Post-transplant complications Neurological complications ... - Nature

Bone Marrow Transplantation (2004) 34, 137–142 & 2004 Nature Publishing Group All rights reserved 0268-3369/04 $30.00

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Post-transplant complications Neurological complications following alemtuzumab-based reduced-intensity allogeneic transplantation I Avivi1, S Chakrabarti2, P Kottaridis1, C Kyriaku1, A Dogan3, DW Milligan2, D Linch1, AH Goldstone1 and S Mackinnon1 1 Department of Haematology, University College London, Birmingham Heartlands Hospital, Birmingham, UK; 2Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK; and 3Department of Histopathology, University College London, Birmingham Heartlands Hospital, Birmingham, UK

Summary: We report the incidence, characteristics and outcome of neurological complications occurring following reducedintensity conditioning (RIC) in 85 patients who received a related/unrelated donor stem cell transplantation following therapy with alemtuzumab, fludarabine and melphalan. Six patients (probability 8.9%) developed severe neurological complications at a median of 151 days (24– 334 days). Five of them presented with progressive peripheral sensori-motor radiculo-neuropathy and/or myelitis, preceded by one or more viral reactivation/ infection. Despite treatment with immunoglobulins/ plasmapheresis/steroids, four died of respiratory failure due to progressive peripheral neurophathy. Viral infection was identified as the only risk factor for the development of neurological complications. Patients who are treated with alemtuzumab-based RIC may have a lower risk of developing regimen-related neurological complications, but are more susceptible to develop peripheral radiculoneuropathy or myelitis. This phenomenon may be possibly related to viral infection associated with delayed immunological recovery or immunological dysregulation caused by alemtuzumab-induced T-cell depletion. Bone Marrow Transplantation (2004) 34, 137–142. doi:10.1038/sj.bmt.1704538 Published online 14 June 2004 Keywords: neurological complications; reduced-intensity conditioning; alemtuzumab

Almost one quarter of the patients who undergo a conventional allogeneic stem cell transplant (SCT) may develop neurological complications within the first year after transplantation, related to drug toxicity, central

Correspondence: Dr I Avivi, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa 31096, Israel; E-mail: [email protected] S Chakrabarti, Department of Haematology, Queen Elizabeth Hospital, Birmingham B15 2TH, UK; E-mail: [email protected] Received 13 October 2003; accepted 27 February 2004 Published online 14 June 2004

nervous system (CNS) hemorrhage or infections.1–4 However, severe neurological complications involving the peripheral nervous system (PNS) are relatively rare, occurring in less than 3% of transplanted patients and presents with acute or chronic inflammatory demyelinating polyneuropathy.2,4–8 An alternative approach for allogeneic SCT, aimed at attenuating treatment-related toxicity by reducing the conditioning chemotherapy dose and increasing the cure rate by inducing a graft-versus-tumour effect, has recently been introduced in patients with haematological malignancies.9–12 We describe the incidence, characteristics and outcome of neurological complication following alemtuzumab-based reduced-intensity SCT (RISCT), emphasizing the relatively high incidence of PNS involvement observed in these patients.

Patients and methods Patients In total, 85 patients underwent nonmyeloablative conditioning in two major collaborating centres between June 1997 and October 2001. The eligibility criteria for receiving reduced-intensity conditioning have been previously described and local ethics committee of the participating centres approved the study design.10,13 Conditioning regimen and GVHD prophylactic therapy. Conditioning treatment consisted of alemtuzumab (IgG1 humanized monoclonal antibody against CD52) 20 mg/day on days 8 to 4; fludarabine 30 mg/m2 from days 7 to 3 and melphalan 140 mg/m2 on day 2. Cyclosporine A (CSA), 3 mg/kg/day was started from day 1 as GVHD prophylaxis, with a targeted level of 200–300 ng/ml for the first 2–3 months, and then tapered down over next 2–3 months. CSA was administered intravenously initially and switched to oral form when suitable. Patients received unmanipulated peripheral blood stem cells from a matched family donor or unmanipulated bone marrow from an unrelated donor (UD). Donor lymphocyte infusion (DLI) was not a part of the protocol and was at the discretion of the treating physician. The usual indications were persistent mixed chimerism or

Neurological complications following reduced-intensity transplantation I Avivi et al

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worsening donor chimerism and persistence, progression or relapse of the disease that warranted the transplant. Supportive care. Antimicrobial prophylaxis consisted of acyclovir and fluconazole or itraconazole from the beginning of conditioning treatment. Pneumocystis carinii prophylaxis was given to every patient with cotrimoxazole 480 mg every 12 h three times weekly, after the absolute neutrophil count exceeded 1.0 109/l. Febrile neutropenic patients were treated with broad-spectrum antibiotics according to the institutional policy of each centre. Patients at risk of cytomegalovirus (CMV) infection were monitored weekly from the start of conditioning treatment to 100 days post transplant by a qualitative PCR assay and pre-emptively treated with ganciclovir or foscarnet.14 Patients were screened for other viruses according to institutional policies as previously described.15,16 Evaluation of neurological complications. The following investigations was carried out in all patients who developed neurological complications post transplant: 1. Clinical and laboratory evaluation of other transplantrelated complications, including signs of graft-versushost disease (GVHD). 2. Evaluation for preceding/concurrent infections (viral/ bacterial and fungal). 3. Biochemical and cytological evaluation of cerebrospinal fluid (CSF). 4. Head and spinal computer tomography (CT) and/or MRI. 5. Physiological conduction studies (if needed). 6. Sural nerve biopsy (if needed).

Results In total, 85 patients aged 18–60 years (median age 44 years) were evaluated (Table 1). A total of 11 patients were transplanted for acute leukaemia/myelodysplastic syndrome (MDS), nine for chronic leukaemias and the rest for lymphoproliferative disorders or myeloma. In all, 33 patients received an UD graft.

Neurological complications Six patients, all male (three with low-grade lymphoma, two with acute myeloid leukaemia/MDS and one with multiple myeloma) developed severe neurological complication requiring hospitalization during the first year following their transplant. The overall probability of neurological complication was 8.9% (95% CI, 1.7–15.4). The onset of the neurological symptoms was at a median of 151 days (range 24–334). Pattern of neurological complications (Table 1). Five patients (patients 1–5) presented with progressive peripheral sensori-motor polyneuropathy occurring at 3–8 months post transplant, whereas one patient (patient 6) only had a CNS involvement, characterized by extrapyramidal symptoms. Bone Marrow Transplantation

Two patients were diagnosed with classical Guillain Barre Syndrome (GBS) or acute demyelinating polyneuropathy (patients 1 and 5) and another had axonal polyneuropathy with sensory ataxia (patient 2). Patient 2 had no clinical signs of GVHD. However, a sural nerve biopsy performed pre-mortem and a post-mortem histology of spleen, lymph node and bone marrow, all showed infiltration of plasma cells and lymphocytes. One patient developed myelitis with progressive limb weakness accompanied by optic neuritis following a varicella zoster virus (VZV) infection involving T8/T9 dermatomes (patient 4) and another had an HHV-7-related transverse myelits (patient 3). The sixth patient (patient 6) presented on day 24 post transplant with extrapyramidal symptoms accompanied with enlarging lesions in the basal ganglia, shown by MRI (Table 1). Treatment and outcome of neurological complication (Table 1). Both patients who presented with classical GBS (patients 1 and 5) were treated with intravenous immunoglobulins (IVIG). One patient (patient 1) had initially responded but progressed 4 weeks later and died, while the other patient (patient 5) failed to respond to IVIG, but showed a slow improvement after being treated with plasmaphersis and rituximab. Unfortunately, he died of respiratory infection 3 months later. The patient with the axonal variety of GBS developed progressive weakness and succumbed to respiratory failure (patient 2). A sural nerve biopsy had shown plasma cell infiltration. The patient who was diagnosed as VZV-related myelitis and optic neuritis (patient 4) was treated with IVIG, acyclovir, steroids and DLI, but despite an initial response, he eventually deteriorated and died. The only survivor was patient 3, who developed an HHV-7-related transverse myelitis, responded to high-dose steroids but still experiences intermittent episodes of urinary retention. The patient who presented with extrapyramidal pathology and basal ganglia lesions (patient 6) was treated empirically with antifungal, antibacterial and anti-toxoplasma therapy and was planned to have a brain biopsy, but died before biopsy was performed. The nonrelapse mortality in the patients with neurological complications was 83.4% (95% CI 53.4–100), compared to 24.3% (95% CI 13.3–35.3) in those without this complication (P ¼ 0.0004). Risk factors for neurological complications. Drug toxicity: Two patients (patients 4 and 5) were on potentially offending medication, receiving steroids and cyslosporin A for acute and chronic GVHD. Patient no. 3 was on low dose steroids as well.

Concurrent GVHD/other autoimmune phenomenon Few patients developed clinical and/or histological signs compatible with GVHD or other immune phenomena. The incidence of chronic GVHD (cGVHD), but not acute GVHD (3/6 vs 27/79, P ¼ 0.66), showed a trend towards a higher incidence in the cohort with neurological complications, compared to those without neurological symptoms.

Table 1

Post transplant outcome: neurological complications

Patient no.

Diagnosis/stem cell source

Neurological complication

Onset of neurological complication post SCT (days)

Preceding viral infection and time post SCT (days)

Therapy of neurological complicationa

Response to therapy

1

MDS/MUD

Sensori-motor polyneuropathy

+142

EBV-r

+128

IVIG ( 2)a

No response

CMV-r Para-flu II

+90 +151 +61

Outcome

Died of respiratory failure, +6 m

2

AML/Sibling

Axonal sensori-motor polyneuropathy+sensorial ataxia

+101

CMV-r

3

MM/MUD

HHV-7 related transverse myelitis

+334

HHV-7 CSF +334 PCR

Steroids

Concurrent GVHD Weakness of limbs (low dose steroids disappeared in less than 1 week. Bladder treatment) retention – still happens occasionally

Alive. Still intermittent episodes of urinary retention

4

NHL/Sibling

Ascending myelitis optic neuritis

+242

Polyoma v

IVIGa,b

Initially had partial response but flared up again

Concurrent GVHD+AIHA (CSA+steroids)

Died of respiratory failure, +11 m

IVIG( 2), rituximab, plasmapheresisa

No response to IVIG Partial response to plasmapheresis Continued to progress,

Concurrent GVHD+AIHA (CSA+steroids)

Died of PCP infection, +12 m

Sural nerve biopsy showed axonal loss+plasma cell infiltration

Died of respiratory failure, +4.5 m


+105

No specific therapya

Concurrent clinical/ histological manifestations of GVHD

HSV +120 Influenza A +193 HZV T8/T9 +200 5

NHL//MUD

Sensori-motor polyneuropathy

+160

6

NHL/Sibling

Extrapyramidal symptoms with progressing lesions in basal ganglia

+24

Persistent CMV-r, started on day +34 Adenovirus +42

No specific therapy. Received antifungal+ for suspected CNS infection

clinically+radiologically

Died of respiratory failure, +67 days In addition, received specific antiviral therapy for concurrent viral reactivation/infection. In addition, received acyclovir and donor lymphocyte infusion for concurrent viral infection.

b

139

Bone Marrow Transplantation

a


140

There was no impact of the donor-status or underlying disease on the incidence of neurological complications.

Preceding/concurrent infections (Table 1) All patients who developed a sensori-motor neuropathy (patients 1–5) had a preceding or concurrent viral infection (Table 1). The absolute lymphocyte count of all patients except patient no. 3 was lower than 0.2 109/l at the time of presentation. CD4 þ T cell counts were measured in patients 3, 4 and 5 as 0.18, 0.04 and 0.08 ( 109/l) respectively. Lineage-specific chimerism data at the time of neurological complication were available for three patients only (patients 3, 4 and 5). Full donor chimerism of T-cell lineage was documented in patients 3 and 5, with mixed T-cell chimerism in patient 4. One more patient (patient 6) had chimerism performed for granulocyte only, whereas another patient (patient 1) had chimerism assessment before and after the appearance of neurological complication (mixed that became full), but not exactly at presentation. Chimerism data were therefore insufficient to make any conclusions about the association of chimerism and neurological complication. There was no correlation with CMV sero-positivity or reactivation, but the probability of severe neurological complication in patients with viral infections (CMV and non-CMV) was 178% (95% CI 5.3–30.3) as compared to none in those without viral infections (log rank P-value ¼ 0.01).

Discussion The low incidence of CNS haemorrhage and infections in this study, which are the major causes of severe neurological complications post conventional allograft,1,3,4 may be attributed to the reduction in the intensity of conditioning and the faster engraftment achieved in this cohort of patients receiving RISCT compared with conventional allograft.10 Interestingly, the most common neurological complications observed in this study were peripheral radiculoneuropathy and myelitis, rather than CNS pathology. There was an association with preceding or concurrent viral infections in all patients with neurological involvement, and patients with documented viral infections were at a greater risk of neurological complications. The pathogenesis of transplant-related GBS (TR-GBS) has not been fully elucidated. Viral infections,5,17 drugs,18–20 immunological deregulation and cGVHD,17,21,22 have all been suggested to be possible causes for TR-GBS; a preceding viral infection such as respiratory viruses, CMV, EBV, has been reported in up to 40% of all GBS cases23 and in a variable percentage of TR-GBS cases5,17,24,25 The pathogenesis of virus-related GBS is not fully understood. A molecular mimicry between the infective pathogen and the peripheral nerves such as ganglioside-like epitopes existing in the pathogen,26,27 a well-known mechanism for ‘Campylobacter-pylori-induced GBS’,28,29 has been suggested to induce demyelinating neuropathy. Antibodies against the Bone Marrow Transplantation

pathogen can crossreact with epitopes on the peripheral nerves, causing their damage.25,26 Despite some evidence to support the ‘crossreacting mechanism’, others failed to confirm its role in different types of ‘viral-related GBS’,30,31 suggesting other mechanisms to be also involved, particularly in transplant patients, whose ability to produce antibodies in response to a viral infection is limited. The possibility of an underlying immune dysregulation was suggested by the occurrence of autoimmune haemolysis with cGVHD in two patients. Another patient who developed axonal type GBS (patient 2) had no clinical symptoms of GVHD, but a sural nerve biopsy showed axonal degeneration with a significant infiltration of plasma cells, histological features that may fit with cGVHD of the PNS.22 There are some more evidences supporting the existence of cGVHD in the PNS:4,7,22 Firstly, the concurrent exacerbation of neurological symptoms and gut or liver GVHD, and secondly, an infiltration of plasma cells or lymphocytes in peripheral nerves, a phenomenon of immunological damage. However, despite the relatively high frequency of classical GBS/GBS subtypes observed with alemtuzumab-based RISCT, cGVHD itself was less frequent than observed with conventional allograft.10 It therefore appears that cGVHD may be involved in some but not all of these cases. T-cell depletion itself (obtained with alemtuzumab in vivo/other methods) can cause various autoimmune complications, including autoimmune haemolytic anaemia and autoimmune thrombocytopenia.32–34 Alemtuzumab therapy has been associated with the development of autoimmune thyroiditis,35 indicating its ability to cause clinical complications related to T-cell dysregulation. Alemtuzumab may therefore have a major role in the development of autoimmune peripheral neuropathy; however, there are no previous reports about similar complications in patients treated with alemtuzumab as part of conventional allograft, nor in patients who received for other indications such as chronic lymphocytic leukaemia. There are almost no reports of peripheral neurological complications following low-intensity SCT without alemtuzumab (apart of one, reporting a peripheral neuropathy accompanied with heamophagocytotic syndrome, attributed to alloreactive T cells).36 This suggests that alemtuzumab is a significant factor in the development of this complication. Severe lymphopenia particularly of CD4 þ T cell subsets was documented in all affected patients, which was responsible for the increased incidence of viral infections in this cohort.14–17 Viral infections either directly or by triggering on an immune-mediated assault in the absence of T-cell regulation caused a severe and often fatal radiculoneuropathy and myelitis. A direct neurotoxic effect of fludarabine-based conditioning regimen is less likely. Firstly, GBS occurred few months following the transplants, and secondly, fludarabine-related neurotoxicity is mainly central, rather than peripheral.37–39 The incidence of radiculopathy in patients undergoing a conventional allografts who receive a higher CSA dose is much lower, suggesting CSA to be less likely to cause this complication. Furthermore, CSA has been rarely described with radiculopathy,40 and only two patients (patients 4 and 5) were receiving CSA at the onset of


141

neurological symptoms. CSA-induced thrombotic microangiopathy mainly affects the CNS characterized by decreasing platelets counts, fragments in peripheral blood film and raised LDH.41 None of those have been observed in our patients. In conclusion, it appears that patients who were treated with alemtuzumab-based RISCT had a low incidence of regimen-related CNS toxicities but they were more likely to develop peripheral neurological complications such as radiculoneuropathy or myelitis. The delayed immunological reconstitution with increased incidence of viral infections, associated with loss of T-cell regulation caused by T-cell depletion and/or cGVHD, might be contributory in the pathogenesis of these complications. Further studies, looking at the possible connection between viral infections and the development of progressive radiculoneuropathy are needed. De-escalation of alemtuzumab dose, which is a part of the current UK multicentre RISCT study protocol, may reduce the risk for viral infections and decrease the incidence of this severe complication.

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