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372 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 373

RELAPSED MALIGNANCY AFTER HCT supplanted DLI for the most part in this setting. DLI alone is typi-
426
427
Relapse following autologous or allogeneic HCT is an ominous clinical cally insufficient to control aggressive hematologic malignancies, and
event. Every effort should be made to verify relapse pathologically, as it thus patients are often treated with reinduction chemotherapy or other
is common for patients to have residual radiographic abnormalities fol- cytoreduction before receiving DLI as consolidation.
lowing transplantation, especially in patients with lymphoma. Patients The major potential adverse effects of DLI are GVHD and marrow
with myeloma have gradual reductions in biochemical markers of dis- aplasia. The risk of GVHD after DLI is at least 20 percent and likely as
428,429
ease which may take several months after autologous HCT to reach high as 50 to 70 percent. Marrow aplasia typically occurs in the
maximal response. Following RIC, the allogeneic GVT effect may take setting of residual host hematopoiesis; when host HSC are eradicated by
weeks to months to result in tumor eradication, and it may be difficult DLI, there may be too few donor HSC to support hematopoietic recov-
430
to distinguish persistent yet slowly regressing disease from slowly pro- ery and prolonged aplasia (>6 weeks) can ensue. Thus, chimerism
gressive disease, particularly with indolent NHL or CLL. should be evaluated before DLI, and DLI should be used with caution in
patients with significant residual host hematopoiesis. There are limited
data on the optimal cell dose of DLI. In a retrospective analysis, doses
Relapse after Autologous Hematopoietic Cell Transplantation greater than 1 × 10 CD3+ cells/kg were associated with a high risk of
8
Disease relapse remains the most common cause of treatment failure GVHD (55 percent) without a corresponding benefit in disease control,
after autologous HCT. Relapse often occurs at sites of previous disease, while doses of 1 × 10 CD3+ cells/kg or less were associated with the
7
suggesting that residual disease within the patient rather than autograft lowest rates of GVHD (21 percent). Modifications of DLI, including
428
contamination is responsible. Additional cytotoxic chemotherapy selection of CD8+ effector lymphocytes or production of cytokine-
417
alone is highly unlikely to be curative in patients relapsing after autol- induced killer cells, are under investigation to improve the safety and
141
ogous HCT, as the disease has already survived supralethal doses of efficacy of this approach.
chemotherapy. Treatment options for patients with relapse after autol-
ogous HCT include irradiation, immunomodulators, and/or targeted
therapies. For selected patients, salvage allogeneic HCT may be feasible FUTURE DIRECTIONS
using RIC. Strategies to reduce the risk of relapse in high-risk patients In recent years, research in HCT has helped to establish alternative-
undergoing autologous HCT include consolidative involved-field radio- donor allotransplantation, improve outcomes through better support-
therapy, antitumor vaccination, maintenance therapy with targeted ive care, and expand transplant eligibility to previously ineligible
418
218
agents, 269,419,420 and planned tandem allogeneic HCT. 421
202
populations using RIC, among other advancements. Current research
directions in HCT are diverse; two avenues among many are briefly
Relapse after Allogeneic Hematopoietic Cell Transplantation summarized here.
Treatment of disease relapse following allogeneic HCT is generally The past several years have seen an explosion of research inter-
unsuccessful. In particular, patients with high-risk malignancies and est in the microbiome and the role of host/microbiome interaction in
early relapse (<100 days after allogeneic HCT) have a dismal progno- regulating immunity. The relevance of this field to allogeneic HCT is
sis, with 2-year overall survival of less than 5 percent. Salvage che- immediately obvious, as the gut and skin are key targets of GVHD.
422
motherapy can result in disease responses, but they are unlikely to be Preclinical evidence suggests that gut microbiota play a critical role
durable. Performing a second myeloablative transplantation procedure in the development of GI GVHD. 431,432 In humans, preliminary evi-
has largely been unsuccessful because of excessive toxicity and TRM dence links changes in the microbiome to respiratory complications,
433
of greater than 50 percent. More recently, selected patients have been GI GVHD, 432,434 bacteremia, and mortality after allogeneic HCT.
435
436
treated with a second allogeneic HCT using RIC. Treatment-related tox- While our understanding of these interactions is still in its infancy and
icity with this approach is not prohibitive and successful disease eradi- the clinical implications of these findings remain unclear, studies are
cation has been reported, although relapse remains the major cause of underway revisiting older strategies, such as total gut decontamination,
death. There is no consensus on whether to use the same donor or as well as more modern efforts to tailor the microbiome to optimize
423
a different donor for second-salvage allogeneic HCT in the setting of transplant outcomes. 437
relapse. More importantly, the majority of patients with relapse after Allogeneic HCT is also under investigation as a platform to pro-
allogeneic HCT are ineligible for second allotransplant because their mote tolerance of solid-organ allografts. Solid-organ transplants typi-
diseases cannot be adequately controlled or cytoreduced. Experimental cally require lifelong immunosuppression to maintain graft function,
therapies with chimeric antigen receptor-bearing autologous T cells or but investigators in the 1990s noted that renal allotransplantation could
other investigational approaches warrant consideration in these cases. be accomplished without immunosuppressive therapy in recipients of
In our view, palliative care is a reasonable option, particularly in the allogeneic HCT, provided that the kidney allograft was obtained from
setting of early or chemorefractory relapse after allogeneic HCT, and the original marrow donor. 438,439 The development of reduced-intensity
should be presented to patients. regimens has spurred research in this field, as these regimens are less
In the setting of retained donor T-cell chimerism, posttransplan- toxic and often produce mixed rather than complete donor chimer-
tation relapse has sometimes been treated by rapidly tapering immu- ism—a desirable characteristic in this setting since mixed chimerism
nosuppressive medications to stimulate a GVT effect. Although this reduces the risk of GVHD.
approach is occasionally successful in patients with indolent malignan- Investigators at Northwestern University described a cohort of
cies such as low-grade NHL or CLL, it is rarely effective against more 15 HLA-mismatched living-donor kidney transplant recipients given
aggressive diseases such as acute leukemias, and carries a high risk of RIC and an infusion of donor marrow enriched with facilitator cells. Six
precipitating severe GVHD. of the 15 patients developed sustained chimerism and were completely
In patients who are off immunosuppression without evidence of withdrawn from immunosuppressive medication without renal allograft
GVHD at the time of relapse, DLI has been used to augment GVT. The rejection. 440,441 Investigators in Boston reported that four of 10 HLA-hap-
mechanism by which DLI works is unclear; it may normalize the T-cell lotype matched living-donor kidney transplant recipients were able to
repertoire or reverse so-called T-cell “exhaustion.” 424,425 Historically, the discontinue immunosuppression for up to 11.4 years without subsequent
best outcomes for DLI have been reported for CML, although TKIs have graft dysfunction after establishment of transient mixed chimerism.
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