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The possible impact of "late" alemtuzumab (administered on days -10 to -8) versus "early" alemtuzumab (-19 to -17) with respect to engraftment and acute/chronic graft-versus-host disease (GvHD) in a group of 25 pediatric patients with sickle cell disease undergoing bone marrow transplantation following conditioning with alemtuzumab, fludarabine, and melphalan is reported. The first 9 patients received "late" alemtuzumab followed by bone marrow transplantation from HLA-matched sibling donors. The next 16 patients undergoing matched sibling transplants received "early" alemtuzumab. In the "late" group, 1 patient (11%) developed acute GvHD. Six patients (67%) achieved sustained engraftment. Three patients (33%) experienced graft rejection, leading to termination of enrollment of patients on this regimen. In the "early" alemtuzumab group, acute and chronic GvHD developed in 43% and 25% patients, respectively. None of the patients experienced graft rejection in this group of patients. Three patients developed stable mixed chimerism and 13 patients demonstrated 100% donor chimerism at 1 year post-transplant and beyond. These results suggest a benefit with respect to engraftment of administering "early" versus "late" alemtuzumab in this reduced-intensity conditioning regimen, however, with the possible cost of an increase in acute, and possibly chronic GvHD.

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age <18 years at 25 pediatric transplantation centers in North America, assessing them predonation, peridonation, and at 1 month, 6 months, and 1 year postdonation. We noted that 71% of children reported pain and 59% reported other symptoms peridonation, with resolution to 14% and 12% at 1 month postdonation. Both older age (age 13 to 17 years versus younger) and female sex were associated with higher levels of pain peridonation, with the highest rates in older females (57% with grade 2-4 pain and 17% with grade 3-4 pain). Multivariate analyses showed a 4-fold increase in risk for older females compared with males age <13 years (P <.001). At 1 year, 11% of 13- to 17-year-old females reported grade 2-4 pain, compared with 3% of males age 13 to 17 years, 0% of females age <13 years, and 1% of males age <13 years (P = .01). Males and females age 13 to 17 years failed to return to predonation pain levels at 1 year 22% and 23% of the time, respectively, compared with 3% and 10% in males and females age <13 years (P = .002). Our data show that females age 13 to 17 years are at increased risk of grade 2-4 pain at 1 year and >20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted., (Copyright © 2019. Published by Elsevier Inc.)

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34 + level before apheresis compared with younger RDs (age > 60, 59 × 10 6 /L; age 41 to 60, 81 × 10 6 /L; age 18 to 40, 121 × 10 6 /L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia <50 × 10 9 /L (26% and 57% after 2 and 3days of collection, respectively). RDs aged 18 to 40 had a higher risk of grades 2 to 4 pain and symptoms pericollection, but donors over age 40 had more persistent pain at 1, 6, and 12 months (odds ratio [OR], 1.7; P = 0.02) and a higher rate of nonrecovery to predonation levels (OR, 1.7; P = .01). Donors reporting comorbidities increased significantly with age, and those with comorbidities that would have led to deferral by National Marrow Donor Program unrelated donor standards had an increased risk for persistent grades 2 to 4 pain (OR, 2.41; P < .001) and failure to recover to predonation baseline for other symptoms (OR, 2.34; P = .004). This information should be used in counseling RDs regarding risk and can assist in developing practice approaches aimed at improving the RD experience for high-risk individuals., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P <0.001] and severe (OR 8.91; P <0.001) pain and toxicities (OR 1.84; P <0.001) with collection. Related stem cell donors were at increased risk of persistent toxicities (OR 1.56; P =0.021) and non-recovery from pain (OR 1.42; P =0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P <0.001) and non-recovery from toxicities (OR 3.71; P <0.001) at one year. Related donors with more significant comorbidities were at especially high risk for grade 2-4 pain (OR 3.43; P <0.001) and non-recovery from toxicities (OR 3.71; P <0.001) at one year. Related donors reporting grade ≥2 pain had significant decreases in Health-Related Quality of Life (HR-QoL) scores at one month and one year post donation ( P =0.004). In conclusion, related PBSC donors with comorbidities are at increased risk for pain, toxicity, and non-recovery at one year after donation. Risk profiles described in this study should be used for donor education, planning studies to improve the related donor experience, and decisions regarding donor deferral. Registered at clinicaltrials.gov identifier:00948636 ., (Copyright© 2019 Ferrata Storti Foundation.)

Blood stream infections (BSI) caused by enteric organisms are associated with a particularly high mortality rate in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We conducted a retrospective multicenter study aiming to analyze the risk factors associated with antibiotic resistance and impact of BSI on transplantation-related mortality (TRM) in children after alloHCT. During the study period from 2004 to 2014, 395 children (mean age, 9.4 years) with at least 1 BSI were included. The incidences of resistant gram-negative rods were 20.7% to piperacillin-tazobactam, 10.9% to cefepime, 21% to ceftazidime, 11.4% to levofloxacin, and 8.16% to meropenem. Thirty-eight percent of Enterococcus spp. isolates were resistant to vancomycin. More than 1 episode of BSI was associated with significant increase in the risk of resistance to piperacillin-tazobactam, cefepime, and vancomycin. On multivariate analysis of risk factors for TRM, achievement of neutrophil engraftment by day 30 was associated with lower TRM (P = .002). However, infection with an antibiotic-resistant organism was not associated with TRM. Development of enteric bacterial BSI after the onset of acute gastrointestinal graft-versus-host disease (GVHD) was the strongest predictor of TRM (hazard ratio, 4.786; 95% confidence interval, 2.833 to 8.087; P < .001). In patients with acute gastrointestinal GVHD who subsequently developed enteric bacterial BSI, the incidence of 1-year TRM was 33.4% (SE = 7%), compared with 15.3% (SE = 2%) for those without acute gastrointestinal GVHD (P = .004). Primary prevention of a first episode of BSI is arguably the most important intervention to decrease antibiotic resistance. It is also imperative that we develop strategies to maintain gastrointestinal health, especially in patients with gastrointestinal GVHD, in an effort to prevent subsequent enteric bacterial BSI and improve survival., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Fifty-two children with symptomatic sickle cell disease sickle cell disease (SCD) (N = 43) or transfusion-dependent thalassemia (N = 9) received matched sibling donor marrow (46), marrow and cord product (5), or cord blood (1) allografts following reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan between March 2003 and May 2014*. The Kaplan-Meier probabilities of overall and event-free survival at a median of 3.42 (range, 0.75-11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for SCD, and 100% and 100% for thalassemia, respectively. Treatment-related mortality (all related to graft versus host disease, GVHD) was noted in three (5.7%) recipients, all 17-18 years of age. Acute and chronic GVHD was noted in 23% and 13%, respectively, with 81% of recipients off immunosuppression by 1 year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at 1 year and beyond; all had discontinued immunosuppression between 4 and 12 months from transplant with no subsequent consequence on GVHD or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond 6 months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of SCD were noted, and pain symptoms subsided within 6 months posttransplant. These findings support using RIC for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.Clinical Trials.gov: NCT00920972, NCT01050855, NCT02435901)., (© 2015 Wiley Periodicals, Inc.)

Mucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The Children's Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population., (Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We report the low incidence of hepatic VOD in pediatric patients with various diagnoses including hematologic malignancies and non-malignant conditions transplanted at our institution. Retrospective review of 188 patients who underwent HSCT and received a combined prophylactic regimen of intravenous heparin, oral glutamine, and ursodiol was undertaken. Analysis of the outcome of VOD revealed only one clinical case with acute myeloid leukemia; the patient developed hepatic VOD 10 days after receiving myeloablative chemotherapy with busulfan and CTX followed by HLA-matched related peripheral blood stem cell transplantation. The low incidence of hepatic VOD in an otherwise high-risk pediatric transplant population is an important observation, which may be partly attributed to this prophylactic regimen, and warrants further randomized clinical trials for confirmation.

Gemtuzumab ozogamicin (GO, MylotargTM) is an antibody-targeted chemotherapy agent that has been studied in acute myeloid leukemia (AML) at first relapse in adults. There is limited experience in pediatric patients. We report six patients with refractory/relapsed CD33+AML who were treated with GO on compassionate-use basis. One patient attained remission. One patient is still alive following hematopoietic stem cell transplantation (HSCT), and one patient died in remission. Two patients were refractory and three patients had a response with <5% blasts in the bone marrow. Fever and chills, hypotension and hypoxia were observed as side effects. Three patients developed veno-occlusive disease (VOD) of the liver. Two of these three patients had persistence of VOD at the time of their deaths. One patient treated postSCT had bone marrow response without VOD. GO should be used cautiously in chemotherapy-refractory AML pediatric patients due to the high incidence of VOD.

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.

Capsule endoscopy is a relatively new technology that has allowed gastroenterologists to visualize the mucosa of the small intestine. This technology is playing an expanding role in both adult and pediatric gastroenterology. In this report, we present an 8-yr-old child following allogeneic hematopoietic cell transplantation who developed large volume bloody diarrhea requiring multiple packed red blood cell transfusions that was resistant to aggressive therapy for GVHD. The capsule endoscopy performed on this patient provided significant information not provided by upper endoscopy and colonoscopy that allowed for successful treatment changes. This case demonstrates that capsule endoscopy is a diagnostic tool that may play an important role in the assessment of patients, including children, with possible GVHD.

The Cord Blood Transplantation Study (COBLT), sponsored by the National Heart, Lung, and Blood Institute, is a phase II multicenter study designed to evaluate the use of cord blood in allogeneic transplantation. In this report, we evaluated the outcomes of cord blood transplantation in 69 patients with lysosomal and peroxisomal storage diseases. Patients with mucopolysaccharidoses I to III, mucolipidoses (ML) II (n = 36), adrenoleukodystrophy (n = 8), metachromatic leukodystrophy (n = 6), Krabbe disease (n = 16), and Tay-Sachs disease (n = 3) were enrolled between August 1999 and June 2004. All patients received the same preparative regimen, graft-versus-host disease (GVHD) prophylaxis, and supportive care. End points included survival, engraftment, GVHD, and toxicity. Sixty-nine patients (64% men; 81% white) with a median age of 1.8 years underwent transplantation with a median cell dose of 8.7 x 10(7)/kg. One-year survival was 72% (95% confidence interval, 61%-83%). The cumulative incidence of neutrophil engraftment by day 42 was 78% (95% confidence interval, 67%-87%) at a median of 25 days. Grade II to IV acute GVHD occurred in 36% of patients. Cord blood donors are readily available for rapid transplantation. Cord blood transplantation should be considered as frontline therapy for young patients with lysosomal and peroxisomal storage diseases.

We report identical twin boys who each had stage IV rhabdoid tumor of the left kidney at the age of 5 months and 2 years, respectively. The 5-month-old boy, despite receiving chemotherapy, died of progressive disease at the age of 12 months. Following resection of the tumor, his twin brother was treated with 6 cycles of combination chemotherapy consisting of cisplatinum, doxorubicin, vincristine, cyclophosphamide, and actinomycin-D alternating with ifosfamide and etoposide. After complete regression of lung and brain metastases, he received high-dose thiotepa, etoposide, and cyclophosphamide, followed by autologous peripheral stem cell rescue. The patient is presently alive and free of disease 6 years posttransplant. High-dose chemotherapy followed by autologous stem cell transplant may be an effective front-line therapeutic approach for patients with metastatic rhabdoid tumor of the kidney.

Interleukin-1 (IL-1) production by endotoxin-stimulated cultured monocytes from 31 participants in grafts of marrow depleted of mature cellular elements by treatment with soybean agglutinin and sheep red blood cells (SBA-E-) and 12 recipients of unfractionated bone marrow were studied and compared with normal controls. Patients were studied prior to marrow transplant (BMT) and at 1 month, 2 to 4 months, and 5 to 6 months post-transplant. Deficiencies in IL-1 production (<50 units) were detected in both transplant groups prior to and at 1 month post-BMT. From 2 to 4 months post-transplant, 67% of the recipients of unmodified marrow and 45% of the recipients of SBA-E- marrow grafts produced a normal level of IL-1. By 5 to 6 months post-transplant and thereafter, the proportions of patients exhibiting deficiencies in IL-1 production in each group were equally low. We also evaluated the impact of early deficiencies of IL-1 on engraftment, hematopoietic function, and immunological reconstitution. Deficiencies in IL-1 production persisting to 2 to 4 months post-BMT did not significantly affect the degree of chimerism or the time to recovery of neutrophil counts to 500/mu l in recipients of either unmodified or T-cell-depleted marrow. Platelet recovery during the first 50 days post-transplant was significantly slower in the IL-1-deficient group, but thereafter rebounded, so that by 4 months post-BMT patients with initial deficiencies in IL-1 production achieved levels comparable with those attained by patients with normal production of IL-1. When we looked at the lymphocyte response to phytohemagglutinin (PHA), there was no difference detected among patients with or without IL-1 deficiency receiving unmodified transplants. In contrast, recipients of T-cell-depleted grafts exhibiting a prolonged deficiency of IL-1 experienced a slower rate of recovery of PHA responses. Our results suggest that IL-1 may play an important role in the early expansion of megakaryocytic precursors following an allogeneic marrow transplant and may facilitate the functional development of allogeneic lymphoid progenitors following a T-cell-depleted marrow graft.

To date, our computer-assisted search failed to report any case involving a gravid patient donating her bone marrow for harvesting. It is known that bone marrow harvesting causes a significant decrease in the donor's blood volume and therefore this can be potentially detrimental to both the mother and the fetus. We report the first case of the gravid donor in which fetal heart rate (FHR) during bone marrow harvesting has been studied. Decreased beat to beat variability and disappearance of accelerations were noted. The FHR returned to normal shortly after the procedure was terminated.

A cytogenetically normal infant with Kostmann syndrome (severe congenital granulocytopenia) was treated with granulocyte colony-stimulating factor, which resulted in a rapid improvement in his neutrophil count and a resolution of recurrent infections. After 11 months of therapy, splenomegaly developed, with thrombocytopenia, anemia, circulating nucleated erythrocytes, and acquired monosomy 7, which evolved during a period of 7 months into acute nonlymphoblastic leukemia. The use of granulocyte colony-stimulating factor in patients with congenital marrow failure disorders may induce or hasten the onset of a malignant transformation.

A patient with acute lymphoblastic leukemia (ALL) who had undergone an allogeneic bone marrow transplant that included high-dose chemotherapy and total body radiation without eye shielding, sustained an isolated relapse of her disease in the iris. A review of ocular leukemic disease is discussed.

Higher hematocrit and serum erythropoietin (EPO) levels have previously been shown in end-stage renal disease patients treated with continuous ambulatory peritoneal dialysis (CAPD) compared with hemodialysis. We investigated whether EPO was produced intraperitoneally in CAPD patients. EPO concentration was 3.5 +/- 0.3 mU/ml by radioimmunoassay in 26 samples of peritoneal dialysis effluent obtained from 15 CAPD patients. EPO was not detectable in the fresh unused dialysate. No correlation was observed between EPO levels in the serum and dialysis effluent. Peritoneal macrophages were isolated from the dialysis effluent of 9 CAPD patients after an overnight dwell. The culture supernatant obtained after 24 h of in vitro culture of a million cells yielded EPO of 3.5 +/- 0.3 mU/ml. Our study demonstrated that peritoneal macrophages from CAPD patients produce EPO on in vitro stimulation, and EPO is present in the dialysis effluent of CAPD patients.

Gaucher disease is the most prevalent lysosomal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid beta-glucosidase and the resultant accumulation of glucosylceramide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocyte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neuronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytogenetic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete reconstitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8-12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12-24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time course and rationale for studies directed to gene therapy via BMT for this disease after introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells of selected Gaucher disease patients.

A 10-year-old boy with Shwachman-Diamond syndrome and severe bone marrow failure was treated with high-dose cyclophosphamide, busulfan, and antithymocyte globulin followed by an infusion of human leukocyte antigen-identical, mixed lymphocyte culture (MLC) non-reactive sibling bone marrow. He developed cardiac arrhythmias and intractable hypotension and died on day 23 posttransplant. Autopsy findings were consistent with cyclophosphamide-induced pancarditis. The bone marrow showed signs of early engraftment. Allogeneic bone marrow transplantation may be a treatment alternative for Shwachman-Diamond syndrome with severe bone marrow failure. However, fatal posttransplant pancarditis due to doses of cyclophosphamide not usually associated with cardiac death may be an unanticipated problem. Further trials of bone marrow transplantation as therapy for this syndrome may be warranted, perhaps using lower doses of cyclophosphamide or substituting for it other immunosuppressive and myelosuppressive agents.

Because several human hematopoietic growth factors have been identified and shown to be effective for treatment of congenital or iatrogenic neutropenias, and cord blood contains stimulatory activities for blood-forming cells, we postulated that identification of these factors and analysis of their regulatory role in normal neonates would provide a rationale for their use in treating neonatal infections associated with neutropenia. We studied the plasma levels of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) and the frequency of granulomonopoietic colony-forming cells (CFU-GM) in the umbilical cord blood of normal term neonates. Plasma growth factor levels were measured by a biologic assay. Circulating hematopoietic progenitors were assayed for colony formation with different recombinant growth factors used as exogenous growth stimulators. The cell cycle status of these progenitors was analyzed by the thymidine suicide technique. At birth the leukocyte count (mean +/- SD) was 11.0 +/- 3.9 x 10(9)L and the neutrophil count was 5.6 +/- 2.6 x 10(9)/L. The incidence of CFU-GM was significantly higher in umbilical cord blood than in normal adult peripheral blood (p less than 0.005) with up to 40% of the cells in S phase (less than 10% in normal adults). Plasma levels of G-CSF and GM-CSF at birth were 40.8 +/- 2.8 U/ml and 19.9 +/- 5.2 U/ml, respectively (normal adult plasma levels 2.5 +/- 1.5 U/ml for G-CSF and undetectable for GM-CSF). These high levels of G-CSF and GM-CSF in umbilical cord blood of normal neonates might play a role in maintaining adequate neutrophil production.

A case of Philadelphia (Ph)-chromosome-positive acute leukemia (AL) is presented who went into remission with disappearance of the Ph1 chromosome and later on developed the chronic phase of chronic granulocytic leukemia (CGL) with reappearance of the Ph1 chromosome. The patient is alive 6+ years following the diagnosis. The entity of Ph1-positive AL is discussed. It is suggested that the patients with Ph1-positive AL who develop CGL have a better prognosis than previously described.

Interleukin-1 (IL-1) production by endotoxin-stimulated, cultured monocytes from 19 patients with lethal congenital immune disorders were studied and compared with normal controls. Lipopolysaccharide (LPS) stimulated IL-1 production was normal in three of three patients with Wiskott Aldrich syndrome (WAS), two of three combined immunodeficiency with T-cell predominance (CIDTP) and nine of 13 with severe combined immunodeficiency (SCID). Monocytes deficient in IL-1 production could be restored to normal production after incubation with indomethacin in three of five deficient patients. Monocytes from the other two patients could not be induced to generate IL-1, suggesting either an intrinsic deficiency or an alternate inhibitory mechanism as the basis for the IL-1 deficiency observed. In patients with SCID who were transplanted with HLA-haplotype disparate, T-cell depleted marrow without preparative chemotherapy, deficiency of monocyte IL-1 production was correlated with graft failure. Immune reconstitution was achieved in IL-1 deficient patients only when donor monocytes were also engrafted. We hypothesize that deficiencies of IL-1 production may contribute to the heterogeneous expression of combined immunodeficiencies, and may also restrict the engraftment and functional development of allogeneic lymphoid progenitors from a T-cell depleted marrow graft.