Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN : TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE

PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE

Authors: Irene Dogliotti and Simone Ferrero

Division of Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino and AOU “Città della Salute e della Scienza di Torino”, Torino, Italy

Corresponding Author Simone Ferrero, MD

Division of Hematology Department of Molecular Biotechnologies and Health Sciences - University of Torino AOU “Città della Salute e della Scienza di Torino” Via Genova 3, 10126 Torino, Italy T: +390116334220-6884 F: +390116963737 E-mail: [email protected]

Research Support SF was supported by: Progetto di Rilevante Interesse Nazionale (PRIN2009) from Ministero Italiano dell'Università e della Ricerca (MIUR), Roma, Italy [7.07.02.60 AE01]; Progetto di Ricerca Sanitaria Finalizzata 2009 [RF-2009-1469205] and 2010 [RF-2010-2307262 to S.C.], A.O. S. Maurizio, Bolzano/Bozen, Italy; Fondi di Ricerca Locale, Università degli Studi di Torino, Italy; Fondazione Neoplasie Del Sangue (Fo.Ne.Sa), Torino, Italy; Fondazione Cassa di Risparmio di Torino (CRT, project codes: 2015.1044 and 2016.0677), Torino, Italy; Associazione DaRosa, Torino, Italy.

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Abstract Mature B-cell disorders have recently become highly curable diseases thanks to the introduction of new treatment strategies; nonetheless, despite evidence of complete remission, many patients affected by lymphoma or myeloma eventually relapse and need salvage therapy. Minimal residual disease (MRD) detection and quantification is a powerful tool to evaluate treatment efficacy, to stratify patients, and to predict long-term outcome. In fact, in the current landscape of novel, highly efficacious but toxic and often costly targeted therapies, early identification of factors predictive of treatment response or refractoriness is the key to avoid overtreatment of patients and thus also to reduce costs for health care system. In this article, we reviewed the prognostic role of MRD in , and . We analyzed published clinical studies and available methodologies, and we described the major ongoing studies of MRD-driven tailored treatment in these diseases. Finally, we discussed novel applications and techniques for MRD identification in hematologic malignancies and future directions of MRD-oriented research. In particular, we hypothesized some possible, next-generation, precision medicine trials in lymphoproliferative diseases based on the most promising currently available biomarkers.

Keywords: lymphoma, MRD, PCR, clinical trial, personalized medicine

Acknowledgements The Authors would like to thank the Fondazione Italiana Linfomi (FIL), Marco Ladetto, Massimo Federico, Alessandro Pulsoni, Sergio Cortelazzo, Christiane Pott, Christian Andersen, Steven Le Gouill and Brad Kahl for sharing the information on MRD-driven clinical trials; Luigia Monitillo and Daniela Drandi for their scientific support; the Authors are grateful to Giorgio Schirripa for language assistance.

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1. Background and rationale: is parallel, powerful pre-treatment prognostic personalized therapy needed in tools, mainly based on clinical scores, have lymphoproliferative diseases? been defined. Some examples are the International Scoring System (ISS) in Lymphoproliferative diseases (LPDs) multiple myeloma (MM), Follicular account for around 5% of all human Lymphoma International Prognostic Index malignant neoplastic diseases; in 2014, (FLIPI) and FLIPI2 in follicular lymphoma 70890 new cases of non-Hodgkin (FL) and Mantle Cell Lymphoma (NHL) were reported in the US, International Prognostic Index (MIPI) in which constituted 4% of all new cancers in mantle cell lymphoma (MCL) (5-8). These both male and female patients (1). In 2015, scores are able to divide patients into the Fondazione Italiana Linfomi (FIL) different risk categories, enabling clinicians registered 3002 new cases of lymphoma in to better foresee the prognosis of each Italy, and 15011 cases from 2010 to 2015 patient. Moreover, biological and genetic (http://www.filinf.it/registro-fil). The inci- features, analyzed through highly sensitive dence rises steadily with age, especially after and innovative laboratory techniques, are age 40, but lymphomas are also among the being integrated into new prognostic indexes most common malignancies in patients and appear to impact on patients’ final between the ages of 20 and 40 years. outcome (R-ISS in MM (9), m7-FLIPI in FL Moreover, the incidence of NHL nearly (10) and MIPI-c in MCL (11)). doubled between 1970 and 1995, and it has slowly continued to rise since then by 1.5% - Other advancements in research have 2% each year. Despite the great been made in the evaluation of individual improvements in the past decades, the response to treatments based on the outcome of LPDs is still quite poor, leading morphological and metabolic results of to a mortality of 4% per year in 2010; NHL imaging studies - such as computed ranks as the ninth most common cause of tomography (CT) scans and cancer-related death in men and the eighth in fluorodeoxyglucose-positron emission women in the US (2, 3). Despite evidence of tomography (FDG-PET), performed both transient complete remission, many patients after the first few courses of chemotherapy with lymphoma eventually relapse and need (“interim-PET”) and at the end of induction a salvage therapy; nonetheless, several steps therapy (12-14); but also based on the forward have been made in the last years. identification of minimal residual disease We have recently gained a better insight into (MRD) through highly sensitive methods. the complex biological and pathogenetical MRD can be defined as the smallest number characterization of these neoplasms, which of malignant cells beyond the sensitivity has also led to an improvement in the level of routine laboratory and imaging diagnostic accuracy. For instance, new techniques that potentially remain during or entities of lymphomas with potentially after appropriate therapy, even when the different prognosis and treatment response patient has no clinical sign of disease. MRD have been identified (4); moreover, detection and quantification are used to traditional imaging assays and laboratory evaluate treatment efficacy and to identify analyses (such as multiparameter flow patients at risk of relapse. Therefore, MRD cytometry, MFC) have been considerably can be a valid tool to stratify patients and to improved, and we are now starting to predict long-term outcome (15). determine the biological mechanisms of resistance to conventional therapies. In

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Thanks to the growing information on apoptotic Bcl-2, is able to restore the molecular cell biology in LPDs, new natural mechanism of apoptosis in CLL and targeted treatments have been developed in lymphoma cells and to overcome the last few years. First, immunotherapy was chemotherapy resistance (26). introduced in clinical practice, particularly rituximab and its derivatives, chimeric anti- The landscape of LPD treatment has CD20 monoclonal (MoAb). therefore changed dramatically and several These agents showed to have a great impact different strategies are currently available. In on disease outcome in all kinds of B-NHL the future, in selected patients, LPDs may and in chronic lymphocytic (CLL), likely become chronic diseases requiring as compared with standard chemotherapy continuous oral, well-tolerated, non- alone (16, 17); oral immunomodulatory chemotherapy agents as maintenance or agents, such as lenalidomide, were first consolidation treatment, while upfront high- approved for MM but were later found to be dose conventional chemotherapy may highly effective as single-agent therapy also remain an option for younger patients with in relapsed/refractory aggressive and highly aggressive diseases. Of note, safety indolent B-cell NHL, including MCL, concerns can arise also with targeted diffuse large B-cell lymphoma (DLBCL), therapies: toxicities can still occur, and FL, because they have direct and especially with continuous therapy and in indirect effects on malignant cells (18). patients receiving multiple drugs for pre- existing comorbidities. The costs of these The approval of oral, non- new agents is also a matter of debate: due to chemotherapeutic agents represents the latest the limited resources of many health care innovation in molecular targeted treatment; systems, selection of patients who will for instance, ibrutinib is a Bruton's tyrosine benefit more from high-cost medications kinase (BTK) inhibitor active on the B-cell will be critical from both ethical and receptor (BCR) signalling pathway, a critical economical points of view. Therefore, early mechanism in the survival of these prediction of treatment response or malignancies. This agent has shown refractoriness is the key to avoid promising activity in certain subtypes of overtreatment of patients and unnecessary DLBCL, in CLL, in relapsed or refractory toxicities, while reducing the costs for health MCL and in Waldenström’s Macro- care systems. A more personalized approach globulinemia (WM), for which it has including newest compounds and aiming at recently received FDA approval (19-23). achieving long-term benefits is therefore Idelalisib, an oral inhibitor of PI3K δ, needed in lymphoma. employs a similar strategy to target the BCR signalling pathway and thus the growth and Among all the available biomarkers survival of malignant B-cells. It has been potentially impacting on clinical outcome, shown to be highly active in relapsed and post-treatment MRD analysis is one of the extensively pre-treated indolent B-NHL, few predictive tools validated in large particularly in a subset of FL patients (24). prospective trials (27-29); therefore, MRD is Combined with rituximab, idelalisib currently the most mature biomarker that can significantly improved progression-free be used to tailor treatment, and it is already survival (PFS) and overall survival (OS) of under evaluation in precision medicine trials relapsed CLL patients with significant in LPDs (30). coexisting medical conditions (25). Finally, In this article, we reviewed the venetoclax, a powerful inhibitor of the anti- prognostic role of MRD in mature LPDs. We

Copyright 2017 KEI Journals. All Rights Reserved Page │4 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE analyzed the methodologies and results from Translocation Cluster” breakpoint, MTC) published clinical trials, and major ongoing relative to t(11;14) due to the widely clinical trials of MRD-driven tailored disperse breakpoint region on BCL1 locus treatment in LPDs. Finally, we addressed (36-38). novel applications and techniques for MRD identification in hematologic malignancies, On the other hand, antigen-receptor and we discussed future directions of MRD- rearrangements of the immunoglobulin oriented research. In particular, we heavy chain (IGH) gene are a widely hypothesized some possible, next- applicable clonality and MRD marker in generation, precision medicine trials in LPDs B-cell disorders. The allele-specific based on the most promising currently oligonucleotide PCR (ASO-PCR) used in available biomarkers. this kind of assay is in fact based on the generation of the specific DNA sequence of the V(D)J junctional region, encoding the 2. Current molecular methods for variable domains of immunoglobulin minimal residual disease (MRD) detection molecules, and this is characteristic of each B-lymphocyte. This occurs during the Real-time quantitative polymerase physiological recombination processes, first chain reaction (RQ-PCR) is currently the in pre-B lymphocytes, and later during the most employed technique for MRD germinal center somatic hypermutation detection in LPDs (with the exception of events. The random insertion and deletion of MFC in MM) (31) and it has been fully nucleotides during this process determine the standardized in the multinational context of “fingerprint-like” sequences of the junctional the EuroMRD group (32). PCR assays are regions of IGH genes, which differ in each based on the amplification of a tumor- lymphocyte and, as a consequence, in each specific molecular marker; primers and lymphoid malignancy (35). Therefore, probes are designed from a chosen DNA junctional regions of malignant lymphoma sequence, which in mature B-cell disorders cells can be used as tumor-specific targets essentially belongs to two categories, i.e. for PCR-based MRD analysis, particularly in chromosomal translocations and antigen- MCL and MM. Indeed, in MCL and MM, receptor rearrangements (15). Tumor neoplastic cells derive from mature B-cells translocation markers, being the hallmark of that do not undergo a continuous somatic lymphoma, remain stable during the natural hypermutation process, in contrast to what history of the disease and are therefore a happens in FL. However, the rate of reliable MRD target; however, often only a successful IGH sequencing is not uniform portion of patients displays a detectable across different histologies - ranging from translocation marker. BCL2/IGH 65-85% in MCL (27, 37, 38) to 50% in MM rearrangement relative to t(14;18) is (39-41) - and, although IGH-based ASO- currently detectable by primers targeting the PCR has a very good sensitivity, it requires Major Breakpoint Region (MBR) and minor the development of patient-specific reagents. breakpoint region (mcr) in no more than 50- Therefore, it is a complex, time consuming 55% of FL (28, 33), and a number of and expensive assay (15). "minor" breakpoints might account for another small percentage of cases (34, 35). Despite the described current Similarly, in MCL only 30-40% of patients limitations, the standardized RQ-PCR is the can be currently monitored through most employed tool for MRD monitoring, at BCL1/IGH rearrangement (“Major least in MCL and FL. It relies on

Copyright 2017 KEI Journals. All Rights Reserved Page │5 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE translocation-derived markers and on IGH to contaminations and still highly dependent rearrangements, which have slightly on ASO-primers (15, 28, 38). Finally, new different performances and can be done both technologies for MRD monitoring have been on bone marrow (BM) and on peripheral introduced in the last few years, and they are blood (PB) samples (15, 32). Nevertheless, likely to overcome some limits of the ASO- many groups continue to perform both RQ- qPCR approach. PCR and nested, qualitative, PCR for MRD monitoring (29, 30, 37). This latter approach Figure 1 describes the main nested and is simpler, faster and slightly more sensitive; RQ-PCR approaches for MRD in mature however, it is less standardized, more prone LPDs.

3. Clinical impact and predictive availability of the MBR and mcr BCL2/IGH role of minimal residual disease (MRD) in rearrangements for nested-PCR analysis in mature B-cell lymphoproliferative more than half of patients. The seminal study disorders by Gribben et al. was the first that demonstrated that anti B-cell monoclonal 3.1. Follicular lymphoma antibodies could induce immunologic ex In the mid-1980s, FL was the first vivo purging of BM by residual lymphoma lymphoma to be studied for MRD due to the cells before autologous stem cell

Copyright 2017 KEI Journals. All Rights Reserved Page │6 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE transplantation (ASCT) (33). Moreover, the negativity and subsequently prolonged PFS absence of detectable MRD in BM after (38.4 v 8.2 months, P < 0.01) (47). purging was strongly associated with an advantage in long-term disease-free survival Many studies showed that MRD (DFS) after ASCT (33). An update of this evaluation before and after ASCT may study with 12 years of follow-up further predict disease outcome in FL patients. In confirmed that MRD positivity was an the pre-rituximab era, among indolent independent adverse predictor of lymphoma patients treated with an progression-free survival (PFS), Hazard intensified high-dose chemotherapy program Ratio (HR) 4.18, 95% CI 1.99-8.8 followed by ASCT, the achievement of post- (p = 0.0002) (42). ASCT molecular remission (MR) was common in patients with FL subtype (70%); Since then, many studies have been the incidence of relapse was markedly lower published on the role of MRD in FL and in patients with durable MRD negativity various prospective clinical trials have been compared with patients who had never designed including MRD analysis as attained MR (8% vs 88%, P < 0.005) (48). secondary endpoint. The first studies Of note, the predictive value of the reported on the ability of novel treatment achievement of MR was repeatedly strategies (such as ASCT and new MoAbs) confirmed, independently of treatment. A to induce MRD clearance in comparison to randomized multicenter study of 136 standard chemotherapy. Standard patients compared 6 courses of R-CHOP chemotherapy alone was not able to with rituximab-supplemented, high-dose, eradicate disease from the PB or BM in the sequential chemotherapy with autografting majority of patients (33, 43), whereas (R-HDS) as first-line therapy in high-risk FL rituximab as single agent or rituximab- patients. MR was achieved in 44% of R- chemotherapy led to a clearance of CHOP and 80% of R-HDS patients (P < BCL2/IGH-positive cells in most patients 0.001) and was predictor of PFS: the (44, 45). Rambaldi et. al evaluated the outcome of patients achieving MR was BCL2/IGH status in BM and PB of 86 FL similar regardless of treatment (29). Similar patients treated with either CHOP or a results were reported in the prospective, sequential R-CHOP scheme: with a median phase III FOLL05 trial (NCT00774826), follow-up of 56 months, the freedom from where untreated FL patients were recurrence (FFR) of MRD negative patients randomized to receive either R-CVP, was 64% as compared to 32% for MRD R-CHOP or R-FM conventional chemo- positive patients (P < 0.006) (43, 46). In immunotherapy. PFS correlated significantly another study including patients treated with with PCR status, with a 3-year PFS of 66% mitoxantrone, chlorambucil and prednisone for MRD negative cases versus 41% at 12 (MCP) ± rituximab, the addition of months for MRD positive cases, respectively rituximab led to a rapid eradication of (P=0.015), and 84% versus 50% at 24 circulating lymphoma cells, with improved months (P=0.014). The prognostic value of clinical response and event-free survival MRD at these time points was confirmed (EFS) for patients with a reduction ≥2 log also in multivariate analysis, regardless of (44). Finally, radio-immunotherapy treatment (49). Even among elderly patients consolidation of complete or partial response receiving a short chemo-immunotherapy with (90)Y-ibritumomab tiuxetan also course plus rituximab consolidation, both the induced high rates of conversion to MRD prognostic role of MRD and the clearing activity of rituximab were confirmed.

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Ladetto et. al investigated the role of tested in large, first-line clinical trials for FL rituximab maintenance after first-line patients. These trials will be extensively chemo-immunotherapy with rituximab, described in the next chapter of the review. fludarabine, mitoxantrone, dexamethasone in elderly patients with advanced FL. 3.2. Mantle cell lymphoma BCL2/IGH MRD was extensively determined on BM cells in a centralized In the pre-rituximab era, molecular Euro-MRD laboratory and conversion to remissions could not be obtained in MCL PCR negativity predicted PFS at all post- patients treated with chemotherapy alone; treatment time points (3-year PFS, 72% vs this was consistent with the extremely poor 39%; P < .007) (28). prognosis of these patients, especially when compared to the better scenario observed in More recently, the first prospective FL (48, 59). The prognosis of MCL patients MRD data on the widely used changed substantially thanks to the Bendamustine-rituximab (BR) regimen have introduction of sequential high dose been published by the StiL group. Zohren et. chemotherapy in to clinical practice, in al prospectively studied PB BCL2/IGH particular with cytarabine and rituximab – levels in 173 first-line FL patients enrolled which for the first time proved to be able to in the multicenter phase III clinical trial induce a MR (60, 61). A subsequent RQ- NHL1-2003 comparing BR with R-CHOP PCR study on a prospective series was (50). Although only 92 patients had a performed in 29 MCL patients treated with follow-up sample analyzed (53% of the high dose chemotherapy + total body entire series, 48 in the BR arm and 44 in the irradiation (TBI), followed by ASCT. MR R-CHOP arm), conversion to post treatment after ASCT was a strong predictor of MRD negativity was observed in 78 of 92 improved outcome, with a median PFS of 92 patients (85%). Irrespective of the study arm, months in the MRD negative group versus MRD positivity was associated with shorter 21 months in the MRD positive group PFS (HR, 3.15; P=0.002) (51). Similar (P < .001). These data were also confirmed impressive data on the potential of BR-like in multivariate analysis (62). regimes in MRD clearance have been recently presented both in prospective and In the larger phase II Nordic MCL2 retrospective series (52, 53). Finally, the trial, 160 young untreated patients received a high activity of bendamustine in MRD dose-intensified induction therapy with R- clearance has been recently reported in the maxi-CHOP alternating with R-high-dose large, prospective, patients series of the cytarabine, followed by ASCT conditioned GADOLIN (NCT01059630) and GALLIUM with BEAM or BEAC scheme (carmustine, (NCT01332968) phase III trials, along with etoposide, cytarabine, and melphalan/ the first clues of a deeper MRD clearing cyclophosphamide), with in vivo purging of potential of the new anti-CD20 MoAb GA- peripheral blood stem cells (PBSC). This 101 in comparison to rituximab (54, 55). approach produced long-term PFS and a significantly higher proportion of MR and Based on the dismal prognostic role of PCR-negative stem cell products as MRD persistence or reappearance and on the compared with the MCL-1 trial (high dose demonstrated potential MRD-reverting CHOP followed by ASCT) (37). activity of rituximab in FL and MCL (30, 56-58), MRD-driven pre-emptive strategies High rates of MR have been observed have been designed to be prospectively in all the subsequent clinical trials containing

Copyright 2017 KEI Journals. All Rights Reserved Page │8 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE rituximab and cytarabine, and an advantage patients (9 MCL and 9 FL); 23 cases of in time to treatment failure (TTF) was also M-rel or MRD persistence were reported and observed in the randomized, phase III were treated with rituximab, which European MCL Network (EuMCLNet) re-induced MR in 17/23 cases. PFS after pre- “Younger” trial (63-65). In particular, emptive treatment was 64% at a median prospective quantitative MRD monitoring follow-up of 6 years (57). A prospective was a secondary endpoint of the two analysis of the efficacy of pre-emptive EuMCLNet phase III trials, namely the treatment was conducted in the Nordic “Younger” and the “Elderly”. The pooled MCL-2 trial, in which a significant (5-fold) MRD data showed that after rituximab-based increase in the RQ-PCR detectable MRD induction treatment, 106 of 190 evaluable level in two consecutive BM or PB samples patients (56%) achieved MR on PB or BM defined M-rel. In case of M-rel with samples; MR resulted in a significantly increasing MRD levels, patients were improved response duration (RD), and offered pre-emptive treatment with emerged to be an independent prognostic rituximab 375 mg/m2 weekly for 4 weeks. factor for RD (hazard ratio 0.4, P .028), Twenty-six patients underwent pre-emptive independently of clinical response, both treatment, and MR was again achieved in before ASCT (in MCL Younger) and during 92%. Median molecular and clinical relapse- maintenance (in MCL Elderly) (27). MRD free survival after pre-emptive treatment thus proved to be a powerful predictor of were 1.5 and 3.7 years, respectively (30, 67). outcome in large prospective studies, both in young and in elderly patients, and in the Both PB and BM are adequate tissues context of ASCT, both pre-transplant and for MRD detection in MCL, but PB showed during post-transplant follow-up. MRD to have a faster disease clearance. Therefore, persistence or reappearance, on the other M-rel in PB is highly predictive of upcoming hand, was associated to a shorter median clinical relapse (11, 66). time to relapse (18 months) (66). Finally, recent trials in MCL employ On the basis of the prognostic MRD to describe the depth of response to relevance of MR, pre-emptive strategies novel treatment schemes and agents, such as were therefore tested in small retrospective lenalidomide, bendamustine and bortezomib trials (56, 57) and in one phase II study to (68-71). obtain MR re-induction, and indirectly to improve PFS (30, 67); in a study by Ladetto 3.3. Multiple myeloma et al., patients experiencing a molecular relapse (M-rel) after R-HDS induction The role of MRD monitoring in MM is therapy, defined as PCR positivity in 2 more recent than in lymphoma; until the consecutive samples in the absence of introduction of “new drugs”, the clinical relapse, were treated with 4 courses achievement of CR was not common in MM of rituximab plus 2 additional infusions if patients and the MRD-negativity status was PCR remained positive, and monitored by often confined only to the small group of nested qualitative PCR and RQ-PCR. After patients undergoing allogeneic 4-6 courses of rituximab, all 4 patients transplantation (40, 72, 73). Moreover, achieved again a MR, and no clinical because of the elevated somatic relapses were recorded at 3, 6, 18, and 62 hypermutation rate of the IGHV gene in months from rituximab re-treatment (56). MM, it was difficult to get a reliable This study was later extended to another 18 molecular marker for MRD studies in a large

Copyright 2017 KEI Journals. All Rights Reserved Page │9 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE subset of patients (41, 74, 75). Therefore, Finally, MRD has recently been used to multicolor (MFC) on BM evaluate the effect of maintenance therapies, samples was the most widely used method to such as lenalidomide (41). detect MRD in MM, and despite a slightly inferior sensitivity, it was more widely Differently from FL and MCL, much applicable than PCR-based technologies (31, less data are available about MRD 74, 76). monitoring on PB samples in MM, as only small numbers of clonal plasma cells can be After the introduction of the novel, detected in PB by sensitive approaches. In non-chemotherapeutic agents (namely the largest retrospective study, MRD by RQ- thalidomide, bortezomib and lenalidomide) PCR was evaluated in 42 MM patients in the 2000s, CR rates have dramatically undergoing high-dose therapy followed by increased, even among transplant-ineligible ASCT as first-line therapy. The MRD level patients (77). Consequently, MRD studies of PB samples was in median 40-fold lower acquired a new importance, both to describe than in paired BM samples. Nonetheless, depth of response achievable with the new patients with MRD negativity at early time drugs and to predict outcome in these points after ASCT (3 months) had a patients. Ladetto et al. firstly described in a prolonged median EFS and OS (52 vs 17 clinical trial the occurrence of durable MRs months; p=0.03). Importantly, sequential in a subset of MM patients achieving at least monitoring of MRD levels in PB was able to very good partial remission after ASCT and predict disease progression in 19 of 29 receiving a bortezomib, thalidomide, and patients (66%) (79). dexamethasone (VTD) consolidation (39). MR rates in BM by nested PCR increased Recently, thanks to the development of from 3% after ASCT to 18% after VTD, and next-generation sequencing (NGS) consolidation was able to induce a reduction techniques, the feasibility of molecular MRD in tumor burden of more than 4 logs by RQ- monitoring has increased and it can be PCR; notably, patients with a MRD value applied to the majority of MM patients (80, lower than the median had significantly 81). Indeed, many ongoing clinical trials are improved outcomes (PFS 100% vs 57%; currently investigating the anti-MM activity P < .001). Mature results of this study after of many new targeted compounds (such as 93 months of median follow-up reported a carfilzomib and daratumumab) by measuring superior OS for patients with MR (72% vs the MRD shrinkage induced by these drugs 48% at 8 years, P = 0.041) and showed that (e.g. in the “FORTE study”, NCT02203643, MRD relapse predicts clinical relapse, with a combining carfilzomib with lenalidomide or median lag between MRD reappearance and cyclophosphamide in newly diagnosed MM salvage treatment of 9 months (78). Similar patients eligible for ASCT). In a small phase results were reported by the Spanish group II trial in newly diagnosed MM patients on 170 patients enrolled in three consecutive treated with carfilzomib-lenalidomide- clinical trials. The first wide comparison dexamethasone, 12-month PFS for MRD- between PCR and MFC was performed in negative vs MRD-positive status by MFC this study, with a good correlation between and NGS was 100% vs 79% (p<0.001) and the two techniques (r=0.881, P<0.001). 100% vs 95% (P = 0.02), respectively (82). Among patients in CR (n=62), PCR was able Finally, to determine the ability of the new to identify two risk groups with different anti-CD38 MoAb daratumumab to further PFS (49 vs 26 months, P=0.001) and OS clear the neoplastic clone beyond CR, MRD (not reached vs 60 months, P=0.008) (74). was assessed on BM by ClonoSEQ™ NGS-

Copyright 2017 KEI Journals. All Rights Reserved Page │10 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE based assay in two large phase III studies, to a lower risk of progression in CASTOR (daratumumab-bortezomib-dexa- MRD-negative patients, even in high-risk methasone versus bortezomib-dexa- subjects (83). methasone) and POLLUX (daratumumab- lenalidomide-dexamethasone versus lena- Table 1 reports the most important lidomide-dexamethasone): daratumumab in published clinical trials assessing the combination with standard of care prognostic role of MRD by classical significantly improved MRD-negative rates molecular methods in mature B-cell at all sensitivity thresholds, leading lymphoproliferative disorders.

4. Ongoing MRD-tailored clinical is to evaluate whether, after conventional trials in mature LPD chemo-immunotherapy, a FDG-PET and MRD response-based maintenance therapy 4.1. Phase III, randomized, FOLL12 with rituximab is not less effective in terms clinical trial of PFS than a standard maintenance in FOLL12 (EudraCT number: 2012- patients with untreated, advanced FL; 003170-60) is a multicenter, phase III, primary objective is to evaluate efficacy of a randomized study sponsored by FIL; its aim response-adapted strategy in defining

Copyright 2017 KEI Journals. All Rights Reserved Page │11 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE maintenance therapy (“personalized by the two standard doses of rituximab 250 medicine”). mg/m²) (90), followed by rituximab maintenance (375 mg/m² every 2 months) This trial started recruitment in 2013 for the remaining 11 infusions. On the and, as of January, 2017, it randomized 595 contrary, experimental arm FDG-PET of the 810 planned patients. Patients with negative (Deauville score 1-3) patients, naïve, previously untreated FL, stage II-IV, defined as low-risk, are further divided into Follicular Lymphoma International two subgroups according to their MRD Prognostic Index 2 (FLIPI2) >0 requiring a status, based on nested-PCR results: MRD therapeutic intervention (according to the negative patients do not receive maintenance GELF criteria) (84, 85) are randomly therapy and are followed up with MRD assigned in a 1:1 ratio to either standard or monitoring every 6 months for two years experimental arm. At baseline, patients are (both PB and BM), whereas MRD positive assessed for molecular BCL2/IGH status patients undergo a cycle of pre-emptive (both major and minor rearrangements) on rituximab therapy with four weekly doses of PB and BM (33, 35) and staged by CT scan rituximab (375 mg/m²) (57). Pre-emptive and FDG-PET scan. (86) Both arms receive treatment should also be repeated in case of induction therapy with either 6 cycles of R- persistent MRD positivity after pre-emptive CHOP followed by 2 additional doses of 2 rituximab or subsequent MRD reappearance rituximab or 6 cycles of BR 90 mg/m plus 2 in MRD negative patients, for a maximum of rituximab courses (at physician discretion). three courses in total. Patients without a At the end of chemo-immunotherapy (“end molecular marker who are FDG-PET of induction”), all patients are assessed for negative do not receive further treatment and disease response by common clinical and are followed up every 6 months without laboratory examinations, CT scan, FDG-PET MRD assessments (see Figure 2). (centrally revised) and BCL2/IGH MRD both on PB and BM, both by qualitative nested PCR and by quantitative RQ-PCR, 4.2. Phase II, multicenter, MIRO’ according to Euro-MRD guidelines (only for clinical trial patients with a molecular marker at The MIRO’ (Molecularly Oriented diagnosis) (32, 35). Immuno-Radio-therapy) study (EudraCT In both arms, patients with stable or number: 2012-001676) is a FIL-sponsored progressive disease (PET positive and less phase II prospective multicenter study for than PR on CT scan) can be assigned to stage I/IIA FL. It aims to evaluate whether a salvage treatment, at physician’s pre-emptive therapy with the new anti-CD20 discretion. In the standard arm, patients monoclonal ofatumumab is able to responding to induction therapy receive reduce or eliminate MRD after conventional standard maintenance with rituximab 375 treatment with local radiotherapy of the mg/m² every 2 months for 2 years. In the involved site(s), which is the current experimental arm, patients with a standard of care in patients with localized FL positive FDG-PET scan (Deauville score 4- (91). This trial started the recruitment in 5) (87-89), regardless of MRD status, are 2015 and, as of January 2017, it enrolled 52 defined as high-risk group and therefore of the 110 planned patients. receive intensified consolidation with radio- 90 In this trial, all the enrolled patients, immunotherapy: a single dose of Y grade 1-3a, stage IA/IIA FL without bulky ibritumomab tiuxetan 0.4 mCi/kg (preceded disease, are assessed for BCL2/IGH status

Copyright 2017 KEI Journals. All Rights Reserved Page │12 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE on PB and BM samples at baseline; they are treatment in adult patients with advanced all treated with involved-field radiotherapy MCL. (IFRT) at doses of 24 Gy in 12 fractions; after radiotherapy, patients lacking a An induction phase with 3 cycles of molecular marker on baseline BM or PB do R-CHOP21 and high-dose (HD) not receive further treatment, but are R-cyclophosphamide was followed by a followed every 3 months without further consolidation phase with 2 cycles of MRD detection. BCL2/IGH positive patients R-HD-Ara-C and a BEAM/FEAM- at baseline are re-staged after radiotherapy conditioned ASCT. Patients achieving at with physical examination, laboratory least partial response were randomized to analysis and MRD evaluation on PB and maintenance with lenalidomide (15 mg once BM. MRD-negative patients stop study daily on days 1-21, every 28 days, for two treatment, while MRD-positive patients years) or observation. IGH-based or receive ofatumumab for 8 weekly doses of BCL1/IGH MRD was examined both on PB 1000 mg total dose: after ofatumumab and BM by ASO qualitative nested PCR and therapy, patients who are still MRD-positive by quantitative RQ-PCR at different time do not repeat treatment. Patients who points: at diagnosis, after R-HD- become MRD-negative are followed with cyclophosphamide, on CD34+ cell harvests, BCL2/IGH detection every 6 months for 3 before and after ASCT, during years: in case of subsequent MRD maintenance/observation and during follow- conversion from negative to positive, up every six months, according to Euro- treatment with ofatumumab is permitted MRD guidelines (only for patients with a maximum twice, with the same schedule molecular marker at diagnosis) (32, 35). (see Figure 2). The primary objective of the According to the well-known activity study is the MRD negativity after of cytarabine in MCL (60, 61), a CD34+ cell ofatumumab: the effectiveness of anti-CD20 harvest is performed after the first course of monoclonal antibody treatment will be R-HD-Ara-C and tested for MRD; a second determined by the proportion of harvest is performed after the second R-HD- negativization of residual BCL2/IGH Ara-C course, only if the first harvest is still positive cells after radiotherapy, evaluated MRD positive (or if the harvest is not by qualitative and quantitative PCR MRD adequate or the patient has no molecular detection. Secondary endpoints include marker for MRD detection) (see Figure 2). clinical response rate, overall, partial and complete response rate, PFS and relapse free The recruitment of the planned 300 survival. patients was completed in August, 2015 and the second interim analysis of the clinical 4.3. Phase III, randomized, results is currently ongoing (as of January, MCL0208 clinical trial 2017). According to the results of the first interim analysis on 260 enrolled patients, a MCL0208 (NCT02354313) is a molecular MRD marker was found in 87% multicenter, phase III, randomized study, of cases: molecular responses after ASCT sponsored by FIL; its aim is to compare were 79% and 50% by nested PCR and 86% lenalidomide maintenance vs observation and 73% by RQ-PCR, on PB and BM, after an intensified induction regimen respectively (65). Importantly, MRD containing rituximab followed by high-dose determination on the first CD34+ cell chemotherapy and ASCT as first line harvest allowed to spare a second

Copyright 2017 KEI Journals. All Rights Reserved Page │13 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE leukapheresis in 147 out of 182 patients the clinical impact of such MRD-driven (81%), further confirming that the use of strategy on patients’ outcome will be better rituximab in combination with high-dose clarified only when more mature data from cytarabine represents a very effective in vivo this trial is available. purging method in MCL patients. However,

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4.4. Other current and planned at 30 months without clinical progression, MRD-driven clinical trials in mature single agent ibrutinib therapy is continued LPDs. for another 12 months. In MRD-negative patients at 30 months no further treatment is The ALTERNATIVE study given, while MRD monitoring should be (NCT02689869) is a prospective, single-arm continued. multicenter phase 2 study, sponsored by the German Low Grade-lymphoma Study Group The ACVDL trial (EudraCT number: (GLSG) in up to 98 subjects with advanced 2011-002751-34) is an open-label phase II stage, previously untreated FL and with high study sponsored by the Vejle Hospital, in tumor burden requiring treatment. The Denmark. The study is conducted in newly primary objective is to evaluate the efficacy diagnosed MM patients and investigates the of the chemotherapy-free combination of efficacy and safety of the combination of ibrutinib and obinutuzumab (GA 101) in this doxorubicin, cyclophosphamide, borte- subset of patients. Primary endpoint is the zomib, dexamethasone and lenalidomide, rate of PFS at 12 months. This trial started followed by consolidation therapy with recruiting patients in April 2016 and aims to bortezomib for subjects who are not in enroll 98 patients. The hypothesis of this molecular CR (mCR). (92) study is that ibrutinib in combination with obinutuzumab will achieve PFS, response This trial started in November 2011, rates and rates of MRD negativity and it has now completed its recruitment, comparable to currently used chemotherapy- with 35 enrolled patients. All patients were containing regimens, such as R-CHOP or assigned to receive at least four cycles of BR. According to the trial design, patients ACVDL in the following combination: receive 6 initial cycles of Ibrutinib 560 mg doxorubicin 50 mg/m2 IV day 1, once daily every day until start of cyclophosphamide 750 mg/m2 IV day 1, maintenance for a total of 24 weeks, in bortezomib 1.3 mg/m2 IV day 2 and 9, association to obinutuzumab 1000 mg I.V. dexamethasone 20 mg PO day 2, 3, 9 and 10 on days 1, 8, 15 of cycle 1 and on day 1 of and lenalidomide 15 mg PO day 1-14 in a cycles 2-6. In patients in clinical remission 21-day cycle. Transplant-eligible patients after the last induction cycle, maintenance proceeded with standard ASCT after four consists of additional 24 months of ibrutinib cycles. Patients not eligible for ASCT plus GA101: Ibrutinib 560 mg/day, and received four additional cycles of ACVDL, GA101 1000 mg I.V. every 2 months for a for a total of eight cycles of ACVDL. total of 24 months. The total duration of Therefore, 18 patients received four ibrutinib plus obinutuzumab therapy is induction cycles of ACVDL followed by therefore 30 months. ASCT and 11 patients received eight induction cycles of ACVDL. In case of According to protocol, MRD central MRD positivity detected by ASO-PCR on molecular monitoring should be regularly BM after induction therapy (both ASCT and performed on PB samples collected before non-ASCT arms) patients who did not attain the start of therapy and at 3, 6, 9, 12, 18, 24 the mCR were offered five cycles of and 30 months. Subsequently, MRD consolidation therapy with subcutaneous analyses are performed every 6 months until bortezomib 1.6mg/m2 day 1, 8, 15 and 22 in clinical progression of the disease or for a a 35-day cycle. Out of 23 candidates, 19 maximum of 4 years (until the end of the patients followed this option, and response study). In patients remaining MRD positive improved in 4 of them (1 SD → CR and 3

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PR → VGPR). In 12 patients treatment The EA4151 trial by the ECOG response was unchanged, and 3 patients (Eastern Cooperative Oncology Group) experienced disease progression. There was intergroup in MCL is a randomized phase III no difference in PFS among patients who trial comparing ASCT consolidation received consolidation therapy and those followed by rituximab maintenance vs. who did not, and the median PFS was 785 rituximab maintenance alone for patients and 581 days, in the two groups respectively with MCL in MRD-negative first CR. [HR 0.96 (95% CI: 0.32;2.91); log-rank Tumor tissue from initial diagnostic biopsy p=0.94 (Christian Andersen, personal will be tested in a central laboratory with the communication). highly sensitive ClonoSEQTM assay (Adaptive Biotechnologies, Seattle, WA, The LyMa101 trial (NCT02896582) is USA) (83); “no marker” patients will receive a multicentric, single arm phase II trial, high-dose chemotherapy and ASCT sponsored by LYSARC (The Lymphoma followed by 2 years of rituximab Academic Research Organization), aiming at maintenance; all patients with a molecular evaluating the efficacy of upfront marker will receive induction therapy; at obinutuzumab (GA101) plus a cytarabine- post-induction restaging, MRD-positive containing regimen, ASCT and a subsequent patients in CR or PR will undergo ASCT + MRD-driven GA101 maintenance in rituximab maintenance, while MRD- younger MCL patients. Treatment consists negative patients in CR will be stratified of 4 cycles of GA101-DHAP every 21 days, using the MIPI-c score and randomized followed by ASCT conditioned with between ASCT plus rituximab maintenance GA101-BEAM; GA101 maintenance is or rituximab maintenance alone. Patient administered every 2 months for 3 years, enrollment is expected to begin in April then when requested according to MRD 2017; estimated sample size will be 689 persistent positivity or reappearance. The patients enrolled in the US and Canada. primary objective of this study is the rate of (Brad Kahl, personal communication) MRD negativity on BM after induction therapy. The LyMa101 trial started in A summary of the ongoing MRD- November 2016 with an estimated driven trials in mature LPD is described in enrollment of 83 MCL patients. Table 2.

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5. Future directions of MRD studies: increasing the number of molecular targets; novel tools, tissues, and entities b) validating the impact of alternative tissue sources, other than BM and PB; c) Despite the described robust demonstrating MRD predictive value in prognostic value in MCL (27) and FL (28), NHL, besides FL and MCL. overall MRD analysis in NHL is not yet used in clinical practice for several reasons. In this scenario, recent technical Firstly, NHL involves multiple sites and not developments offer major opportunities. In exclusively PB and BM; secondly, available particular, "next generation" MRD assays MRD studies have focused only on some with broader applicability, increased NHL subtypes (mainly FL and MCL); reproducibility, reduced labor-intensiveness finally, current MRD tools are complex and and high standardization potential, are under not applicable to all patients. Actually, MRD development. These include droplet-digital detection has substantial advantages over PCR (ddPCR), NGS-based assays and use of alternative disease monitoring tools alternative molecular targets. Indeed, ddPCR (including novel imaging) in terms of safety, will be rapidly implemented in the routine sensitivity, length of event anticipation and MRD diagnostics of NHL. Based on recently costs. However, to become a strategic tool published results, this tool - relying on for treatment personalization in NHL, absolute rather than relative quantification of substantial implementation is needed, tumor invasion - correlates very well with particularly in terms of: a) developing the standardized RQ-PCR and is able to simpler and more applicable tools and overcome some of its intrinsic limitations,

Copyright 2017 KEI Journals. All Rights Reserved Page │18 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE allowing more patients to be studied for system lymphoma (PCNSL) (104), stage I MRD, particularly those with low-infiltrated FL or WM (105); finally, it is likely to baseline tumor samples or with no available decrease or avoid invasive diagnostic MFC data (93). procedures (BM biopsy or lumbar puncture) to monitor MRD. Moreover, NGS does not rely on patient-specific reagents, and it might All these advances in MRD provide more standardized approaches in methodology will play a central role in the routine diagnostics. NGS can find an development of future, no-profit clinical immunoglobulin-based MRD marker in the trials aiming at investigating tailored majority of patients, it can reach higher treatment options in multiple NHL subtypes. sensitivity levels and is a valid strategy to describe tumor clonal heterogeneity and evolution (80, 81, 94, 95). In addition, other 6. Conclusions NGS-based techniques, such as targeted- MRD monitoring in lymphoma is locus amplification (TLA), can provide a essential to offer patients tailored therapies, newly identified, translocation-based MRD based on their specific risk of relapse. Many marker in patients without an IGH-derived national research groups are already carrying molecular marker, and may help to perform out clinical trials to optimize treatment, MRD analysis on subsequent follow-up mainly in FL and MCL, and, in such studies, samples (96, 97). consolidation and maintenance therapies are Finally, alternative DNA sources, such modulated on the basis of the patient’s MRD as plasma, urine and cerebrospinal fluid, can profile (Table 2). allow a polidistrectual MRD analysis, Such strategies not only represent an targeting the circulating tumor DNA opportunity for patients, as they can (ctDNA), which will widen the MRD substantially improve quality of life, but they application in most NHL subtypes. CtDNA can also reduce costs for the national is already employed in molecular oncology healthcare system (105, 106). The need to to investigate the most common driving best use novel agents has certainly led to a mutations of solid tumors, in order to target growing interest in tailored treatment. In specific treatments (98). In hematology, the fact, by selecting the best drug and feasibility of ctDNA detection and appropriate combinations for each patient, monitoring has been already retrospectively physicians can be able to reduce toxicities proven in aggressive, non-leukemic tumors, and costs. In addition, imaging studies and such as DLBCL and HL (99-101). several biomarkers are being investigated as Therefore, ctDNA analysis might overcome possible prognostic factors, and they may some limitations of the current MRD considerably improve stratification of approach in NHL. First, it can avoid false- lymphoma patients at diagnosis. negative MRD results: as ctDNA gives a better representation of tumor masses Ideally, future clinical trials should (lymph nodes) rather than leukemic disease, include a two-step approach for risk ctDNA might help in localized relapses, not stratification, in order to build up a real detectable either in PB or in BM; in addition, personalized medicine for lymphoma it may extend the application of MRD to (Figure 3). The first step of such non- or less leukemic disorders, such as stratification may consist in a thorough DLBCL (102, 103), primary central nervous baseline risk evaluation, which takes into

Copyright 2017 KEI Journals. All Rights Reserved Page │19 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE account conventional prognostic scores, be extended thanks to their progressive novel imaging data (e.g. the PET-derived standardization and growing applications. Total Metabolic Tumor Volume, TMTV) Both MRD and FDG-PET will become (106) and novel biomarkers that can predict fundamental in the treatment decision- disease aggressiveness and response to making process at the end of induction targeted treatments. Therefore, novel therapy: based on these tools, clinicians may interventional trials could include different choose subsequent treatments, ranging from treatments for different risk groups: simple observation to consolidation and intensified treatments, including molecularly maintenance strategies with emerging drugs. targeted compounds, could be used for high- risk patients, while less intense strategies In conclusion, personalized medicine could be adopted for low-risk cases. The represents the next step in the treatment of second step of risk stratification may consist mature B-cell diseases. A deeper in a re-evaluation of the relapse risk after understanding of the molecular mechanisms induction treatment: disease restaging will in each individual tumor can be achieved become more and more MRD-centered, thanks to a “total prognostic assessment” thanks to the increase in feasibility and approach. In the near future, such approach sensitivity of laboratory techniques. will be crucial to offer tailored and effective Moreover, the role of metabolic response by therapies to patients with highly FDG-PET and other new imaging tools will heterogeneous diseases like lymphoma.

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Lymphoma Group. Blood. 43. Rambaldi A, Lazzari M, Manzoni C, 2008;112(7):2687-93. Carlotti E, Arcaini L, Baccarani M, et al. Monitoring of minimal residual disease after 38. Ghione P, Monitillo, L., Barbero, D., CHOP and rituximab in previously untreated Verardo, G., Drandi, D., Grimaldi, D., patients with follicular lymphoma. Blood. Genuardi, E., Mantoan, B., Cavallo, F., 2002;99(3):856-62. Vasta, M., Zaja, F., Visco, C., Cortelazzo, S., Ladetto, M., Ferrero, S. A Technical 44. Hirt C, Schuler F, Kiefer T, Schwenke Comparison Between Igh And Bcl1/Igh C, Haas A, Niederwieser D, et al. Rapid and Molecular Markers For Minimal Residual sustained clearance of circulating lymphoma Disease Analysis In Mantle Cell Lymphoma. cells after chemotherapy plus rituximab: SIES meeting abstract. 2016. clinical significance of quantitative t(14;18) PCR monitoring in advanced stage follicular 39. Ladetto M, Pagliano G, Ferrero S, lymphoma patients. Br J Haematol. Cavallo F, Drandi D, Santo L, et al. Major 2008;141(5):631-40. tumor shrinking and persistent molecular remissions after consolidation with 45. Ghielmini M, Schmitz SF, Cogliatti bortezomib, thalidomide, and SB, Pichert G, Hummerjohann J, Waltzer U, dexamethasone in patients with autografted et al. Prolonged treatment with rituximab in myeloma. Journal of clinical oncology : patients with follicular lymphoma official journal of the American Society of significantly increases event-free survival Clinical Oncology. 2010;28(12):2077-84. and response duration compared with the standard weekly x 4 schedule. Blood. 40. Ladetto M, Ferrero S, Drandi D, 2004;103(12):4416-23. Festuccia M, Patriarca F, Mordini N, et al. Prospective molecular monitoring of 46. Rambaldi A, Carlotti E, Oldani E, minimal residual disease after non- Della Starza I, Baccarani M, Cortelazzo S, et myeloablative allografting in newly al. Quantitative PCR of bone marrow diagnosed multiple myeloma. Leukemia. BCL2/IgH+ cells at diagnosis predicts 2015. treatment response and long-term outcome in follicular non-Hodgkin lymphoma. Blood. 41. Oliva S, Gambella M, Gilestro M, 2005;105(9):3428-33. Muccio VE, Gay F, Drandi D, et al. Minimal residual disease after transplantation or 47. Goff L, Summers K, Iqbal S, lenalidomide-based consolidation in Kuhlmann J, Kunz M, Louton T, et al. myeloma patients: a prospective analysis. Quantitative PCR analysis for Bcl-2/IgH in a Oncotarget. 2016. phase III study of Yttrium-90 Ibritumomab Tiuxetan as consolidation of first remission 42. Brown JR, Feng Y, Gribben JG, in patients with follicular lymphoma. Journal Neuberg D, Fisher DC, Mauch P, et al. of clinical oncology : official journal of the Long-term survival after autologous bone American Society of Clinical Oncology. marrow transplantation for follicular 2009;27(36):6094-100. lymphoma in first remission. Biology of blood and marrow transplantation : journal 48. Corradini P, Ladetto M, Zallio F, of the American Society for Blood and Astolfi M, Rizzo E, Sametti S, et al. Long- Marrow Transplantation. 2007;13(9):1057- term follow-up of indolent lymphoma 65. patients treated with high-dose sequential

Copyright 2017 KEI Journals. All Rights Reserved Page │24 Medical Research Archives, Vol. 5, Issue 5, May 2017 PERSONALIZED MEDICINE IN LYMPHOMA: TAILORING TREATMENT ACCORDING TO MINIMAL RESIDUAL DISEASE chemotherapy and autografting: evidence Fase Ii Della Fondazione Italiana Linfomi that durable molecular and clinical remission (FIL). SIE meeting abstracts. 2015. frequently can be attained only in follicular subtypes. Journal of clinical oncology : 53. Galimberti S EG, Ciabatti E, Grassi S, official journal of the American Society of Metelli MR, Guerrini F et al. Galimberti S, Clinical Oncology. 2004;22(8):1460-8. Ercolano G, Ciabatti E, Grassi S, Metelli MR, Guerrini F et al. Rituximab- 49. Galimberti S, Luminari S, Ciabatti E, bendamustin: an effective treatment for Grassi S, Guerrini F, Dondi A, et al. minimal residual disease eradication in Minimal residual disease after conventional patients affected by follicular lymphoma. treatment significantly impacts on SIES meeting abstracts. 2016;Abstract C060. progression-free survival of patients with follicular lymphoma: the FIL FOLL05 trial. 54. Pott C, Belada, D., Danesi, N., Clinical cancer research : an official journal Fingerle-Rowson, G., Gribben, J., Harbron, of the American Association for Cancer C., Hoster, E., Kahl, B. S., Mundt, K., Research. 2014;20(24):6398-405. Sebban, C., Sehn, L. H., Cheson, B. D. Analysis of Minimal Residual Disease in 50. Rummel MJ, Niederle N, Maschmeyer Follicular Lymphoma Patients in Gadolin, a G, Banat GA, von Grunhagen U, Losem C, Phase III Study of Obinutuzumab Plus et al. Bendamustine plus rituximab versus Bendamustine Versus Bendamustine in CHOP plus rituximab as first-line treatment Relapsed/Refractory Indolent Non-Hodgkin for patients with indolent and mantle-cell Lymphoma. Blood. 2015. lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. 55. Pott C, Hoster, E., Kehden, B., Lancet. 2013;381(9873):1203-10. Unterhalt, M., Herold, M., van der Jagt, R. H., Janssens, A., Kneba, M., Mayer, J., 51. Zohren F, Bruns I, Pechtel S, Pocock, C., Danesi, N., Fingerle-Rowson, Schroeder T, Fenk R, Czibere A, et al. G., Harbron, C., Mundt, K., Marcus, R. E., Prognostic value of circulating Bcl-2/IgH Hiddemann, W. Minimal Residual Disease levels in patients with follicular lymphoma in Patients with Follicular Lymphoma receiving first-line immunochemotherapy. Treated with Obinutuzumab or Rituximab Blood. 2015;126(12):1407-14. As First-Line Induction Immunochemotherapy and Maintenance in 52. Boccomini C, Ladetto, M., Rigacci, L., the Phase 3 GALLIUM Study. Blood. Rattotti, S., Evangelista, A., Ferrero, S., 2016;128:613. Volpetti, S., Mantoan, B., Meli, E., Freilone, R., Corradini, P., Franceschetti, S., Rusconi, 56. Ladetto M, Magni M, Pagliano G, De C., Stelitano, C., Dutto, F., Puccini, B., Marco F, Drandi D, Ricca I, et al. Rituximab Bolis, S., Salvi, F., Fabbri, A., Billio, A., induces effective clearance of minimal Tucci, A., Balzarotti, M., Vitolo, U. residual disease in molecular relapses of Sicurezza Ed Efficacia Di Una Breve mantle cell lymphoma. Biology of blood and Chemioimmunoterapia Di Prima Linea Con marrow transplantation : journal of the Rituximab, Bendamustina E Mitoxantrone American Society for Blood and Marrow (R-Bm) Seguita Da Consolidamento Con Transplantation. 2006;12(12):1270-6. Rituximab Nei Pazienti Anziani Affetti Da Linfoma Follicolare In Stadio Avanzato: 57. Ferrero S, Monitillo L, Mantoan B, Risultati Finali Di Uno Studio Prospettico Di Barbero D, Genuardi E, Barbiero S, et al.

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Rituximab-based pre-emptive treatment of in mantle cell lymphoma. Blood. molecular relapse in follicular and mantle 2006;107(6):2271-8. cell lymphoma. Annals of hematology. 2013;92(11):1503-11. 63. Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, et 58. Morschhauser F, Recher C, Milpied N, al. Addition of high-dose cytarabine to Gressin R, Salles G, Brice P, et al. A 4- immunochemotherapy before autologous weekly course of rituximab is safe and stem-cell transplantation in patients aged 65 improves tumor control for patients with years or younger with mantle cell lymphoma minimal residual disease persisting 3 months (MCL Younger): a randomised, open-label, after autologous hematopoietic stem-cell phase 3 trial of the European Mantle Cell transplantation: results of a prospective Lymphoma Network. Lancet. multicenter phase II study in patients with 2016;388(10044):565-75. follicular lymphoma. Annals of oncology : official journal of the European Society for 64. Callanan MB, Delfau, M., Macintyre, Medical Oncology. 2012;23(10):2687-95. E., Thieblemont, C., Oberic, L., Gyan, E., Bouabdallah, K., Gressin, R., Damaj, G., 59. Andersen NS, Donovan JW, Borus JS, Casasnovas, O., Ribrag, V., Gimenez, E., Poor CM, Neuberg D, Aster JC, et al. Failure Hermine, O., & Le Gouill, S. Predictive of immunologic purging in mantle cell Power of Early, Sequential MRD Monitoring lymphoma assessed by polymerase chain in Peripheral Blood and Bone Marrow in reaction detection of minimal residual Patients with Mantle Cell Lymphoma disease. Blood. 1997;90(10):4212-21. Following Autologous Stem Cell Transplantation with or without Rituximab 60. Gianni AM, Magni M, Martelli M, Di Maintenance; Interim Results from the Nicola M, Carlo-Stella C, Pilotti S, et al. LyMa-MRD Project, Conducted on Behalf Long-term remission in mantle cell of the Lysa Group. Blood. lymphoma following high-dose sequential 2015;126(23):338. chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). 65. Cortelazzo S. MM, Ladetto M., Blood. 2003;102(2):749-55. Ferrero S., Ciccone G., Evangelista A., Mian M., Di Rocco A., Chiappella A., Rossi G., 61. Magni M, Di Nicola M, Devizzi L, Re A, Zinzani P. L., Balzarotti M., Cavallo Matteucci P, Lombardi F, Gandola L, et al. F., Rusconi C., Gotti M., Arcaini L., Gobbi Successful in vivo purging of CD34- M., Gomes M. Molinari A., Liberati A.M., containing peripheral blood harvests in Michieli M., Latte G., Cabras M. G., Novero mantle cell and indolent lymphoma: D., Paulli M., Zamò A., Chilosi M., Federico evidence for a role of both chemotherapy M., Vitolo U. High Dose Sequential and rituximab infusion. Blood. Chemotherapy With Rituximab And ASCT 2000;96(3):864-9. As First Line Therapy In Adult MCL Patients: Clinical And Molecular Response 62. Pott C, Schrader C, Gesk S, Harder L, Of The MCL0208 Trial, A FIL Study. EHA Tiemann M, Raff T, et al. Quantitative Meeting abstracts. 2015. assessment of molecular remission after high-dose therapy with autologous stem cell 66. Pott C, Macintyre E, Delfau-Larue M- transplantation predicts long-term remission H, Ribrag V, Unterhalt M, Kneba M, et al. MRD Eradication Should be the Therapeutic

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Goal in Mantle Cell Lymphoma and May 50403 (Alliance). ASH - Hematol Oncol,. Enable Tailored Treatment Approaches: 2013. Results of the Intergroup Trials of the European MCL Network. Blood. 72. Corradini P, Voena C, Tarella C, 2014;124(21):147-. Astolfi M, Ladetto M, Palumbo A, et al. Molecular and clinical remissions in 67. Kolstad A, Pedersen L. B., Eskelund, multiple myeloma: role of autologous and C. W., Husby, S., Grønbæk K., Jerkeman allogeneic transplantation of hematopoietic M., Laurell A., Räty, R., Elonen, E., cells. Journal of clinical oncology : official Andersen, N.S., de Nully Brown, P., Geisler, journal of the American Society of Clinical C.H. Molecular Monitoring and Tailored Oncology. 1999;17(1):208-15. Strategy with Pre-Emptive Rituximab Treatment for Molecular Relapse; Results 73. Martinelli G, Terragna C, Zamagni E, from the Nordic Mantle Cell Lymphoma Ronconi S, Tosi P, Lemoli RM, et al. Studies (MCL2 and MCL3) with Median Molecular remission after allogeneic or Follow-up of 8.5 Years. ASH annual autologous transplantation of hematopoietic meeting abstracts. 2016;abstract n° 146. stem cells for multiple myeloma. Journal of clinical oncology : official journal of the 68. Zaja F ea. Rituximab, lenalidomide, American Society of Clinical Oncology. bendamustine second line therapy in mantle 2000;18(11):2273-81. cell lymphoma: a phase II study of the Fondazione Italiana Linfomi (FIL). ICML 74. Puig N, Sarasquete ME, Balanzategui Abstracts 2015:014. ICML Abstracts A, Martinez J, Paiva B, Garcia H, et al. 2015;014. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in 69. Visco C, Chiappella A, Nassi L, Patti multiple myeloma. A comparative analysis C, Ferrero S, Barbero D, et al. Rituximab, with flow cytometry. Leukemia. bendamustine, and low-dose cytarabine as 2014;28(2):391-7. induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 75. Ferrero S, Capello D, Svaldi M, Boi 2 trial from Fondazione Italiana Linfomi. M, Gatti D, Drandi D, et al. Multiple Lancet Haematol. 2016. myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes. 70. Albertsson-Lindblad A, Kolstad A, Haematologica. 2012;97(6):849-53. Laurell A, Raty R, Gronbaek K, Sundberg J, et al. Lenalidomide-bendamustine-rituximab 76. Paiva B, Vidriales MB, Cervero J, in untreated mantle cell lymphoma > 65 Mateo G, Perez JJ, Montalban MA, et al. years, the Nordic Lymphoma Group phase Multiparameter flow cytometric remission is I+II trial NLG-MCL4. Blood. 2016. the most relevant prognostic factor for multiple myeloma patients who undergo 71. Kaplan LD, Jung, S. H. , Bartlett, N. autologous stem cell transplantation. Blood. C. , Johnson, J. , Byrd, J. . Bortezomib 2008;112(10):4017-23. maintenance (BM) vs consolidation (BC) following aggressive immunochemotherapy 77. Palumbo A, Hajek R, Delforge M, and autologous stem cell transplant (ASCT) Kropff M, Petrucci MT, Catalano J, et al. for untreated mantle cell (MCL): CALGB Continuous lenalidomide treatment for newly diagnosed multiple myeloma. The

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