Page 389 - Williams Hematology ( PDFDrive )

364 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 365

suffer from substantial selection bias; presumably patients with relapsed 54 percent and 29 percent for patients transplanted in CR1 and beyond
or refractory AML were not transplanted indiscriminately, but only if CR1, respectively, in the pre–tyrosine kinase inhibitor (TKI) era. 262
their physicians felt they had an above-average chance of responding. The development of TKIs targeting bcr/abl has markedly improved
These success rates are therefore very unlikely to pertain to the over- the prognosis of Ph+ ALL. With the incorporation of TKI therapy into
all population of adults with relapsed or refractory AML. Attempts pretransplant induction and posttransplant maintenance, Ph+ ALL now
have been made to construct prognostic tools to identify the subset of carries one of the best prognoses of all forms of adult ALL, even with
patients most likely to benefit from allogeneic HCT, and some author- nonmyeloablative conditioning. 261,263 Most authorities continue to rec-
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ities have argued that allogeneic HCT is underused in this population. ommend allogeneic HCT as postremission therapy for adults with ALL
Currently there is no single standard of care for treatment of patients in the TKI era. The pediatric literature suggests that it may be safe to
with AML in refractory relapse or primary induction failure; reason- forgo allotransplantation in favor of TKI-based chemotherapy alone in
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able options include additional salvage chemotherapy to induce remis- Ph+ ALL, but these data cannot be extrapolated to the adult setting
sion; enrollment on a clinical trial; allogeneic HCT (in carefully selected because of the very different clinical behavior of adult versus pediatric
patients); and palliative care, and the optimal choice must be individu- ALL. For adults with Ph+ ALL who are not candidates for allotrans-
alized based on patient characteristics and donor availability. plantation, TKI-containing chemotherapy regimens coupled with close
monitoring of minimal residual disease may be an alternative, but this
Acute Lymphoblastic Leukemia approach has not been tested in clinical trials.
Allogeneic HCT is widely used in adult patients with ALL, especially
those patients with high-risk features (most often defined as white blood Myeloma
cell count at diagnosis >30,000 [or >100,000 in T-cell ALL], adverse Autologous HCT is not curative in myeloma, but a number of random-
cytogenetics, progenitor B-cell immunophenotype, age >60 years, or ized clinical trials have demonstrated prolongation of event-free survival
failure to achieve CR within 4 weeks of induction chemotherapy). by a median of approximately 1 year when single or double autologous
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Patients with none of these features are considered to have standard-risk HCT is incorporated into the treatment program. 265–267 Some of these
disease; there is no clear “favorable-risk” population in adult ALL. While trials also reported improved overall survival with autologous HCT. In
the advisability of allogeneic HCT is uncontroversial as postremission addition, early autologous HCT is associated with an improved quality
therapy for adults with high-risk ALL, it is also the treatment of choice of life in patients with myeloma, likely because it is associated with a
for eligible adults with standard-risk ALL in CR1. Several large geneti- shorter period of chemotherapy. However, these studies were per-
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cally randomized prospective trials have demonstrated a survival bene- formed before the introduction of modern highly active antimyeloma
fit for allogeneic HCT in CR1 for adults with standard-risk ALL. 257,258 A therapies such as thalidomide, lenalidomide, and bortezomib. In 2014,
2013 meta-analysis confirmed the benefit of upfront allogeneic HCT for results were published from a randomized trial comparing upfront
adults 35 years of age or younger; for older adults, the benefit was more tandem autologous HCT to lenalidomide-based maintenance therapy
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difficult to demonstrate owing to increasing TRM. As with all geneti- after induction with lenalidomide and dexamethasone. Patients ran-
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cally randomized clinical trial data, these findings apply only to patients domized to upfront autologous HCT had significantly improved 4-year
with HLA-identical sibling donors, strictly speaking, although many overall survival compared to those randomized to the nontransplant
authorities extrapolate the observed benefit to HLA-matched unrelated arm (81.6 percent vs. 65.3 percent, p = 0.02; Fig. 23–1). Patients ran-
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donors and possibly even alternative donors on the basis of generally domized to the nontransplantation arm remained eligible for autolo-
equivalent outcomes. gous HCT at the time of myeloma progression, but only 62.8 percent
On the basis of existing data, we believe that myeloablative allo- actually received autologous HCT, suggesting that delayed autologous
geneic HCT is the optimal therapy for all eligible adults with ALL in HCT is not feasible for many patients as a result of rapid clinical dete-
CR1 and available HLA-identical sibling donors—a recommendation rioration following relapse. These results support the continued role
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supported by a recent Cochrane Library systematic review. Alloge- of upfront autologous HCT as the standard of care for medically fit
neic HCT is likely also the optimal therapy for those with HLA-matched patients with myeloma in the modern era, although several caveats
unrelated donors, although this recommendation relies more on extrap- apply. First, the maintenance regimen in the nontransplantation arm
olation from data in the HLA-identical sibling setting. The decision consisted of low-dose melphalan in combination with lenalidomide and
to proceed with alternative-donor allogeneic HCT in a patient with dexamethasone, and it is unclear whether these findings can be gener-
standard-risk ALL in CR1 is less clear-cut and depends on patient pref- alized to other, more commonly used maintenance regimens. Second,
erence and institutional comfort level. In any case, we believe that all patients randomized to upfront autologous HCT received planned tan-
adults with ALL should be referred for transplantation consultation early dem autologous HCT with intravenous melphalan 200 mg/m condi-
2
in their course to assist in determining the optimal treatment approach. tioning for each transplant. This approach is relatively uncommon, as
Conditioning-regimen intensity appears to play a major role in the tandem autologous HCT has fallen out of favor based on evidence that
success of allogeneic HCT for ALL. Results with nonmyeloablative allo- it does not improve overall survival. In current practice, second autol-
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geneic HCT for Philadelphia chromosome–negative (Ph–) ALL beyond ogous HCT is usually reserved for patients who fail to achieve at least
CR1 have been poor, with virtually no survivors. For older adults with a very good partial remission after first autologous HCT, and is often
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2
Ph– ALL who are not candidates for intensive conditioning, the optimal performed using a lower dose of intravenous melphalan (140 mg/m )
approach remains unclear, particularly for those beyond CR1. as conditioning. As a result, it is unclear whether the benefit observed
Philadelphia Chromosome–Positive Acute Lymphoblastic in this trial extends to the setting of single autologous HCT. Nonethe-
Leukemia The postremission management of patients with Phila- less, upfront autologous HCT continues to be widely used in myeloma,
delphia chromosome–positive (Ph+) ALL deserves special attention. and the recent trial adds support for this approach, particularly since
Historically, Ph+ ALL carried a very poor prognosis with conventional nearly 40 percent of patients intended to undergo transplantation never
chemotherapy, and this chromosomal abnormality was considered a received the intervention.
high-risk feature. High-dose TBI-based conditioning and allotrans- Allogeneic HCT remains the only therapy thought to be poten-
plant has historically been the standard of care for postremission ther- tially curative in myeloma, and has been widely studied, most often as
apy of Ph+ ALL in adults, and resulted in 10-year overall survivals of part of a tandem autologous/allogeneic double-transplant approach.

Kaushansky_chapter 23_p0353-0382.indd 364 9/19/15 12:47 AM