Efficacy of Intrathecal Rituximab In the Management of CNS Relapse of Aggressive HIV Related Lymphoma
Authors: Ramamoorthy Suthanthira Kannan , Kumar Vishnu , Scientist R 
Published: October 2019

Abstract
Abstract 4929
Intrathecal rituximab is not routinely used in the treatment of CNS involvement of Leukemia and Lymphomas. However, we had to use it in a patient who presented with aggressive relapse of HIV related lymphoma. He had multiple adverse prognostic factors such as HIV related lymphoma, relapse within few months of primary treatment, old age, extensive CNS disease (multiple cranial nerve involvement) with bone marrow involvement.
This patient Mr X was admitted with complaints of swelling in the left side of face slowly growing on 4 months duration. He had no h/o of fever or weight loss. No deviation of angle of mouth or drooling of saliva. He has been a known diabetic on oral antihypoglycemic drugs for the past 10 years. He was found to have HIV positivity 5 years back and had been on anti retroviral therapy since then.
On examination the swelling was 7×4cm in size in the left parotid extending 3 cm in front of ear to 5cm below the angle of mandible, well defined with surface appearing smooth. Biopsy confirmed it as Diffuse Large B cell lymphoma. Immunohistochemistry showed the cells to be positive for CD 20, CD79a, LCA with lamda restriction and negative for CD 3 and CD10. Ki 67 was positive in 20% of cells only. LDH was 461 U/L (230-460). Other biochemical parameters and blood counts were normal. Bone marrow was not involved. He has been staged as Stage IE with IPI score of 1/5. He had slightly low CD4 count at diagnosis. His anti retroviral medications include Lamividine 300mg, Tenofovir 300 mg combination od, Ritonavir 50mg, Iopinavir 200mg combination od. His HIV viral load remained undetectable. CD 4 counts regained normal levels at the end of chemotherapy cycles (see Table 1).
He was started on continuous infusion CDE regimen (Cyclophosphamide, Doxorubicin and Etoposide) and tolerated the chemotherapy well. He was admitted with neutropenic sepsis every time after 3rd cycle and severe nuetropenia (ANC <500) never persisted for more than 4 days. He had a PET scan (whole body) after 3 cycles which was negative. He did not receive intra-thecal chemotherapy as LDH was not elevated. He presented a month later of completing chemotherapy with severe body pain and headache and within 3 days developed cranial nerve palsies (bilateral VI, right X11 and extra pyramidal signs in right leg.) His CT and MRI brain were normal. CSF showed 620 lymphocytes/cu mm. Flow cytometry on the CSF cells showed positivity for CD19, CD20 and monoclonal for lamda. This confirmed CNS involvement with lymphoma.
Meanwhile the platelet count had dropped immediately to 80 × 10 9/L. Bone marrow showed infiltration with blasts (~ 35% showing deep blue cytoplasm with intense vacuolation). Cytogenetics and FISH could not be done. LDH was 1600 U/L (Normal up to 460 U/L). Flow cytometry showed CD 20, CD19, CD10, CD45 positivity with lamda restriction. Hence it is probable that the patient had Diffuse Large Cell Lymphoma- Burkitts like. He was planned and started on R Hyper CVAD regimen.
In view of florid CNS manifestation with marrow involvement it was decided to give intrathecal rituximab in addition to triple IT. After informed consent, he was given 10 mg of rituximab in 5ml normal saline followed by triple Intrathecal with methotrexate, cytosine and hydrocortisone and given twice during each cycle as per the protocol. Intrathecal rituximb was given one dose at each cycle. He received a total of 12 cycles of triple IT. The abnormal lymphoid cells in CSF disappeared after the first intra-thecal chemotherapy He was started on R hyper CVAD with 75 % of dose reduction. His neutropenic period was not unduly prolonged and was manageable. He went into remission after the first cycle and the CNS status improved slowly and at the end of second cycle there was no residual neurological deficit. After 4 cycles, the dose had to be halved in view of prolonged neutropenia and hence it was decided to stop with 6 cycles. He received cranio-spinal RT after 6 cycles and has remained in continuous remission for more than 6 months so far.Table 1:CD4/CD8 Ratios at various time points of treatment:CD3 (716-2130)CD4 (354-1100)CD8 (192-980)Ratio (0.57-2.03)At diagnosis123921510010.22At CNS relapse14108804901.79Post 4 cycles of hyper CVAD126024010200.23End of therapy14257506751.11

Conclusion:
Eventhough this observation was made in one patient, the dramatic response in this patient who otherwise would have had very poor prognosis, may warrant its use in patients with florid CNS manifestations.

Disclosures:
Off Label Use: Rituximab has been used extensively in B cell lymphomas. However its use as an intrathecal medicine is still in trials and is not generally recommended in all patients.