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Therapy-related acute leukemia in two patients with multiple sclerosis treated with Mitoxantrone
Biomedicine & Pharmacotherapy 66 (2012) 173–174
Available online at
www.sciencedirect.com
Original article
Therapy-related acute leukemia in two patients with multiple sclerosis treated with Mitoxantrone Natasa Colovic a,b, Nada Suvajdzic a,b,*, Nada Kraguljac Kurtovic b, Vesna Djordjevic b, Marija Dencic Fekete b, Jelena Drulovic a,c, Ana Vidovic a,b, Dragica Tomin a,b a b c
Faculty of Medicine, University of Belgrade, Dr Subotic´a 8, 11000 Belgrade, Serbia Clinic of Hematology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Koste Todorovic´a 2, 11000 Belgrade, Serbia Clinic of Neurology, Clinical Center of Serbia, Dr Subotica 6, 11000 Belgrade, Serbia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 August 2011 Accepted 31 October 2011
Two cases of therapy-related acute leukemia (TRAL) after the use of Mitoxantrone for the treatment of secondary progressive multiple sclerosis (MS) are reported. They were extracted from the group of 42 consecutive patients with TRAL diagnosed and treated in single centre between 2000–2010. They were the only two with MS and the only two treated with Mitoxantrone. The first patient was a 43-year-old male with a previous history of MS of 15-year-duration, who developed acute promyelocytic leukemia 9 months following Mitoxantrone therapy (cumulative dose 120 mg). The second patient was a 55-yearold female suffering from MS for 16 years, who developed acute mixed-phenotype leukemia, T/myeloid type, with 46,XX,del(7)(p13)[12]/47,XX,idem,+3/[6]/46,XX[2], 15 months after completion of Mitoxantrone therapy (cumulative dose 100 mg). Acute mixed-phenotype leukemia, T/myeloid type is for the first time described in the context of prior Mitoxantrone therapy. Although the incidence of TRAL in relation to Mitoxantrone pretreatment is rare, we should be vigilant for the prompt identification of this adverse event. ß 2011 Elsevier Masson SAS. All rights reserved.
Keywords: Therapy-related Mitoxantrone Acute leukemia Multiple sclerosis
1. Introduction Mitoxantrone is a DNA-topoisomerase inhibitor used in the treatment of progressive and relapsing multiple sclerosis (MS). As a potential consequence of prolonged immunosuppression and direct mutagenic effect, an increased risk of therapy-related acute myeloid leukemia has been reported in patients with MS treated with Mitoxantrone [1,2]. Two cases of therapy-related acute leukemia (TRAL) in patients with previous MS, treated with Mitoxantrone in a single Center are described.
2. Patient 1 Our first patient was a male, 43 years old at the time of leukemia onset. He was initially diagnosed with MS in 1992 at the age of 28. Up to 2001, he had experienced one relapse per 1–2 years, with complete neurological resolution after administration of methylprednisolone (1000 mg IV daily for 3 days). In 2001 and 2002, there were multiple severe relapses resulting in incomplete remissions. In 2003, the patient suffered deterioration of gait and his walking difficulty progressed to Kurtzke’s Expanded Disability Status Scale* Corresponding author. Tel.: +381 064 27 762 27. E-mail address: [email protected] (N. Suvajdzic). 0753-3322/$ – see front matter ß 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2011.10.004
EDSS [3] score 6.0. In 2004, Mitoxantrone infusions at 12 mg/m2 were administered every 3 months for a total of six infusions (cumulative dose 120 mg). The last dose was given in June 2006. Nine months later, in February 2007, profuse bleeding occured. Laboratory tests showed a hemoglobin (Hb) level of 69 g/L, white blood cell (WBC) count of 15.8 109/L, 67% of which were promyelocytes, and a platelet (Plt) count of 16 109/L. Hematologic work-up demonstrated leukemic promyelocytes in bone marrow and the presence of t(15;17)(q22;q12) in 15 out 20 analyzed metaphases, consistent with acute promyelocytic leukemia (APL). After receiving induction and first consolidation according to the PETHEMA-99 [4] protocol with subsequent remission, he abandoned treatment. After 6 months he relapsed and died. 3. Patient 2 Our second patient was a 55-year-old woman first affected with MS at the age of 39, in 1994. In 1998 she started weekly intramuscular treatment with 30 mg interferon b-1a. She experienced multiple relapses treated with methylprednisolone, 1000 mg daily for 3 days, which were followed by incomplete remissions. In 2007, 13 years after MS onset, she underwent a progressive decline in ambulation ability to the point that she required bilateral walking assistance. Her EDSS score at that time was 6.5. Subsequently, interferon b-1a was discontinued, and then
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N. Colovic et al. / Biomedicine & Pharmacotherapy 66 (2012) 173–174
she received a total of five Mitoxantrone infusions at 12 mg/m2, every 3 months (cumulative dose 100 mg). However, she deteriorated further and became wheelchair dependent. On December 2009, 15 months after her last Mitoxantrone infusion, she was referred to the hematologist due to pancytopenia. On admission she was paraplegic with urinary incontinence, pale, with bilateral neck lymphadenopathy and enlarged ulceronecrotic tonsils. Laboratory analyses were as follows: Hb 105 g/L, WBC 5.6 109/L (blasts 38%, segmented 1%, lymphocytes 28%, monocytes 32%, eosinophils 1%), Plt 86 109/L. Her bone marrow was hypercellular with 67% of blasts, whereas 45% of them were myeloperoxidase (MPO) positive. Immunophenotyping of the whole bone marrow sample by flow cytometry showed two abnormal blast populations with a different but overlapping immunophenotypic profiles consistent with mixed-phenotype acute leukemia, T/myeloid type. First population with lower granularity (CD45low/SSClow, 30% NC) expressed complex immunophenotypic profile characterized as T-lineage early cells with myeloid lineage associated antigens expression (CD34+, CD71+, cCD3+intermed, CD7+high, CD5+low, CD4+low, CD117+, CD13+, CD33+low, CD15, cyCD68+low, cyCD79a+low, cyMPO ). The second population with higher granularity (CD45low/SSCintermed, 60% NC) expressed complex immunophenotypic profile characterized as myelo/monocytic early cells with expression of T-cell associated antigens (HLA-DR+, CD34+, CD71+, aMPO+, CD117+, CD13+, CD33+high, CD15+high, CD11b+, CD11c+, CD64+high, cyCD68+hetero, CD14+hetero, CD7+low, CD4+low, cyCD3 ). The karyotype was as follows: 46,XX,del(7)(p13)[12]/47,XX,idem,+3/[6]/46,XX[2]. BCR/ ABL and MLL rearrangements were not detected. The patient received the ‘‘3+’’ scheme (Cytosine-arabinoside 2 170 mg IV in continuous infusion for 1–7 days and Doxorubicin 80 mg IV 1 h infusion for 1–3 days). Shortly after she died of sepsis in aplasia. 4. Discussion We report two patients with TRAL occurring 9 and 15 months, respectively, after completion of Mitoxantrone treatment, administered for secondary progressive MS. One of them contracted APL, according to literature, the most frequent Mitoxantrone-associated leukemic type [1,2,5,6]. The other patient developed mixedphenotype TRAL of T/myeloid type, a leukemic type for the first time described in the context of prior Mitoxantrone therapy. Those two patients were extracted from the group of 42 consecutive patients with TRAL diagnosed and treated in a single centre between 2000–2010. They were the only two with MS and the only two treated with Mitoxantrone. In 2002, Mitoxantrone was approved by the FDA for the treatment of worsening relapsing–remitting, secondary progressive and progressive relapsing MS [5]. Subsequently, reports describing the development of TRAL in MS patients following Mitoxantrone have been accumulating [1,2,6–10]. The incidence is variable ranging from 0.15% to 0.80%, though the true occurence is assumed to be undereported [7,8]. To our best knowledge 56 such cases have been reported in the literature [11], 65.6% of which were therapy-related APL [7,9]. The median latency period to TRAL was 18.5 months (range: 4–60) [8]. Furthermore, a relationship between risk of TRAL and total dose of Mitoxantrone has been suggested [8]. Over 80% of cases occured in patients exposed to more than 60 mg/m2 with a relative risk of 1.44 (CI95%: 1.18–1.70) comparing total dose more than 60 mg/m2 against less than 60 mg/ m2. Recently the analysis of twelve cases of Mitoxantrone related APL in patients with MS disclosed the presence of preferential sites of DNA damage induced by Mitoxantrone in PML and RARA genes that might underlie the propensity for this subtype of leukemia to appear after Mitoxantrone administration [10].
The most frequently detected cytogenetic aberrations in TRAL related to previous DNA-topoisomerase II inhibitor therapy are balanced translocations involving chromosome bands 11q23 and 21q22 [12]. Furthermore, aberrations of chromosome 7 have been also described in TRAL in the form of monosomy 7, interstitial deletion involving 7q32-q36 breakpoint region and terminal 7q deletion with 7q22 or 7q32 breakpoint regions [11]. In a karyotype of our second patient deletion of short arm of chromosome 7 (7p13) was detected as a single aberration in 12 cells, while in six of them, del(7)(p13) was accompanied with trisomy 3. It is of interest that PURB gene, encoding functionally cooperative proteins in the Pur family, is localized to chromosome band 7p13. This gene product is a sequence-specific, single-stranded DNA-binding protein and is implicated in the control of both DNA replication and transcription. Deletion of this gene has been associated with MDS and AML [13]. As far as we know, this is the first case with this aberration in t-My/T leukemia. Even though Mitoxantrone has been demonstrated to benefit MS patients and TRAL is rather rare in patients with MS, cautious selection of MS patients for Mitoxantrone treatment and longer follow-up after therapy completion are mandatory. In addition it would be important to assess prospectively the true occurrence of TRAL in the MS population, with and without Mitoxantrone treatment. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements This study was supported by the Ministry of Education and Science of the Republic of Serbia: projects No 41004 and175031. References [1] Arruda WO, Montua MB, Oliveria MS, Ramina R. Acute myeloid leukaemia induced by mitoxantrone. Arq Neuropsiquiatr 2005;63:327–9. [2] Woo DA, Collins RH, Rossman HS, Stuve O, Frohman EM. Mitoxantroneassociated leukemia in multiple sclerosis-case studies. Int J MS Care 2008;10:41–6. [3] Kurtzke JF. Rating neurologic instrument in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–52. [4] Sanz MA, Vellenga E, Rayo´n C, Dı´az-Mediavilla J, Rivas C, Amutio E, et al. Riskadapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004;103:1237–43. [5] Goodkin DE. Therapy-related leukemia in mitoxantrone patients (letter). Mult Scler 2003;9:426. [6] Ghalie RG, Mauch E, Edan G, Hartung HP, Gonsette RE, Eisenmann S, et al. A study of therapy-related acute leukemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 2002;8:441–5. [7] Pascual A, Tellez N, Bosca I, Mallada J, Belenguer A, Abella´n I, et al. Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler 2009;8:1303–10. [8] Ellis R, Bogglid M. Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it? Mult Scler 2009;15:505–8. [9] Ammatuna E, Montesinos P, Hasan SK, Ramadan SM, Esteve J, Hubmann M, et al. Presenting features and treatment outcome of acute promyelocytic leukemia arising after multiple sclerosis. Haematologica 2011;96:621–5. [10] Hasan SK, Buttari F, Ottone F, Voso MT, Hohaus S, Marasco E, et al. Risk of acute promyelocytic leukemia in multiple sclerosis. Coding variants of DNA repair genes. Neurology 2011;76:1059–65. [11] Mariott JJ, Miyasaki JM, Gronsethe G, O’Connor PW, Evidence Report:. The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis. Report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology 2010;74:1410–1. [12] Arber DA, Slovak ML, Popplewell L, Bedell V, Ikle D, Rowley JD, et al. Therapyrelated acute myeloid leukemia/myelodysplasia with balanced 21q22 translocations. Am J Clin Pathol 2002;117:306–13. [13] Bergemann AD, Ma ZW, Johnson EM. Sequence of cDNA comprising the human pur gene and sequence-specific single-stranded-DNA-binding properties of the encoded protein. Mol Cell Biol 1992;12:5673–82.
Available online at
www.sciencedirect.com
Original article
Therapy-related acute leukemia in two patients with multiple sclerosis treated with Mitoxantrone Natasa Colovic a,b, Nada Suvajdzic a,b,*, Nada Kraguljac Kurtovic b, Vesna Djordjevic b, Marija Dencic Fekete b, Jelena Drulovic a,c, Ana Vidovic a,b, Dragica Tomin a,b a b c
Faculty of Medicine, University of Belgrade, Dr Subotic´a 8, 11000 Belgrade, Serbia Clinic of Hematology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Dr Koste Todorovic´a 2, 11000 Belgrade, Serbia Clinic of Neurology, Clinical Center of Serbia, Dr Subotica 6, 11000 Belgrade, Serbia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 25 August 2011 Accepted 31 October 2011
Two cases of therapy-related acute leukemia (TRAL) after the use of Mitoxantrone for the treatment of secondary progressive multiple sclerosis (MS) are reported. They were extracted from the group of 42 consecutive patients with TRAL diagnosed and treated in single centre between 2000–2010. They were the only two with MS and the only two treated with Mitoxantrone. The first patient was a 43-year-old male with a previous history of MS of 15-year-duration, who developed acute promyelocytic leukemia 9 months following Mitoxantrone therapy (cumulative dose 120 mg). The second patient was a 55-yearold female suffering from MS for 16 years, who developed acute mixed-phenotype leukemia, T/myeloid type, with 46,XX,del(7)(p13)[12]/47,XX,idem,+3/[6]/46,XX[2], 15 months after completion of Mitoxantrone therapy (cumulative dose 100 mg). Acute mixed-phenotype leukemia, T/myeloid type is for the first time described in the context of prior Mitoxantrone therapy. Although the incidence of TRAL in relation to Mitoxantrone pretreatment is rare, we should be vigilant for the prompt identification of this adverse event. ß 2011 Elsevier Masson SAS. All rights reserved.
Keywords: Therapy-related Mitoxantrone Acute leukemia Multiple sclerosis
1. Introduction Mitoxantrone is a DNA-topoisomerase inhibitor used in the treatment of progressive and relapsing multiple sclerosis (MS). As a potential consequence of prolonged immunosuppression and direct mutagenic effect, an increased risk of therapy-related acute myeloid leukemia has been reported in patients with MS treated with Mitoxantrone [1,2]. Two cases of therapy-related acute leukemia (TRAL) in patients with previous MS, treated with Mitoxantrone in a single Center are described.
2. Patient 1 Our first patient was a male, 43 years old at the time of leukemia onset. He was initially diagnosed with MS in 1992 at the age of 28. Up to 2001, he had experienced one relapse per 1–2 years, with complete neurological resolution after administration of methylprednisolone (1000 mg IV daily for 3 days). In 2001 and 2002, there were multiple severe relapses resulting in incomplete remissions. In 2003, the patient suffered deterioration of gait and his walking difficulty progressed to Kurtzke’s Expanded Disability Status Scale* Corresponding author. Tel.: +381 064 27 762 27. E-mail address: [email protected] (N. Suvajdzic). 0753-3322/$ – see front matter ß 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biopha.2011.10.004
EDSS [3] score 6.0. In 2004, Mitoxantrone infusions at 12 mg/m2 were administered every 3 months for a total of six infusions (cumulative dose 120 mg). The last dose was given in June 2006. Nine months later, in February 2007, profuse bleeding occured. Laboratory tests showed a hemoglobin (Hb) level of 69 g/L, white blood cell (WBC) count of 15.8 109/L, 67% of which were promyelocytes, and a platelet (Plt) count of 16 109/L. Hematologic work-up demonstrated leukemic promyelocytes in bone marrow and the presence of t(15;17)(q22;q12) in 15 out 20 analyzed metaphases, consistent with acute promyelocytic leukemia (APL). After receiving induction and first consolidation according to the PETHEMA-99 [4] protocol with subsequent remission, he abandoned treatment. After 6 months he relapsed and died. 3. Patient 2 Our second patient was a 55-year-old woman first affected with MS at the age of 39, in 1994. In 1998 she started weekly intramuscular treatment with 30 mg interferon b-1a. She experienced multiple relapses treated with methylprednisolone, 1000 mg daily for 3 days, which were followed by incomplete remissions. In 2007, 13 years after MS onset, she underwent a progressive decline in ambulation ability to the point that she required bilateral walking assistance. Her EDSS score at that time was 6.5. Subsequently, interferon b-1a was discontinued, and then
174
N. Colovic et al. / Biomedicine & Pharmacotherapy 66 (2012) 173–174
she received a total of five Mitoxantrone infusions at 12 mg/m2, every 3 months (cumulative dose 100 mg). However, she deteriorated further and became wheelchair dependent. On December 2009, 15 months after her last Mitoxantrone infusion, she was referred to the hematologist due to pancytopenia. On admission she was paraplegic with urinary incontinence, pale, with bilateral neck lymphadenopathy and enlarged ulceronecrotic tonsils. Laboratory analyses were as follows: Hb 105 g/L, WBC 5.6 109/L (blasts 38%, segmented 1%, lymphocytes 28%, monocytes 32%, eosinophils 1%), Plt 86 109/L. Her bone marrow was hypercellular with 67% of blasts, whereas 45% of them were myeloperoxidase (MPO) positive. Immunophenotyping of the whole bone marrow sample by flow cytometry showed two abnormal blast populations with a different but overlapping immunophenotypic profiles consistent with mixed-phenotype acute leukemia, T/myeloid type. First population with lower granularity (CD45low/SSClow, 30% NC) expressed complex immunophenotypic profile characterized as T-lineage early cells with myeloid lineage associated antigens expression (CD34+, CD71+, cCD3+intermed, CD7+high, CD5+low, CD4+low, CD117+, CD13+, CD33+low, CD15, cyCD68+low, cyCD79a+low, cyMPO ). The second population with higher granularity (CD45low/SSCintermed, 60% NC) expressed complex immunophenotypic profile characterized as myelo/monocytic early cells with expression of T-cell associated antigens (HLA-DR+, CD34+, CD71+, aMPO+, CD117+, CD13+, CD33+high, CD15+high, CD11b+, CD11c+, CD64+high, cyCD68+hetero, CD14+hetero, CD7+low, CD4+low, cyCD3 ). The karyotype was as follows: 46,XX,del(7)(p13)[12]/47,XX,idem,+3/[6]/46,XX[2]. BCR/ ABL and MLL rearrangements were not detected. The patient received the ‘‘3+’’ scheme (Cytosine-arabinoside 2 170 mg IV in continuous infusion for 1–7 days and Doxorubicin 80 mg IV 1 h infusion for 1–3 days). Shortly after she died of sepsis in aplasia. 4. Discussion We report two patients with TRAL occurring 9 and 15 months, respectively, after completion of Mitoxantrone treatment, administered for secondary progressive MS. One of them contracted APL, according to literature, the most frequent Mitoxantrone-associated leukemic type [1,2,5,6]. The other patient developed mixedphenotype TRAL of T/myeloid type, a leukemic type for the first time described in the context of prior Mitoxantrone therapy. Those two patients were extracted from the group of 42 consecutive patients with TRAL diagnosed and treated in a single centre between 2000–2010. They were the only two with MS and the only two treated with Mitoxantrone. In 2002, Mitoxantrone was approved by the FDA for the treatment of worsening relapsing–remitting, secondary progressive and progressive relapsing MS [5]. Subsequently, reports describing the development of TRAL in MS patients following Mitoxantrone have been accumulating [1,2,6–10]. The incidence is variable ranging from 0.15% to 0.80%, though the true occurence is assumed to be undereported [7,8]. To our best knowledge 56 such cases have been reported in the literature [11], 65.6% of which were therapy-related APL [7,9]. The median latency period to TRAL was 18.5 months (range: 4–60) [8]. Furthermore, a relationship between risk of TRAL and total dose of Mitoxantrone has been suggested [8]. Over 80% of cases occured in patients exposed to more than 60 mg/m2 with a relative risk of 1.44 (CI95%: 1.18–1.70) comparing total dose more than 60 mg/m2 against less than 60 mg/ m2. Recently the analysis of twelve cases of Mitoxantrone related APL in patients with MS disclosed the presence of preferential sites of DNA damage induced by Mitoxantrone in PML and RARA genes that might underlie the propensity for this subtype of leukemia to appear after Mitoxantrone administration [10].
The most frequently detected cytogenetic aberrations in TRAL related to previous DNA-topoisomerase II inhibitor therapy are balanced translocations involving chromosome bands 11q23 and 21q22 [12]. Furthermore, aberrations of chromosome 7 have been also described in TRAL in the form of monosomy 7, interstitial deletion involving 7q32-q36 breakpoint region and terminal 7q deletion with 7q22 or 7q32 breakpoint regions [11]. In a karyotype of our second patient deletion of short arm of chromosome 7 (7p13) was detected as a single aberration in 12 cells, while in six of them, del(7)(p13) was accompanied with trisomy 3. It is of interest that PURB gene, encoding functionally cooperative proteins in the Pur family, is localized to chromosome band 7p13. This gene product is a sequence-specific, single-stranded DNA-binding protein and is implicated in the control of both DNA replication and transcription. Deletion of this gene has been associated with MDS and AML [13]. As far as we know, this is the first case with this aberration in t-My/T leukemia. Even though Mitoxantrone has been demonstrated to benefit MS patients and TRAL is rather rare in patients with MS, cautious selection of MS patients for Mitoxantrone treatment and longer follow-up after therapy completion are mandatory. In addition it would be important to assess prospectively the true occurrence of TRAL in the MS population, with and without Mitoxantrone treatment. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgements This study was supported by the Ministry of Education and Science of the Republic of Serbia: projects No 41004 and175031. References [1] Arruda WO, Montua MB, Oliveria MS, Ramina R. Acute myeloid leukaemia induced by mitoxantrone. Arq Neuropsiquiatr 2005;63:327–9. [2] Woo DA, Collins RH, Rossman HS, Stuve O, Frohman EM. Mitoxantroneassociated leukemia in multiple sclerosis-case studies. Int J MS Care 2008;10:41–6. [3] Kurtzke JF. Rating neurologic instrument in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–52. [4] Sanz MA, Vellenga E, Rayo´n C, Dı´az-Mediavilla J, Rivas C, Amutio E, et al. Riskadapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004;103:1237–43. [5] Goodkin DE. Therapy-related leukemia in mitoxantrone patients (letter). Mult Scler 2003;9:426. [6] Ghalie RG, Mauch E, Edan G, Hartung HP, Gonsette RE, Eisenmann S, et al. A study of therapy-related acute leukemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 2002;8:441–5. [7] Pascual A, Tellez N, Bosca I, Mallada J, Belenguer A, Abella´n I, et al. Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler 2009;8:1303–10. [8] Ellis R, Bogglid M. Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it? Mult Scler 2009;15:505–8. [9] Ammatuna E, Montesinos P, Hasan SK, Ramadan SM, Esteve J, Hubmann M, et al. Presenting features and treatment outcome of acute promyelocytic leukemia arising after multiple sclerosis. Haematologica 2011;96:621–5. [10] Hasan SK, Buttari F, Ottone F, Voso MT, Hohaus S, Marasco E, et al. Risk of acute promyelocytic leukemia in multiple sclerosis. Coding variants of DNA repair genes. Neurology 2011;76:1059–65. [11] Mariott JJ, Miyasaki JM, Gronsethe G, O’Connor PW, Evidence Report:. The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis. Report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology 2010;74:1410–1. [12] Arber DA, Slovak ML, Popplewell L, Bedell V, Ikle D, Rowley JD, et al. Therapyrelated acute myeloid leukemia/myelodysplasia with balanced 21q22 translocations. Am J Clin Pathol 2002;117:306–13. [13] Bergemann AD, Ma ZW, Johnson EM. Sequence of cDNA comprising the human pur gene and sequence-specific single-stranded-DNA-binding properties of the encoded protein. Mol Cell Biol 1992;12:5673–82.