Introduction

Chronic lymphocytic leukemia (CLL) is a clonal cancer of the immune system. Some aspects of immunity in CLL are paradoxical; for example, although persons with CLL have too many B-cells, they are immune deficient. Also, considerable data suggest that alterations in immune state moderate the course of CLL. The most convincing example is immune mechanisms associated with an allogeneic bone marrow or blood cell transplant following high doses of anti-leukemia drugs with or without radiation. Here, after adjusting for other predictive variables for leukemia relapse, persons developing graft-versus-host disease (GvHD) are said to be less likely to have recurrent CLL than those without GvHD (see below). Conversely, removing T-cells from an allograft is claimed to increase leukemia relapse risk even after adjusting with GvHD. These immune-mediated effects are collectively termed as graft-versus-leukemia (GvL). At this juncture we use the term GvL to indicate any immune-mediated anti-leukemia effect in a transplant recipient. Later we discuss whether GvL can be distinguished from GvHD and whether GvL can operate in settings where the anti-leukemia effector cells and target CLL cells are genetically identical except for mutations related to leukemia.

Although allotransplants after high-dose drugs with or without radiation cure rare persons with CLL, unlike other therapies, their use is relatively uncommon. One barrier to wider use of allotransplants is that people with CLL are typically too old (median age, 65 years). Attempts to expand use of allotransplants to these older persons include lowering doses of pretransplant anti-leukemia drugs and/or radiation (mini- or reduced intensity conditioning (RIC) allotransplants). Another approach to expanding transplants to older persons is autotransplants. There are, however, important caveats to using these approaches. As RIC allotransplants use lower doses of pretransplant drugs with or without radiation than conventional allotransplants, eradicating residual CLL cells in the recipient requires a potent immune-mediated GvL effect. Likewise, although autotransplants use high doses of drugs with or without radiation, they cannot cure CLL unless some immune perturbation concomitant with the transplant eradicates CLL cells unavoidably present in the graft.

As indicated, success of allo- and autotransplants depends on an effective anti-CLL GvL effect. Such an effect, if it exists, might also be used in a non-transplant setting to cure people with CLL. Here, we consider whether there are convincing data of an immune-mediated GvL effect in CLL. Our approach, similar to our strategy in acute lymphoblastic leukemia, acute myelogenous leukemia (AML) and chronic myelogenous leukemia, compared leukemia relapse risks in diverse transplant-related settings.^{1, 2, 3, 4}

Allotransplants versus autotransplants

Conventional allotransplants

Risk of leukemia relapse after autotransplants for CLL exceeds 50% at 3 years.^{5, 6, 7} This contrasts with a 3-year leukemia relapse risk of 10–20% after conventional allotransplants (namely allotransplants after high doses of anti-leukemia drugs with or without radiation). Furthermore, although leukemia relapse risk after autotransplants is continuous and un-ending, relapse risk after allotransplants is stable at 5–10 years.^{8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18} Finally, allotransplants are effective in persons with advanced, drug-resistant CLL,^{9, 10} whereas autotransplants are not.¹⁹ These striking differences in leukemia relapse risk pattern and activity after allo- and autotransplants might reflect one or more variables that differ between these groups including subject selection, an allogeneic versus autologous immune background, GvHD, leukemia contamination of the graft or combinations of these variables. Insight into which if any of these variables operate can be studied by comparing leukemia relapse risk in recipients of allotransplants with and without GvHD (see below).

RIC allotransplants

Data from RIC allotransplants in CLL also support an immune-mediated GvL effect.^{20, 21, 22, 23, 24, 25, 26, 27, 28, 29} Here, where relatively low doses of anti-leukemia drugs with or without radiation are given pretransplant, most of the anti-leukemia effect is likely from GvL associated or not with GvHD. Table 1 summarizes data from eight studies. Transplant-related mortality (TRM) was 7–26% and 2-year probability of relapse was 7–48%. Reasonable outcomes are also reported in persons with unfavorable leukemia prognostic factors like unmutated V_H genes and/or 11q and 17p chromosome abnormalities.²⁵

Table 1 - Studies on RIC allotransplants in CLL.

Full table

Ritgen et al.³⁰ studied minimal residual leukemia (MRL) in nine subjects after RIC allotransplants. MRL kinetics were bi-phasic: a modest decrease in leukemia cells early after transplant followed by a marked reduction after about 3 months. Similarly, Schetelig et al.²⁰ reported disappearance of CD5/CD19 co-expressing cells (presumably CLL cells) only after about 4 months after transplant. Furthermore, Ritgen et al.³¹ reported a stronger correlation between leukemia eradication and chronic GvHD and/or donor lymphocyte infusions (DLI; see below) than with pretransplant conditioning. Subjects in this study had a poor prognosis (unmutated V_H genes) but responded favorably to a presumed GvL effect. This contrasts with data from autotransplants (see above) where molecular responses are rare.

Relationship between GvL and GvHD

In most studies of leukemia relapse after allotransplants, extensive chronic GvHD correlates with a lower leukemia relapse risk. This is especially so after allotransplants for AML and myelodysplastic syndrome;^{1, 2, 3, 4} similar trends are reported for lymphoma and CLL.³² Dreger et al.²¹ reported a correlation between chronic GvHD and likelihood of achieving complete remission after a conventional allotransplant: complete remission was achieved in 43 of 44 subjects developing chronic GvHD but only 14 of 33 subjects without chronic GvHD. Similarly, there was only one relapse among 37 evaluable subjects with chronic GvHD versus 19 relapses in 40 subjects without chronic GvHD. These data indicate that subjects with chronic GvHD are more likely to achieve complete remission and less likely to relapse than subjects without chronic GvHD.

In another study of time-dependent post-transplant correlates in allotransplant recipients with CLL, Sorror et al.²² reported median intervals from transplant to onset of acute and chronic GvHD of 1.4 and 4.5 months. Median intervals from transplant to disappearance of pretransplant CLL-associated cytogenetic abnormalities, CD5/CD19-co-expressing CLL cells, enlarged lymph nodes and molecular evidence of CLL were 3–12 months. Although these data show a correlation between GvHD and anti-leukemia effects, they do not address causality. Likewise, onset of GvHD was earlier among recipients of unrelated versus related allotransplants who also had more complete remissions and fewer leukemia relapses. These correlations, although consistent with a GvL effect may have other explanations. For example, development of GvHD might trigger therapy with corticosteroids and/or other drugs with anti-leukemia effects. This possibility is not critically evaluated. Another possibility is that GvHD might result in the release of molecules that inhibit growth of leukemia cells by non-immune mechanisms like growth inhibition. In another report of 30 allotransplants recipients, there was evidence for a strong GvL effect associated with acute and chronic GvHD resulting in rare relapses.³³

Transplants from genetically identical twins

Analysis of data of leukemia relapse risk among recipients of genetically identical twin transplants can quantify the anti-leukemia effects of pretransplant drugs and radiation of a potential GvL effect in a non-allogeneic setting. Unfortunately, such data are reported few in number. Pavletic et al.^{34, 35} reported 19 subjects transplanted between 1980 and 2001 with bone marrow or blood cell transplants after high doses of pretransplant anti-leukemia drugs with or without radiation. Four of 13 subjects achieving complete remission relapsed with a 5-year cumulative relapse risk of 52% (95% confidence interval, 27–77%). Although the broad confidence interval precludes definitive interpretation, this rate seems higher than that after allotransplants but lower than after autotransplants. These data are consistent with a GvL effect. Other reports are of fewer cases and less informative.^{36, 37, 38, 39, 40}

Donor lymphocyte infusions

Anti-leukemia effects of DLI on recurrent CLL are useful in evaluating whether or not there is a GvL effect. This is especially so after RIC allotransplants where GvL is needed for leukemia eradication. There are several reports of eradication of persistent and/or recurrent CLL after transplant.^{18, 20, 21, 22, 28, 30, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52} Most report small numbers of subjects; only two had more than 10.^{21, 28} Overall, 43 of 92 subjects responded; 35 achieved complete remission and eight partial remission. Although some responses were sustained, there was often insufficient follow-up for critical evaluation. Responses were best in subjects with fewer leukemia cells: about 50% in persons with MRL versus <20% in those with extensive CLL. Analysis of one report of an especially high response rate in advanced CLL after DLI is complicated by concomitant use of rituximab.⁴⁵ Similarly, more responses to DLI were seen after T-cell deplete versus T-cell replete RIC allotransplants.^{18, 28, 48} These data are also compatible with reports of cases where tapering after transplant immune suppression correlated with a clinical anti-leukemia effect and onset of acute and/or chronic GvHD.⁵³ In summary, data from studies of DLI and modulation of post-transplant immune suppression support the notion of an allogeneic GvL effect in CLL.

T-cell responses after allotransplants

The role of T-cells in preventing relapses is suggested by the increased relapse rates after T-cell depleted allograft.¹⁸ Gribben et al. reported data of donor CD4- and CD8-T-cell responses after transplant to CLL-specific immunoglobulin idiotype after RIC allotransplants.⁵⁴ Idiotype-specific T-cells were detected in 17 of 26 subjects, a median of 100 days after transplant. Increased response frequency coincided with subsequent development of chronic GvHD. These cells killed recipient CLL cells in vitro. Kollgaard et al.⁴⁹ analyzed the clonotype of CD8-T-cells following RIC allotransplants. They showed that an early dynamic phase is followed by the appearance of stable T-cell clonotypes several months after transplant coinciding with clinical anti-leukemia response. Data from these studies are consistent with the concept of GvL in CLL.

Conclusions and implications

The data we review support the notion of a strong GvL effect in CLL. Others have reached similar conclusions with less extensive analyses.^{29, 34, 35} However, a more critical analysis of GvL in CLL requires considering detailed data from larger numbers of allograft recipients with and without GvHD, recipients of T-cell-depleted allograft and genetically identical twin transplant recipients.

Because of this probable GvL effect in CLL, conventional or RIC allotransplants offer the greatest likelihood of curing persons with CLL. Autotransplants may have some use but, because they lack a GvL effect, are unlikely to cure CLL. As most data supporting GvL in CLL are from studies of allotransplants, it is less certain that this anti-leukemia effect operates in settings where the anti-leukemia effector cells and target CLL cells are genetically identical except for mutations related to the leukemia. This potential limitation has strong implications on whether immune therapy of CLL will work in non-allotransplant settings.

The focus of our review is on the concept of GvL in CLL, not on the best therapy of CLL now or in the future. We are not unaware, however, of additional implications that might be drawn from our conclusions regarding GvL in CLL. For example, are alternative donor transplants likely to be better than HLA-identical sibling transplants because of more GvHD or are umbilical cord blood cell transplants likely to be worse because of less GvHD. In every clinical transplant setting studied to date it has not been possible to convincingly separate GvL effects from GvHD. We see no reason why this should differ in CLL but data are needed to study this question. Until such data are available it seems safest to consider GvL and GvHD in CLL highly confounded. Thus, the best transplant strategy for CLL, a complex interaction of TRM risk (including GvHD) and leukemia relapse risk, can only be determined in large randomized clinical trials.

Another controversial issue not addressed by our analysis is the best timing for a transplant in CLL. Although some reason that immune therapy is most likely to be effective when there are fewer leukemia cells, there are few convincing data that the GvL-mediated anti-leukemia effects of transplants are better when done earlier after adjusting for diverse biases including time-to-treatment, leukemia stage and subject attrition after failure of conventional therapies. Again, appropriate power randomized trials are needed to answer this question.

In conclusion, immune-mediated anti-leukemia effects in CLL offer a new therapy option in an otherwise uncurable cancer. Determining how best to use this modality is an important challenge.

References

1. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562. | PubMed | ISI | ChemPort |
2. Gale RP, Horowitz MM, Ash RC, Champlin RE, Goldman JM, Rimm AA et al. Identical-twin bone marrow transplants for leukemia. Ann Intern Med 1994; 120: 646–652. | PubMed | ISI | ChemPort |
3. Butturini A, Gale RP. Graft versus leukemia in humans. Cancer Treat Res 1995; 76: 299–314. | PubMed | ChemPort |
4. Passweg JR, Tiberghien P, Cahn JY, Vowels MR, Camitta BM, Gale RP et al. Graft-versus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia. Bone Marrow Transplant 1998; 21: 153–158. | Article | PubMed | ISI | ChemPort |
5. Pavletic ZS, Bierman PJ, Vose JM, Bishop MR, Wu CD, Pierson JL et al. High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Ann Oncol 1998; 9: 1023–1026. | Article | PubMed | ChemPort |
6. Esteve J, Villamor N, Colomer D, Cervantes F, Campo E, Carreras E et al. Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia 2001; 15: 445–451. | Article | PubMed | ISI | ChemPort |
7. Milligan DW, Fernandes S, Dasgupta R, Davies FE, Matutes E, Fegan CD et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood 2005; 105: 397–404. | Article | PubMed | ISI | ChemPort |
8. Michallet M, Archimbaud E, Bandini G, Rowlings PA, Deeg HJ, Gahrton G et al. HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry. Ann Intern Med 1996; 124: 311–315. | PubMed | ISI | ChemPort |
9. Khouri IF, Przepiorka D, van BK, O'Brien S, Palmer JL, Lerner S et al. Allogeneic blood or marrow transplantation for chronic lymphocytic leukaemia: timing of transplantation and potential effect of fludarabine on acute graft-versus-host disease. Br J Haematol 1997; 97: 466–473. | Article | PubMed | ChemPort |
10. Pavletic ZS, Arrowsmith ER, Bierman PJ, Goodman SA, Vose JM, Tarantolo SR et al. Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 2000; 25: 717–722. | Article | PubMed | ISI | ChemPort |
11. Michallet M, Thiebaut A, Dreger P, Remes K, Milpied N, Santini G et al. Peripheral blood stem cell (PBSC) mobilization and transplantation after fludarabine therapy in chronic lymphocytic leukaemia (CLL): a report of the European Blood and Marrow Transplantation (EBMT) CLL subcommittee on behalf of the EBMT Chronic Leukaemias Working Party (CLWP). Br J Haematol 2000; 108: 595–601. | Article | PubMed | ISI | ChemPort |
12. Horowitz MM, Montserrat E, Sobocinski K, Giralt S, Khouri IF, Schmitz N. Hematopoietic stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL). Blood 2000; 96: 522A.
13. Esteve J, Montserrat E, Dreger P, Meloni G, Pavletic S, Catovsky D et al. Stem cell transplantation (SCT) for chronic lymphocytic leukemia (CLL): outcome and prognostic factors after autologous and allogeneic transplants. Blood 2001; 98: 482A.
14. Khouri IF, Keating MJ, Saliba RM, Champlin RE. Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 2002; 4: 217–221. | Article | PubMed | ChemPort |
15. Doney KC, Chauncey T, Appelbaum FR. Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 2002; 29: 817–823. | Article | PubMed | ISI | ChemPort |
16. Michallet M, Michallet AS, Le QH, Bandini G, Rowlings PA, Deeg HJ et al. Conventional HLA-identical sibling bone marrow transplantation is able to cure chronic lymphocytic leukemia. A study from the EBMT and IBMT Registries. Blood 2003; 102: 474A. | Article | ChemPort |
17. Pavletic SZ, Khouri IF, Haagenson M, King RJ, Bierman PJ, Bishop MR et al. Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol 2005; 23: 5788–5794. | Article | PubMed |
18. Gribben JG, Zahrieh D, Stephans K, Bartlett-Pandite L, Alyea EP, Fisher DC et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood 2005; 106: 4389–4396. | Article | PubMed | ISI | ChemPort |
19. Montserrat E, Esteve J, Schmitz N, Dreger P, Meloni G, Catovsky D et al. Autologous stem-cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL): results in 107 patients. Blood 1999; 94: 397A.
20. Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 2003; 21: 2747–2753. | Article | PubMed | ISI | ChemPort |
21. Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J et al. Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia 2003; 17: 841–848. | Article | PubMed | ISI | ChemPort |
22. Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 3819–3829. | Article | PubMed | ISI |
23. Dreger P, Stilgenbauer S, Boettcher S, Bunjes D, Ottinger H, Beelen D et al. Long-term disease control of poor-risk chronic lymphocytic leukemia (CLL) by allogeneic stem cell transplantation with nonmyeloablative conditioning (NST): interim results of a prospective study. Ann Oncol 2005; 16: 43–44. | Article |
24. Dreger P, Brand R, Milligan D, Corradini P, Finke J, Lambertenghi DG et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 2005; 19: 1029–1033. | Article | PubMed | ISI | ChemPort |
25. Caballero D, Garcia-Marco JA, Martino R, Mateos V, Ribera JM, Sarra J et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clin Cancer Res 2005; 11: 7757–7763. | Article | PubMed | ChemPort |
26. Brown JR, Kim T, Li SL, Stephans K, Fisher DC, Cutler C et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant 2006; 12: 1056–1064. | Article | PubMed |
27. Khouri IF. Reduced-intensity regimens in allogeneic stem-cell transplantation for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 2006; 390–397.
28. Delgado J, Thomson K, Russell N, Ewing J, Stewart W, Cook G et al. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood 2006; 107: 1724–1730. | Article | PubMed | ChemPort |
29. Dreger P, Corradini P, Kimby E, Michallet M, Milligan D, Schetelig J et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21: 12–17. | Article | PubMed | ChemPort |
30. Ritgen M, Stilgenbauer S, von Neuhoff N, Humpe A, Bruggemann M, Pott C et al. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 2004; 104: 2600–2602. | Article | PubMed | ISI | ChemPort |
31. Ritgen M, Lange A, Stilgenbauer S, Dohner H, Bretscher C, Bosse H et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood 2003; 101: 2049–2053. | Article | PubMed | ISI | ChemPort |
32. Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005; 23: 1993–2003. | Article | PubMed | ISI |
33. Toze CL, Galal A, Barnett MJ, Shepherd JD, Conneally EA, Hogge DE et al. Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease. Bone Marrow Transplant 2005; 36: 825–830. | Article | PubMed | ChemPort |
34. Pavletic S, Zhou GM, Sobocinski K, Doney K, DiPersio J, Feremans W et al. Identical-twin transplants for B-cell chronic lymphocytic leukemia (B-CLL). Blood 2004; 104: 909A–910A. | Article |
35. Pavletic SZ, Zhou G, Sobocinski K, Marti G, Doney K, DiPersio J et al. Genetically-identical-twin transplants for B-cell chronic lymphocytic leukemia (submitted).
36. Bandini G, Michallet M, Rosti G, Tura S. Bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant 1991; 7: 251–253. | PubMed | ChemPort |
37. Deane M, Singer C, Lawler M, McElwaine S, Gomez K, Prentice HG. Acute skin GVHD following syngeneic BMT for CLL. Bone Marrow Transplant 1998; 22: 1207–1209. | Article | PubMed | ChemPort |
38. Khouri IF, Keating MJ, Vriesendorp HM, Reading CL, Przepiorka D, Huh YO et al. Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol 1994; 12: 748–758. | PubMed | ISI | ChemPort |
39. Toze CL, Shepherd JD, Connors JM, Voss NJ, Gascoyne RD, Hogge DE et al. Allografting for indolent lymphoid neoplasms. Ann Oncol 2000; 11 (Suppl 1): 59–61. | Article | PubMed |
40. Toze CL, Shepherd JD, Connors JM, Voss NJ, Gascoyne RD, Hogge DE et al. Allogeneic bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia. Bone Marrow Transplant 2000; 25: 605–612. | Article | PubMed | ChemPort |
41. Siegert W, Beyer J, Kingreen D, Blasczyk R, Baurmann H, Schwella N et al. Treatment of relapse after allogeneic bone marrow transplantation with unmanipulated G-CSF-mobilized peripheral blood stem cell preparation. Bone Marrow Transplant 1998; 22: 579–583. | Article | PubMed | ChemPort |
42. Marks DI, Lush R, Cavenagh J, Milligan DW, Schey S, Parker A et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 2002; 100: 3108–3114. | Article | PubMed | ISI | ChemPort |
43. Alyea EP, Canning C, Neuberg D, Daley H, Houde H, Giralt S et al. CD8+ cell depletion of donor lymphocyte infusions using cd8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study. Bone Marrow Transplant 2004; 34: 123–128. | Article | PubMed | ChemPort |
44. Bethge WA, Hegenbart U, Stuart MJ, Storer BE, Maris MB, Flowers MED et al. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood 2004; 103: 790–795. | Article | PubMed | ChemPort |
45. Khouri IF, Lee MS, Saliba RM, Andersson B, Anderlini P, Couriel D et al. Nonablative allogeneic stem cell transplantation for chronic lymphocytic leukemia: impact of rituximab on immunomodulation and survival. Exp Hematol 2004; 32: 28–35. | Article | PubMed | ISI | ChemPort |
46. Peggs KS, Thomson K, Hart DP, Geary J, Morris EC, Yong K et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses. Blood 2004; 103: 1548–1556. | Article | PubMed | ISI | ChemPort |
47. Wolff D, Steiner B, Stilgenbauer S, Kahl C, Leithauser M, Junghanss C et al. Treatment with campath-1H for relapsed chronic lymphocytic leukemia after allogeneic peripheral blood stem cell transplantation does not abrogate the development of chronic GVHD. Europ J Haematol 2004; 72: 145–148. | Article |
48. Russell NH, Byrne JL, Faulkner RD, Gilyead M, Das-Gupta EP, Haynes AP. Donor lymphocyte infusions can result in sustained remissions in patients with residual or relapsed lymphoid malignancy following allogeneic haemopoietic stem cell transplantation. Bone Marrow Transplant 2005; 36: 437–441. | Article | PubMed | ChemPort |
49. Kollgaard T, Petersen SL, Hadrup SR, Masmas TN, Seremet T, Andersen MH et al. Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation. Leukemia 2005; 19: 2273–2280. | Article | PubMed | ChemPort |
50. Porter DL, Levine BL, Bunin N, Stadtmauer EA, Luger SM, Goldstein S et al. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood 2006; 107: 1325–1331. | Article | PubMed | ChemPort |
51. Rondon G, Giralt S, Huh Y, Khouri I, Andersson B, Andreeff M et al. Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant 1996; 18: 669–672. | PubMed | ISI | ChemPort |
52. Soligo D, Motta M, Borsotti C, Ibatici A, Cortelezzi A, Lambertenghi DG. Reduced intensity conditioning allogeneic transplant for advanced chronic lymphocytic leukemia. Haematologica 2004; 89: 885–886. | PubMed |
53. Mehta J, Powles R, Singhal S, Iveson T, Treleaven J, Catovsky D. Clinical and hematologic response of chronic lymphocytic and prolymphocytic leukemia persisting after allogeneic bone marrow transplantation with the onset of acute graft-versus-host disease: possible role of graft-versus-leukemia. Bone Marrow Transplant 1996; 17: 371–375. | PubMed | ChemPort |
54. Munker R, Reibke R, Kolb HJ. Graft-versus-host and graft-versus-leukemia reactions: a summary of the Seventh International Symposium held in Garmisch-Partenkirchen, Germany, February 22nd–25th, 2006, Tolerance and Immunity, an update on lymphoid malignancies. Bone Marrow Transplant 2006; 38: 593–607. | Article | PubMed | ChemPort |

Acknowledgements

Drs Alaine Berrabi (Department of Hematology, Kaplan Medical Centre, Rehovot, Israel), Hillard M Lazarus (Ireland Cancer Center, Case Western Reserve University, Cleveland, OH, USA) and Steven Pavletic (GvHD and Autoimmunity Unit, Experimental Transplant and Immunology Branch, NIH, Bethesda, MD, USA) gave useful comments.