AbstractWe report the clinical features and treatment outcome of 33 patients with multiple sclerosis who developed acute promyelocytic leukemia. Thirty patients were previously exposed to mitoxantrone. The median latency period between treatment initiation and acute promyelocytic leukemia diagnosis was 32 months. The PML-RARA bcr1 iso-form was identified in 87% of cases. Twenty-nine (90%) patients achieved hematologic remission after all-trans retinoic acid and chemotherapy (n=31) or arsenic trioxide and all-trans retinoic acid. Consolidation included modified chemotherapy or arsenic trioxide. At a median follow up of 26 months, 23 patients are in complete remission, 4 relapsed and one developed secondary leukemia. The 5-year cumulative incidence of relapse and overall survival were 23% and 68%, respectively. Although treatment heterogeneity and suboptimal post-remission therapy must be taken into account, overall results and development of secondary leukemia in one patient suggest that effective and less toxic agents like arsenic trioxide warrants further investigation in this context.
Secondary acute promyelocytic leukemia (APL) has been frequently reported as a late complication of chemotherapy (therapy-related APL [t-APL]).1–3 Topoisomerase II (topo-II) inhibitors such as mitoxantrone (MTZ), epirubicin, adriamycin, and etoposide are the chemotherapy compounds most frequently associated with development of t-APL by inducing DNA double strand breaks.4–6 Among them, MTZ is the most commonly implicated agent.5,6 The latency between exposure to topo-II inhibitors and the development of t-APL is relatively short (< 3 years) and t-APL typically occurs without an antecedent myelodysplastic phase.3,4 Although t-APL developing after chemotherapy for a primary cancer has been reported frequently, only a few cases of t-APL arising after treatment of non-malignant diseases have been described so far. In the past few years, however, an increasing number of reports on t-APL occurring after multiple sclerosis (MS) have been published.5,6
MS is a chronic autoimmune demyelinating disease of the central nervous system characterized by variable periods of relapse and remission of neurological symptoms and progression of disability over time. MTZ was the first immunosuppressive drug approved in the US and Europe as a single agent for treatment of relapsing-remitting (RRMS) or progressive MS.7 We recently investigated at the genomic level the location of DNA breakpoints in t-APL arising after MS. Interestingly, this analysis revealed a distinct distribution of chromosome 15 breakpoints as compared to de novo APL, biased towards disruption of chromosome 15 breakpoints within PML intron 6. Moreover, we reported that breakpoints in MTZ-treated cases fell at high frequency within an 8-bp region corresponding to a previously described “hotspot” identified in t-APL arising after treatment of breast cancer with regimens containing anthracyclines.8,9
In the present study, we report on the presenting features and treatment outcome of 33 patients who developed APL on a background of MS, including 30 who received MTZ for their primary disease.
Design and Methods
A call for studying t-APL cases was started in 2008 in the Italian GIMEMA group and extended subsequently to several European centers. This study initially included the characterization at the genomic level of “hotspot” breakpoints in both PML and RARA genes. Genomic studies of PML and RARA of 23 out of 33 patients included in the present series have been reported in two separate articles,8,9 while the clinical features and outcome of 14 of 33 patients have been included in one of these previous reports.8 MS patients received therapy according to the disease form as indicated.7 The diagnosis of t-APL was confirmed in all cases by reverse-transcriptase polymerase chain reaction (RT-PCR) or FISH detection of the PML-RARA hybrid gene.10 FLT3 mutation screening for internal tandem duplications (ITD) was carried out as described.11 APL was treated in all but one case with ATRA and anthracycline based combination chemotherapy induction according to treatment protocols active in various countries.12–16 These protocols included the AIDA 2000 of the Italian GIMEMA study group,12 the PETHEMA LPA2005,13 and the PETHEMA LPA 99,14 UK MRC AML1515 and the German AMLCG.16 All protocols received approval from the corresponding IRB and/or ethical committees. Patients were enrolled in the respective trials prospectively and were treated accordingly after signing informed consent. One patient (UPN 18) was treated without chemotherapy during induction, as detailed below (see Results and Discussion).
Unadjusted time-to-event analyses were performed using the Kaplan-Meier estimate.17 The probability of relapse was also estimated by the cumulative incidence method (for marginal probability).18,19 Overall survival (OS) was calculated from the date of starting induction therapy, while cumulative incidence of relapse (CIR) was calculated from the date of CR.20 For CIR analysis, death in CR and development of secondary leukemia were considered as a competing cause of failure.18,19 For all estimates in which the event “relapse” was considered as an end point, hematologic and molecular relapse, as well as molecular persistence at the end of consolidation were each considered as uncensored events.20 Computations were performed using the 3D, 4F, 1L, and 2L programs from the BMDP statistical library (BMDP Statistical Software, Los Angeles, CA, USA), and R 2.7.2 software package for CIR and Fine and Gray model.
Results and Discussion
Thirty-three patients with APL developed after MS are included in the study. Patient data were collected retrospectively from Italy (n=14), Spain (n=10), UK (n=3), Germany (n=3), Greece (n=2), and Austria (n=1) as summarized in Table 1. Detailed information about the type of primary disease (MS) was available for 28 patients. MS was categorized as relapsing-remitting disease (n=16), secondary progressive (n=8) and primary progressive (n=4). Thirty out of 33 patients were treated with MTZ for their primary disease and 21 of them were exposed to MTZ only, while 9 patients received more than one immuno-suppressive agent. Three patients were not exposed to MTZ and received other treatments including steroids (UPN 12), interferon-beta (UPN 10) and sequential steroids, interferon-beta and azathioprine (UPN 25). The median latency period between MS diagnosis and occurrence of APL was 91 months (range 18–336 months). MTZ doses were available for 28 patients with a median cumulative dose of 112 mg MTZ (range 14–242 mg). Median time elapsed between the first exposure to MTZ and APL diagnosis was 32 months (range 4–76 months).
Data related to APL presenting features are summarized in Table 2. The PML-RARA transcript type was available in 30 cases. Twenty-six (87%) patients had bcr1 (or “long” isoform) and 4 (13%) the bcr3 (or “short”) transcript (Table 1). One patient showed concomitant rearrangements of the BCR-ABL and PML-RARA genes in leukemic cells, as shown by FISH analysis and RT-PCR. The results for FLT3 ITD mutational analysis at diagnosis were available for 19 patients and showed this alteration in 3 of them (16%).
After APL diagnosis, one patient died of cerebral hemorrhage on day 1 prior to receiving any treatment. Three patients died during induction because of infection, differentiation syndrome, and CNS bleeding, respectively. Of the evaluable 29 patients in CR after induction, 21 received the planned consolidation cycles according to the previously mentioned protocols,12–16 7 patients (6 in the GIMEMA AIDA-2000 and one in the German AML trials) received modified consolidation therapy deviating from planned protocols and one patient died after first consolidation due to infection. As to patients receiving modified consolidation, 3 (UPN 4, UPN 5 and UPN 17) received idarubicin 5mg/m for four consecutive days during the second course of consolidation replacing MTZ and 3 patients (UPN 28, UPN 30 and UPN 32) received consolidation with ATO and ATRA. UPN 33 enrolled in the German trial AMLCG received cytarabine and ATRA for consolidation together with one patient (UPN 18) who was not enrolled in any of these protocols.
All 28 evaluable patients achieved molecular remission after consolidation and 20 of them received some type of maintenance as detailed in Table 3. After a median follow up of 26 months (range 3–82 months), 23 patients are in continuous complete remission (CCR) at a median time of 23 months (range 2–82), while 4 patients (14%) relapsed at a median time of 29 months (range 26–31). One patient (UPN 8) developed sAML with 11q23 rearrangement two years after achieving CR. The 5-year OS and CIR rates were 68% and 23%, respectively (Figure 1A and B).
Compared to de novo APL, among our patients there was a predominance of females with a female/male ratio of 1.75. This finding most likely reflects the higher frequency of MS in females. As to the biological characteristics, compared to de novo APL12,21 we found in this series a skewed distribution of PML-RARA isoforms with increased frequency of the bcr1 type. We believe that this finding might be correlated with the reported “hotspot” present in the PML gene intron 6 that appears to be more susceptible to MTZ-induced DNA breakpoints.7,8 Concerning other molecular lesions hereby analyzed, the frequency of FLT3-ITD was slightly inferior in MS-tAPL as compared to de novo APL.
t-APL typically occurs without an antecedent myelodys-plastic phase and after a relatively short (< 3 years) latency period from exposure to topo-II inhibitors.3,4 Only a few cases of t-APL arising after treatment of non-malignant diseases and in particular after MS have been described so far.5,6 Median time elapsed between the first exposure to MTZ and APL diagnosis was 32 months (range 4–76 months), in keeping with latency reported for t-APL occurring after a primary tumor.1–3
With respect to treatment outcome, we observe that OS in this series was slightly inferior to that reported for de novo APL patients receiving current standard therapy.12,13 However, patients in this study were collected from several European countries and were not homogeneously treated, particularly as concerns the post-induction phase (Table 3). In particular, also in the light of elevated MTZ cumulative doses previously given for MS, some investigators elected to decrease the amount of post-induction chemotherapy by omitting or substituting MTZ in consolidation. In fact, 2 of the 4 patients who relapsed did not receive anthracyclines in consolidation (UPN 28) or in maintenance (UPN 29) while the third patient (UPN 7) did not receive any maintenance based on the study protocol. Due to this level of heterogeneity and to the limited number of patients in this series, it is difficult to draw firm conclusions on the optimal treatment for MS-tAPL. However, the occurrence of 3 deaths due to treatment-related toxicity (including one in CR) and of one case of secondary AML may raise concerns on excessive exposure to chemotherapy and in particular to MTZ.
Recently, the PETHEMA group reported a cumulative incidence of sAML of 2.2% at six years for patients with de novo APL treated with standard ATRA and anthracycline-based chemotherapy.21 In addition, the outcome of patients with t-APL after ATO containing front-line therapy was found to be comparable to conventional induction therapy containing anthracyclines.22 It seems, therefore, reasonable, at least in the post-induction phase, to suggest the use of effective agents with different toxicity profile such as ATO for this particular subset of t-APLs, as well as for those APL cases which developed after a primary cancer treated with chemotherapy.
We are indebted to to Drs. Chiara Cattaneo, Antonio Ledda, Enrico Montefusco, Francesco Di Raimondo, Mariaenza Mitra, Maria Teresa Lupo Stanghellini, Maria Teresa Voso, Lorella Melillo, Richard Schlenk, Wolgang Sperr and Paolo Bernasconi who contributed some of the patient data for the present study.
- Authorship and Disclosures The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the full text of this paper at www.haematologica.org.
- Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.
- Funding: this work was partially supported by Associazione Italiana per la Ricerca sul Cancro (AIRC).
- Received October 29, 2010.
- Revision received December 13, 2010.
- Accepted December 21, 2010.
- Pollicardo N, O’Brien S, Estey EH, al-Bitar M, Pierce S, Keating M. Secondary acute promyelocytic leukemia: characteristics and prognosis of 14 patients from a single institution. Leukemia. 1996; 10(1):27-31. PubMedGoogle Scholar
- Pulsoni A, Pagano L, Lo Coco F, Avvisati G, Mele L, Di Bona E. Clinico-biological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience. Blood. 2002; 100 (6):1972-6. PubMedhttps://doi.org/10.1182/blood-2001-12-0312Google Scholar
- Beaumont M, Sanz M, Carli PM, Maloisel F, Thomas X, Detourmignies L. Therapy related acute promyelocytic leukemia. J Clin Oncol. 2003; 21(11):2123-37. PubMedhttps://doi.org/10.1200/JCO.2003.09.072Google Scholar
- Pedersen-Bjergaard J, Christiansen DH, Desta F, Andersen MK. Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2006; 20(11):1943-9. PubMedhttps://doi.org/10.1038/sj.leu.2404381Google Scholar
- Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B. DNA Topoisomerase II in Therapy-Related Acute Promyelocytic Leukemia. N Engl J Med. 2005; 352(15):1529-38. PubMedhttps://doi.org/10.1056/NEJMoa042715Google Scholar
- Pascual AM, Téllez N, Boscá I, Mallada J, Belenguer A, Abellán I. Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler. 2009; 15(11):1303-10. PubMedhttps://doi.org/10.1177/1352458509107015Google Scholar
- Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2003; 61(10):1332-8. PubMedGoogle Scholar
- Hasan SK, Mays AN, Ottone T, Ledda A, La Nasa G, Cattaneo C. Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood. 2008; 112(8):3383-90. PubMedhttps://doi.org/10.1182/blood-2007-10-115600Google Scholar
- Hasan SK, Ottone T, Schlenk RF, Xiao Y, Wiemels JL, Mitra ME. Analysis of t(15;17) Chromosomal Breakpoint Sequences in Therapy-related Versus de novo Acute Promyelocytic Leukemia: Association of DNA Breaks with Specific DNA Motifs at PML and RARA Loci. Genes Chromosomes Cancer. 2010; 49(8):726-32. PubMedhttps://doi.org/10.1002/gcc.20783Google Scholar
- van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999; 13(12):1901-28. PubMedhttps://doi.org/10.1038/sj/leu/2401592Google Scholar
- Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia. 2002; 16(11):2185-9. PubMedhttps://doi.org/10.1038/sj.leu.2402723Google Scholar
- Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adult patients younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010; 116(17):3171-9. PubMedhttps://doi.org/10.1182/blood-2010-03-276196Google Scholar
- Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010; 115(25):5137-46. PubMedhttps://doi.org/10.1182/blood-2010-01-266007Google Scholar
- Sanz MA, Martín G, González M, León A, Rayón C, Rivas C. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA Group. Blood. 2004; 103(4):1237-43. PubMedhttps://doi.org/10.1182/blood-2003-07-2462Google Scholar
- Burnett AK, Hills RK, Grimwade D. Idarubicin and ATRA is as effective as MRC chemotherapy in patients with acute promyelocytic leukaemia with lower toxicity and resource usage: Preliminary results of the MRC AML15 trial. Blood. 2007; 110:181a. Google Scholar
- Lengfelder E, Haferlach C, Saussele S, Haferlach T, Schultheis B, Schnittger S, High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia. 2009; 23(12):2248-58. PubMedhttps://doi.org/10.1038/leu.2009.183Google Scholar
- Kaplan EL, Meier P. Nonparametric estimations from incomplete observations. J Am Stat Assoc. 1958; 53(282):457-81. https://doi.org/10.2307/2281868Google Scholar
- Gray RJ. A class of K-sample test for comparing the cumulative incidence of a competing risk. Ann Stat. 1988; 16(3):1141-54. https://doi.org/10.1214/aos/1176350951Google Scholar
- Pepe MS, Mori M. Kaplan-Meier, marginal or conditional probability curves in summarizing competing risks failure time data?. Stat Med. 1993; 12(8):737-51. PubMedhttps://doi.org/10.1002/sim.4780120803Google Scholar
- Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T. Definition of relapse risk and role of non-anthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000; 96(4):1247-53. PubMedGoogle Scholar
- Montesinos P, González JD, González J, Rayón C, de Lisa E, Amigo ML. Therapy-Related Myeloid Neoplasms in Patients With Acute Promyelocytic Leukemia Treated With All-Trans-Retinoic Acid and Anthracycline-Based Chemotherapy. J Clin Oncol. 2010; 28(24):3872-9. PubMedhttps://doi.org/10.1200/JCO.2010.29.2268Google Scholar
- Dayyani F, Kantarjian H, O’Brien S, Pierce S, Jones D, Faderl S. Outcome of therapy-related acute promyelocytic leukemia with or without arsenic trioxide as a component of frontline therapy. Cancer. 2011; 117(1):110-5. PubMedhttps://doi.org/10.1002/cncr.25585Google Scholar