Decitabine in Older Patients with AML: Quality of Life Results of the EORTC-GIMEMA-GMDS-SG Randomized Phase III Trial.

We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes compared to those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) to IC (3+7) in older fit AML patients. HRQoL was a secondary endpoint, and it was assessed with the EORTC QLQ-C30 and the QLQ-ELD14. The following scales were a priori selected for defining the primary endpoint: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also prior to allo-HSCT and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm (76% [95% CI, 69 to 82] v 88% [95% CI, 82 to 93]; odds ratio, 0.43 [95% CI, 0.24 to 0.76], P=.003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and post-allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, while this was the case for those in the 3+7 arm, in four out of the five primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC, may be preferable to current standard IC (3+7), in fit older AML patients. ClinicalTrials.gov (NCT02172872).

Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling.

BACKGROUND: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. AIM: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. METHODS: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. RESULTS: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13-3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08-7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95-1.91], p = 0.10), which did not translate into a significant survival benefit. CONCLUSION: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

Significant impact of antibiotic exposure on GI-GVHD, NRM, and GRFS following allogeneic HCT with non-myeloablative Flu-TBI conditioning.

BACKGROUND: Acute gastro-intestinal graft-versus-host disease (GI-GVHD) and non-relapse mortality (NRM) after allogeneic HCT are closely related to loss of microbial diversity and intestinal dominance by single taxa resulting from the use of antibiotics, dietary changes, and mucosal barrier injury. There is a paucity of data on the impact of use of antibiotics in HCT after Flu-TBI-based non-myeloablative (NMA) conditioning where there is absence of mucositis and limited malnutrition. METHODS: We did a retrospective single-center analysis of patients receiving Flu-TBI-based NMA HCT for a high-grade myeloid malignancy, mostly AML, and MDS, or acute lymphoblastic leukemia (ALL). We analyzed the impact of pre-engraftment antibiotic exposure, prophylactic ciprofloxacin, and or treatment with broad-spectrum cephalosporin/carbapenem, on HCT outcomes, with a focus on the incidence of acute GI-GVHD by day 180 and NRM at 1 year. RESULTS: A total of 150 patients were evaluable with a median age of 62 years. Antibiotics were used in 90 patients; 60 prophylactic use only and 30 therapeutic use with or without previous prophylaxis. Antibiotic use resulted in a significant higher incidence of GI-GVHD Stage 1-4; 29% (26/90) versus 5% (3/60) in those not receiving antibiotics (OR 8.1 (95% CI 2.3-28.3), p = 0.001). Use of antibiotics resulted in higher 1-year NRM (19% (17/90) versus 10% (6/60), HR 2.3, p = 0.06), and decreased 2-year GRFS (42% (38/90) versus 55% (33/60), HR 1.7, p = 0.04), but did not impact RFS or OS. CONCLUSIONS: Use of antibiotics was related to the occurrence of GI-GVHD, NRM, and GRFS in patients receiving truly NMA HCT. Therefore, in the absence of mucositis and low incidence of bacteremia, antibiotics can and should be used restrictively in this setting.

10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes. METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants. FINDINGS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group. INTERPRETATION: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics. FUNDING: Janssen Pharmaceuticals.

Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia.

BACKGROUND: Transfusion guidelines regarding platelet-count thresholds before the placement of a central venous catheter (CVC) offer conflicting recommendations because of a lack of good-quality evidence. The routine use of ultrasound guidance has decreased CVC-related bleeding complications. METHODS: In a multicenter, randomized, controlled, noninferiority trial, we randomly assigned patients with severe thrombocytopenia (platelet count, 10,000 to 50,000 per cubic millimeter) who were being treated on the hematology ward or in the intensive care unit to receive either one unit of prophylactic platelet transfusion or no platelet transfusion before ultrasound-guided CVC placement. The primary outcome was catheter-related bleeding of grade 2 to 4; a key secondary outcome was grade 3 or 4 bleeding. The noninferiority margin was an upper boundary of the 90% confidence interval of 3.5 for the relative risk. RESULTS: We included 373 episodes of CVC placement involving 338 patients in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval [CI], 1.27 to 4.70). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI, 0.75 to 7.93). A total of 15 adverse events were observed; of these events, 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement. CONCLUSIONS: The withholding of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter did not meet the predefined margin for noninferiority and resulted in more CVC-related bleeding events than prophylactic platelet transfusion. (Funded by ZonMw; PACER Dutch Trial Register number, NL5534.).

A difficult to treat Leishmania infantum relapse after allogeneic stem cell transplantation.

Here we describe a complicated case of a relapsed Leishmania infantum infection after an allogeneic stem cell transplantation (allo-SCT) for primary myelofibrosis. Three years earlier the patient had been diagnosed with a hemophagocytic lymphohistiocytosis secondary to a visceral Leishmania infantum infection, for which he was effectively treated with a cumulative dose of 40 mg/kg liposomal amphotericin B. During the first disease episode he was also diagnosed with primary myelofibrosis for which he received medical follow-up. One year later ruxolitinib was started due to progressive disease. No Leishmania relapse occurred. Nevertheless, the marrow fibrosis progressed, and an allo-SCT was performed. Two months after allo-SCT prolonged fever and a persistent pancytopenia occurred, which was due to a relapse of visceral Leishmaniasis. The infection was refractory to a prolonged treatment with liposomal amphotericin B with a cumulative dose up to 100 mg/kg. Salvage treatment with miltefosine led to reduction of fever within a few days and was followed by a slow recovery of pancytopenia over the following months. The Leishmania parasite load by PCR started to decline and after 3.5 months no Leishmania DNA could be detected anymore and follow-up until ten months afterwards did not show a relapse.

Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Invasive Fungal Disease in Patients with Myeloid Malignancies: A Retrospective Cohort Study of a Diagnostic-Driven Care Pathway Withholding Mould-Active Prophylaxis.

OBJECTIVES: Patients receiving remission induction therapy for acute myeloid leukaemia (AML) are at high risk of developing invasive fungal disease (IFD). Newer therapies with targeted antileukemic agents and the emergence of azole resistance pose a challenge to the strategy of primary antifungal prophylaxis. We report the experience of a diagnostic-driven care pathway (DCP) for the management of IFD in these patients, using only culture-directed mould inactive prophylaxis. METHODS: Retrospectively, we used a single-centre study of consecutive patients receiving intensive chemotherapy for myeloid malignancies between 2014 and 2021. DCP consisted of serial cultures and serum galactomannan (sGM) screening, CT imaging, and bronchoscopy to direct targeted antifungal treatment. IFD was classified according to the 2020 EORTC/MSGERC criteria. RESULTS: A total of 192 patients with myeloid malignancies received 300 courses of intensive chemotherapy. There were 14 cases of invasive yeast infections and 18 of probable/proven invasive mould disease (IMD). The incidence of probable/proven IMD during the first cycle of remission-induction chemotherapy was 4.6% (n = 9). sGM remained negative in all cases of invasive aspergillosis (IA), with positive mycology findings in bronchoalveolar lavage. All-cause mortality was 9.4% (n = 18) 100 days after starting chemotherapy and was comparable between patients with or without IFD. The fungal-related mortality was 1% (n = 2). CONCLUSION: Diagnostic-driven based management without universal mould active prophylaxis is a feasible strategy in the management of IFD and limits unnecessary antimould treatment during intensive chemotherapy. The poor performance of serial serum galactomannan screening in detecting IA warrants further investigation.

Posaconazole bioavailability of the solid oral tablet is reduced during severe intestinal mucositis.

OBJECTIVES: This study aimed to describe the absolute oral bioavailability of the solid oral formulation of posaconazole and the impact of severe intestinal mucositis in haematology patients. This study also aimed to describe posaconazole protein binding in haematology patients. METHODS: A pharmacokinetic study was performed of patients receiving induction chemotherapy or a haematopoietic cell transplantation who were randomized to receive 7 days of intravenous posaconazole therapy followed by 9 days of oral therapy, or vice versa. Patients received a posaconazole licensed dose until day 12, after which a reduced once-daily dose of 200 mg was given. At days 7, 12, and 16, blood samples were obtained for pharmacokinetic curves, and trough samples were collected on all other days. Total and unbound posaconazole pharmacokinetics were analyzed by population pharmacokinetic modelling. The presence of severe intestinal mucositis was assessed by plasma citrulline levels and analyzed as a binary covariate using 10 µmol/L as the cut-off. Monte Carlo simulations were performed to simulate posaconazole exposure at a steady state. RESULTS: Twenty-three patients were included for analysis, with 581 total posaconazole concentrations and 91 paired unbound concentrations. Absolute bioavailability in the final model was estimated at 51.4% (percentage relative standard error (%RSE): 56.5) and 67.6% (%RSE: 75.0) in patients with and without severe intestinal mucositis, respectively. Posaconazole unbound fraction was estimated at 2.7% (%RSE: 3.9). DISCUSSION: Posaconazole bioavailability is reduced in haematological patients with severe intestinal mucositis, requiring an increase in oral posaconazole dose to 400 mg twice daily on day 1, followed by 400 mg once daily or a switch to intravenous therapy.

Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial.

Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004.

Anti-thymocyte globulin with CsA and MMF as GVHD prophylaxis in nonmyeloablative HLA-mismatched allogeneic HCT.

Nonmyeloablative regimens are used for allogeneic hematopoietic cell transplantation (HCT) of older or medically unfit patients, but successful outcome is still hindered by graft-versus-host disease (GVHD), especially in the setting of HLA-mismatched HCT. New GVHD prophylaxis strategies are emerging, including the triple drug strategy, that improve the GVHD-free and relapse-free survival (GRFS). Because the impact of ATG in HLA-mismatched Flu-TBI-based nonmyeloablative HCT has not been investigated, we did a retrospective analysis in three Dutch centers. 67 patients were evaluable, with a median age of 56 years. Overall survival, relapse-free survival and GRFS at 4 years were 52%, 43%, and 38%, respectively. NRM findings and cumulative incidence of relapse at 4 years were 26% and 31%, respectively. At 1-year grade II-IV had occurred in 40% of the patients, and the incidence of moderate-severe chronic GVHD incidence was 16%. Acknowledging the limitations of retrospective analyses, we conclude that the use of ATG for HLA-mismatched truly nonmyeloablative Flu-TBI HCT is feasible and results in acceptable long term outcomes, especially with regards to GRFS. We consider ATG in combination with cyclosporin and mycophenolate mofetil as an alternative for the triple drug strategy that uses sirolimus for GVHD prophylaxis in this particular setting.

Low relapse risk in poor risk AML after conditioning with 10-day decitabine, fludarabine and 2 Gray TBI prior to allogeneic hematopoietic cell transplantation.

Patients with poor risk acute myeloid leukemia (AML) have a dismal outcome. We hypothesized that combining decitabine with a standard non-myeloablative (NMA) conditioning regimen prior to allogeneic hematopoietic cell transplantation (allo HCT), might decrease the relapse incidence. We conducted a multicenter prospective phase II study (NCT02252107) with 10-day decitabine (20 mg/m2/day) integrated in a standard non-myeloablative conditioning regimen (3 days fludarabine 30 mg/m2 with 2 Gray total body irradiation (TBI)). Patients with AML ≥ 18 years in 1st (in)complete remission (CR/CRi) with a poor or very poor risk profile, as defined by the HOVON-132 protocol, were eligible. Results: Forty-six patients (median age 60; range 23-74) were included. Median follow up time was 44 months (range 31-65 months). The cumulative 1-year incidence of relapse and NRM were respectively 23% and 11%. Incidence of grade III-IV acute graft-vs-host-disease (GVHD) and severe chronic GVHD were 13% and 20%, respectively. One-year OS was 70%. Application of ELN 2017 risk classification to the study cohort revealed a cumulative one-year relapse rate of respectively 31% and 13% for the adverse and intermediate risk patients. To conclude, the 10-day DEC/FLU/TBI conditioning regimen prior to allo HCT in poor risk AML patients is effective and feasible.

Pretransplantation MRD in Older Patients With AML After Treatment With Decitabine or Conventional Chemotherapy.

The predictive value of measurable residual disease (MRD) for survival in acute myeloid leukemia (AML) has been firmly established in younger patients treated with intensive chemotherapy. The value of MRD after treatment with decitabine in older patients is unknown. This retrospective analysis included patients ≥60 years of age with AML who received an allogeneic hematopoietic cell transplantation (alloHCT) after treatment with decitabine or intensive chemotherapy. Of the 133 consecutively transplanted patients, 109 had available pretransplantation MRD analyses (by flowcytometry [threshold 0.1%]). Forty patients received decitabine treatment (10-day schedule), and 69 patients received intensive chemotherapy (7 + 3 regimen). Patients who received decitabine were older (median 67 versus 64 years) and more often had MRD (70% versus 38%). OS after alloHCT was comparable in both groups. In the chemotherapy group, MRD-positive patients had a significantly higher relapse probability (subdistribution hazard ratio [sHR] 4.81; P= .0031) and risk of death (HR 2.8; P= .02) compared to MRD-negative patients. In the decitabine group there was no significant association between the presence of MRD and relapse (sHR 0.85; P= .83) or death (HR 0.72; P= .60). Pretransplantation MRD in patients receiving decitabine treatment does not have similar predictive value for relapse or survival in older AML patients receiving an alloHCT, compared to patients receiving intensive chemotherapy.

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.

Anakinra: efficacy in the management of fever during neutropenia and mucositis in autologous stem cell transplantation (AFFECT-2)-study protocol for a multicenter randomized double-blind placebo-controlled trial.

BACKGROUND: Since decades, fever and infections have been the most important complications of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. Neutropenia has long been considered to be the most important risk factor for these complications. However, recent studies have shown that not neutropenia, but the development of mucositis is the most important cause of these complications. Currently, limited options for the prevention and treatment of mucositis are available, of which most are only supportive. The pro-inflammatory cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of mucositis. Pre-clinical studies of chemotherapy-induced mucositis have shown that recombinant human IL-1 receptor antagonist anakinra significantly ameliorated intestinal mucositis. In our pilot study AFFECT-1, we examined the safety and maximal tolerated dose of anakinra in patients with multiple myeloma, treated with high-dose melphalan (HDM) and autologous HSCT, selecting a dose of 300 mg daily for the phase IIb trial. The aim of the AFFECT-2 study is to determine the efficacy of anakinra in preventing fever during neutropenia (FN) and mucositis in this study population. METHODS/DESIGN: A multicenter, randomized, placebo-controlled, double-blind phase IIb trial will be conducted. Ninety patients with multiple myeloma scheduled for treatment with HDM and autologous HSCT will be included. Patients will be randomized between intravenous treatment with anakinra (300 mg) or placebo. Each group will be treated from day - 2 (day of HDM; day 0 is HSCT) up until day + 12. Outcome measures will be assessed at baseline, during admission, at discharge or day + 30, at day + 90, and + 1 year. The primary outcome will be reduction of FN. Secondary outcome measures include mucositis scores, bloodstream infections, citrulline levels, quality of life, and fatigue severity. DISCUSSION: The AFFECT-2 trial will examine the efficacy of anakinra in the management of fever during neutropenia and mucositis in patients with multiple myeloma treated with HDM and autologous HSCT. The results of this study may provide a new treatment option for these important complications. Also, this study will give us more insight in the pathophysiology of mucositis, including the role of IL-1 and the role of the microbiota in mucositis. TRIAL REGISTRATION: Clinicaltrials.gov NCT04099901 . Registered on September 23, 2019. EudraCT: 2018-005046-10.

BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment.

Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans.

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT - A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party.

Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 µg/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, p < 0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.