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366 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 367

Comparisons of tandem autologous/autologous versus tandem autol- allotransplantation. 179,181 The optimal timing of allogeneic HCT in indo-
ogous/RIC allogeneic HCT have yielded conflicting results. Improved lent NHL remains to be determined, particularly as indolent NHL can
overall survival with allotransplantation was seen in an Italian random- often be treated effectively with conventional chemotherapy for years or
ized study of 162 patients and in long-term followup of the EBMT-N- even decades. For more aggressive relapsed NHL or for relapsed HL after
MAM2000 trial involving 257 patients, 272–274 although the relapse rate failed autografting, allogeneic HCT remains the only potentially curative
remained high at 60 percent even after allografting. In contrast, three salvage option. However, with these more aggressive malignancies, it is
273
other large randomized trials failed to demonstrate an overall sur- essential that patients be chemoresponsive and, ideally, in a PET-negative
vival advantage with allografting. 275–277 The largest trial addressing this CR in order to proceed to allotransplantation, as otherwise relapse is
question was completed by the BMT-CTN and enrolled 710 myeloma nearly universal before GVT effects can become established. 291,292
278
patients randomized between auto-auto and auto-allo approaches.
This trial found no benefit in overall or progression-free survival with
allografting. These results, along with a 2013 meta-analysis of random- COMPLICATIONS OF HEMATOPOIETIC
279
ized trials which similarly found no benefit to allotransplantation, CELL TRANSPLANTATION
have led to a loss of enthusiasm for allogeneic HCT in myeloma. Some
authors have argued that survival improvements with allogeneic HCT Table 23-3 lists the complications associated with HCT; the most com-
273
require longer followup. Nonetheless, given existing data, allogeneic mon are discussed below. The first 100 days following transplantation
HCT in myeloma is typically reserved for younger patients with very are the time of greatest risk for recipients of autologous and allogeneic
high-risk disease or those who have failed autologous HCT, and is ide- HCT. Care by physicians skilled in the management of patients under-
ally performed in the context of a clinical trial. going these procedures is of critical importance.

Non-Hodgkin Lymphoma and Hodgkin Lymphoma GRAFT FAILURE
Patients with chemosensitive aggressive and highly aggressive lympho-
mas beyond CR1 have an improved overall survival with high-dose Graft failure is defined as the lack of donor hematopoietic cell engraft-
therapy followed by autologous HCT compared to best-of-care salvage ment following autologous and allogeneic HCT. Criteria are predomi-
chemotherapy. 280,281 The benefit of autologous HCT appears restricted to nantly operational, and graft failure is divided into primary (early) and
patients with chemosensitive disease. Patients with negative 18-fluoro- secondary (late) phases. The consequences of graft failure are signifi-
deoxyglucose (FDG)-PET imaging prior to transplantation have signifi- cant, and include high risks of death from infection, hemorrhage, or
cantly better outcomes than patients with residual FDG-avid disease at relapsed malignancy.
the time of transplant. 197,282,283 Historically, autologous HCT produced
long-term disease-free survival in approximately 50 percent of patients Primary (Early) and Secondary (Late) Graft Failure
284
with chemosensitive relapsed lymphoma. More recent studies have Myeloid engraftment has commonly been defined as the first of three
paradoxically demonstrated poorer cure rates (approximately 20 consecutive days on which the absolute neutrophil count exceeds
8
percent) with autologous HCT for relapsed B-cell NHL in the rituximab 5 × 10 /L. Myeloid engraftment typically occurs within 21 days of the
285
era. One possibility is that rituximab-containing first-line chemother- graft infusion, irrespective of graft source. Platelet recovery is more vari-
apy is successful in curing a greater number of patients, but also selects ably defined, often as the first day of a platelet count of at least 20, 50, or
9
for patients with particularly resistant disease in the setting of relapse. 100 × 10 /L, sustained without transfusion for 7 days. Platelet recovery
Autologous HCT is sometimes used as consolidation for high-risk may be substantially delayed compared with myeloid recovery, particu-
lymphomas in CR1, especially in mantle cell lymphoma, where autolo- larly with lower CD34+ cell doses or UCB allografts. A hemoglobin level
gous HCT in CR1 has been shown to extend progression-free survival of at least 8 g/dL without transfusion support is an accepted threshold
in a phase III randomized trial. Autologous HCT in mantle cell lym- for red cell engraftment. These criteria were derived from the predict-
286
phoma is most effective when performed early in the disease course, 287,288 able kinetics seen after myeloablative conditioning. With RIC, many
and thus eligible patients with mantle cell lymphoma should be referred patients never develop severe cytopenias, and thus engraftment in these
for transplant consultation during their induction course to discuss the settings is usually defined, at least in part, by assessment of donor chi-
risks and benefits of consolidative autologous HCT. Outside the setting merism in the blood or marrow. In these settings, graft loss is typically
of mantle cell lymphoma, there are few B-cell lymphomas where data defined by donor chimerism of less than 5 percent in blood CD3+ cells.
clearly support consolidative autologous HCT in CR1. Nevertheless, Primary graft failure is defined as failure to achieve these threshold
patients with so-called “double-hit” lymphomas (those mutated at both counts or donor chimerism levels at any point beyond day +28. Iso-
c-MYC and either bcl-2 or bcl-6) are viewed as particularly high-risk lated cytopenias does not necessarily herald graft failure, as they may be
and sometimes treated with autologous HCT in CR1. However, two transitory phenomena related to infection, medications, lineage-specific
recent studies have questioned the need for this approach; in both, immune-mediated cytopenias, or GVHD. Secondary (late) graft failure
patients with double-hit lymphomas who achieved PET-negative CR occurs in patients who initially meet criteria for engraftment but sub-
with induction therapy had excellent overall survival (75 to 83 percent), sequently lose graft function in at least two cell lines. Late graft fail-
and autologous HCT in CR1 was not considered beneficial. 289,290 Autol- ure is more often associated with allogeneic HCT than with autologous
ogous HCT is also often advocated as consolidation for patients with transplantation; possible causes include graft rejection related to resid-
T-cell lymphomas in CR1, with the exception of anaplastic lymphoma ual host immunity, persistent or progressive malignancy, low donor cell
kinase-positive (ALK+) large cell lymphoma. Definitive data support- yield, medication side effects, infection, or GVHD.
ing this practice are not available, but this approach appears reasonable
in view of the very high relapse rate associated with these lymphomas. Graft Rejection and Poor Graft Function
Allogeneic HCT is highly active and potentially curative for NHL, Graft rejection is a subset of primary or secondary graft failure caused
particularly indolent NHL. Excellent disease-free survival has been by immune-mediated rejection of donor cells by residual host effector
reported with both early and late allogeneic HCT in indolent NHL, cells. A diagnosis of graft rejection requires analysis of blood or mar-
even in heavily pretreated patients and those with active disease at row for donor hematopoietic chimerism; graft rejection is defined as

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