Graft-Versus-Myeloma

Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation

Summary:

In all, 41 multiple myeloma (MM) patients received an antithymocyte globulin (ATG), fludarabine, and busulfan-based reduced intensity conditioning (RIC) for allogeneic stem cell transplantation (allo-SCT) from HLA-identical siblings. In total, 29 patients (70%) were in partial remission, one patient in complete remission, and 11 (27%) with progressive disease at the time of allo-SCT. Median time between diagnosis and allo-SCT was 24 months. The cumulative incidences of grade II–IV and grade III–IV acute graft-versus-host disease (GVHD) were 36% (95% CI, 21–51%) and 7% (95% CI, 2–20%), respectively. Overall, 10 patients developed limited chronic GVHD, whereas seven developed an extensive form (cumulative incidence, 41% (95% CI, 26–56%) at 2 years). With a median follow-up of 389 days, the overall cumulative incidence of transplant-related mortality (TRM) was 17% (95% CI, 6–28%). In all, 11 patients (27%) are in continuous complete remission, and the Kaplan–Meier estimates of overall survival (OS) and progression-free survival (PFS) at 2 years were 62% (95% CI, 47–76%) and 41% (95% CI, 23–62%), respectively. PFS and OS were significantly higher in patients with chronic GVHD as compared to patients without chronic GVHD (P=0.006 for PFS and P=0.01 for OS). Collectively, these data demonstrate that RIC allo-SCT can mediate a potentially curative graft-versus-myeloma effect with an acceptable incidence of toxicity and TRM.

Multiple myeloma (MM) is a lymphoid malignancy with a median survival of 3 years.1 Despite the development of numerous conventional chemotherapy regimens, there has been little progress in improving the survival of patients with MM.1 High-dose chemotherapy with autologous stem cell transplantation (SCT) can result in prolonged response duration and survival.2, 3, 4, 5, 6, 7, 8, 9 Unfortunately, few, if any, patients with MM who receive high-dose therapy are cured.10 On the other hand, extensive clinical and experimental data support an important role for a graft-versus-tumor (GVT) effect in eradicating a number of different tumor cells in patients who receive allogeneic stem cell transplantation (allo-SCT).11, 12 Specifically, it has been shown that a graft-versus-myeloma (GVM) effect can be induced against MM even in patients who have been heavily pretreated or who relapse after high-dose therapy.13, 14, 15, 16 However, these promising results are often achieved at the cost of high treatment-related morbidity and mortality, considered as a contraindication to the use of standard myeloablative allo-SCT as a classical treatment strategy for MM patients.17, 18 As a possible less toxic alternative to standard myeloablative allo-SCT, reduced intensity conditioning (RIC) regimens for allo-SCT, combining highly immunosuppressive drugs or using low-dose total body irradiation, have been shown to induce durable donor cell engraftment with a relatively low rate of procedure-related toxicity and clinically effective GVT effect in some cases.19, 20, 21, 22, 23, 24, 25, 26, 27 Recently, it has been shown that application of RIC allo-SCT for MM, may temper the frequency of transplant-related toxicities, and allow a sustained disease-free survival in a significant proportion of patients.28, 29, 30, 31 However, specific data on the potential benefit of RIC allo-SCT for MM are still sparse and poorly defined. This report describes the results of 41 consecutive MM patients who received an antithymocyte globulin (ATG), fludarabine, and busulfan-based RIC for allo-SCT from HLA-identical siblings.

Patients and methods

Patients and donors

Study design

In all, 41 consecutive patients who received an RIC allo-SCT from HLA-identical donors for MM were included in this study. Patients were treated in a joint program between the Institut Paoli-Calmettes (Marseille), the CHU de Bordeaux (Bordeaux), the CHU Edouard Herriot (Lyon), and the Centre Jean-Perrin (Clermont-Ferrand) between June 1999 and March 2003. Approval for the study was obtained from institutional review boards at the four participating centers and corresponding local ethical committees. Written informed consent was obtained from each patient and donor. All donors were HLA-A-, HLA-B-, and HLA-DR-identical siblings. The primary aim of the study was to analyze engraftment and transplant-related mortality (TRM). Other objectives included determining the incidence of GVHD and disease response.

Conditioning regimen

The preparative regimen was adapted from that reported by Slavin et al,21 with fludarabine (Fludara; Schering AG, Lys-Lez-Lannoy, France) 30 mg/m2 for 6 or 5 consecutive days, oral busulfan 4 mg/kg/day for 2 consecutive days and ATG (Thymoglobuline; Sangstat, Lyon, France) 2.5 mg/kg/day for 5, 4, 3, or 1 day as indicated hereinafter. As part of the protocol, the ATG dose administered during conditioning was progressively decreased from 12.5 to 2.5 mg/kg.19 The first 24 patients received the higher total ATG dose of 12.5 mg/kg (n=11), 10 mg/kg (n=3) and 7.5 mg/kg (n=10), while the next 17 patients received the lower total ATG dose of 5 mg/kg (n=5) and 2.5 mg/kg (n=12).

Supportive care

Patient management (antibacterial and antiviral prophylaxis, transfusion policy) was performed according to the standard procedures of each center and was expected to be the same in all patients for a given center.

GVHD prophylaxis

In total, 13 patients received cyclosporine A (CsA) and short-course methotrexate (15 mg/m2 on day 1 and 10 mg/m2 on days 3 and 6) as GVHD prophylaxis.32 The remaining 28 patients received CsA alone at a dose of 3 mg/kg/day by continuous intravenous infusion, and changed to twice daily oral dosing as soon as tolerated. The CsA doses were adjusted to achieve blood levels between 150 and 250 ng/ml and to prevent renal dysfunction. CsA was tapered starting on day 90 if no GVHD appeared.

Graft source

In total, 14 patients (34%) received a bone marrow (BM) graft collected under general anesthesia, whereas 27 patients (66%) received peripheral blood stem cells (PBSC). For PBSC collection, donors were treated with granulocyte-colony-stimulating factor (G-CSF) (Filgrastim, Amgen, Neuilly-sur-Seine, France) at a dose of 10 μg/kg/day for 5 days. The day of BM or PBSC infusion was designated as day 0. The graft was analyzed for content of hematopoietic progenitors (CD34+ cells) and CD3+ lymphoid cells using standard flow cytometry procedures.

Clinical outcomes and GVHD assessment

Clinical outcomes after allo-SCT that were recorded included time of neutrophil and platelet engraftment, time to start, and severity of acute GVHD (aGVHD); chronic GVHD (cGVHD); disease relapse or progression, progression-free survival (PFS), and overall survival (OS). Time to neutrophil engraftment was defined as the first of 3 consecutive days in which the ANC exceeded 500/μl. Time to platelet engraftment was defined as the first of 3 days a platelet count was >20 000/μl without a need for platelet transfusion during a 5-day period. Acute and chronic GVHD were graded according to standard criteria.33, 34, 35, 36 Chronic GVHD was defined as any GVHD developing after day 100 including the progressive form if it followed as a direct extension of aGVHD. Other forms of cGVHD included the quiescent (onset after the resolution of aGVHD) and the de novo (not preceded by aGVHD) forms.

Donor leukocyte infusions (DLI)

Patients who relapsed after allo-SCT or who showed evidence of disease progression or had persistent disease without any sign of GVHD after immunosuppressive therapy withdrawal, were candidates for DLI ranging between 1 × 105 and 1 × 107 CD3+cells/kg. Patients with mixed hematopoietic chimerism beyond 3 months after allo-SCT were also candidates for pre-emptive DLI. Donors underwent a leukapheresis without cytokine mobilization for donor lymphocyte procurement.

Assessment of response

Disease progression was defined as re-emergence of MM (if a complete remission had been reached), or implied at least a 25% increase in M-protein from a prior stable condition, or development of new extramedullary disease.28 TRM was defined as death without evidence of disease progression. The response to treatment was defined according to the European Group for Blood and Marrow Transplantation (EBMT) criteria.37

Statistics

All data were computed using SPSS for Windows (SPSS, Inc, Chicago, IL, USA) and SEM software (SILEX, Mirefleurs, France). The Mann–Whitney test was used for comparison of continuous variables. Categorical variables were compared using the χ2 test. The probability of developing aGVHD or cGVHD was depicted by calculating the cumulative incidence with relapse and death without relapse or aGVHD or cGVHD as competing risks.38 Cumulative incidence estimates were also used to measure the probability of relapse or progression.38 Probabilities of PFS and OS were estimated from the time of allo-SCT using the Kaplan–Meier product-limit estimates.39 Differences between groups were tested using the log-rank test when Kaplan–Meier analysis was performed.

Results

Patients and disease characteristics

Patients and disease baseline characteristics are shown in Table 1. Briefly, the median age of recipients was 52 (range, 35–61) years. In all, 24 donor–recipient pairs (58%) were sex mismatched. Totally, 29 patients (70%) were in partial remission after salvage therapy given before allo-SCT, whereas only one patient was in complete remission. The remaining 11 patients (27%) were in refractory or progressive disease stage at the time of allo-SCT. In total, 34 patients (83%) received at least one autologous SCT in the course of their disease prior to entering this study. In patients who received an autologous SCT, the median time between allo-SCT and autologous transplantation was 4 (range, 2–57) months. Median time between the initial diagnosis of MM and allo-SCT was 24 (range, 6–146) months. Patients were not treated in a combined autologous/allo-SCT strategy. Patients in this series received a median ATG dose of 7.5 (range, 12.5–2.5) mg/kg.

Table 1 Patient and disease characteristics

Engraftment and GVHD

Table 2 summarizes transplant-related events. In this series, two patients died at days 5 and 7 after allo-SCT from a severe respiratory distress syndrome associated with septicemia. Another patient had a cerebral hemorrhage during conditioning, likely due to a cerebral vascular malformation. A fourth patient had persistent cytopenia with recurrent infections and died at day 69 post-allo-SCT of disease progression. The remaining 37 patients reached a sustained ANC of more than 500/μl at a median of 17 (range, 0–27) days. Platelet engraftment occurred at a median of 10 (range, 0–32) days. In all, 37 patients (90%) were evaluable for aGVHD. Two patients (5%; 95% confidence interval (CI), 1–18%) developed grade I aGVHD. The cumulative incidences of grade II–IV and grade III–IV aGVHD were 36% (95% CI, 21–51%) and 7% (95% CI, 2–20%), respectively (Figure 1a). The median time to onset of aGVHD was 34 (range, 14–85) days. The skin was the most common target of aGVHD, being involved in 13 of the 17 patients (76%) developing aGVHD; the gastrointestinal tract was involved in seven of these patients (41%) and the liver in five patients (29%). Over all, 33 patients (80%; 95% CI, 66–94%) survived beyond day 100 and were evaluable for cGVHD. Overall, cGVHD developed in 17 patients at a median time of 105 (range, 100–365) days after allo-SCT. In the 33 patients evaluable for cGVHD, 10 developed limited cGVHD, whereas seven developed clinical extensive cGVHD. The cumulative incidence of cGVHD (both limited and extensive cGVHD) was 41% (95% CI, 26–56%) (Figure 1b). Immunosuppressive treatments duration and types were assessed in all patients included in this study. At time of last follow-up, 29 patients (71%) were off all immunosuppressive therapy, and the median time for immunosuppressive therapy discontinuation was 86 days post-allo-SCT (range, 10–414). Among patients who experienced aGVHD, four patients needed high-dose steroids (prednisone, 2 mg/kg/day or above). Moreover, four GVHD patients needed a second-line immunosuppressive regimen (mycophenolate mofetil, n=2; ATG, n=1; and total lymphoid irradiation, n=1) replacing or being in addition to first-line salvage therapy, because of CsA and steroid-refractory or clinically worsening GVHD.

Table 2 Transplant-related events
Figure 1
figure1

Cumulative incidence of GVHD. (a) Acute GVHD; (b) chronic GVHD.

Donor leukocyte infusions

Overall, 14 patients (34%) in this series received up to four escalating doses of DLI starting at a median time of 145 (range, 62–680) days post-allo-SCT. DLI were given to establish full donor chimerism (n=3) or to patients who relapsed or who showed evidence of disease progression or had persistent disease without any sign of GVHD after immunosuppressive therapy withdrawal (n=11). GVHD occurred in two patients among the 14 who received DLI (one grade I and one grade III). Among patients receiving DLI for disease progression, four (36%) subsequently achieved partial remission.

Transplant-related mortality, disease response, and outcome

Of the 41 patients included in this study, 21 patients (53%; 95% CI, 38–68%) achieved an objective disease response during the follow-up period [complete remission (CR), n=10; partial remission, n=11], in addition to the one patient who was already in CR at the time of allo-SCT. The median follow-up of patients in CR was 12 (median, 2–33) months. Among patients in CR, eight experienced cGVHD (three extensive and five limited), of whom two are still under immunosuppressive therapy at time of last follow-up. Interestingly, three patients needed DLI to establish full donor chimerism before achieving CR.

Two patients had stable disease, three were not assessable for disease response because of early death, and 14 (34%; 95% CI, 20–48%) did not have any detectable disease response and progressed after allo-SCT (Table 3). Among the patients who survived beyond day 100 after allo-SCT and who had an objective disease response, 13 (65%) experienced limited or extensive cGVHD as compared to only four (31%) in those who did not respond (P=0.05). At time of last follow-up, 18 patients (44%) had died and 23 (56%) are still alive with a median follow-up of 389 (range, 74–1270) days, of whom 18 have responded, 10 in CR and eight in PR (Table 3). Overall, disease progression or relapse occurred in 21 patients (51%; 95% CI, 36–66%) at a median time of 131 (range, 24–1001) days post-allo-SCT. The majority of deaths (n=11; 61% of all deaths) were directly attributed to disease progression or relapse. One death was attributed to severe aGVHD, while four patients died of infections. Overall cumulative incidence of TRM (n=7) was 17% (95% CI, 6–28%) occurring at a median of 68 (range, 1–122) days post-allo-SCT. Interestingly, the cumulative incidence of TRM (n=5) was 18% (95% CI, 6–38%) in the 27 patients aged over 50 years, and 14% (95% CI, 2–44%) in the 14 patients aged under 50 (P=NS). The Kaplan–Meier estimate of OS and PFS at 2 years were 62% (95% CI, 47–76%) and 41% (95% CI, 23–62%), respectively. Interestingly, PFS and OS were significantly higher in patients with cGVHD (n=17) as compared to patients without (n=16) cGVHD (P=0.006 for PFS and P=0.01 for OS) (Figure 2a and b). Thus, because cGVHD by definition begins on day 100 following allo-SCT, we attempted to detect prognostic factors for better OS in patients who survived beyond day 100. When comparing the group of patients with cGVHD and the group of patients without cGVHD, all relevant prognostic factors (age, gender, CMV serostatus, disease status at allo-SCT, time from diagnosis to allo-SCT, monoclonal component type, disease stage, autologous SCT prior to allo-SCT, stem cell source, stem cell dose, ATG dose, GVHD prophylaxis, acute GVHD, DLI, overall follow-up) were not significantly different between the two groups (data not shown), further supporting the protective effect of cGVHD on disease progression or relapse.

Table 3 Disease response and outcome
Figure 2
figure2

Progression-free and overall survival according to chronic GVHD. (a) Progression-free survival after allo-SCT in patients with (n=17) and without (n=16) chronic GVHD (whatever its form); (b) overall survival after allo-SCT in patients with (n=17) and without (n=16) (whatever its form).

Discussion

In this study, we have analyzed the outcome of 41 high-risk MM patients given HLA-identical allo-SCT following ATG-based RIC. Although 66% of the patients in this study were aged over 50 years, overall TRM did not exceed 17% confirming the significantly lower TRM associated with RIC when compared to TRM rates reported with conventional myeloablative allo-SCT.17, 40, 41, 42 Our results suggest that in a busulfan, fludarabine, and ATG-based RIC, an objective GVM effect can be achieved without an increased risk of GVHD-related mortality. Allo-SCT for MM using myeloablative conditioning regimens has been the subject of controversy over the years because of the high rate of GVHD and TRM without a clear benefit from a GVM effect.43, 44 As of June 2002, 105 MM patients who received a RIC allo-SCT have been reported,45 with further evidence in other publications that the use of RIC allo-SCT for MM is rapidly growing.30, 46, 47, 48 However, issues related to TRM rate, GVHD incidence, and proof of a GVM effect are still unresolved because of considerable heterogeneity in patient selection criteria, conditioning regimens, timing of RIC allo-SCT (after autologous transplantation, in complete or partial remission, or after relapse), and comorbid conditions (age and exclusion criteria due to other organ dysfunction). In the series of RIC allo-SCT for MM reported by Badros et al,28 TRM in the first 100 days was 10% comparing favorably with results obtained in the myeloablative setting from the same institution. However, in that study, the cumulative incidence of aGVHD was relatively high (58%). Moreover, a more recent report from the same group (likely representing an update) included 45 patients, with 17 patients reported to have died from transplant-related complications giving an overall incidence of TRM of 38%,49 in line with other results from Majolino et al50 showing a 30% rate of TRM. In contrast to Majolino et al,50 who used a full dose of busulfan and melphalan regimen, the RIC regimen used by Badros et al (melphalan 100 mg/m2) is clearly of low intensity decreasing the risk of early TRM. Such a high long-term incidence of TRM might be explained by the systematic use of early pre-emptive DLI and a very short duration of immunosuppressive therapy.28 In our series, DLI were only administered to patients who had mixed donor–recipient chimerism or to patients who relapsed or who showed evidence of disease progression or had persistent disease without any sign of GVHD after immunosuppressive therapy withdrawal. Moreover, the overall GVHD-related mortality was impressively low (only one patient in this series). It is likely that the incorporation of ATG as part of the RIC regimen provided a powerful tool of in vivo T-cell depletion significantly decreasing the risk of deleterious GVHD without compromising the GVM effect.51 In this regard, we have previously shown a significant impact of ATG on GVHD, related to a dose-dependent in vivo T-cell depletion, effectively modulating the risk of GVHD after RIC allo-SCT.19

Although containing an intermediate dose of an alkylating agent (busulfan), it is unlikely that our ATG-based conditioning regimen alone could result in a long-term disease control because the majority of patients had relapsed after multiple chemotherapy regimens including autologous SCT with high-dose alkylating agents. However, such a regimen allows durable engraftment, and possibly, some level of disease control until the GVM could be mounted. At present, the immunosuppressive dose of the most commonly used agents necessary to allow engraftment of allogeneic stem cells is not well defined. Also, it is likely that patients heavily immunocompromised by prior therapy (different lines of prior chemotherapy including high-dose chemotherapy) are most likely to engraft, develop GVHD, allowing for establishment of the GVM effect and long term disease control. Although myeloma-specific cytotoxic T lymphocytes have been described in different settings,52, 53, 54 and a GVT effect has been observed in some hematological malignancies without clinically significant GVHD,55, 56 and although a longer follow-up is still needed, the GVM effect in our study, as in most other studies, was closely related to cGVHD. The latter is in line with previous data from both the myeloablative and RIC allogeneic transplantation settings12, 19, 57, 58, 59 showing that despite important efforts to separate immune effectors responsible for GVHD and GVT, the allogeneic GVT effect cannot yet be reliably dissociated from GVHD that is the major determinant associated with lower progression and better survival. In this study, the impact of stem cell source or ATG dose on GVHD incidence and outcome could not be assessed as it has been already shown in our previous studies,19, 60 likely because of the limited number of patients. Alternatively, we could not detect a significant impact of other factors such as disease status before allo-SCT or the number of prior autologous transplantations that influenced the final outcome separate from GVHD. This might be also due to the relatively small number of patients in this study. Thus, further large studies with a longer follow-up are needed to identify potential disease characteristics impacting outcome and the most suitable allo-SCT timing that is more likely to induce a beneficial and durable GVM effect. In this regard, Maloney et al31 have recently shown that a combination of planned autologous transplantation immediately followed by RIC allo-SCT after recovery is feasible and may result in a high rate of objective disease responses and low TRM in the first 100 days after allo-SCT.31

We conclude that in addition to a decreased rate of procedure-related toxicities, the relatively high response rate observed in our series warrants developing a ‘global’ RIC approach designed to enhance the GVM effect of allo-SCT. Assessment of the potential morbidity associated with cGVHD adjusted for quality of life may be crucial determinants for the ultimate outcome and are obvious targets of investigations into improving the safety of RIC allo-SCT approaches for MM.

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Acknowledgements

M Mohty was supported by grants from the ‘Association Méditerranéenne pour le Développement, de la Transplantation’ (Marseille, France) and from the ‘Ligue contre le Cancer du Gard’ (Nimes, France). We thank FB Petersen, MD (University of Utah Health Sciences Center, Salt Lake City, Utah) for critical reading of the manuscript. We thank the nursing staff for providing excellent care for our patients. We also thank the following physicians for their dedicated patient care and important study contributions: N Vey, RT Costello, R Bouabdallah, A Charbonnier, JM Schiano de Collela, C Chabannon, P Ladaique (Institut Paoli-Calmettes); and B Choufi, O Tournilhac (Centre Jean Perrin).

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Mohty, M., Boiron, J., Damaj, G. et al. Graft-versus-myeloma effect following antithymocyte globulin-based reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 34, 77–84 (2004). https://doi.org/10.1038/sj.bmt.1704531

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Keywords

  • Allogeneic stem cell transplantation
  • multiple myeloma
  • reduced intensity preparative regimen, graft-versus-tumor effect

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