Overview

Hematopoietic cell transplantation (HCT) has curative potential for patients with various lymphoid and hematopoietic diseases, and conceivably for select patients with solid tumors. However, HCT carries considerable risks of treatment-related morbidity and mortality, and disease recurrence after transplantation remains a problem. Intensification of the preparative (conditioning) regimen in young and otherwise healthy patients has resulted in lower relapse rates but has also been associated with higher rates of non-relapse/treatment-related mortality. The probability of treatment-related mortality increases with increasing patient age, an important fact as many of the diseases that are potentially cured by HCT occur more frequently in older patients.

Until the mid-1990s, few patients above the age of 55 years were offered allogeneic HCT, in particular from unrelated donors. However, recent publications describe cohorts of patients with median ages of 55–60 years, and even patients more than 70 years of age have been transplanted successfully.^{1, 2, 3, 4, 5, 6} Although contemporary individuals in their 60s and 70s may be fitter than patients a generation ago, HCT in this age bracket has been made possible only by major changes in transplant strategies. First, clinical trials showed convincingly that beyond a certain level of conditioning intensity overall and relapse-free survival were not further improved, as non-relapse mortality counterbalanced any gain from prevention of relapse.⁷ Second, experiments in murine models and in clinical studies showed that allogeneic donor cells mediated immunological effects, which targeted not only healthy tissues and caused graft-versus-host disease (GVHD) but also reacted against malignant cells.^{8, 9} This 'graft-versus-tumor (GVT) effect' contributed to the elimination of malignant cells. Third, Slavin et al.¹⁰ and Kolb et al.¹¹ showed clinical GVT activity of donor lymphocyte infusions (DLI) even if given in the relapse setting after HCT. Administering additional donor cells preemptively to high-risk patients might prevent disease recurrence, and if given with therapeutic intent to patients who relapsed after HCT, remission re-induction might be achieved (Schleuning M et al. Blood 2004; 104: 89a, 299 (abstract); Slavin S et al. Blood 1996; 88: 418a, 1661 (abstract)). Fourth, Storb et al. were able to demonstrate sustained engraftment of donor hematopoiesis in canine models after total body irradiation (TBI) with doses as low as 200 cGy, dependent on post-grafting immunosuppression, and with the use of granulocyte-colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPC) as a source of stem cells (Yu C et al. Blood 1997; 90: 318b (abstract) and Sandmeir et al.¹² and Storb et al.¹³) Finally, based on the work by Strober et al.,¹⁴ the use of total lymphoid irradiation combined with the administration of anti-thymocyte globulin (ATG) for conditioning has yielded very encouraging results, particularly in patients with lymphoid malignancies.¹⁵

Clinical trials also show high rates of engraftment with a regimen consisting solely of 200 cGy TBI, and the subsequent addition of fludarabine (Flu) (termed non-myeloablative conditioning by the investigators) improved the engraftment rates from 80 to >95% (Maris MB et al. Blood 2000; 96: 520a; 2239 (abstract)). This strategy was very effective in patients with certain diagnoses, especially lymphoid malignancies. The success rates in patients with myelodysplastic syndromes (MDSs) and myeloproliferative disorders (MPDs), however, have lagged behind, primarily owing to high relapse rates and graft failure (Cao TM et al. Blood 2000; 96: 170a, 734 (abstract)). Retrospective analyses showed that, in addition to the use of PBPC instead of marrow, a significant factor determining engraftment (and preventing disease progression) was the use of pre-transplant induction chemotherapy, which only a minority of patients with MDS or MPD had received (Cao TM et al. Blood 2000; 96: 170a, 734 (abstract) and de Lima¹⁶). Moreover, at least one recent study showed that the intensity of post-grafting immunosuppression affected outcome: the incidence of graft failure in patients given Flu+200 cGy TBI and PBPC from unrelated donors was significantly reduced by the administration of mycophenolate mofetil (MMF) three times, rather than twice, a day.¹⁷ Finally, several retrospective studies in patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) suggested a higher probability of survival in remission after reduced-intensity/non-myeloablative conditioning and transplantation from unrelated donors compared to human leukocyte antigen (HLA)-identical sibling donors.^{1, 18, 19} Thus, the allogeneic GVT effect of PBPC from unrelated donors may be more powerful than that of PBPC from HLA-identical siblings.

Figure 1 shows examples of conditioning regimens, developed by various transplant teams, ordered by estimated regimen intensity. With increasing intensity, the severity and frequency of toxicity and mortality generally increases. Conversely, with decreasing intensity, there is less toxicity, but also a decrease in antitumor efficacy;¹⁶ transplant success (engraftment and disease eradication) increasingly depends upon the GVT effect of transplanted donor cells.²⁰ The GVT effect, in turn, will vary depending on the type of donor (HLA-identical versus non-identical, related versus unrelated), the composition and activation status of the donor cell inoculum (marrow versus PBPC, T-cell depleted and others) (Schmitz N et al. Blood 2000; 96: 481a, 2068 (abstract)) and the diagnosis and disease stage, among other factors. Recent data suggest that mobilization with G-CSF analogs may result in a PBPC product with GVT activity but without significant GVHD, due in part to activation of invariant CD1d-restricted natural killer T (iNKT) cells.²¹

Figure 1.

Partial spectrum of conditioning regimens of various intensities, their impact on toxicity and the dependence of transplant success upon GVT effects. BU=busulfan; CY=cyclophosphamide; TBI=total body irradiation; FLU=fludarabine; AraC=cytosine arabinoside; THY=thymoglobulin; CD52=anti-CD52 antibody (alemtuzumab). ^*TBI at 1200 cGY; ^†200 cGy; ^‡3.2–16 mg/kg; ^§90–250 mg/m².

Full figure and legend (14K)

With these considerations in mind, it is clear that one cannot simply contrast conventional (myeloablative) with reduced-intensity (non-myeloablative) regimens. Indeed, there are numerous factors (some of which may not yet have been identified) that must be considered when selecting a conditioning regimen.

The patient

As patients age, their biologic reserve declines, and the capacity to repair tissue and organ damage decreases. At the same time, however, the probability of developing malignancies increases (although recent research suggests that the senescence of cells, which underlies the reduced repair capacity, may provide protection against cancer). Nevertheless, older patients are more likely to suffer from comorbid conditions, which will affect the candidacy for transplantation.^{5, 22, 23} Reduced-intensity regimens are better tolerated in these patients than aggressive high-dose therapy. In the setting of reduced-intensity transplantation, a possible consequence for certain diseases may be a higher probability of disease persistence or progression compared to outcome with conventional HCT.^{16, 24, 25} However, there is only a limited understanding of how persistence of the disease in patients affects interactions with the transplanted donor cells, and how those interactions can be manipulated to the patient's advantage (Figure 2). For example, recent data have emphasized the role of host antigen-presenting cells for GVHD, and it remains to be determined how conditioning regimens of different intensities modify cytokines, chemokines and functions of those cells.²⁶ Better insights into cellular and molecular cross-talk in the peri-/early post-HCT period should lead to improved methodologies, which more fully exploit GVT responses.

Figure 2.

Schematic comparison of patient cell (heavy lines)/donor cell (thin lines) relationship after high-intensity (myeloablative) and low-intensity (non-myeloablative) conditioning. Solid lines represent situation of sustained engraftment; broken lines are indicative of graft failure/non-engraftment. The prolonged coexistence of patient and donor cells allows for 'sensitization' of donor cells and elimination of residual host cells (upward arrows). However, there is also the possibility of patient donor reactive cells (downward arrows), which may lead to graft failure.

Full figure and legend (27K)

The disease

Non-malignant disorders are generally easier to cure by HCT than malignancies. The primary barrier to transplant success is immunological in nature, and immunosuppression rather than 'cytotoxicity' is the primary objective of conditioning, to allow for donor cell engraftment.^{27, 28, 29} Immunosuppression should have been achieved by the time the donor cells are infused.

Although immunosuppression is also a primary objective of the conditioning regimen in patients with malignant disorders, another objective is to reduce the burden of malignant cells in the patient. A reduced tumor burden should enhance the ability of donor cells to overtake the remaining malignant cells and eliminate the disease. Available data indicate that this goal may also be achieved with delayed interventions, such as DLI in some (Schleuning M et al. Blood 2004; 104: 89a, 299 (abstract)) but not all³⁰ situations. However, the success rate of these delayed interventions also depends upon the kinetics of the patient's disease, and may be greater with diseases such as chronic myeloid leukemia (CML) or CLL than it is with acute lymphoblastic leukemia (ALL).³¹ Thus, disease type and stage are important factors to consider when planning the best transplant strategy.

Pre-HCT induction chemotherapy

Disease recurrence after HCT has remained a problem even with myeloablative conditioning regimens. For some diagnoses, MDS in particular, disease recurrence appears to be an even greater problem with reduced-intensity transplants (Cao TM et al. Blood 2000; 96: 170a, 734 (abstract)). A retrospective analysis of results in patients with MDS transplanted at the Fred Hutchinson Cancer Research Center suggested that pre-HCT chemotherapy reduced the risk of post-HCT relapse, although it did not result in improved post-transplant relapse-free survival.³² However, in at least one study pre-HCT chemotherapy was a significant factor for donor cell engraftment.³³ No prospective data are currently available, and it is difficult to draw firm conclusions from retrospective analyses. It is possible that pre-HCT chemotherapy selects for 'treatment-sensitive' patients who might have fared better after HCT, even without prior therapy.³² If this is the case, then investigations should be directed at identifying these patients for whom the most promising approach might be to go directly to HCT. As patients who received and responded to pre-HCT chemotherapy had comparable transplant outcomes with myeloablative and non-myeloablative regimens, these data suggest that a myeloablative (high-dose) regimen did not offer an advantage for this patient cohort.²⁴

Source of hematopoietic stem cells

Hematopoietic stem cells derived from different sources may exert different donor-versus-host immune effects. As these effects are essential for the success of HCT in general and for low-intensity regimens in particular, they must be carefully considered when discussing transplant strategies.

Several retrospective and prospective trials of HLA-identical sibling transplants have shown lower rates of relapse in patients with high-risk disease with the use of PBPC instead of marrow.^{34, 35, 36} A randomized trial comparing marrow and PBPC from unrelated donors is currently ongoing. In patients conditioned with non-myeloablative regimens, PBPCs are used almost exclusively as a source of stem cells, based on the observation that the use of marrow was associated with significantly higher rates of graft failure and disease progression.³³ However, the incidence of chronic GVHD tends to be significantly higher with the use of PBPCs. This may provide an advantage – a greater GVT effect – in patients with malignant disorders with a high risk of relapse. The allogeneic effect of unrelated donor cells may be stronger than that of cells from HLA-identical related donors, and several studies suggest a superior outcome with unrelated donors, for example, in patients with CLL (Sorror ML et al. Biol Blood Marrow Transplant 2004; 10: 26 (abstract)) or mantle cell lymphoma.¹ An enhanced allogeneic effect does not appear desirable in patients with non-malignant disorders, such as aplastic anemia, where marrow should, presumably, remain the source of stem cells. If the donor cell inoculum – T-cell subsets, natural killer (NK) cells, CD34⁺ cell dose – and the recipient environment – in particular, antigen-presenting cells, can be engineered in such a way that GVHD is prevented (and the GVT effect preserved), these recommendations may change (Baron F et al. Blood 2004; 104: 735a; 2753 (abstract) and Shlomchik et al.;²⁶ Liu et al.;³⁷ Anderson et al.³⁸) Prevention of GVHD also appears to be an essential requirement for the successful application of post-transplant immunotherapy (see below).

Post-transplant manipulations

HCT, by definition, represents cellular immunotherapy. Non-myeloablative/reduced-intensity conditioning regimens take advantage of donor cell-mediated GVT effects. These effects 'compensate' for the reduction in cytotoxic intensity of the conditioning regimen, although the resulting scenario is likely to be more complex. On the one hand, more intensive conditioning regimens have been associated with more frequent or more severe GVHD,^{39, 40} which might also be associated with more potent GVT effects. However, lower intensity regimens may lead to different alterations in cytokine profiles and antigen presentation by host cells and, as a result, induce more potent donor–anti-host reactivity (see above).³⁸ There is no consensus as to how the incorporation of antibody preparations, be it polyclonal ATG, monoclonal anti-CD52 antibody or other, used as part of the conditioning regimen, carry over into the post-transplant period and, therefore, affect donor/host interactions.^{25, 41, 42} However, those interactions must be better understood if immunotherapy is to be further developed and exploited. Others have recently proposed the administration of cyclophosphamide several days after HCT in patients who received marrow cells from haploidentical relatives.⁴³ Such an approach may eliminate alloreactive donor lymphocytes and thereby reduce the risk of GVHD.

The administration of DLI after HCT has been effective in inducing remission in patients with residual disease or relapse,^{25, 42, 44, 45} and in converting to full-donor chimerism, somewhat dependent on the proportion of donor cells present before DLI.^{42, 44, 45, 46} There may also be a place for DLI in a preemptive manner in patients who are at high risk for relapse after HCT (Schleuning M et al. Blood 104: 89a, 299 (abstract)). These interventions, however, continue to carry a risk of serious morbidity and even mortality from GVHD. Recent investigations into the role of donor and host NK cells in graft-versus-leukemia (GVL) and GVH reactions suggest that more precisely targeted, less toxic, immune strategies are possible (Baron F et al. Blood 2005; 106: 119a, 398 (abstract) and Goulmy⁴⁷and Bleakley and Riddell⁴⁸). Prospective typing of transplant donors and recipients for polymorphisms in genes such as HA-1,⁴⁹ HB-1,⁵⁰ BCL2A1,⁵¹ P2X5⁵² or PANE1⁵³ that encode hematopoietic-cell-specific minor histocompatibility (H) antigens could, for example, identify antigens on recipient cells that might serve as targets for antigen-specific immune therapy, using vaccination or adoptive transfer of donor-derived effector cells.^{47, 48, 54} One potential risk of adoptive T-cell therapy that targets minor H antigens is the induction or exacerbation of GVHD. However, GVHD that occurs during or after adoptive T-cell therapy may not necessarily be owing to therapeutically administered T cells, but rather to T cells contained in or derived from the donor hematopoietic cell graft. Thus, successful development of adoptive T-cell therapy that targets minor H antigens will require prevention or control of acute and chronic GVHD, without sacrificing immune reconstitution. It remains to be determined whether selective T-cell depletion of the hematopoietic cell graft or the additional infusion of regulatory T cells can achieve that goal. Post-transplant adjuvant immune strategies could also target non-polymorphic antigens such as WT1,⁵⁵ BCMA⁵⁶ and NY-ESO-1⁵⁷ that are overexpressed by malignant hematopoietic cells.

Summary and conclusion

Over the past decade, important insights have been gained regarding differences between high-dose and non-myeloablative/reduced-intensity regimens, marrow and PBPC, the importance of donor/host interactions, pre-HCT and post-HCT manipulations, and the impact of patient comorbid conditions on post-HCT outcome. More disease-specific trials, dose optimization studies and well-controlled, randomized prospective protocols are needed to determine the ultimate utility of specific conditioning regimens.

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Acknowledgements

This work was supported by Grants HL36444, HL082941, CA78902 and CA106512, National Institutes of Health, Bethesda, MD, USA. I thank Bonnie Larson and Helen Crawford for help with manuscript preparation.