PROBLEM SUMMARY MEMO (PSM)

DIAGNOSIS

DISEASE BACKGROUND

• Sinusoidal infiltration pattern (spleen, liver, bone marrow)
• Hepatosplenomegaly with systemic B symptoms
• Cytopenias (anemia, thrombocytopenia, leukopenia)
• Absence of peripheral lymphadenopathy (uncommon)
• Predominantly affects young males; associated with immune dysregulation in ~20% of cases
• Immunophenotype: CD2+, CD3+, CD7+, CD4-, CD8-, γδ TCR+
• Frequent chromosomal abnormalities: isochromosome 7q, trisomy 8, SETD2 and STAT5B mutations
• Median OS approximately 1 year; 5-year OS <15%

CLINICAL PROBLEM LIST

Problem 1: Post-Allogeneic Transplant Relapse

• Allo-HCT is the strongest consolidation strategy for HSTCL and remains the only potentially curative modality for eligible patients
• In the US multicenter HCT cohort (Moustafa et al., 2024, PMID 38431075; n=53), 3-year cumulative incidence of relapse post allo-HCT was 35% (95% CI: 21-57%)
• Post-allo relapse in HSTCL carries an extremely poor prognosis; median survival after relapse is measured in weeks to a few months
• Graft-versus-lymphoma (GvL) effect, when present, has not proven sufficient to prevent relapse in many cases
• Per 2025 EBMT guidelines, allo-HCT is strongly recommended as first-line consolidation for HSTCL - its failure in this patient defines a refractory/ultra-high-risk state

• Assess chimerism status (mixed vs. full donor)
• Evaluate for graft failure vs. true disease relapse
• Consider donor lymphocyte infusion (DLI) if GvL activity is plausible and adequate organ function permits
• Re-transplant is rarely feasible but may be discussed in select patients achieving a response
• Clinical trial enrollment is strongly preferred given no standard of care

Problem 2: Hemophagocytic Lymphohistiocytosis (HLH)

• Malignant γδ T cells directly trigger uncontrolled immune activation and macrophage hyperstimulation
• HLH in this setting is a direct manifestation of active lymphoma - controlling the underlying malignancy is the primary therapeutic objective
• Represents a cytokine storm state (IFN-γ, IL-6, IL-18 dysregulation)

1. Treat the underlying malignancy first - malignancy-associated HLH is best controlled by treating the driving malignancy
2. An etoposide-containing regimen is the backbone of HLH management when lymphoma is the trigger
3. High-dose corticosteroids (dexamethasone preferred for CNS penetration) should be continued until HLH resolves
4. For refractory HLH: consider ruxolitinib (JAK1/2 inhibitor), anakinra (IL-1 blockade), or emapalumab (anti-IFN-γ) as targeted HLH agents
5. If HLH persists after lymphoma-directed therapy, HLH-94 protocol rescue may be employed

• Ferritin (daily/every-other-day trending)
• Fibrinogen, triglycerides (every 48-72 h)
• CBC with differential (daily)
• sIL-2R (soluble CD25) - baseline and weekly
• LFTs, bilirubin (every 48-72 h)
• Coagulation profile (daily)

Problem 3: Active Disease (Relapsed/Refractory HSTCL)

• Clinical: hepatosplenomegaly, B symptoms, cytopenias
• Radiologic: FDG-PET/CT to document extent of disease
• Histologic: bone marrow biopsy to assess infiltration pattern and re-confirm γδ phenotype
• Molecular: repeat flow cytometry, TCR γδ rearrangement, cytogenetics

Problem 4: CD38-Positive Disease

• CD38 is a transmembrane glycoprotein expressed on activated T cells, B cells, and plasma cells
• CD38 expression on HSTCL/T-cell neoplasms opens a therapeutic window for anti-CD38 monoclonal antibody strategies
• Daratumumab (anti-CD38 IgG1κ mAb) is the primary agent of interest

• Daratumumab + brentuximab vedotin has been reported in relapsed T-ALL post allo-SCT with metabolic complete response after 1 cycle (Haematologica 2023)
• CD38 is uniformly expressed on T-ALL blasts with persistent expression post-chemotherapy
• Preclinical xenograft models demonstrate daratumumab efficacy in T-cell tumors
• No prospective trial data in HSTCL specifically; use is off-label and experimental

• Anti-CD38 therapies can cause T-cell fratricide (destruction of non-malignant CD38+ T cells), leading to immunosuppression and infectious risk
• This is especially relevant post-allo-HCT where immune reconstitution is already compromised
• Donors' T cells and residual normal T cells may be depleted by daratumumab

• Daratumumab + brentuximab vedotin (if CD30 co-expressed)
• Daratumumab + gemcitabine-based backbone
• Daratumumab + bendamustine (off-label; limited precedent)
• Enrollment on anti-CD38 trial preferred

INTEGRATED PROBLEM SUMMARY TABLE

RECOMMENDED WORKUP (IMMEDIATE)

1. Repeat bone marrow biopsy - confirm γδ phenotype, assess blast burden, hemophagocytosis
2. FDG-PET/CT - document extent of post-allo relapse
3. Chimerism studies (BM and peripheral blood) - mixed chimerism may support DLI
4. Infectious workup - EBV PCR, CMV, fungal serology (exclude infectious HLH trigger)
5. HLH panel - ferritin, triglycerides, fibrinogen, sIL-2R (soluble CD25), NK cell activity
6. Full flow cytometry - confirm CD38 expression level/density (important for daratumumab dosing strategy)
7. CNS evaluation (LP) - if any neurological symptoms, given post-allo immunosuppressed state
8. Comprehensive metabolic panel, LFTs, coagulation - baseline organ function for therapy planning

THERAPEUTIC STRATEGY RECOMMENDATIONS

Immediate (Acute HLH Management)

• Dexamethasone 10 mg/m²/day (IV) - cornerstone of HLH control
• Etoposide 150 mg/m² IV q3 days x 2 then weekly - lymphoma-directed HLH control
• Treat concurrently with lymphoma-directed salvage if hemodynamically stable
• Avoid delay in starting lymphoma-directed therapy

Lymphoma-Directed Salvage (Active Disease)

• First priority: clinical trial enrollment - no standard of care exists for post-allo HSTCL relapse
  • Seek trials for: CD38-directed agents, CAR-T (CD5/CD7-targeted), bispecific antibodies, novel PTCL agents
• If no trial available:
  • Daratumumab (given CD38+) in combination with gemcitabine ± oxaliplatin or bendamustine
  • Consider addition of brentuximab vedotin if CD30 co-expression present
  • Ruxolitinib (HLH-directed JAK inhibition) may have dual benefit for HLH and disease activity

DLI Consideration

• If mixed chimerism documented: DLI may be considered with caution
• Risk of severe GVHD is high in the setting of active HLH and active disease
• Low-dose DLI with close monitoring if pursued

Re-Transplant

• Second allo-HCT: only if disease responds to salvage and adequate performance status/organ function; discussed in tumor board/multidisciplinary setting

PROGNOSIS

• Median OS post-allo relapse in HSTCL: weeks to months (no large dataset; individual case reports)
• 5-year OS for HSTCL overall: <15% (Blood Advances 2025, PMID 39874497)
• Malignancy-associated HLH adds significant independent mortality risk
• CD38 expression provides an actionable target but anti-CD38 therapy in this setting has limited published evidence

KEY REFERENCES

1. Moustafa MA et al. "A US Multicenter Collaborative Study on Outcomes of HCT in HSTCL." Transplant Cell Ther. 2024. PMID: 38431075
2. Schwartz LF et al. "Hepatosplenic T-cell lymphoma in children and adolescents." Blood Adv. 2025. PMID: 39874497
3. Zoref-Lorenz A et al. "Malignancy-associated HLH: mechanisms, diagnosis, and treatment." Leuk Lymphoma. 2025. PMID: 39656557
4. Bron D et al. "Hepatosplenic T-cell lymphoma: treatment challenges." Curr Opin Oncol. 2021. PMID: 34409955
5. EBMT Practice Recommendations 2025 - Indications for HCT and CAR-T for haematological diseases. Bone Marrow Transplantation. 2025.
6. Goldman-Cecil Medicine, International Edition - Hepatosplenic T-cell Lymphoma; Hemophagocytic Lymphohistiocytosis sections.
7. Harrison's Principles of Internal Medicine 22E (2025) - Mature T-cell and NK-cell neoplasms.

Disclaimer: This PSM is generated for clinical reference and educational purposes. All therapeutic decisions must be made by the treating physician in the context of the patient's full clinical picture, institutional protocols, and multidisciplinary tumor board discussion. Clinical trial enrollment is strongly recommended for this ultra-rare, post-transplant relapsed disease setting.