Page 1792 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 104

INDICATIONS AND OUTCOMES OF ALLOGENEIC

HEMATOPOIETIC CELL TRANSPLANTATION FOR

HEMATOLOGIC MALIGNANCIES IN ADULTS

Mehdi Hamadani and Parameswaran N. Hari

BACKGROUND MPD) and acute lymphoblastic leukemia (ALL) currently constitute
the three most common indication of allogeneic transplantation
1
Thomas et al first reported long-term leukemia-free survival fol- (Fig. 104.1).
lowing human leukocyte antigen (HLA) identical sibling hemato- Improved immunosuppression and supportive care and the use of
poietic cell transplantation (HCT) in patients with refractory acute RIC have led to an increase in allogeneic HCT for older adults in
leukemia in the 1970s. Since then, allogeneic HCT has evolved to recent years. Only 4% of allogeneic HCT recipients in 1987–1992
become a frequently used and effective therapy for many hema- were older than 50 years. In 2013, 34% were older than 55 years and
tologic malignancies. Changes in both HCT and nontransplant 10% were 65 years or older. Allogeneic transplantation in patients
therapies have modified the indications and applicability of HCT without HLA-identical siblings was facilitated by establishment of
over time. In chronic myelogenous leukemia (CML), HCT (once large unrelated donor registries. In 1987–1992, <10% of HCTs for
the mainstay for cure), is now largely supplanted by molecularly hematologic malignancies used unrelated donors; in 2013, this figure
targeted therapy. In recent years, and especially after the advent of was >50%. More transplantation in older adults and increasing use
reduced intensity conditioning (RIC) in the late 1990s, allogeneic of unrelated donors were the main reasons for the steady growth in
HCT is increasingly used in older patients and as a salvage strategy allogeneic HCT over the last decade. Similarly, the use of haploidenti-
for lymphoma or myeloma not responding to chemotherapy or cal related donor HCT is on the rise. In 2001, less than 50 related
autologous HCT. Transplant-related mortality (TRM), while steadily donor haploidentical transplants were reported to the CIBMTR,
declining, still remains a challenge. General principles, indications compared with nearly 500 transplants in 2013.
and optimal timing of allogeneic HCT for hematologic malignan-
cies and long-term outcomes following HCT are discussed in this
chapter. CONDITIONING REGIMENS
Allogeneic HCT involves administration of a conditioning (or
preparative) regimen of chemotherapy (with or without radiation) Historically, conditioning regimens included myeloablative doses of
and immune suppressive medications, followed by infusion of donor cytotoxic drugs with or without radiation, intended not only to
hematopoietic progenitor cells. Most patients then receive prolonged provide disease control, but also host immunosuppression (to prevent
(several months) therapy with immune suppressive agents to prevent graft rejection). Myeloablative regimens for hematologic malignan-
or treat graft-versus-host disease (GVHD). The purpose of the con- cies often involve a combination of cyclophosphamide (commonly
ditioning regimen is generally twofold: to eradicate malignant cells 60 mg/kg/day for 2 days) and total-body irradiation (TBI) (5–15 Gy,
and to eliminate host immune cells (capable of rejecting even HLA- single or fractionated doses). Many regimens substitute busulfan
identical sibling donor cells). The ability to restore hematopoiesis (typically 3.2 mg/kg/day intravenously for 4 days or pharmacokinetic
with donor hematopoietic progenitor cells permits the administration guided similar dose) in place of TBI. Posttransplant survival rates
of substantially higher (myeloablative) doses of cytotoxic therapy, with cyclophosphamide and TBI and with cyclophosphamide and
than is otherwise possible. Although originally regarded primarily as busulfan (BuCy) are similar though recent prospective data suggest
a way of rescuing patients from therapy-induced marrow aplasia, it an advantage for BuCy in myeloid malignancies (AML/MDS/CML).
is now accepted that graft-versus-malignancy (GVM) effects con- Other drugs such as etoposide, melphalan and thiotepa, are some-
ferred by alloreactive donor cells contribute substantially to cancer times added to or substituted for cyclophosphamide and/or busulfan
eradication and longer-term relapse prevention. in a variety of regimens in efforts to provide better, generally disease-
specific, antineoplastic activity. Large prospective trials comparing
efficacy of these regimens are lacking. A CIBMTR study suggested
PATIENT POPULATION better outcomes in ALL in second complete remission (CR2) with
either higher doses of TBI or substitution of cyclophosphamide by
Accompanying the growth of HCT, a coordinated, international etoposide in a standard dose TBI regimen.
effort evolved to collect and analyze data on transplant outcomes Myeloablative conditioning regimens are associated with signifi-
through the International Bone Marrow Transplant Registry cant risk of regimen-related toxicity. Toxicity can be minimized and
(IBMTR), established in 1972. The IBMTR affiliated with the efficacy improved with careful pharmacokinetic monitoring of certain
United States (US) National Marrow Donor Program (NMDP) in drugs, e.g., busulfan. Another strategy for lowering treatment related
2004 to become the Center for International Blood and Marrow mortality is by reducing the dose-intensity of the conditioning
Transplant Research (CIBMTR). The CIBMTR currently collects regimen. This approach uses lower doses of cytotoxic drugs and/or
data on HCT outcomes from more than 400 transplant centers radiation to facilitate donor cell engraftment and relies more on
worldwide and on all allogeneic transplants in the US. In 2013, GVM effects to eradicate malignant cells. The lower doses of cytotoxic
approximately 9600 allogeneic transplants were performed in adults agents produce less host tissue damage and less inflammatory cytokine
(age >18 years) in the US. These data show that hematologic malig- secretion resulting in lower rates of regimen-related morbidity and
nancies (and premalignant conditions) remain the most common mortality. Use of RIC regimens has greatly increased the applicability
indications for allogeneic HCT. Acute myeloid leukemia (AML), of allogeneic HCT in patients ineligible for traditional myeloablative
myelodysplastic syndrome/myeloproliferative disorders (MDS/ regimens because of age or comorbidities. The development of these

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