Anne B. Warwick

Pregnancy after Hematopoietic Cell Transplantation: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR)

Preservation of fertility after hematopoietic cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N = 99) and nonmalignant disorders (N = 79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative (MA) allogeneic HCT (12 women, 50 men), and nonmyeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were MA in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5 to 10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or MA conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility, and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts.

Clinical guide to fertility preservation in hematopoietic cell transplant recipients.

With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient–physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients.

Outcomes following mechanical ventilation in children undergoing bone marrow transplantation

Between 1976 and 1992, 869 patients <19 years of age underwent bmt at the university of minnesota for a variety of malignant and non-malignant disorders. one hundred and ninety-six required mechanical ventilation (mv) at some time from the start of pre-bmt cyto reduction through the first year following bmt. reasons for mv included respiratory compromise, upper airway management and non-pulmonary indications for respiratory support. in multivariate models, underlying diagnosis, receipt of hla-mismatched marrow and the presence of acute graft-versus-host disease (agvhd) were independent predictors of the need for mv. indication for mv, underlying diagnosis, and presence of agvhd were independent predictors of successful extubation. overall survival at 2 years was 14% among mv patients and 52% among non-mv patients. while the need for mv during bmt reduces the overall likelihood of survival, 40% of children who required mv were successfully extubated; 35% of these extubated patients were long-term survivors. this outcome is better than that reported for adult bmt patients requiring respiratory support, who show survival of <5% at 6 months following bmt. our data suggest extrapolation of outcome data from adult to pediatric patients is not appropriate and aggressive care of pediatric patients requiring respiratory support is not futile.

Physician perceptions and practice patterns regarding fertility preservation in hematopoietic cell transplant recipients

Physician practice variation may be a barrier to informing hematopoietic cell transplant (HCT) recipients about fertility preservation (FP) options. We surveyed HCT physicians in the United States to evaluate FP knowledge, practices, perceptions and barriers. Of the 1035 physicians invited, 185 completed a 29-item web-survey. Most respondents demonstrated knowledge of FP issues and discussed and felt comfortable discussing FP. However, only 55% referred patients to an infertility specialist. Most did not provide educational materials to patients and only 35% felt that available materials were relevant for HCT. Notable barriers to discussing FP included perception that patients were too ill to delay transplant (63%), patients were already infertile from prior therapy (92%) and time constraints (41%). Pediatric HCT physicians and physicians with access to an infertility specialist were more likely to discuss FP and to discuss FP even when prognosis was poor. On analyses that considered physician demographics, knowledge and perceptions as predictors of referral for FP, access to an infertility specialist and belief that patients were interested in FP were observed to be significant. We highlight variation in HCT physician perceptions and practices regarding FP. Physicians are generally interested in discussing fertility issues with their patients but lack educational materials.

Mifamurtide in Metastatic and Recurrent Osteosarcoma: A Patient Access Study with Pharmacokinetic, Pharmacodynamic, and Safety Assessments

This non‐randomized, patient‐access protocol, assessed both safety and efficacy outcomes following liposomal muramyl‐tripeptide‐phosphatidylethanolamine (L‐MTP‐PE; mifamurtide) in patients with high‐risk, recurrent and/or metastatic osteosarcoma.

Second malignancies after autologous hematopoietic cell transplantation in children.

Childhood autologous hematopoietic cell transplant (auto-HCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1487 pediatric auto-HCT recipients to investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), central nervous system tumors (14%) and Wilms tumor (2%). Median follow-up was 8 years (range, <1–21 years). SMNs were reported in 35 patients (AML/myelodysplastic syndrome (MDS)=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from auto-HCT was 2.60% (AML/MDS=1.06%, solid tumors=1.30%). We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis or use of TBI or etoposide as part of conditioning. OS at 5-years from diagnosis of SMNs was 33% (95% confidence interval (CI), 16–52%). When compared with age- and gender-matched general population, auto-HCT recipients had 24 times higher risks of developing SMNs (95% CI, 16.0–33.0). Notable SMN sites included bone (N=5 SMNs, observed (O)/expected (E)=81), thyroid (N=5, O/E=53), breast (N=2, O/E=93), soft tissue (N=2, O/E=34), AML (N=6, O/E=266) and MDS (N=7, O/E=6603). Risks of SMNs increased with longer follow-up from auto-HCT. Pediatric auto-HCT recipients are at considerably increased risk for SMNs and need life-long surveillance for SMNs.

Tacrolimus (FK506) in allogeneic bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation

Severe aplastic anemia (SAA) is a frequent complication of orthotopic liver transplantation for non-typeable viral hepatitis. Allogeneic bone marrow transplantation (BMT) may successfully reconstitute hematopoiesis but the optimal conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in such patients are unknown. Allogeneic BMT was undertaken in an 8-year-old male patient who developed SAA 6 weeks after cadaveric orthotopic liver transplantation for fulminant hepatic failure secondary to presumed non-typeable viral hepatitis. The preparative regimen for his HLA genotypically identical sibling BMT consisted of cytoxan and anti-thymocyte globulin. Tacrolimus (FK506) and prednisone, used to prevent liver graft rejection, were supplemented with methotrexate on post-BMT days, 1, 3, 6 and 11 for GVHD prophylaxis. Engraftment proceeded promptly and without complications. Transfusion dependence resolved 6 weeks after BMT. The patient is alive and well 1 year after his BMT on FK506 and prednisone without any signs of GVHD or liver allograft rejection. This case is the first demonstration of the feasibility of continuing FK506 used for prevention of liver graft rejection as GVHD prophylaxis for allogeneic BMT.

Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes.

We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel approaches are needed to minimize relapse risk and long-term transplantation morbidity in this population.

Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: a Children's Oncology Group study.

Pemetrexed is a multi‐targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile.

Management of adults with Wilms’ tumor: recommendations based on international consensus

Since Wilms’ tumor occurs rarely in adults, there are no standard treatments available. Most adult patients will be diagnosed unexpectedly following nephrectomy for presumed renal cell carcinoma. Outcome for adults is inferior compared with children, although better results are reported when treated within pediatric trials. Multiple factors, including the unfamiliarity of adult oncologists and pathologists with Wilms’ tumors, lack of standardized treatment and consequent delays in initiating the appropriate risk-adapted therapy, may contribute to the poor outcome. A standardized approach for the management of adult Wilms’ tumors is proposed with the aim to limit treatment delay after surgery and encourage a uniform approach for this rare disease and thereby improve survival. These recommendations are based on discussions held with representatives of the renal tumor committees of the Society of Paediatric Oncology and Children’s Oncology Group, and have been updated with a review of more recently published institutional and trial experience of adults treated on pediatric protocols. They provide a critical evaluation of the current evidence for the management of adult Wilms’ tumors and propose details of how current pediatric therapeutic guidelines could be adapted for use in adults.