When considering treatment options for patients who relapse after alloHSCT, several issues transcend disease specificity. Other than the successes documented years ago using DLI for relapsed CML, there is remarkably limited data on the use of DLI and non-DLI therapies in other clinical situations. The lack of data regarding treatment options and outcomes results from many factors. Patients who relapse after transplant are an extremely heterogeneous group. Some may be quite ill and may still be suffering from morbidities of transplant. Some may have had, or still have, active GVHD and may or may not be on immune suppression. Furthermore, the biology and responsiveness of diseases that relapse rapidly after transplant are likely very different than diseases that relapse later after transplant. Treatment options and responses are likely to be very different in these different patient groups. This heterogeneity leads to enormous selection bias that can be compounded by reporting bias where only the best and most promising results are disseminated. Treatment options are also affected by prior therapies and the previous failed transplant. HLA-identical sibling transplants usually have access to their previous donor. Cord blood recipients never do, and DLI from an unrelated donor may be delayed and may or may not have higher risks. Therefore, there is obviously no single standard approach to treating relapse after alloHSCT.
It is unknown whether GVT induction for relapse is a generalized allogeneic effect or has disease specific targets. It is also not known whether GVT induction can be effectively separated from GVHD. It is still unclear whether there is a relationship between cell dose and toxicity with DLI, and it is not known whether there is a dose-response effect, or rather a minimal threshold dose that must be achieved before anti-tumor responses occur. Whether these dose effects might be disease or disease-state specific is also unanswered.
There are clinical situations where responses to DLI consistently have been poor and maneuvers to improve GVT induction need to be tested rapidly and comprehensively. It is imperative to study and understand mechanisms leading to relapse in order to develop and use the proper strategy for a specific disease or specific patient. For instance, in some cases, relapse of acute leukemia or MDS after haploidentical alloHSCT has been associated with loss of recipient-specific HLA expression. In these cases, conventional DLI would not be expected to be effective, assuming HLA class I and II antigens are necessary targets for GVT induction. In cases where relapses may be associated with ineffective T-cell activation, either because of tumor suppression, lack of co-stimulatory molecules, or T-cell associated defects, ex-vivo activation of donor T cells prior to infusion may restore GVT activity. There are also clear instances where second transplant is a reasonable and effective option, and considerations of the proper disease and patient population, conditioning regimen intensity, and donor choice for second alloHSCT need to be re-visited.
Alternatives to cellular therapies to treat relapse should not be neglected. It has been difficult to use and study conventional and novel agents since the dosing regimens and toxicity profiles may be very different in post-transplant patients. Outcomes likely depend on prior therapy, disease activity, timing of relapse, GVHD and other coincident toxicities, as well as many other factors. Furthermore, anecdotal observations suggest an interaction between ongoing GVT effects and various other therapeutic interventions. Well designed clinical trials in specific diseases are going to be necessary to test the activity and role for these therapies, particularly in situations where cellular therapies have been ineffective. Measurements of immunological effects in addition to disease outcomes will be needed to make progress in managing disease relapse with conventional and biological therapies. In addition, we must overcomes the general reluctance of study sponsors and investigators to include prior transplant recipients on trials studying promising new therapies; these often unsubstantiated exclusions may deprive patients of potential major benefits and slow progress in developing relapse therapies.
A number of strategies deserve careful study and might include preparation and pre-treatment of the patient to either induce a minimal disease state or perhaps alter the malignant cells and environment to enhance T-cell recognition and GVT activity. Alternatively, manipulation of the donor cell product through selection, activation, or targeting may enhance GVT activity. Studying to role of other cellular effectors such as NK cells and dendritic cells to enhance GVT will also be important. In many cases a combination of these strategies may be required for maximal effect. Combining immunologic approaches with novel chemotherapy or biological therapies in a multimodality approach may ultimately be required. Given the multitude of confounding issues, and the relatively small numbers of patients, the committee on Treatment of Relapse for this Workshop was unanimous in acknowledging the need for well designed international cooperative trials to rapidly test and disseminate the best strategies for relapse treatment after transplant. Information gathered in the relapse setting could, at least in theory, provide crucial pathophysiological information that may ultimately improve treatments.
Despite all the uncertainties, there is no doubt that novel biological agents and allogeneic immunotherapy have the ability to be very potent and durable anti-cancer therapies. Detailed study of the current role for DLI, and exploring new applications of cellular and other biological therapy continues to hold great promise for the very dire clinical scenario of relapsed disease after alloHSCT.