Amos Kedar

Unrelated cord blood transplantation in children with sickle cell disease: Review of four-center experience

Abstract:  UCBT was performed in seven children with SCD and stroke (HLA match 4/6 n = 5; 5/6 n = 2). Four received myeloablative regimens (BU, CY, ATG plus FLU in one patient). One had primary graft failure, three had sustained engraftment, two with grade III–IV GVHD (one died, one developed chronic GVHD), one with stable mixed chimerism. Three patients treated with reduced‐intensity regimens (FLU, BU or CY, ATG, TLI) failed to engraft; one engrafted after second UCBT (HU, TT, RXA, ALZ, TBI). Four patients (57%) developed viral infections. Engraftment, GVHD, and infection remain challenges.

Medulloblastoma: time–dose relationship based on a 30-year review

PURPOSE Time-dose relationships have proven important in many cancer sites. This study evaluates the time factors involved in the successful postoperative radiotherapy of medulloblastoma, based on a 30-year experience in a single institution. METHODS AND MATERIALS Fifty-three patients with medulloblastoma received postoperative craniospinal radiotherapy with curative intent between 1963 and 1993. Seven patients (13%) underwent biopsy alone, 28 patients (53%) had subtotal excision, and 18 patients (34%) had gross total excision. Eleven patients received adjuvant chemotherapy. The mean posterior fossa dose was 53.1 Gy; most patients received 54.0 Gy (range, 34.3 to 69.6 Gy). For 41 patients receiving once-a-day therapy, the mean dose was 50.6 Gy (range, 34.3 to 56.0 Gy). For 12 patients receiving twice-a-day therapy, the mean dose was 61.8 Gy (range, 52.6 to 69.6 Gy). Minimum follow-up was 2 years, and median follow-up was 10.7 years. Survival, freedom from relapse, and disease control in the posterior fossa were calculated using the Kaplan-Meier method, and multivariate analysis was performed for prognostic factors. Variables related to radiotherapy were examined, including dose to the craniospinal axis, dose to the posterior fossa, fractionation (once-a-day vs. twice-a-day), use of adjuvant chemotherapy, risk group [high (> or =T3b or > or =M1) or low (< or =T3a and M0-MX)], interval between surgery and radiotherapy (excluding patients receiving chemotherapy before radiotherapy), and duration of radiotherapy. RESULTS At 5 and 10 years, overall survival rates were 68 and 64%, respectively, and freedom-from-relapse rates were 61 and 52%, respectively. Rates of disease control in the posterior fossa at 5 and 10 years were 79 and 68%, respectively. At 5 years, absolute survival rates after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78%, respectively (p=0.04), and posterior fossa control rates were 27, 89, and 83%, respectively (p=0.004). Duration of the treatment course was the only radiotherapy-related variable with a significant impact on freedom from relapse and posterior fossa control. For patients whose radiation treatment duration was < or =45 days, posterior fossa control was 89% at 5 years, compared with 68% for those treated for >45 days (p=0.01). Duration of treatment also affected freedom from relapse at 5 years: < or =45 days (76%) compared with >45 days (43%), p=0.004. CONCLUSION Our study demonstrates that if adequate doses are used, then radiotherapy treatment duration will significantly affect the outcome in terms of control of disease in the posterior fossa and freedom from relapse. Fractions of at least 1.75 Gy given once a day, or a twice-a-day regimen should yield optimal local control results.

Topical Review Article: Brainstem Glioma: I. Pathology, Clinical Features, and Therapy

Gliomas that arise in the brain stem have been associated with a poor prognosis. Diagnostic neuroimaging readily identifies the tumor as it extends between normal brainstem structures. Histologic sampling of tumor with stereotactic methods is notoriously unreliable in establishing a definitive prognosis. Clinical trials that incorporate high-dose chemotherapy, autologous bone marrow rescue, and irradiation hold promise of better tumor control by overcoming the inaccessibility of the central nervous system to standard doses of chemotherapy. We review the pathology, clinical features, neuroimaging features, and current therapeutic concepts relative to brainstem glioma. The pediatric neurologist has a pivotal role in identifying and monitoring children with this malignancy. (J Child Neurol 1993;8:112-128).

Atrial natriuretic peptide as a marker for doxorubicin‐induced cardiotoxic effects

Doxorubicin is an effective antineoplastic agent, but it frequently causes dose‐related cardiotoxic effects. Because the atrial natriuretic peptide (ANP) level is elevated in children with heart defects, the authors measured the ANP levels in children to determine whether ANP might serve as a simple diagnostic indicator of cardiotoxic effects. Sixteen patients, 5 to 19 years of age, who were being treated with doxorubicin (45 mg/m2 body surface area) for various malignancies had ANP levels measured in plasma. There was a group of six children, with a significant peak of plasma ANP (pANP) levels 3 weeks after the administration of the drug. Of these six patients, five had received high cumulative doses of doxorubicin (160 to 370 mg/m2), and two of them went into congestive heart failure without a previous decline in left ventricular ejection fraction, a standard technique for monitoring cardiac function during treatment with doxorubicin. The other ten patients had normal ANP levels throughout the study, and signs of cardiac dysfunction did not develop. None of the patients in the control group who had cancer and were not treated with doxorubicin and none of the healthy volunteers had elevated ANP levels. These preliminary results suggest that pANP may be useful as an early and sensitive indicator for doxorubicin‐related myocardial damage. Cancer 1992; 69:1492‐1497.

Autoimmune disorders complicating adolescent hodgkin's disease

Four adolescents with Hodgkins disease also developed autoimmune diseases. There were two idiopathic thrombocytopenic purpura (ITP), one polymyositis, and one scleroderma. The first two patients developed ITP in the absence of a spleen, and with their Hodgkins disease in remission. The first patient with Hodgkins disease has been continuously free of cancer for over five years. The second patient was a 17‐year‐old male whose Hodgkins disease recurred, but whose disease was in remission at the time the ITP occurred. The polymyositis occurred in an 18‐year‐old youth when he was in his initial remission for his Hodgkins disease, but his disease subsequently recurred two years later. This youth presented with Coombs positive autoimmune hemolytic anemia. The polymyositis did not respond to therapy, and he is left with severe muscle wasting and weakness; however, the polymyositis is now quiescent. The scleroderma occurred in an 18‐year‐old female who had been continuously free of Hodgkins disease for eight years. The scleroderma did not respond to drug therapy and she now has moderate skin changes, but remains in continuous remission of her Hodgkins disease. Although there are a few reports of Hodgkins disease and concurrent autoimmune disorders, physicians dealing with cancer in adolescents should be aware of this association.

Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease

Summary:The lack of healthy HLA-identical sibs limits the use of allogeneic hematopoietic cell transplantation in children with high-risk sickle cell disease (SCD). We evaluated unrelated placental blood cell transplantation (UPBCT) after a preparative regimen of busulfan, cyclophosphamide and antithymocyte globulin in three children with SCD who had cerebrovascular accidents (CVAs) and did not have HLA-matched sib donors. The placental blood cell units were matched with the recipients at four of six HLA-A, HLA-B and HLA-DRB1 antigens. Neutrophil levels above 0.5 × 109/l occurred at 23, 38 and 42 days after UPBCT, and platelet levels above 50 × 109/l without transfusions occurred at 62, 81 and 121 days after UPBCT. All patients developed acute graft-versus-host disease (GVHD; two grade II, one grade III), and one developed extensive chronic GVHD. One patient had graft failure and autologous hematopoietic recovery. Two patients have complete donor hematopoietic chimerism without detectable hemoglobin S or symptoms of SCD at 40 and 61 months, respectively, after UPBCT. These observations demonstrate the feasibility of UPBCT in children with SCD. Further studies of UPBCT for SCD are needed but, because of risks of procedure-related morbidity and graft rejection, should be restricted to pediatric patients with high-risk manifestations of SCD.

Outcome after radiotherapy of primary spinal cord glial tumors

Primary spinal cord tumors are rare, and treatment recommendations are therefore difficult. We reviewed a 22-year experience of postoperative radiotherapy for spinal cord tumors to elucidate prognostic factors and recommendations. Twenty-two patients with spinal cord tumors were treated from 1969-1991. Ten patients had ependymomas, of which two were high grade. Twelve had astrocytomas, of which 4 were high grade. Karnofsky status, age, extent of resection, tumor histology, grade, and radiation dose were evaluated, as well as degree of clinical improvement after treatment based on change in Karnofsky status. Ependymomas achieved 100% local control with postoperative radiotherapy. Grade and dose were of indeterminate significance because of these excellent results. High-grade astrocytomas all recurred and caused death. Disease recurred in 1 of 8 patients with low-grade astrocytic or mixed astrocytic tumors. The only prognostic variables of significance were histology, grade, and change in Karnofsky status after treatment. Radiation of primary spinal cord tumors is rare. In nearly all cases, local fields may be used. Improvement in Karnofsky status after radiotherapy may predict better survival. Treatment recommendations for these rare tumors are discussed.

Thalidomide in Children Undergoing Bone Marrow Transplantation: Series at a Single Institution and Review of the Literature

Thalidomide has one of the most notorious drug histories because of its teratogenicity. Its widespread use in the 1960s led to a worldwide epidemic of phocomelia in inborns; this in turn led to its complete ban in most of the world. However, it has now been licensed for selected indications including graft-versus-host-disease (GVHD) after bone marrow transplantation, wasting associated with tuberculosis and human immunodeficiency virus infection, and leprosy. Little is known, however, about its use in children in these settings. Therefore, we report our experience and review the literature on thalidomide in children for GVHD after bone marrow transplantation. We studied 6 patients, 2 with chronic GVHD, 2 with acute GVHD, and 2 with acute GVHD progressing into chronic disease. One patient with chronic GVHD had a complete response, whereas the other had a partial response. Side effects consisted primarily of sedation and constipation, which are reported previously and well known side effects. None had neuropathy. One patient had rash, eosinophilia, and early pancreatitis that began shortly after initiation of thalidomide, persisted, and resolved only after discontinuation of thalidomide. Eosinophilia and pancreatitis are both previously unreported side effects or associated findings of thalidomide treatment. Review of the literature reveals three major studies of thalidomide in GVHD; of these two included children and adults together, and one in which age range of patients was not mentioned. In addition, four series of children receiving only thalidomide are reported. These series contained 1 to 14 patients each. Results show efficacy in at least 50% of children with chronic GVHD and little or no efficacy in children with exclusively acute GVHD. Side effects are similar to those reported in adults and consisted mostly of sedation and constipation, both of which subsided over time and resolved after discontinuing the drug. We speculate on the reasons for which thalidomide is more effective in chronic, compared with acute, GVHD in children, and make recommendations for future study.

Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation

The pharmacokinetics of tacrolimus have been studied in healthy volunteers and in adults undergoing bone marrow transplantation. However, there is little information on the pharmacokinetics of tacrolimus in children undergoing BMT. We studied pharmacokinetics of tacrolimus in seven patients (age 8–17 years) undergoing allogeneic stem cell transplantation. Four patients received matched unrelated donor (MUD) transplants, two underwent HLA-matched related donor transplants, and one underwent an umbilical cord blood donor transplant. All patients received tacrolimus by continuous infusion at 0.03–0.04 mg/kg/day beginning on the day prior to transplant. Tacrolimus whole blood concentrations were monitored by microparticle enzyme immunoassay. Our goal was to maintain a blood tacrolimus level of 10–20 μg/ml. Once patients were tolerating oral medications, tacrolimus infusion was converted to oral dosing using a 4:1 conversion. Dose of tacrolimus and resulting tacrolimus concentrations were recorded and the total body clearance of tacrolimus was calculated retrospectively. The mean clearance, based on first steady-state tacrolimus concentrations necessary for achieving a therapeutic level (10–20 μg/ml), was 108.1 ml/h/kg (range 79.7–142.0 ml/h/kg), greater than that reported in adult BMT patients (71 ± 34 ml/h/kg). The average dose required to achieve that therapeutic range was 0.0354 mg/kg/day as an intravenous continuous infusion. Over the entire course of intravenous tacrolimus, mean clearance was 97.0 ml/h/kg (range 33.4–153.3 ml/h/kg). In six of the seven patients, clearance values dropped after 2–4 weeks of therapy by an average of 32.5 ml/h/kg. In two patients, sharp drops in clearance were temporally related to changes in liver function tests. Three of the seven patients died of severe acute GVHD; all these had undergone matched unrelated donor transplantation, and two of these three had initial clearance levels over 120 ml/h/kg. Thus, children appear to have more rapid tacrolimus clearance than adults and may need to begin therapy earlier in order to obtain stable and optimal levels. More studies are needed to confirm these preliminary results.

Response of osteogenic sarcoma to the combination of etoposide and cyclophosphamide as neoadjuvant chemotherapy.

A Phase II study of the combination of etoposide (VP‐16) and cyclophosphamide (CPM) was conducted in an attempt to identify active and potentially less toxic agents for treating patients with osteogenic sarcoma (OS). VP‐16 was given as a 72‐hour infusion for a total dose of 600 mg/m2. CPM was given as six pulses of 300 mg/m2 every 12 hours for a total dose of 1800 mg/m2. Seventeen newly diagnosed patients, including five (29%) with metastatic disease, were evaluated before and after two courses of VP‐16 and CPM for clinical, radiologic, and biochemical (serum alkaline phosphatase [SAP] responses of the primary tumor and metastases. Fifteen (88%) patients achieved complete or partial clinical responses. Fourteen (82%) patients achieved radiologic responses. Thirteen (87%) of 15 patients with higher than normal SAP levels for their age showed partial or complete responses. Three (60%) of the five patients with metastatic disease achieved complete or partial responses. The only major toxicity was myelosuppression, which led to 21 (62%) brief admissions after 34 courses of chemotherapy for intravenous antibiotic therapy for fever and neutropenia, without associated mortality. It was concluded that the combination of VP‐16 and CPM is effective chemotherapy for both primary and metastatic OS. Although myelosuppression is inevitable, it is rapidly reversible in the drug dosages used. Further studies are needed to evaluate the effect of these drugs in combination with established agents in improving the disease‐free survival of patients with OS.