Should minimal residual disease monitoring be the standard of care for all patients with acute promyelocytic leukemia?

TY - JOUR

T1 - Should minimal residual disease monitoring be the standard of care for all patients with acute promyelocytic leukemia?

AU - Grimwade, David

AU - Tallman, Martin S.

N1 - Funding Information: David Grimwade ⁎ [email protected] Department of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Tower Wing, Guy's Hospital, London SE1 9RT, UK ⁎ Corresponding author. Tel.: +44 207 188 3699; fax: +44 207 188 2585. Martin S. Tallman 1 [email protected] Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA 1 Tel.: +1 212 639 3842; fax: +1 212 639 3841. David Grimwade writes: The case for adopting molecular monitoring for minimal residual disease (MRD) as a standard of care for patients with acute promyelocytic leukemia (APL) to guide therapy has become overwhelming and accordingly has been recommended in national and international treatment guidelines [1,2]. These recommendations take into account a substantial body of evidence that has accumulated over the last two decades, based on analysis of patients receiving standard all trans retinoic acid (ATRA) and anthracycline-based treatment protocols. In the pioneering studies, a number of groups established that testing of follow-up bone marrow (BM) samples for presence of PML–RARA fusion transcripts using qualitative reverse transcriptase polymerase chain reaction (RT-PCR) assays could not only identify patients with subclinical levels of disease, but also provided evidence that achievement of molecular remission (CRm) is critical to achieve cure [3–7]. Accordingly, documentation of CRm has been adopted as a standard response criterion in APL, lending further support to routine use of MRD monitoring [8]. Early studies also clearly demonstrated that clinical relapse is predicted by recurrence of PCR positivity; whereas, PCR negativity in sequential follow-up marrows predicts a favorable prognosis [3–7,9]. Considering that occurrence of frank relapse of APL is accompanied by a significant risk of death as a result of the associated bleeding diathesis and evidence that impending relapses can be reliably predicted by RT-PCR, there was a strong rationale for investigation of MRD monitoring as a tool to direct pre-emptive therapy in order to improve outcomes for APL patients. The first study was conducted by the GIMEMA group over a decade ago, which suggested a survival advantage for early treatment intervention [10]. While it is accepted that this study suffered from a number of limitations in that it used a non-randomized historical comparison and did not adjust for time-shift bias, the case for MRD-directed therapy was further strengthened by a prospective study by the PETHEMA group showing much poorer survival in patients salvaged in frank relapse as compared to those treated in molecular relapse with comparable therapy [11]. Both of these studies predated the introduction of arsenic trioxide (ATO) as salvage therapy in APL; however, a more recent prospective study from the UK Medical Research Council (MRC) has also shown a benefit for MRD monitoring to direct pre-emptive therapy involving ATO [12]. Indeed, the MRC study showed that this agent is associated with significantly less toxicity when used to treat submicroscopic levels of disease than when it is deployed in frank relapse, eliminating problems with induction of hyperleukocytosis and the associated differentiation syndrome which often requires admission to intensive care and can be potentially fatal [12]. In addition to the application of MRD testing to predict relapse following consolidation, direct pre-emptive therapy and help exclude underlying residual disease in the context of unexpected cytopenias during or after treatment, there is a strong case for using molecular monitoring to help inform decisions regarding transplantation in patients relapsing following front-line therapy. Autograft is known to be an effective salvage therapy in APL [13,14]; however, the GIMEMA group were the first to show the relationship between pre-transplant MRD status of the patient and the harvest material and outcome following autograft [15]. Patients with evidence of MRD and transplanted with a PCR positive graft invariably relapsed, whereas, the majority of those transplanted in molecular CR with a PCR negative graft remained in remission. The GIMEMA group has also shown that patients with persistent PCR positivity following front-line ATRA and anthracycline chemotherapy can be salvaged by allogeneic transplant [16]. These data have recently been confirmed in a UK study investigating outcome following transplant in patients relapsing following ATRA + chemotherapy and salvaged with ATO [17]. Twelve of 13 autografted in molecular CR with a PCR negative harvest remain in remission at a median of 2 years. Of 13 patients subject to allograft, including 10 with persistent PCR positivity following salvage therapy, 9 are in ongoing molecular remission [17]. There is therefore a strong evidence base for use of sequential MRD monitoring to direct treatment of relapse; in this setting achievement and maintenance of CRm are prerequisites for disease cure, which is a highly realistic aim with available therapies. Accordingly, use of molecular monitoring to guide treatment of relapse and inform transplant choice has been adopted in the International APL treatment recommendations [2]. Having established that assessment of MRD should be considered a standard of care for patients with APL, the next question that arises is the most appropriate monitoring schedule. While conventional end-point RT-PCR assays have proved highly informative, they lack the capacity to distinguish between rising and falling numbers of fusion transcripts (reviewed [18]). Importantly, they also cannot reliably identify poor quality samples that could potentially give rise to “false negative” results [18]. This problem has been solved with the advent of real-time quantitative PCR (RQ-PCR), which affords a number of further advantages compared to conventional end-point assays including improved sensitivity (typically ∼1 in 10 − log = 0.02), associated with improved survival at a cost of £4700 per quality adjusted life year (QALY) [12]. This is in accordance with an Australian Governmental health economic report, which found molecular diagnostics and MRD monitoring to be cost-effective in APL, at an estimated cost of £2800–7000/QALY [22]. 4 ), more rapid turnaround time, decreased risk of contamination and ease of standardization, facilitating comparison of results between laboratories (reviewed [19]). A significant step forward in the realization of MRD-directed therapies in APL was the development of internationally standardized RQ-PCR assays for PML–RARA transcripts, which was one of the major achievements of the European Union supported Europe Against Cancer (EAC) program [20]. To establish the most appropriate monitoring schedule, sequential paired peripheral blood (PB) and BM samples were analyzed prospectively in a large UK study applying the standardized EAC assay in 406 patients treated with ATRA and anthracycline-based chemotherapy, including 303 entered in the MRC AML15 trial [12]. In multivariable analysis, MRD monitoring provided the strongest predictor of disease relapse, more powerful than presenting white blood cell count, which is widely used to direct therapy. Patients with persistent PCR positivity or recurrent PCR positivity, with rising PML–RARA fusion transcripts invariably relapsed unless pre-emptive therapy was successfully delivered. In this study, which involved the analysis of almost 7000 samples, key parameters were defined pertinent to the development of optimal and reliable monitoring schedules. As recognized in the international APL guidelines [2], provision of diagnostic material for molecular diagnostics is crucial to define PML–RARα isoform type to ensure that the correct assay is used for MRD detection in the particular patient. Key factors that influence the most appropriate frequency of MRD testing are assay sensitivity (determined by relative level of fusion gene expression in leukemic blasts—typically 1 in 10 4 ) and the kinetics of disease relapse (median 1 PML–RARA transcript rise per month) [12]. Analysis of over 2000 paired samples showed that PB affords inferior sensitivity (median of 1.5 log lower) compared to marrow [12], meaning that BM is the sample type of choice for sequential MRD monitoring, where the aim is to deliver pre-emptive therapy to prevent clinical relapse [1,2,12]. The limited sensitivity afforded by PB generally leaves too small a time window of opportunity (or indeed no time window) between molecular conversion and frank relapse [12,21]. Taking into account the maximal achievable sensitivity of the assays and the kinetics of disease relapse, 3-monthly BM examination is recommended until 36 months post-consolidation (after which, risk of subsequent relapse is very low). We have shown that application of this schedule can predict the majority of impending relapses, which can be prevented with pre-emptive therapy using ATO [12]. Adoption of this strategy led to a significant reduction in overall frank relapse rate in the MRC AML15 trial as compared to the previous MRC trial (AML12) in which comparable ATRA and anthracycline based therapy was used, but routine MRD monitoring was not performed (5% relapse rate versus 12% at 3 years, p While MRD monitoring has been shown to improve outcome in the context of ATRA and anthracycline-based therapies, there is concern that many APL patients are currently over-treated. With the availability of molecularly targeted agents there has been an increasing trend towards de-intensification of therapy, with interest in chemotherapy-free schedules based on ATRA and ATO [23–27]. However, as treatment intensity is reduced, MRD monitoring using optimized schedules assumes greater importance as a safeguard to identify rapidly those patients requiring additional therapy. Overall, APL has provided a valuable model for the use of molecular diagnostics coupled with MRD monitoring to develop a personalized medicine approach. While molecular assessment of MRD has generally been adopted as a standard of care in APL, ongoing studies are addressing the clinical utility of this strategy in other subtypes of AML in which relapse rates are much higher and hence the benefits of MRD monitoring are likely to be even greater. Acknowledgements DG gratefully acknowledges Leukaemia and Lymphoma Research of Great Britain and the National Institute for Health Research for support of minimal residual studies in the UK National Cancer Research Institute AML trials. Support of the Minimal Residual Disease Workpackage (WP12) of the European LeukemiaNet is also gratefully acknowledged. References [1] Milligan DW, Grimwade D, Cullis JO, et al. Guidelines on the management of acute myeloid leukaemia in adults. Br J Haematol. 2006;135:450–74. [2] Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91. [3] Lo Coco F, Diverio D, Pandolfi PP, et al. Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet. 1992;340:1437–8. [4] Miller WH Jr, Levine K, DeBlasio A, Frankel SR, Dmitrovsky E, Warrell RP Jr. Detection of minimal residual disease in acute promyelocytic leukemia by a reverse transcription polymerase chain reaction assay for the PML/RAR-alpha fusion mRNA. Blood. 1993;82:1689–94. [5] Diverio D, Pandolfi PP, Biondi A, et al. Absence of reverse transcription-polymerase chain reaction detectable residual disease in patients with acute promyelocytic leukemia in long-term remission. Blood. 1993;82: 3556–9. [6] Diverio D, Rossi V, Avvisati G, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. GIMEMA-AIEOP Multicenter “AIDA” Trial. Blood. 1998;92: 784–9. [7] Jurcic JG, Nimer SD, Scheinberg DA, DeBlasio T, Warrell RP Jr, Miller WH Jr. Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood. 2001;98:2651–6. [8] Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–9. [9] Grimwade D, Howe K, Langabeer S, Burnett A, Goldstone A, Solomon E. Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML–RARalpha and RAR alpha-PML assessment in patients who ultimately relapse. Leukemia. 1996;10: 61–6. [10] Lo Coco F, Diverio D, Avvisati G, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94: 2225–9. [11] Esteve J, Escoda L, Martín G, et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all- trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia. 2007;21:446–52. [12] Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27:3650–8. [13] de Botton S, Fawaz A, Chevret S, et al. 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Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease. Leukemia. 2003;17:1930–3. [17] Kishore B, Stewart A, Jovanovic J, Craddock C, Grimwade D. Arsenic trioxide and stem cell transplantation is an effective salvage therapy in patients with relapsed APL. Br J Haematol. 2010;149 (Suppl. 1):22 (abstract) [18] Grimwade D. The significance of minimal residual disease in patients with t(15;17). Best Pract Res Clin Haematol. 2002;15:137–58. [19] Freeman SD, Jovanovic JV, Grimwade D. Development of minimal residual disease directed therapy in acute myeloid leukemia. Semin Oncol. 2008;35:388–400. [20] Gabert JA, Beillard E, van der Velden VHJ, et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia. 2003;17:2318–57. [21] Ommen HB, Schnittger S, Jovanovic JV, et al. Strikingly different molecular relapse kinetics in NPM1c, PML–RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood. 2010;115:198–205. [22] Medical Services Advisory Committee report of Australian Government Department of Health and Ageing. Polymerase chain reaction in the diagnosis and monitoring of patients with PML–RARα and PLZF-RARα gene rearrangement in acute promyelocytic leukaemia. MSAC ref 9a (ii). 2003 http://www.msac.gov.au/ [23] Estey EH, Giles FJ, Kantarjian H, et al. Molecular remissions induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Blood. 1999;94:2230–5. [24] Shen, ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As 2 O 3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2004;101:5328–35. [25] Mathews V, George B, Lakshmi KM, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006;107:2627–32. [26] Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107:3469–73. [27] Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17:131–4. Martin Tallman writes: The successful treatment of patients with acute promyelocytic leukemia (APL) represents one of the major triumphs in the field of hematologic malignancies. Historically, the disease was associated with a high rate of early mortality, most often attributable to catastrophic hemorrhage [1,2]. Among patients who survived induction, the 5-year disease-free survival (DFS) was modestly better than that of patients with other subtypes of AML at approximately 40%. Since the introduction of all- trans retinoic acid (ATRA) almost 2 decades ago into routine clinical practice, only two factors, early death and relapse, remain major impediments in the ability to cure all patients. Despite improvements in supportive care with very aggressive blood product support, in the current era early death remains the single most important challenge in the treatment of newly diagnosed patients with APL [3]. Early death is most often associated with a high white blood cell count (WBC) at presentation, late diagnosis and delayed treatment initiation [3]. Factors which predict for early death specifically due to hemorrhage include an abnormal creatinine, increased peripheral blast count, and the presence of coagulopathy [4]. While the early death rate reported in large clinical trials is approximately 10%, population-based studies in which all patients seen at the institution are reported, reveal a higher early death rate of approximately 20–30% [5,6]. These facts are particularly relevant since there is no primary resistance to ATRA-based therapy and if patients survive induction their long-term outcome is excellent [4]. Over the last decade, relapse in APL, while not completely eliminated, has been remarkably reduced. With ATRA plus anthracycline-based chemotherapy, the overwhelming majority of patients are cured of their disease. Indeed, recent studies of large numbers of patients report complete remission (CR) rates of more than 90%, disease-free survival (DFS) rates of 85% and overall survival (OS) rates of more than 90% [7–9]. The relapse rate among low-and intermediate-risk patients is approximately 5%. Even among high-risk patients, the relapse rate is approximately 10% when intermediate-dose cytarabine is included in consolidation [7,8,10]. Among patients who do relapse, a second CR (molecular) is achieved in almost 90% with arsenic trioxide (ATO) [11]. Among patients treated early in the ATRA era, late relapses (more than 4 years after CR) did occur and in one series represented 13% of all relapses. Such patients often present with high-risk disease. Among these patients a second CR was obtained in 94% of patients with ATO and the 4-year survival from late relapse was 77% demonstrating the high likelihood of very effective salvage therapy. Arsenic trioxide is so effective in patients with relapsed APL that it has recently been combined with ATRA as induction therapy for newly diagnosed patients. Initial studies combined ATO with ATRA and chemotherapy with a CR rate of 95%, and 5-year relapse-free survival of 95% and the outcome was not influenced by the initial WBC [12]. Subsequently, ATO was given with ATRA and minimal chemotherapy only to control the WBC [13,14]. With this approach, only 3 of 82 patients relapsed. ATO has also been shown to be effective as a single agent [15]. Among very low-risk patients (WBC 20,000/μL) treated with single agent ATO without ATRA or any chemotherapy, the event-free and OS was 100%. Other patients did not fare as well suggesting that most patients with newly diagnosed APL require more than single agent ATO. Ghavamzadeh and colleagues administered single agent ATO for induction followed by one additional course of ATO as a consolidation [16]. Among patients achieving CR, the 1- and 3-year survivals were 95.5% and 87.6%, respectively. The 2-year DFS of 63.7% suggests that for many patients only 2 courses of ATO alone are not sufficient. When 2 courses of ATO were administered as an early consolidation following conventional ATRA plus anthracycline-based chemotherapy, the relapse rate at 1-year among low- and intermediate-risk patients was 2% and 3%, respectively and 9% among high-risk patients [17]. The outstanding results achieved with either ATRA plus anthracyclines for low- and intermediate-risk patients, with either intermediate-dose cytarabine in induction or consolidation, or ATO as part of consolidation for high risk patients have generated controversy regarding the value of molecularly monitoring for minimal residual disease (MRD). Tests to detect the PML–RARalpha fusion transcript are widely available, easy to obtain from the patient and clearly predict for relapse. However, with such remarkably effective therapy even among high-risk patients, are there subgroups which can be identified for whom molecular monitoring for MRD is most valuable? Although it can be done, how important is it to detect relapse early, particularly in the ATO era? Several characteristics are putative factors which identify patients at high risk for relapse. The expression of the FLT3 -ITD mutation is relatively common in patients with APL and may confer a less favorable prognosis. A study from the United Kingdom suggested that while the induction death rate in such patients was higher, the relapse rate and overall survival was not different from that of patients without the mutation [18]. Similarly, the European APL Group found that the presence of the FLT3 -ITD mutation did not influence CR rate or relapse rate, nor induction death rate [19]. FLT3 mutations were associated with high WBC and the microgranular variant morphology. The GIMEMA group discovered that the FLT3 mutation conferred a trend for an inferior outcome with respect to DFS and relapse risk [20]. Recent studies suggest that long FLT3 -ITD mutations and reduced PML–RARalpha levels were independent predictors of short relapse-free survival [21]. Interestingly, Mathews and colleagues reported that the presence of FLT3 mutations did not influence the outcome of patients when treated with single agent ATO [22]. The microgranular variant of APL (M3v) has been possibly associated with an inferior outcome compared with that of patients with classical APL in some studies [4,23]. However, in a study of a large number of patients with the M3v, it appears that variant morphology itself is not independently associated with a less favorable prognosis [24]. There are likely other factors which are currently unknown and which may be molecular in nature, which will emerge in future studies as more sensitive predictors of relapse than WBC. More than a decade ago, Lo Coco and colleagues suggested that early salvage therapy at the time of molecular relapse among patients prospectively monitored molecularly may provide a better outcome than salvage chemotherapy given at the time of hematologic relapse (historical control population) [25]. However, the 2-year overall survival for the historical cohort patients was 44%, considerably lower than achieved currently with ATO-based strategies [26]. A similar conclusion was arrived at in another comparison [27]. Again, salvage therapy for patients with both molecular or hematologic relapse included chemotherapy and ATRA, but not ATO. Therefore, the question of the benefit of early intervention with optimal salvage therapy with ATO at the time of molecular relapse remains open. At the present time, it seems reasonable to monitor patients with high-risk disease. Serious doubts can be raised about the value of molecular monitoring among patients with low- and intermediate-risk disease if they are treated with contemporary strategies and followed with routine complete blood counts. Patients with a known history of APL and their physicians will anticipate bleeding as a manifestation of relapse. The optimal schedule for monitoring patients presenting with high-risk disease should be the subject for future research. Nevertheless, since hematologic relapse occurs at a median of 3 months from the first positive molecular test, patients should be tested frequently [28]. Molecular monitoring in APL may, in fact, have become less important for the majority of patients as therapeutic strategies have evolved with less MRD to detect. References [1] Cordonnier C, Vernant JP, Brun B, Heilmann MG, Kuentz M, Bierling P, Farcet JP, Rodet M, Duedari N, Imbert M, et al. Acute promyelocytic leukemia in 57 previously untreated patients. 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Long FLT3 internal tandem duplications and reduced PML–RARalpha expression at diagnosis characterize a high-risk subgroup of acute promyelocytic leukemia patients. Haematologica. 2010;95:745–51. [22] Mathews V, Thomas M, Srivastava VM, et al. Impact of FLT3 mutations and secondary cytogenetic changes on the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with a single agent arsenic trioxide regimen. Haematologica. 2007;9:994–5. [23] Bassan R, Battista R, Viero P, d’Emilio A, Buelli M, Montaldi A, Rambaldi A, Tremul L, Dini E, Barbui T. Short-term treatment for adult hypergranular and microgranular acute promyelocytic leukemia. Leukemia. 1995;9:238–43. [24] Tallman M, Kim HT, Schiffer CA, et al. Microgranular variant (M3 V) of acute promyelocytic leukemia (APL) does not have a worse prognosis than classical APL in the ATRA era: A report of 153 patients treated on Intergroup 0129 and PETHEMA LPA96 and LPA99. Blood. 2004;104:116a (abstract). [25] Lo Coco F, Diverio D, Avvisati G, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94:2225–29. [26] Thirugnanam R, George B, Chendamarai E, et al. Comparison of clinical outcome of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant. 2009;15:597–609. [27] Esteve J, Escode L, Martin G, et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of early intervention. Leukemia. 2007;21:446–452. [28] Diverio D, Rossi V, Avvisati G, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. GIMEMA-AIEOP Multicenter “AIDA” Trial. Blood. 1998;92:784–789. David Grimwade writes: It is agreed that the role of MRD monitoring should be kept under constant review in the light of developments in treatment approach. Indeed, patients presenting with WBC 10) in whom relapse risk exceeds 10% and therefore there is a much greater benefit for sequential MRD monitoring (10% survival benefit at 5 years at a cost of £1350/QALY) [1]. In this group careful surveillance is also merited due to the increased risk of relapses that involve extramedullary sites, particularly the central nervous system. Apart from routine MRD monitoring in high risk patients, molecular assessment at time of relapse is essential to confirm PML–RARA positivity to predict a favorable response to ATO (distinguishing 9 /l (defined above as low and intermediate risk) who account for ∼70% of APL have an extremely low risk of relapse with current treatment protocols that involve ATRA and anthracycline-based chemotherapy. In the recent MRC study we found that there was only a marginal benefit for sequential MRD monitoring in this group (1% survival benefit at 5 years, at a cost of £14,300 per QALY) [1]. Therefore, for these patients it would be appropriate to restrict MRD assessment to marrows taken following consolidation courses of therapy in order to confirm achievement of molecular remission (with assays affording a sensitivity of at least 1 in 10 4 ). Having reached this therapeutic goal, MRD monitoring could quite reasonably be discontinued at the post-consolidation timepoint; although it is recognized that some patients and their clinicians may prefer to continue molecular surveillance until 3 years post-consolidation for reassurance and also to allow the opportunity for early treatment intervention in the unlikely event that the disease recurs. The situation is very different in patients with high risk APL (WBC bone fide relapse from therapy-related MDS/AML which is ATO resistant). Based on the available evidence it would also seem prudent to use MRD monitoring to guide salvage therapy, including type of transplant according to the molecular response. Finally, it is proposed that MRD monitoring be considered standard practice in all experimental protocols that involve novel and deintensified treatment approaches, to help achieve further refinement of management, allowing development of individualized therapy that minimizes toxicity without compromising disease cure. Reference [1] Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27:3650–8. Martin Tallman writes: For patients with low- and intermediate-risk APL treated with current ATRA plus anthracycline-based chemotherapy, once molecular CR is documented it appears that routine molecular monitoring can likely be abandoned. High-risk patients remain a “thorn in the side” of physicians treating APL. With a relapse risk of approximately 10% among such patients, molecular monitoring is justified. In the unlikely event of relapse, salvage therapy with ATO followed by autologous hematopoietic cell transplantation is highly effective [1]. Even with effective contemporary initial therapies, whether ATRA plus anthracycline-based strategies or ATRA plus ATO approaches, high-risk patients have a lower response rate and approximately twice the relapse rate compared with others [2,3]. The question can be asked: at what specific relapse rate is molecular monitoring justified? The issue is complicated because many factors must be considered including the cumulative cost of serial testing, the implications of discovering evidence of minimal residual disease, the probability of successful treatment at the time of minimal residual disease versus at the time of hematologic relapse, potential anxiety generated in anticipation of frequent testing (including the psychological impact of requests for early repeat MRD analyses prompted by equivocal results or provision of poor quality samples that yield suboptimal sensitivity and which may heighten concern of disease relapse) and the patient's frame of reference. Personal philosophy, on the part of both the physician and the patient, may prompt divergent views. While the focus of this Commentary has been to address the role of molecular monitoring once in CR, increased efforts towards improving initial therapy in high-risk patients to further prevent, rather than detect, relapse should be a major focus of clinical research and the subject of another Commentary in the future. References [1] Thirugnanam R, George B, Chendamarai E, et al. Comparison of clinical outcome of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant. 2009;15:597–609. [2] Sanz MA, Montesinos P, Rayon C, et al. 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 (E-pub). [3] Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans retinoic acid, arsenic trioxide and gemtuzumab ozogamicin. J Clin Oncol. 2009;27:504–10.

PY - 2011/1

Y1 - 2011/1

UR - http://www.scopus.com/inward/record.url?scp=78650177461&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650177461&partnerID=8YFLogxK

U2 - 10.1016/j.leukres.2010.06.018

DO - 10.1016/j.leukres.2010.06.018

M3 - Editorial

C2 - 20674017

AN - SCOPUS:78650177461

SN - 0145-2126

VL - 35

SP - 3

EP - 7

JO - Leukemia Research

JF - Leukemia Research

IS - 1

ER -