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360 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 361

An alternate form of irradiation is radioimmunotherapy, which pneumonitis, as well as decreased overall and disease-free survival, with
involves the use of antibodies to deliver locally acting radionucleotides BU/FLU, raising the concern that this regimen is inferior to BU/CY. 173,174
to targeted sites. In theory, this strategy could provide excellent targeted
antitumor effects without increased systemic toxicity. Clinical trials
incorporating anti-CD45 monoclonal antibodies conjugated to radio- REDUCED-INTENSITY TRANSPLANTATION
90
131
active iodine ( I) or yttrium ( Y) show promising early results in both The demonstration that immune-mediated mechanisms are critical in
the autologous and the allogeneic setting. 155–158 One approach to further eradicating malignancy after allotransplant challenged the rationale for
improving the targeting of radiation is the use of α-particle emitters. relatively toxic full-dose conditioning. A number of reduced-intensity
Alpha particles have a very short effective range but carry immense regimens have been developed which have lower regimen-related toxic-
kinetic energy, making them an attractive option to maximize malig- ity but are sufficiently immunosuppressive to allow full donor engraft-
nant cell killing while minimizing bystander damage. Preclinical studies ment, shifting the responsibility for tumor eradication largely or entirely
211
213
using bismuth-213 ( Bi) and astatine-211 ( At) have demonstrated to immunologic GVT effects. The development of RIC is one of the
efficacy, 159–162 and this approach is currently being translated into clin- most transformative advances in the field of allogeneic HCT in the past
ical trials. several decades, as it has allowed the expansion of eligibility for alloge-
neic HCT to older and less medically fit patients who would otherwise
CHEMOTHERAPY-ONLY REGIMENS be ineligible for high-dose conditioning. Additionally, patients with rel-
atively indolent disease may not require the immediate cytoreductive
Autologous capacity of an aggressive preparative regimen and may be particularly
Patients with NHL or HL have often received prior intensive local radio- suitable candidates for transplantation using RIC. These regimens are
therapy, often to the mediastinum, which results in a high incidence also useful in patients with nonmalignant diseases where the goal is
of fatal interstitial pneumonitis following TBI. Therefore, non-TBI- strictly the establishment of donor hematopoiesis; examples include
163
containing conditioning regimens were developed. The choices of genetic disorders, autoimmune diseases, and the induction of tolerance
drugs include agents that can be significantly dose-escalated and have in combined solid-organ and same-donor marrow transplantation.
improved tumor cell killing at higher doses, yet have nonoverlapping A variety of RIC regimens with differing dose intensities have
toxicities; for example, a common preparative regimen for autologous been developed. One significant regimen came from detailed studies in
HCT in lymphoma includes 1,3-bis(2-choloroethyl)-1-nitrosurea (car- a canine model using a backbone of low-dose 2 Gy TBI followed by
mustine or bis-chloroethylnitrosourea [BCNU]), VP-16, and CY. postgrafting immunosuppression with mycophenolate mofetil (MMF)
164
The dose-limiting non-hematologic toxicity of BCNU affects the lungs; and cyclosporine (CSP). This work was translated to patients with
175
VP-16 affects the liver; and CY, the heart. Consequently, using these a variety of malignancies and resulted in reliable donor engraftment
drugs below the maximally tolerated doses results in relatively low with the addition of intravenous FLU 90 mg/m . This reduced-in-
2 176
regimen-related toxicity but maximizes tumor cell kill to overcome tensity regimen has been used successfully in more than 1000 patients
drug resistance. Many other chemotherapy-only regimens have been with a wide variety of malignancies, especially in older patients and
developed for autologous HCT according to similar principles, includ- those with more indolent diseases such as follicular NHL or chronic
ing BCNU, etoposide, cytarabine, and melphalan (BEAM) (for lympho- lymphocytic leukemia (CLL). 177–179 Another commonly used RIC regi-
mas) and high-dose melphalan (for myeloma). men consists of intravenous FLU (between 90 and 150 mg/m ) and CY
2
(between 900 and 2,000 mg/m ). This regimen, combined with ritux-
2 180
90
Allogeneic imab or Y ibritumomab tiuxetan, has produced excellent long-term
181
A variety of chemotherapy-only conditioning regimens have been disease-free survival in patients with indolent lymphoma. A third
developed for allogeneic HCT. The most widely used combines oral common reduced-intensity regimen was developed in a rodent model
busulfan (BU), at a total dose of 16 mg/kg given over 4 days, with CY at using fractionated low-dose total lymphoid irradiation (TLI) combined
a total dose of 120 mg/kg given intravenously over 2 days (referred to as with depletive T-cell antibodies (antithymocyte serum), which showed
BU/CY). 165,166 A randomized comparison between fractionated TBI plus that recipients were protected from GVHD induction by donor-derived
182
CY (TBI/CY) and BU/CY in patients transplanted for CML demon- T cells. Rodents conditioned with this approach did not develop lethal
strated that the BU/CY regimen was better tolerated, but there was no acute GVHD despite the infusion of megadoses of donor T lymphocytes.
significant difference in overall or event-free survival, TRM, or GVHD TLI and antithymocyte serum altered residual host T-cell subsets to favor
incidence. The development of intravenous BU further improved regulatory NK/T cells which suppress GVHD by polarizing the infused
167
the availability and tolerability of this regimen, although steady-state donor T cells toward secretion of noninflammatory cytokines such
plasma concentrations remain variable after intravenous BU and thera- as IL-4, and by promoting expansion of donor CD4+CD25+FoxP3+
183
peutic drug monitoring arguably remains necessary. 168,169 Interestingly, T . This approach was successfully translated to clinical transplanta-
regs
pretreatment with BU may deplete hepatic glutathione and thus poten- tion; patients conditioned with TLI and antithymocyte globulin (ATG)
tiate the toxicity of CY. 170,171 Reversing the sequence of conditioning developed sustained donor-derived hematopoiesis with very low inci-
agents (from BU/CY to CY/BU) has been studied as a means of reduc- dences of acute GVHD and TRM. 184,185 The relative merits of RIC versus
ing regimen-related toxicity, and this alteration to the regimen has been high-dose conditioning continue to be studied; a national multicenter
associated with reduced exposure to toxic CY metabolites and a lower prospective randomized trial comparing high-dose to RIC in patients
risk of hepatotoxicity. 172 with acute myeloid leukemia (AML) or myelodysplastic syndrome
Other high-dose chemotherapy-only conditioning regimens remain (MDS) is ongoing under the auspices of the BMT-CTN.
in use on an institution-, disease-, and patient-specific basis. The most
common modification to BU/CY is the substitution of fludarabine Mixed Chimerism Following Reduced-Intensity Conditioning
(FLU) for CY (BU/FLU). This regimen has been proposed to avoid the A feature common to all RIC protocols is the incomplete eradication,
hepatotoxicity of CY and to reduce regimen-related toxicity compared at least initially, of host hematopoietic elements. As a consequence, a
to BU/CY. However, two recent randomized clinical trials comparing significant percentage of patients have mixed donor–recipient chimer-
BU/CY and BU/FLU have found increased risks of graft rejection and ism for months after transplantation before fully converting, if ever, to

Kaushansky_chapter 23_p0353-0382.indd 360 9/19/15 12:46 AM