Myeloma Allogeneic transplantation for multiple myeloma - Nature

Bone Marrow Transplantation (2001) 28, 841–848  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Myeloma Allogeneic transplantation for multiple myeloma: further evidence for a GVHD-associated graft-versus-myeloma effect R Le Blanc, S Montminy-Me´tivier, R Be´langer, L Busque, D Fish, D-C Roy, J Kassis, J Boileau, R Lavalleé, D Be´langer, F Letendre, J He´bert, G Sauvageau, C Perreault and J Roy Division of Hematology-Immunology, Hoˆpital Maisonneuve-Rosemont, Montreal, Canada; and Department of Medicine, Universite´ de Montreál, Montreál, Que´bec, Canada

Summary: We report a series of 37 consecutive patients with multiple myeloma (MM) who received an allograft between 1990 and 2000 at our institution. Median age was 47 years, and nearly 70% of patients were Durie–Salmon stage III. A median of five cycles of chemotherapy were given before transplant, with a median interval between diagnosis and transplant of 9.3 months. We report a nonrelapse mortality rate of 22% with a median followup period of 40 months, whereas complete remission (CR) rate at 12 months is estimated at 57%. Treatment failure rate and overall survival at 40 months are estimated at 52% and 32%, respectively. The number of chemotherapy cycles prior to allotransplantation achieved borderline statistical significance as a poor prognosis factor for overall survival (P ⴝ 0.05), while the presence of chronic graft-versus-host disease (cGVHD) was significantly correlated with CR achievement (P ⴝ 0.036). Our study confirms that early allografting in MM can yield toxicity rates significantly lower than those associated with historical cohorts, and supports the hypothesis that cumulative chemotoxicity has a negative influence on mortality and survival rates. More importantly, our study clearly demonstrates an association between cGVHD and CR and brings further evidence in favor of a graft-versus-myeloma effect. Bone Marrow Transplantation (2001) 28, 841–848. Keywords: allogeneic hematopoietic stem cell transplantation; multiple myeloma; graft-versus-host disease; graftversus-myeloma effect

patients. However, its precise role still remains to be better determined given the unacceptably high treatment-related mortality (TRM) rates – ranging from 30% to 55% – not compensated for by modest complete remission (CR) rates – ranging from 25% to 55% – in historical cohorts.1– 8 These poor results are further compromised by a high risk of relapse, leading to median survival rates that compare unfavorably to autologous HSCT.1 Historical cohorts have included series of heavily treated patients with refractory disease. For instance, 50% and 70% of patients in the Seattle cohort and the European Bone Marrow Transplant Registry, respectively, had chemoresistant disease: both groups reported TRM rates close to 50%.2,8 In contrast, more recent studies (Table 1) including less heavily treated patients with chemosensitive disease have yielded lower TRM rates ranging from 10–30%. Unfortunately, the achievement of lower TRM has not yet translated into a survival advantage as long-term overall survival (OS) rates still disappointingly hover around 30– 50% in larger series. That allotransplant offers lower CR and OS rates gives relevance to the fundamental question of alloreactivity potential of the graft, ie the existence of a graft-versus-myeloma (GVM) effect. It is in this context that we undertook a retrospective study of all patients who underwent allogeneic transplant for MM at our institution.

Table 1

Recent series of allotransplantation in multiple myeloma

Transplant center (Ref.)

Multiple myeloma (MM) is still largely considered an incurable condition, with a median survival ranging from 60 months for Durie–Salmon stage IA to 6 months for stage IIIB disease. To this day, allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only approach believed to offer a potential cure for a select group of Correspondence: J Roy, Hoˆpital Maisonneuve-Rosemont, 5415 Boul de l’Assomption, Montreál, QC, Canada H1T 2M4 Received 27 April 2001; accepted 2 August 2001

Vancouver 199524 Nottingham 199725 Toronto 19976 Bologna 199828 Palermo/Torino 199822 Michigan 199926 Netherlands 199923 EBMT 2001 (Group 2)29 Total and weighted averages

n

TRM (%)

CR (%)

OS (mo)

19 13 22 19 10 21 11 223 338

16 23 27 37 10 19 18 30 27

58 77 42 42 70 71 45 60 58

46% (36) 69% (70) 32% (36) 26% (48) 80% (18) 60% (25) 82% (36) 50% (48) —

n ⫽ number of patients; TRM ⫽ treatment-related mortality; CR ⫽ complete remission; OS ⫽ overall survival.

Allogeneic transplantation for MM R Le Blanc et al

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Patients and methods Records of all consecutive 37 patients who received allogeneic bone marrow or peripheral blood stem cell transplants between 1990 and 2000 at Hoˆ pital MaisonneuveRosemont, Montre´ al, Canada were retrospectively reviewed. Follow-up information was gathered until 1 November 2000. Eligilibity criteria Patients were referred to our tertiary care bone marrow transplant center by community hematologists for consideration of allo-HSCT. To be eligible for sibling allo-HSCT, patients had to be 55 years old or younger with symptomatic progressive disease, a Karnorfsky score above 70, and without any significant comorbidity. Multiple myeloma staging at the time of initial diagnosis was performed according to Durie and Salmon.9 Extensive bone disease was defined as three or more lytic lesions on skeletal survey. Donors and graft harvesting All donors were siblings, HLA-matched at six loci (HLAA, -B, and -DR␤1), except for one case of a single mismatch at a DR␤1 locus. Between 1990 and 1995, all recipients received bone marrow grafts obtained from donors harvested under general anesthesia, whereas blood stem cells were used afterwards. None of the grafts were T cell-depleted. Supportive care All patients received irradiated blood products. CMVseronegative recipients received CMV-seronegative blood products. Trimethoprim-sulfamethoxasone was given from the start of the preparative regimen until either granulocyte engraftment or a first episode of febrile neutropenia. Posttransplantation, TMP-SMX prophylaxis against Pneumocystis carinii was reinstated on discharge from the hospital and maintained for a minimum of 6 months or until discontinuation of immunosuppression. Low dose acyclovir (250 mg/m2 twice) was given prophylactically to all HSVseropositive patients. From 1990 until 1997, high-dose acyclovir (500 mg/m2 three times daily) was given to CMVseropositive recipients or recipients of a graft from a CMVseropositive donor.10 After 1997, all such patients were enrolled on a pre-emptive therapy study.11 Most patients (33/37) received 500 mg/kg of immunoglobulin intravenously weekly from day ⫹1 until day ⫹100. G-CSF was not routinely given post-transplant, but administered according to the attending physician’s clinical judgment. GVHD prophylaxis consisted of cyclosporin A (CsA) and short course methotrexate.12 CsA levels were maintained between 250 and 550 nmol/l. Donor lymphocyte infusions (DLIs) were given to a few patients with relapsing or progressing myeloma. Since the efficacy of DLIs in MM was still largely undocumented during the period covered by this study, it was left to the

Bone Marrow Transplantation

discretion of the attending physician to decide whether the patient’s condition warranted their use or not. Response criteria Regimen-related toxicity, liver veno-occlusive disease (VOD), and GVHD were assessed and graded according to standard criteria.13–19 Response to chemotherapy prior to allogeneic transplant was categorized according to SWOG response gradations as CR, partial remission (PR), stable disease (SD), or progressive disease (PD).20 Chemosensitivity prior to transplantation was defined as a greater than 50% reduction in plasma monoclonal protein or greater than 90% reduction in urine monoclonal protein and absence of progression of bone disease at the time of transplant. Preparative regimens consisted of cyclophosphamide 120 mg/kg and total body irradiation (TBI) 2 Gy twice daily for 3 days in 25 patients; busulfan 16 mg/kg and cyclophosphamide 120–200 mg/kg in seven patients; melphalan 140 mg/m2 and TBI in three patients; busulfan, cyclophosphamide and melphalan in one patient; and BCNU, VP-16, arabinoside and cyclophosphamide (BEAC) in one patient. Post-transplantation studies were performed prospectively at 3, 6, 12 months and yearly. They included serum protein electrophoresis with immunofixation, bone marrow aspiration and biopsy, serum ␤2-microglobulin level, and a skeletal survey. In addition, most patients also had serum protein electrophoresis with immunofixation performed every 4 weeks during the immediate peri-transplant period. CR post-transplantation – or post-DLI – was defined as the absence of a monoclonal paraprotein or light-chain component in the serum and urine using conventional electrophoresis with immunofixation, normal marrow cellularity with less than 5% plasma cells, and absence of disease progression on skeletal survey. Transient monoclonal or oligoclonal peaks arising during immune reconstitution were ignored. PR was defined as a reduction greater than 50% in the pre-transplant serum paraprotein level, a urine light-chain excretion of less than 0.2 g/day, and absence of bony disease progression. Stable disease was defined as a reduction of less than 50% in serum or urine paraprotein, and absence of bony disease progression. Relapse in a patient who had previously achieved a CR was defined as either of the following: reappearance of the initial paraprotein; marrow plasmacytosis greater than 5%; or clear evidence of disease progression on skeletal survey. Post-transplant progressive disease in a partial responder or a patient with stable disease was defined as an increase greater than 10% in serum paraprotein, doubling of daily urine paraprotein excretion, development of hypercalcemia, or bone disease progression. Patients who died prior to day ⫹120 from treatment complications were excluded from treatment response analysis. Statistical analysis Time-to-failure endpoint-type analysis included CR, treatment failure (TF), and OS analysis. CR, TF and OS curves were produced using Kaplan–Meier estimates,21 with curve comparisons made by the log-rank test. Death from any


cause was considered an event for OS. As we sought to study the clinical efficacy of allografting only in the subgroup of patients surviving the procedure, TRMs were censored events for the computation of CR and TF rate estimates. Since disease-free survival (DFS) assessment has CR achievement as a prerequisite and since a significant percentage of our patients only achieved PR, it appeared more meaningful to assess disease status post-allografting in terms of TF. Disease relapse, disease progression, or disease-related death were considered events for TF. Preliminary univariate analyses (likelihood ratio ␹2 and t-tests) using 0.05 alpha value were used to identify factors that could be used to build Cox proportional hazard regression models for OS, TF, TRM and CR rates. Variables examined were stage at diagnosis, chemotherapy (number of cycles or regimens prior to allo-HSCT), exposure to melphalan prior to transplant, time from diagnosis to transplant, age at transplant, date of transplant, disease status at alloHSCT, donor and recipient sex match, and presence or absence of aGVHD and cGVHD. Analyses showed that only two such models using a single variable – a model for CR using cGHVD occurrence, and a model for OS using number of cycles of chemotherapy pre-transplant – could be built. We therefore conducted bivariate Cox models for CR and OS only in order to assess more precisely the risk associated with the predictors.

therapy (range from two to 33) received. Median duration of disease from diagnosis to transplant was 9.3 months, ranging from 4 to 41 months. First, second, third or fourthline chemotherapy regimens varied during the period reviewed, with preference being given to VAD in more recent years. As represented in Table 3, a majority of patients (86%) received at least one cycle of VAD, of whom approximately half were not given any additional regimens. Thirteen patients (35%) were exposed to lowdose melphalan-based regimens. Of the seven subjects treated with high-dose (140–200 mg/m2) melphalan prior to allotransplantation, six received autologous stem cell support, including one who underwent tandem autologous transplants followed by three cycles of CHOP salvage therapy. Local radiation therapy was given to almost half (18/37) of our patients. Response rates to cytoreductive chemotherapy are given in Table 3. At the time of transplant, 17 patients were in CR (46%), nine in PR (24%), and six (16%) had stable disesase. Approximately two-thirds (67%) had chemosensitive disease and 20% had refractory disease. Response or chemosensitivity could not be evaluated in five (14%) patients, either because of non-secretory MM (two patients) or lack of information concerning the initial paraprotein level (three patients).

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Transplant data Results Patient population and response to cytoreduction Pre-transplant patient characteristics data are given in Table 2. Median age was 47 years; most patients had a high tumor burden, with 68% having stage III disease and 62% extensive bone disease. Patients in our cohort were not heavily pre-treated, with medians of only one chemotherapy regimen (range from one to four) and five cycles of chemo-

Table 2

The source of hematopoietic stem cells was blood for 19 patients (51%), who received an average of 6.5 ⫻ 106 CD34⫹/kg. There were no engraftment failures. Overall, median times to achieve a granulocyte count ⭓0.5 ⫻ 106/l and platelet count ⭓20 ⫻ 109/l on 3 consecutive days were 20 (range 11–30) and 19 days (range 7–123), respectively. There was an acceptable toxicity rate following allografting. As shown in Table 4, only three cases of severe (grade III–IV) regimen-related toxicity were observed. These included one case of gastro-intestinal grade III toxicity, one case of grade III glottal edema requiring preventative intu-

Patients’ characteristics at diagnosis n ⫽ 37 (%)

Table 3

Pre-allografting chemotherapy n ⫽ 37 (%)

Age in years Median Range

47 25–53

Sex Male Female

22 (59) 15 (41)

Monoclonal protein IgG IgA Light chain only Non-secreting ␬ light chain restriction ␭ light chain restriction

22 7 6 2 26 11

(59) (19) (16) (5) (70) (30)

Stage at diagnosis IA IIA IIIA IIIB Extensive bone disease

8 4 20 5 23

(22) (11) (54) (14) (62)

Prior regimens VAD only VAD and others MP only MP and others MP and VAD only ASCT with HD melphalan Disease status at transplant Complete remission Partial remission Stable disease Unevaluable Chemosensitivity at transplant Sensitive Resistant Unevaluable

17 32 2 13 8 6

(46) (86) (5) (35) (22) (16)

17 9 6 5

(46) (24) (16) (14)

25 (67) 7 (20) 5 (13)

VAD ⫽ vincristine, adriamycin, dexamethasone; MP ⫽ melphalan, prednisone; ASCT ⫽ autologous stem-cell transplant; HD ⫽ high-dose. Bone Marrow Transplantation


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Table 4

Treatment-related morbidity and mortality n ⫽ 37 (%)

Regimen-related toxicity None Grade I Grade II Grade III Grade IV Acute GVHD Grade I Grade II Grade III Grade IV Chronic GVHD Limited Extensive Nonrelapse mortality

3 18 13 2 1

(8) (49) (35) (5) (3)

2 5 8 1

(5) (14) (22) (3)

1 (3) 14 (38) 8 (22)

bation, and one case of severe stomatitis that led to upper airways obstruction, respiratory failure, anoxic brain damage and death. There were three cases of moderate VOD. Mortality before day 120 was 16% (6/37). Causes of death included: sepsis (n ⫽ 2), CMV pneumonia (n ⫽ 1), respiratory failure (n ⫽ 1), grade III acute GVHD (n ⫽ 1), and multi-organ failure (n ⫽ 1). There were 14 cases (38%) of grade II–IV acute GVHD contributing to the death of two patients. Finally, there was one case of limited and 14 cases (38%) of extensive chronic GVHD (cGVHD). Overall, we report a nonrelapse mortality rate of 22% (8/37) post-transplant, a statistic that includes two patients who suffered late (⬎day ⫹120) treatment-related deaths caused by GVHD. Clinical efficacy Twenty-five patients were evaluable for response: 15 patients (41%) achieved CR; seven (19%) achieved PR; and three (8%) died of PD. Four patients (11%) were unevaluable post-transplant, either because of non-secreting myeloma (n ⫽ 2), short (⬍120 days) follow-up post-allografting (n ⫽ 1), or lack of information (n ⫽ 1). CR was thus achieved in 60% of evaluable patients and 41% overall, while PR was achieved in 28% of evaluable patients and 19% overall. Median time to CR achievement was 128 days, with some later remissions, including one documented on day ⫹290 (see next section). Chemosensitivity as a predictor of response was also examined. Of the 18 evaluable patients with chemosensitive disease prior to transplant, 10 (56%) achieved CR, seven (39%) achieved PR, while one died of PD on day ⫹401. Notably, of the five evaluable patients with chemoresistant disease, three patients were still in CR on day ⫹1013, ⫹887 and ⫹145, respectively; two patients suffered early death secondary to multi-organ failure and PD. At a median follow-up of 40 months, we observed three relapses among the 15 patients achieving CR. One patient with early relapse subsequently developed extensive cGVHD and went into a second lasting CR (⬎1048 days). One patient received DLIs (total of 0.5 ⫻ 108 CD3⫹/kg) Bone Marrow Transplantation

without response, while the last relapsing patient died of PD without any further intervention. Disease progression occurred in five of seven patients achieving PR post-transplant, three of whom received DLIs. One patient achieved a lasting CR after receiving one DLI (0.7 ⫻ 108 CD3⫹/kg) and developing GVHD. One patient received two cycles of VAD followed by four DLIs (total of 3.0 ⫻ 108 CD3⫹/kg), and achieved PR without GVHD. One patient received two cycles of VAD followed by two DLIs (total of 1.3 ⫻ 108 CD3⫹/kg), without a response. All three patients with PD after allografting were unresponsive to VAD, or DLIs. Post-transplant outcomes Of interest for the confirmation of a putative GVM effect are the kinetics of CR achievement after allografting. The Kaplan–Meier estimates of achieving CR as a function of time are shown in Figure 1. The curve yields a CR achievement probability estimate of 57%, which reaches a plateau on day ⫹290. Only one patient with PD received one DLI during this period, without achieving any type of response. Occurrence of cGHVD is found to be a strong predictor of CR achievement, with a probability estimate almost reaching 80% for evaluable patients with cGVHD, and a P-value of 0.033 by log-rank test when comparing the subgroups with and without cGVHD (Figure 2). The Kaplan–Meier probability estimate for TF is 53% at 40 months (Figure 3). Not unexpectedly, disease progression was observed in most (82%) patients who achieved PR only, in sharp contrast to a probability of relapse for patients achieving CR of only 30% (P ⫽ 0.038 by log-rank, figure not shown). Finally, Kaplan–Meier probability estimates of OS for the entire cohort is 32% at 40 months (Figure 4). A bivariate Cox model confirms cGHVD as predictor of CR, with an OR of 3.40 (P ⫽ 0.036) and a 95% confidence interval (CI) of 1.08–10.7. Similarly, the number of cycles of chemotherapy received prior to allotransplantation had a negative impact on OS, with an overall risk (OR) of 1.07 (P ⫽ 0.05), that is, a 7% increased risk of death per cycle of chemotherapy received, and a 95% CI of 1.01–1.15. Discussion We report an overall non-relapse mortality rate of 22% in a cohort of 37 consecutive patients allografted for MM. This rate is much lower than the expected rate of approximately 50% observed in earlier literature,2,3,7,8 and more in keeping with those reported in contemporary MM series (Table 1)6,22–26 or after allotransplantation for other pathologies. A possible explanation for these encouraging results is that reduced TRM is expected whenever allotransplantation is performed early, in less heavily pretreated patients whose disease has not yet reached a state of refractoriness.8 This is concordant with our observation that the number of chemotherapy cycles prior to allo-HSCT reached statistical significance in our cohort as a negative predictor of survival. It should be emphasized that correlation between cumulative chemotoxicity, refractory status, and higher TRM rates in allotransplantation is not unique to MM, but has been observed in other diseases of mature lymphocytes


845

1.00 0.90

Complete remission (%)

0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00

0

2

4

6

8

10

12

14

16

18

16

18

Time to complete remission (months) Figure 1 Kaplan–Meier estimates of complete remission. 1.00 0.90

Complete remission (%)

0.80 0.70 No cGVHD (n = 4) cGVHD (n = 11)

0.60 0.50

(P = 0.033 by long-rank)

0.40 0.30 0.20 0.10 0.00

0

2

4

6

8

10

12

14

Time to complete remission (months) Figure 2 Complete remission achievement in presence or absence of cGHVD.

such as CLL.27 Lastly, another possible explanation for decreased TRM rates might be the improvement in supportive care over the past decade.28,29 That allogeneic HSCT may be a curative therapeutic modality for MM is shown by our own cohort. We found a significant CR probability estimate of 57% at 12 months for evaluable patients with a low relapse rate estimate of 30% in those achieving CR. The most important conclusion stemming from our retrospective study is that achievement of CR, a prerequisite for long-term disease-free survival, correlates significantly with the occurrence of cGVHD. To our knowledge, this is the first time that such a statistical correlation has been documented in a sizeable cohort, thus adding to the increasing evidence that a graft-versusmyeloma (GVM) effect may occur in an alloimmune setting.1,30–32 Our data also provide other evidence in favor of a GVM effect. First, two of the five patients with relapsing disease who received donor lymphocyte infusions (DLIs) had a response. Secondly, one patient with early

relapse subsequently developed severe extensive cGVHD leading to a second lasting CR. Thirdly, the gradual tempo of CR achievement post-transplant observed in our cohort might be the translation of a de novo alloimmune process whereby the donor immune system identifies host plasmacytes amongst potential targets of alloreactivity. In that respect, it is interesting to note that the rising slope of CR achievement in Figure 1 coincides with the post-transplant immunosuppression taper. Lastly, three of five patients with chemoresistant disease prior to transplant are still in CR. All these observations suggest the existence of a GVM-type alloreactive effector arm. The relatively high treatment-failure probability estimate of 53% at 4 years in our cohort, reaching 82% for those achieving only PR, indicates that one-half of our patients did not fully benefit from the putative GVM alloreactivity. It should be stressed that our CR definition was in clinical rather than molecular terms; this has important implications since relapses from CR may, in fact, represent progression Bone Marrow Transplantation


846

1.00 0.90

Treatment failure (%)

0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00

0

6

12

18

24

30

36

42

48

54

42

48

54

Time to treatment failure (months) Figure 3 Kaplan–Meier curve estimate of treatment failure. 1.00 0.90

Overall survival (%)

0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00

0

6

12

18

24

30

36

Survival time (months) Figure 4 Kaplan–Meier curve estimate of overall survival.

from a stage of minimal (molecular) residual disease. It is therefore clear that much remains to be done in order to optimize the putative GVM response since – unlike CML where an anti-neoplastic immune response is the norm rather than a hope33 – MM cells appear to be either less immunogenic, or less susceptible to the effector arm of the immune response. Optimization of the GVM effect requires a predictive model of an effective graft anti-tumor response, that is, the uncovering of the determinants and effectors of a potent GVM effect. In this respect, it would be of interest to study the immunogenicity of clonal immunoglobulins, tumorassociated antigens such as those of the MAGE family,34 or minor histocompatibility antigens complexed with MHC molecules.35,36 The prognostic value of cytogenetic abnormalities – and their molecular correlates such as integrity of the apoptotic machinery – should be better assessed as determinants of the myelomatous clone global susceptibility to the GVM effect. Finally, better identification of Bone Marrow Transplantation

the graft/DLI subpopulation(s) responsible for the respective GVM and the GVH effects may ultimately lead to their uncoupling to yield a properly targeted curative modality for MM. Future trials of allogeneic transplantation in MM will need to address the key issues of how to further minimize TRM rates, maximize CR rates, and prevent relapses. One could hope to minimize TRM rates by uncoupling the cytoreductive aspect of allo-HSCT from its GVM aspect. This could be done by performing early and rapid cytoreductive therapy which may include high-dose chemotherapy with autologous HSCT characterized by low TRM rates,23 followed by non-myeloablative allo-HSCT. Optimization of CR rates could then be achieved by exploiting the GVM effect through rapid withdrawal of immunosuppression, prospective DLIs,31 and perhaps immunomodulation with interferon.37 Quality of CRs should be assessed in molecular terms38 in order to initiate immunomodulation in a timely fashion. Short of generating a CR, GVHD induced


by immunomodulation could be considered a surrogate end-point, since our series demonstrates that occurrence of GVHD correlates with CR achievement. In summary, we report an overall nonrelapse mortality rate of 22% in a cohort of 37 patients allotransplanted for MM. Our estimates of CR, TF, and OS rates were 57%, 52%, and 32%, respectively, at 40 months. The number of chemotherapy cycles reached statistical significance as a poor prognosis factor for OS. In contrast, cGVHD was strongly associated with CR. Our findings, in addition to the temporal kinetics of CR achievement, attaining CR in some patients despite chemoresistant disease, and the effectiveness of DLIs, all support the existence of a GVM effect which will require further optimization in future studies.

Acknowledgements

13 14 15

16 17 18

Dr Le Blanc is the recipient of a Fujisawa Canada fellowship. 19

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