Monzr M. Al Malki

Background: Febrile neutropenia is a critical emergency construct, but infection and sepsis can occur without fever. Objective: To examine the clinical evidence of nonfebrile neutropenic infection, potential mechanisms of an attenuated febrile response, physiological body-temperature variation, and limitations of clinical thermometry. Methods: A narrative review was supplemented by a targeted, transparently documented three-domain evidence map of published systematic syntheses, thermometry-accuracy studies, and oncology-neutropenia cohorts, updated on 1 November 2026. No new exhaustive systematic review or meta-analysis was performed. Results: A synthesis of 36 studies (7636 healthy adults) reported site-specific oral and rectal temperature distributions of 35.73–37.41 °C and 36.32–37.76 °C (mean ± 2 SD), which do not establish a universal core-temperature interval. Peripheral and oral thermometers demonstrated pooled fever-detection sensitivities of 0.64 and 0.53, respectively, in non-neutropenia-specific populations. Nonfebrile infection proportions included 9/69 (13.0%) severe ICU infection episodes and 70/186 (37.6%) bloodstream infections without a recorded temperature ≥ 38.0 °C in a separate oncology-neutropenia cohort; an additional post-transplant corticosteroid cohort is discussed separately. These denominators do not permit a meaningful pooled incidence of afebrile neutropenic sepsis. Conclusions: Fever-based clinical pathways remain essential, but suspected infection, physiological deterioration, and organ dysfunction warrant evaluation irrespective of temperature.

Donor types influence outcomes after allogeneic hematopoietic cell transplantation (HCT), but their relative impact in the post-transplant cyclophosphamide (PTCy) era is uncertain. We performed a multicenter retrospective cohort study using Center for International Blood and Marrow Transplant Research data for adults with acute leukemia or myelodysplastic syndromes undergoing first HCT from matched sibling donors (MSD), 8/8 matched unrelated donors (MUD), 7/8 mismatched unrelated donors (MMUD), or haploidentical donors between 2017 and 2023 with PTCy-based graft-versus-host disease (GVHD) prophylaxis. The primary cohort included 12,617 patients: 1,263 MSD, 4,117 MUD, 1,426 MMUD, and 5,811 haploidentical recipients. In multivariable models adjusted for donor age and clinical covariates, overall survival (OS) was lower with MUD (hazard ratio [HR], 1.16; 95% CI, 1.00-1.34, p=0.004), MMUD (HR, 1.32; 95% CI, 1.12-1.55, p<0.001), and haploidentical donors (HR, 1.43; 95% CI, 1.24-1.64, p<0.001) compared with MSD. GVHD-free, relapse-free survival (GRFS) was similar for MUD and MSD (reference) but lower with MMUD and haploidentical donors. Compared to MSD, all other donor groups had lower relapse risk but higher non-relapse mortality and acute GVHD, with similar chronic GVHD. In sensitivity analyses excluding donor-age adjustment, compared to MSD, OS was similar for MUD and MMUD, and GRFS was improved with MUD and similar for MMUD and haploidentical donors. These findings suggest that PTCy narrows outcome differences across donor types, shifting donor selection from rigid hierarchies and supporting timely HCT using the best available donor.

HLA-mismatched unrelated donor (MMUD) hematopoietic cell transplantation (HCT) has emerged as an effective therapy for adult patients with hematologic malignancies. The MMUD ACCESS trial, which incorporated posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis, demonstrated a combined overall survival of 81% in enrolled patients, 59% of whom were from ethnically diverse groups. Given that PTCy is also associated with significant bacterial and viral infections, we defined infection burden in the full adult cohort (N = 268) using infections graded according to an international standard (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0). Infection density (number of infections per 100 days at risk), cumulative incidence of infection, and frequency of pathogen types were categorized by post-HCT time, conditioning intensity, level of donor HLA mismatch, and presence of acute GvHD (aGvHD). Of 465 CTCAE grade 2 to 5 infections recorded in 183 (68%) adults, 176 (38%) were significant or life-threatening, and most (296 [64%]) occurred within the first 100 days. Infection density at days 0 to 30 was significantly higher than at other times and was similar by conditioning and level of HLA mismatch, as were pathogen types and isolates. Multivariable analysis showed that aGvHD is significantly associated with infection. Finally, 21 (7.8%) patients died of infection. Results show significant infection burden using standard-dose PTCy in the MMUD HCT setting, irrespective of conditioning and level of donor HLA mismatch, and serve as a benchmark for trials investigating reducing infection burden after MMUD HCT. This trial was registered at www.clinicaltrials.gov as NCT04904588.

PURPOSE: To evaluate the efficacy and safety of the cluster of differentiation 47–targeted antibody magrolimab plus azacitidine (Magro/Aza) versus azacitidine alone in treatment-naïve patients with higher-risk myelodysplastic syndromes (MDS) in the phase III ENHANCE study (ClinicalTrials.gov identifier: NCT04313881 ). METHODS: Based on the Revised International Prognostic Scoring System, patients with intermediate- to very-high-risk MDS were randomly assigned to receive Magro (1 mg/kg on days [D]1 and 4; 15 mg/kg on D8; 30 mg/kg on D11 and D15, and then once per week for five doses, followed by 30 mg/kg maintenance doses once every 2 weeks)/Aza (75 mg/m ² daily on D1-7 or on D1-5 and 8-9 in 28-day cycles) or matched placebo plus azacitidine (Placebo/Aza). Dual primary end points were complete remission (CR) rate (per 2006 International Working Group criteria) and overall survival (OS). RESULTS: At final analysis, 539 patients were randomly assigned to Magro/Aza (n = 268) or Placebo/Aza (n = 271) arms. Baseline characteristics were generally well balanced between treatment arms. In the Magro/Aza versus Placebo/Aza arms, the CR rate was 21.3% versus 23.6% (odds ratio, 0.876 [95% CI, 0.585 to 1.312]; P = .5218), and median OS was 15.9 versus 18.6 months (hazard ratio, 1.203 [95% CI, 0.947 to 1.528]; P = .1299). Magro/Aza had a higher incidence of grade ≥3 adverse events (AEs; 92.8% v 79.2%), AE-associated study drug discontinuations (24.0% v 12.1%), serious AEs (71.9% v 51.5%), and fatal AEs (15.2% v 9.8%) versus Placebo/Aza. CONCLUSION: ENHANCE did not meet the primary end points of CR rate and OS, and showed more frequent severe AEs in patients treated in the Magro/Aza arm.

Posttransplant cyclophosphamide (PTCy) to prevent graft‐versus‐host disease (GVHD) improves outcomes in recipients of HLA mismatched unrelated donor (MMUD) allogeneic hematopoietic cell transplantation (allo HCT). Outcomes of MMUD HCT using PTCy in patients requiring reduced intensity or non‐myeloablative conditioning (RIC/NMA) are not well described. The Phase II, prospective, ACCESS trial sought to evaluate PTCy‐based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell allografts. Here, we report combined results of RIC/NMA recipients treated in the initial study ( N = 70) and a planned expansion cohort ( N = 123). The number of centers participating in the expansion protocol was 33 compared to 13 in the initial study. Median participant age was 65.0 (range: 22.9–78.9) and the HCT comorbidity index was high‐risk (≥ 3) in 65 (33.7%). Donor HLA matching was < 7/8 in 62 (32.1%) participants. One‐year survival was 79.6% (95% confidence interval: 73.2–84.7) and was similar between HLA 7/8‐ and HLA < 7/8‐matched donor recipients. Survival was similar between participants in the initial study (78.6%) and the expansion cohort (80.3%) indicating generalizability of this strategy. One‐year incidence of severe infection (Grade 3–5) was 39% (32%–46.9%). The 1‐year incidence of non‐relapse mortality and relapse estimates were 12.5% (8.3%–17.6%) and 17.3% (12.3%–23%), respectively. MMUD with PTCy‐based GVHD prophylaxis and RIC/NMA conditioning was safe and effective to facilitate HCT. Outcomes were similar in the expansion cohort that enrolled from a greater number of centers. Post‐HCT infections were prevalent.

ACCESS is a prospective, multicenter phase II trial evaluating peripheral blood stem cell (PBSC) transplantation using 4-7/8 HLA-mismatched unrelated donors (MMUD) with post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate. Adults undergoing first HCT with myeloablative (MAC) or reduced-intensity/nonmyeloablative (RIC/NMA) conditioning were enrolled, with donors aged 18-35 years and matched at 4/8-7/8 HLA loci by high-resolution typing. This expanded analysis includes all enrolled adult PBSC recipients, including the protocol-specified RIC/NMA cohort expansion, to improve precision of outcome estimates and provide descriptive analyses by HLA match level. Among 268 adults, 183 received 7/8 and 85 received <7/8 MMUD grafts; 82.4% of the <7/8 cohort received 6/8 grafts. Median follow-up among survivors was 11.9 months. At 1-year, overall survival was 78.6% (95% CI, 71.9-83.9) in the 7/8 cohort and 85.6% (95% CI, 76.0-91.5) in the <7/8 cohort. One-year relapse, non-relapse mortality, and GVHD-free relapse-free survival were 17.1%, 13.7%, and 51.1% versus 22.8%, 8.4%, and 54.6%, respectively. The cumulative incidence of grade II-IV and grade III-IV acute GVHD by day 100 was 36.6% and 7.7% in the 7/8 cohort versus 28.3% and 5.9% in the <7/8 cohort. Moderate-to-severe chronic GVHD at 1 year was 11.3% versus 7.7%, respectively. Among adult ACCESS recipients treated on a uniform young-donor PBSC/PTCy platform, short-term outcomes with predominantly 6/8 MMUD transplantation were encouraging. Because donor match level was not prospectively assigned and between-group comparisons were exploratory, these findings are descriptive and should not be interpreted as establishing equivalence with 7/8 MMUD transplantation. (Registered as NCT04904588 at CT.gov)

The importance of HLA mismatch in haploidentical hematopoietic cell transplantation (HaploHCT) with post-transplant cyclophosphamide (PTCy) is debated. If HLA mismatch does impact outcomes, a molecular mismatch model could predict transplant outcomes more effectively than allele mismatch. In this retrospective study, we quantified molecular HLA disparity using eplet mismatch for 265 patient-donor pairs undergoing HaploHCT with PTCy for hematologic malignancy. We discovered an interaction among eplet mismatch (EpMM), HLA class, and mismatch vector that was associated with clinical outcomes. This interaction was termed Class-wise HLA Imbalance of Mismatched Eplets (CHIME), which comprised risk scores of 0, 1, and 2. The CHIME score retained association with non-relapse mortality (CHIME 1 vs. 0, HR 2.85 (1.10–7.37); CHIME 2 vs. 0, HR 3.63 (1.36–9.68), adjusted p = 0.046) and severe aGvHD grade III-IV (CHIME 1 HR 7.82 (1.03–59.22); CHIME 2 HR 8.08 (1.01–64.63), adjusted p = 0.046) after adjustment for transplant-related variables. The CHIME score, when combined with CD3 cell dose, correlated with higher rates of cytokine release syndrome (CRS). The CHIME model may improve clinical outcome prediction over HLA antigen or allele mismatch.

PURPOSE: For patients with hematologic malignancies, relapse is the leading cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Frequently, relapses are explained by immune evasion through alterations of human leukocyte antigens (HLAs), but determinants and clinical consequences remain poorly defined. METHODS: We analyzed 533 relapses of hematologic cancers after allo-HCT from different donor types, conducted at 27 centers worldwide. Genomic loss of mismatched HLA (HLA loss) was assessed using a newly developed next-generation sequencing pipeline. Clinical and immunogenetic factors associated with HLA loss were evaluated. Using HLA data from approximately 5 million individuals, a web-based tool to infer HLA incompatibility phasing was developed. RESULTS: HLA loss occurred in 15.6% of relapses, with significant variation according to donor type (28.7% haploidentical family, 7.2% unrelated adult, 2.7% cord blood, P < .0001). The distribution of HLA mismatches across the patient's haplotypes, predicted through the phasing tool, was strongly associated with HLA loss, with an incidence of 27.6% when HLA mismatches were in the same haplotype, compared with 5.4% if present on different haplotypes ( P < .0001). HLA loss affected postrelapse outcomes, abrogating the efficacy of original donor lymphocyte infusions, with significant survival advantage by second allo-HCT from a different donor. CONCLUSION: The likelihood of HLA loss varies significantly according to the number and positioning of HLA mismatches between patient and donor. A newly developed phasing tool enables reliable prediction of its risk, supporting informed donor selection. Routine assessment of HLA loss at relapse is warranted, as it critically affects the success of immunologic salvage therapies.