Patient-specific management plan

1. Immediate priorities: stabilize and confirm disease biology

• Admit or manage at a center able to provide urgent chemotherapy, transfusion support, infectious-disease input, and transplant-cell therapy support.
• Confirm that the current syndrome is active lymphoma-associated HLH, not infection alone, GVHD flare, drug toxicity, graft failure, or a combination.
• Re-stage and characterize relapse:
  • Bone marrow aspirate/biopsy with morphology, flow cytometry, TCR phenotype, cytogenetics/FISH or NGS if available.
  • Document CD38 intensity and distribution by flow/IHC. Also assess potential actionable markers: CD52, CD30, PD-1/PD-L1, JAK/STAT-pathway alterations, and EBV status where appropriate.
  • PET-CT or contrast CT as clinically feasible, liver/spleen assessment, and chimerism including donor T-cell chimerism.
• HLH monitoring at least daily initially: fever curve, CBC, ferritin, fibrinogen, triglycerides, LDH, liver function, bilirubin, coagulation/DIC panel, renal function, soluble IL-2 receptor if locally available, and infection surveillance.

2. Treat active HLH while launching lymphoma-directed salvage

• Start dexamethasone-based HLH control promptly.
• Use etoposide-based therapy, often dose-reduced for hepatic dysfunction, renal dysfunction, cytopenias, performance status, and the post-transplant setting.
• The lymphoma-directed regimen should incorporate etoposide when feasible rather than treating HLH in isolation.
• Consider cytokine-directed adjuncts such as ruxolitinib only in an expert HLH program, particularly when hyperinflammation remains uncontrolled, but do not allow this to delay lymphoma cytoreduction.

• Broad microbiologic evaluation and empiric antimicrobials as indicated for neutropenic fever or sepsis.
• CMV, EBV, adenovirus, HHV-6, fungal testing as directed by transplant context.
• Irradiated, leukoreduced blood products, aggressive correction of hypofibrinogenemia/DIC, tumor lysis prophylaxis, and antimicrobial prophylaxis tailored to immunosuppressive regimen.
• Avoid escalating immunosuppression unless required for significant GVHD, after joint transplant and lymphoma review.

3. Lymphoma salvage options: choose a regimen that is feasible in active HLH

4. CD38 positivity: daratumumab is investigational, not a proven standard

• within a clinical trial or after multidisciplinary review,
• combined with a more credible lymphoma/HLH-control strategy rather than relied on alone in fulminant disease,
• with attention to additive post-transplant infection risk, cytopenias, hypogammaglobulinemia, viral reactivation, and transfusion compatibility interference.

5. Post-allogeneic relapse strategy

• Donor chimerism, especially T-cell chimerism
• Current GVHD and immunosuppression
• Time from transplant
• Donor availability
• Prior DLI exposure and response
• Active infection burden

1. Taper immunosuppression where safe, to augment graft-versus-lymphoma effect.
2. Consider donor lymphocyte infusion (DLI) only after careful assessment of disease tempo, chimerism, active GVHD, infection, and organ function.
3. Consider a second allogeneic transplant only in highly selected patients who achieve meaningful disease and HLH control, have adequate performance status, and have a feasible donor/cellular strategy.

6. Suggested sequence for this case

1. Today: confirm HLH activity and infectious triggers; start dexamethasone and urgent etoposide-containing management if organ-threatening HLH is present; broad infectious coverage/support.
2. Within 24-72 hours: marrow and chimerism assessment, disease re-staging, CD38/CD52 confirmation, transplant immunosuppression review, and formal lymphoma-transplant-HLH conference.
3. Once stabilized: deliver the most feasible lymphoma-directed salvage regimen, ideally etoposide-containing in view of active HLH.
4. After initial response: taper immunosuppression if safe; consider DLI or a cellular/transplant strategy; pursue trial enrollment.
5. If refractory hyperinflammation or lymphoma: reassess for ruxolitinib-containing HLH control, alemtuzumab if CD52-positive and infectious risk is acceptable, and an urgent trial referral. Daratumumab may be discussed only as an evidence-limited CD38-directed option.

Key cautions

• Do not delay lymphoma treatment while repeatedly treating HLH alone.
• Do not give DLI during uncontrolled HLH, sepsis, or active significant GVHD without a specialized transplant decision.
• Do not assume CD38 positivity predicts daratumumab response in HSTCL.
• Active HLH at the time of another transplant is associated with poorer outcomes, so the immediate target is disease and inflammatory control before cellular consolidation.