of the most important treatments for leukemia and MDS, and SCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Characteristics and Outcomes of 82 Patients with Mixed-Phenotype Acute Leukemia

Objectives: Mixed-phenotype acute leukemia(MPAL) is a rare disease and comprises 2% to 5% of all acute leukemia. Outcomes for MPAL are worse than both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).The complex phenotype exhibited by this type of leukemia resulted in a myriad of treatment approaches.In our study, we retrospective analysis 82 patients in clinical trail, treatment strategy and prognosis.Method: eighty-two patients diagnosed with MPAL at Nan fang hospital from 2006 to 2017 using either EGIL or 2008 WHO criteria were analyzed. Comparison the treatment effect and outcomes between different therapy types.Result: eighty-two patients, including 60 males and 22 females with a median age of 29 years (range, 2 months-72 years), were studied. 61 patients (77%) were older than 18years, 73patients met the criteria for MPAL via EGIL, 68via WHO2008, and 59of these were reported to satisfy both definitions. fifty one of these cases (62.2%) had a B/myeloid phenotype, Twenty four of these cases (29.3%) had a T/myeloid phenotype. The other cases (8.5%) showed immunophenotypic evidence of a B, T, and myeloid lineage in one blast population. Among the 82 cases, 57 cases with successful cytogenetic studies, 20(35.1%) had normal karyotypes and 37patients(64.9%) had abnormal karyotypes. Twelve patients (21.05%) translocation between chromosomes 9 and 22, five (8.8%) patients had 11q23/MLL translocations. Twelve patients (21.05%) had a complex karyotype and eight patients (14%) had other karyotype. The rarity of this disease and the fact that patients with MPAL are excluded from most AML and ALL clinical trials further complicates guidance about therapy. Of the 82 cases, 75 patients underwent the complete first course of treatment and complete remission rate was 49.8%. treatment approaches utilizing therapy for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and so-called “hybrid” therapy mixing elements of both are 51.9%, 16.7% and 66.7% respectively (P=0.003).OS and EFS with hybrid induction therapy and ALL like induction were not significantly different than those with AML induction by either definition (P>0.05). A total of 60 patients received consolidation treatment, 21 patients received the chemotherapy while 39 patients received stem cell transplant (HSC). The total Median EFS was 21months, in Chemotherapy group and HSC group, the Median EFS was 6 months and 40 months respectively, The 3-year EFS was 26.1% and 55.6% respectively (P=0.038). The total Median OS was 21 months, Median OS showed a significant survival benefit for starting with chemotherapy as compared to HSC( 12 months and 43 months respectively (P=0.001)), The 3-year OS was 19.1% and 57.7% respectively.Conclusion: In this study, ALL like induction therapy or “hybrid” therapy was associated with a more than three-fold greater CR rate than AML therapy. SCT therapy showed a trend for an association with higher OS and EFS for MPAL .Key words: MPAL, Immunophenotype,Treatment strategyFundingKey Sci-Tech Research Projects of Guangdong Province (2014A02021102). DisclosuresFan:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

Prophylaxis for aspergillosis in patients with haematological malignancies: pros and cons

ABSTRACTIntroduction: Along with new diagnostic options, comes the recent development of novel antifungal agents that expanded the spectrum of activity over traditional treatments contributing to the successful management of fungal diseases. Nevertheless, invasive fungal infections (IFI) represent a major hindrance to the favorable outcome of patients with hematologic malignancies. According to these observations, an appropriate prevention of IFI occurring in hematologic patients should be considered of paramount importance. However, the wide use of antifungal agents may facilitate the emergence of resistance and may be associated to the occurrence of severe adverse events and eventually may significantly increase the cost of therapeutic procedures.Areas covered: The aim of present review is to analyze advantages and disadvantages of primary antifungal prophylaxis (PAP) in hematologic patients.Expert commentary: Patients with AML/MDS undergoing intensive chemotherapy and patients receiving stem cell transplantation are at high risk of IFI, and therefore may benefit form PAP, although several additional factors should be carefully evaluated in our decision-making approach, including the local epidemiology and the prompt availability of diagnostic facilities. The advent of new treatment options for hematologic patients such as target therapies might facilitate the rise of new risk categories so far underestimated.

Light chain type predicts organ involvement and survival in AL amyloidosis patients receiving stem cell transplantation

AbstractWe evaluated the impact of light chain type, lambda (λ) or kappa (κ), on disease features and outcomes in patients with immunoglobulin light chain (AL) amyloidosis receiving stem cell transplant at the Mayo Clinic between October 2002 and August 2016. Patients with λ AL amyloidosis had higher rates of renal and neurological involvement (λ 69% vs κ 57%, P = .02 and λ 16% vs κ 9%, P = .03, respectively). Patients with κ AL amyloidosis had more hepatic involvement (λ 7% vs κ 18%, P = .0003). Complete response rate was 43% for both groups and overall response rates were similar (λ 85% vs κ 91%, P = .12). Patients with κ light chain amyloidosis had better progression-free and overall survival (PFS: λ 74 months vs κ 101 months, P = .0064 and OS: λ 121 months vs κ not reached, P = .003). Mayo stage 2004 was more predictive of survival in the λ cohort (median OS of 143 months stage I vs 77 months stage II vs 33 months stage III, P < .0001) than in the κ cohort (median OS not reached for stage I and II and 102 months for stage III, P = .044). Conditioning dose predicted survival in the λ cohort only (median OS 149 months for melphalan 200 mg/m2 vs 50 months for melphalan <200 mg/m2, P < .0001; median OS κ not reached for melphalan 200 mg/m2 or <200 mg/m2, P = .38). On multivariate analysis, light chain type remained an independent predictor of survival. Light chain type predicts organ involvement and survival in patients with AL amyloidosis receiving stem cell transplant.

A Cohort of 169 Chronic Granulomatous Disease Patients Exposed to BCG Vaccination: a Retrospective Study from a Single Center in Shanghai, China (2004-2017).

Clinical diagnosis and treatment for chronic granulomatous disease (CGD) have advanced greatly in recent years. However, CGD patients in China have unique clinical features and infection spectrums, which are challenging to their caretakers. Here, we summarized the clinical characteristics, genetic features, treatment, and prognosis of CGD in a single center in Shanghai. One hundred sixty-nine CGD patients were recruited between January 2004 and May 2017 based on clinical diagnosis. Electronic medical charts were reviewed to collect clinical data. Among the 169 patients recruited, CYBB mutations were identified in 150 cases, whereas CYBA mutations were identified in 7 cases, NCF1 in 5, and NCF2 in 7. The medium age at onset was 1month (interquartile range 1-3). The medium age at diagnosis was 8months (interquartile range 3-19). The most common infection sites were the lung (95.9%), lymph node (58.5%), skin (45.4%), intestinal (43.1%), and perianal (38.5%). Bacillus Calmette-Guérin (BCG) infections were common (59.2%). In addition, other non-infectious complications were also common, including anemia (55.4%) and impaired liver functions (34.6%). Thirty-one patients received stem cell transplantation. By the end of this study, 83/131 patients survived. Similar to other non-consanguineous populations, X-linked CGD accounted for the majority of the cases in China. However, BCG infections were a clinical challenge unique to China. In addition, severe infections were the major cause of death and the overall mortality was still high in China.

Clinical Outcomes of Repeated Intraventricular Transplantation of Autologous Bone Marrow Mesenchymal Stem Cells in Chronic Haemorrhagic Stroke. A One-Year Follow Up

Object:Stroke, one of the most devastating diseases, is a leading cause of death and disability throughout the world and is also associated with emotional and economic problems. The main goal of this study was to investigate the clinical outcome of the intraventricular transplantation of bone marrow mesenchymal stem cells (BM-MSCs) in post-haemorrhagic stroke patients.Method:This study was done consisting of eight patients with supratentorial haemorrhagic stroke, who had undergone 24 weeks of standard treatment of stroke with stable neurological deficits. All of the patients received stem cell transplantation intraventricularly using autologous BM-MSCs. Six months and Twelve months after stem cells treatment, the clinical outcomes were measured using the National Institute of Health Stroke Scale (NIHSS) and adverse effect also observed.Result:The results of this study showed improvement of NIHSS score values before and after the treatment in five patients. No adverse effects or complications were detected during the 1-year observation.Conclusion: Intraventricular transplantation of BM-MSCs has shown benefits in improving the functional status of post-haemorrhagic stroke patients with no adverse effect.

Correction of: Development of a Web-Based Intervention for Addressing Distress in Caregivers of Patients Receiving Stem Cell Transplants: Formative Evaluation With Qualitative Interviews and Focus Groups.

[This corrects the article DOI: 10.2196/resprot.7075.].