Donor Lymphocyte Infusion and Graft-versus-Myeloma: Comparison
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Donor lymphocyte infusion (DLI) has the potential to significantly deepen the response after allogeneic stem cell transplantation (ASCT) in multiple myeloma (MM). Subsequently, DLI offers the opportunity for long-term progression-free and, most importantly, overall survival for patients with MM. DLI application is a complex procedure, whereby many factors need to be considered (e.g., patient-oriented factors prior to application, disease-specific factors, as well as possible combinations with further therapies during and after DLI). There are two settings in which DLI can be given, they are as follows: as a salvage option in progressive disease or in the prophylactic setting for MM patients with resolved disease to further deepen the response.

Donor lymphocyte infusion (DLI) has the potential to significantly deepen the response after allogeneic stem cell transplantation (ASCT) in multiple myeloma (MM). Subsequently, DLI offers the opportunity for long-term progression-free and, most importantly, overall survival for patients with MM. DLI application is a complex procedure, whereby many factors need to be considered (e.g., patient-oriented factors prior to application, disease-specific factors, as well as possible combinations with further therapies during and after DLI). There are two settings in which DLI can be given, they are as follows: as a salvage option in progressive disease or in the prophylactic setting for MM patients with resolved disease to further deepen the response.

  • graft-versus-myeloma
  • donor lymphocyte infusion
  • myeloma
  • allogeneic stem cell transplantation
  • prophylaxis
  • salvage
  • relapse

1. Introduction

Multiple myeloma (MM) is a yet incurable hematologic malignancy that has benefited from the advent of novel agents over the last decade. Despite major advances in treating MM throughout the disease course, allogeneic stem cell transplantation (alloSCT) remains a potentially curative treatment option [1,2]. However, the application of alloSCT is increasingly challenged by new therapies and its inherent association with treatment-associated morbidity and mortality [3,4]. Therefore, the proper incorporation of alloSCT within a whole (immune-) therapeutic environment, which improves outcome of specific subgroups of patients, needs yet to be identified, especially in the advent of ever-improving outcomes using novel agents [5,6,7].

Multiple myeloma (MM) is a yet incurable hematologic malignancy that has benefited from the advent of novel agents over the last decade. Despite major advances in treating MM throughout the disease course, allogeneic stem cell transplantation (alloSCT) remains a potentially curative treatment option [1][2]. However, the application of alloSCT is increasingly challenged by new therapies and its inherent association with treatment-associated morbidity and mortality [3][4]. Therefore, the proper incorporation of alloSCT within a whole (immune-) therapeutic environment, which improves outcome of specific subgroups of patients, needs yet to be identified, especially in the advent of ever-improving outcomes using novel agents [5][6][7].

Alloreactive immune effector cells originating from an MM-free graft may exert graft-versus-myeloma (GVM) effects, which can lead to the long-term control of disease [8]. One immunotherapeutic approach post-alloSCT is donor lymphocyte infusion (DLI), which is believed to augment these GVM effects supporting MM control, by deepening responses [9,10]. On the other hand, DLI may cause graft-versus-host disease (GVHD), which could become life threatening if it is acute, whereas even chronic GVHD may be important for the exertion of GVM effects [11]. Here, we present a comprehensive review of the role and the potential benefits and risks of DLI in post-alloSCT therapy for MM.

Alloreactive immune effector cells originating from an MM-free graft may exert graft-versus-myeloma (GVM) effects, which can lead to the long-term control of disease [8]. One immunotherapeutic approach post-alloSCT is donor lymphocyte infusion (DLI), which is believed to augment these GVM effects supporting MM control, by deepening responses [9][10]. On the other hand, DLI may cause graft-versus-host disease (GVHD), which could become life threatening if it is acute, whereas even chronic GVHD may be important for the exertion of GVM effects [11]. Here, we present a comprehensive review of the role and the potential benefits and risks of DLI in post-alloSCT therapy for MM.

2. Prophylactic Setting

Although DLI was mostly given in the context of refractory or progressive disease posttransplant (see above), this modality of immunotherapy has also been adopted for and incorporated into the prophylactic post-alloSCT setting for patients with resolved disease. These prophylactic applications of DLI using a prespecified schedule or planned escalated incremental doses during T-cell reconstitution may enhance donor-derived T-cell reconstitution and further support the GVM effect.

One early single-center analysis of 24 patients undergoing CD6 T-cell-depleted alloSCT from HLA-identical sibling donors between 1996 and 1999 evaluated prophylactic CD4+ DLI 6 to 9 months after alloSCT [12]. All patients, including patients with complete remission after alloSCT, were eligible to receive DLI if there was no evidence of GVHD and if they were not receiving medication for GVHD. The first 11 patients received a single infusion of 3 × 10

7

 cells/kg, and 3 patients received a single infusion of 1 × 10

7

 cells/kg. After DLI, no other immune-modulating therapy nor prophylaxis for GVHD was given. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted, resulting in 6 complete responses and 4 partial responses in patients with previous persistent disease. After DLI, 50% of the patients developed higher-grade acute GVHD (grades > 2). Survival at 2 years for all patients was 55%, and progression-free survival was 42%. The 14 patients receiving DLI showed a better 2-year progression-free survival of 65% when compared with a historical cohort of MM patients. This study also highlights the importance of patient selection and management, since only 58% of the included patients could actually receive DLI.

A long-term follow-up and single-center study of prophylactic DLI [13] recently underlined these findings, but also highlighted the complexity of the alloSCT treatment platform [14]. This study had a long-term follow-up of >5 years. A total of 61 patients with MM, who did not relapse nor develop disease progression after alloSCT, were treated with prophylactic escalating DLI, including a total of 132 DLI procedures. The overall response rate was high (77%). Thirty-three patients (54%) upgraded their remission status, with a quarter of patients even achieving molecular remission. The cumulative incidence of acute GVHD was moderate (33%), and no treatment-related mortality was observed. After a median follow-up of 69 months from the first DLI, 8-year progression-free and overall survival were 43% and 67%, respectively, with rates of 62% and 83% for patients in molecular remission. In multivariable analysis, molecular remission was the only independent prognostic factor for progression-free survival, while for overall survival, only cytogenetics were significantly associated with survival (i.e., worse outcome for high-risk cytogenetics). In that study, no impact of novel agents was observed. However, the use of novel agents was associated with more DLI procedures [13,15,16]. Furthermore, patients who received unstimulated DLI had a higher risk of acute GVHD, which was not associated with higher response rates in comparison with those who received G-CSF-stimulated T cells that were obtained from the original alloSCT product. These findings are in line with a recent comparison of stimulated and unstimulated DLI, showing no significant differences regarding response, survival, and safety [17]. The main results of the studies in both the prophylactic and salvage setting are listed in 

A long-term follow-up and single-center study of prophylactic DLI [13] recently underlined these findings, but also highlighted the complexity of the alloSCT treatment platform [14]. This study had a long-term follow-up of >5 years. A total of 61 patients with MM, who did not relapse nor develop disease progression after alloSCT, were treated with prophylactic escalating DLI, including a total of 132 DLI procedures. The overall response rate was high (77%). Thirty-three patients (54%) upgraded their remission status, with a quarter of patients even achieving molecular remission. The cumulative incidence of acute GVHD was moderate (33%), and no treatment-related mortality was observed. After a median follow-up of 69 months from the first DLI, 8-year progression-free and overall survival were 43% and 67%, respectively, with rates of 62% and 83% for patients in molecular remission. In multivariable analysis, molecular remission was the only independent prognostic factor for progression-free survival, while for overall survival, only cytogenetics were significantly associated with survival (i.e., worse outcome for high-risk cytogenetics). In that study, no impact of novel agents was observed. However, the use of novel agents was associated with more DLI procedures [13][15][16]. Furthermore, patients who received unstimulated DLI had a higher risk of acute GVHD, which was not associated with higher response rates in comparison with those who received G-CSF-stimulated T cells that were obtained from the original alloSCT product. These findings are in line with a recent comparison of stimulated and unstimulated DLI, showing no significant differences regarding response, survival, and safety [17]. The main results of the studies in both the prophylactic and salvage setting are listed in 

Table 1

 and 

Table 2

.

Table 1.

 Results of prophylactic donor lymphocyte infusion (DLI).

Study (Year) N Graft Type Dose (Range), ×10

Table 2.

 Results of salvage DLI.

Study (Year)

N

Graft Type

6 Cells/kg Response, %

Dose (Range), ×106 Cells/kg

Acute GVHD, n		 Survival

Response, %

Acute GVHD, n

Survival
Alyea [12] (2001) 14 MRD 10–30 86 7 PFS: 65% 2y

Lokhorst [9] (1997)

13

MRD

1–330

62

9

54% 1y
Badros [18] (2001) 14 MRD 120–220 86 10 OS: 69% 1y

Salama [20] (2000)

25

MRD/MUD

2–224

36

13

48% 1y

 Peggs [19] (2003) 20 MRD/MUD

Lokhorst [21]

1–100

(2004)

50 3 PFS: 30% 2y OS: 71% 2y

54

MRD

1–500

52

31

PFS: 19m

OS: 23m

 Kröger [10]

(2009)		 32 MRD/MUD 0.5–200 78 13 PFS: 54% 5y

El-Cheikh [22] (2012)

9

MRD/MUD

10–100

75

1

PFS: 50% 2y OS: 69% 2y

 Gröger [13]

(2018)		 61 MRD/MUD 0.3–100 77 7 PFS: 43% 8y OS: 67% 8y
Abbreviations: MRD, matched related donor; MUD, matched unrelated donor; GVHD, graft-versus-host disease; y, years; m, months; N, number; DLI, donor lymphocyte infusion; PFS, progression-free survival; OS, overall survival.

Montefusco

[

23

]

(2013)

19

MRD/MUD

0.5–100

68

2

PFS: 31% 3y OS: 73% 3y

Abbreviations: MRD, matched related donor; MUD, matched unrelated donor; GVHD, graft-versus-host disease; y, years; m, months; N, number; DLI, donor lymphocyte infusion; PFS, progression-free survival; OS, overall survival.

3. Salvage Setting

Donor lymphocyte infusions have long been an important strategy for patients with hematologic malignancies who have experienced relapse after alloSCT [24]. Early on, the most impressive results have been obtained in patients with post-alloSCT relapsed chronic myelogenous leukemia, especially when initiated in patients with cytogenetic relapse or in those who have relapsed into the chronic phase [25,26]. In the late 1990s, the first reports suggested antitumor effects in MM patients. In 1996, Tricot et al. [8] reported the achievement of complete remission with a single dose of CD3+ cells in an MM patient who had progressed after alloSCT, providing the first proof-of-concept for utilizing DLI to induce a GVM effect.

Donor lymphocyte infusions have long been an important strategy for patients with hematologic malignancies who have experienced relapse after alloSCT [24]. Early on, the most impressive results have been obtained in patients with post-alloSCT relapsed chronic myelogenous leukemia, especially when initiated in patients with cytogenetic relapse or in those who have relapsed into the chronic phase [25][26]. In the late 1990s, the first reports suggested antitumor effects in MM patients. In 1996, Tricot et al. [8] reported the achievement of complete remission with a single dose of CD3+ cells in an MM patient who had progressed after alloSCT, providing the first proof-of-concept for utilizing DLI to induce a GVM effect.

Soon after that, one retrospective study evaluated the impact of DLI in 13 patients with relapsed MM after alloSCT [9]. The patients received a total of 29 DLIs with T-cell doses ranging from 1 × 10

6

/kg to 33 × 10

7

/kg. Doses, sometimes with escalated levels, were repeated if no response or another relapse was observed after DLI. Eight patients responded, with 4 even achieving complete remission, while the others achieved partial remission. Median time from dli to response was 6 weeks. Major toxicities were secondary to GVHD, which was observed in >50% of patients and in >80% of the responders. Fatal aplasia was seen in 2 patients who responded. The only prognostic factors for response were single T-cell doses >1 × 10

8

/kg and the occurrence of acute GVHD. This first experience identified the importance of individual dosing schemes and acute GVHD, suggesting escalating doses until the maximum response has been achieved.

A follow-up and extension included 27 patients who received 52 DLI courses for a median of 30 months after alloSCT [21]. Fourteen patients (52%) responded to DLI, with 6 patients achieving complete remission (22%). Five patients remained in remission for more than 30 months after DLI. Acute GVHD was present in 55% of the patients. Two patients died due to aplasia. The median overall survival was 18 months. Comparing responders and DLI-resistant patients, the median survival was not reached compared with 11 months. In two patients, sustained molecular remission was observed. Again, one key factor that was associated with response was a cell dose >1 × 10

8

/kg.

Subsequently, a study from 4 Dutch transplant centers was reported [27], analyzing 54 patients (with a median age of 52 years), of whom 50 showed relapse following myeloablative partially T-cell-depleted alloSCT, and 4 following non-T-cell-depleted myeloablative alloSCT. Most patients received high-dose cyclophosphamide and total body irradiation (12 Gy) conditioning. A total of 95 DLI procedures (range, 1–7) for a median of 20 months were given. The T-cell doses of DLI varied between 1 × 10

6

 and 5 × 10

8

 cells/kg. Most patients received a starting dose of 1 × 10

7

 cells/kg. Dose escalation was done in the absence of response and acute GVHD until 3 months after the first DLI. Forty patients received reinduction therapy before DLI with vincristine/adriamycin/dexamethasone, dexamethasone alone, or melphalan alone. Response rates were comparable with previous findings, and progression-free and overall survival were 19 and 23 months, respectively. Acute GVHD after DLI was the strongest predictor of response. In patients with deletion of chromosome 13, as determined by double-color fluorescence in situ hybridization (FISH), no difference in outcome was seen.

Another study on dose-escalating salvage DLI was undergone in patients receiving reduced-intensity conditioning [28]. Grade 3–4 acute GVHD was found in 14% of patients and 1 patient died because of grade 4 acute GVHD. Despite the lower median cell dose for unrelated DLI (1 × 10

6

 compared with 4.7 × 10

6

 CD3+ cells/kg for related DLI), only the unrelated DLI recipients showed acute GVHD. With respect to responses, 19% showed complete response and partial remission, respectively. Stable disease was seen in 29%, while 33% of patients showed progressive disease. Median time from dli and response was 2 months. One-third of patients showed response after the first DLI. The median follow-up from DLI was 7 months, and 71% of the patients were alive, with three patients still in complete remission at the last follow-up at 8–14 months.

To assess the impact of combination approaches, a prospective phase 2 study evaluated the efficacy and safety of the combination of bortezomib/dexamethasone followed by DLI [23]. Patients received 3 cycles of bortezomib/dexamethasone followed by escalated doses of DLIs in the cases of response or at least stable disease. Fourteen days after the third course, and in the absence of acute GVHD, DLI was administered every 6 weeks at escalating cell doses, for up to 4 infusions. For the transplants from HLA-identical siblings, the infusions were done at the following cell doses: 5 × 10

6

 CD3+/kg, 1 × 10

7

 CD3+/kg, 5 × 10

7

 CD3+/kg, and 1 × 10

8

 CD3+/kg. For transplants from HLA-mismatched siblings or matched unrelated donors, the infusion scheme consisted of 5 × 10

5

 CD3+/kg, 1 × 10

6

 CD3+/kg, 5 × 10

6

 CD3+/kg, and 1 × 10

7

 CD3+/kg. In the case of complete remission before the first DLI, the patients received only the first 2 DLI doses. The study included 19 patients with a median age of 57 years. Fourteen patients received HLA-identical sibling alloSCT and 5 received matched unrelated donor alloSCT. Before DLI, the response rate was 62%, including 1 complete remission. After DLI, the response rate was 68%, observing a significant deepening of responses, showing 3 stringent complete responses and 2 complete responses. At a median follow-up of 40 months, 3-year progression-free survival and overall survival rates were 31% and 73%, respectively. Notably, no severe GVHD was seen.

4. DLI and Patterns of Disease Progression

To date, the clinical kinetics of alloreactive T cells in controlling MM progression or even inducing regression are not fully understood. An efficient GVM response requires accurate targeting of malignant cells by antigen-specific T cells in all sites of MM infiltration. While homing of T cells to the bone marrow was found to happen constitutively, other tissues may need ligand specificity of T cells, or inflammatory environments [30,31]. As a result, the strength of the immune response may differ and result in differential progression patterns of MM after cellular therapy such as alloSCT and DLI [32].

To date, the clinical kinetics of alloreactive T cells in controlling MM progression or even inducing regression are not fully understood. An efficient GVM response requires accurate targeting of malignant cells by antigen-specific T cells in all sites of MM infiltration. While homing of T cells to the bone marrow was found to happen constitutively, other tissues may need ligand specificity of T cells, or inflammatory environments [29][30]. As a result, the strength of the immune response may differ and result in differential progression patterns of MM after cellular therapy such as alloSCT and DLI [31].

One study hypothesized that alloSCT and DLI modulate patterns of MM progression. To test this, marrow and focal progression were assessed as separate events in a cohort of 43 patients who underwent alloSCT with planned DLI in comparison with outcomes of a cohort of 12 patients who did not receive alloSCT [33]. After DLI, complete disappearance of MM cells in the bone marrow occurred in 86% of evaluable patients. The probabilities of so-called bone marrow progression-free survival at 2 years after DLI was 62%. In contrast, the probability of focal progression-free survival was 28%. In sum, donor-derived T-cell responses effectively reduce bone marrow infiltration, while focal progression did not seem to be successfully influenced.

One study hypothesized that alloSCT and DLI modulate patterns of MM progression. To test this, marrow and focal progression were assessed as separate events in a cohort of 43 patients who underwent alloSCT with planned DLI in comparison with outcomes of a cohort of 12 patients who did not receive alloSCT [32]. After DLI, complete disappearance of MM cells in the bone marrow occurred in 86% of evaluable patients. The probabilities of so-called bone marrow progression-free survival at 2 years after DLI was 62%. In contrast, the probability of focal progression-free survival was 28%. In sum, donor-derived T-cell responses effectively reduce bone marrow infiltration, while focal progression did not seem to be successfully influenced.

In contrast, one study from Minnema et al. [32] showed that the treatment of extramedullary relapse after alloSCT, using DLI in combination with bortezomib or thalidomide, showed complete responses and did not differ in comparison with those who did not have extramedullary relapse. Notably, patients with only skin involvement showed complete response after DLI, while patients with multiple involvements of the kidney, skin, and lymph nodes showed no response. Whether antitumor effects are not only site-specific when comparing marrow and extramedullary sites, but also organ-specific, needs to be addressed in future studies.

In contrast, one study from Minnema et al. [31] showed that the treatment of extramedullary relapse after alloSCT, using DLI in combination with bortezomib or thalidomide, showed complete responses and did not differ in comparison with those who did not have extramedullary relapse. Notably, patients with only skin involvement showed complete response after DLI, while patients with multiple involvements of the kidney, skin, and lymph nodes showed no response. Whether antitumor effects are not only site-specific when comparing marrow and extramedullary sites, but also organ-specific, needs to be addressed in future studies.

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