Summary Cytomegalovirus is one of the most important infections to occur after allogeneic haematopoietic stem cell transplantation (HSCT), and an increasing number of reports indicate that cytomegalovirus is also a potentially important pathogen in patients treated with recently introduced drugs for hematological malignancies. Expert recommendations have been produced by the 2017 European Conference on Infections in Leukaemia (ECIL 7) after a review of the literature on the diagnosis and management of cytomegalovirus in patients after HSCT and in patients receiving other types of therapy for haematological malignancies. These recommendations cover diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management of cytomegalovirus disease. Antiviral drugs including maribavir and letermovir are in development and prospective clinical trials have recently been completed. However, management of patients with resistant or refractory cytomegalovirus infection or cytomegalovirus disease is a challenge. In this Review we summarise the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies.

Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)

// Christelle Retiere 1 , 2, 8 , Catherine Willem 1, 2, 8 , Thierry Guillaume 2, 3, 8 , Henri Vie 1, 2, 8 , Laetitia Gautreau-Rolland 2, 8 , Emmanuel Scotet 2, 8 , Xavier Saulquin 2, 8 , Katia Gagne 1, 2, 4, 8 , Marie C. Bene 5, 8 , Berthe-Marie Imbert 6, 7, 8 , Beatrice Clemenceau 2, 8 , Pierre Peterlin 3 , Alice Garnier 3 and Patrice Chevallier 2, 3, 8 1 Etablissement Francais du Sang, Nantes, France 2 CRCINA, INSERM, CNRS, Universite d’Angers, Universite de Nantes, Nantes, France 3 Hematology Department, CHU, Nantes, France 4 LabEx Transplantex, Universite de Strasbourg, France 5 Hematology/Biology Department, CHU, Nantes, France 6 INSERM, Centre de Recherche en Transplantation et Immunologie, UMR1064, Universite de Nantes, Nantes, France 7 Service de Virologie, CHU Nantes, Nantes, France 8 LabEx IGO “Immunotherapy, Graft, Oncology”, Nantes, F-44000, France Correspondence to: Christelle Retiere, email: christelle.retiere@efs.sante.fr Keywords: allogeneic bone marrow transplantation; post-transplant cyclophosphamide; immune reconstitution; immunology Received: May 31, 2017      Accepted: November 01, 2017      Published: January 27, 2018 ABSTRACT We have compared prospectively the outcome and immune reconstitution of patients receiving either post-transplant cyclophosphamide (PTCY) ( n = 30) or anti-thymocyte globulin ATG ( n = 15) as Graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation (allo-SCT). The outcome and immune reconstitution of patients receiving either of these two regimens were compared prospectively. This study allowed also to investigate the impact of PTCY between haplo-identical vs matched donors and of clofarabine as part of the RIC regimen. The γ/δ T-cells, α/β T-cells (CD8 + and CD4 + ), NK T-cells, NK cells, B-cells, Tregs and monocytes were analyzed by flow cytometry from a total of 583 samples. In the PTCY group significant delayed platelets recovery, higher CD3+ donor chimerism, higher HHV-6 and lower EBV reactivations were observed. Early survival advantage for CD4+ T-cells, Tregs and α/β T-cells was documented in the PTCY group while it was the case for α/β T-cells, NK cells and monocytes in the ATG group. Higher counts of NK and monocytes were observed at days +30 and/or day+60 in the ATG group. Both results were retained even in the case of mismatched donors. However, higher percentages of CD4+ T-cells, α/β T-cells and Tregs were observed with haplo-identical donors in the PTCY group. Finally, clofarabine was responsible for early survival advantage of NK T-cells in the PTCY group while it abrogated the early survival advantage of γ/δ T-cells in the ATG group. In conclusion, there are marked differences in the immunological effects of ATG vs PTCY as GVHD prophylaxis for RIC PBSC allo-SCT.

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Impact on early outcomes and immune reconstitution of high-dose post-transplant cyclophosphamide vs anti-thymocyte globulin after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation.

Haploidentical Transplantation with Post-Transplant Cyclophosphamide versus Unrelated Donor Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105–1 × 108 cells/kg/dose) were administered on days −2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database. After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype. Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 (
 https://clinicaltrials.gov/ct2/show/NCT01904136
 ).

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Decrease post-transplant relapse using donor-derived expanded NK-cells.

// Zhenyang Gu 1, 2, * , Li Wang 1, 3, * , Lei Yuan 1, * , Wenrong Huang 1 , Meng Li 1 , Lixun Guan 1 , Qingyi Wang 4 , Zhe Gao 1 , Shasha Zhao 1 , Lan Luo 1 , Feiyan Wang 1 , Nan Yang 1 , Daihong Liu 1 , Jon C. Aster 2 and Chunji Gao 1 1 Department of Hematology, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China 2 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA 3 Department of Hematology and Oncology, Laoshan Branch, No. 401 Hospital of Chinese PLA, Qingdao, China 4 Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Chunji Gao, email: gaochunji@medmail.com.cn Jon C. Aster, email: jaster@rics.bwh.harvard.edu Keywords: post-transplant cyclophosphamide, haploidentical, hematopoietic cell transplantation, HLA-matched, similar outcomes Received: January 17, 2017     Accepted: June 02, 2017     Published: June 29, 2017 ABSTRACT Background: Outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PT-Cy) have greatly improved. It remains unknown whether haplo-HCT with PT-Cy was associated with poor outcomes when compared with HLA-matched HCT. To address this issue, we performed a meta-analysis to compare outcomes of haplo-HCT with PT-Cy with those of HLA-matched HCT. Methods: A systematic search for case-control studies were performed in PubMed, Embase and Cochrane Library databases. Using a random model, the risk ratios (RRs) and 95% confidence intervals (95% CI) were pooled for the final analysis. Results: Nine case-control studies including 2258 patients (827 patients in the haplo-HCT with PT-Cy group, 748 controls from HLA-matched related donors (MRD), and 683 controls from HLA-matched unrelated donors (MUD)) met the inclusion criteria. No differences were found between haplo-HCT with PT-Cy and HLA-matched HCT with regard to acute graft-versus-host-disease (GVHD), non-relapse mortality, relapse, progression free survival and overall survival. However, haplo-HCT with PT-Cy was found to be associated with a lower incidence of moderate to severe chronic GVHD (Haplo vs MRD: RR=0.54; 95% CI=0.39-0.75; Haplo vs MUD: RR=0.70; 95% CI=0.56-0.88). Conclusions: The results of this meta-analysis suggest that haplo-HCT with PT-Cy can achieve comparable outcomes with those of HLA-matched HCT. Haploidentical donors can be a feasible and valid alternative when conventional HLA-matched donors are unavailable.

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Comparative Outcomes after Haploidentical or Unrelated Donor Bone Marrow or Blood Stem Cell Transplantation in Adult Patients with Hematological Malignancies.

9055 Background: IO treatment (tx) has transformed the care of pts with mNSCLC, persistently demonstrating significant survival benefits over chemotherapy. Prior analyses have shown OS and PFS are shorter in the real-world (rw) setting compared with randomized clinical trials (RCTs). A contributing factor may be the more diverse sociodemographic characteristics of pts in the rw. Race and socio-economic status (SES), in particular, have been associated with disparities in cancer outcomes, which may be related to inequalities in healthcare access. One aim of CORRELATE was to assess whether outcomes differ based on sociodemographic characteristics in pts receiving IO in the rw setting. Methods: Eligible pts from the US Flatiron Enhanced Datamart database had mNSCLC (progressed or de novo), started 1L IO tx between Nov 1 2016 and May 31 2021, and met eligibility criteria based on 6 RCTs (KEYNOTE [KN]-024, KN-189, KN-407, IMpower150, CheckMate [CM] 9LA and CM 227) for IO regimens approved in the US for mNSCLC. Flatiron’s area-level measure of SES, available for pts treated at community oncology centers, was based on a validated composite index and has 5 levels (highest [5] to lowest [1]). Multivariate Cox regression models were used to determine the association of sociodemographic variables (age, sex, race, US region and SES) with OS and rwPFS separately; smoking history, ECOG performance status (PS) and PD-L1 expression were also included in the models, as were any pairwise interactions that were statistically significant ( P< 0.05). Results: 2070 pts with non-missing data on the variables of interest were included in the dataset: 60% were aged ≥65 y, 86% white, 55% male and 53% were from the US Southern region. SES was relatively evenly distributed (SES 1–5: 18%, 22%, 21%, 24% and 15%, respectively); 41% of pts had PD-L1 ≥50% (17% unknown PD-L1 expression), 61% had ECOG PS 1 and 92% were former/current smokers. Median OS was 13.3 mos (95% CI 12.3–14.7); median rwPFS was 5.9 mos (5.6–6.2). In the multivariate analyses, race, region and SES did not have a statistically significant association with either OS or rwPFS. Older age (≥65 y; P= 0.0091) and male sex ( P< 0.0001) were associated with a higher risk of death (HR [95% CI] 1.16 [1.04–1.29] and 1.28 [1.15–1.43], respectively). For rwPFS, the interaction between sex and smoking status was statistically significant ( P= 0.0312); specifically, female non-smokers had a higher risk of progression or death vs female smokers (HR 1.45 [95% CI 1.15–1.82]). Conclusions: Our results from a nationally representative dataset of pts with mNSCLC treated at non-academic facilities show that, in pts who had equivalent access to IO tx, the OS and rwPFS benefits derived from IO were similar, irrespective of race, region or SES. More efforts are required to identify and address barriers of access to care to ensure that all pts receive appropriate cancer tx.

Assessment of sociodemographic disparities in outcomes among pts with metastatic NSCLC (mNSCLC) receiving select immuno-oncology (IO) regimens: CORRELATE.

Ling Cai

Papers

Comparative Outcomes after Haploidentical or Unrelated Donor Bone Marrow or Blood Stem Cell Transplantation in Adult Patients with Hematological Malignancies.

Assessment of sociodemographic disparities in outcomes among pts with metastatic NSCLC (mNSCLC) receiving select immuno-oncology (IO) regimens: CORRELATE.