Page 1173 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPTER 83 Hematopoietic Stem Cell Transplantation for Malignant Diseases 1137

the use of busulfan and TBI found no statistically significant in the initial treatment of CML, will reduce the numbers of
difference in survival or disease-free survival for patients with patients requiring HSCT in the management of their disease.
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CML or AML. Specific regimens are commonly used in the Organizations, such as American Society of Blood and Marrow
treatment of certain malignancies, such as dose-intensive mel- Transplantation, have published guidelines for treatment and
phalan in the treatment of MM and carmustine (BCNU)–contain- reviews of the efficacy of treatment, identifying areas requiring
ing regimens used in the treatment of lymphoma. additional research. 39,40
CLINICAL PEARLS Acute Myelogenous Leukemia
Conditioning Regimens for Hematopoietic Stem The primary clinical questions in HSCT in the treatment of
Cell Transplantation (HSCT) Transplantation AML concern patient selection and timing of treatment. Most
patients with AML will achieve remission with initial chemo-
Autologous HSCT therapy, but even with appropriate postremission consolidation,
• Allows dose-intensive therapy the majority of patients (≈65%) will relapse within 1–2 years.
• Allows use of marrow-toxic agents Older age, the presence of defined cytogenetic abnormalities,
• Regimens designed for optimal tumor cytotoxicity inability to achieve a complete remission (CR) with the initial
course of therapy, and history of a preceding marrow disorder
Allogeneic HSCT
• Must achieve adequate patient immunosuppression (reduce host- or receipt of prior chemotherapy (“secondary AML”) are predic-
versus-graft [HvG] reaction) to achieve engraftment tors for failure of nontransplantation therapy. Patients with these
• Allows but does not require dose-intensive therapy adverse risk factors may be offered HSCT in first remission in
• Allows but does not require marrow-toxic agents place of nontransplantation consolidation chemotherapy. Numer-
• Need not be tumor specific ous studies of patients entering their first remission compared
standard consolidation therapy with dose intensification with
The myeloablative conditioning regimens currently used have auto- or allo-HSCT. In general, auto-HSCT was not shown to
been tested in dose-escalation studies to achieve the maximal toler- be more effective than nontransplantation consolidation che-
ated doses in otherwise healthy patients. Nonmarrow toxicities, motherapy, whereas allo-HSCT had the lowest risk of relapse.
such as pneumonitis, mucositis, and hepatic venoocclusive disease, Despite the higher transplantation-related complications, in at
limit further dose escalation of standard TBI- or chemotherapy- least two major studies, patients assigned to allo-HSCT achieved
based regimens. New approaches include the addition of targeted a significantly better disease-free survival (DFS) compared with
therapies to the conditioning regimen, such as tumor-directed patients assigned to either chemotherapy or auto-HSCT. Allo-
mAbs or radioimmunoconjugates that will not increase the toxicity HSCT in first remission is particularly beneficial for patients
to other organs. Tandem transplantation with the combination of with adverse risk features, achieving about a 50–70% DFS, and
a dose-intensive regimen with auto-HSCT followed, after recovery is the treatment of choice for patients with adverse risk cytogenet-
from the immediate regimen-related toxicities, by allo-HSCT ics or leukemia that arises from prior chemotherapy or other
using a reduced-intensity regimen is a novel approach to combine marrow diseases.
the benefits of each transplantation modality.
Hematological malignancies are predominantly diseases Myelodysplastic Syndromes
of older adults. The potent GvT effect that is observed after Myelodysplastic syndrome (MDS) comprises a heterogeneous
allo-HSCT allows allograft recipients to be treated with lower- group of clonal hematological disorders characterized by expan-
dose nonmyeloablative regimens with the immunosuppressive sion of abnormal HSCs engendering variable degrees of cytopenia
properties of the regimen to reduce HvG reactions and facilitate and frequent evolution to AML. Currently, allo-HSCT is the
engraftment becoming more important than direct cancer cytotox- only modality of treatment that can achieve long-term control
icity. The primary requirement in developing a reduced-intensity of disease; auto-HSCT is not feasible because of the inability to
regimen is the need to achieve adequate immunosuppression collect normal HSCs from these patients. The best results are
to permit the development of hematopoietic chimerism, which seen in patients with earlier-stage disease, although for patients
became feasible with the development of the purine analogue with earlier stage MDS, a “watchful waiting” approach, with
family of drugs. A variety of regimens are available, including transplantation performed at the time of disease progression,
combinations of fludarabine with melphalan and fludarabine may be appropriate.
with busulfan. Among the least toxic are regimens that involve
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a single fraction of TBI, based on the work by Storb et al., who Chronic Myelogenous Leukemia
proposed that the HvG reaction leading to HSC rejection and Allo-HSCT is an appropriate treatment for CML with long-term
the GvH reaction could both be modified by an appropriate survival rates >80% for younger patients undergoing related donor
immunosuppressive regimen administered after transplantation, transplantation within the first year after diagnosis. However,
allowing a reduction in the intensity of the pretransplantation inhibitors of the tyrosine kinase (TK) encoded by the Philadelphia
conditioning regimen. 37,38 chromosome have relegated transplantation to the treatment of
patients with advanced disease or the rare patient with CML not
HSCT FOR INDIVIDUAL DISEASES responsive to that targeted therapy. The probability of long-term
survival is lower for patients who undergo allo-HSCT more than 1
The treatment of diseases by auto- or allo-HSCT continues to year after diagnosis and for patients with more advanced diseases.
evolve as the understanding of the biology of these diseases The effect of prior therapy with a TK inhibitor on the outcome
becomes more clearly understood. Improvements in nontrans- of transplantation is not known. CML is highly responsive to
plantation treatments available to patients, such as the develop- the immunological GvT effect, and many patients in relapse
ment of targeted tyrosine kinase inhibitors, which are very effective after transplantation can be salvaged by the administration of