Correspondence 1916 F Lorenzo V Second Department of Internal Medicine, Mie K Nishii University School of Medicine, 1504-208 E Usui Edobashi, Tsu, Mie, Japan N Katayama H Shiku

References

1 Nishii K, Usui E, Katayama N, Lorenzo VF, Nakase K, Kobayashi T et al. Characteristics of t(8;21) acute myeloid leukemia (AML) with additional chromosomal abnormality: concomitant trisomy 4 may constitute a distinctive subtype of t(8;21) AML. Leukemia 2003; 17: 731–737. 2 Beghini A, Magnani I, Ripamonti CB, Larizza L. Amplification of a novel c-Kit activating mutation Asn(822)-Lys in the Kasumi-1 cell line: a t(8;21)-Kit mutant model for acute myeloid leukemia. Hematol J 2002; 3: 157–163. 3 Cairoli R, Grillo G, Beghini A, Tedeschi A, Ripamonti CB, Larizza L et al. C-Kit point mutations in core binding factor leukemias: correlation with white blood cell count and the white blood cell index. Leukemia 2003; 17: 471–472. 4 Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U et al. Identification of mutations in the coding sequence of the proto- oncogene c-kit in a human mast cell leukemia cell line causing ligand- independent activation of c-kit product. J Clin Invest 1993; 92: 1736–1744. 5 Longley Jr BJ, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ et al. Activating and dominant inactivating c-KIT catalytic domain mutations Figure 1 Detection of c-kit mutation in exon 17 in a t(8;21) in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci AML with trisomy 4 case. (a) Expression of c-kit exon 17 was detected USA 1999; 96: 1609–1614. in the cells from normal bone marrow (BM) and t(8;21) AML 6 Ning ZQ, Li J, Arceci RJ. Activating mutations of c-kit at codon 816 with trisomy 4 sample using RT-PCR analysis. b-globulin was used confer drug resistance in human leukemia cells. Leukemia Lymphoma as a control. (b) Sequence of the RT-PCR products show that the 2001; 41: 513–522. second nucleotide A of the Asp816 codon (amino acid 2468) was 7 Ma Y, Zeng S, Metcalfe DD, Akin C, Dimitrijevic S, Butterfield JH et al. The c-KIT mutation causing human mastocytosis substituted with T, resulting in an Asp to Val amino-acid change is resistant to STI571 and other KIT kinase inhibitors; kinases with (Asp816Val). enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 2002; 99: 1741–1744. 8 Inokuchi K, Yamaguchi H, Tarusawa M, Futaki M, Hanawa H, Tanosaki S et al. Abnormality of c-kit oncoprotein in certain patients c-kit mutation and clinical outcome, a larger group of patients is with chronic myelogenous leukemia – potential clinical significance. necessary. Leukemia 2002; 16: 170–177. Current efforts are now directed to investigate the effect of tyrosine 9 Nishii K, Katayama N, Miwa H, Shikami M, Usui E, Masuya M et al. kinase inhibitor on this subset of patients for a better therapeutic Non-DNA-binding Ikaros isoform gene expressed in adult approach. B-precursor acute lymphoblastic leukemia. Leukemia 2002; 16: 1285–1292. 10 Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Acknowledgements Morra E et al. C-kit mutations in core binding factor leukzemias. Blood 2000; 95: 726–727. 11 Beghini A, Ripamonti CB, Castorina P, Pezzetti L, Doneda L, Cairoli R This work was supported by research grants Grant-in-Aid for et al. Trisomy 4 leading to duplication of a mutated KIT allele in acute Scientific Research (C, KAKENHI: 13671060, 15591002) from myeloid leukemia with mast cell involvement. Cancer Genet Cyto- Japan Society for the Promotion of Science (JSPS). genet 2000; 119: 26–31.

Prolonged molecular remission after arsenic trioxide and all-trans retinoic acid for acute promyelocytic leukemia relapsed after allogeneic stem cell transplantation

Leukemia (2003) 17, 1916–1917. doi:10.1038/sj.leu.2403050 describe a patient, now 10.5 years since the initial diagnosis of APML, in ongoing remission for 36 months postarsenic for third relapse after an TO THE EDITOR allograft. APML with t(15;17) was diagnosed in a 27-year-old female in July We read with interest the recent correspondence by Tedeschi et al1 1992. CR was achieved with all-trans retinoic acid (ATRA) and describing an arsenic-induced molecular remission in a patient followed by consolidation chemotherapy with daunorubicin and with relapsed promyelocytic leukemia (APML) postallograft.1 In cytosine arabinoside (ara C). this patient, the duration of complete remission (CR) from initial She relapsed 3 years after the initial diagnosis. CR2 was achieved remission to relapse preallograft was 12 months, from allograft with ATRA and an allograft from a histocompatible brother using until relapse was 11 months and postarsenic was 14 + months. We peripheral blood progenitor cells (PBPC) and busulfan-cyclophos-

Leukemia Correspondence 1917 phamide conditioning was performed in January 1996. No acute type was not available until after the third relapse in our patient. It is graft versus host disease (GVHD) occurred despite a rapid taper of likely that regular molecular monitoring would have detected cyclosporine (ceased d63). A second relapse occurred 11 months relapse earlier than hematological relapse and early intervention at post-transplant. ATRA was ineffective; she then received two that point would have minimized the morbidity associated with cycles of idarubicin 12 mg/m2 daily for 3 consecutive days. reinduction treatment in a patient with florid disease.4 We now CR3 was documented after the first cycle, with cytogenetics routinely follow our APML patients, treated with chemotherapy showing only normal male metaphases. The second cycle was alone or post-transplant for relapsed disease, with molecular followed by the infusion of unmodified PBPC from her donor monitoring.5 without GVHD prophylaxis and interferon alfa-2b 1-3MU three Arsenic achieves a high rate of CR in patients with relapsed APML times weekly at count recovery. This was complicated 2 months who have not been previously transplanted, with an estimated later by significant cutaneous oral and vaginal GVHD; interferon relapse-free survival of 56% at 18 months.6 Our patient is in was ceased. hematological remission almost 3 years after arsenic and ATRA and A third relapse occurred in January 2000, 35 months after has exceeded the longest duration of any previous remission. It is CR3. The marrow blast percentage was greater than 90%, worth noting that she responded to arsenic without ATRA for the first characteristic of all the previous relapses. Cytogenetic evolution cycle, having been resistant to idarubicin/ATRA the previous month. was documented, with the appearance of abnormalities of chromo- We elected subsequently to use arsenic in combination with ATRA somes 8 and 21, not previously recognized, in addition to t(15;17). based on in vivo evidence in a mouse model that they may ATRA and idarubicin were ineffective. She then received arsenic synergize in eradicating leukemia cells.7 Whether this combination 10 mg i.v. daily for 28 days each alternate month for seven cycles. A is superior to arsenic alone has not, to our knowledge, been clearly single dose of 500 mg araC was given with the first cycle and ATRA established in the clinical setting. 70 mg total daily dose was given concomitantly with arsenic for the Further experience is required to determine if the optimal therapy remaining six cycles. Treatment was complicated by a sensory for relapsed APML postallograft is arsenic7ATRA, immunomodula- peripheral neuropathy. Morphological remission was obtained after tion or a combination of both. Our approach is to use quantitative the first cycle. Cytogenetics were unsuccessful after the first two PCR to guide management. Patients with confirmed molecular-only cycles; a normal male (donor) karyotype was demonstrated after the relapse who have not had significant GVHD have withdrawal of third cycle. Serial marrows subsequently have demonstrated on- immunosuppression and/or donor leukocyte infusion; arsenic is going CR4 by cytogenetic and since April 2001 by molecular reserved for patients who do not respond to this approach or those criteria, the latter initially using a qualitative RT-PCR assay with hematological relapse. (sensitivity one in 10000) for PML/RARa transcripts. The latest 1 1 assessment was in February 2003, 37 months after her third relapse. A Grigg Bone Marrow Transplant Service, Department of R Kimber2 Clinical Haematology and Medical Oncology, A quantitative RT-PCR assay (sensitivity one in 10000) was negative. 1 Donor-only cells were detected by cytogenetics; FISH analysis J Szer The Royal Melbourne Hospital, Parkville, Victoria, Australia; a showed normal arrangement of the PML and RAR genes in 416 2Department of Haematology, Royal Hobart cells. Hospital, Hobart, Tas, Australia This case is notable for a number of features. Firstly, it describes an unusual pattern of multiple late relapses over 8 years in a patient with APML. Series with long-term follow-up of APML suggest that References 2 late relapses are relatively uncommon. 1 Tedeschi A, Cairoli R, Marenco P, Nosari A, Tresoldi E et al. Molecular Secondly, the third relapse occurred despite significant extensive remission and reconstitution of a full chimera with arsenic trioxide in a chronic GVHD after the reinfusion of donor stem and T cells patient with acute promyelocytic leukemia relapsed after allogeneic without GVHD prophylaxis. While the duration of the CR after this bone marrow transplantation. Leukemia 2002; 16: 2455–2456. reinfusion was longer than the initial CR post-transplant, suggestive 2 Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M et al. Induction therapy with idarubicin alone significantly influences of graft vs APML effect, this may have been due to concomitant event-free survival duration in patients with newly diagnosed idarubicin therapy that was not given for the relapse immediately hypergranular acute promyelocytic leukemia: final results of the pretreatment.2 To our knowledge, the unequivocal existence of a GIMEMA randomized study LAP 0389 with 7 years of minimal graft vs APML effect, such as a durable remission of relapsed APML follow-up. Blood 2002; 100: 3141–3146. postallograft occurring after the withdrawal of immunosuppression 3 Diverio D, Rossi V, Avvisati G, De Santis S, Pistilli A, Pane F et al. Early detection of relapse by prospective reverse transcriptase-polymerase or the infusion of donor leukocytes without concomitant chemo- chain reaction analysis of the PML/RARa fusion gene in patients with therapy, has not been reported in the literature. A lower relapse acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multi- rate for allografts vs autografts in CR2 has been reported in centre ‘AIDA’ trial. Blood 1998; 92: 784–789. abstract form (Sanz MA et al. Blood 2000; 96: 11; abstract 2247), 4 Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM but updated results from the European APML group suggest et al. Therapy of molecular relapse in acute promyelocytic leukemia. that relapse due to infusion of molecularly positive autologous Blood 1999; 94: 2225–2229. 5 Applegate TL, Iland HJ, Mokany E, Todd AV. Molecular monitoring of cells may explain this observation (De Botton S et al. Blood acute promyelocytic leukemia using DzyNA reverse transcription-PCR. 2002; 100: 11; abstract 816). These latter results demonstrated a Clin Chem 2002; 48: 1858–1860. high rate of durable remission in patients autografted in CR2 6 Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, using cells without molecular evidence of disease and suggest Calleja E et al. United States multicenter study of arsenic trioxide in that myeloablative conditioning may be more important than relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: a graft vs APML effect in eradicating disease in the transplant 3852–3860. 7 Lallemand-Breitenbach V, Guillemin MC, Janin A, Daniel MT, Degos context. L, Kogan SC et al. Retinoic acid and arsenic synergize to eradicate Recent literature has highlighted the utility of molecular leukemic cells in a mouse model of acute promyelocytic leukemia. monitoring for PML / RARa transcripts in APML.3 Monitoring of this J Exp Med 1999; 189: 1043–1052.

Leukemia