Neurology -- Correspondence for Brassat et al., 59 (6) 954-955

Correspondence published:

Reply to Letter to the Editor: David Brassat (22 January 2003)

Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS: J Howard Jaster, Harvey B. Niell, F. Curtis Dohan Jr, and Thomas W. Smith (22 January 2003)

Reply to Letter to the Editor 22 January 2003

David Brassat
Hopital Purpan Toulouse Cedex France
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Re: Reply to Letter to the Editor

dbrassat{at}yahoo.fr David Brassat

The authors thank Jaster et al. for their thoughtful comments.
All the diagnosis criteria for secondary leukemia induced by topoisomerase II inhibitors were present in our patient: latency of up to 3 years between treatment administration and onset of leukemia, absence of a myelodysplastic phase, M5 FAB type, and balanced translocation in chromosome 11 that disrupts the MLL gene. [3] Hence we feel that the diagnosis of TRAL was established in our case with a high level of evidence.
Nevertheless it is reasonable to raise the possibility of a paraneoplastic syndrome in a patient presenting with a demyelinating disorder. Since there is no published research with in vitro or in vivo animal data, clinically based approach used by Jaster et al is of great interest. They found numerous cases where MS has been described in association with various conditions including acute or chronic leukemia, lymphoma, seminoma and colon cancer. Based on those observations, they speculate that MS-like demyelination could be related to paraneoplastic syndrome. We found 10 cases of acute leukemia in MS patients reported in the literature. In three of them treatment with mitoxantrone preceded the acute leukemia, [1, 4, 5] and TRAL was diagnosed with a high level of evidence. In six cases treatment with chlorambucil preceded the acute leukemia. [6] In the last case, [2] a Philadelphia-positive acute leukemia occurred 9 years after onset of neurologic symptoms. Overall, those 10 cases do not suggest MS-like paraneoplastic disorder. We speculate that if a MS-like paraneoplastic disease related to leukemia was misdiagnosed as MS, the prevalence of acute leukemia in a large MS cohort should be higher than in the general population. We do not found any data for prevalence of leukemia in MS patients compared to general population. In the French cohort of 802 MS patients treated by mitoxantrone, a second case of TRAL has been reported. [5] As a result the incidence of TRAL in MS patients who received mitoxantrone may be approximately 0.25%. [7] Albeit low, this incidence is greater than the risk of de novo acute myeloid leukemia in the general population (from 0.001% at age 20 to 0.03% at age 70 in the UK). However, it is unlikely that misdiagnosed paraneoplastic syndromes could explain the two cases of leukemia in the French cohort. Although interesting, the hypothesis formulated by Jaster et al of a MS-like paraneoplastic disorder in patients with leukemia as opposed to leukemia induced by mitoxantrone in MS patients is not supported by the literature.
References:
1.Brassat D, Recher C, Waubant E, et al. Therapy related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology 2002;59:954-955.
2.Meloni G, Capria S, Salvetti M, et al. Autologous peripheral blood stem cell transplantation in a patient with multiple sclerosis and concomitant Ph+ acute leukemia. Haematologica 1999;84:665-667.
3. Rowley JD, Olney HJ. International workshop on the relationship of prior therapy to balanced chromosome aberrations in therapy-related myelodysplastic syndromes and acute leukemia: overview report. Genes Chromosomes Cancer 2002 ;33:331-345.
4. Vicari AM, Ciceri F, Folli F, Lanzi R, Colombo B, Comi G, Camba L. Acute promyelocytic leukemia following mitoxantrone as single agent for the treatment of multiple sclerosis. Leukemia 1998;12:441-442.
5. Radu TD, Marc D, Herve V. Acute myeloid leukaemia(AML) induced by mitoxantrone Mult Scler 2002(S1) P342, S127.
6. Aymard JP, Witz F, Conroy T, et al. Acute leukemia secondary to the treatment of multiple sclerosis with chlorambucil. Rev Neurol 1985;14:152-154.
7. Ghalie RG, Mauch E, Edan G, et al. A study of therapy-related acute leukemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 2002;8:441-445.

Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS 22 January 2003

J Howard Jaster
Delta Medical Center Memphis TN,
Harvey B. Niell, F. Curtis Dohan Jr, and Thomas W. Smith
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Re: Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS

neuro_journal{at}urmc.rochester.edu J Howard Jaster, et al.

We read with interest the report by Brassat et al. [1] describing the development of acute myeloblastic leukemia (AML) in a young woman following treatment of MS with mitoxantrone. The authors presented adequate evidence to reasonably support their conclusion that AML in this case occurred as a �therapy related acute leukemia.� The authors also discussed the rarity of this occurrence and were able to reference only one other similar case. All of this not withstanding, the authors did not mention that MS has been associated with various types of leukemia in various other treatments [2, 3, 4, 5]. This group of cases taken together might tend to suggest an occasional association of leukemia with MS itself rather than an association of leukemia with mitoxantrone or with any of the particular therapies reported. This group of cases may also be a bridging point between two other groups of cases, both of which report an association between malignancy and demyelination in the CNS.
In one group [6, 7] colon carcinoma is treated with 5-fluorouracil (5 -FU), an antineoplastic antimetabolite, together with levamisole, an immunomodulator, as adjuvant therapy, and this is occasionally followed by the discovery of demyelinating lesions of the brain. The brain demyelinating lesions in all cases are considered to be caused by 5-FU and levamisole, although an observational bias is possible since a high percentage of patients with colon carcinoma were treated with 5-FU and levamisole, and a relatively small number of patients with subsequent brain demyelination have been reported. Recently leucovorin has been used with 5-FU in adjuvant therapy of colon cancer, yet no cases of brain demyelination have been associated with this combination.
In the other group, involving seminoma, there has recently been speculation regarding the possibility that demyelination in the brain may occasionally occur as a paraneoplastic disorder. A few cases referenced elsewhere [8] have generated interest in this possibility and various patterns of brain demyelination have been described. None of these cases has mentioned a therapeutic agent as playing a causal role in either brain demyelination or malignancy.
Considering these three groups together may be essential to eventually solving the many problems presented by each. In the leukemia group, CNS demyelination may [1, 5] or may not [3, 4] precede malignancy, and a variety of therapies are utilized in these cases. In the colon cancer group, brain demyelination typically follows malignancy and is associated entirely with specific therapeutic agents. In the seminoma group, neither malignancy nor brain demyelination is associated with therapeutic agents.
We speculate that some cases of brain demyelination may occur as a paraneoplastic disorder associated with various malignancies. The etiology, scope, and other specific details of this phenomenon currently remain obscure. We further speculate that some pharmaceutical agents may play a potentiating role in causing such brain demyelination but that a necessary, if not sufficient (in the case of colon cancer), causal role may be played by the presence of malignancy. Cellular and clinical data both suggest that levamisole may be capable of playing such a potentiating role.
In the case of Brassat et al. we speculate that MS may have occurred prior to leukemia as a paraneoplastic disorder, and that mitoxantrone may have played no role in causing leukemia.
References:
1.Brassat D, Recher C. Waubant E, et al. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS. Neurology 2002;59:954-955.
2.Hilbe W, Berger T, Konwalinka G, et al. Cladribine treatment of a patient with hairy cell leukemia and concomitant multiple sclerosis. Acta Haematol 1999;102:99-100.
3.Kataoka I, Shinagawa K, Shiro Y, et al. Multiple sclerosis associated with interferon-alpha therapy for chronic myelogenous leukemia. Am J Hematol 2002;70:149-153.
4.Saito N, Tanaka T, Matsuda S, et al. [A case of inflammatory demyelinative myelopathy after bone marrow transplantation]. Rinsho Shinkeigaku 2000;40:556-560.
5.Meloni G, Capria S, Salvetti M, et al. Autologous peripheral blood stem cell transplantation in a patient with multiple sclerosis and concomitant Ph+ acute leukemia. Haematologica 1999;84:665-667.
6.Mak W. Cheng PW, Cheung RTF. Leukoencephalopathy following chemotherapy for colonic carcinoma. Clinical Radiology 2001;56;333-335.
7.Savarese DM, Gordon J, Smith TW, et al. Cerebral demyelination syndrome in a patient treated with 5-fluorouracil and levamisole. The use of thallium SPECT imaging to assist in noninvasive diagnosis�a case report. Cancer 1996;77:387-394.
8.Jaster JH, Dohan FC Jr, O�Brien TF. Demyelination in the brain as a paraneoplastic disorder: candidates include some cases of seminoma and central nervous system lymphoma [letter]. J Neurol Neurosurg Psychiatry 2002;73:352.