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ORIGINAL REPORTS
January 31, 2011

Donor Lymphocyte Infusions Modulate Relapse Risk in Mixed Chimeras and Induce Durable Salvage in Relapsed Patients After T-Cell–Depleted Allogeneic Transplantation for Hodgkin's Lymphoma

Publication: Journal of Clinical Oncology

Abstract

Purpose

Reduced-intensity conditioning has minimized nonrelapse-related mortality rates after allogeneic transplantation in patients with Hodgkin's lymphoma, and relapse has now become the major cause for treatment failure. We aimed to assess the impact of donor lymphocyte infusions (DLIs) on relapse incidence when administered for mixed chimerism and their utility as salvage therapy when given for relapse.

Patients and Methods

This study reports the outcomes of 76 consecutive patients with multiply relapsed or refractory Hodgkin's lymphoma who underwent allogeneic transplantation that incorporated in vivo T-cell depletion. Forty-two patients had related donors and 34 had unrelated donors. DLIs were administered in a dose-escalating fashion to 22 patients for mixed chimerism (median time of first dose, 9 months post-transplantation) and to 24 patients for relapse.

Results

Three-year donor lymphocyte–related mortality was 7%, relating mainly to the induction of graft-versus-host disease. Nineteen (86%) of 22 patients receiving donor lymphocytes for mixed chimerism converted to full donor status. Four-year relapse incidence was 5% in these 22 patients compared with 43% in patients who remained relapse free but full donor chimeras at 9 months post-transplantation (P = .0071). Nineteen (79%) of 24 patients receiving donor lymphocytes for relapse responded (14 complete responses, five partial responses). Four-year overall survival from relapse was 59% in recipients of donor lymphocytes, contributing to a 4-year overall survival from transplantation of 64% and a 4-year current progression-free survival of 59% in all 76 patients.

Conclusion

These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkin's lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion.

Introduction

The refinement of strategies to reduce nonrelapse-related mortality (NRM) has facilitated more widespread application of allogeneic hematopoietic stem-cell transplantation (aHSCT), but despite considerable advances, further improvements in outcome remain limited by both graft-versus-host disease (GVHD) and relapse. These two factors remain intimately linked. GVHD contributes significantly to NRM and to morbidity, particularly following unrelated donor aHSCT. Conversely, prevention of GVHD with T-cell depletion (TCD) has been linked to slower immune reconstitution, a greater incidence of stable mixed chimerism (bidirectional tolerance) and reduced graft-versus-tumor activity.1,2 Unfortunately, the benefits of reduced NRM associated with reduced-intensity conditioning have been offset to various degrees by increased relapse risk,3,4 and there is currently little consensus on optimal therapeutic strategies in these relapsed patients and little significant data on long-term outcomes.5,6
Hodgkin's lymphoma (HL) is associated with a relatively high risk of relapse following reduced-intensity transplantation (44% to 81% at 2 to 3 years),713 regardless of pretreatment response status.3 Reduction in NRM from 43% to 61% at 1 to 3 years with conventional myeloablative regimens4,1417 to 3% to 25% with reduced-intensity approaches713,18 has therefore resulted in disease relapse becoming the commonest cause for treatment failure. Identifying strategies that reduce relapse or more effectively provide salvage therapy for relapsing patients is an imperative. The existence of a clinically exploitable graft-versus-HL (GVHL) effect has been suspected for some time on the basis of the association of GVHD with lower relapse rates and a relatively limited experience of responses to donor lymphocyte infusions (DLIs),15,19 although the impact of TCD, which is often taken as a surrogate for the importance of graft-versus-tumor activity, remains controversial.2,20 Experience with DLI has been extended more recently, but numbers remain small. Response rates in most series range from 35% to 55%,2,7,912,18 mirrored by the European Group for Blood and Marrow Transplantation (EBMT) registry experience (13 of 41; 32%),20 but few have been durable. Excluding those in our series, ongoing responses have been reported in only two (13%) of 15 at 9 to 12 months,9,12,18,21 with an estimated median overall survival (OS) following DLI of only 20 months in the EBMT series.20
Several factors could contribute to rates and durability of responses following DLI, including disease bulk at the time of DLI and whether relapse occurs in the setting of failed alloreactivity (ie, in the presence of GVHD, or potentially following most T-cell replete transplantation protocols). Both have been shown to be important factors influencing responsiveness to DLI in chronic myeloid leukemia.22,23 We report outcomes in patients receiving T cell-depleted aHSCT for HL, demonstrating strikingly low relapse rates in those receiving DLI for mixed chimerism, coupled with frequent and durable responses in patients receiving DLI for relapse.

Patients and Methods

Patients

Seventy-six patients with biopsy-proven HL underwent reduced-intensity transplantation incorporating in vivo TCD with alemtuzumab at our institution between October 1997 and June 2009. Patient characteristics are listed in Table 1. This high-risk cohort included 50 patients (66%) with primary resistant disease, all of whom had experienced failure of at least one line of salvage therapy and 27 of whom had relapsed following an autograft. The other 26 patients were all beyond first complete response (CR), and 18 had relapsed following an autograft. The analysis is retrospective, including 25 patients who were previously reported2,7 (included here with an additional 6 years of follow-up).
Table 1. Patient Demographics and Clinical Characteristics
CharacteristicAll Patients (N = 76)Mixed Chimeras Receiving DLI (n = 22)Full Donor Chimeras Not Receiving DLI (n = 18)Relapsed Patients (n = 31)
No.%No.%No.%No.%
Age, years        
    Median31253532
    Range13-5914-4720-4918-55
Sex        
    Male42 11 15 19 
    Female34 11 3 12 
Histology        
    Nodular sclerosis6991198616892787
    Mixed cellularity34151626
    Lymphocyte-depleted23151613
    Nodular lymphocyte predominant2315  13
Primary resistant5066125513722168
Failed autograft4559115011612168
Prior lines of therapy        
    Median5555
    Range2-102-83-83-8
Status at transplant        
    CR1722627422413
    PR3242104510561755
    Refractory26346274221032
    Untested relapse11      
Donor        
    MRD425518826331755
    MUD293831410561239
    MMUD571521126
Conditioning        
    FM-C6383167314782890
    BEAM-C1317627422310
Follow-up from transplantation, years        
    Median2.42.42.63.3
    Range0.8-12.10.8-10.61.2-12.10.9-11.5
Abbreviations: DLI, donor lymphocyte infusion; CR, complete response; PR, partial response; MRD, HLA-matched related donor; MUD, 10/10 HLA-matched unrelated donor; MMUD, 8-9/10 HLA-mismatched unrelated donor; FM-C, fludarabine, melphalan, Campath (alemtuzumab; Genzyme, Cambridge, MA); BEAM-C, carmustine, etoposide, cytarabine, melphalan, alemtuzumab.

Study Design

End points were incidence and cause of mortality, incidence of GVHD, incidence of relapse, and response to therapy. GVHD was assessed according to consensus guidelines. Patients treated earlier in the series (n = 10) were restaged by using conventional computed tomography (CT) criteria.24 The remaining 66 patients (87%) were restaged with positron emission tomography–CT (PET-CT) following transplantation by using the GE Advance PET scanner and the GE LightSpeed multislice spiral CT (GE Medical Systems, Buckinghamshire, United Kingdom), as previously described.25 PET scans were assessed visually by a core team of experienced nuclear medicine physicians, in keeping with the most recent consensus recommendations.24 Relapse was defined by recurrence or progression of [18F]fluorodeoxyglucose (FDG) –avid lesions in sites of prior disease, with or without new sites. In patients in whom FDG-avid lesions occurred only in new sites, relapse was confirmed by biopsy if accessible; otherwise, an interval scan was performed at 6 to 8 weeks to confirm progression in the absence of other potentially causative pathology. Chimerism was assessed by polymerase chain reaction analysis of short tandem repeat loci every 3 months.7 Patients were eligible to receive dose-escalating DLI from 6 months post-transplantation for mixed chimerism or earlier for relapse, starting with 1 × 106 CD3+ T cells/kg for mixed chimerism and between 1 × 107 and 1 × 108 CD3+ T cells/kg for relapse in those with matched related donors or between 1 × 106 and 1 × 107 CD3+ T cells/kg for those with unrelated donors.26 Cyclosporine was withdrawn before consideration of DLI, and chimerism analyses were repeated 8 to 10 weeks later to confirm the need for donor lymphocytes in mixed chimeras. Donor lymphocytes were not given to patients with active GVHD or improving chimerism. Debulking chemotherapy was used at the discretion of the attending physician.

Statistical Analysis

Data were analyzed according to previously published guidelines for assessment of outcomes after transplantation.27 Time-to-event outcomes with competing risks (ie, NRM, donor lymphocyte–related mortality [DLRM], relapse rate [RR], and GVHD) were estimated as cumulative incidence curves with relapse being a competing risk for NRM and DLRM, death in remission a competing risk for RR, and death without GVHD a competing risk for GVHD. NRM was defined as death from causes other than relapse. DLRM was defined as death following DLI from causes other than relapse. Comparison of cumulative incidence curves was performed by the method of Fine and Gray. Actuarial curves were estimated according to the Kaplan-Meier method for OS, progression-free survival (PFS) and current PFS (cPFS). PFS was measured from transplantation until relapse or death from any cause. Patients in ongoing remission following DLI given for relapse were censored at latest follow-up in cPFS analyses. Further statistical comparisons were performed by using Fisher's exact test, t test, or Mann-Whitney U test as appropriate. P values < .05 were considered significant.

Results

Engraftment and Toxicity

Data on engraftment, NRM, and GVHD incidence before DLI are outlined in Table 2. Ninety DLIs were administered to 45 patients (22 for mixed chimerism and 24 for relapse, including one initially treated for mixed chimerism; Table 1). Median follow-up from first DLI was 2.1 years (range, 0.3 to 8.5 years) in surviving patients. Post-DLI GVHD contributed substantially to the overall burden of GVHD. Only one patient receiving DLI for mixed chimerism developed grades 2 to 4 acute GVHD. Four others developed de novo extensive chronic GVHD. Grades 2 to 4 acute GVHD developed in eight patients receiving DLIs for relapse (grade 2, n = 2; grade 3, n = 3; and grade 4, n = 3) and de novo extensive chronic GVHD developed in five patients. Thus 23% of patients receiving DLI for mixed chimerism and 54% of patients receiving DLI for relapse developed GVHD, which required systemic immunosuppression. The 5-year cumulative incidence of either extensive chronic GVHD before DLI or GVHD requiring systemic immunosuppression after DLI was 31% (24% related donor v 40% unrelated donor; P = .2339). The DLRM calculated from time of first DLI was 7% at 3 years, with no significant difference according to whether DLIs were administered for mixed chimerism or relapse (5% v 9%; P = .4894) or according to donor type (7% related donor v 7% unrelated donor; P = .7520).
Table 2. Engraftment, GVHD Before DLI, and Nonrelapse-Related Mortality
CharacteristicAll PatientsRelated DonorUnrelated DonorP
No.%Cumulative Incidence (%)95% CINo.%Cumulative Incidence (%)95% CINo.%Cumulative Incidence (%)95% CI
Engraftment in days*             
    Neutrophils > 0.5 × 109/L            .8116
        Median11  11  11   
        Range8-25  8-25  9-18   
    Platelets > 20 × 109/L            .7908
        Median11  11  11   
        Range3-167  3-167  8-31   
Acute GVHD (grades 2 to 3)1317  37  1029  .0143
Chronic GVHD  137 to 25  125 to 28  145 to 36.9451
Nonrelapse-related mortality  1710 to 28  125 to 27  2413 to 43.2092
Abbreviations: GVHD, graft-versus-host disease; DLI, donor lymphocyte infusion.
*
Occurred in 75 (99%) of 76 patients.
There were no cases of grade 4 GVHD.
Causes included infection (n = 9), GVHD (n = 1), GI hemorrhage (n = 1), intracranial hemorrhage (n = 1), thrombotic thrombocytopenia purpura (n = 1), and acute myeloid leukemia (n = 1).

Relapse

Relapse occurred in 31 patients, with a 4-year cumulative incidence of 44%. Nine patients underwent biopsy to confirm relapse, and three underwent biopsy as diagnostic procedures in the setting of new FDG-avid lesions being reported as likely to represent infection. Relapse was confirmed in eight of the former and excluded in all of the latter (toxoplasmosis, n = 1; Mycobacterium avium, n = 1; and nonspecific inflammatory cells, n = 1). In the remaining patient, an endobronchial ultrasound-guided transbronchial needle aspiration failed to confirm relapse, but there was subsequent widespread progression on PET-CT. There was no significant difference in relapse incidence according to donor type (45% related donor v 44% unrelated donor at 4 years; P = .7536; Fig 1A). Relapse was significantly lower in the group that developed clinically significant GVHD (acute grades 2 to 4 or chronic). In this cohort, the cumulative incidence was 22% at 4 years compared with 53% in those without clinically significant GVHD (P = .0188; Fig 1B).
Fig 1. Cumulative incidence curves for relapse (A) for patients with matched related (blue) versus unrelated (gold) donors, (B) for patients with acute grades 2 to 4 or chronic graft-versus-host disease (GVHD; blue) versus those with only grade 1 or no GVHD (gold), (C) in those remaining relapse free at 9 months for patients receiving donor lymphocyte infusions (DLIs) for mixed chimerism (gold) versus those with full donor chimerism not receiving DLIs (blue) and those with mixed chimerism not receiving DLIs (gray), and (D) for full donor chimeras remaining relapse free at 9 months with (blue; n = 9) versus without (gold; n = 9) prior or current active GVHD.

Donor Lymphocytes for Mixed Chimerism

The median time to first donor lymphocyte dose was 287 days (approximately 9 months) in the mixed chimera cohort (Table 1). The median number of doses was two per patient (range, one to five doses). Nineteen patients converted to full donor status, one had falling levels of recipient chimerism coincident with development of GVHD before death, one had falling levels of recipient chimerism at last analysis, and one remains stable (< 5% recipient chimerism). The overall response rate was therefore 95%. Thirteen of the 19 patients who converted to full donor status had no evidence of GVHD.
Only one patient receiving DLI for mixed chimerism relapsed, resulting in a 4-year relapse incidence of 5%. For comparison, a further 22 patients remained progression-free at 9 months post-transplantation and did not receive DLIs. Their outcomes were compared with the outcomes of those receiving DLIs for mixed chimerism. Three patients received transplantations early in the program, and DLI was not given despite mixed chimerism. All three patients relapsed while remaining mixed chimeras. One further patient had falling levels of recipient chimerism and was managed expectantly. Levels began to rise at 12 months coincident with relapse. Sixteen patients were full donor chimeras by 6 months, and the final two were mixed chimeras but with active GVHD and subsequently converted to full donor status. The 4-year cumulative incidence of relapse in this group with full donor chimerism (n = 18; Table 1) was 43% (P = .0071; Fig 1C). Relapse risk seemed largely confined to the subgroup without active or prior significant acute GVHD (58% v 11%; Fig 1D). These relapse outcomes are summarized in Appendix Table A1 (online only).

Management of Relapse

Seven of the 31 relapsed patients did not receive DLIs. Reasons included active GVHD (n = 3) and early progression in patients who were refractory to salvage before transplantation (n = 2). One patient received radiotherapy only. All six died between 45 and 494 days following relapse. The seventh patient developed GVHD following cessation of cyclosporine with subsequent partial response, consolidated with radiotherapy.
Ten of the 24 patients receiving DLIs for relapse also received cytoreduction either before DLI (n = 7), between escalating doses due to disease progression (n = 2), or as consolidation following DLI (n = 1). The approach to such salvage was not prescriptive and included radiotherapy (n = 3), chemotherapy (n = 6), or a combination of both (n = 1). This group had relapsed significantly earlier following transplantation (median, 207 days; range, 88 to 596 days) than those not receiving cytoreduction (median, 458 days; range, 161 to 1544 days; P = .0377). There were no significant differences between the groups in terms of numbers relapsing with localized nodal disease or clinical stage at relapse (data not shown).
A median of two doses of donor lymphocytes were administered to those with related donors and those with unrelated donors, although the maximum dose differed according to donor type (median, 3 × 107 CD3+T cells/kg for related donors v 1 × 107 CD3+T cells/kg for unrelated donors; P = .0075). Fourteen patients achieved a metabolic CR and five achieved a metabolic partial response, giving an overall response rate of 79% (Fig 2). Response rates did not differ significantly according to donor type (77% for related donors v 82% for unrelated donors; P = 1.00) or time from transplantation to relapse (responders: median, 9 months; range, 3 to 51 months; nonresponders: median, 17 months; range, 6 to 32 months; P = .4772, Mann-Whitney test). Response rates were no higher in those receiving salvage chemoradiotherapy before DLI versus those receiving DLI alone in terms of either overall response (71% v 93%; P = .2474) or complete response (43% v 71%; P = .6384). Any trend was in the opposite direction, perhaps reflecting more aggressive underlying disease biology (earlier relapse) in those given salvage therapy. Patient numbers per group are too small to allow meaningful comparison according to disease status at the time of transplantation, but chemo-refractory disease did not preclude response, which occurred in four of six patients. Prior GVHD did not preclude an antitumor response, which occurred in seven of 10 patients, although it was predictive of recurrent GVHD, which occurred in all 10 patients, occurring more severely than the original episode in five. Four patients responded without GVHD.
Fig 2. Positron emission tomography-computed tomography (PET-CT) images of biopsy-proven relapse and response to donor lymphocyte infusions. (A) Whole-body PET image of patient with biopsy-proven submandibular, supraclavicular, and subpectoral relapse (arrows). (B) CT image showing submandibular lymphadenopathy (arrows). (C) Fused PET-CT image showing [18F]fluorodeoxyglucose-avid submandibular lymphadenopathy. (D)-(F) Corresponding whole-body PET, CT, and PET-CT images 6 months after DLI (3 × 106 CD3+ T cells/kg), demonstrating complete metabolic response maintained beyond 3 years. Red lines indicate level of CT cuts shown in (B), (C), (E), and (F).
Responses proved durable in the majority of patients. Five of the responders subsequently relapsed or progressed (two complete responders at 1.8 and 2.3 years following last DLI and three partial responders at 0.4, 0.5, and 1.2 years). Responses were maintained in 11 surviving patients at a median of 2.2 years (range, 0.3 to 8.5 years from DLI), including nine patients who did not receive salvage chemoradiotherapy. The cumulative incidence of relapse at 3 years from last DLI in the responders was 36% (Fig 3A). Excluding the three patients who died from GVHD-related complications, all of whom maintained CRs, post-DLI responses exceeded post-transplantation responses in 12 of 16 patients, and in three of the others, responses were ongoing at the time of analysis (Fig 3B).
Fig 3. Outcomes after relapse. (A) Cumulative incidence of relapse or progression from time of last donor lymphocyte infusion (DLI) in responding patients. (B) Difference in duration of response after DLI and response after transplantation presented as (response duration post-DLI) – (response duration post-transplantation) for each patient. Gold bars represent ongoing responses; blue bars represent patients who relapsed or progressed after an initial response to DLI. Patients dying of donor lymphocyte–related mortality are excluded. HSCT, hematopoietic stem-cell transplantation.
Four-year OS from relapse was 59% in those receiving DLIs. Although this cohort clearly represents a selected subgroup of relapsed patients with better prognosis, OS remained encouraging, even when all relapsed patients were included (47% at 4 years). This contributed to an actuarial 4-year OS from transplantation of 64% for the entire cohort of 76 patients (Fig 4A). Although actuarial 4-year PFS was 39% (Fig 4B), 4-year cPFS was 59%, reflecting the high salvage rates of relapsed patients with DLIs.
Fig 4. Kaplan-Meier survival estimates for the entire cohort of 76 patients. (A) Overall survival. (B) Progression-free survival (blue) and current progression-free survival (gold) illustrating the impact of salvage donor lymphocyte infusions.

Discussion

These data illustrate the therapeutic potential of GVHL, demonstrating that durable salvage and potential cure are achievable goals in patients with HL who relapse following aHSCT that incorporates in vivo TCD. Furthermore, the results suggest that preemptive DLI based on the detection of mixed chimerism may reduce relapse risk, in part explaining the apparently paradoxical reports documenting a lack of impact of TCD on RRs in HL.
Although there is relatively little data published on outcomes following DLI in HL, the current data appear somewhat discordant with the literature,912,18 and potential reasons for this merit consideration. Among these, two clear factors differentiate our experience from that of others: first, the delivery of DLI in the context of T-cell–depleted transplantations and second, the use of combined modality PET-CT to trigger intervention in the vast majority of patients (22 of 24; 92%). TCD is associated with a lower risk of GVHD and higher incidence of stable mixed chimerism. The two are likely linked, with the generation of a state of bidirectional tolerance associating with a lower incidence of harmful alloreactivity. However, such tolerance is predicted to result in a higher relapse incidence following TCD, providing the justification for the use of DLI in this setting. There is clear precedent for this in chronic myeloid leukemia, in which mixed chimerism in the T-cell lineage is associated with a higher incidence of disease relapse in the myeloid lineage.28 Our data demonstrate that DLIs are highly effective at converting mixed donor chimeras to full donor chimeras following TCD, illustrating development of a graft-versus-lymphohematopoietic system effect that can be delivered in the absence of overt GVHD in many cases, as in murine models.29 Restoration of this level of alloreactivity may successfully deliver a graft-versus-lymphoma effect, the potency of which may be enhanced in the setting of minimal residual disease, particularly in a tumor such as HL, which is characterized by establishment of an immunologically hostile tumor microenvironment. Indeed, much of the tumor mass in classical HL is composed of immunosuppressive Foxp3+ regulatory T cells and Tr1 cells that secrete interleukin-10, which are not part of the malignant clone30 but would be potential targets for alemtuzumab-mediated depletion. Establishment of this immune activity in patients with no overt evidence of disease may be beneficial in preventing relapse. In this regard, the use of PET-CT to guide intervention for relapse may also have relevance.
Although there is still controversy regarding the appropriate interpretation of PET studies and their utility in directing therapy, our data offer some indication of their potential for guiding DLI. Combined modality imaging allows earlier intervention in the majority of patients relapsing with lymphoproliferative disorders,25 although concerns have been raised regarding false positives. It seems unlikely that our high response rates represent overtreatment of nonrelapsed patients, because our relapse rates are among the lowest reported for HL despite the incorporation of TCD. Furthermore, we attempted to biopsy all patients in whom interpretation may have been equivocal and have confirmed relapse in eight of nine patients reported as suggestive of relapse. Subsequent progression was confirmatory in the ninth patient. We believe that early intervention at a time of lower disease burden and of a potentially less immunosuppressive microenvironment is likely to provide at least part of the explanation for the efficacy of T-cell immunotherapy in our patients.
It is surprising that DLIs in mixed chimeras appear so effective at reducing relapse when compared with that in established full donor chimeras. Differences in disease characteristics between the groups could contribute, although there were no statistically significant differences in terms of the number of patients with primary resistant disease (P = .3319), lines of prior therapy (P = .5371), or response status at transplantation (P = .4294; Table 2). Delayed DLI and conversion of mixed chimerism could be preferentially associated with enhanced antitumor activity, as has been suggested in murine models.31 It also is possible that the sensitivity of chimerism assays is an important factor. This may be as low as 3% to 5% with short tandem repeat polymerase chain reaction.32 More sensitive techniques might detect low-level recipient chimerism in full donor chimeras without active GVHD and, in these patients, DLI might have a similar impact on relapse risk as demonstrated in mixed chimeras. Alternatively, DLI might prove equally effective in full donor chimeras, although the lack of a useful surrogate for development of desired alloreactivity might increase the risk of GVHD.
We conclude that our data establish the potency of the GVHL effect following T-cell depleted HSCT and suggest that preemptive DLI based on mixed chimerism may reduce relapse risk. Although formal comparison with other series is not possible, the relapse incidence compares favorably with that in other reports, as do the high response rates and durability of responses to donor lymphocytes in relapsed patients. GVHD remains problematic following DLI in the relapsed setting, but overall incidence compares favorably with T-cell–replete protocols, even when post-DLI GVHD is incorporated. The combination of a modest NRM rate, modulated relapse risk, and high salvage rates following relapse delivers encouraging OS and current PFS rates in this high-risk cohort.
See accompanying editorial on page 952

Authors' Disclosures of Potential Conflicts of Interest

The author(s) indicated no potential conflicts of interest.

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Appendix

Table A1. Summary of Outcomes in Those Remaining Alive and Relapse Free by 9 Months According to Chimerism Status
Chimerism StatusGVHDDonor LymphocytesNo. of PatientsNo. of Relapses
MixedNoNo44
MixedNoYes221
Full donorYesNo91
Full donorNoNo96
Abbreviation: GVHD, graft-versus-host disease.

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Published In

Journal of Clinical Oncology
Pages: 971 - 978
PubMed: 21282545

History

Published online: January 31, 2011
Published in print: March 10, 2011

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Authors

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Karl S. Peggs [email protected]
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Irfan Kayani
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Noha Edwards
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Panagiotis Kottaridis
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Anthony H. Goldstone
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
David C. Linch
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Rachael Hough
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Emma C. Morris
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Adele Fielding
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Ronjon Chakraverty
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Kirsty J. Thomson
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.
Stephen Mackinnon
From the University College London Cancer Institute, University College London Hospitals National Health Service Foundation Trust, and Royal Free Hospital, London, United Kingdom.

Notes

Corresponding author: Karl S. Peggs, Department of Haematology, UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley St, London WC1E 6BT United Kingdom; e-mail: [email protected].

Author Contributions

Conception and design: Karl S. Peggs, Stephen Mackinnon
Provision of study materials or patients: Karl S. Peggs, Panagiotis Kottaridis, Anthony H. Goldstone, David C. Linch, Rachael Hough, Emma C. Morris, Ronjon Chakraverty, Kirsty J. Thomson, Stephen Mackinnon
Collection and assembly of data: Karl S. Peggs, Irfan Kayani
Data analysis and interpretation: Karl S. Peggs, Irfan Kayani, Noha Edwards, Stephen Mackinnon
Manuscript writing: All authors
Final approval of manuscript: All authors

Disclosures

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Funding Information

Supported by funding from the Department of Health and Cancer Research United Kingdom for the National Institute for Health Research Biomedical Research Centres and Experimental Cancer Medicine Centres at University College London Hospitals/University College London, and at the Royal Free Hospital, London, United Kingdom.

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Karl S. Peggs, Irfan Kayani, Noha Edwards, Panagiotis Kottaridis, Anthony H. Goldstone, David C. Linch, Rachael Hough, Emma C. Morris, Adele Fielding, Ronjon Chakraverty, Kirsty J. Thomson, Stephen Mackinnon
Journal of Clinical Oncology 2011 29:8, 971-978

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