Immune-Modulating Drugs and Hypomethylating Agents to Prevent or Treat Relapse after Allogeneic Stem Cell Transplantation

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Review

Immune-Modulating Drugs and Hypomethylating Agents to

Prevent or Treat Relapse after Allogeneic Stem Cell

Transplantation

Nicolaus Kröger

1,*

, Thomas Stübig

1

, Djordje Atanackovic

2

1Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2Department of Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Article history: Received 27 July 2013 Accepted 15 September 2013 Key Words:

Immune-modulatory drugs Allogeneic stem cell transplantation

Graft-versus-leukemia-effect Hypomethylating agents Graft-versus-host disease

a b s t r a c t

Allogeneic stem cell transplantation is a curative treatment option for many hematological diseases, and the numbers of transplantations are steadily increasing worldwide. Major progress has been made in lowering treatment-related mortality by reducing intensity of the conditioning regimen and by improving supportive care (eg, for infectious complications). Accordingly, relapse after allogeneic stem cell transplantation has become the major cause for treatment failure. Major efforts to prevent or treat relapse are focused on cellular-(T cell, natural killer cell), cytokine-, or antibody-based strategies to enhance the graft-versus-tumor effect or circumvent immunoescape. In the more recent years, new classes of agents have shown activity in several hematological malignancies, and besides their immediate antitumor activity, most of them also possess immune-modulatory qualities that may be useful alone or in combination with adoptive immunotherapy after allogeneic stem cell transplantation to enhance graft-versus-tumor effects. Here, we summarize the current knowledge and potential use of 2 of these compounds in preventing or treating relapse after allo-geneic stem cell transplantation, namely immune-modulating drugs and hypomethylating agents.

Ó 2014 American Society for Blood and Marrow Transplantation.

INTRODUCTION

Allogeneic stem cell transplantation (allo-SCT) is an effective and curative treatment approach for hematological malignancies. The curative potential is mainly attributed to a strong graft-versus-leukemia (GvL) reaction mediated by allogeneic T lymphocytes and natural killer (NK) cells, which target leukemic recipient cells by distinct mechanisms. Donor lymphocyte infusion (DLI) after transplantation may augment the GvL effect and is, therefore, widely used to prevent or treat relapse after allo-SCT. However, DLI is associated with an increased risk of acute and chronic graft-versus-host disease (GvHD), and the majority of studies have shown a strong correlation between response to DLI and occurrence of GvHD. Furthermore, the effectiveness of DLI depends on the underlying disease, and responses differ substantially between relapsed chronic myeloid leukemia (>80%), multiple myeloma (30% to 40%), non-Hodgkin’s lymphoma (40% to 50%), acute myelogenous leukemia/ myelodysplastic syndrome (AML/MDS) (15% to 30%), and acute lymphoblastic leukemia (10% to 20%) [1]. To reduce the risk of GvHD, CD8-depleted, CD4-enriched, or suicide geneemanipulated T cells have been investigated by several

groups [2-6]. Generation of T cells specific for

minor-histocompatibility antigens or tumor-specific antigens is under clinical evaluation[7-9]. To increase the efficacy of DLI, immunosuppression before DLI or combination with cyto-kine treatment (eg, interferon-

a

/GM-CSF or interleukin-2)

can also be used[10-12]. New efforts are currently under-taken to boost GvL effect either by adoptive transfer of leukemia-specific T cells [13], or by post-transplantation

vaccines [14]. Donor-derived NK cells exert GvL effect

without causing GvHD[15], because NK cells are thought to specifically target host-antigenepresenting cells of hemato-poietic origin, and, therefore, prevent the presentation of alloantigens to donor T cells. The antileukemic effect of NK cells may be best explained by predominant interaction of activating receptors such as killer immunoglobulin-like receptors (KIR) with the leukemic target cell[16-18]. Over-all, despite the efficacy of cellular therapy, there is still need to improve results of adoptive cell therapy treatment after allo-SCT for reducing related complications such as GvHD as well as improving remission rate, duration, and risk of relapse.

In addition to the development of more specific and

effective cell therapies, novel immune-modulatory drugs may be used as post-transplantation therapies alone or in combination with adoptive immunotherapy to augment GvL effects of allo-SCT and/or DLI. Ideally, a drug used as a single agent or in combination with adoptive immuno-therapy should (1) exert additive antitumor effects either by increasing immunologically mediated graft-versus-tumor reactions and/or immediate anti-tumor mechanism; (2) have the capacity to reduce the risk of GvHD while maintaining the GvL effect; (3) show a favorable toxicity profile for early application after allo-SCT; and (4) be able to inhibit immu-nosuppressive and tolerance mechanisms in the host.

Here, we focus on the immune-modulatory properties of immune-modulating drugs (IMIDs) and hypomethylating agents that may be used after hematopoietic stem cell transplantation, either alone or in combination with adop-tive immunotherapy, to augment GvL effects.

Financial disclosure: See Acknowledgments on page 171.

* Correspondence and reprint requests: Prof. Dr. Med. Nicolaus Kröger, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.

E-mail address:n.kroeger@uke.de(N. Kröger).

1083-8791/$e see front matter Ó 2014 American Society for Blood and Marrow Transplantation.

http://dx.doi.org/10.1016/j.bbmt.2013.09.009

American Society for Blood

ASBMT

and Marrow Transplantation

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IMMUNE-MODULATING DRUGS (IMIDS)

Immune-modulating drugs are thalidomide and its analogues, lenalidomide and pomalidomide. These drugs have an immediate antiproliferative effect on multiple

myeloma, non-Hodgkin’s lymphoma, and other

hemato-logical malignancies. In addition, antiangiogenic,

anti-inflammatory, and immune-modulatory properties may

contribute to antitumor effects; however, in vivo mecha-nisms mediating tumor responses remain to be elucidated. Thalidomide, a synthetic derivative of glutamic acid, which caused birth defects in the late 1950s and early 1960s, was thefirst IMID to be investigated with regard to its

immune-modulating properties. The latter include

antigen-independent stimulation of T cells and activation of NK cells[19]. It was later shown that second-generation IMIDs, such as lenalidomide and pomalidomide, are even more potent stimulators of T cellemediated immunity[20].

Activation of T cells requires signaling through the T cellereceptor, for example provided by antigen-presenting cells (APC), in combination with costimulating signals. IMIDs stimulate only T cells that have been previously activated by APC, such as dendritic cells. This activation abrogates

costimulation by APCs [21,22] and leads to a production

of Th1-type cytokines (interleukin-2, interferon-

g

) and a down-regulation of Th2-type cytokines (interleukin-4 and interleukin-10) [19]. T cell proliferation and cytokine production is significantly more amplified after stimulation with lenalidomide and pomalidomide compared with thalidomide; however, the clinical relevance of thisfinding remains to be determined. Molecular mechanisms mediating the IMID-induced proliferation and activation of T cells may involve transcriptional activity of activated protein-1 [23], increased tyrosine phosphorylation of CD28 on T cells

[21,22], and activation of the PI3K-signaling pathway in

activated T cells [21,22]. In vitro studies have shown that despite the increase of interleukin-2, generation of regula-tory T cells is inhibited. However, in vivo data suggest an increase of FoxP3þ regulatory T cells after treatment with lenalidomide; however, this was interpreted as a counter-regulatory effect [24-26], as an increase of HLA-DRþ acti-vated T cells preceded the increase of regulatory T cells[25]. IMIDs also stimulate the innate immune system, including

gd

-T cells, NK cells, and NKT cells [20,21,27].

Lenalidomide increases dendritic celleinduced NKT cell

expansion and secretion of interferon-gamma[28]. Thalid-omide, lenalidThalid-omide, and pomalidomide increase NK cell proliferation in the presence of interleukin-2[21], but only

lenalidomide and pomalidomide enhance

antibody-dependent cellular cytotoxicity, and natural cytotoxicity of NK cells[28,29]. The presence of cyclosporine A may abro-gate IMID-induced NK cell cytotoxicity, suggesting inter-leukin-2-dependency of NK cell activation and proliferation [27]. Furthermore, in the presence of IMIDs, activated NK cells produce cytokines, such as monocyte chemotactic protein and granulocyte-macrophage colony stimulating factor, in response to antibody-coated target cells, which might attract tumor-specific T cells and dendritic cells[30].

Lenalidomide was tested in a dose-finding study after

allo-SCT in multiple myeloma patients [31]. Lenalidomide was given between day 100 and day 180, and the maximal tolerable dose was 5 mg. Major toxicity was occurrence of acute GvHD, which was observed in 38% of the patients. Immune monitoring showed an early increase of

g

-interfer-onesecreting CD4þ and C8þ T cells, which may explain the onset of GvHD. In addition, an increase of NK cellemediated

toxicity was seen, and the complete response rate increased from 24% to 42%. A correlation between response and NK cell and T cell activation was also noted. A similar incidence of

GvHD has been observed by the HOVON group[32], which

started lenalidomide at a dose of 10 mg 1 to 6 months after nonmyeloablative allo-SCT for multiple myeloma. They

observed an increase of HLA-DRþ T cells, as well as of

regulatory T cells, but without correlation to clinical outcome. In patients without complete remission after allo-SCT, the remission status improved in 37% of the patients after lenalidomide treatment, mainly by conversion from partial response to very good partial response or complete response.

Lenalidomide as salvage therapy in relapsed myeloma patients after allo-SCT induced an overall response rate of 66% including 8% CR with only mild grade I to II GvHD in 12%

of the patients. In vivo measurement by flow cytometry

showed significant increase of activated NK (NKp44) as well as T cells (CD3þHLA-DRþ)[25].

Although all studies reported high remission rates of lenalidomide given after allo-SCT in myeloma patients, which could be even higher than after autologous stem cell transplantation [33], the effect of lenalidomide on GvHD remains controversial. Lenalidomide in combination with DLI was investigated in 12 myeloma patients who relapsed after allo-SCT. DLI was administered after 2 cycles of lenali-domide in an escalating mode, and no GvHD was seen[34].

In another study, lenalidomide was investigated as

post-transplantation therapy in MDS or AML with

del(5q)-abnormality. Lenalidomide (10 mg/day) was started at a median of 2.5 months after allo-SCT without dexa-methasone. The study was stopped prematurely because 6 out of 10 patients developed acute GvHD grade III or IV [35]. In another trial, 16 myeloma patients who relapsed after allo-SCT received lenalidomide (25 mg/daily), either alone or in combination with dexamethasone, resulting in an overall response rate of 88%, and GvHD was seen only in patients who received lenalidomide without dexamethasone (5 of 13) [26]. These trials suggested that lenalidomide can cause acute GvHD if given early after transplantation, and the risk of GvHD is lower if the drug is given later or in combination with dexamethasone.

Thalidomide given with a median dose of 200 mg as salvage treatment for relapse after allo-SCT was investigated in 33 patients by the Société Française de Greffe et de Moelle et Thérapie Cellulaire. An objective response was seen in 29% of the patients, but 5 patients (15%) developed acute GvHD [36]. Low-dose thalidomide (100 mg), followed by DLI for progressive disease or residual disease after allo-SCT, was investigated in 18 patients with multiple myeloma post-allograft[37]. Only 2 patients developed mild GvHD, and the overall response was 67%, including 22% complete remis-sions. In summary, IMIDs have immune-stimulatory prop-erties, which can be used effectively after allo-SCT, but because of the T cellestimulating effect, the risk of inducing GvHD should be considered. (Table 1)

HYPOMETHYLATING AGENTS

Methylation plays a central role in epigenetic regulation of gene expression[38]. Cancer cells use hypermethylation to switch off a vast number of genes that are responsible for growth inhibition, differentiation, and apoptosis [39]. Further epigenetic modifications are used extensively in CD4 T cells to regulate linage commitment. DNA-methyl-transferase-inhibitors azacytidine (AZA) or decitabine are

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clinically active in MDS and AML, and given their favorable toxicity profile, they represent a treatment modality that can be used also after allo-SCT[40]. 5-AZA incorporated in both RNA and DNA, unlike decitabine, which is only incorporated

in DNA[41]. The mechanism by which AZA exerts an

anti-tumor effect in MDS and AML remains not completely understood. Several immunological mechanisms induced by hypomethylating agents might contribute to their activity in MDS and AML. In addition to its effect on gene modification for cell growth and differentiation, 5-AZA treatment leads to upregulation of tumor-associated antigens, such as cancer-etestis antigens, thereby potentially augmenting immune recognition of malignancies [42-44]. In vitro studies with cultured T cells demonstrated a decrease of CD8þ T cells

accompanied by an increase in CD4þ T cells after 5-AZA

treatment. In addition, numbers of interferon-

g

þ T-helper-1-cells (Th1), as well as CD4þ and CD8þ memory T cells, were strongly suppressed. Proportions of CD4þFoxP3þT cells (regulatory T cells) showing a characteristic expression of inhibiting cytokines: IL-10 and TGF-

b

increased in a dose-dependent manner and, interestingly, 5-AZAetreated CD8þ T cells showed a significantly reduced capacity to kill AML cells, independently from modulation by CD4þ T regulatory cells[45]. Therefore, despite the ability to increase

tumor-specific antigens on tumor cells, the effect of

hypo-methylating agents on immune system is more suppressive. In addition to the effect on T cellemediated immunity, hypomethylating agents also influence innate immunity. KIR expression and variability are regulated by methylation in NK cells. KIR hypomethylation is associated with KIR expression and diversity [46]. Treatment of NK cells with the hypo-methylating agent decitabine induces KIR expression on NK

cells, and thereby enhances KIR variability[47]. Tabl

e 2 Immune-Modulating Drugs and Hypometh y lating Ag ents after Allog eneic S tem Cell T ransplantation Drug Author Indication Dosage Major Toxicity Outcome Lenalidomide Wolschke [31] Multiple myeloma (maintenance) 5 m g to 1 5 m g (DLT: 5 m g) 38% GvHD CR increase from 24% to 42% Kneppers [32] Multiple myeloma (maintenance) 10 mg 43% GvHD response improvement in 37% El-Cheikh [34] Multiple myeloma (relapse) plus DLI 8% neutropenia 75% ORR, only 8% GvHD Minnema [26] Multiple myeloma (relapse) 25 mg with or without dexamethasone Myelosuppression 88% ORR, GvHD only in patients without dexamethasone Lioznov [25] Multiple myeloma (relapse) 15 mg to 25 mg Myelosuppression ORR 66%, activated NK and T cells [ Sockel [35] MDS/AML wi th del(5q) 10 mg GvHD (60% grade III to IV) prematurely stopped Thalidomide Kröger [37] Multiple myeloma (relapse or MRD) (n ¼ 18) 100 mg plus DLI Weakness response in 67% (CR 22%), no severe GvHD Mohty [36] Multiple myeloma (relapse) (n ¼ 31) 200 mg 15% GvHD response in 29% 5-Azacytidine plus DLI Czibere [54] AML/MDS (relapse post allo-SCT) (n ¼ 226) 5  100 mg/m 2plu s DLI 33% GvHD response in 72% incl. 23% CR Lübbert [48] AML/CMML (relapse post allo-SCT) (n ¼ 26) 100 mg/m 2day 1 to 3 every 3 w eeks plus DLI Neutropenia 4  CR, 13  SD, acute GvHD in 8% Schröder [55] AML/MDS (relapse post allo-SCT) (n ¼ 25) 100 mg/m 2day 1 to 7 plus DLI Neutropenia 5  CR, 3  PR, 8  SD 5-Azacytidine alone Platzbecker [51] AML/MDS, (MRD positive) (n ¼ 20) 7  100 mg/m 2up to 4 cycles Neutropenia 80% response with increase in donor chimerism or stabilization, but 65% relapse Goodyear [56] AML (maintenance) 36 mg/kg BW  5 starting on day þ 42 Mild GvHD Regulatory T cells [[ , tumor-speci fi c T cells [[ de Lima [52] AML/MDS (maintenance after allo-SCT ) (n ¼ 40) 40 mg to 120 mg 5  starting day þ 42 (1-4 cycles) Thrombocytopenia 1 year OS: 77%, 32 mg/m 2optimal dose Jabbour [53] AML/ALL (maintenance) (n ¼ 8) 80 mg to 200 mg 5  starting 1 to 1 2 months after SCT (up to 2 years) Mild hematotoxicity 3  relapse, 7  alive (4  CR) Decitabine plus SCT Ravandi [50] AML/MDS (dur ing conditioning regimen) 10 doses Graft failure 8  CR/PR DLT indicates dose-limiting toxicity; CR, complete response; PR, partial response; SD, stable disease; GvHD, graft-versus-host disease; DLI, don or lymphocyte infusion; ORR, objective response rate; NK, natural killer; MDS, myelodysplastic syndrome; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; allo-SCT, allogeneic stem cell transplantation; OS, overall survival; MRD, matched related donor; BW, body weight. Table 1

Immune-Modulating Properties of Novel Drugs Drug Properties IMIDs Thalidomide Lenalidomide Pomalidomide In vitro:

CD4 and CD8 and T cell costimulation[19,21,22]

T regulatory cell suppression[20]

Th1-cytokine production[[23]

DC-induced NKT cell expansion[[27]

NK cell activation[21,25]

NK cell ADCC[[27,29]

Gamma/delta T cells/NKT cells[[20,21,27]

In vivo (human): Increase in activated T cells (CD3þ/HLADRþ)[25,33]

Increase in T regulatory cells (delayed)[24e26,33]

Increase in NKp44cells[25]

Hypomethylating agents

5-Azacytidine In vitro:

Expression of canceretestis antigens [[ on malignant cells[42,45,46] T regulatory[[[47] Th1YY[47] In vivo: T regulatory[[[53] CD8þ T cell response to tumor-specific antigens [[[53]

Decitabine NK cells: KIR expression[[[47]

DC indicates dendritic cells; NK, natural killer; IMID, immune-modulating drugs; KIR, killer immunoglobulin-like receptors.

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Hypomethylating agents have been used after allo-SCT [48]. The combination of hypomethylating agents and DLI might be favorable, taking the enhanced expression of HLA molecules as well as canceretestis antigens into account, which might make leukemic cells more vulnerable to donor T cell attack[44,49]. Decitabine has been used in relapsed leukemia patients as single-agent salvage therapy with second stem cell transplantation[50]. Graft failure has been observed when decitabine was given too close after stem cell transplantation, and the authors suggest an interference of hypomethylating agent or its metabolite with stem cell homing. 5-AZA was mostly used as salvage therapy for recurrent disease after stem cell transplantation or even

when ongoing relapse was detected by decrease of CD34þ

cell lineage chimerism. Using single-agent 5-AZA in those patients with a decrease of CD34 lineage chimerism to less than 80%, 50% of the patients achieved a complete chimerism and 30%, a stable donor CD34þ cell chimerism[51]. 5-AZA as maintenance therapy has been shown to be feasible without obvious increase in GvHD after transplantation [52,53]. 5-AZA in combination with DLI for relapsed leukemia or MDS patients has shown to be feasible with low risk of GvHD and moderate toxicity, which was mainly hematotoxicity. Furthermore, considerable response rates, even in patients with high-risk cytogenetics, have been observed (seeTable 2)

[54,55]. In 27 patients after allo-SCT for AML, to whom 5-AZA

was given at a dose of 36 mg/kg of body weight starting day þ42 post-transplantation, an increase of T regulatory cells was noted, and also in some patients, CD8þ T cell responses to Wilms tumor antigen or melanoma-associated

antigen-1 was seen [56]. Hypomethylating agents are

currently used in clinical trials after allo-SCT.

In summary, using post-transplantation drug therapy is of clinical interest to prevent relapse. Because of the tumor-specific activities, hypomethylating agents have been used primarily in myeloid malignancies, whereas immune-modulating drugs have been more frequently used in plasma cell disorders. Immune-modulatory properties of IMIDs can be used mainly to stimulate, via T and NK cell activation, GvL effect with the risk of GvHD, whereas hypo-methylating agents can be used to avoid severe GvHD without obvious increase of risk of relapse. Therefore, depending on the primary aim for intervention, both drugs can be used in combination with other cellular therapies such as DLI. Prospective studies are warranted to reduce the risk of relapse after allo-SCT.

ACKNOWLEDGMENTS

Financial disclosure: N.K. received research grants from Celgene. D.A. and T.S. have nothing to disclose.

Authorship statement: N.K. studied literature and wrote the manuscript. T.S. and D.A. studied literature and approved thefinal manuscript.

Conflict of interest statement: N.K. has received a research grant from Celgene; F.A. and T.S. have no conflicts of interest. REFERENCES

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