Addition of Anti-thymocyte Globulin in Allogeneic Stem Cell Transplantation With Peripheral Stem Cells From Matched Unrelated Donors Improves Graft-Versus-Host Disease and Relapse Free Survival

Anti-thymocyte globulin (ATG) is commonly used to prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To evaluate the impact of ATG as part of the GvHD prophylaxis in our institution, we report the outcome of 415 patients with matched unrelated donors (MUD) transplanted for hematological malignancies with or without ATG from 2005 to 2019 at Oslo University Hospital, Norway. The following groups were compared: (1) 154 patients transplanted with peripheral blood stem cells (PBSC) without ATG 2005-2014. (2) 137 patients transplanted with bone marrow stem cells (BMSC) 2005-2019. (3) 124 patients transplanted with PBSC and ATG (PBSC + ATG) 2014-2019. Three years survival was similar in the groups, 61% following allografting with PBSC, 54% with BMSC, and 59% with PBSC + ATG. Acute GvHD grade III-IV was 14%, 14%, and 7%; chronic GvHD was 81%, 32, and 26%; and extensive cGvHD 44%, 15%, and 6% in the corresponding groups. Both acute and chronic GvHD were significantly reduced in the PBSC + ATG-versus the PBSC group (p < 0.05 and p < 0.001 respectively).Transplant-related mortality (TRM) was 33%, 25%, and 17% (p = 0.18). Graft versus host disease and relapse free survival (GRFS) at 3 years was 43 %, 43%, and 64% in the groups. Adding ATG to the GvHD prophylaxis regimen of MUD allo-HSCT with PBSC resulted in a substantial reduction of both acute and chronic GvHD without compromising the disease control, reflected in a superior 3 years GRFS

Lung transplantation for bronchiolitis obliterans syndrome after allo-SCT

Chronic GVHD (cGVHD) associated bronchiolitis obliterans syndrome (BOS) is a serious complication after allo-SCT, and lung transplantation (LTx) may be the ultimate treatment option. To evaluate this treatment, data on all patients with LTx after allo-SCT ever performed in Sweden, Norway, Denmark and Finland were recorded and compared with survival data from the Scandiatransplant registry. In total, LTx after allo-SCT had been performed in 13 patients. Allo-SCT was done because of AML (n = 6), CML (n = 3), ALL (n = 2), immunodeficiency (n = 1) and aplastic anemia (n = 1). All developed clinical cGVHD, with median interval from allo-SCT to LTx of 8.2 (0.7-16) years. Median age at LTx was 34 (16-55) years, and the median postoperative observation time was 4.2 (0.1-15) years. Two patients died, one due to septicemia, the other of relapsing leukemia, after 2 and 14 months, respectively. Four developed BOS, one of these was retransplanted. The survival did not significantly differ from the survival in matched LTx controls, being 90% 1 year and 75% 5 years after LTx compared with 85% and 68% in the controls. We therefore suggest that LTx may be considered in carefully selected patients with BOS due to cGVHD after allo-SCT

Bayesian Inference for Optimization of Interim Analysis in Clinical Trials By Incorporation of Historical Data:Reanalysis of the HOVON AML 132 Clinical Trial

Background:Prospective randomized trials remain pivotal to evaluate the benefit of new therapies. Primary endpoints typically focus on long-term endpoints after study completion, whereas interim analyses are monitoring safety and toxicity. Although the traditional or frequentist approach is widely used to analyze endpoints and anticipate the number of events needed upon trial completion, it is limited by the need for prior assumptions of the expected treatment effect, long-term follow-up, and conservative stopping rules. Bayesian inference might overcome these limitations, for which prior knowledge is combined with new data to compute the posterior distribution, enhancing the strength of the ongoing trial. This study aims to evaluate whether a Bayesian approach using historical data as prior knowledge might support decision-making at interim time points of the HO132 phase 3 clinical trial for patients with acute myeloid leukemia (AML), that was recently reported (Löwenberg et al, 2021).Methods:In the HO132 trial, 927 patients aged 18 to 65 years with newly diagnosed AML were randomized between intensive induction ± lenalidomide. The primary endpoint EFS was not different between experimental and control treatment (HR 0.99, p=0.96). After excluding 64 patients for lenalidomide dose selection, three interim analyses were retrospectively introduced after inclusion of 150, 300 and 600 patients to assess whether the lack of efficacy emerged early during conduct of the trial. The control treatment arm was reinforced using 445 historical control treatment patients from the preceding AML trial (HO102). Patients of both control arms were matched 1:1 using propensity scores based on age and leukemia risk. At each interim analysis, posterior distributions were calculated for endpoints including complete remission (CR) after induction, minimal residual disease (MRD) in CR, early death within 2 months, and EFS. The posterior distributions were summarized to provide point estimates and 95% credible intervals (CI) on the treatment difference and hazard ratio (HR) between both arms. For binary outcomes, the probability of success (range 0-100%) of the control versus the experimental treatment was computed. For EFS, the probability of the HR being below 0.76 was calculated, which was the assumed effect size in the HO132 statistical plan. A probability of &lt;10% was considered as the futility threshold.Results:We compared HO132 experimental treatment with control treatment reinforced with matched historical patients for the previously mentioned endpoints. The proportion of patients obtaining CR was lower with experimental compared with control treatment at interim analysis 1 (Fig 1A, treatment difference: -9.0% [95% CI -19.9 to 1.4]) and the probability for demonstrating a superior CR rate with experimental treatment was 4%. At interim analysis 2 and 3 the treatment difference was -8.1% [95% CI -16.3 to 0.001] and -9.8% [95% CI -18.6 to -4.1] with a probability of success of 3% and 0%, respectively.Patients in CR and assigned to the experimental treatment arm were less often MRDneg compared with control at every interim analysis (treatment difference: -10.3% [95% CI -28.7 to 8.0]; -8.1% [95% CI -21.5 to 5.6]; -5.6% [95% CI -14.5 to 3.4], respectively), with a respective probability not meeting the futility stopping rule of 13%, 12% and 11%.Early deaths were more frequently observed with experimental treatment versus control (treatment difference: 5.5% [95% CI -0.7 to 12.8]), with 4% probability of fewer early deaths with experimental treatment than control at interim analysis 1. The treatment differences for early death at interim analyses 2 and 3 were 3.5% (95% CI -1.7 to 9.2) and 2.0% (95% CI -1.9 to -6.0) with a probability of 10% and 15%, respectively.EFS was similar between both arms at interim analysis 2 and 3 (HR 1.00, and HR 1.04, respectively, Fig 1B), with a median follow-up time of 10 and 16 months, respectively. At interim analysis 2, this resulted in a probability of 4% reaching the anticipated HR of 0.76, which probability was 0% at interim analysis 3.Conclusion:Reanalyzing the prospective conduct of the HO132 study using Bayesian inference identified a low probability of success of the experimental treatment at three successive putative interim analyses based on important efficacy markers. Consequently, a low probability of efficacy during trial conduct might support early termination of the trial

Relationship between clinical and BK virological response in patients with late hemorrhagic cystitis treated with cidofovir: a retrospective study from the European Group for Blood and Marrow Transplantation.

To investigate the relationship between clinical response and modification of BK viremia, we assessed retrospectively 32 cases of hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT that were treated with i.v. cidofovir (CDV). They were 22 men (69%) and 10 women (31%) with a median age of 24 years, range 3-62. The median number of CDV doses was 3, range 1-8, and the treatment lasted for a median of 3 weeks, range 1-10. Clinical improvement of HC was observed in 27 patients (84%). In 12 of 32 episodes (37.5%), BK viremia was determined before every CDV administration and a complete clinical response was observed in 10 of 12 patients (83%), the reduction of BK viremia load being \ue2f61 log by 2 weeks after starting CDV. Nephrotoxicity related to CDV was observed in nine patients. Among 26 patients with 100-day follow-up, 4 of 4 patients who had a complete clinical response by 30 days were alive vs 16 of 22 (73%) who did not have the resolution of HC in this time frame. We conclude that in patients with HC, the response to CDV treatment is usually associated with a significant reduction of BK viremia load

Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial.

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article, part II, we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. There are several studies demonstrating that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared to MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include “–omics” based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics and proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses