Myeloma

Donor leukocyte infusions for multiple myeloma

Abstract

Donor leukocyte infusion (dli) has well-documented activity in cml, but the role of dli in other diseases is less well defined. to evaluate the strategy in multiple myeloma (mm) we evaluated 25 mm patients from 15 centers who were treated with dli. patients with persistent or recurrent disease after allogeneic bmt received dli from the original marrow donor (23 matched related, one mismatched family, and one matched unrelated). chemotherapy was given before dli in three patients. two of 22 patients responded completely to dli alone and three patients responded to the combination of dli and chemotherapy. nine patients who had not had sufficient disease control after dli were given additional dlis; five of these patients had either complete (two) or partial (three) responses. thirteen of 25 evaluable patients developed acute gvhd and 11 of 21 evaluable patients developed chronic gvhd; all responders developed gvhd. no patients developed post-dli pancytopenia. four patients had responses which lasted >1 year after DLI, three patients had responses which lasted <1 year, and three patients had ongoing responses but with follow-up <1 year. In conclusion, DLI has anti-myeloma activity but the strategy is limited by no response or short duration of response in a significant percentage of patients and by significant GVHD in the majority of the responders. Bone Marrow Transplantation (2000) 26, 1179–1184.

Main

Data from animal experiments and clinical observations strongly support the existence of a graft-versus-leukemia (GVL) effect of allogeneic bone marrow transplantation (BMT).12345 Based on the power of this effect and its mediation by donor immune cells, several groups have treated patients in relapse after allogeneic BMT with donor leukocyte infusions (DLI) from their original bone marrow donor.678910111213 Leukocytes are collected from the donor by leukapheresis or phlebotomy and infused, generally without concurrent immunosuppression. DLI is most effective for chronic myelogenous leukemia (CML). Complete responses to DLI are seen in approximately 70% of patients with CML in early cytogenetic relapse or chronic phase.1113 Graft-versus-host disease (GVHD) occurs in approximately 60% of patients and is closely correlated with disease response.13

The role of DLI in multiple myeloma (MM) is less certain. Several case reports and small series have documented an apparent graft-versus-myeloma (GVM) effect of DLI,1314151617181920212223 and a recent review of the literature24 suggested an approximately 66% likelihood of response to DLI in myeloma. However, because of the relatively small number of patients reported thus far, and because of the potential for positive reporting bias, the overall usefulness of the approach in MM remains uncertain. To investigate further the role of DLI in MM, we analyzed 25 cases reported from 15 BMT centers.

Patients and methods

Design

We collected detailed information from 15 BMT centers about DLIs in 25 patients with MM. Data were collected retrospectively in 13 patients and prospectively in 12. Information collected included the following: demographics – patient sex and age; diagnosis – disease, date of diagnosis, treatment before BMT, and response to treatment; BMT – pre-BMT disease status, donor relationship, sex, and degree of histocompatibility, whether the BMT was T cell depleted, occurrence of acute and chronic GVHD; post-BMT relapse – date and extent of relapse, donor chimerism at relapse, and treatment of relapse and response to treatment; DLI – disease extent, pre-DLI chemotherapy and response, date of DLI, total nucleated cell dose, mononuclear cell dose, T cell dose, and concomitant cytokine usage; post-DLI response and complications – response to DLI and date, occurrence of pancytopenia and date, treatment of pancytopenia and response, occurrence and grade of acute GVHD, occurrence and extent of chronic GVHD, treatment of GVHD, response of GVHD to treatment, infectious complications, post-DLI relapse date, and extent of relapse; and last contact – performance status, GVHD status, and date and cause of death. For the purpose of this analysis, data from retrospective and prospective patients were pooled. Four of the patients were reported previously.13

Definitions

Relapse was defined as the recurrence or progression of M-protein after previous post-transplant documentation of disappearance or stabilization of M protein by protein electropheresis or immunofixation. Complete response following DLI was defined as disappearance of M-protein by protein electropheresis and immunoelectropheresis and bone marrow with less than 5% plasma cells. Partial response following DLI was defined as less than complete response but 50% reduction in M protein. Acute and chronic GVHD were graded by standard clinical criteria.2526 Pancytopenia was defined by the occurrence of an absolute neutrophil count less than 500/μl and/or platelet count less than 20000/μl, not deemed to be due to disease or chemotherapy. Patients who received chemotherapy before DLI were considered unevaluable for response to DLI. Patients were considered evaluable for acute GVHD and chronic GVHD if they survived 30 and 100 days post DLI, respectively.

Results

Patient demographics

Twenty-five MM patients received DLI (Table 1).

Table 1  Patient characteristics

Pre-DLI therapy

Three patients received chemotherapy shortly before the first DLI (melphalan 140 mg/m2 in two patients, EPOCH regimen (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) in one). One of these patients received chemotherapy before a second DLI as well (EPOCH regimen). A fourth patient received chemotherapy before a third DLI (VAD (vincristine, doxorubicin, dexamethasone)).

DLIs

Donor leukocytes were not manipulated in vitro. Cell doses were reported differently by different centers. In 18 cases, T cell dose was reported (median 1.0 × 108/kg, range 0.02–2.24). In two cases, the mononuclear cell dose was reported (1.65 and 3.2 × 108/kg) and in four cases, the total nucleated cell dose was reported (median 3.22 × 108/kg, range 1.63–5.55). In one case, no cell dose was available. Three patients received granulocyte colony-stimulating factor (G-CSF) mobilized DLI and 19 received unmobilized DLI; this information was not reported in three cases. One patient received interferon alpha before DLI, two patients received interferon alpha after DLI, and one patient received interferon alpha before and after DLI. One patient received cyclosporine and methylprednisolone for GVHD prophylaxis after DLI. The median follow-up duration after DLI was 56 weeks (range, 7–334+). Nine patients received more than one DLI (discussed below).

Disease response to first DLI

Two of 22 patients who received no pre-DLI chemotherapy achieved complete remission at 4 and 6 weeks post DLI (Table 2); duration of remission in these two patients was 10 and 26 weeks. Although one patient (reported previously13) relapsed at 10 weeks with detectable M-protein, the M-protein level remained low to absent (0–0.5 g/dl) for 398 weeks when he died of pneumonia associated with chronic GVHD; this patient had had chemotherapy-refractory disease before BMT with a persistently elevated serum M-protein of 1.7 g/dl at 4 months post BMT, immediately before DLI. The three patients who received DLI shortly after chemotherapy achieved complete remission at 3, 4 and 5 weeks post DLI that lasted for 26 weeks (after EPOCH), and 127 and 148+ weeks (after high-dose melphalan).

Table 2  Response to DLIa

Second and subsequent DLI

Nine patients received a second DLI a median of 16 weeks after the first (range 8–38 weeks) (Table 2). The T cell dose was reported in seven cases (median 3.3 × 108/kg, range 0.15–5.16), the mononuclear cell dose was reported in one case (0.63 × 108/kg), and no dose was available in one case. One patient received interferon alpha before and after DLI. One patient had relapsed after having initially responded to chemotherapy/DLI; the second DLI was also given after chemotherapy but the patient did not respond. The other eight patients had not responded to the initial DLI. One died 1 week after the second DLI of progressive disease. Two responded completely to the second DLI; the first complete responder died of GVHD 8 weeks after DLI with bone marrow remission documented at autopsy, and the second complete responder had a response documented at 17 weeks that has lasted for 49+ weeks. Two patients attained partial remissions at 6 and 3 weeks which have lasted for 24+ and 29+ weeks. Three patients did not respond to the second DLI but one of these received two additional DLIs; he had a partial response to the third DLI (cell dose 0.88 × 108 CD3+ cells/kg), given in combination with VAD chemotherapy, that lasted for 33 weeks, and a partial response to a fourth DLI (cell dose 4.1 × 108 CD3+ cells/kg) which has lasted for 8+ weeks.

Complications

With first and subsequent DLIs considered together, 13 of 25 evaluable patients developed acute GVHD (one grade I, six grade II, five grade III, one grade IV), and 11 of 21 evaluable patients developed chronic GVHD (six limited and five extensive). No patient developed pancytopenia deemed to be due to DLI. One patient died of GVHD and two died of infection.

Relationship of GVHD with response

Six of seven responding patients who were evaluable for acute GVHD developed acute GVHD and four of five responders who were evaluable for chronic GVHD developed chronic GVHD. Four patients developed neither acute nor chronic GVHD; none of these patients had disease responses.

Relationship of cell dose with outcome

Table 3 shows the relationship of cell dose with GVHD and tumor response. Patients receiving cell doses of 1 × 108 T cells/kg were more likely to have both GVHD and anti-tumor responses. Five patients did not respond to lower cell doses which were not associated with GVHD but did respond to subsequent DLIs with higher cell doses that were associated with GVHD.

Table 3  Association of cell dose with GVHD and responsea for patients whose T cell dose was recordedb

Survival

At a median follow-up of 56 weeks (median follow-up of 78 weeks for survivors), 12 of the 25 patients were alive, two free of disease, and 10 with disease (including three patients with ongoing partial remissions). Thirteen patients had died, 10 of progressive disease, one of GVHD, and two of infection.

Gauging the overall benefit of DLI

In an attempt to better understand the overall usefulness of DLI (alone or in combination with chemotherapy) in the management of MM patients we categorized benefit in terms of none (no disease response), minimal (disease response lasting less than 1 year), possible (ongoing response but with less than 12 months follow-up), and definite (response lasting 12 months) (Table 4). In addition, we assessed the cost paid for benefit in terms of severe GVHD (grade III–IV acute GVHD or extensive chronic GVHD) and toxic death. Thus, by this analysis, four of 25 patients definitely benefited, but three at the cost of significant GVHD. Three patients possibly benefited, two at the cost of severe GVHD, and three patients had minimal benefit (two at the cost of severe GVHD – one fatal). Fifteen of 25 patients definitely did not benefit and three of these 15 patients had the combination of no disease response and severe GVHD.

Table 4  Gauging the overall benefit of DLIa

Discussion

Our study of 25 patients confirms that lasting complete responses are possible in MM patients treated with DLI. With first and second DLIs considered together, four of 22 patients who were evaluable for response to DLI alone attained complete remissions; three additional patients attained partial remissions. Three additional patients attained complete remission after receiving DLI in combination with chemotherapy. GVHD (acute and/or chronic) occurred in 18 patients; all responding patients developed GVHD.

Several other cases of DLI in MM have been reported (recently reviewed by Mehta and Singhal24). Responses were seen in approximately two-thirds of patients. As in our study, GVHD was common and was closely correlated with response. Lokhorst et al16 reported a series of 13 patients. Responses occurred in eight patients (four CR, four PR). Acute GVHD occurred in 66% of the patients and in 87% of the responders; chronic GVHD occurred in 56% of the patients and 85% of the responders. As in our study, Lokhorst et al found that dose escalation led to response in some patients. In their study three patients, and in our study five patients did not respond to initial lower cell doses which were not associated with GVHD, but did respond to higher doses which were associated with GVHD. It is not possible, however, to rule out the possibility that apparent responses to the second DLI were actually to the first DLI, although the long interval between first and second DLI (median 16 weeks) makes this seem less likely.

Thus, it is clear from our report and several others that DLI can be associated with a significant GVM effect, which is usually associated with GVHD. However, the response rate in our series was lower than that reported in the aggregate literature. Our series is larger than others and its being derived from a registry may lessen the likelihood of positive reporting bias. However, drawbacks from analysis of registry data include heterogeneity of treatment regimens and intercenter differences in assessing and grading some outcomes. It should also be pointed out that responses in myeloma may be difficult to assess since corticosteroids, used to treat GVHD, may have significant anti-myeloma activity as well. Thus, it will be necessary to analyze additional cases to estimate better the likelihood of response to DLI in MM.

While it is certainly noteworthy that a GVM effect appears to exist, we believe it is important to address the overall usefulness of DLI as a treatment strategy. Thus, we have attempted to gauge how many patients in our study actually benefited from the approach in terms of long-term disease control and to gauge what price was paid for disease control. We found that only four patients (16%) had responses that lasted more than 1 year; three of these patients had significant (grade III acute or extensive chronic GVHD). Three patients had responses that lasted less than a year (two with significant GVHD, one fatal). Three additional patients have ongoing response (two with significant GVHD) but short follow-up. On the other hand, 15 patients did not respond, and three of these patients had the unfortunate combination of no response and significant GVHD.

Similarly, in the report by Lokhorst et al,16 although eight of 13 patients had a response, only three of these had responses that lasted more than 1 year and all of the long-lasting responses were associated with significant GVHD. Likewise, Tricot et al18 reported four MM patients who completely responded to DLI; however, all four developed severe GVHD and died of GVHD or associated infections. Thus, it would appear that long-term responses to DLIs in myeloma are not common and are usually associated with significant patient morbidity. It is possible that newer approaches to DLI, such as suicide gene-transduced T cells2728 and CD8+-depleted T cell infusions212223242526272829 might be associated with less GVHD while maintaining GVM.

There are several potential reasons for lack of efficacy of DLI in many cases of MM. Given the close association of disease response with GVHD, it is possible that GVM is not a tumor-specific phenomenon, but rather an alloreactive phenomenon. Certain donor–recipient pairs may be inherently more histocompatible than other pairs at minor histocompatibility antigens and thus less likely to experience significant GVHD with associated GVM. An alternative explanation is that myeloma cells may not serve as good targets for donor T cells in some instances due to poor expression of HLA, adhesion and co-stimulatory molecules.30 The potential clinical relevance of such issues in MM has yet to be established.

In conclusion, although our findings confirm the existence of a GVM effect which can be effectively harnessed in some cases, we would suggest that the percentage of myeloma patients who benefit in the long run from DLI, as currently practiced, may be relatively low. This underscores the need for additional research into mechanisms of GVM and mechanisms of resistance to GVM. Such research may lead to more effective and less toxic methods of adoptive immunotherapy in this disease.

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Acknowledgements

We thank Shanna Morris for data management, Jane Pryor for assistance in manuscript preparation and the Leukemia Association of North Central Texas for financial support.

Author information

Correspondence to RH Collins.

Appendix: study participants

Appendix: study participants

The following transplant centers contributed to this study by reporting patients: Baylor, Dallas: R Collins (n = 6); Vancouver General Hospital: T Nevill (n = 3); Johns Hopkins University: D Marcellus (n = 3); City of Hope: P Parker (n = 2); Arizona Cancer Center: A Briggs (n = 1); LDS Hospital: C Ford (n = 1); MD Anderson Cancer Center: S Giralt (n = 1); UCSF: C Linker (n = 1); Hospital de Sant Pau, Barcelona: R Martino (n = 1); Christchurch Hospital, New Zealand: N Patton (n = 1); Ohio State University: S Penza (n = 1); St Louis University: S Pincus (n = 1); University of Rochester: A Rapoport (n = 1); UCLA: M Territo (n = 1); Rocky Mountain Cancer Center: R Rifkin (n = 1)

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Salama, M., Nevill, T., Marcellus, D. et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 26, 1179–1184 (2000). https://doi.org/10.1038/sj.bmt.1702685

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Keywords

  • multiple myeloma
  • donor leukocyte infusions
  • adoptive immunotherapy

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