Maryam Ebadi

Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.

A large number of elderly patients with acute myeloid leukemia (AML) are not offered treatments with curative intent, such as allogeneic stem cell transplantation (SCT), because of fears of toxicity and perceived futility of intensive treatment. Therefore, the outcomes of SCT in elderly AML patients remain poorly defined. We performed a meta-analysis of all previous articles up until September 22, 2015 of SCT in AML patients >60 years. The primary endpoints were relapse-free survival (RFS) and overall survival (OS) at 6 months and at 1, 2, and 3 years. A total of 13 studies (749 patients) were included. The pooled estimates and 95% confidence intervals (CI) for RFS at 6 months, 1 year, 2 years, and 3 years were 62% (95% CI, 54% to 69%), 47% (95% CI, 42% to 53%), 44% (95% CI, 33% to 55%), and 35% (95% CI, 26% to 45%), respectively. The corresponding numbers for OS were 73% (95% CI, 66% to 79%), 58% (95% CI, 50% to 65%), 45% (95% CI, 35% to 54%), and 38% (95% CI, 29% to 48%), respectively. We found no evidence of publication bias in our primary endpoints, with the exception of relapse, where there appeared to be a relative lack of small studies with high relapse rates. Sensitivity analysis did not identify an overtly influential study for our primary endpoints, with 1 exception in 2-year RFS analysis. The present analysis argues against significant publication bias and demonstrates consistency among reports despite differences in patient-, disease-, center-, and transplantation-related characteristics. Our results suggest that reduced-intensity SCT is a viable treatment option for elderly AML patients with a 3-year RFS of 35% for those over the age of 60. These results argue against using age per se as the sole criterion against SCT and would help remove some of the barriers that often preclude curative intent treatment. Correct identification of patients who would benefit from SCT can improve outcomes in this frequently undertreated population.

Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma: a systematic review and meta-analysis.

Allogeneic stem cell transplantation (allo-SCT) outcomes in patients with Hodgkin lymphoma (HL) remain poorly defined. We performed a meta-analysis of allo-SCT studies in HL patients. The primary endpoints were 6-month, 1-year, 2-year and 3-year relapse-free survival (RFS) and overall survival (OS). A total of 42 reports (1850 patients) was included. The pooled estimates (95% confidence interval) for 6-month, 1-year, 2-year and 3-year RFS were 77 (59–91)%, 50 (42–57)%, 37 (31–43)% and 31 (25–37)%, respectively. The corresponding numbers for OS were 83 (75–91)%, 68 (62–74)%, 58 (52–64)% and 50 (41–58)%, respectively. There was statistical heterogeneity among studies in all outcomes. In meta-regression, accrual initiation year in 2000 or later was associated with higher 6-month (P=0.012) and 1-year OS (P=0.046), and pre-SCT remission with higher 2-year OS (P=0.047) and 1-year RFS (P=0.016). In conclusion, outcomes of allo-SCT in HL have improved over time, with 5–10% lower non-relapse mortality and relapse rates, and 15–20% higher RFS and OS in studies that initiated accrual in 2000 or later compared with earlier studies. However, there is no apparent survival plateau, demonstrating the need to improve on current allo-SCT strategies in relapsed/refractory HL.

Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region

Summary Evidence supports a role of antibody-dependent cellular cytotoxicity (ADCC) toward transitional epitopes in the first and second constant (C1-C2) regions of gp120 (A32-like epitopes) in preventing HIV-1 infection and in vaccine-induced protection. Here, we describe the first successful attempt at isolating the inner domain (ID) of gp120 as an independent molecule that encapsulates the A32-like region within a minimal structural unit of the HIV-1 Env. Through structure-based design, we developed ID2, which consists of the ID expressed independently of the outer domain and stabilized in the CD4-bound conformation by an inter-layer disulfide bond. ID2 expresses C1-C2 epitopes in the context of CD4-triggered full-length gp120 but without any known neutralizing epitope present. Thus, ID2 represents a novel probe for the analysis and/or selective induction of antibody responses to the A32 epitope region. We also present the crystal structure of ID2 complexed with mAb A32, which defines its epitope.

Pretransplant Gut Colonization with Intrinsically Vancomycin-Resistant Enterococci (E. gallinarum and E. casseliflavus) and Outcomes of Allogeneic Hematopoietic Cell Transplantation

Pretransplant gut colonization with intrinsically vancomycin-resistant enterococci (iVRE) (Enterococcus gallinarum and Enterococcus casseliflavus) is uncommon and with unknown clinical impact. In a matched-pairs analysis of patients with versus without iVRE colonization (n = 18 in each group), we demonstrated significantly higher 2-year overall survival (86% [95% confidence interval, 52% to 96%] versus 35% [95% confidence interval, 8% to 65]; P <.01) and lower nonrelapse mortality (P <.01) among colonized patients. Putative metabolomes differentiated iVRE from E. faecalis/faecium and may contribute to a healthier gut microbiome in iVRE-colonized patients.

SN-38 Conjugated Gold Nanoparticles Activated by Ewing Sarcoma Specific mRNAs Exhibit In Vitro and In Vivo Efficacy

The limited delivery of chemotherapy agents to cancer cells and the nonspecific action of these agents are significant challenges in oncology. We have previously developed a customizable drug delivery and activation system in which a nucleic acid functionalized gold nanoparticle (Au-NP) delivers a drug that is selectively activated within a cancer cell by the presence of an mRNA unique to the cancer cell. The amount of drug released from sequestration to the Au-NP is determined by both the presence and the abundance of the cancer cell specific mRNA in a cell. We have now developed this technology for the potent, but difficult to deliver, topoisomerase I inhibitor SN-38. Herein, we demonstrate both the efficient delivery and selective release of SN-38 from gold nanoparticles in Ewing sarcoma cells with resulting efficacy in vitro and in vivo. These results provide further preclinical validation for this novel cancer therapy and may be extendable to other cancers that exhibit sensitivity to topoisomerase I inhibitors.

Absence of early HHV-6 reactivation after cord blood allograft predicts powerful graft-versus-tumor effect

Approximately 75% of cord blood transplant (CBT) recipients experience human herpes virus‐6 (HHV‐6) reactivation. Considering the immunomodulatory effects of HHV‐6, we hypothesized that early HHV‐6 reactivation may influence the risk of relapse of the underlying hematologic malignancy. In 152 CBT recipients with hematological malignancies, we determined the association between HHV‐6 reactivation by day +28 and 2‐year cumulative incidence of relapse. In univariate analysis, the absence of HHV‐6 reactivation (n = 32) was associated with less relapse (26 [18‐35]% vs. 7 [0‐17]% in groups with vs. without HHV‐6 reactivation, respectively; P = .03). This difference was due to a remarkably low relapse incidence among patients without HHV‐6 reactivation. In multivariable analysis, the absence of HHV‐6 reactivation was associated with less relapse (hazard ratio [95% confidence interval]: 0.2 [0.05‐0.9], P = .03). This association was independent of patient‐, disease‐, and transplant‐related characteristics known to influence the risk of relapse. Natural killer cell and T‐cell reconstitution at day +28 were similar between patients with vs. without HHV‐6 reactivation. Our results suggest that CB allografts not complicated by HHV‐6 reactivation by day +28 have a powerful graft‐versus‐tumor effect. Knowledge about early HHV‐6 reactivation may stratify patients at day +28 into low vs. high relapse risk groups.

Prognostic value of prior consolidation in acute myeloid leukemia patients undergoing hematopoietic cell transplantation in minimal residual disease-negative first complete remission: CORRESPONDENCE

To the Editor: Prognostic factors among acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic cell transplantation (HCT) in minimal residual disease (MRD)-negative first complete remission (CR1) are unknown. Previous studies of MRD in the transplant setting either did not consider prior consolidation in analysis or had too few patients without consolidation. In a single-center retrospective analysis at the University of Minnesota, we addressed the question: In AML patients undergoing HCT in MRD-negative CR1, does a history of prior consolidation provide additional prognostic information for relapse? Our hypothesis was that among MRD-negative patients, where MRD status is no longer a variable, specifics of previous treatments may reflect varying depths of remission and hence may be prognostic. We evaluated 126 patients with the following inclusion criteria: (i) Age > 18 years, (ii) AML in CR1 after 1-2 cycles of intensive induction chemotherapy, with or without consolidation (defined as ≥1 g/m/day cytarabine after achieving CR1), (iii) First allogeneic HCT between 2003 and 2016, (iv) Available standard-sensitivity 4-color flow cytometry results from a bone marrow aspiration at diagnosis and after completion of all previous chemotherapy (induction [s] with any consolidation) within 1 month prior to HCT, and (v) Flow cytometry-based MRD-negative status at the time of HCT. We found that prior consolidation was associated with lower risk of relapse (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.27-0.92, P = 0.025). Understanding the limitations of single-center studies, we recognized that the results warranted testing in a multi-center study. In addition, as there is no single standard MRD detection method, different centers and laboratories use different methods with different sensitivities. Therefore, the second goal of the present study was to explore the effects of this heterogeneity in the real-world setting. A total of 111 new patients (2007-2017) with similar inclusion criteria were retrospectively identified in a collaborative study between the University of Minnesota and Washington University in St. Louis. All pathology data (including a subset of primary histograms) were reviewed by at least one pathologist (MAL and/or KV). For theUniversity ofMinnesota cases, an in-house standard-sensitivity flow cytometry (4 color/4 tube prior to 2016; 10 color/2 tube beginning in 2016) with a lower limit of detection of 0.5% was performed. At Washington University, an inhouse 5 color/1 tube method was used to enumerate blasts prior to 2016. After reviewing paired diagnostic and post-treatment flow cytometry cases, samples with greater than 4% blastswith an immunophenotype similar to diagnosis were considered “positive” and excluded. Beginning in 2016, the in-house method at Washington University changed to an 8 color/1 tube method with an estimated lower limit of detection of 0.5-1%. A subset of the samples was sent to a reference laboratory for high-sensitivity MRD analysis. This laboratory used a 4 color/8 tube method with a lower limit of detection of 0.1%. For the purposes of this study, the in-house methods in both universities were grouped as “low sensitivity” and the reference labmethod as “high sensitivity.” Of the 111 patients, 96were transplanted atWashington University and 15 at the University of Minnesota. Patients included in our previous single-center study were not included here. Table 1 compares baseline patient-, disease-, and treatment-related characteristics between the groups with (n = 80, 72%) vs without (n = 31, 28%) consolidation. Patients with prior consolidation more frequently required only one induction cycle to achieve CR1 (P < 0.01), less frequently had a history of myelodysplastic syndrome (MDS; P < 0.01), and had a shorter diagnosisto-CR interval (P < 0.01), higher HCT-specific comorbidity index (HCTCI; P < 0.01), and, as expected, longer CR-to-HCT interval (P < 0.01). Backward regression analysis was performed in a Fine and Gray proportional hazards model with prior consolidation (>0 vs 0 cycle) and MRD detection sensitivity (high vs low) forced in. Predetermined covariates included conditioning intensity (reduced-intensity vs myeloablative), number of induction cycles (2 vs 1), prior MDS (yes vs no), and the 2017 European LeukemiaNet cytogenetic/genetic risk group (adverse vs favorable/intermediate). In this analysis, prior consolidation (hazard ratio [HR]: 3.2, 95% confidence interval [95%CI]: 0.9-10.8, P = 0.07) and MRD detection sensitivity (3.3 [0.7-15.7], P = 0.12) did not significantly change the risk of relapse. Reduced-intensity conditioning and prior MDS were significant predictors of relapse (4.3 [1.8-10.1] and 6.3 [2.4-16.5], respectively; P < 0.01 for both). Since the primary endpoint of interest was relapse, we evaluated whether nonrelapse mortality (NRM) as a competing risk influenced the number of patients alive and at risk for relapse between the groups with vs without consolidation. This analysis did not show any significant association (HR [95%CI] for NRM, with vs without consolidation: 0.7 [0.3-1.8], P = 0.45). In conclusion, this multi-center study did not reproduce the results of our previous single-center report. Potential reasons include population heterogeneity and differences in MRD detection methodology and sensitivity. As new MRD detection techniques are Received: 14 August 2018 Accepted: 20 August 2018