Preparative Regimens for HSCT

Examples of commonly used preparative regimens are included in Table 98-2. The nonhematologic toxicity differs based on the preparative regimen administered.

Myeloablative Preparative Regimens In both autologous and allogeneic HSCT, infusion of stem cells circumvents dose-limiting myelosuppression, maximizing the potential value of the steep dose-response curve to alkylating agents and radiation, suppressing the host immune system, and creating space in the marrow compartment to facilitate engraftment. The preparative regimen is designed to eradicate immunologic-ally active host tissues (lymphoid tissue and macrophages) and to prevent or minimize the development of host-versus-graft reactions. Most allogeneic preparative regimens for the treatment of hematologic malignancies contain either cyclophosphamide, radiation, or both. The combination of cyclophosphamide and total-body irradiation (TBI) was one of the first preparative regimens developed and is still used widely today. This regimen is immunosuppressive and has inherent activity against hemato-logic malignancies (e.g., leukemias and lymphomas). TBI has the added advantage of being devoid of active metabolites that might interfere with the activity of donor hem-atopoietic cells. In addition, TBI eradicates residual malignant cells at sanctuary sites such as the CNS. Modifications of the cyclophosphamide-TBI preparative regimen include replacing TBI with other agents (e.g., busulfan) or adding other chemothera-peutic or monoclonal agents to the existing regimen in hopes of minimizing long-term toxicities. In the case of a mismatched allogeneic HSCT with a substantially increased chance of graft rejection, ATG also may be added to the preparative regimen to further immunosuppress the recipient.

Table 98-2 Commonly Used Preparative Regimens for HSCTa

Typ^ofHSCi P>F|Mr*Hv*fitglirnn Dfrn^chfrdulfr for Adulli

DciiiSehid ul l* far Pidlilrli Pjllrnli

AlldOcnHt'

Allogeneic, ¿nil clog WJ^'

Ajtole^wji1

HyetaahLilAieCyi ft I

NVetoablalive ButY

UyriiftlhL'il Ji' |i| AW (CMmuvNnftfletopoilite/-cylaralwWmelphalan)

AliCgeneii: Ncvam/eKwiilfHi^eSu-fLU

f.V W) rnu/k)/:!.!/ IV on J ion-iKulivi? d*r> bctae TBI 1 jMO-1,5 7S rjch fi4CliCfl3(«J<Fvei' l-?ddyi flu 1 mq/kf per dcKie po or ClS rrui/kq p»

dew ft cveiy & lyjuii * 16(Jokj; CV Ml mj/fcjrtjtf IV i Lilly X 2 tLiy^

following BLi C'JiiTiuilirw 3W V fnopQiidi 400-800 mijAn' IV given ouer

CymjUne «O-ljSOOrr^in'IVgiwn

Melphatan HO mgAn IV f ludjiatiliie iO mg/m'Miy IV on (toy 10 today -SfrtKwpd hy tjuiulfan I rugA^AJOit UO Cvtry d liOurS X 8 dos« tjni-S

fVSOmr|r'liq/diay IVon JtonsKutlrt" dayi before TBI IjMO-1,575 pjdifrjtrkmdlledo™ l-7tliy4

Eu I mgrtg per dose po or OA mgvfcg per do&e tv every frhourc* 16 (Jews; CY 120-200 ing/lq IV qriTOQv^f i-4 rtiyi lotting FiU

CMiMBtlnt JKUng/Tn'IV

FmfXrtirto fUU-Kifl mg/m IV given aueM (lay«.

Melpiulan NOmg/m1 IV

Flixfjribiie 30 mq/iin'ytliy IVcnday lOKKJiy -4 fnHnwm) by huwrtMi I mg/fcjrtkw po ev?ry 6 homl * 3 tkMtt on ctjyi -G Jriij -4

8L.I. bu^wlldivCY c yit>ijh(sphjrrii(fc FLU. iludjubin^; T8I. (uMl (jtxty iruduHo"

<P.*fCflU urUlir^Cnrvp H5C < J«? iC<|uii«t 10 unttircJO (JitlrirtSfiUiil it iCCninQ TO CtTitlH? Jj«l(tJlji O^jn furK [¡Oil £"iOl TO idlfliniSl ration of il* preparative regimen Therrfare, m; iianttairt dosage ¡edue lions hAvd rai n?njl (K Heparif (tyvfiinction be ipfommenrteil f(x kired piepaiative regiment. Any dowje neduc tioni baser) on renal c* tiepatk d^liincliofi should be conudered cm a casetiy-caw bain per iiiilHuliOiVS f*0(«Cl?,

The optimal myeloablative preparative regimen remains elusive. The long-term outcomes of busulfancyclophosphamide (BU-CY) and cyclophosphamide-TBI (CY-TBI) in patients with AML and CML, the more common indications for allogeneic HSCT, have been compared in a meta-analysis of four clinical trials.18 Equivalent rates of long-term complications were present between the two preparative regimens, except that there was a greater risk of cataracts with CY-TBI and alopecia with BU-CY Overall and disease-free survivals were similar in patients with CML, whereas there was a trend for improved disease-free survival with CY-TBI in AML patients. Thus, the preparative regimen can be tailored to the primary disease and to the degree of HLA compatibility.

Nonmyeloablative Preparative Regimens A nonmyeloablcitive preparative regimen is less toxic than a myeloablative regimen in hopes of being able to offer the benefits of an allogeneic HSCT to more patients. A nonmyeloablative HSCT is based on the concept of donor immune response having a graft-versus-tumor effect.

Because of the severe regimen-related toxicity of a myeloablative preparative regimen, the use of HSCT traditionally was limited to younger patients with minimal comorbidities. Most patients diagnosed with cancer are elderly and thus, myeloablative HSCT could not be offered to a substantial portion of cancer patients. The concept of donor immune response having a graft-versus-tumor effect gave rise to the theory that a strongly immunosuppressive, but not myeloablative, preparative regimen (i.e., a nonmyeloablative transplant may result in a state of chimerism in which the recipient and donor are coexisting. The toxicity and efficacy of nonmyeloablative transplants are being evaluated in patients with malignant and nonmalignant conditions who are not eligible for a myeloablative HSCT.

FIGURE 98-1. Schema for nonmyeloablative transplantation. Recipients (R) receive a nonmyeloablative preparative regimen and an allogeneic HSCT. Initially, mixed chimerism is present with the coexistence of donor (D) cells and recipient-derived normal and leukemia/lymphoma (Rl) cells. Donor-derived T cells mediate a graft-versus-host hematopoietic effect that eradicates residual recipient-derived normal and malignant hematopoietic cells. Donor-lymphocyte infusions may be administered to enhance graft-versus-tumor effects. (From Ref. 19.)

FIGURE 98-1. Schema for nonmyeloablative transplantation. Recipients (R) receive a nonmyeloablative preparative regimen and an allogeneic HSCT. Initially, mixed chimerism is present with the coexistence of donor (D) cells and recipient-derived normal and leukemia/lymphoma (Rl) cells. Donor-derived T cells mediate a graft-versus-host hematopoietic effect that eradicates residual recipient-derived normal and malignant hematopoietic cells. Donor-lymphocyte infusions may be administered to enhance graft-versus-tumor effects. (From Ref. 19.)

A nonmyeloablative preparative regimen allows for development of mixed chimerism (defined as 5% to 95% peripheral donor T cells) between the host and recipient to allow for a graft-versus-tumor effect as the primary form of therapy (Fig. 98-1). Chi-merism is assessed within peripheral blood T cells and granulocytes and bone marrow using conventional (e.g., using sex chromosomes for opposite-sex donors) and molecular (e.g., variable number of tandem repeats) methods for same-sex donors.

The nonmyeloablative preparative regimen does not completely eliminate host normal and malignant cells. Donor cells eradicate residual host hematopoiesis, and the graft-versus-tumor effects generally occur after the development of full donor T-

cell chimerism. After engraftment, mixed chimerism should be present and is shown by the presence of both donor- and recipient-derived cells. Autologous recovery should occur promptly if the graft is rejected. The intensity of immunosuppression required for engraftment depends on the immunocompetent of the recipient and the histocompatibility and composition of the HSCT.19 More intensive cond it i oning regimens that are required for engraftment in the setting of unrelated-donor- or HLA-mismatched-related HSCT recently have been termed reduced-intensity myeloablative transplants. After chimerism develops, donor-lymphocyte infusion can be administered safely in patients without GVHD to eradicate malignant cells.

Nonmyeloablative preparative regimens typically consist of a purine analog (e.g., fludarabine) in combination with an alkylating agent or low-dose TBI. Adverse effects in the early post-transplant period are decreased because of the lower-intensity preparative regimen, thus making HSCT available to patients who in the past were not healthy or young enough to receive a myeloablative preparative regimen. The risk of GVHD remains with nonmyeloablative transplant; the GVHD prophylaxis regimens are reviewed in the GVHD section below. Presently, nonmyeloablative transplant is not indicated as first-line therapy for any malignant or nonmalignant conditions although research is ongoing. Nonmyeloablative transplantation is being evaluated for cancers sensitive to a graft-versus-tumor effect (e.g., CML and AML), in older patients, or for those with comorbidities who would not be able to tolerate a myeloablative HSCT.

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