From bloodjournal.hematologylibrary.org by guest on July 13, 2011. For personal use only.
2002 100: 1104-1105 doi:10.1182/blood-2002-04-1271
Leukoencephalopathy and papovavirus infection after treatment with chemotherapy and anti-CD20 monoclonal antibody Paola Matteucci, Michele Magni, Massimo Di Nicola, Carmelo Carlo-Stella, Caterina Uberti and Alessandro M. Gianni
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From bloodjournal.hematologylibrary.org by guest on July 13, 2011. For personal use only. 1104
BLOOD, 1 AUGUST 2002 䡠 VOLUME 100, NUMBER 3
CORRESPONDENCE
To the editor: Leukoencephalopathy and papovavirus infection after treatment with chemotherapy and anti-CD20 monoclonal antibody Goldberg et al1 recently reported a few unusual viral infections after high-dose chemotherapy with autologous blood stem cell rescue associated to peritransplantation rituximab. In their paper, the authors describe 4 cases of either JC papovavirus or cytomegaloviral (CMV) infections after chemotherapy and rituximab administration. Although a direct correlation with anti-CD20 therapy remains to be demonstrated, concerns were expressed about the clustering of these rituximab-treated cases in view of the broad and increasing use of the anti-CD20 monoclonal antibody in nonHodgkin lymphoma (NHL) treatment. We report here one additional case of progressive multifocal leukoencephalopathy associated with peritransplantation rituximab in a heavily pretreated lymphoma patient. A 56-year-old man had a clinical history of Hodgkin disease, nodular sclerosis, diagnosed in 1974. He had stage II E A disease and was treated with a mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) regimen for 6 cycles, subtotalnodal irradiation, and splenectomy, achieving a complete clinical remission. In October 1998 he was diagnosed as having diffuse large cell NHL, stage IV A. At that time, slides of both diagnoses were evaluated, confirming the 2 different diseases. Between November 1998 and July 1999 he received cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHO[P]) for 6 cycles, and then mesna, ifosfamide, mitoxantrone, and etoposide (MINE) for 6 cycles, achieving a complete remission. He was admitted in our department 1 year later with progressive disease, presenting with enlarged cervical nodes and pulmonary, bone, and bone marrow disease localizations. Serological tests for hepatitis B virus (HBV), hepatitis C virus (HCV), HIV 1/2, CMV, Epstein-Barr virus (EBV), herpes zoster virus (HZV), herpes simplex virus (HSV) 1 and 2, and Toxotest were positive, except for HIV 1/2, indicating past exposure to the corresponding pathogen. Active infection by HCV-RNA genotype 2a/2c was also demonstrated (Table 1). The patient underwent salvage high-dose sequential chemotherapy, including 6 overall doses of rituximab at 375 mg/m2 (R-HDS).2 The treatment lasted from July 2000 to January 2001 and comprised dexamethasone, cytarabine, and cisplatin ([D]HAP) for 3 cycles 3 cyclophosphamide 5.6 g/m2 plus 2 rituximab 375 mg/m2 infusions before stem cell harvest 3 cytosine arabinoside 1.5 g/m2 every 12 hours for 6 days 3 stem cell rescue and Table 1. Main laboratory and serological tests Before R-HDS
After R-HDS
Neurological symptoms
Neutrophils/L
5740
4510
1570
Lymphocytes/L
4020
2150
2940
Serum Ig, mg/%
1050
1230
730
HBV-DNA, pg/mL
subsequent stem cell harvest, both preceded by rituximab 375 mg/m2 infusion 3 etoposide 2.4 g/m2 plus cisplatin 100 mg/m2 plus stem cell rescue 3 high-dose BCNU, etoposide, cytosine arabinoside, and melphalan (HD-BEAM) plus stem cell rescue. Two additional weekly doses of rituximab, 375 mg/m2, ended the treatment. Stem cells harvested after chemotherapy with cytosine arabinoside plus rituximab were negative for lymphoma cell contamination (as assessed by polymerase chain reaction [PCR] using a patient’s specific primer) and were used to support the final myeloablative BEAM regimen. The patient achieved a complete clinical and molecular remission. The treatment was well tolerated, and the patient was discharged in good clinical conditions. Consolidation radiotherapy (30 Gy) on sacral region was given on an outpatient setting. On day ⫹20 from the end of treatment, the patient developed an asymptomatic CMV infection, documented by a positive pp65 assay (3 and 4 positive nuclei/200 000 cells), and was treated with gancyclovir in our outpatient department until negativization of the assay in 2 consecutive controls. Seven months later, the patient presented with progressive pulmonary and bone disease, confirmed by computed tomography (CT)–scan as well as by histological and immunophenotypic analysis of the pulmonary localizations. At that time, complete serological tests were repeated, confirming the presence of HCV-RNA. The patient was treated with vinorelbine (25 mg/m2) in association with rituximab, 375 mg/m2, for 7 overall courses, achieving a partial response. In February 2002, soon after the end of the last dose of rituximab, the patient experienced mental status changes and ataxia. A brain CT scan revealed multiple hypodense lesions, while magnetic resonance imaging (MRI) showed areas of white matter disease consistent with a demyelinating process. A cerebrospinal fluid examination was positive for BK papovavirus DNA. Despite treatment with cidofovir, the patient died in April 2002. The present report adds to the list of unusual viral infections in patients treated with high-dose chemotherapy and rituximab. Of note, the BK papovavirus isolated here causes leukoencephalopathy with 10-fold less frequency3 compared with the JC papovavirus responsible for the 2 cases of progressive multifocal leukoencephalopathy reported by Goldberg et al.1 The contributory role of rituximab, if any, is only tentative and far from being proved.4,5 However, this additional case further strengthens the need for an accurate surveillance and reporting of rare viral infections that might occur in heavily pretreated lymphoma patients receiving peritransplantation rituximab. Paola Matteucci, Michele Magni, Massimo Di Nicola, Carmelo Carlo-Stella, Caterina Uberti, and Alessandro M. Gianni
0
0
0
Positive
Positive
Positive
2 ⫻ 10e7
2 ⫻ 10e8
2 ⫻ 10e7
EBV-IgG
Positive
Positive
Positive
HSV-IgG
Positive
Positive
Positive
HZV-IgG
Positive
Positive
Positive
References
CMV-IgG
Positive
Positive
Positive
1.
CMV-pp65
Negative
Positive
Negative
HIV 1/2
Negative
Negative
Negative
HBc IgG HCV-RNA, copies/mL
Correspondence: Paola Matteucci, Istituto Nazionale Tumori, Medical Oncology C, Milan, Italy
Goldberg SL, Pecora AL, Alter RS, et al. Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab. Blood. 2002;99:1486-1488.
From bloodjournal.hematologylibrary.org by guest on July 13, 2011. For personal use only. BLOOD, 1 AUGUST 2002 䡠 VOLUME 100, NUMBER 3
2.
Magni M, Di Nicola M, Devizzi L, et al. Successful in vivo purging of CD34containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion. Blood. 2000;96: 864-869.
3.
Vago L, Cinque P, Sala E, et al. JCV-DNA and BKV-DNA in the CNS tissue and CSF of AIDS patients and normal subjects: study of 41 cases and review of the literature. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;12:139-146.
CORRESPONDENCE
1105
4.
Horwitz SM, Breslin S, Negrin RS, et al. Adjuvant rituximab after autologous peripheral blood stem cell transplant results in delayed immune reconstitution with increase in infectious complications [abstract]. Blood. 2000;96:707a.
5.
Flohr T, Hess GR, Kreiter S, Meyer RG, Huber C, Derigs G. Immune reconstitution after autologous CD34-positive selected peripheral blood stem cell transplantation combined with rituximab for refractory B-cell non-Hodgkin’s lymphoma [abstract]. Blood. 2000;96:709a.
To the editor: Acquired resistance to imatinib mesylate: selection for pre-existing mutant cells Branford and colleagues have reported on the development of resistance to imatinib mesylate in patients with chronic myeloid leukemia (CML) and with Ph⫹ acute lymphoblastic leukemia (ALL) treated with this drug. Their report highlights the biologic interest of this phenomenon, which, at the same time, is cause for considerable concern from the clinical point of view. These and other previous studies2-7 demonstrate that there are various mechanisms of resistance to imatinib. In a substantial proportion of patients, the basis for resistance is a genetic change in the BCR-ABL gene itself: particularly, point mutations within the protein tyrosine kinase (PTK) domain. This genetic mechanism has 2 interesting implications. First, it must be highly specific for imatinib; there is no reason to expect that there would be cross-resistance with any other commonly used chemotherapeutic agent. Everything leads one to believe that clinical resistance to imatinib, just like antibiotic resistance in bacteria, arises through a process whereby the drug itself selects for rare pre-existing mutant cells, which gradually outgrow drug-sensitive cells. Although this will require a very high sensitivity, it should be possible to find ways to detect such rare mutant cells in pretreatment samples. Second, as we all share the excitement of imatinib being the herald of a new generation of antitumor agents,8-10 we may still have to learn some of the implications. “Conventional” cytotoxic agents target fundamental processes within the cell, such as DNA replication or the mitotic spindle. In principle, certain mutations in any of the genes involved in one such process could confer resistance toward a cytotoxic agent that is directed against that process. But since the genes involved in, say, DNA replication are indispensable in every cell, there may be enormous constraints for a mutation in any of them to yield a cell that is drug-resistant and viable at the same time. By contrast, since the inhibition of the normal Abl PTK by imatinib has relatively few side effects, it must mean that its function is dispensable in most cells, including normal granulocytes: therefore, there may be less stringent constraints for a mutation in the ABL gene to produce a PTK that is no longer inhibited by imatinib in a cell that is viable. The same reasoning may be extended to other genes that are involved in this or in any other of the multiple signal-transduction pathways known to exist in various types of cells and that, when mutated in tumors, are attractive targets for new drugs11,12 Thus a relatively high frequency of resistance mutations may be a price to pay for the target specificity and consequent reduced toxicity of new chemotherapeutic agents. Is this going to be a major deterrent to the use of these drugs, or even to their development? Of course we hope not. Indeed, it is conceivable that new analogs can be synthesized that will break through the most common mutations conferring resistance to imatinib. But more in general, we can perhaps apply the principles learned from infectious diseases, where the use of a drug combina-
tion has been a time-honored approach aiming to minimize the risk of antibiotic resistance, since the statistical probability of a single bacterial cell having 2 rare mutations must be very low. There is every reason to assume that the same principles apply to mammalian somatic cells. One wonders whether, in a not too distant future, initial therapy of CML with imatinib alone will be frowned upon, just like single antibiotic therapy for tuberculosis would be frowned upon today. It seems not impossible that, just as “triple” or “quadruple” therapy is the standard of care today for infections by M tuberculosis, a 2-drug approach13 (perhaps cytosine-arabinoside or even the old busulphan together with imatinib) might become the standard of care for newly diagnosed CML. Lucio Luzzatto and Junia V. Melo Correspondence: Junia V. Melo, Department of Haematology, Imperial College of Science, Technology & Medicine, Hammersmith Hospital, Ducane Rd, London W12 ONN, United Kingdom; e-mail:
[email protected]
References 1. Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002;99:3472-3475. 2. Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000;96:10701079. 3. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876-880. 4. Barthe C, Cony-Makhoul P, Melo JV, Reiffers J, Mahon FX. Roots of clinical resistance to STI-571 cancer therapy. Science. 2001;293:2163. 5. Kreil S, Muller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance in CML patients after STI571 (Glivec) therapy [abstract]. Blood. 2001;98:435a. 6. Hofmann WK, Jones LC, Lemp NA, et al. Ph(⫹) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood. 2002;99:1860-1862. 7. von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002;359:487-491. 8. Goldman JM, Melo JV. Editorial: Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1084-1086. 9. Savage DG, Antman KH. Imatinib mesylate: a new oral targeted therapy. N Engl J Med. 2002;346:683-693. 10. Mauro MJ, O’Dwyer M, Heinrich MC, Druker BJ. STI571: a paradigm of new agents for cancer therapeutics. J Clin Oncol. 2002;20:325-334. 11. Shtil AA. Signal transduction pathways and transcriptional mechanisms as targets for prevention of emergence of multidrug resistance in human cancer cells. Curr Drug Targets. 2001;2:57-77. 12. Ramirez DM, Rodriguez-Gonzalez A, Lacal JC. Targeting new anticancer drugs within signalling pathways regulated by the Ras GTPase superfamily (Review). Int J Oncol. 2001;19:5-17. 13. Krystal GW. Mechanisms of resistance to imatinib (STI571) and prospects for combination with conventional chemotherapeutic agents. Drug Resist Updat. 2001;4:16-21.
