Catastrophic engraftment injury: refractory capillary leak syndrome after transplantation in multiple myeloma
Materials and Methods/Case Presentation/Objective:
A 76-year-old female with Revised International Staging System stage III lambda light-chain MM achieved a very good partial response after 4 cycles of daratumumab, bortezomib, lenalidomide, and prednisone. Following dose-reduced melphalan conditioning due to age, she received dimethyl sulfoxide (DMSO) cryopreserved stem cell transplant (day 0) and granulocyte colony-stimulating factor (G-CSF) for neutrophil recovery (days 5-13). Days 2-10 showed progressive edema, weight gain, and dyspnea as well as diffuse ground-glass opacities (GGOs) and pleural effusions on CT. By engraftment (day 12), she had worsening hypoxemia despite aggressive diuresis and empiric antimicrobial coverage. IVIG was given on days 11 and 27. Days 13-17 showed progressive upper extremity edema, followed by transient stabilization (days 22-26).
On day 28, discharge was cancelled for acute hypoxia with worsening GGOs on repeat CT. Dexamethasone 10 mg was initiated on day 29 for suspected ES, transitioned to prednisone 0.75 mg/kg (day 31), escalated to 40 mg (day 36), then 60 mg (day 38). Pneumomediastinum was identified on day 38, without apparent cause. She was intubated on day 39, with thoracic surgery then placing a chest tube (day 40). Pulse-dose methylprednisolone (day 41) and off-label tocilizumab (day 43), for elevated IL-6, were administered without improvement. Day 44 imaging showed progressive GGOs, pneumomediastinum, and pneumothorax. Care was then withdrawn at the family's request, and she passed away.
Results/Description/Main Outcome Measure(s):
This case illustrates how multiple endothelial insults may converge to produce fulminant, irreversible CLS. MM itself is associated with baseline endothelial dysfunction, and prior bortezomib exposure carries known vascular toxicity, establishing a potentially vulnerable state before transplant. DMSO, a cryoprotectant, can trigger histamine release leading to hypotension, bronchospasm, and increased endothelial permeability. While typically transient, this histamine-mediated injury may prime the vasculature for sustained capillary leak in susceptible patients. G-CSF independently promotes CLS through neutrophil activation and cytokine amplification. The temporal overlap of G-CSF with the onset of progressive edema creates a window of compounded endothelial stress. Her unprovoked pneumomediastinum may have been a clinical sign.
Elevated IL-6 supported cytokine-driven endothelial injury as a central mechanism, yet tocilizumab on day 43 failed to halt the process, suggesting endothelial damage had progressed beyond cytokine-mediated reversibility. The patient also received 15 consecutive days of escalating corticosteroids without response, supporting fulminant CLS rather than uncomplicated ES, which typically responds to steroids within 24-48 hours.
Conclusion(s).: CLS should be considered in post-HSCT patients with progressive edema and pulmonary injury refractory to diuresis and corticosteroids. Patients with multiple endothelial risk factors- MM, DMSO exposure, G-CSF, prior bortezomib, advanced age- may benefit from early cytokine monitoring and a lower threshold for cytokine-targeted therapy before irreversible damage occurs. Identifying these converging insults early may inform risk stratification and guide timely intervention in future cases.
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