Post-autologous transplant maintenance therapies in ... - Nature

Bone Marrow Transplantation (2015) 50, 1393–1404 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt

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Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet? N Epperla1, TS Fenske1, HM Lazarus2 and M Hamadani1 Disease relapse after autologous hematopoietic transplant (auto-HCT) remains the number one cause of post-transplant therapy failure and mortality. The last decade has seen a proliferation of clinical studies looking at the prevention of post-auto-HCT therapy failure with various maintenance strategies. The benefit of such therapies is in turn dependent on disease histology and timing of transplantation. Although high dose therapy (HDT) provides durable responses in chemosensitive relapsed diffuse large B-cell lymphoma (DLBCL), a sizable subset experiences disease relapse. Unfortunately, the addition of rituximab as a post-auto-HCT maintenance strategy did not improve survival outcomes. The preliminary results with programmed death -1 (PD-1) Ab as post-auto maintenance in DLBCL is promising but requires randomized validation. In follicular lymphoma, the 5- and 10-year PFS rates are ~ 60% and 31%, respectively. Although the addition of rituximab improved PFS, there is no survival benefit, to date. Disease relapse after auto-HCT in mantle cell lymphoma (MCL) is not uncommon. Rituximab maintenance in this setting provides a PFS benefit. Given the poor prognosis of post-auto-HCT failures in MCL, maintenance can be considered on a case-by-case basis. In chemosensitive relapsed Hodgkin lymphoma, addition of brentuximab vedotin after auto-HCT improved 2-year PFS (65 vs 45%) and can be considered as an option for maintenance therapy post auto-HCT, in select higher risk patients. Ongoing trials evaluating the efficacy of post-auto-HCT maintenance with novel agents (for example, immunomodulators, proteasome inhibitors, PD-1 inhibitors, Bruton’s tyrosine kinase inhibitors and so on) will likely change the practice landscape for lymphoma patients following HDT and auto-HCT. Bone Marrow Transplantation (2015) 50, 1393–1404; doi:10.1038/bmt.2015.184; published online 17 August 2015

INTRODUCTION Hodgkin and non-Hodgkin lymphomas (NHL) constitute the second most common indication for high dose therapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT).1 In chemotherapy-responsive relapsed lymphoid malignancies, auto-HCT can provide long-term disease control. Regardless of the underlying histology or remission status at transplantation, disease relapse or progression remains the number one cause of post-auto-HCT therapy failure and mortality (Figure 1). Prevention of disease relapse post autografting in lymphoid malignancies remains an unmet medical need. Disease relapse following auto-HCT occurs via two possible mechanisms. Most patients relapse likely due to the proliferation of a resistant clone of lymphoma cells (or lymphoma stem cells) surviving the HDT. A minority may experience relapse owing to re-infusion of an autograft contaminated by lymphoma cells.2 To circumvent the problem of autograft contamination by lymphoma cells, several studies examined the role of ex vivo purging (by monoclonal antibodies, CD34+ cell selection and so on)3,4 and in vivo purging (for example, rituximab with mobilization)5,6 of autologous stem cell products. However, randomized data suggest no benefit from purged auto-HCT.7 Similarly, intensifying HDT with radioimmunotherapy-based conditioning regimens8 have likewise not demonstrated improved HCT outcomes. A handful of studies have looked at auto-HCT followed by a tandem reduced-intensity allogeneic HCT in lymphoid malignancies.9,10 However, no randomized data are available to support the use of

this approach. Moreover, advanced age, comorbidities and matched-donor availability makes such a tandem HCT approach theoretically applicable to only a small fraction of lymphoma population. Over the last decade, several studies have shown improved survival outcomes with maintenance immunotherapies applied after conventional chemoimmunotherapies in patients with lymphoid malignancies.11–13 Owing to the excellent safety profile of maintenance therapies in the non-transplant setting, this modality has now been investigated post auto-HCT in lymphoid malignancies. In this article, we review the role of post-auto-HCT maintenance therapies in Hodgkin lymphoma and NHL, along with an overview of novel agents that can serve as future maintenance strategies in a post-auto-HCT setting. DIFFUSE LARGE B-CELL LYMPHOMA The vast majority of diffuse large B-cell lymphoma (DLBCL) patients experience disease relapse early after auto-HCT. In a recent CIBMTR (Center for International Blood and Marrow Transplant Research) study,14 nearly three-quarters of relapses in DLBCL were seen within the first 9 months following auto-HCT. A landmark analysis of DLBCL patients surviving first 9 months without relapse/progression, showed a 5-year PFS P of 480%, suggesting that an effective strategy to prevent early post-autograft therapy failures in DLBCL can theoretically translate into significant improvements in patient outcomes.

1 Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA and 2Division of Hematology-Oncology, Department of Medicine, Case Comprehensive Cancer Center, University Hospitals Case Medical Center, Cleveland, OH, USA. Correspondence: Dr M Hamadani, Associate Professor of Medicine, Division of Hematology & Oncology, Medical College of Wisconsin & CIBMTR, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA. E-mail: [email protected] Received 27 May 2015; revised 30 June 2015; accepted 6 July 2015; published online 17 August 2015

Post-autograft maintenance in lymphomas N Epperla et al

Primary disease (69%) Organ failure (4%)

Comments

Secondary malignancy (2%)

Other (18%)

Bone Marrow Transplantation (2015) 1393 – 1404

61 (R) vs 65 (O) (4 years) 85 (16 months)

—

91

100

80 (R) vs 71 (O) (4 years) 52 (R) vs 56 (O) (4 years) 72 (16 months) 84.5

269 R = 139; O = 130 242 R = 122; O = 120 66

NR NR 79 19

100 (3 years) 83 (3 years) 100 12

80 (5.5 years) —

Rituximab 375 mg/m2 (q 3 months for a total of 8 doses) Single arm Rituximab 375 mg/m2 q 3 months for 2 years prospective Retrospective Rituximab 375 mg/m2 (80% q week and 20% q mo) Randomized Rituximab 375 mg/m2 (weekly prospective for 4 doses) Randomized Rituximab 375 mg/m2 (q 8 weeks for 1 year) prospective Prospective phase II Pidilizumab 1.5 mg/kg (q 42 days for 3 cycles) Armand et al.20

Gisselbrecht et al.

Haioun et al.18

Tsirigotis et al.

Zhang et al.16

17

19

Retrospective

Lim et al.15

15

100

OS (%) Percent CS at HCT N Maintenance schedule Study design Author

Table 1.

Does rituximab maintenance improve outcomes post auto-HCT in DLBCL? Studies evaluating the role of maintenance therapies in DLBCL are summarized in Table 1.15–20 A small case series by Lim et al.15 (n = 15) provided preliminary feasibility data for maintenance in DLBCL after auto-HCT (Table 1). A subsequent, pilot study (n = 12), using post-auto-HCT maintenance with rituximab in high-risk DLBCL reported a 3-year PFS of 83% and overall survival (OS) of 100%.16 These studies paved way for a large prospective randomized study, where high-risk DLBCL (n = 269) undergoing an upfront auto-HCT consolidation in first remission, were randomized to a brief rituximab course (four weekly doses) vs observation. In patients who achieved a CR following HDT, this brief rituximab exposure provided statistically significant better event-free survival (Table 1).18 Because upfront auto-HCT in first remission in DLBCL is not considered the standard-of-care, caution must be exercised in extrapolation of these data to relapsed DLBCL patients undergoing auto-HCT. Of note, quality-of-life assessments in this study showed rapid recovery (as early as day 100) in all the tested quality-of-life subdomains after auto-HCT, and rituximab maintenance did not seem to negatively influence the qualityof-life parameters.21 The more clinically relevant question of rituximab maintenance in DLBCL patients after failing first-line therapies was addressed in the CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study. In this trial (after an initial randomization of patients between two different salvage therapies), a second randomization of relapsed DLBCL patients after auto-HCT to either rituximab maintenance (every 2 months for 1 year) or observation alone was performed (Table 1). Rituximab maintenance in this study provided no event-free survival, PFS or OS benefit. However, an unplanned subset analysis suggested a possible benefit of maintenance rituximab in female patients.19 This finding likely is a reflection of less rapid rituximab clearance in females, and resultant higher serum rituximab concentrations.22 This observation could suggest a benefit of rituximab post auto-HCT in female subjects (and possibly in males using higher doses of rituximab), but this hypothesis needs further investigation. In addition to lack of randomized data supporting the use of maintenance rituximab for relapsed DLBCL, uncontrolled data suggest prolonged hypogammaglobulinemia extending beyond 2 years when using this approach in the post-auto-HCT setting.15,16

Studies evaluating the role of rituximab as maintenance therapy post auto-HCT in diffuse large B-cell lymphoma

Figure 1. Causes of death after autologous transplantation. A full color version of this figure is available at the Bone Marrow Transplantation journal online.

PFS/EFS (%)

Years 2010-2012

Abbreviations: CS = chemo-sensitive; EFS = event-free survival; f/u = follow-up; HCT = hematopoietic transplant; NR = not reached; O = Observation arm; ORR = overall response rate; OS = overall survival; pts = patients; q = every; R = rituximab arm.

Infection (8%)

Relapse-free survival 100% (5.5 years)

Causes of death after autologous transplantation (US data)

Prolonged hypogammaglobulinemia in two patients Compared with controls, maintenance improves PFS and OS Patients underwent auto-HCT upfront in first remission 4-year EFS was 52% for Rituximab arm, while 53% for observation arm ORR was 51% (CR of 34%) in pts with measurable disease after auto-HCT

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1395 Maintenance therapy based on 'cell of origin' Gene expression profiling defines three distinct molecular signatures in DLBCL: activated B-cell-like (ABC), germinal center B-cell-like (GCB) and primary mediastinal B-cell lymphoma.23 Constitutive activation of the NF-kB signaling pathway is the hallmark of ABC DLBCL that leads to cell survival, proliferation and inhibition of apoptosis.24,25 This is mediated by constitutive activation of the CBM (formed by CARD11, BCL10 and MALT1) complex and constitutive MYD88 pathway.25–27 Activation of CBM occurs through activating mutations in CARD11 (~ 10%) or chronic active B-cell receptor (BCR) signaling (mediated through the BCR and downstream kinases) engaging the CBM pathway.26 Approximately 20% of ABC DLBCL have gain-of-function mutations in BCR (CD79b),25 while downstream kinases in the BCR pathway include spleen tyrosine kinase (SYK), PI3K, Bruton tyrosine kinase (BTK) and protein kinase C β (PKCβ). MYD88 is an adapter for Toll-like receptors27 and ~29% of ABC DLBCL have constitutively active MYD88 mutant (L265P).27 EZH2 in cooperation with BCL6 mediates lymphomagenesis in GCB DLBCL.28 PTEN is a tumor-suppressor gene that regulates phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and either deletion or loss of PTEN (55%) (commonly seen in GCB) can lead to the activation of PI3K/ AKT/mTOR pathway.29 Of note, BCL2 is overexpressed in both subtypes albeit through different mechanisms. BTK inhibitors Preclinical studies have shown that the inhibition or knockdown of BTK hampers cell survival. In the phase I and II studies,30,31 ibrutinib, a BTK inhibitor, showed greater single-agent activity in ABC subtype of relapsed/refractory de novo DLBCL, likely secondary to constitutively active BCR signaling in this subtype. In the near future, BMT-CTN/Alliance phase III study will evaluate the utility of using ibrutinib as post-auto-HCT maintenance in ABC DLBCL, defined using the nanostring platform. Proteasome inhibitors The constitutive activation of this NF-kB pathway in ABC DLBCL allows the cell to remain immortal and foster resistance against traditional chemotherapeutic agents. In a study of 49 patients with relapsed or refractory DLBCL who were treated with single-agent bortezomib and intensive chemotherapy, bortezomib had no efficacy as a single agent. However, when combined with chemotherapy, it improved outcomes in patients with the non-GCB subtype of DLBCL in greater magnitude than those of patients with the GCB subtype.32 A large phase III trial is ongoing to evaluate the efficacy of adding bortezomib in the relapsed/ refractory setting as well as in the frontline setting in combination with R-CHOP.33 Currently, a phase II study is ongoing using bortezomib in combination with vorinostat (histone deacetylase (HDAC) inhibitor) after auto-HCT (NCT00992446). Immunomodulators Lenalidomide is an immunomodulatory agent that demonstrated activity in relapsed/refractory aggressive B-cell NHL.34 A retrospective analysis carried out by Hernandez-Ilizaliturri et al.35 demonstrated an increase in the overall response rate (ORR), CR and PFS in the non-GCB/ABC subtype of DLBCL. Currently, an ongoing trial (NCT01241734; lenalidomide maintenance; phase I/II) is looking at lenalidomide maintenance post auto-HCT in DLBCL. PI3K/AKT/mTOR pathway PTEN deletion or loss is more common in GCB DLBCL, and leads to the activation of PI3K/AKT/mTOR pathway.29 In a phase II study of heavily pretreated patients with DLBCL, combination of © 2015 Macmillan Publishers Limited

everolimus and rituximab had an ORR of 38% with a median PFS of 8.1 months and OS of 37% (median of 12 months). However, there was no significance in the GCB vs ABC subtypes.36 Currently, there is an ongoing trial looking at the everolimus and rituximab combination after HDT as a maintenance therapy in CD 20+ B-cell lymphomas (NCT01665768). BCL-2 inhibitor DLBCL patients who express c-MYC and BCL2 (by immunohistochemistry) irrespective of MYC/BCL2 gene rearrangement, have poor outcomes regardless of the ABC or GCB subtype.37,38 ABT-199 is a selective BCL2 inhibitor with responses noted in 38% of patients with relapsed DLBCL in a phase I study.39 Currently, there are multiple trials ongoing using ABT-199 as a single agent or in combination with other drugs. The remarkable single-agent activity of ABT-199 in relapsed DLBCL and its frequent high expression (~66% in ABC and ~ 30% GCB subtypes) makes it an attractive agent to eradicate residual disease post HDT in this aggressive histology. Bromodomain and extraterminal inhibitor JQ1 is a small-molecule inhibitor of the bromodomain and extraterminal family of bromodomain proteins, with the highest affinity for BRD4.40 BRD4 facilitates active transcription by acting as a scaffolding factor that associates with acetylated chromatin. Through this mechanism, BRD4 contributes to malignant transformation by increasing the expression of oncogenes such as c-MYC. JQ1 prevents binding of BRD4 to chromatin by competitive inhibition.41 Trabucco et al.42 showed that JQ1-mediated inhibition of BRD proteins in both ABC and GCB subtypes of DLBCL lead to c-MYC-dependent cell death or cycle arrest. Thus, JQ1 presents a valuable therapeutic option in patients with overexpression of c-MYC, BCL2 and or BCL6, which is otherwise a very difficult patient population with dismal prognosis. Checkpoint inhibitors Programmed death 1 (PD-1) is a T-cell co-receptor that binds to the ligand B7 to maintain an immunosuppressive tumor microenvironment. PD-L1 is expressed on suppressor immune cells in the tumor microenvironment and in a subset of DLBCL43–46 where it may alter the composition and function of tumor-infiltrating lymphocytes,47 and therefore represents a valid therapeutic target. Early after auto-HCT, the majority of the circulating leukocytes are natural killer (NK) cells, CD45RO+ memory/effector cells and monocytes, which comprise anti PD-1 monoclonal Ab target populations and whose presence has been associated with a favorable prognosis in DLBCL tumors.48–50 In DLBCL patients, post-auto-HCT PD-1 blockade may prevent PD-1mediated exhaustion of antitumor lymphocytes, leading to the eradication of residual disease and improvement in transplant outcomes. In a multicenter phase II trial (Table 1), an anti-PD-1 monoclonal Ab, pidilizumab, was administered to patients with relapsed or refractory DBLCL following auto-HCT. The 16-month PFS was 72% in the overall population and 70% in the subgroup of high-risk patients who had a positive positron emission tomography scan at the end of salvage therapy. Remarkably, 51% of patients with residual disease after transplant responded to the treatment, and 34% of these patients had CR without significant autoimmune toxicity.20 Although promising, these results have not been confirmed in a prospective randomized trial yet. Currently, a phase II study with pembrolizumab (NCT02362997) in the post-auto-HCT setting is ongoing. CAR-T-cell therapy CD19 is an Ag expressed on malignant and normal B cells. Chimeric Ag receptors (CARs) are fusion proteins incorporating Bone Marrow Transplantation (2015) 1393 – 1404


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Ag-recognition domains and T-cell activation domains.51–55 T cells expressing anti-CD19 CARs recognize and kill CD19 target cells.56–62 In the study by Kochenderfer et al.,63 of the 15 patients with advanced NHL, 8 achieved CR, 4 achieved PR, 1 had stable lymphoma, and 2 were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion.63 Currently, a phase I trial is ongoing to evaluate the efficacy of CAR-T-cell therapy in relapsed/refractory aggressive NHL after HDT and auto-HCT as a maintenance strategy (NCT01840566). This is built on the premise that HDT with auto-HCT would provide a lymphodepleting platform for the infusion of CAR T cells leading to enhanced antitumor activity. FOLLICULAR LYMPHOMA (FL) Registry data from European Group for Blood and Marrow Transplantation (EBMT)64 and CIBMTR generally show no plateau in relapse rates of FL after autografting.65 Because maintenance immunotherapies (with rituximab) in FL have shown benefit after both front-line11 and subsequent chemoimmunotherapies,66,67 the application of rituximab maintenance following auto-HCT seemed to be a logical next step, as a strategy for relapse prevention. Do we have promising results with rituximab in post-auto-HCT maintenance? The EBMT recently reported the efficacy and safety of rituximab, as in vivo purging before transplantation and as a maintenance strategy after HDT and auto-HCT in patients with relapsed FL, in a randomized trial. In this study, 280 rituximab-naïve patients with relapsed FL were randomly assigned to auto-HCT with or without in vivo rituximab purging, followed by a second randomization to rituximab maintenance therapy (once every 2 months for a total of four infusions) or observation.68 At a median follow-up of 8.3 years, rituximab maintenance when compared with observation, resulted in superior PFS at 10 years (54 vs 37%), but did not translate into an improvement in OS (73 vs 68%). In addition, maintenance rituximab was associated with a higher (albeit statistically non-significant) rate of late neutropenia. Considering the fact that this study enrolled rituximab-naïve patients, the lack of a survival benefit in this study is worth noting. It is plausible that the relatively short maintenance schedule used in this trial is responsible for this observation. Randomized trials in FL in the non-transplant setting have shown no OS or PFS benefit with rituximab maintenance, when using a shorter course (~8 months) of maintenance, as used in the EBMT study.69 Combination therapy with proteasome inhibitors and HDAC inhibitors as post-auto-HCT maintenance therapy—Does it work? The combinations of proteasome and HDAC inhibitors have both synergistic and additive effects. Targeting both the proteasome and aggresome pathways in tumor cells with bortezomib and HDAC6 inhibitors, respectively, induces greater accumulation of polyubiquitinated proteins with resultant cellular stress and apoptosis.70,71 Specifically, proteasome inhibition drives the formation of aggresomes, which are dependent on the interaction of HDAC6 with tubulin and dynein complex.70 The inhibition of HDAC6 (in addition to proteasome inhibition) leads to increased hyperacetylation of tubulin and generation of polyubiquitinated proteins, thereby increasing cellular stress response and leading to Bone Marrow Transplantation (2015) 1393 – 1404

apoptosis.70–72 The combination of bortezomib and vorinostat results in enhanced cytochrome-c release, caspase and PARP cleavage, and inactivation of NF-κB, followed by apoptosis.73 Several phase I and II studies with single agent bortezomib in relapsed/refractory FL were unimpressive74–77 including a phase III study78 where it was used in combination with rituximab. After understanding the synergy between the proteasome and HDAC inhibitors and convincing results in multiple myeloma79,80 with this combination therapy, currently, there is an ongoing study evaluating this combination therapy (NCT00992446; bortezomib in combination with vorinostat; phase II) in post-auto-HCT setting. Immunomodulators Although rituximab maintenance is unlikely to improve postauto-HCT therapy failures, the role of other novel approaches as maintenance therapies post auto-HCT in FL warrants further investigation. Ongoing post-auto-HCT maintenance clinical trials involving FL patients are evaluating the role of immune modulators (NCT01035463; lenalidomide maintenance; phase I/II) as a maintenance option. PI3K inhibitor Idelalisib is an oral tyrosine kinase inhibitor that selectively targets the PI3K p110 isoform δ (PI3Kδ) with great potency. PI3Kδ is hyper-activated in B-cell malignancies and has a key role in the BCR pathway.81 In a phase II study of relapsed indolent lymphomas, Idelalisib demonstrated an ORR of 57% with a median duration of response of 12.5 months and median PFS of 11 months.82 There are currently phase II and III trials ongoing testing the efficacy of Idelalisib as a single agent and in combination with other drugs. Idelalisib either alone or in combination can be a potential therapeutic strategy as a postauto-HCT maintenance strategy, with the caveat that prolonged use of this agent has been associated with life-threatening episodes of diarrhea. MANTLE CELL LYMPHOMA (MCL) Maintenance rituximab after induction chemoimmunotherapies has been shown to improve OS in older patients with MCL.13 In MCL, the prevention of relapse or progression after auto-HCT is crucial, because outcome after auto-HCT relapse is dismal with a median survival of only 23 months.83 Rituximab maintenance post auto-HCT in MCL—what can we expect? Several retrospective and a few prospective studies have evaluated maintenance rituximab in MCL (Table 2).84–87 Dietrich et al.86 compared post-auto-HCT maintenance rituximab (administered within a prospective phase II study NCT 01933711) with a retrospective MCL patient cohort getting no maintenance (but transplanted during the same time period of aforementioned trial). The study showed that the 2-year PFS was significantly better in the maintenance rituximab compared with no maintenance rituximab cohort (90% and 65%, respectively, P = 0.014). On univariate analysis, OS was not statistically different (90% in maintenance rituximab and 84% in no maintenance rituximab); however, after multivariate adjustment for other factors maintenance rituximab was strongly associated with both PFS and OS benefit (Table 2).86 The only randomized phase III trial to study maintenance therapy in the post-auto-HCT setting in MCL was conducted by the LYSA, GOELAMS (Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang) and GELA (Groupe d'Etude des Lymphomes de l'Adulte). Patients achieving a CR or PR to auto-HCT (n = 238) were randomized to maintenance rituximab © 2015 Macmillan Publishers Limited


Retrospective

Prospective phase III Rituximab 375 mg/m2 IV (every 2 months for 3 years)

Dietrich et al.86

Le Gouill et al.87


Abbreviations: CS = chemo-sensitive; EFS = event-free survival; HCT = hematopoietic transplant; HR = hazard ratio; MR = maintenance rituximab; O = observation arm; ORR = overall response rate; OS = overall survival; R-BEAM = rituximab, carmustine, etoposide, cytarabine and melphalan; R = rituximab arm; R-DHAP = rituximab, dexamethasone, cytarabine and cisplatin.

All patients received four courses of R-DHAP followed by auto-HCT. The conditioning regimen of auto-HCT was R-BEAM (R = 500 mg/m2) 93.2 (R) vs 81.5 (O) (2 years) 81.4

Retrospective Graf et al.85

2

Lim et al.

93.4 (R) vs 93.9 (O) (2 years)

90 (R) vs 84 (O) 90 (R) vs 65 (O)

In the landmark analysis at D 100 after auto-HCT 3-year PFS and OS were statistically better in the MR compared with the no MR group. Patients in both the arms were well matched. The median observation time was 56 months. HR of 0.40 HR of 0.33 Almost all the pts who received MR

157 R = 50; O = 107 72 R = 22; O = 50 238 R = 119; O = 119

Delayed Ig reconstitution was seen in all patients and persisted beyond the rituximab maintenance period.

Rituximab 375 mg/m (q 3 months for 2 years starting day+100) Rituximab 375 mg/m2 (variable dosing schedule but median doses = 8) Rituximab 375 mg/m2 (every 3 months for 2 years) Retrospective

67 57 100 8

n Maintenance Design

84

Author

Table 2.

Studies evaluating the role of rituximab maintenance after auto-HCT in mantle cell lymphoma

OS (%) PFS/EFS (%) % CS at HCT

Comments

1397 (n = 119) or wait and watch (n = 119) arms. The 2-year event-free survival and PFS were statistically different between the two arms, favoring the maintenance rituximab, however, there was no difference in OS (Table 2).87 Final data with mature follow-up and complete toxicity assessment have not yet been reported. Immunomodulators—hope is alive in post-auto-HCT setting Among lymphoid malignancies, the therapeutic landscape of MCL is rapidly changing with several new agents approved for therapy in relapsed/refractory setting in the last 2–3 years. Lenalidomide has shown significant activity in relapsed/refractory MCL leading to its approval as a single agent in this patient group.88 Fondazione Italiana Linfomi, an ongoing randomized phase III study, is evaluating the role of lenalidomide maintenance after upfront auto-HCT consolidation in MCL (NCT02354313). BTK inhibitors Proliferation of B cells is mediated through constitutive activation of BCR signaling pathway and BTK is an essential component of this pathway responsible for cell survival and proliferation. Ibrutinib, a BTK inhibitor, has shown impressive activity in relapsed/refractory MCL,89 which lead to its use as a maintenance agent after auto-HCT in clinical trials. Currently, there are two ongoing trials; one is a US single-arm phase II trial using ibrutinib as maintenance therapy after intensive induction programs (with or without auto-HCT) (NCT02242097) in previously untreated MCL patients, and the other is a European randomized prospective study (the ‘TRIANGLE’ study) looking at the impact of adding ibrutinib to induction and maintenance therapy for first-line treatment of MCL. The role of auto-HCT in patients receiving ibrutinib containing front-line therapies is not known. Proteasome inhibitors In a phase II, multicenter PINNACLE study, bortezomib showed excellent response rates as a single agent in relapsed/refractory MCL patients (1-year survival rate was 69% overall and 91% in responding patients).90 Even in a front-line setting as a combination therapy, bortezomib has shown excellent activity.91 Currently, an ongoing trial evaluating the combination of bortezomib and vorinostat (HDAC inhibitor) in the postauto-HCT setting (NCT00992446). Preemptive therapy with rituximab—is it the same as post-auto-HCT maintenance? Minimal residual disease (MRD) monitoring with PCR) for Ig heavy chain and/or bcl-1 rearrangement was used in the MCL-2 trial.92 Preemptive treatment with rituximab achieved a second molecular remission in 92% of the patients (n = 26) experiencing molecular relapse (PCR+ for Ig heavy chain rearrangement) post auto-HCT. After preemptive treatment, median clinical and molecular relapse-free survivals were 3.7 and 1.5 years, respectively. Though strictly speaking, preemptive therapy is not post-transplant maintenance; it is akin to the post-auto-HCT maintenance therapy but needs further investigation. CLASSICAL HODGKIN LYMPHOMA The standard-of-care for patients with chemosensitive relapsed/ refractory Hodgkin lymphoma (HL) has been HDT with auto-HCT, providing a cure for approximately 50% of patients.93 However, despite auto-HCT being the standard-of-care for relapsed/ refractory HL for over 10 years, further improvement in outcomes after auto-HCT have not been realized in recent years. Thus, the strategy of post-auto-HCT maintenance has been evaluated in hopes of further improving the outcomes. Bone Marrow Transplantation (2015) 1393 – 1404


1398 Drug–Ab conjugates Brentuximab vedotin is an anti-CD30 Ab conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Brentuximab derives its antitumor activity by binding the ADC to CD30-expressing cells, leading to internalization of the ADC–CD30 complex followed by proteolytic cleavage and release of monomethyl auristatin E. Monomethyl auristatin E disrupts the microtubule network by binding to tubulin within the cell, thereby causing cell cycle arrest and apoptotic death of the cell.94 In a phase II study, brentuximab vedotin produced an overall response rate (ORR) of 75% HL patients who had relapsed or progressed after auto-HCT (n = 102) with manageable toxicity.95 This paved the path to prospective, multicenter, phase III randomized study (Athera trial) wherein 329 Hodgkin patients at increased risk of progression post auto-HCT, who had been treated with a minimum of two prior systemic therapies and had either achieved a remission (CR or PR) or had stable disease at the time of auto-HCT, were randomized to receive brentuximab vedotin (n = 165) or placebo (n = 164) (every 3 weeks for up to 16 cycles). Patients were eligible for the study if they met one of the following criteria: primary refractory disease following first-line therapy, first remission duration of less than 12 months or extranodal involvement at the start of salvage chemotherapy. Patients on the placebo arm who experienced disease progression were allowed to receive brentuximab vedotin as part of a different study. After a median follow-up of 2 years, median PFS was 42.9 months for patients on the brentuximab vedotin arm compared with 24.1 months for those in the placebo arm (hazard ratioo 1 across all subgroups in the brentuximab arm).96 In this study, prior therapy with brentuximab vedotin was not permitted. Therefore, an important question moving forward will be whether the AETHERA data are applicable to Hodgkin lymphoma patients with a history of exposure to brentuximab vedotin prior to auto-HCT. HDAC inhibitors HDACs are a family of enzymes that remove acetyl groups from lysine residues on histone and non-histone proteins, which regulate several oncogenic pathways, including cell cycle progression, survival, angiogenesis and immunity.97–101 Panobinostat is a potent pan-HDAC inhibitor with activity in Hodgkin lymphoma.102 In a phase II study by Younes et al.,103 heavily pretreated relapsed or refractory Hodgkin patients were administered panobinostat 40 mg orally three times per week. Reductions in tumor size were observed in 74%, with 27% achieving CR or PR. Unfortunately, the PATH study evaluating panobinostat maintenance post auto-HCT in Hodgkin lymphoma was terminated early owing to slow accrual.104 Although efficacy could not be formally evaluated owing to the small number of patients (n = 41) in this trial, it is interesting to note that more patients from the placebo arm discontinued from the study because of disease progression (28.6% placebo arm vs 14.8% panobinostat arm).104 Immunomodulators Lenalidomide has shown modest activity (n = 38, ORR of 19%) as a single agent in patients with relapsed or refractory HL in a phase II trial.105 Currently, a pilot study is ongoing to evaluate the feasibility of lenalidomide as a maintenance therapy post auto-HCT in relapsed/refractory HL (NCT01207921). Checkpoint inhibitors The results of two separate phase I trials with PD-1 inhibitors (nivolumab and pembrolizumab) have shown promising results in patients with relapsed/refractory classical Hodgkin lymphoma. In the nivolumab trial, of the 23 patients who received nivolumab, Bone Marrow Transplantation (2015) 1393 – 1404

the objective response rate was 87%, with 17% achieving a complete response and 70% a partial response; the remaining 13% had stable disease.106 In the pembrolizumab study, of the 29 patients treated with pembrolizumab, the ORR was 66%, with 21% achieving a complete response and 45% a partial response after 12 weeks.107 This led to a phase II study evaluating the efficacy of the PD-1 inhibitor, pembrolizumab, in HL as a post-auto-HCT maintenance therapy (NCT02362997). T-CELL LYMPHOMAS In mature T-cell lymphomas front-line therapies (for example, with CHOP) with or without auto-HCT consolidation, remains associated with high relapse rates. Several novel agents (for example, pralatrexate, romidepsin, brentuximab, belinostat and alisertib) have shown promising activity in relapsed refractory T-cell lymphoma and have recently been granted Food and Drug Administration approval. Of particular interest are the HDAC inhibitors (romidepsin, ORR of 29%, and belinostat, ORR of 26–28%),108,109 Ab drug conjugate (brentuximab vedotin, ORR of 86%)110 and aurora kinase inhibitors (alisertib).111 Owing to their encouraging activity in the relapsed refractory setting, HDAC inhibitors are currently undergoing evaluation in the postauto-HCT maintenance setting either alone (romidepsin, NCT01908777) or as combination therapy (vorinostat with bortezomib, NCT00992446). Brentuximab vedotin and alisertib are other potential drugs that warrant evaluation as posttransplant maintenance agents. FUTURE DIRECTIONS Novel agents Moving forward, to further improve outcomes for HL patients undergoing auto-HCT, efforts need to be focused on evaluating novel consolidation or maintenance strategies, possibly with agents not used in induction chemoimmunotherapies. Tables 3A and 3B, and Table 4 summarize the novel agents that are currently being studied in relapsed/refractory aggressive and indolent B-cell NHL and T-cell lymphomas and could be potentially studied in post-auto-HCT setting in future. Consolidation and/or maintenance with monoclonal antibodies (to cite a few—anti-CD 79b (Polatuzumab Vedotin), anti CD19 (MEDI 551) and anti-CD20 (Obinutuzumab and Veltuzumab)), HDAC inhibitors (Belinostat), PDL-1 inhibitors (MPDL3280A), Bcl-2 inhibitors (ABT-199), Aurora A kinase inhibitors (Alisertib) and mTOR/PI3K inhibitors (SAR245409) in the post-auto-HCT setting seems to be a potential area of further investigation. Maintenance with novel agents offers several potential advantages. Unlike rituximab, in certain histologies, some novel agents exhibit better single-agent activity (for example, ibrutinib for MCL, idelalasib for FL) and may provide a greater degree of disease control. Application of checkpoint inhibitors (PD-1 or PD-L1 antibodies) can capitalize on the reconstituting immune system post transplantation to provide better immune surveillance, and their known limited myelosuppressive potential could also be advantageous in the post-auto-HCT period of maturing hematopoiesis. It is also critical to keep in perspective practical considerations and barriers toward translating a promising maintenance approach into an approved maintenance agent in the clinic, including challenges in designing randomized studies in rare histologies and inherent accrual issues in such protocols, regulatory requirements for eventual Food and Drug Administration approval and often limited efficacy of promising agents in randomized/controlled setting. © 2015 Macmillan Publishers Limited


Targets PD-L1 expressed on tumor cells and tumor-infiltrating immune cells Anti PD-1 monoclonal Ab

MPDL3280A

mAb directed against CTLA4

Ipilimumab

Phase I with brentuximab vedotin

Phase I/II with lenalidomide Phase I/II with 90Yepratuzumab (antiCD22) Phase I/II with rituximab Phase I/II with RT and ipilimumab Phase I with rituximab

Phase II (with ICE/DHAP Phase Ib/II with lenalidomide

Phase I

Phase II

Phase II

Phase II

Phase I

Phase I/II (with GA101)

Phase I with GA101

Study design

Indication (not in post-autoHCT maintenance

NCT01896999 RR HL

NCT02205333 DLBCL NCT02254772 Low grade recurrent B-cell lymphoma NCT01729806 RR B-cell lymphoma

NCT01147393 FL

NCT02271945 RR aggressive B-cell lymphomas NCT02181738 Classical HL after failure of auto-HCT NCT02181738 Classical HL after failure of auto-HCT NCT02038946 RR FL who failed therapy with both CD20 Ab and an alkylating agent NCT02038933 RR DLBCL after failure of auto-HCT NCT00983619 RR advanced B-cell malignancies NCT01453205 RR DLBCL NCT01582776 RR follicular and aggressive B-cell lymphomas (DLBCL/MCL) NCT01995669 Relapsed indolent NHL

NCT02220842 RR FL and DLBCL

Ongoing trial

Engraftment syndrome and or autologous GVHD Engraftment syndrome and or autologous GVHD

Neutropenia, myelosuppression, infectious complications

Neutropenia

Pneumonitis, engraftment syndrome Pneumonitis, engraftment syndrome

Pneumonitis

Potential adverse events of post-auto-HCT setting

Abbreviations: ADCC = Ab-dependent cellular cytotoxicity; CTCLA4 = cytotoxic T-lymphocyte-associated Ag-4; DHAP = R-DHAP = dexamethasone, cytarabine and cisplatin; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HCT = hematopoietic transplant; HL = Hodgkin lymphoma; mAb = monoclonal Ab; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; ORR = overall response rate; PDL-1 = programmed death ligand 1, PD-1 programmed death 1; RR = relapsed/refractory.

mAb directed against CTLA4

A fully humanized mAb directed against the CD20 Ag

Veltuzumab

Ipilimumab

Fully humanized IgG1 mAb that selectivity Neutropenia binds to extracellular domain of the CD20 Ag on malignant human B cells

Obinutuzumab (GA101)

mAb against receptor OX40 (CD134) Toll-like receptor 9 (TLR9) agonist

IgG1k ADCC enhanced anti-CD19 mAb

MEDI-551

MEDI6469 SD-101

Blocks PD-1 on tumor-infiltrating immune cells

Toxicity (grade 3/4)

Nivolumab

MEDI0680 (AMP-514)

Mechanism of action

Drug

PD-1/PDL-1 inhibitors and monoclonal Ab currently studied in relapsed/refractory aggressive and indolent B-cell lymphomas that can potentially be studied in the post-auto-HCT maintenance setting

Table 3A.


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Oral selective small-molecule inhibitor of the anti-apoptotic protein Bcl-2

Oral small molecule targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) kinases Oral selective small-molecule inhibitor of the serine/threonine protein kinase Aurora A kinase

Oral selective small-molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class I PI3K

Oral small-molecule inhibitor of BTK

ABT-199 (GDC-0199)

SAR245409

Idelalisib (GS -1101)

Ibrutinib

Second generation BTK inhibitor Oral small molecule inhibitor of CRM1 (exportin 1 or XPO1)

ONO-4059 Selinexor (KPT-330)

Rash, Diarrhea, transaminitis

Diarrhea, transaminitis

Thrombocytopenia, neutropenia, leukopenia, lymphopenia, anemia, febrile neutropenia, oral mucositis

General physical health deterioration, diarrhea, hypophosphatemia, lung infection and cortical cataracts

Neutropenia, anemia, thrombocytopenia, leukopenia, lymphopenia

Anemia, neutropenia

Toxicities (grade 3/4) (AEs relevant to auto-HCT shown in bold text)

Indication (not in post-auto-HCT maintenance

NCT01328626 RR NHL

Ongoing trial

Phase I with R-ICE Phase I/II with Carfilzomib Phase II Phase Ib with lenalidomide Phase I Phase II

Phase III with rituximab Phase III with BR

NCT01695941 RR MCL and low grade NHL

Phase I with Bortezomib and Rituximab Phase II with +/Rituximab Phase I/II

NCT01659255 RR NHL NCT02227251 RR DLBCL

NCT01849263 RR FL NCT01766583 RR B-cell lymphomas

NCT01732913 Previously treated indolent NHL NCT01732926 Previously treated indolent NHL NCT02219737 RR DLBCL NCT02269085 RR MCL

NCT01306643 Previously treated low grade lymphoma

NCT01812005 RR B-cell NHL

NCT01567709 Lymphoid malignancies

NCT01897012 RR B-cell and T-cell lymphomas

Phase I with Vorinostat

Phase I with Romidepsin

Phase II with BR vs NCT02187861 RR FL BR alone Phase II NCT01403636 RR lymphoproliferative malignancies (DLBCL, FL, MCL and CLL/SLL)

Phase I with R or G NCT02055820 NHL and DLBCL and CHOP Phase I with BR NCT01594229 RR NHL

Phase I

Study design

8/23 pts had SD and 1/23 pt had CR

Primary end point of ORR (n = 28) of at least 25% in FL was achieved in Stage 1

ORR (n = 26) of 61.5%

ORR (n = 29) of 55%

Prelim data

Abbreviations: AE = adverse event; BR = bendamustine and rituximab; BTK = Bruton's tyrosine kinase; DLBCL = diffuse large B-cell lymphoma; FL = foillicular lymphoma; G = ABT-199; HCT = hematopoietic transplant; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; ORR = overall response rate; pts = patients; R = rituximab; SLL = small lymphocytic lymphoma.

Second generation BTK inhibitor

CC-292

Alisertib (MLN8237)

Mechanism of action

Drug

setting

Table 3B. Small-molecule-targeted therapies currently studied in relapsed/refractory aggressive and indolent B-cell lymphomas that can potentially be studied in the post-auto-HCT maintenance


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1401 Table 4. Drugs–Ab drug conjugates and vaccines currently studied in relapsed/refractory aggressive and indolent B-cell lymphomas that can potentially be studied in the post-auto-HCT maintenance setting Drug/Vaccine

Mechanism of action

Toxicities relevant to postauto-HCT setting

Ixazomib (MLN9708)

Proteasome inhibitor

Belinostat

HDAC inhibitor

Peripheral neuropathy, Phase II diarrhea, rash Fatigue, myelosuppression Phase I with Carfilzomib Phase II with Ibritumomab Tiuxetan Myelosuppression, fatigue Phase I/II with BR Phase II with R-DHAP Phase II Phase II with IL-2 after combination chemotherapya Phase I with IL-2

Temsirolimus

mTOR inhibitor

Autologous tumor-based vaccine (GM.CD40L)

Build an effective immune response to kill cancer cells.

Autologous tumor cell vaccine Polatuzumab Vedotin

Build an effective immune response to kill cancer cells. Ab–drug conjugate that targets Neutropenia CD 79b on the B-cell receptor complex

SAR3419

Ab–drug conjugate that Vision abnormalities, targets CD 19 myelosuppression Ab–drug conjugate that targets CD 70 Ab–drug conjugate that targets CD 37 Neutropenia, peripheral neuropathy Ab–drug conjugate that targets CD 25

SGN-75 IMGN529 ADCT-301

Study design

Ongoing trial

Indication (not in post-auto-HCT maintenance

NCT02158975

RR cutaneous and PTCL RR NHL

NCT02142530 NCT01686165 NCT01078142 NCT01653067 NCT00838955 NCT00101101

Phase II with Rituximab or GA101 and Bendamustine Phase II

NCT02257567

Advanced or recurrent FL RR FL or DLBCL

NCT01472887

CD 19+ RR DLBCL

Phase I Phase 1

NCT01015911 NCT01534715

CD 70+ RR NHL RR NHL

Phase I

NCT00020462

Relapsed aggressive B-cell NHL Relapsed FL or MCL RR DLBCL RR HL Relapsed or de novo MCL

RR NHL and HL

Abbreviations: DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HCT = hematopoietic transplant; HDAC = histone deacetylase; HL = Hodgkin lymphoma; IL = interleukin; MCL = mantle cell lymphoma; mTOR = mammalian target of rapamycin; NHL = non-Hodgkin lymphoma; R-DHAP = rituximab, dexamethasone, cytarabine and cisplatin; RR = relapsed/refractory. aCombination therapy includes either CHOP or Hyper CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine).

NK cell infusion—think outside the box Because of their ability to recognize and lyse a broad range of tumor cells, NK cells are promising candidates for cancer therapy.112 In the non-transplant setting, combined therapy with haploidentical NK cell infusion and interleukin-2 administration resulted in CR for 26% of AML patients.113 An infusion of haploidentical allogeneic NK cells has also been applied to patients with poor prognosis in HL.114 In addition, T-cell-depleted donor lymphocyte infusions containing alloreactive NK cells prevent relapses after allo-HCT by potentiating graft-vs-tumor effects.115 Recent studies have shown that HDAC inhibitors116,117 and heat shock 90 inhibitors118 upregulate the expression of NKG2D (activating receptors on NK cells) ligands, MICA and MICB on the tumor cells, thereby rendering tumor cells more susceptible to NK-cell-mediated cytotoxicity. Combination therapy of HDAC inhibitor with NK cell infusion post auto-HCT in future may provide effective antitumor effect and could be akin to postauto-HCT maintenance. MRD analysis—a promising approach Application of maintenance therapies to eradicate MRD post auto-HCT in lymphoid malignancies warrants investigation. Recently, the NCI group has shown that the detection of circulating tumor DNA using next-generation sequencing in DLBCL patients in remission after first-line therapies, identifies patients at risk of recurrence before clinical evidence of disease relapse.119 Using this approach of MRD detection after auto-HCT in DLBCL (and potentially other lymphoid malignancies) to identify patients who may benefit from maintenance therapies (selective targeting of patients at high risk of relapse) would not be an unreasonable approach going forward. The role of MRD in FL has been a topic of debate for more than a decade now. A recent Italian study (FIL FOLL05 trial) has tried to answer this question. In this study, MRD analysis was carried out using BCL2/IGH rearrangement on bone marrow samples in FL © 2015 Macmillan Publishers Limited

patients. MRD negativity at 12 and 24 months both in CR and in PR patients resulted in an improved PFS.120 Likewise, adopting this approach post auto-HCT in FL patients would identify patients at risk for relapse and may help direct preemptive and/or maintenance therapies in a risk-adaptive manner. MRD monitoring with PCR for Ig heavy chain and/or Bcl-1 rearrangement was used in the MCL-2 trial, following auto-HCT.92 In MRD-positive patients, preemptive treatment with rituximab achieved a second molecular remission in 92% of the patients. Such patients achieving a second molecular remission after preemptive rituximab, had a median relapse-free survival of 3.7 years. CONCLUSION In the past, studies looking at gene marking to detect the origin of relapse after auto-HCT in animal models,121 lead to the trials of ex vivo and in vivo purging techniques of autologous stem cell products. However, the negative results of subsequent randomized trials lead to studies looking for better disease control in autograft recipients. The success of immunotherapies as maintenance agents in NHL in the non-transplant setting invigorated investigations evaluating this strategy in the post-transplant setting. Although there were mixed results, these studies have paved the way for testing rationally designed, novel agents in the post-auto-HCT setting. With better molecular understanding of the intracellular machinery and advent of newer therapeutic agents, the day is not far when the constellation of effective salvage treatments followed by HDT and post-autograft disease-specific ‘precision’ maintenance therapies will develop into ‘total treatment’ programs capable of providing durable remissions in a majority of lymphoid malignancies. CONFLICT OF INTEREST The authors declare no conflict of interest.



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