●      Allogeneic hematopoietic stem cell transplantation (allo-HCT) paradigms are changing, but acute graft-versus-host disease (aGvHD) is still a common life-threatening complication:

○      ~30-50% of patients will develop aGvHD post allo-HCT

○      Up to 35% of patients develop severe aGvHD

○      aGvHD becomes refractory to systemic steroid therapy in ~50% of patients

○      2-fold increase in non-relapse mortality

○      High economic burden driven by hospitalizations and re-admissions

●       Gastrointestinal (GI) tract involvement is a leading cause of morbidity and mortality in aGvHD

○      Earliest manifestations include loss of appetite, early satiety, dyspepsia, and weight loss. May progress to severe vomiting, abdominal pain, profuse diarrhea, and GI bleeding

○      The GI tract is a primary tissue system damaged in aGvHD, leading to a compromised mucosal barrier, protein loss, and overall malabsorption

○      GI involvement in ~70% of patients with grade II-IV aGvHD

○      GI aGVHD is a major risk factor for steroid-resistant aGvHD: 73% of patients develop steroid resistance within 2 weeks after stage 3 or 4 GI aGvHD onset

○      25% overall survival rate at 2 years after onset of stage 3 or 4 GI aGvHD

●      There is huge variability in clinical practices for third-line treatment of GI aGvHD (CHRONOS study; n=64): extracorporeal photopheresis 27%, etanercept 22%, vedolizumab 16%, infliximab 9%, others (alpha-1-proteinase inhibitor, antithymocyte immunoglobulin, alemtuzumab, inolimomab, methotrexate, allogeneic mesenchymal stem cells, antilymphocyte serum, mycophenolic acid, sirolimus, teduglutide)

○      14 different third-line treatments were used

○      92% of patients received a single agent as third-line treatment

●      Therefore, it is crucial to define steroid-refractory aGvHD:

○      Progression of aGVHD after 3 days of treatment with methylprednisolone 2mg/kg per day equivalent

○      Progression to a new organ after treatment with methylprednisolone 1mg/kg per day equivalent for skin and acute upper GI aGvHD

○      Lack of improvement after 7 days of treatment with methylprednisolone 2mg/kg per day equivalent

○      Recurrence during or after steroid taper (<0.4mg/kg)

■      What about being steroid-dependent?

■      What about steroid-intolerant patients?

●      As well as to define ruxolitinib-refractory aGvHD:

○      Progression of aGvHD compared with baseline after ≥5-10 days of treatment based on either objective increase in stage/grade or new organ involvement

○      Lack of improvement in aGvHD (partial response or better) compared with baseline after at least 14 days of treatment

○      Loss of response, defined as objective worsening of aGvHD determined by an increase in stage, grade, or new organ involvement at any time after initial improvement

○      Absence of complete response/very good partial response (CR/VGPR) at day (D)28? Is D14 more appropriate than D28?

■      What about ruxolitinib-dependent patients?

■      What about ruxolitinib-intolerant patients?

●      Ruxolitinib is not an option in patients with severe cytopenias and/or infections

○      Can the use of biomarkers stratify ruxolitinib-refractory patients at D7?

●      Strong rationale to modify microbiota in aGvHD and allo-HCT complications by fecal microbiotherapy (FMT): FMT helps to restore tissue tolerance (metabolites, pathways), and supports immune tolerance

○      Open questions regarding specific additional mechanisms currently support the application of multidonor and broad FMT

 ●      MaaT013 for Ruxolitinib-refractory Acute Graft-versus-Host Disease with Gastrointestinal Involvement: Final Results from the ARES Phase III Trial

○      FMT has shown promising results in pilot studies involving patients with refractory GI aGvHD

○      MaaT013 is made of allogeneic, full-ecosystem pooled biotherapeutic intestinal microbiota manufactured by MaaT Pharma in Lyon, France

○      Here, the authors report the final results from ARES (NCT04769895), a multicenter, open-label, phase 3 study exploring the pooled allogeneic microbiotherapy MaaT013 in subjects with refractory GI aGvHD previously treated with systemic steroids and ruxolitinib

■      Given the absence of an approved 3rd line strategy or 2nd line strategy in ruxolitinib-intolerant patients and the extremely poor prognosis of these patients, who are mostly left with no viable therapeutic option, a single-arm open-label design was proposed

■      Allo-HCT recipients with GI aGvHD, identified as corticosteroid-refractory and either refractory or intolerant to ruxolitinib, were eligible. The treatment included rectal administration of 3 MaaT013 doses (D1, D5, D10)

●      Key exclusion criteria: Cytomegalovirus colitis, lines of aGvHD treatment other than corticoids and ruxolitinib, overlap chronic GvHD, hyperacute GvHD, active uncontrolled infection

■      Each MaaT013 dose contained a minimum of 1.35×10¹¹ viable bacteria. A supplementary MaaT013 dose was authorized in case of relapse after D28 if CR/VGPR was achieved before D28

■      The primary endpoint was  GI-overall response rate (GI-ORR) at D28 assessed by an independent review committee

■      66 adult subjects with grade II-IV GI aGvHD were enrolled and received at least one MaaT013 dose (median=3; range, 1-4). Median age at informed consent was 55.5 years (range, 24-76). Most subjects presented with grade III (58%) or IV (33%) aGvHD; 86% were steroid-resistant and 14% (n=9) steroid-dependent, all were resistant to ruxolitinib.  77% of patients had exclusive lower GI involvement. Responses for all-organ ORR were similarly frequent with D28 ORR of 64%

■      The study met its primary endpoint, with a D28 GI-ORR of 62% (n=41, 95% confidence interval, 0.49-0.74), significantly higher than the pre-established 22% threshold (p<0.0001)

■      MaaT013 demonstrated an acceptable safety profile despite the vulnerability of subjects with refractory GI aGvHD 

●      The paradox still holds mechanistically: PTCy's alloreactive T-cell depletion remains proportional to HLA mismatch burden. In matched related donors, the alloreactive clone is small (1 in 10,000 cells). PTCy cannot fully eliminate it. This mechanistic reality has not changed

●      The mycophenolate mofetil (MMF)-free insight changes the Risk/Benefit: Previous trials using PTCy + tacrolimus + MMF in matched donors showed excess infections (BMT CTN 1703). The CAST study omitted MMF entirely. The result: no higher non-relapse mortality, no extra cytomegalovirua infections, same safety profile as standard. The antimetabolite, not PTCy, was driving infections

●      CAST study: Benefit in Graft-versus-Host Disease (GvHD)-Prevention, Not Graft-versus-Leukemia (GvL): The graft-relapse-free survival gain in CAST is driven entirely by GvHD reduction, not relapse. Relapse rates are similar. This is consistent with the paradox: PTCy prevents GvHD even with a small alloreactive target, but cannot enhance the GvL effect

●      Where the Paradox Now Focuses: The PTCy paradox in 2025-2026 is no longer “does PTCy work with matched donors?” (it does, CAST study confirms). The question sharpens to: Why doesn't PTCy improve GvL/overall survival in matched settings, and how do we address relapse, the remaining dominant cause of failure?

●      PTCy is not a universal GvHD prophylaxis optimized for all donor contexts (needs better partners!).

○      It is a precision tool for eliminating a large, proliferating alloreactive T-cell clone, a condition that is abundant in haploidentical transplants and minimal in matched donor transplants. 

●      Cytokine release syndrome (CRS) in haploidentical hematopoietic stem cell transplantation occurs in >50% with peripheral blood stem cell transplant and 20% with bone marrow transplant

○      Differentiate from the transient post-infusion febrile reaction due to anti-HLA against donor-specific antibodies

○      CRS starts >6 hours post-infusion and improves after post-transplant cyclophosphamide (PTCy)

○      Treat with a short course of steroids (without fear) or as CRS after chimeric antigen receptor (CAR) T-cells (there are no guidelines to follow)

●      Why do we start broad-spectrum antibiotics (BSA) in the first days after CAR T-cell infusion?

○      Why YES?:

■      We follow guidelines (ECIL and others); starting BSA is standard-of-care in patients with neutropenia or who will be neutropenic in the next 2 days who develop fever

○      Why NOT?

■      To preserve the microbiota; the risk of bacterial infection is <5%; lymphodepletion chemotherapy is actually mild and produces little or no mucosal damage, and thus the risk of bacteremia is very low

●      Empirical therapy in multi-drug-resistant bacteria colonized neutropenic patients:

○      Ceftazidime-avibactam: KPC-producer, OXA-producer, DTR Pseudomonas. Data available: Yes, KPC

○      Meropenem-vaborbactam: KPC-producer. Data available: No

○      Imipenem-relebactam: KPC-producer, OXA-producer, DTR Pseudomonas. Data available: Not in colonized

○      Cefiderocol: KPC-producer, OXA-producer, MBL-producer, DTR Pseudomonas. Data available: No

○      Aztreonam-avibactam: MBL producer. Data available: No

○      Ceftolozane-tazobactam: DTR pseudomonas. Data available: Yes.

●      Empirical therapy should cover resistant Gram-negative bacteria (See the ECIL-10 guidelines)

●      Combination therapy is not recommended routinely in all febrile neutropenic patients

●      The benefits of empirical combination therapy cannot be excluded in patients with Gram-negative bacteriemia

●      Situation when anti-Gram-positive coverage is indicated:

○      When using agents with limited Gram-positive activity, particularly in patients with severe mucositis

○      Suspicion of catheter-related infection or skin and soft-tissue infection

○      Sepsis, septic shock, or pneumonia (regardless of colonization status)

○      Methicillin-resistant Staphylococcus aureus coverage in colonized patients

●      Refractory herpes simplex virus (HSV) infection

○      The lack of clinical improvement in HSV-positive mucocutaneous lesion(s) after at least 7 days of appropriately dosed, directed anti-HSV therapy, in the absence of other plausible causes of mucositis, such as recent high-dose chemotherapy, irradiation, oral aGvHD, fungal, or other viral infection or

○      The occurrence of a new HSV-positive mucocutaneous lesion(s) after receiving appropriately dosed, directed anti-HSV therapy for at least 7 days (excluding prophylaxis and suppressive antiviral therapy).

○      Frequency of HSV-resistance:

■      Immunocompetent 0-1%

■      Hematopoietic cell transplant (HCT) recipients 0-14%

●      Risk factors: recurrent infections, high-risk transplants (haploidentical, cord), HSV-seronegative donor, prior HCT, HSV-2, inadequate/intermittent antiviral therapy.

○      The most common manifestation of mucocutaneous infections causes pain and results in decreased quality of life in affected patients. More severe manifestations, including visceral HSV disease, have been reported but are rare, probably due to a lower pathogenicity of the mutant strains

○      However, refractory or resistant (R/R) HSV infection after HCT has been associated with poor outcome including renal injury, need for hospitalization, and even death (Chemaly et al; CID 2025)

○      Management alternatives of R/R HSV infections:

■      In high-level acyclovir resistance (UL23 mutation): foscarnet, cidofovir

■      In low-level acyclovir resistance (UL23 mutation): Increased dose/continuous infusion of acyclovir or foscarnet/cidofovir

■      If there is multidrug resistance (UL30 mutation): Pritelivir (targets the viral helicase-primase complex; expanded access). Virus-specific T-cells (single case reports)

●      Refractory cytomegalovirus (CMV) infection

○      CMV viremia (DNAemia or antigenemia) that increases (ie, >1 log₁₀ increase in CMV DNA levels in the same blood compartment from the peak viral load as measured in the same laboratory and/or with the same commercial assay) or

○      Persists (≤1 log₁₀ increase or decrease in CMV DNA levels) after at least 2 weeks of appropriate antiviral therapy

●      PTCy platform modification (40mg/kg on days +3/+4, growth-colony stimulating factor, and letermovir) improved post-transplant outcome: faster neutrophil and platelet engraftment, reduced early bloodstream infections, CMV reactivation, and non-relapse mortality versus conventional PTCy 50mg/kg

●      Previous colonization appears to predict subsequent bloodstream infections due to Carbapenem-Resistant Enterobacterales (CRE; mainly  Klebsiella pneumoniae carbapenemase-producing strains [KPC]), and Extended-Spectrum Beta-Lactamase-producing Enterobacterales (ESBL-E). Scarce information regarding Psudomonas aeruginosa. Data obtained from studies has certain limitations.

○      Surveillance should be performed in high-risk patients (allogeneic HCT recipients, acute myeloid leukemia)

○      Previous colonization/infection due to multidrug resistant Gram-negative bacilli (MDR-GNB)should guide empiric antibiotic therapy

●      Antibiotics can be discontinued after at least 7 days of treatment when all symptoms and clinical signs of infection are resolved, and infection is microbiologically eradicated: with neutrophil recovery (AIIu), without neutrophil recovery (BIIu). Data from: ECIL-10 guidelines)

●      Beta-lactam-based combination therapy when:

○      Infection due to:

■      Stenotrophomonas maltophilia

■      Acinetobacter baumannii

○      Infection due to CRE (particularly MBL) or difficult-to-treat resistant P. aeruginosa in the following scenarios:      

■      Critically ill patients with sepsis or septic shock

■      Uncontrolled infection source

■      Pneumonia

■      Infections due to a pathogen with minimal inhibitory concentration values near the resistance breakpoint

○      Backbone of the combination therapy: beta-lactam

○      Combination with: aminoglycosides, fluoroquinolones, fosfomycin, colistin (aerosolized)

○      The use of beta-lactams in extended infusions has been shown to improve PK/PD target attainment in patients with febrile neutropenia. Its use in infections due to MDR-GNB should be considered 

●      High response rates and excellent overall survival (OS) with immunosuppressive therapy (IST)

●      Relapse remains a major issue

○      Not associated with lower OS

○      Patients may require ongoing medical therapy or hematopoietic cell transplantation (HCT)

●      Disease refractoriness and high-risk clonal evolution worsen OS

●      Emerging data on how to predict risk of high-risk clonal evolution post IST + eltrombopag

○      Data “In press” (NEJM Evidence): “Risk stratification for 6-month responders based on somatic profile”:

■      Low-risk clonal profile: No somatic mutations; single or multiple mutations in PIGA, BCOR/L1, DNMT3A, or others in non-selected myelodysplastic syndrome (MDS) genes

●      Complete blood count (CBC) monitoring; if progressive cytopenia: bone marrow (BM) evaluation/karyotyping and somatic testing

○      Relapse: IST or HCT 

○      Myeloid neoplasm (MN): HCT

■      Intermediate-risk clonal profile: Single or multiple mutations in ASXL1 or U2AF1 without co-mutations in selected MDS genes

●      CBC monitoring + periodic BM examinations and somatic mutation testing; if progressive cytopenia:

○      Relapse: HCT > IST

○      MN: HCT

■      High-risk clonal profile: RUNX1 somatic mutation; single or multiple mutations in ASXL1 or U2AF1 with any additional co-mutations in selected MDS genes

●      CBC monitoring + Yearly BM examinations and somatic mutation testing; if progressive cytopenia:

○      Relapse: HCT > IST

○      MN: HCT 

1. EBMT Consensus on transplantation in Hodgkin lymphoma (HL)

●      Which HL patients are candidates for autologous hematopoietic cell transplantation (auto-HCT)?

○      Auto-HCT is the standard of care for relapse or refractory (R/R) patients in advanced stage and sensitive disease after salvage therapy

○      For patients with early-stage disease and abbreviated prior therapy, treatment with chemotherapy +/- brentuximab-vedotin (BV) and/or checkpoint inhibitors (CPI) +/- radiotherapy can be considered

●      Which is the optimal salvage therapy regimen prior to auto-HCT in HL patients?

○      The decision will depend on previous treatments received, disease status at relapse, and the time to relapse

○      Include BV and/or CPI to salvage chemotherapy

●      Is achieving a metabolic complete response (CR) essential before proceeding with Auto-HCT?

○      Metabolic CR should be tried to be achieved before auto-HCT using salvage chemotherapy w/wo BV/CPIs

○      Auto-HCT is recommended in patients in partial response (PR) with low-volume disease who have received BV and CPI as part of the salvage regimen

●      What is the role of radiotherapy before or after auto-HCT?

○      When considered, early consultation with a radiation oncologist is recommended

○      Radiotherapy to positron emission tomography (PET)-positive lesions before auto-HCT can be considered

○      Radiotherapy can be considered for patients with persistent PET-positive lesions after auto-HCT

○      Radiotherapy, including a significant dose to the lungs, should be used cautiously

●      What is the optimal conditioning regimen before Auto-HCT?

○      No prospective randomized trials indicate the superiority of any preparatory regimen over another. However, BEAM is the most frequently used

○      In case of shortage of BCNU, LEAM or TEAM (thiotepa 5-7mg/kg max) are an option

●      Which patients should receive consolidation/maintenance after Auto-HCT? Drugs and duration? Influence of pretransplant use and sensitivity?

○      BV consolidation in BV-naïve HL patients not in complete remission (CR) pre-transplant and/or with ≥1 high-risk factor (following the AETHERA trial) is recommended

○      The panel supports BV consolidation in HL with ≥1 high-risk factor and limited prior BV exposure (≤4-6 cycles), provided no BV-refractoriness

○      Recommended BV duration: up to 16 cycles total (including pre-auto-HCT cycles), unless unacceptable toxicity or relapse/progression

○      Off-label CPI consolidation (pembrolizumab, nivolumab) may be considered in HL with high-risk factors and BV-refractory disease or BV-intolerance. Benefit should be weighed against potential immune-related side effects

○      Off-label consolidation with BV plus CPI can be considered in patients who are not refractory and not intolerant to BV. Benefit should be weighed against potential immune related side effects

●      Which patients are candidates for Allo-HCT?

○      Consolidation with allo-HCT is recommended for eligible patients, post-BV and CPI exposure (eligibility defined as relapse after auto-HCT, adequate organ function, physical conditions, including performance status, and sensitive disease prior to allo-HCT)

○      Allo-HCT may be postponed in patients in CR post CPI, since many of these patients can achieve long-lasting remissions

○      For refractory patients, decision to allograft should be done on an individual basis

○      Time interval between the last dose of CPIs and allo-HCT is preferably at least 6 weeks if clinically feasible

○      Consider the use of bridging therapy before allo-HCT in order to reduce the risk of relapse

●      Transplantation modalities of Allo-HCT in HL patients

○      Donor selection by recommended order:

■      HLA-matched sibling donor

■      HLA-matched unrelated donor (MUD)

■      HLA-haploidentical donor (mismatched related donor [MMRD]) or HLA-mismatched unrelated donor (MMUD) using PTCy for both

■      Cord blood (CB) should be avoided in adults except if no alternative donor is available

○      Conditioning regimen:

■      Reduced intensive conditioning ([RIC]; such as fludarabine-melphalan, fludarabine and busulfan 2 days, fludarabine plus cyclophosphamide plus total body irradiation) should be preferred

■      In patients at high risk of relapse (such as absence of metabolic CR), conditioning regimens with higher intensity (but reduced organ toxicity) may be considered (e.g., thiotepa one day, busulfan two days, and fludarabine)

■      BEAM-based conditioning could be considered in allo-HCT as first transplant

●      Transplantation modalities of allo-HCT in HL patients?

○      GvHD prophylaxis:

■      PTCy is the recommended GvHD prophylaxis independently of the donor type (particularly in CPI pre-treated patients)

■      Other methods of T-cell depletion (e.g., antithymocyte globulin or campath plus donor lymphocyte infusion [DLI]) could be considered for HLA-identical siblings or unrelated donor

●      How to prevent and manage relapse after Allo-HCT?

○       Maintenance therapy

■      No recommendation for maintenance therapy after allo-HCT outside of clinical trials

■      Clinical trials / new biomarkers to be developed

○      Treatment of relapse:

■      Tapering immunosuppression treatment

■      Chemotherapy

■      DLI w/wo BV (CPI with a note of caution)

■      BV

■      CPIs with a note of caution

■      Prospective clinical trials

■      Radiotherapy can be considered for patients with persistent PET-positive lesions after allo-HCT

2. EBMT Consensus on transplant and cellular therapy in mantle cell lymphoma

●      Auto-HCT indications

○      1L, without access to Bruton’s tyrosine kinase inhibitors (BTKi): auto-HCT consolidations is recommended

○      1L, with BTKi

■      High-risk (TP53+, Ki-67>30%): consider auto-HCT consolidation

■      Standard-risk: consider omission of auto-HCT

○      2L: no role for auto-HCT in the salvage setting

●      Auto-HCT eligibility

○      Age: There is no high-level evidence supporting the use of consolidative auto-HCT in 1L in patients older than 65 years

○      Disease status: Auto-HCT is not recommended in patients who do not achieve at least a PR on induction therapy

●      CAR T-cell therapy eligibility

○      There are no strictly defined age limits and single comorbidities that preclude CAR T-cell eligibility in mantle cell lymphoma (MCL)

○      Performance status, comorbidity, and age collectively define individual CAR T-cell eligibility

●      Holding and bridging

○      Treatment goal of holding/bridging is symptom control and keeping the patient stable, rather than achieving minimal tumor load prior to CAR T-cell therapies

○      Avoid delaying CAR T-cell therapy if already available, unless there is massive disease progression

○      There is no standard approach for holding/bridging in MCL; the choice is based on the aggressiveness of the disease, prior treatments, age, comorbidities, available options, expected turnaround, and the need for systemic vs. local disease control

●      Response surveillance

○      There is currently no established role for post-CAR T-cell measurable residual disease monitoring and/or PET surveillance as part of clinical routine

●      Maintenance

○      There is currently no role for post-CAR T-cell consolidation or maintenance, e.g., with CD20 antibodies or BTKi, outside of clinical trials

●      Allo-HCT eligibility

○      Age: Allo-HCT can be performed in patients with MCL aged 65 years or older, but the increasing risk of non-relapse mortality should be considered

○      Disease status: Although an unresponsive disease strongly affects outcome, allo-HCT can provide durable disease control in patients with refractory MCL

○      Conditioning: RIC should be preferred. The RIC regimen used should be one that the centre is familiar with

○      Donor and stem cell source

■      MRD > MUD > MMUD/MMRD > CB

■      Both peripheral blood and bone marrow are acceptable sources