Minimal residual disease monitoring: a new era for childhood ALL

Minimal residual disease monitoring: a new era for childhood ALL

Comment Morab-004, and olaratumab. A recent press release has reported that eribulin had an overall survival advantage compared with dacarbazine in a...

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Morab-004, and olaratumab. A recent press release has reported that eribulin had an overall survival advantage compared with dacarbazine in a randomised phase 3 trial in patients with leiomyosarcoma and liposarcoma. Additionally, a first-line trial of maintenance pazopanib (NCT02367651) is underway, and another comparing doxorubicin with gemcitabine plus docetaxel (Eudra CT 2009-014907-29) has closed to enrolment. The results of the phase 3 trial in which patients with leiomyosarcoma and liposarcoma are randomly assigned to trabectedin or dacarbazine (NCT01343277) are eagerly awaited, and will have implications for the further development of trabectedin. The French Sarcoma Group plan to undertake a phase 3 trial of the doxorubicin and trabectedin combination compared with standard therapy. Although limiting the study of this regimen to leiomyosarcoma is encouraged, the difficulty will lie in defining the standard treatment in the control group, particularly in the context of ongoing trials. Beyond histology-specific trials, identification of predictive molecular and imaging biomarkers might prove helpful for the selection of patients for clinical trial participation and treatment. By undertaking well designed trials such as that by Pautier and colleagues,7 the therapeutic options available to treat soft-tissue sarcoma according to subtype will hopefully increase.

Jonathan Noujaim, Winette T A van der Graaf, *Robin L Jones Sarcoma Unit, Royal Marsden Hospital, London SW3 6JJ, UK (JN, RLJ); Radboud University Medical Center, 6525 GA Nijmegen, Netherlands (WTAvdG) [email protected] 1

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Bathan AJ, Constantinidou A, Pollack SM, Jones RL. Diagnosis, prognosis, and management of leiomyosarcoma: recognition of anatomic variants. Curr OpinOncol. 2013; 25: 384–89. Maki R, Wathen JK, Patel S, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Oncol 2007; 25: 2755–63. Demetri G, Chawla S, von Mehren M, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol 2009; 27: 4188–96. van der Graaf WTA, Blay J-Y, Chawla S, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879–86. Blay J-Y, von Mehren M, Samuels B, et al. Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma. Clin Cancer Res 2008; 14: 6656–62. Sessa C, Perotti A, Noberasco C, et al. Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer. Eur J Cancer 2009; 45: 1153–61. Pautier P, Floquet A, Chevreau C, et al, for the French Sarcoma Group. Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial. Lancet Oncol 2015; published online March 18. http://dx.doi.org/10.1016/S1470-2045(15)70070-7. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014; 15: 415–23. Ford R, Schwartz L, Dancey J, et al. Lessons learned from independent central review. Eur J Cancer 2009; 45: 268–74. Le Cesne A, Blay J-Y, Domont J, et al. Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial. Lancet Oncol 2015; 16: 312–19

Minimal residual disease monitoring: a new era for childhood ALL Published Online March 20, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70123-3 See Articles page 465

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Morphological assessment of treatment response has been largely replaced by minimal residual disease monitoring in studies of acute lymphoblastic leukaemia (ALL), which has led to a substantial change of criteria that define complete remission and leukaemia relapse. Modern methods for the study of minimal residual disease include molecular genetic assays, such as realtime quantitative PCR (rtPCR) or flow cytometry. These methods are highly sensitive; rtPCR can detect as few as one leukaemic cell in 100 000 normal cells and four-colour flow cytometry achieves similar results.1,2 International efforts have been made to optimise and standardise methods, and guidelines have been provided by the BIOMED Concerted Action

and subsequently the EuroMRD Consortium.3,4 Thus, measurement of minimal residual disease with methods based on PCR-based or flow cytometry has been valuable for the prediction of outcomes in childhood and adult ALL.5,6 Minimal residual disease levels during remission induction are the most important prognostic indicators in ALL. Some investigators have suggested that minimal residual disease levels can be used to better assign patients into risk groups and tailor the intensity of treatment. Thus, reduction of intensity for patients without detectable or low level minimal residual disease can potentially reduce treatment-related side-effects whereas intensifying treatment for those with high www.thelancet.com/oncology Vol 16 April 2015

minimal residual disease can achieve higher cure rates in this group.7,8 Although findings of several studies have already shown the effect of minimal residual disease monitoring, the study by Pui and colleagues9 in The Lancet Oncology is the first trial prospectively showing the clinical utility of minimal residual disease levels during and after remission induction, and gives the most important checkpoints to guide treatment of childhood ALL. The study is especially notable because sequential minimal residual disease measurements were already part of the risk stratification and guidance of treatment decisions. The data presented are based on the St Jude Total Therapy XV study (NCT00137111) including 498 cases of childhood ALL between 2000 and 2007;10 thus, the investigators reviewed many patients with remarkably long follow-up. The previous study10 provided clear guidelines for sequential minimal residual disease monitoring in the context of modern risk-based treatment of childhood ALL, and for incorporating this information into the design of future risk-based protocols. In the most recent study by Pui and colleagues,9 risk assignment to establish treatment intensity based on minimal residual disease assessments were most effective at days 19 and 46 of remission induction. Importantly, irrespective of provisional risk classification, the 10-year event-free survival was worse for patients with minimal residual disease greater or equal to 1% on day 19 and even those with former low risk were shifted to standard-risk therapy. By contrast, in the provisional low-risk patients, a minimal residual disease level lower than 1% at day 19 was favourable irrespective of the day 46 value, and patients remained in the low-risk group. This study is the first to show that minimal residual disease levels during remission induction treatment have important prognostic and therapeutic implications even in the context of minimal residual diseaseguided treatment. Conversely, the data suggest that sequential minimal residual disease monitoring after remission induction is clinically useful only for patients with detectable minimal residual disease at the end of induction therapy. Patients with high or persistent minimal residual disease levels during remission induction therapy are candidates for more intensive treatment or novel agents to improve their poor prognosis. Finally, the present study can inform the design of future risk-based www.thelancet.com/oncology Vol 16 April 2015

H Piguet/Cnri/Science Photo Library

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protocols. However, minimal residual disease assays are restricted by their technical complexity and, in the case of flow cytometry, by the requirement for expert interpretative skills. Advances in new technologies like next-generation sequencing will hopefully expedite the process and make the detection of minimal residual disease much easier.11,12 Pui and colleagues provide important data that will change treatment strategies in paediatric ALL. New minimal residual disease methods in addition to future risk-based treatment protocols could potentially usher in a new era in childhood ALL. Moreover, these data can hopefully be used to inform future studies of minimal residual disease in adult ALL as well as to start the assessment of minimal residual disease-guided treatment in other haematological cancers. Susanne Schnittger MLL Munich Leukaemia Laboratory, 81377 Munich, Germany [email protected] SS declares part ownership of the MLL Munich Leukaemia Laboratory. 1

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van der Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 2003; 17: 1013–34. Coustan-Smith E, Song G, Clark C, et al. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood 2011; 117: 6267–76. van Dongen JJ, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–317. Bruggemann M, Schrauder A, Raff T, et al. Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia 2010; 24: 521–35.

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Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet 1998; 351: 550–54. van Dongen JJM, Seriu T, Panzer-Grünmayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 1731–38. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 2013; 14: 199–209. Vora A, Goulden N, Mitchell C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol 2014; 15: 809–18.

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Pui C-H, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol 2015; published online March 19. http://dx.doi.org/10.1016/ S1470-2045(15)70082-3. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–41. Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood 2012; 120: 5173–80. Logan AC, Zhang B, Narasimhan B, et al. Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia 2013; 27: 1659–65.

Non-inferiority trials: why oncologists must remain wary

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Heightened interest in comparative effectiveness research has made head-to-head comparisons between anti-cancer drugs increasingly common. One strategy is to show non-inferiority of a therapy to another in terms of efficacy and to rely on improvements in safety (toxicity), quality of life, convenience, or cost to guide the choice. Many noninferiority trials have followed this model, which raises questions regarding the use of non-inferiority designs in comparative effectiveness research. We address three issues that affect non-inferiority trials: the arbitrary nature of what constitutes a non-inferior therapy; the problem of censorship and its effect on outcomes; and the arbitrary choice of what represents an advantage if non-inferior efficacy is established. As the US Food and Drug Administration (FDA) noted,1 the design and interpretation of noninferiority trials “is a formidable challenge”. Sometimes erroneously thought of as equivalence trials, non-inferiority trials do not show superiority of the test drug, but “show the new treatment is not inferior to an unacceptable extent”. But as others have noted,2,3 and as summarised in the appendix, the margin of non-inferiority is often inadequately justified. The variable and often arbitrary thresholds show an absence in consensus of what constitutes “an unacceptable extent”, with hazard ratios (HR) for non-inferiority ranging from 1·049 to 1·43. Note that, unlike superiority trials that aim for statistically significant HRs of less than 1, non-inferiority trials choose HRs greater than 1—ie, values that, with their confidence intervals, represent the limits of how much worse the experimental therapy can be, yet

still be considered non-inferior. The desired efficacy of the experimental drug relative to that of the reference drug also varies greatly (appendix). The large distribution of these two non-inferiority margins (ie, HRs and percentage of efficacy retained) underscore the arbitrary nature of the choices and, in our view, render many choices questionable. Consider, for example, capecitabine for metastatic breast cancer. Regulatory approval of adding capecitabine to docetaxel after failure of a prior anthracycline-containing regimen was based on the gains achieved in a superiority trial by adding standard dose capecitabine (1250 mg/m² twice daily) to docetaxel. Although outcomes were statistically significant, with HRs of 0·652 (95% CI 0·545–0·780, p=0·0001) for time to progression and 0·775 (95% CI 0·634–0·947, p=0·0126) for overall survival, the absolute gains of 1·9 months in progression-free survival and 3 months in overall survival achieved were modest. The non-inferiority trial summarised in the appendix compared the addition of a lower (825 mg/m² twice daily) or standard dose capecitabine to docetaxel, thereby seeking to improve tolerability with the lower capecitabine dose without compromising efficacy.4 Yet, as this and other trials show, a guarantee that “the test drug is not any (even a little) less effective than the control can only be demonstrated by showing the test drug is superior. What non-inferiority trials seek to show is that any difference between the two treatments is small enough that the new drug has at least some effect or, in many cases, an effect that is not too much smaller than the active control”.1 But when the gains of the reference drug are modest, as with www.thelancet.com/oncology Vol 16 April 2015