Medical and Pediatric OncologyVolume 28, Issue 1 p. 78-78 Reply to Shaw Naynesh R. Kamani MD, Corresponding Author Naynesh R. Kamani MD Bone Marrow Transplant Program, Miami Children's Hospital, Miami, FL 33155Bone Marrow Transplant Program, Miami Children's Hospital, Miami, FL 33155Search for more papers by this authorCharles S. August MD, Charles S. August MD Bone Marrow Transplant Program, Miami Children's Hospital, Miami, FL 33155Search for more papers by this author Naynesh R. Kamani MD, Corresponding Author Naynesh R. Kamani MD Bone Marrow Transplant Program, Miami Children's Hospital, Miami, FL 33155Bone Marrow Transplant Program, Miami Children's Hospital, Miami, FL 33155Search for more papers by this authorCharles S. August MD, Charles S. August MD Bone Marrow Transplant Program, Miami Children's Hospital, Miami, FL 33155Search for more papers by this author First published: 07 December 1998 https://doi.org/10.1002/(SICI)1096-911X(199701)28:1<78::AID-MPO17>3.0.CO;2-6Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume28, Issue1January 1997Pages 78-78 RelatedInformation

Purpose Graft rejection remains a serious problem in patients transplanted for severe aplastic anemia. Although additional immunosuppression with irradiation may decrease graft failure, significant sequelae may ensue. We evaluated a nonirradiation containing conditioning regimen for children with severe aplastic anemia with matched sibling donors utilizing cyclophosphamide and anti-thymocyte globulin (ATG). To accelerate myeloid recovery, GM-CSF was used posttransplant. Patients and Methods Twelve patients, with a median age of 3 years underwent BMT from HLA identical sibling (n = 11) or syngeneic (n = 1) donors. Conditioning was cyclophosphamide 50 mg/kg X 4 days and anti-thymocyte globulin 30 mg/kg X 3 days. GM-CSF was administered at 10 μg/kg until a neutrophil count of 1,000 was achieved. Cyclosporine alone was used for graft-versus-host disease prophylaxis. Results All patients achieved durable engraftment at follow-up of 5–51 + months, with the exception of the identical twin. Median time to neutrophil counts >200/μl, 500/μl, and 1,000/μl were 12, 13, and 15 days, respectively. Acute GVHD of less than or equal to grade II occurred in four patients; one patient had grade III. This has resolved in all but one. Conclusion The nonradiation conditioning regimen of cyclophosphamide/ATG appears to achieve durable engraftment in transfused children with matched sibling donors. GM-CSF may accelerate myeloid recovery without exacerbating GVHD, but its contribution to allogeneic transplant required further study.

We report the toxicity and efficacy of a new conditioning regimen for bone marrow transplantation (BMT) in children with poor prognosis neuroblastoma (NBL). Twenty-seven patients with poor prognosis NBL were treated with teniposide (360 mg/m2) or etoposide (500 mg/m2), thiotepa (600-900 mg/m2), and 1200 cGy fractionated total body irradiation (fTBI) followed by autologous marrow rescue (n = 19) or allogeneic BMT from HLA-identical siblings (n = 8). The two patients who received teniposide, 600 mg/m2 thiotepa and fTBI had minimal toxicity but relapsed 4 and 12 months post-auto BMT. The next two patients received 750 mg/m2 thiotepa, 500 mg/m2 etoposide and TBI. They tolerated the conditioning regimen well and are alive and in remission 77 and 75 months post-BMT. At the next thiotepa dose level (900 mg/m2), the first two allograft recipients both experienced fatal regimen-related toxicity. All subsequent allograft recipients received 750 mg/m2 thiotepa and autograft recipients received 900 mg/m2 thiotepa. As of 1 April 1995, eight of the 19 patients who received autologous marrow are surviving disease-free 21 to 77 months post-BMT. Nine autograft recipients relapsed at 2 to 37 months following transplantation. One patient died of hepatic veno-occlusive disease 2 months after auto BMT, and one of pneumonia 6 months post-transplantation. Three allograft recipients have relapsed at 6, 10 and 39 months post-transplant and three are alive and in remission 75, 53 and 27 months post-BMT. Overall, 11/27 patients (41%) are alive and in remission 21-77 months (median 47 months) following BMT. A conditioning regimen consisting of 500 mg/m2 etoposide, thiotepa (750 mg/m2 for allograft recipients and 900 mg/m2 for autograft recipients) and 1200 cGy fTBI has acceptable toxicity and is at least as effective as melphalan-containing regimens in the treatment of high-risk NBL.

Twenty children with acute leukemia between 3 and 19 years of age underwent allogeneic bone marrow transplantation from HLA-matched sibling donors after conditioning with total-body irradiation (1,200 cGy in six fractions of 200 cGy twice daily for 3 days) and high dose cytosine arabinoside (3 g/m2 given every 12 hours for 12 doses). Three patients died with acute toxicity. Six patients developed grade II acute graft versus host disease. With a median follow-up of 68 months (range 26-96 months), thirteen children (65%) are alive and in remission with Karnofsky scores of 90-100%. A patient with AML in resistant relapse went into remission but relapsed and died 5 months post-transplantation. Three other patients relapsed, 8, 12, and 16 months post BMT. Our results suggest that this conditioning regimen is associated with high but manageable acute toxicity and may be highly effective in controlling leukemia resistant to conventional chemotherapy.

Six children are reported with neuromuscular complications of allogenic bone marrow transplantation. Myositis occurred in 4, chronic inflammatory demyelinating neuropathy in 1, and myasthenia gravis in 1. Chronic graft-versus-host disease was present in 3. The onset following bone marrow transplant may be delayed.

A bone marrow transplant (BMT) protocol including surgical excision, local and total body irradiation, and high dose multiagent chemotherapy based on melphalan and bone marrow rescue has been in effect for children with high risk or relapsed neuroblastoma at the Children's Hospital of Philadelphia since 1979. The initial results were reported in 1984 [August et al.: J Clin Oncol 2:609-616,1984]. This report updates the initial results and those that followed changes in the original conditioning regimen. Forty-two patients were treated between May 1979 and November 1987, and included 27 whose disease had relapsed and 15 who received BMT as part of primary treatment. Allogeneic marrow was given to 12 and autologous marrow to 30; in 7 of these 30, the marrow was purged with monoclonal antibodies and magnetic beads. The 4-year actuarial survival rate is 29%. Ten patients died of early treatment-related complications, 18 died of progressive disease, and 2 died of late complications (1 AIDS and 1 acute myelogenous leukemia). Censoring the two late complications the actuarial 4-year relapse-free survival rate becomes 32%. The longest interval after BMT to relapse was 20 months. There was no significant difference in the survival for patients transplanted following relapse or in first remission. The better survival for patients rescued with autologous marrow (30%) is not statistically significantly different from the result with allogeneic marrow (17%). (C) 1994 Wiley-Liss, Inc.

PURPOSEIn an effort to evaluate the usefulness of bone marrow transplantation, the Childrens Cancer Group (CCG) initiated a multiinstitutional study comparing bone marrow transplantation versus chemotherapy after successful induction of remission for previously untreated children and young adults with acute myeloid leukemia.PATIENTS AND METHODSFrom 1979 to 1983, 508 patients were entered onto this study and 490 were treated. After induction, patients with an HLA mixed leukocyte culture (MLC)-compatible sibling underwent bone marrow transplantation. Patients not eligible for bone marrow transplantation were eligible for randomization to two chemotherapy maintenance regimens. All patients undergoing bone marrow transplantation were conditioned with cyclophosphamide and total-body irradiation (TBI). Methotrexate was used to prevent or modify graft-versus-host disease (GVHD).RESULTSThree hundred eighty-one patients achieved bone marrow remission (78%). Eighty-nine patients had an HLA/MLC-compatible sibling donor and were eligible for bone marrow transplantation, and 252 had no match. Comparison of survival estimates for patients eligible for transplantation versus not eligible at 3 years (52% v 41%), 5 years (50% v 36%), and 8 years (47% v 34%) showed a significant difference in favor of bone marrow transplantation (P < .05). Disease-free survival (DFS) demonstrated similar results. Application of a cure model to the results showed a better outcome for those eligible for transplantation (P = .04). Patients randomized between the two chemotherapy regimens did not show any significant difference between those treated with a continuous maintenance versus a cyclic regimen (P = .16).CONCLUSIONChildren and young adults who successfully achieved a remission with multiple-agent chemotherapy who had an HLA/MLC-compatible donor and were thus eligible for an allogeneic bone marrow transplant had better survival than those not eligible for transplantation.

Rickets is a common and paradoxical feature of infantile malignant osteopetrosis and results from the inability of osteoclasts to maintain a normal calcium-phosphorus balance in the extracellular fluid. Despite a markedly positive total body calcium balance, rickets arises when the serum calcium x phosphorus product is insufficient to mineralize newly formed chondroid and osteoid. In five children with malignant infantile osteopetrosis, there were clinical, radiographic, biochemical, and histologic findings of rickets. Characteristic biochemical abnormalities included hypocalcemia, hypophosphatemia, and elevated levels of serum acid phosphatase, alkaline phosphatase, c-terminal parathyroid hormone, and 1,25-dihydroxyvitamin D. The urinary calcium/creatinine ratio was markedly depressed. The serum calcium x phosphorus product was below 30 in all children at the time the rickets was diagnosed, and above 40 by the time the rickets had resolved. Baseline bone density measurements were markedly elevated in all children (> 5 standard deviation above normal) and showed even significant increases (> 7 SD) when the rickets was treated with vitamin D and calcium. The children showed marked clinical improvement, decreased lethargy, increase in mobility and activity, and stimulation of appetite, without any additional adverse hematologic or neurologic effects. The rickets was reversible in all children: in one by HLA-identical sibling bone marrow transplantation and in four by physiologic doses of vitamin D and calcium. The parathyroid and renal responses to hypocalcemia were appropriate, but glucocorticoids, used in treating the hematologic complications of the disease, may have blunted the intestinal response to maximal vitamin D stimulation. This latter blockade can be overcome by increasing dietary calcium. By liberalizing rather than by restricting calcium and phosphorus intake, hypocalcemia can be minimized, phosphorus metabolism can be improved, and rickets can be cured.

We report the experience of 14 centers which have used the combination of cytosine arabinoside (ara-C; 24-36 g/m2) and total body irradiation (TBI) to prepare 213 patients with acute lymphoblastic leukemia (ALL) for allogeneic BMT. The overall 3-year disease-free survival (DFS) probability is 38% (95% CI: 31-45%); 75 patients died of complications and 51 relapsed. Multivariate analysis identified three factors independently associated with outcome: age, remission/relapse status and patient-donor relationship. The 3-year DFS probability is 52% (41-63%) for the 106 patients aged 0-11 and 25% (16-33%) for the 104 aged 11+ years; the DFS probability was 54% (34-74%), 41% (32-49%) and 19% (5-33%) for those in first remission, later remissions and relapse respectively. Older patients suffered both more toxic deaths and more relapses than young ones. No other covariate was found to predict for outcome. The results using ara-C-TBI are similar to those achieved using cyclophosphamide plus TBI to prepare ALL patients for BMT, perhaps because a seemingly lower relapse rate is offset by more toxic deaths particularly in older patients. Therapeutic trials should focus on reducing toxicity while maximizing antileukemic efficacy, and should stratify for patient and disease-related factors.

Rickets is a common and paradoxical feature of infantile malignant osteopetrosis and results from the inability of osteoclasts to maintain a normal calcium-phosphorus balance in the extracellular fluid. Despite a markedly positive total body calcium balance, rickets arises when the serum calcium x phosphorus product is insufficient to mineralize newly formed chondroid and osteoid. In five children with malignant infantile osteopetrosis, there were clinical, radiographic, biochemical, and histologic findings of rickets. Characteristic biochemical abnormalities included hypocalcemia, hypophosphatemia, and elevated levels of serum acid phosphatase, alkaline phosphatase, c-terminal parathyroid hormone, and 1,25-dihydroxyvitamin D. The urinary calcium/creatinine ratio was markedly depressed. The serum calcium x phosphorus product was below 30 in all children at the time the rickets was diagnosed, and above 40 by the time the rickets had resolved. Baseline bone density measurements were markedly elevated in all children (> 5 standard deviation above normal) and showed even significant increases (> 7 SD) when the rickets was treated with vitamin D and calcium. The children showed marked clinical improvement, decreased lethargy, increase in mobility and activity, and stimulation of appetite, without any additional adverse hematologic or neurologic effects. The rickets was reversible in all children: in one by HLA-identical sibling bone marrow transplantation and in four by physiologic doses of vitamin D and calcium. The parathyroid and renal responses to hypocalcemia were appropriate, but glucocorticoids, used in treating the hematologic complications of the disease, may have blunted the intestinal response to maximal vitamin D stimulation. This latter blockade can be overcome by increasing dietary calcium. By liberalizing rather than by restricting calcium and phosphorus intake, hypocalcemia can be minimized, phosphorus metabolism can be improved, and rickets can be cured.

Prenatal diagnosis of X-linked severe combined immunodeficiency in a male fetus made possible elective neonatal bone marrow transplantation before onset of symptoms. Bone marrow transplantation was performed by using T-cell-depleted maternal marrow that had been cryopreserved 2 years earlier, at the time that his older affected brother underwent transplantation. The second patient had less morbidity and more rapid reconstitution of his immune function.

Bone marrow transplantation has been undertaken with encouraging results as therapy for a wide variety of lysosomal storage diseases. We report a case of Niemann-Pick disease Type IA in which, despite the presence of only mild hypotonia with depressed reflexes, the clinical course of the disease appeared to be only slightly modified by this procedure, which was performed at the earliest practical opportunity. The patient was diagnosed early when asymptomatic, because of a family history of an affected sibling who died at 14 months. He received a bone marrow transplant from an HLA-identical, MLC non-reactive sibling donor, whose leukocyte sphingomyelinase activity was in the homozygote normal range. There was adequate engraftment as evidenced by persistently normal leukocyte sphingomyelinase activities, and there was no evidence of graft-versus-host disease. Visceral storage and neurological impairment were less rapidly progressive than in his untreated sibling but he eventually died at 30 months. Autopsy confirmed that this was essentially due to the effects of the underlying Niemann-Pick disease. We conclude that despite some success in other neurovisceral lysosomal storage disorders, bone marrow transplantation is not likely to be an adequate treatment for Niemann-Pick disease Type IA.

Forty-one patients with high-risk neuroblastoma were treated between September 1977 and December 1987 at the Children's Hospital of Philadelphia with supralethal chemotherapy and total-body irradiation rescued by bone marrow transplantation. Twenty-six patients were treated following relapse and 15 were newly diagnosed. At the time of evaluation, January 1991, 11 of 41 patients (26.8%) remained in complete remission. Actuarial survival rates of patients transplanted following relapse were 0.35 and 0.31 at 2 and 5 years, respectively, and actuarial disease-free survival rates were 0.38 at 12 months and 0.27 at 24 months. The 2- and 5-year actuarial survival values for the patients with newly diagnosed disease were 0.53 and 0.25, respectively, and the 12-and 24-month disease-free survival rates were 0.47 and 0.27, respectively. There was no significant difference in survival between these groups. Twenty-nine of the 41 patients reviewed were available for analysis of the effect of local treatment. Thirteen had a combination of surgery and radiation (RT), 2 had surgery alone, 9 had RT alone, and in 5 patients no local treatment was given. The local relapse rate was 17%; it was 15% following surgery plus RT and 22% following RT alone. The failure rate combining local and distant relapse is 62% for surgery plus RT and 44% for RT alone. Although a local relapse rate of 17% is imperfect, it is a relatively small contribution to the overall relapse of 62%.

Cardiac toxicity is a potential complication of bone marrow transplantation because recipients frequently receive cardiotoxic chemotherapy and/or irradiation before transplantation. Most studies indicate that transient cardiac toxicity occurs within weeks of transplantation, but few studies have evaluated either cardiac status before or late after transplantation. Cardiac performance was assessed via cycle ergometry in 20 children and young adults before transplantation and 31 other children and young adults after transplantation. Mean survival time in the group post-transplantation was 3.9 years with a range of 11 months to 12.1 years. Left ventricular size and shortening fraction at rest were assessed via echocardiography. Data were compared to those of 70 healthy subjects from our laboratory. Patients before and after transplantation had normal oxygen consumptions and cardiac indices at rest. During exercise, however, patients treated for cancer both before and after bone marrow transplantation had reduced exercise times, reduced maximal oxygen consumptions, and reduced ventilatory anaerobic thresholds. Cardiac reserve, as judged by the response of the cardiac output during exercise, was reduced severely. There were no significant differences between the groups tested before and after transplantation. Patients who had been treated for aplastic anemia, who had received less intensive therapy before transplantation, performed significantly better than did patients treated for cancer. Despite these findings, only four patients had abnormalities by echocardiography. In conclusion, before transplantation patients with oncologic diagnoses had serious limitations in exercise performance, most likely as a result of the effects of the cardiotoxic therapy given as part of their conventional cancer therapy. Long-term survivors of bone marrow transplantation also had similar abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

3. Von Noorden GK, Crawford ML. The sensitive period. Trans Ophthalmol Soc UK 1979;99:442-6. 4. Robb R. Children's ophthalmologic problems. Hospital Pract April 1977:107-15. 5. Merlob P, Sivan Y, Reisner SH. Anthropomorphic measurements of the newborn infant. Birth Defects 1984;20(7):8-14. 6. Neweomb R. The causes of blindness in children: a review of the literature. J Am Optom Assoc April 1977:48(4). 7. Francois J. Surgical results of congenital cataract: the Belgian experience. Ophthalmic Forum 1984;2(3):126-8. 8. Brown C, Hanna C. Use of dilute drugs for routine cycloplegia and mydriasis. Am J Ophthalmol 1978;86:820-4. 9. Palmer E. Drug toxicity in pediatric ophthalmology. J Toxicol Cutan Ocul Toxicol 1982;1(3):181-210. 10. Palmer EA. How safe are ocular drugs in pediatrics? Ophthalmology 1986;93:1038-40. 11. Caputo AR, Sehnitzer RE. Systemic response to mydriatic eyedrops in neonates: mydriatics in neonates. J Pediatr Ophthalmol Strabismus 1978;15:109-22.

Hurler syndrome is a mucopolysaccharide disorder resulting from an heritable deficiency in alpha-L-iduronidase, an enzyme required in the catabolism of heparan sulfate and dermatan sulfate glycosaminoglycan (GAGs). The resultant intracellular accumulation of GAG leads to disruption of the intracellular and extracellular environment and dysfunction of multiple organ systems. Among the most noted manifestations of this disease is disproportionate short trunk dwarfism, which develops during the first years of life. Histochemical and electron-microscopic observations on a 30-month-old child with Hurler syndrome showed marked irregularities in chondrocyte orientation within the growth plate, along with disruption of the normal columnar architecture. Vacuolization with enlargement of the cellular border was the characteristic ultrastructural finding. An heritable abnormality in the enzymatic degradation of structural glycosaminoglycans leads to profound disruption of the normal mechanisms of growth and development.