Potential Benefit of Ruxolitinib in Suspected Ocular and Neurological Transplant‐Associated Thrombotic Microangiopathy After Allogeneic Stem Cell Transplantation: A Case Report and Review

ABSTRACT

We describe a rare case of suspected delayed‐onset TA‐TMA with ocular and neurological involvement following allo‐HSCT. The condition was refractory to standard therapies; neurological improvement was temporally associated with ruxolitinib initiation, suggesting a possible GVHD overlap. This report supports a multidisciplinary approach to complex post‐transplant endothelial injury and supports further investigation of JAK inhibition in selected cases.

Key Clinical Message

Suspected delayed‐onset transplant‐associated thrombotic microangiopathy may rarely present with ocular and neurological involvement long after allogeneic transplantation. This case highlights diagnostic overlap with GVHD‐related endothelial injury, the need for multidisciplinary assessment, and the potential, hypothesis‐generating role of JAK inhibition in selected complex post‐transplant presentations.

1. Introduction

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a potentially curative treatment option for various hematologic malignancies, particularly high‐risk acute myeloblastic leukemia (AML). While it provides a beneficial graft‐versus‐leukemia (GVL) effect, allo‐HSCT is also associated with substantial risks, including conditioning‐related toxicity, opportunistic infections, and graft‐versus‐host disease (GVHD).

Among these complications, transplant‐associated thrombotic microangiopathy (TA‐TMA) is a rare but potentially life‐threatening syndrome. It arises from sustained endothelial activation and dysregulation of the complement cascade, resulting in microangiopathic hemolytic anemia, thrombocytopenia, and multiorgan involvement—most frequently renal and neurological. The incidence of TA‐TMA ranges from 0.8% to 36% depending on the diagnostic criteria used, with mortality rates between 6% and 34% based on risk stratification and treatment response [1, 2]. Diagnosis of TA‐TMA remains challenging due to its heterogeneous clinical presentation and variable timing of onset. The modified Jodele criteria are currently used to support diagnosis and risk‐based therapeutic decision‐making [3].

Ocular involvement in TA‐TMA is exceedingly rare and likely underrecognized, despite the risk of irreversible visual sequelae. Only three cases have been reported to date. The first, published in 2018, involved an 18‐year‐old patient who underwent allo‐HSCT for relapsed pre B‐cell acute lymphoblastic leukemia [4]. He developed TA‐TMA five and a half months after allo‐HSCT with permanent vision loss despite treatment. The second, reported in 2024, involved a 17‐year‐old patient who recovered visual function following both systemic and local therapy [5]. The third, reported in 2026, involved a CAR‐T cell therapy bridging to allogeneic hematopoietic stem cell transplantation which triggered Purtscher‐like retinopathy [6].

Ocular manifestations of TA‐TMA are characterized by a severe occlusive microangiopathy primarily involving the precapillary arterioles. The fundoscopic examination shows diffuse cotton‐wool spots, intraretinal hemorrhages, and can mimic a Purtscher‐like retinopathy resulting from focal ischemic infarcts. Advanced cases may present with serous retinal detachment due to choroidal fibrin thrombi, and can lead to permanent macular ischemia. Fluorescein angiography may reveal retinal vessel occlusion and areas of vascular nonperfusion. Early recognition of these funduscopic findings is crucial, as they often correlate with systemic disease activity and risk of irreversible visual loss [7].

Here, we report the case of a 62‐year‐old woman who developed suspected TA‐TMA with bilateral ocular involvement 18 months following allo‐HSCT for AML. The disease was refractory to plasma exchange and complement blockade; hematologic parameters showed only partial improvement with defibrotide, whereas neurological status improved after ruxolitinib initiation. Given the rarity and severity of this presentation, this case contributes to increasing clinician awareness and may inform therapeutic strategies in complex, immune‐mediated, or GVHD‐overlapping forms of post‐transplant endothelial injury.

2. Case History

A 62‐year‐old woman with no significant past medical history presented to the emergency department with febrile dyspnea in March 2020. Laboratory tests revealed hyperleukocytosis at 98 × 10⁹/L with 88% circulating blasts, in the absence of disseminated intravascular coagulation (DIC) or tumor lysis syndrome. A diagnosis of AML, French‐American‐British (FAB) classification type 4, was established. Cytogenetic and molecular profiling showed a normal karyotype, no MLL rearrangement, FLT3‐ITD wild‐type, and pathogenic mutations in NPM1, IDH2, PTPN11, and NRAS.

Induction chemotherapy with idarubicin (12 mg/m² on Days 1–3) and cytarabine (200 mg/m², on Days 1–6) was initiated on April 17, 2020. The treatment course was complicated by septic shock, requiring intensive care unit (ICU) admission and preventing the administration of consolidation chemotherapy. Despite these complications, the patient achieved both cytological and molecular remission following induction (Figure 1). However, a combined molecular and morphological relapse occurred 8 months later.

FIGURE 1.

Quantification of NPM1 measurable residual disease in blood and bone marrow over time. Technical threshold < 0.001.

Salvage therapy consisted of two courses of intermediate‐dose cytarabine (1500 mg/m² every 12 h on Days 1, 3, and 5), which resulted in a complete cytological remission and a marked reduction in the NPM1 transcript level. The patient subsequently underwent allo‐HSCT from a matched sibling donor in May 2021. A fludarabine‐busulfan‐based myeloablative conditioning regimen was used, comprising fludarabine 30 mg/m² from Day −6 to Day −2 and busulfan 3.2 mg/kg from Day −5 to Day −3. Graft‐versus‐host disease (GVHD) prophylaxis included ciclosporin (initiated at 3 mg/kg and tapered off by Day +120), rabbit anti‐thymocyte globulin (2.5 mg/kg on Days −3 and −2) and methotrexate (15 mg/m² on Day 1 and 10 mg/m² on Days 3, 6, 11). Following the withdrawal of immunosuppressive therapy in September 2021, the patient showed no signs of graft‐versus‐host disease (GVHD), with a total blood chimerism of 97.5% (100% in the myeloid lineage and 58% in the lymphoid lineage). In this context, a schedule of three prophylactic donor lymphocyte infusions (DLIs) was proposed and administered at escalating doses of 1 × 10⁶ CD3⁺ cells/kg, 5 × 10⁶ CD3⁺ cells/kg, and 1 × 10⁷ CD3⁺ cells/kg between December 2021 and March 2022. The post‐transplant course was uneventful, and the patient remained in sustained complete hematologic remission (Figure 1).

The graft source was peripheral blood stem cells with an infused CD34‐positive cell dose of 12.36 × 10⁶/kg and a total nucleated cell dose of 8.52 × 10⁸/kg.

In July 2022, 14 months after allo‐HSCT, she developed localized herpes zoster of the left upper limb, which resolved with a 7‐day course of oral valacyclovir (1000 mg three times daily).

In September 2022, two months later, she presented with new‐onset left eye visual disturbance, generalized malaise, gait instability, and transient aphasia. Neurological and ophthalmologic examinations were initially unremarkable. Brain magnetic resonance imaging (MRI) showed only a few periventricular FLAIR hyperintensities, interpreted as degenerative and vascular in origin. All symptoms gradually resolved within days.

Ten days after this episode, on September 30th 2022, the patient was referred to the ophthalmologic emergency department for bilateral central scotoma, with concomitant decrease in visual acuity.

3. Methods (Differential Diagnosis, Investigations, and Treatment)

Funduscopic evaluation revealed multiple pale retinal areas (Figure 2a). Optical coherence tomography (OCT) demonstrated focal band‐like hyperreflectivity within the inner nuclear layer (INL), consistent with paracentral acute middle maculopathy (PAMM) (Figure 2b). These findings are indicative of acute ischemia localized to the deep capillary plexus (DCP). Complementary fluorescein angiography confirmed areas of retinal non‐perfusion, while neuroimaging via repeat brain MRI showed no interval progression of prior lesions (Figure 3).

FIGURE 2.

(a) Color fundus photograph of the left eye of our patient on September 30, 2022. Note the presence of a cotton wool spot (circled in blue) and of a whitish area (indicated with a green arrow) near the macula, indicating capillary non‐perfusion. (b) Horizontal macular OCT B‐scan passing through the fovea of the left eye of our patient on September 30, 2022. There is a prominent hyperreflectivity of the middle retinal layers, specifically involving the inner nuclear layer (INL). These findings are consistent with Paracentral Acute Middle Maculopathy (PAMM), reflecting ischemia of the deep capillary plexus (DCP).

FIGURE 3.

Timeline of clinical events from initial acute myeloid leukemia (AML) diagnosis to the onset of ophthalmologic symptoms. Allo‐HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; DLI, donor lymphocyte infusion.

Three differential diagnoses were considered. First, a herpetic infection was suspected, given the recent history of VZV reactivation. Intravenous acyclovir was initiated at a dosage of 10 mg/kg every 8 h. However, polymerase chain reaction (PCR) testing for HSV and VZV in both cerebrospinal fluid (CSF) and aqueous humor returned negative. Second, a central nervous system relapse of AML was evaluated. Bone marrow aspiration showed no excess of blasts; the complete blood count was normal aside from macrocytosis, and residual disease was undetectable in both peripheral blood and CSF by molecular assays. Third, autoimmune vasculitis was considered. Empiric treatment with intravenous methylprednisolone (500 mg/day from October 7–9) was initiated, followed by a tapering course of corticosteroids. Comprehensive autoantibody screening—including anti‐PR3, anti‐MPO, ASCA, anti‐CCP, antinuclear, anticardiolipin, onconeural antibodies, rheumatoid factor, and angiotensin‐converting enzyme—was negative.

On October 13, the patient developed pancytopenia. Laboratory tests revealed hemolytic anemia (hemoglobin 8.4 g/dL, 3–5 schistocytes per high‐power field), proteinuria, and memory disturbances. A diagnosis of thrombotic microangiopathy (TMA) was made based on microangiopathic hemolytic anemia, thrombocytopenia, elevated lactate dehydrogenase (LDH), undetectable haptoglobin, and proteinuria in the absence of acute kidney injury or hypertension. Urinary investigations at onset showed proteinuria of 3.48 g/day. Proteinuria subsequently improved after treatment, with values of 1.76 g/day on October 18. ADAMTS13 activity was within the normal range, effectively excluding thrombotic thrombocytopenic purpura. In the post‐transplant context, and after exclusion of infectious, malignant, and autoimmune mimics, the working diagnosis was suspected late‐onset TA‐TMA, while renal chronic GVHD/immune‐mediated endothelial injury was also considered given the late timing and proteinuric presentation. Renal biopsy was not performed.

The patient underwent three sessions of plasma exchange in the intensive care unit (October 13, 14, and 16), without sustained clinical or laboratory improvement. The second session, on October 14, was complicated by a generalized seizure requiring orotracheal intubation. The sedation was discontinued on October 21st with an appropriate awakening. Eculizumab was initiated on October 16 (900 mg), followed by a second dose (1200 mg) on October 21. This was associated with transient hematologic improvement and neurological recovery sufficient to allow extubation on October 21. However, signs of hemolysis soon recurred, with schistocytes exceeding 10 per field, haptoglobin < 0.10 g/L, LDH > 800 IU/L, and worsening cytopenias (hemoglobin 7.3 g/dL, platelet count 50 × 10⁹/L).

Corticosteroids were maintained at 1 mg/kg, and eculizumab was continued. On October 24, defibrotide was introduced at 25 mg/kg/day to address endothelial injury and microthrombi formation. A gradual improvement in laboratory parameters was observed, yet the patient remained neurologically confused (no GCS available) with persistent visual impairment immediately before ruxolitinib. Given the combination of bilateral ocular involvement and central nervous system symptoms, an overlapping GVHD/immune‐mediated endothelial injury process was suspected. Ruxolitinib (5 mg twice daily) was initiated on November 2, along with an intravitreal corticosteroid injection of the right eye (Figure 4). Neurological improvement was observed after JAK inhibition, with recovery of baseline neurological status. Due to increased hemorrhagic risk, defibrotide was discontinued on November 7, and a final dose of eculizumab (1200 mg) was administered on November 12.

FIGURE 4.

Fluctuations of hemolysis parameters over time and in response to therapeutic interventions.

From an ophthalmological perspective, the course of visual impairment was reviewed chronologically. In September 30, 2022, visual acuity was 6/10 in the right eye and 8/10 in the left eye; at the worst stage on October 27, it was below 1/10 in both eyes. On November 3, after initiation of plasma exchange, eculizumab and defibrotide, and one day after ruxolitinib initiation and concomitant intravitreal corticosteroid injection of the right eye, visual acuity was 4/10 in the right eye and 3/10 in the left eye. Follow‐up OCT revealed no new lesions; previously identified PAMM lesions showed significant regression and evolved toward focal areas of retinal atrophy, corresponding to retinal ischemic perivascular lesions (RIPL) (Figure 5). The temporal association between visual improvement and ruxolitinib should therefore be interpreted cautiously because systemic therapies and local corticosteroid treatment were administered in close succession.

FIGURE 5.

Horizontal macular OCT B‐scan through the fovea of the left eye on September 30, 2022 and November 9, 2022. The previously noted retinal hyperreflectivity has decreased, giving way to retinal thinning and atrophy. There is an associated disorganization of the retinal layers, which now appears irregular.

4. Results (Outcome and Follow‐Up)

At last follow‐up, in May 2026, the patient had fully recovered both hematologically and neurologically. However, persistent bilateral visual impairment predominantly affecting the right eye persisted, with visual acuity measured at 4/10 in the right eye and 9/10 in the left, attributed to irreversible bilateral macular ischemia. She remained in sustained complete hematologic remission four years after allo‐HSCT (Figure 1). Ruxolitinib was continued at a dose of 5 mg twice daily because of the suspected GVHD‐overlap inflammatory process, with excellent clinical and hematologic tolerance and no reported adverse events.

5. Discussion

We report a rare case of suspected thrombotic microangiopathy (TMA) following allogeneic hematopoietic stem cell transplantation (allo‐HSCT), with both ocular and neurological involvement and a possible chronic GVHD/immune‐mediated endothelial injury overlap. The presentation was notably delayed and showed only partial response to multiple therapies, including plasma exchange, complement inhibition, and defibrotide, whereas marked neurological improvement was observed after initiation of ruxolitinib.

This case presents several atypical features. First, the timing of TA‐TMA onset was unusually delayed. While two incidence peaks are classically described, an early peak around Day +30 and a late peak around Day +200 post‐transplantation [8], our patient developed TA‐TMA approximately 18 months after allo‐HSCT. Such a delayed manifestation emphasizes the need for prolonged clinical vigilance, even beyond the first post‐transplant year, particularly when new neurological or ophthalmological symptoms arise.

An important alternative or overlapping diagnosis was renal chronic GVHD, particularly because the event occurred late after allo‐HSCT and proteinuria can occur in chronic GVHD with a nephrotic‐syndrome phenotype. In the absence of renal biopsy, and pending complete urinary sediment documentation, we cannot formally exclude a GVHD‐related immune‐mediated renal/endothelial process. We therefore describe the event as suspected late‐onset TA‐TMA with possible chronic GVHD overlap rather than as definitive isolated TA‐TMA [9].

Second, the clinical presentation was dominated by ocular manifestations consistent with Purtscher‐like retinopathy, in conjunction with fluctuating neurological symptoms. To date, ocular involvement in TA‐TMA remains exceedingly rare and likely underdiagnosed. To our knowledge, only two prior cases have been reported in the literature, both in adolescents (aged 17 and 18 years), and both associated with partial visual loss despite treatment [4, 5].

Purtscher‐like retinopathy is classically described as a retinal arteriolar occlusive syndrome associated, in the context of TA‐TMA, with thrombotic microangiopathy. It is characterized by a sudden, painless decrease in visual acuity in the absence of ocular redness. On funduscopic examination, it manifests as Purtscher flecken—multiple whitish retinal patches—which correspond to paracentral acute middle maculopathy (PAMM) lesions on optical coherence tomography (OCT) [10]. PAMM lesions represent ischemia of the deep retinal capillary plexus, leading to hyperreflectivity of the inner nuclear and inner plexiform layers on OCT. They may occur in various ischemic conditions and reflect localized microvascular compromise. Over time, PAMM lesions evolve into ischemic sequelae, known as RIPL, characterized by focal atrophy of the inner nuclear layer and compensatory expansion of the outer nuclear layer, as observed in our case. When located in the macula—particularly within the foveal region—PAMM and RIPL lesions can result in irreversible central visual loss.

The first reported case involved an 18‐year‐old patient who had received allo‐HSCT for relapsed B‐cell lymphoblastic acute leukemia and developed TA‐TMA five and a half months later. TA‐TMA presented with hemolytic anemia and proteinuria and was treated with plasma exchange and eculizumab [4]. Two weeks later, the patient experienced a drop in visual acuity, with fundoscopy showing macular edema and retinal hemorrhages. A diagnosis of Purtscher‐like retinopathy was made. The patient was treated with intravitreal injections of triamcinolone acetonide (4 mg/0.1 mL), which allowed stabilization of the ocular findings.

The second case was a 17‐year‐old patient who developed decreased visual acuity following allogeneic hematopoietic stem cell transplantation. Ophthalmologic examination revealed signs consistent with Purtscher‐like retinopathy, including pre‐papillary cotton wool spots, macular edema, and retinal hemorrhage [5]. The patient underwent pan‐retinal photocoagulation, which led to resolution of macular edema and improvement in visual acuity.

From a therapeutic perspective, the patient's condition proved refractory to plasma exchange and complement blockade with eculizumab, with only transient hematologic improvement. Defibrotide provided modest benefit, yet neurological symptoms and visual deficits persisted. Notably, the introduction of ruxolitinib—a selective JAK1/JAK2 inhibitor—was associated with marked neurological recovery. Although ruxolitinib is not approved for TA‐TMA, its use in steroid‐refractory acute and chronic graft‐versus‐host disease (GVHD) is well established and supported by phase III data [11].

The temporal sequence also limits causal interpretation. Eculizumab was followed by transient hematologic improvement and recovery of consciousness sufficient for extubation, and defibrotide was introduced before ruxolitinib. The sustained neurological recovery after JAK inhibition is therefore hypothesis‐generating rather than definitive proof of ruxolitinib efficacy. An additional argument that could potentially explain the role of ruxolitinib is that in TA‐TMA, cytokine activation contributes to endothelial injury. Ruxolitinib has demonstrated anti‐inflammatory activity in the central nervous system (CNS), owing to its ability to cross the blood–brain barrier (BBB). The neurological effects observed in our patient could therefore be explained by its good BBB penetration [12].

In our case, the suspected coexistence of TA‐TMA and subclinical or atypical GVHD—affecting the central nervous system and ocular tissues—led us to initiate ruxolitinib, although it has been reported in the literature as a potential risk factor for the development of TA‐TMA [10]. The JAK–STAT signaling pathway plays a critical role in GVHD pathogenesis and has also been implicated in endothelial activation, a central mechanism in TA‐TMA. This case supports the hypothesis of a pathophysiological overlap between TA‐TMA and GVHD, possibly driven by persistent immune‐mediated endothelial injury and chronic inflammation.

Altogether, this observation highlights the need for a flexible, multidisciplinary, and sequential treatment approach in refractory TA‐TMA, and calls for exploration of alternative therapeutic targets beyond complement inhibition—particularly in cases with extra‐renal involvement or poor response to anti‐C5 therapy.

Suspected TA‐TMA or immune‐mediated post‐transplant endothelial injury can manifest in delayed and atypical forms, including isolated or predominant ocular involvement. This case illustrates the importance of early recognition and multidisciplinary evaluation in the presence of unexplained neurological or visual symptoms, even long after allo‐HSCT. The clinical improvement observed after ruxolitinib initiation suggests a potential role for JAK inhibition in selected complex or GVHD‐overlapping presentations, but causality cannot be established from a single case with sequential therapies. Further studies are warranted to elucidate the pathophysiological interplay between endothelial injury, inflammation, and immune dysregulation in TA‐TMA, and to assess the therapeutic potential of the JAK–STAT pathway.

Author Contributions

Lise‐Marie Pillet: data curation, formal analysis, writing – original draft, writing – review and editing. Antoine Arandilla: formal analysis, investigation, validation, writing – review and editing. Gaëtan Sauvetre: formal analysis, validation, writing – review and editing. Paul Goupillou: formal analysis, investigation, writing – review and editing. Adrien Lefevre: formal analysis, investigation, writing – review and editing. Maximilien Grall: formal analysis, investigation, writing – review and editing. Antoine Bonnevalle: formal analysis, investigation, writing – review and editing. Bertrand Bourre: formal analysis, investigation, writing – review and editing. Dominique Penther: formal analysis, investigation, writing – review and editing. Sophie Porcheron: formal analysis, writing – review and editing. Fabrice Jardin: formal analysis, validation, writing – review and editing. Mustafa Alani: formal analysis, investigation, writing – review and editing. Sydney Dubois: formal analysis, validation, writing – review and editing. Vincent Camus: conceptualization, formal analysis, methodology, supervision, validation, writing – review and editing.

Funding

The authors have nothing to report.

Consent

Written informed consent for publication of this case and associated images was obtained from the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this manuscript are available from the corresponding author upon reasonable request.