Page 437 - Hematology_ Basic Principles and Practice ( PDFDrive )

358 Part IV Disorders of Hematopoietic Cell Development

patients and siblings should be arranged. If FA is confirmed by DEB deteriorating counts, or a BM blast count of greater than 5%; or (3)
or MMC testing, genetic diagnosis should be offered to the family. overt AML. Decision to transplant for milder, relative indications
On a separate visit, imaging studies should be requested to search for should be made on a case-by-case basis.
internal anomalies. Imaging using radiation should be minimized as Three caveats about transfusional supportive care before HSCT
much as possible because of the carcinogenic risk. When all the results are (1) more than 20 exposures to blood products is a risk factor that
from the workup have been compiled, a follow-up visit with the adversely affects engraftment and survival posttransplant; (2) use of
patient and family is arranged to discuss the diagnosis, management directed donations from family members may cause alloimmuniza-
options, and prognosis. A referral to a genetic counselor should ensue. tion to an antigen that can increase the risk of graft rejection after a
High-resolution human leukocyte antigen (HLA) typing of the matched sibling donor or haploidentical related HSCT; and (3)
patient and immediate family members is recommended shortly after single-donor apheresis platelets should be requested when required
the diagnosis is established to determine potential matched-related and the product should be leukodepleted and irradiated.
donors in case HSCT becomes necessary. Most published studies for matched related donor HSCT have
If the patient is stable, has only minimal to moderate hematologic used one of the following protocols: (1) cyclophosphamide, ATG,
changes, and does not have transfusion requirements, a period of and total-body irradiation (TBI); (2) fludarabine, cyclophosphamide,
observation is indicated. During this time, subspecialty consultations and ATG; or (3) cyclophosphamide alone. In several studies usage of
(e.g., with orthopedic surgeons, urologists, gynecologists, and otolar- radiation-containing regimens in the setting of FA and matched
yngologists) can be arranged. Blood counts should be monitored related donor HSCT was shown to be associated with higher toxicity
every 1 to 3 months to determine their stability. In a stable patient and lower long-term overall survival than nonradiation regimens and
with mild cytopenias, blood counts can be monitored every 3 months, have gradually been avoided. Fludarabine, a purine antimetabolite
and BM evaluation should be performed annually. Falling counts, a with potent immunosuppressive and myeloablative properties with
clonal BM cytogenetic abnormality, or prominent multilineage dys- minimal toxicity to other tissues, continues to gain favor as an effec-
plasia require more frequent clinic visits and blood and BM sampling tive adjunct to preparative regimens. Transplant centers usually
to monitor for progression to severe aplastic anemia, MDS, or AML. intensify the cytoreductive regimen when the patient has MDS or
Spectral karyotyping (SKY), fluorescent in situ hybridization (FISH), AML. Disease-free survival data for TBI-based protocols vary between
and comparative genomic hybridization of BM cells can enhance the 64% and 89%. Disease-free survivals for non-TBI protocols are as
diagnostic capability. high as 93% using cyclophosphamide alone. The risk of primary or
A surveillance program for solid cancers should be initiated at least secondary graft failure is 5% to 10%, and the risk of acute GVHD
annually. After the age of 10 years or 1 year after HSCT, the oral ranges from 8% using cyclosporine and methotrexate prophylaxis to
cavity should be examined every 6 months for signs of malignant 55% using cyclosporine alone.
change because the risk in untransplanted patients with FA is 700- Hematopoietic stem cell transplantation using HLA-mismatched
fold that of the general population. Dentists, oral surgeons, or head related donors, matched or one-antigen mismatched unrelated
and neck surgeons should be periodically recruited after the age of donors, or cord blood carries a higher risk of complications and a
10 years or after HSCT to screen for head and neck squamous cell lower disease-free survival than matched sibling donor HSCT. The
carcinomas by rhinopharyngoscopy using a flexible endoscope. best outcome predictors are recipients younger than 10 years old,
Beginning at age 13 years, all women with FA should undergo annual recipient seronegativity for CMV, history of fewer than 20 exposures
gynecologic screening because the relative risk of vulvar squamous to blood products, and use of fludarabine in the cytoreductive
cell carcinoma is 4000-fold higher and cervical cancer is 200-fold regimen. Risk factors adversely affecting survival are an HLA-
higher than that of the general population. Human papilloma virus mismatched donor, an FA phenotype with three or more congenital
(HPV) DNA can be detected in 84% of FA squamous cell carcinoma malformations, and prior administration of androgen therapy. The
specimens from various anatomic sites. Although the role of HPV in latter factor might be related to the delay in transplant rather than
FA carcinogenesis is controversial, quadrivalent HPV vaccine is still the therapy itself. Indications for an alternate donor HSCT are
recommended for boys and girls with FA at 9 years of age as a possible identical to those for a matched sibling donor HSCT.
preventive approach. Provided that no extended family members are suitable BM or
Growth should be serially documented, and when growth velocity peripheral blood stem cell donors, unrelated BM donors are sought
or stature falls below expectations, endocrine evaluation is needed to and identified by searching donor and umbilical cord blood registries.
identify growth hormone deficiency. Diabetes mellitus occurs more An acceptable unrelated donor should be fully matched by high-
commonly in FA, and random glucose levels should be evaluated resolution typing for all HLA-A, B, C, and DRB1 antigens, a so-called
annually or biannually. Based on the degree of hyperglycemia found 8/8 match. A second choice is a one-antigen mismatch in a BM
on initial testing, fasting glucose levels and glucose tolerance tests donor. Matched or one-antigen mismatched banked umbilical cord
should be performed. Screening for hypothyroidism should also be blood is equally suitable to a one-antigen mismatched BM donor and
performed annually. is an option. The last choice is a two-antigen mismatched cord blood.
Using cord blood cells from unrelated donors, engraftment and
Hematopoietic Stem Cell Transplantation survival are comparable to related or unrelated BM, although engraft-
Hematopoietic stem cell transplantation is the only curative therapy ment is slower with cord blood. The incidence of acute and chronic
for the hematologic abnormalities of FA: aplastic anemia, MDS, and GVHD is reduced with cord blood grafts even in one or two HLA
AML. The best donor source is an HLA-matched sibling in whom antigen mismatched transplants. Three-year published survival rates
thorough history, physical examination, blood counts, HbF, chromo- after unrelated HSCT for FA range between 40% and 75%.
some breakage testing, and ideally genetic testing have excluded a Haploidentical HSCT from a haploidentical related donor using
diagnosis of FA. Initial efforts to transplant patients with FA using CD34(+) positively selected cells with or without T cell-depletion
standard preparative regimens and graft-versus-host disease (GVHD) and reduced-intensity regimens have gained interest because of the
prophylaxis were plagued by two serious and often lethal problems, almost universal availability of such donors (parents). Data is still
severe cytotoxicity from chemotherapy and irradiation, and exagger- limited, but engraftment has been seen in most patients, and 5-year
ated GVHD. Reduced-intensity HSCT protocols that remain mye- overall survival of up to 83% has been reported. Failures are mainly
loablative for patients with FA were subsequently introduced and caused by graft rejection, acute and chronic GVHD, and
improved outcomes ensued. Research is constantly ongoing for the infections.
most effective strategies. Molecular technology has led to preimplantation genetic diagnosis
Absolute indications for a matched sibling donor HSCT are (PGD) coupled with in vitro fertilization (IVF) and selection of
(1) severe underproductive cytopenias and transfusion dependency; HLA-matched embryos for implantation. This is an option for
(2) high-risk MDS with chromosomal clonal abnormalities like parents who have a child with FA and a defined FANC mutation but
monosomy 7, partial trisomies and tetrasomies of 3q26q29 and without a matched sibling donor. If the mother is fertile, eggs are