Page 1682 - Hematology_ Basic Principles and Practice ( PDFDrive )

1500 Part VIII Comprehensive Care of Patients with Hematologic Malignancies

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testosterone, and normal progression through puberty. Evidence of particularly after exposure to dexamethasone between the ages of 10
germ cell damage can occur and is more likely among patients treated and 20 years. This complication usually develops during or shortly
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after puberty. Semen analyses have been normal in approximately after completion of therapy but may progress over time. 151–153 Mattano
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two-thirds of men after high-dose cyclophosphamide and several men et al described the magnitude of risk and associated risk factors for
have fathered normal children. Men treated with TBI-based regimens development of osteonecrosis in children with ALL treated on Chil-
who have not received prior testicular irradiation generally retain dren’s Oncology Group therapeutic protocols. The cumulative inci-
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normal Leydig cell function, regardless of their age at treatment. dence was 9.3% at 3 years; the incidence was higher in older patients
Germ cell dysfunction occurs in all men treated with TBI-based regi- (14.2% for patients ≥10 years of age vs. 0.9% for patients <10 years
mens and azoospermia is the rule; however, some younger males (age of age) and higher among whites than African Americans. Further-
<25years at HCT) without chronic GVHD have showed some degree more, the incidence was higher among patients randomized to receive
of spermatogenesis following standard-dose TBI. 139 two 21-day dexamethasone courses versus one course.
Female patients treated with high-dose cyclophosphamide alone Osteonecrosis is increasingly being reported among HCT
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retain normal ovarian function regardless of age at exposure, although recipients. 154–157 Campbell et al conducted a retrospective cohort
these subjects may be at an increased risk for early menopause as they study and described the cumulative incidence of osteonecrosis to be
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reach the third decade of life. These individuals can sustain a 2.9% among autologous HCT recipients, 5.4% among allogeneic
normal pregnancy resulting in normal offspring. Females treated with HCT recipients, and 15% among unrelated donor HCT recipients.
busulfan and cyclophosphamide are at very high risk for ovarian Among allogeneic HCT recipients, male sex, presence of chronic
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failure and premature menopause. The outcome of ovarian func- GVHD, and exposure to cyclosporine, tacrolimus, prednisone, and
tion after TBI appears to be determined by the age at exposure. mycophenolate mofetil rendered patients at increased risk, in particu-
Approximately 50% of prepubertal girls receiving fractionated TBI lar among patients with a history of exposure to three or more drugs.
enter puberty spontaneously and premature ovarian failure is seen in The mean latency period was 18 months. The hip joint was the most
all patients who are older than 10 years of age when treated with commonly involved joint (80%); however, the knee, wrist, and ankle
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TBI. Pregnancies among survivors of TBI are at an increased risk joints were also affected. The cumulative incidence of surgery (mainly
for spontaneous abortion, premature labor, and low-birthweight arthroplasty) approached 31% at 1 year from osteonecrosis diagnosis.
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offspring. 142 Li et al conducted a case-control study of children who underwent
Assessment for gonadal dysfunction includes a thorough history allogeneic HCT and found that children at highest risk included
and physical examination; additionally, a morning serum testosterone those who underwent transplant during the period of rapid pubertal
level in males and serum estradiol, follicle-stimulating hormone level, growth and those who received myeloablative conditioning and
and luteinizing hormone level in females, should be obtained during immunosuppression for treatment of GVHD.
early adolescence and as clinically indicated in patients with delayed Osteopenia (bone density 1–2.5 standard deviations below mean)
or arrested puberty or who have symptoms of gonadal dysfunction. or osteoporosis (bone density >2.5 standard deviations below mean)
Semen analysis may be obtained in sexually mature males desiring to is commonly seen in survivors of hematologic malignancies. 159–161
know their fertility status. 82,143,144 Risk factors include therapy with corticosteroids, methotrexate (at
higher doses), and cranial irradiation with resultant pituitary insuf-
ficiency or gonadal dysfunction. Survivors of HCT are also at
PREGNANCY OUTCOMES increased risk for reduced bone mineral density; identified risk factors
in these patients include treatment with corticosteroids for chronic
Offspring of survivors of childhood hematologic malignancies do not GVHD, prior cranial irradiation (resulting in growth hormone
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appear to be at increased risks for cancer or congenital malforma- deficiency), and gonadal failure. Lifestyle factors that increase the
tions. 145,146 In a study of 593 adult survivors of childhood ALL, risk for osteopenia include lack of regular weight-bearing exercise,
15.7% (93 out of 593) of survivors (mean age: 22.6 years) had given inadequate calcium and vitamin D intake, smoking, and excessive
birth to or fathered a total of 140 live-born offspring, compared with alcohol consumption. 162,163
29.8% (122 out of 409) of sibling controls (mean age: 25.2 years). Detection and diagnosis of musculoskeletal sequelae depend
There was no significant difference in the rate of birth defects between largely on anticipating these issues in vulnerable hosts, on taking a
offspring of survivors (3.6% [5 out of 140]) versus sibling controls careful history, and on performing a thorough physical examination.
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(3.5% [8 out of 228]; RR: 1.02; 95% CI: 0.34–3.05). In a review Pain or a history of fractures may be the only indication of osteone-
of pregnancy outcomes of participants in the Childhood Cancer crosis or osteoporosis. Because of progress with various interventions
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Survivor Study, the offspring of survivors were more likely to be (including the use of calcium supplementation, calcitonin, bisphos-
premature (born before 37 weeks’ gestation) compared with the phonates, and hormone replacement in patients with gonadal failure),
survivors’ female siblings (odds ratio [OR]: 1.9; 95% CI: 1.4–2.4; the COG LTFU guidelines recommend a baseline dual-energy x-ray
p < .001); and the offspring of women who received uterine radiation absorptiometry or quantitative CT scan for survivors a minimum of
at a dose of more than 5 Gy were more likely to be small for gesta- 2 years following completion of treatment, with repeat studies as
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tional age (OR: 4.0; 95% CI: 1.6–9.8; p = .003). The frequency of clinically indicated. Joint recommendations for monitoring long-
premature birth was not related to prior maternal exposure to alkylat- term survivors of HCT by the EBMT/CIBMTR/ASBMT suggest a
ing agents, but prior exposure to doxorubicin or daunorubicin screening dual-photon densitometry performed at 1 year after trans-
increased the risk for low birthweight independent of pelvic irradia- plantation in adult women or for any patient who has received pro-
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tion history. There were no significantly increased rates of congenital longed treatment with corticosteroids or calcineurin inhibitors.
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anomalies or genetic diseases in the offspring of survivors who Screening for osteonecrosis is not recommended 82,83 ; however, clini-
received potentially mutagenic therapy (i.e., radiation or alkylating cians should maintain a high level of suspicion for patients with
agents). exposure to irradiation or prolonged corticosteroids.
MUSCULOSKELETAL EFFECTS NEUROCOGNITIVE EFFECTS
Osteonecrosis is a painful and debilitating condition that develops Childhood cancer survivors are at increased risk for neurocognitive
when the blood supply to the bone is disrupted, usually in areas of impairment. Cranial radiation has long been associated with neuro-
terminal circulation. The condition is believed to be the result of cognitive late effects, 164–166 typically a dose of 24 Gy is associated with
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vascular compromise with resultant death of bone and cell tissues or cognitive deficits, although antimetabolite chemotherapy and
disruption of bone-repair mechanisms. 149,150 Osteonecrosis has been corticosteroids have also been implicated as potential contributors to
reported after conventional therapy for hematologic malignancies, neurocognitive impairment. 168–171 Additional risk factors include