Correspondence 2455 neurotoxicity.2–3 The CSF clearance of ara-C is similar to that of the CSF bulk flow rate. Furthermore, there is little conversion of ara-C to uracile arabinoside in the brain and CSF. Thus, the obstructed CSF flow due to the massive number of leukemic cells and their lysis could result in a high CSF concentration of ara-C and/or a prolonged exposure of cerebellum to ara. C. Unfortunately, the methotrexate or ara-CTP levels were not measured in the patient’ CSF. To our knowl- edge, neurotoxicity due to intrathecal ara-C has not been previously reported. This observation confirms that protocols for overt meningeal leukemia should be designed with lower rather than higher dosages of intrathecal drugs, not only for methotrexate but also for ara-C. We would like to caution against the systematic use of ara-C in the initial intrathecal treatment of these overt CNS leukemias.

F Legrand11Service d’He´matologie, Hopital Robert Debre´, S Dorgeret2 Paris, France; 2Service de Radiologie, Hopital C Saizou3 Robert Debre´, Paris, France; 3Service de M Duval1 Reanimation, Hopital Robert Debre´, Paris, France E Vilmer1

References

1 Vilmer E, Suciu S, Ferster A, Bertrand Y, Cave´ H, Thyss A, Benoit Figure 3 MR imaging performed 2 days after the last CT coronal Y, Fournier M, Souillet G, Robert A, Nelken B, Millot F, Lutz P, T2-weighted sequence. The cerebellum is still enlarged, and shows Railland X, Mechinaud F, Boutard P, Behar C, Chantraine J-M, hyperintensity of the cortex, due to oedema (?). Plouvier E, Laurreys G, Brock P, Uyttebroeck A, Margueritte G, Plantaz D, Norton L, Francotte N, Gyselinck J, Waterkeyn C, Solbu G, Philippe N, Otten J. Long-term follow up of three randomized preparation used for the intrathecal treatment was checked (100 mg trials (58831, 58832, 58881) in childhood acute lymphoblastic with 5 ml of solvent) and the dose (1.6 ml for 30 mg) administered leukemia: a CLCG-EORTC report. Leukemia 2000; 14: 2257– was correct. 2266. The mechanisms involved in this CNS toxicity could be toxic 2 Balis FM, Poplack DG. Central nervous system pharmacology of exposure of the cerebellum to ara-C. As has been suggested for metho- antileukemic drugs. Am J Pediat Hemat 1989; 11: 74–86. trexate, the presence of overt meningeal leukemia may predispose to 3 Pochedly C. Neurotoxicity due to CNS therapy for leukemia. Med the increased CSF concentration of ara-C and to the development of Pediatr Oncol 1977; 3: 101–115.

Molecular remission and reconstitution of a full chimera with arsenic trioxide in a patient with acute promyelocytic leukemia relapsed after allogeneic bone marrow transplantation

Leukemia (2002) 16, 2455–2456. doi:10.1038/sj.leu.2402716 plete remission after induction treatment with a persistence of the tran- script at the RT-PCR. The molecular complete remission was obtained TO THE EDITOR after the second consolidation therapy. After 12 months from CR, 8 months from the PML/RAR␣ negativity, Recently, the therapeutic effect of arsenic trioxide (As2O3) has been while on maintenance therapy with alternating methotrexate, 6-mer- proven in acute promyelocytic leukemia (APL) patients in relapse and captopurine, and all-trans retinoic acid (ATRA) according to the proto- at diagnosis by several groups in China.1 On the basis of the impress- col, the patient showed a molecular relapse of the disease detected ive results obtained in the pilot trial of the Memorial Sloan-Kettering in two bone marrow samples collected 3 weeks apart. He received Cancer Center,2 92% complete remission (CR) rate in relapsed APL ATRA for 1 month as salvage treatment followed by chemotherapy patients, in the United States a multicenter study has been conducted with mitoxantrone and high-dose Ara-C for 4 consecutive days. As to evaluate the efficacy and tolerability of As2O3 for remission induc- soon as a second molecular remission was achieved he underwent tion and consolidation in a larger population of APL patients who had allogeneic bone marrow transplantation from an HLA-identical relapsed from prior retinoic and anthracycline-based chemotherapy.3 brother. The conditioning treatment consisted of cyclophosphamide In this study the authors reported an 85% CR rate with a relapse free and TBI; cyclosporine and short-term methotrexate were administered survival rate at 18 months of 56%. for graft-versus-host disease (GVHD) prophylaxis. The clinical course Here, we report a patient with APL who was treated with As2O3 was unremarkable, the patient did not experience acute or chronic while in second relapse after allogeneic bone marrow transplantation. GVHD and cyclosporine was slowly tapered until discontinuation at The patient, a 53-year-old male, was diagnosed in July 1998 with the 7th month. At the posttransplant restaging, 3 months after bone APL, at diagnosis cytogenetic showed a normal karyotype while with marrow reinfusion, he was in complete hematological and molecular reverse transcriptase polymerase chain reaction (RT-PCR) assay a remission and bone marrow showed a complete donor chimerism. PML/RAR␣ transcript with a bcr3 isoform was identified. The patient Eleven months from transplant a second relapse occurred, bone was treated according to the GIMEMA AIDA trial4 reaching a com- marrow trephine showing the presence of a diffuse interstitial infil- tration of abnormal promyelocytes. Conventional cytogenetic analysis revealed 46,XY while the PML/RAR␣ fusion gene was detected both Correspondence: A Tedeschi, Divisione di Ematologia, Ospedale Nig- at RT-PCR and interphase FISH analysis. A mixed chimerism was dem- uarda Ca’Granda, Piazza dell’Ospedale Maggiore, Milano Italy; onstrated in the bone marrow mononuclear cell sample, with 50% of Fax: +390264442033 host cells. The peripheral blood examination revealed a WBC Received 11 June 2002; accepted 21 June 2002 5.7 × 109/l; Hb 11 g/dl, platelets 84 × 109/l; no blasts were observed in the peripheral blood smears.

Leukemia Correspondence 2456 After written informed consent was obtained the patient received conversion to complete donor chimerism to be obtained. The patient

As2O3 as salvage treatment, the drug being administered at the dosage did not experience myelosuppression and GVHD was not observed of 10 mg daily for 40 days. To prevent the development of symptoms during the reconstitution of donor bone marrow chimerism. identical to the retinoic acid syndrome, dexamethasone at the dosage Finally, a body of life-threatening adverse events has been fre-

of 25 mg/day was added in the first 10 days of treatment. quently reported during treatment with As2O3; the tolerance to ther- Bone marrow aspirate performed after 15 days from the beginning apy in our case was impressive without any sign of toxicity. of treatment, to assess drug efficacy, showed the disappearance of visible leukemic cells while the PML/RAR␣ transcript persisted. The A Tedeschi11Division of Hematology, Niguarda Ca’ patient did not experienced extra-haematological toxicity. As regards R Cairoli1 Granda Hospital Milano, Italy; 2Division hematological toxicity we observed a transient grade 1 neutropenia, P Marenco1 of Hematology, San Bortolo Hospital according to WHO criteria, and a grade 2 thrombocytopenia; the A Nosari1 Vicenza, Italy patient showed complete platelet recovery within 10 days from ther- E Tresoldi1 apy discontinuation. The bone marrow evaluation at the end of treat- E Di Bona1 ment confirmed the morphological CR, PML/RAR␣ was not detected M Montillo1 by RT-PCR, and a fully donor chimerism was restored. The patient E Morra1

was consolidated with additional two courses of As2O3 for 25 days at the same dosage of 10 mg/day every 2 months without any hemato- logical or extrahematological toxicity. After 14 months the patient is still in a third morphological and References molecular remission maintaining complete donor chimerism. The analysis of the clinical history of this patient shows that the 1 Shen ZX, Chen CQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang best salvage treatment approach was difficult to establish since he had W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma already received an allogeneic bone marrow transplant. J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY. Use of arsenic Donor lymphocyte infusion to induce a graft-versus-leukemia (GVL) trioxide (As2O3) in the treatment of acute promyelocytic leukemia effect is a feasible approach in patients relapsing after allogeneic bone (APL): II. Clinical efficacy and pharmacokinetics in relapsed marrow transplant. The role of this procedure in recurrent acute patients. Blood 1997; 89: 3354–3360. myeloid leukemias has not been well established and no data regard- 2 Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti ing the effect in APL have been reported. Furthermore, our patient LJ, Corso D, DeBlasio A, Gabrilove J, Scheineberg DA, Pandolfi would not have experienced any advantage from GVL reactivity after PP, Warrel RP Jr. Complete remission after treatment of acute pro- the allogeneic transplant. In fact, he did not develop GVHD after allo- myelocytic leukemia with arsenic trioxide. N Engl J Med 1998; geneic transplant, even if the possibility of a GVL effect cannot be 339: 1341–1348. excluded in the absence of GVHD for reactivity against unique leuke- 3 Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Cal- mia-associated antigens. In addition, the duration of the second CR leja E, Stone RM, Kalycio M, Scheinberg DA, Steinherz P, Sievers was shorter than the first one. EL, Coutre` S, Dahlberg S, Ellison R, Warrel RP. United States multi- Morbidity of salvage treatment with cytotoxic drugs is potentially center study of arsenic trioxide in relapsed acute promyelocytic elevated in such heavily pretreated patients, and in addition, intensive leukemia. J Clin Oncol 2001; 19: 3852–3860. chemotherapy could determine myelosuppression of the residual 4 Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernas- donor marrow. coni C, Broccia G, Cerri R, Falda M, Fioritoni G, Leoni F, Liso V, Both ATRA and As2O3 have been considered in the treatment of Petti MC, Rodeghiero F, Saglio G, Vegna ML, Visani G, Jehn U, patients with relapsed disease. Although ATRA in monochemotherapy Willemze R, Muus P, Pellicci PG, Biondi A, Lo Coco F. Molecular induces CR by morphologic criteria, the neoplastic clone is not elim- remission in PML/RAR␣-positive acute promyelocytic leukemia by inated when the drug is used as a single agent particularly in patients combined all-trans retinoic acid and idarubicin (AIDA) therapy. with overt disease.5 Furthermore, remissions have typically lasted no Blood 1997; 90: 1014–1021. more than a few months, due to the rapid occurrence of retinoid resist- 5 Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani ance.6 Our patient had already been exposed twice to ATRA having EM, Biondi A, Rossi G, Carlo-Stella C, Selleri C, Martini B, Spec- received the drug within the previous 12 months thus enhancing the chia G, Mandelli F. Therapy of molecular relapse in acute promye- risk of development of ATRA resistance. locytic leukemia. Blood 1999; 94: 2225–2229. As2O3 has been established as a highly effective therapy for patients 6 Delva L, Cornic M, Balitrand N, Guidez F, Miclea JM, Delmer A, with relapsed APL and recent observations indicate that this agent Teillet F, Fenaux P, Castaigne S, Degos L, Chomienne C. Resist- is more potent than ATRA for inducing molecular remission. To our ance to all-trans retinoic acid (ATRA) therapy in relapsing acute knowledge, this is the first report describing the role of As2O3 in promyelocytic leukemia: study of in vitro ATRA sensitivity and obtaining a sustained complete molecular remission in an APL patient cellular retinoic acid binding protein levels in leukemic cells. relapsing after allogeneic bone marrow transplantation. Although 3 Blood 1993; 82: 2175–2181. CR in five cases relapsing after BMT have been recently reported in 7 Chen GQ, Shi Xg, Tang W, Xiong SM, Zhu J, Cai X, Han ZG, Ni the United States multicenter trial, the type of bone marrow transplant, JH, Shi GY, Jia MM, He KL, Niu C, Ma J, Zhang P, Zhang TD, the molecular status after salvage treatment and the CR duration have Paul P, Naoe T, Kitamura K, Miller W, Waxman S, Wang ZY, de 3 not been reported. The role of As2O3 in triggering cell apoptosis and The H, Chen SJ, Chen Z. Use of arsenic trioxide (As2O3) in the 7 inducing partial differentiation has been demonstrated. In the present treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts case the suppression of the abnormal clone after the first course of dose-dependent dual effects on APL cells. Blood 1997; 89: therapy allowed not only a long-lasting molecular remission but a 3345–3353.

Leukemia