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© 2000 American Society for Clinical Oncology Donor Lymphocyte Infusions for Relapsed Multiple Myeloma After Allogeneic Stem-Cell Transplantation: Predictive Factors for Response and Long-Term OutcomeFrom the Department of Haematology, University Medical Center Utrecht, Utrecht; University Hospital St. Radboud, Nijmegen; University Hospital Dijkzigt, Rotterdam; Amsterdam Medical Center, Amsterdam; and Leiden University Medical Center, Leiden, the Netherlands; and University Hospital Nottingham, Nottingham, United Kingdom. Address reprint requests to Henk M. Lokhorst, MD, PhD, University Medical Center Utrecht, Department of Haematology (G.03.647), PO Box 85500, 3508 GA Utrecht, the Netherlands; email H.Lokhorst @digd.azu.nl.
PURPOSE: To determine the efficacy, toxicity, and long-term outcome and prognostic factors of donor lymphocyte infusions (DLI) in patients with relapsed multiple myeloma (MM) after allogeneic stem-cell transplantation (AlloSCT). MATERIALS AND METHODS: Twenty-seven patients received 52 DLI courses at a median of 30 months after the previous AlloSCT. Reinduction therapy was administered to 13 patients before DLI. RESULTS: Reinduction therapy was successful in eight of 13 patients. Fourteen patients (52%) responded to DLI, including six patients (22%) who achieved a complete remission (CR). Five patients responded after T-cell dose escalation in subsequent DLIs. Four patients experienced relapse or disease progression (three from partial response and one from CR). Five patients remain in remission more than 30 months after DLI. Major toxicity was acute and chronic graft-versus-host disease (GVHD), which was present in 55% and 26% of patients, respectively. Two patients died from bone marrow aplasia. Median overall survival of all patients was 18 months. Overall survival was 11 months for DLI-resistant patients and has not been reached for the responding patients. In two patients, sustained molecular remission was observed. The factors that were correlated with response to DLI were a T-cell dose of more than 1.108 cells/kg, response to reinduction therapy, and chemotherapy-sensitive disease before AlloSCT. CONCLUSION: These data confirm the potential and durable graft-versus-myeloma effect of DLI in patients with relapsed MM after AlloSCT. Future studies should be aimed at increasing response rates, especially in patients with chemoresistant disease, and reducing toxicity by limiting GVHD. Adjuvant DLI seems an attractive and promising approach for patients who do not achieve a molecular remission after AlloSCT.
DONOR LYMPHOCYTE infusions (DLI) have become an important strategy for patients with hematologic malignancies who have experienced relapse after allogeneic stem-cell transplantation (AlloSCT).1-3 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 who have relapsed into chronic phase. In this category of patients, 70% to 80% complete remissions have been reported after DLI.4 Data on other malignancies are relatively scarce. DLI in acute leukemias or myelodysplastic syndrome have been less effective, with only few cases achieving remissions.5,6 This may be due to the rapid proliferation of acute leukemias and the fact that the time to response after DLI is often prolonged. Alternatively, it may be that acute leukemia and myelodysplastic cells do not express the suitable target antigens for recognition by donor cytotoxic (T) cells. Also, in multiple myeloma (MM), several anecdotal reports have shown that DLI can restore remissions in patients with relapse after AlloSCT, demonstrating the existence of a graft-versus-tumor effect in myeloma as well (graft versus myeloma [GVM]).7-11 So far, the mechanism of the graft-versus-leukemia (GVL)/GVM reaction is largely unknown. It is likely that T cells and NK cells exert an alloimmune reaction, because DLIs in syngeneic twins have been unsuccessful.12 Several studies indicate that minor histocompatibility antigens (mHa) expressed on hematopoietic normal and malignant cells are targets for GVM/GVL reactions.13,14 However, GVM/GVL may occur without graft-versus-host-disease (GVHD), suggesting that GVL and GVHD may not always be mediated by the same population of effector cells and that a reaction against leukemia/myeloma-specific antigens may exist as well.15 In a previous report, we showed the potency of donor leukocytes to induce remissions in patients with relapsed MM after AlloSCT.16 A high T-cell dose of DLI (> 1.108 T cells/kg) was the only predictive factor for response in this small series of 13 patients. Although response to DLI tended to be associated with acute and chronic GVHD, this correlation was not statistically significant. Unanswered important issues include the long-term toxicity, durations of response, and survival after DLI-induced remissions. We now present the results of DLI in relapsed MM after AlloSCT in a larger group of patients with a prolonged follow-up period. The outcome shows that sustained remissions may be achieved, especially in patients who receive a high T-cell dose after previous response to reinduction therapy. These results may be of help for the design of prospective studies of DLI either as salvage therapy or as prophylactic adoptive immunotherapy as a strategy to prevent posttransplantation relapse in MM.
Patient Characteristics Patients who were refractory to or who experienced relapse after AlloSCT were candidates for DLI. Patients with World Health Organization (WHO) performance status of 4, active GVHD, severe infection, and abnormal renal and liver function were ineligible for the study (creatinine > 180 µm/L, bilirubin twice the normal value). A total of 27 patients were included. Thirteen patients have been described before16; their follow-up has been updated. Twenty-five patients received a partial T-cell–depleted graft, containing 1 to 7 x 105 T cells/kg. These patients received prophylactic immunosuppression consisting of cyclosporine only. Two patients received a non–T-cell–depleted graft; immunosuppression in these patients consisted of cyclosporine combined with methotrexate. All patients received a transplant from HLA identical siblings. In the outcome of active GVHD, immunosuppressive treatment was stopped 3 months after AlloSCT. In all patients, immunosuppression was stopped at least 1 month before DLI was given. Patient characteristics are listed in Table 1.
DLIs A total of 52 DLI procedures were performed at a median of 30 months (range, 5 to 96 months) after AlloSCT. T-cell dose varied between 1 x 106 and 5 x 108 T cells/kg. Patients who showed no response after at least 12 weeks were candidates for repetitive courses of DLI with escalated T-cell doses. Thirteen patients received reinduction therapy before DLI was given. Eight patients were treated with vincristine, doxorubicin, and dexamethasone (VAD),18 four patients received pulse dexamethasone 40 mg/d, and one patient received intermediate-dose melphalan 70 mg/m2.19 The decision to give reinduction therapy before DLI was not formal but depended on criteria such as symptomatic disease, rapidly progressive disease, and availability of the donor. Characteristics of DLIs, including cumulative numbers of T cells infused, are listed in Table 2.
Definition of Response and Relapse A partial remission (PR) was defined as at least 50% reduction in myeloma proteins in serum and urine lasting for at least 2 months and accompanied by improvement of clinical symptoms and other parameters like normalization of hemoglobin. A complete remission (CR) was defined as complete disappearance of myeloma proteins from serum as determined by immunofixation and from urine as determined by immunofixation and absence of bone marrow monoclonal plasma cells. A molecular remission was defined as a negative polymerase chain reaction (PCR) reaction in bone marrow samples as determined with a patient-specific allelic-specific oligonucleotide PCR (ASO-PCR) measured on at least two different time points.20 The sensitivity to detect malignant myeloma cells is between 1:104 and 1:10.5 Relapse was defined as reappearance of myeloma proteins or, in patients with PR, as doubling of myeloma proteins measured at least twice on two separate time points. Response criteria were used to evaluate both response to reinduction therapy and to DLI.
Definition of GVHD
Reinduction Therapy According to the criteria as outlined under Definition of Response and Relapse, five of eight patients responded to VAD, two of four patients responded to dexamethasone, and one of one patient responded to intermediate-dose melphalan. No CR was achieved after reinduction therapy.
Outcome of DLIs Two responding patients died from DLI-induced bone marrow aplasia at 2 and 3 months post-DLI. From the remaining 12 responding patients, four patients experienced relapse at 2, 3, 16, and 16 months after DLI. Three patients experienced relapse from PR and one from CR. Five patients are still in remission more than 30 months post-DLI (Fig 1).
Fourteen patients have died. Median overall survival (OS) of the whole group of patients was 18 months (Fig 2). Median OS for nonresponding patients was 11 months and has not been reached for the patients responding to DLI (Fig 3).
Predictive Factors for Response and Survival The only factors that were correlated with response to DLI were a T-cell dose greater than 1.0 x 108 T cells/kg, response to reinduction therapy, and remission before AlloSCT (Table 3). Although there was a strong tendency for more responses in patients with acute and chronic GVHD, the association was not significant, nor was there a positive correlation between the existence of a complete donor chimerism in the peripheral blood before DLI, the occurrence of GVHD after previous AlloSCT, and the time interval between AlloSCT and DLI. For OS, only female sex was statistically significant. The other factors tested (B2 microglobulin > 4 mg/L, previous infection with cytomegalovirus, WHO performance status, response to DLI, and occurrence of GVHD) were not significant.
Toxicity The major toxicity was acute GVHD, which was present in 56% of patients (15 of 27) after 38% of the DLI courses (20 of 52). Four patients developed severe grade 3 acute GVHD. Chronic GVHD was present in seven patients and was extensive in three and limited in four patients. There was no significant correlation between T-cell dose and the occurrence of GVHD. Bone marrow aplasia was recorded in five patients. Four of these patients were complete donor chimeras (T and non-T cells in the peripheral blood) and one patient was a mixed chimera at the time at which DLI was given; three of five patients had grade 3 acute GVHD when bone marrow aplasia occurred. Two patients died from septicemia during bone marrow aplasia. Both patients had not received reinduction chemotherapy. One patient died from cardiomyopathy. This patient was treated with three courses of VAD before AlloSCT and three courses of VAD before DLI.
Follow-Up of Two Patients in CR With ASO-PCR
These data confirm the potential and durable GVM effect of donor lymphocytes in patients with relapsed myeloma after AlloSCT. Fourteen (52%) of 27 patients responded to DLI, including six patients who achieved a CR. Until now, four patients have experienced relapse or have shown progression of disease: one from CR and three from PR. Two of these patients responded for the second time to a new series of DLI, and one of them is in a 24-month ongoing molecular remission after the addition of interferon alfa-2a. These findings indicate that in patients with relapsed disease after DLI, a repeated infusion of fresh donor lymphocytes should be considered. The median time of follow-up of the patients who are still in remission is 31 months. One patient has a sustained CR (including a negative PCR in consecutive bone marrow samples) for more than 6 years after DLI. Five other patients are still in remission more than 30 months post-DLI. In these patients, remission duration after DLI is exceeding remission time after the previous AlloSCT. These results clearly demonstrate the long-term efficacy of DLI in several patients and the possible curative potential of alloreactivity in MM. The high response rate to DLI observed in our study may be partly due to the fact that 25 of 27 patients initially received T-cell depleted transplants and that these patients were exposed to a large number of donor T cells for the first time with the administration of DLI.
Unfortunately, the overall prognosis for patients with relapsed MM treated with DLI remains rather poor. The median duration of survival for all patients was 18 months, mainly due to the short survival duration (median, 11 months) of refractory patients. A first step to improvement will therefore be an increase in the response rate to DLI. This, however, requires a better understanding of the molecular basis of GVM, ie, the effector cells and target antigens involved. Several reports note the association between GVHD and GVL suggesting that mHa expressed on both tumor cells and on normal cells function as targets for donor-derived cytotoxic T cells.5,11,24-26 Collins et al4 reported that 90% of patients who achieved CR after DLI had GVHD. Alyea et al,11 using CD4+ DLIs, found that all patients with a response had GVHD. On the other hand, it is obvious from other reports15 as well as from our patients that GVL and GVM may occur without GVHD. In six of 14 patients with response to DLI, this occurred without any signs or symptoms of GVHD. This might indicate that some responding patients had subclinical GVHD and a clinical GVM directed toward minor histocompatibility antigens, although it cannot be excluded that tumor-specific antigens were involved as well. It is also likely that different effector cells may be operating in GVM or GVL. Claret et al27 infused CD4+-enriched DLI but noted CD8+ expansions in responding patients. Both CD4+ and CD8+ leukemia-reactive cytotoxic T lymphocytes that recognize mHa have been generated from patients after AlloSCT.28,29 In our patients, the only predictive factors for response were a high T cell dose of DLI ( The major toxicity of DLI consisted of acute and chronic GVHD, which was present in 56% and 26% of patients, respectively. No predictive factors for the occurrence of GVHD could be identified, although there was a tendency for more GVHD in patients receiving higher T-cell doses. The most severe complication was bone marrow aplasia, which was present in 19% of patients and caused by excessive GVHD and the low number of residual donor hematopoietic cells, resulting in a treatment-related mortality rate of 11%. Future strategies aimed at improvement of outcome of DLI should therefore include procedures to limit GVHD. This may be achieved by an escalating-dose regimen of DLI starting with a much lower dose, which was found to be equally effective with significantly less toxicity.33 Other strategies are now being explored and consist of selective depletion of CD8+ cells or transduction of donor T cells with suicide genes.34,35 At present, however, it is not known whether the GVL/GVM potency of such modified DLI is affected as well. So far, there are no data available that show that alloimmune reactivity improves the long-term outcome of MM.36 One of the reasons for this is the high treatment-related mortality rate of AlloSCT in MM.37 An argument in favor of AlloSCT in MM is the rather high frequency of molecular remissions that is observed in patients with a CR after AlloSCT, although sustained molecular remissions after autologous SCT may be achieved as well.38-41 Our data show that molecular remissions may occur after DLI even in patients who achieved only PR after the previous AlloSCT. It therefore seems attractive to use the GVM potential of donor lymphocytes after less toxic myeloablative schemes. One possibility might be to administer pre-emptive DLI to restore GVM several months after a vigorous T-cell depleted AlloSCT.42-45 The other possibility might be to use nonmyeloablative chemotherapy and AlloSCT followed by DLI.46,47 Both strategies are now being explored in MM and the results are awaited. In conclusion, DLI is an effective therapy for treating patients with relapsed MM after AlloSCT and may induce long-term remissions in several patients. Future studies should be aimed at increasing response rate while reducing toxicity by limiting GVHD. Such goals may be achieved by treating all patients with reinduction therapy and by stratifying T-cell dose in DLI depending on response to the reinduction chemotherapy.
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Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91:756–763, 1998 Submitted November 18, 1999; accepted April 25, 2000. This article has been cited by other articles:
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TOP
ABSTRACT
INTRODUCTION
-IFN, interferon alfa. •, positive PCR bands; 
, no bands detected.
1 x 108 T cells/kg) and chemotherapy-sensitive disease before DLI and AlloSCT. The last observation might implicate that classic chemotherapy resistance mechanisms are also involved in resistance to alloreactivity. It may also be that DLI is only effective when tumor load is reduced. This is supported by published data both in mice and humans.
