Infection (2014) 42:445–447 DOI 10.1007/s15010-013-0579-8
CASE REPORT
Successful treatment of AIDS-associated, primary CNS lymphoma with rituximab- and methotrexate-based chemotherapy and autologous stem cell transplantation T. Wolf • T. Kiderlen • J. Atta • C. Stephan G. Kann • H.-R. Brodt • C. Brandts
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Received: 11 October 2013 / Accepted: 23 December 2013 / Published online: 20 January 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Primary central nervous system lymphoma (PCNSL) is an Epstein–Barr virus (EBV)-associated, acquired immunodeficiency syndrome (AIDS)-defining malignancy. Even in the HAART (highly active antiretroviral therapy) era, in which the survival of patients with PCNSL has improved and the incidence has sharply reduced [1, 2], the median survival time is \6 months [1]. PCNSL has become a rare disease and, consequently, there is no consensus and only anecdotal evidence on the best treatment. Options include high-dose methotrexate (MTX) and radiotherapy. In the non-human immunodeficiency virus (HIV) setting, sequential high-dose MTX/cytarabin regimens followed by autologous stem cell transplantation (SCT) have been shown to improve 5-year overall survival from 69 to 87 % [3]. The addition of radiation therapy to such regimens, however, was found to be associated with increased neurotoxicity [4]. There is currently no data on the feasibility and efficacy of such protocols in the clinical setting of HIV. We report here on a young patient who was administered high-dose MTX/cytarabin chemotherapy combined with rituximab, followed by autologous peripheral SCT (PSCT) without radiotherapy, and achieved a durable complete remission.
This case was presented at the 14th EACS Conference, October 16–19th, 2013, Brussels, Belgium. T. Wolf (&) C. Stephan G. Kann H.-R. Brodt Department of Medicine II—Infectious Diseases, HIV Center, Hospital of the J. W. Goethe University, Theodor Stern Kai 7, 60596 Frankfurt, Germany e-mail:
[email protected] T. Kiderlen J. Atta C. Brandts Department of Medicine II—Hematology/Oncology, Hospital of the J. W. Goethe University, Frankfurt, Germany
A 36-year-old male was transferred to our infectious diseases ward from a neurology department where he had been admitted with a series of generalized seizures, an acute paresis of the left upper limb and aphasia as well as disorientation. Imaging showed two brain lesions, one frontal and one parietal. As the patient had cutaneous kaposi sarcoma (KS) lesions, he was tested for HIV and found to be positive. The initial CD4 count was 96/ll. Serological testing was negative for toxoplasmosis and cryptococcal antigen. Cerebral biopsy showed a highly proliferative diffuse large cell lymphoma positive for EBV and the B cell marker CD20. The cerebral spinal fluid showed a high HIV load of 12,600 copies/ml (peripheral blood 817,000/ml) and was negative for Polyomavirus JC (John Cunningham) based on PCR assay. Antiretroviral therapy with tenofovir/ emtricitabine, raltegravir and ritonavir-boosted darunavir was initiated. This therapy was chosen in order to achieve a faster decay of HIV with integrase inhibitors, as well as to provide a potential independent effect of protease inhibitors on the KS. The HIV load decreased to \20 copies/ml after 4 months. Combination antiretroviral therapy (cART) was administered throughout the complete chemotherapy and PBSCT treatment and continues to be administered to date. Staging revealed no further manifestation, and PCNSL was diagnosed. Chemotherapy containing two doses of rituximab (2 9 375 mg/m2), high-dose MTX (3,500 mg/m2) and cytarabin (2,000 mg/m2) was initiated. This was used analogously to a large phase 2 trial (EUDRA-CT no. 2009-012432-32, IELSG 32). No further seizures occurred, and the neurological deficits and the disorientation resolved within 2 weeks. The patient received two cycles of treatment, which were tolerated with moderate hematotoxicity (lowest neutrophile count 0.01/nl, lowest platelet count 4/nl).
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As KS flared with the first cycle, rituximab was then omitted in the second. After cycle two, apheresis of peripheral CD34? hematopoietic stem cells was successful, and imaging revealed a mixed response with a regression of the parietal lesion and a stable manifestation of the frontal lesion. Cycles 3 and 4 consisted of rituximab, cytarabin and thiotepa. Staging revealed a partial response of all cerebral lesions and a stable status of the KS. High-dose chemotherapy was performed with bis-chloroethylnitrosourea (BCNU; 400 mg/m2) and thiotepa (5 mg/m2), followed by peripheral blood stem cell transplantation (PBSCT) of 2 9 106 CD34?/kg body weight on day 6. Prophylactically, we administered cotrimoxazole 960 mg three times a week, levofloxacin in the case of neutropenia of\500/ll and, after the appearance of Herpes labialis following the first cycle, aciclovir 400 mg four times daily. The patient underwent magnetic resonance imaging for 5 months after the PBSCT. On day 153, there was a complete response with residual scars and no signs of active lymphoma (Fig. 1). Fig. 1 Magnetic resonance imaging of two central nervous system lesions at baseline (a, b) and after the completion of chemotherapy showing a complete remission (c, d)
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After PBSCT, two major episodes occurred. Firstly, KS progressed substantially after high-dose chemotherapy with new lung and pharyngeal lesions, necessitating the use of liposomal doxorubicin (20 mg/m2) 60 days after transplantation. Five cycles of liposomal doxorubicin were administered, achieving a partial remission. Secondly, the patient experienced graft failure with increasing pancytopenia and required weekly erythrocyte and platelet transfusions as well as intermittent stimulation with granulocyte colony-stimulating factor. Bone marrow biopsy then revealed hypocellularity with reduced granulopoesis. The neutrophile count recovered to levels of [500/ml 120 days after transplantation, and there were no additional AIDS-defining complications. The intravenous port system needed to be removed because of suspected infection and blood counts stabilized thereafter. There was also a febrile episode after the first cycle which did respond well to therapy with imipenem/cilastin. There were no severe complications in the long period until engraftment. In terms of the
Successful treatment of AIDS-associated PCNSL
tolerability of high-dose MTX, there were no episodes of mucositis worse than the World Health Organization’s grade 1. Interestingly, the combination with tenofovircontaining c-ART did not result in nephrotoxicity. At the time of writing this case report, the cognitive function of the patient had returned to normal and no neurotoxicity was experienced. In summary, we report the case of a young HIV patient who received intensive effective chemotherapy with rituximab, high-dose MTX, cytarabin, BCNU, thiotepa and PBSCT with a successful clinical result. Significant, yet manageable complications occurred, including severely delayed engraftment. Possible explanations for these complications are the reactivation of KS and subsequent chemotherapy as well as the presence of port infection. HIV-related causes, including viral replication and the hematotoxicity of the antiretroviral agents, are less likely reasons in our opinion because the viral load was \20/ml before transplantation, and the cytoxicity of modern antiretrovirals is by far lower than that from older nucleoside reverse transcriptase inhibitors. However, these factors cannot be fully excluded. Particular attention has to be given to hematotoxicity and additional opportunistic infections when applying such a protocol. A close collaboration between infectious diseases and hematology subspecialties and further studies are evidently required.
447 Conflict of interest There was no financial or material support provided for this work. TW had board memberships, received consultancy fees, payment for lectures and travel grants from Abbvie, BMS, Gilead, MSD, Oxford Immunotec and ViiV. HRB had board memberships, received consultancy fees, payment for lectures and travel grants from Gilead, Janssen, MSD, Pfizer and ViiV. CS received consultancy fees from Abbvie, BMS, Boehringer, Gilead, Janssen, MSD, ViiV. JA, GK and CB have no disclosures.
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