Melvin H. Freedman

Prevention of Cardiac Disease by Subcutaneous Deferoxamine in Patients with Thalassemia Major

We examined the efficacy of long-term subcutaneous deferoxamine therapy in the prevention of iron-related cardiac disease in patients with thalassemia major who began treatment after the age of 10 years. Of 36 such patients without preexisting cardiac disease, 19 did not comply with the program of chelation therapy. Over the course of treatment (1977 to 1983) serum ferritin and aspartate aminotransferase levels fell in the compliant group, from mean values (+/- S.D.) of 4765 +/- 2610 to 2950 +/- 1850 ng per milliliter and 58.1 +/- 22 IU to 30 +/- 20 IU per liter, respectively (P less than 0.05), but rose in the noncompliant group, from 5000 +/- 2316 to 6040 +/- 2550 ng per milliliter and 56.6 +/- 20 to 90 +/- 35 IU per liter, respectively. Only one patient in the compliant group acquired cardiac disease and died of fulminant congestive heart failure. In contrast, 12 noncompliant patients acquired cardiac disease, and 7 died. In addition, the mean age of the compliant population (18.9 +/- 4.5 years) now approaches the mean age of acquisition of cardiac disease in the noncompliant group (19 +/- 4.3). These data demonstrate that compliance with treatment with deferoxamine may protect patients from cardiac disease induced by iron overload.

Shwachman syndrome: Phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar

OBJECTIVES With the use of clinical data from a large international cohort, we evaluated and compared affected siblings and isolated cases. STUDY DESIGN Data from 116 families were collected, and patients conforming to our predetermined diagnostic criteria were analyzed. Phenotypic manifestations of affected siblings and singletons were compared with the use of t tests, Wilcoxon scores, and chi2 analysis. RESULTS Eighty-eight patients (33 female, 55 male; median age 5.20 years) fulfilled our predetermined diagnostic criteria for Shwachman syndrome; 63 patients were isolated cases, and 25 affected siblings were from 12 multiplex families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86) displayed a low serum trypsinogen concentration. Patients older than 4 years more often had pancreatic sufficiency. Neutropenia occurred in 98%, anemia in 42%, and thrombocytopenia in 34%. Myelodysplasia or cytogenetic abnormalities were reported in 7 patients. Short stature with normal nutritional status was a prominent feature. CONCLUSIONS Clinical features among patients with Shwachman syndrome varied between patients and with age. Similarities in phenotype between isolated cases and affected sibling sets support the hypothesis that Shwachman syndrome is a single disease entity.

Shwachman–Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is an inherited marrow failure disorder with varying cytopenia, pancreatic dysfunction, and metaphyseal dysostosis. SDS is also characterized by a risk of myelodysplasia and leukemia in up to one third of the patients. Over the last 5 years, major advances have been made in understanding the bone marrow phenotype. The gene associated with the disease, SBDS, has recently been identified. Herein we provide an update on the clinical features, the hematopoietic defects, and the genetics of the disease as they are currently understood. We also review the diagnostic and therapeutic approaches to the hematological complications in the syndrome.

Shwachman syndrome: Exocrine pancreatic dysfunction and variable phenotypic expression

BACKGROUND & AIMS Shwachman syndrome is an inherited condition with multisystemic abnormalities, including exocrine pancreatic dysfunction. The aim of this study was to evaluate the occurrence and progression of features in a large cohort of patients. METHODS Clinical records of 25 patients with Shwachman syndrome were reviewed. RESULTS Mean birth weight (2.92 +/- 0.51 kg) was at the 25th percentile. However, by 6 months of age, mean heights and weights were less than the 5th percentile. After 6 months of age, growth velocity was normal. Severe fat maldigestion due to pancreatic insufficiency was present in early life (fecal fat, 26% +/- 17% of fat intake; age, < 2 years). Serial assessment of exocrine pancreatic function showed persistent deficits of enzyme secretion, but 45% of patients showed moderate age-related improvements leading to pancreatic sufficiency. Neutropenia was the most common hematologic abnormality (88%), but leukopenia, thrombocytopenia, and anemia were also frequently encountered. Patients with hypoplasia of all three bone marrow cellular lines (n = 11) had the worst prognosis; 5 patients died, 2 of sepsis and 3 of acute myelogenous leukemia. Other findings included hepatomegaly and/or abnormal liver function test results and skeletal abnormalities. CONCLUSIONS A wide and varied spectrum of phenotypic abnormalities among patients with Shwachman syndrome is described. Pancreatic acinar dysfunction is an invariable abnormality. Patients with severe bone marrow involvement may have a guarded prognosis.

Juvenile myelomonocytic leukemia and Noonan syndrome.

A questionnaire survey was conducted of patients with homozygous sickle cell anemia (Hb SS) and sickle cell beta(0)-thalassemia (Hb S-beta(0)) between 5 and 20 years of age to determine the prevalence and characteristics (number of episodes, timing, duration, cause, or precipitating event) of priapism. Ninety-eight male patients or their parents were surveyed by the same male investigator using a structured verbal interview, which was modified according to the age of the patient. Ninety-four patients had Hb SS and four Hb S-beta(0) thalassemia. Eleven (11%) patients were known to have experienced priapism previously. In response to the questionnaire, 16 of the remaining 87 (18%) patients reported having had priapism on one or more occasions. The actuarial probability of experiencing priapism by 20 years of age was 89% (+/- 9%). The mean age at the initial episode was 12 years, the mean number of episodes per patient was 15.7 (median, 1; range, 1-100), and the mean duration of an episode was 125 minutes. Episodes typically occurred around 4:00 am, and 75% of the patients surveyed had at least one episode starting during sleep or upon awakening from sleep. The prevalence of priapism in children and adolescents with SCA is much higher than previously described. Since early intervention and treatment may prevent irreversible penile fibrosis and impotence, patients and parents should be educated about this complication in advance of its occurrence.

Effect of Age at the Start of Iron Chelation Therapy on Gonadal Function in β-Thalassemia Major

BACKGROUND Patients with transfusion-dependent thalassemia major tend to have abnormal growth and sexual maturation at puberty, presumably as a result of pituitary iron overload. This study was designed to determine whether chelation therapy with deferoxamine before the age of puberty would ameliorate this problem. METHODS We examined 40 patients over 14 years of age with transfusion-dependent thalassemia major. The 19 patients in group A (mean [+/- SD] age at study, 17.0 +/- 1.5 years) had begun nightly treatment with subcutaneous deferoxamine before the age of 10 (mean age at start of treatment, 7.5 +/- 1.8 years). The 21 patients in group B (mean age, 24.1 +/- 3.8 years) had begun treatment after the age of 10 (mean age at start of treatment, 14.4 +/- 4.7 years). RESULTS The abnormal findings were essentially confined to sexual development. The final height did not differ between groups or from the mean parental height in each group. Ninety percent of the patients in group A had normal sexual development, as compared with 38 percent of those in group B (P = 0.001). Outcomes were correlated with indexes of iron overload; the patients in group A had lower serum ferritin levels before chelation treatment (P = 0.01) and lower average serum ferritin levels during treatment (P = 0.005). CONCLUSIONS Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation.

Growth failure and bony changes induced by deferoxamine.

We reviewed the linear growth and growth plate morphology in all children with homozygous beta thalassemia followed in Toronto, for whom monthly height percentiles were available before, and for a 36-month period after, the initiation of nightly subcutaneous deferoxamine therapy. All patients were less than 7 years of age when begun on deferoxamine, and had received nightly deferoxamine for a minimum of 36 months. Marked abnormalities of the metaphyseal growth plate were readily observed in the distal ulnar, radial, and tibial metaphyses in 11 of 37 patients in whom a significant decline in mean height percentile was also noted. (In 10 of these 11 patients, height was less than the 15th percentile after 36 months.) These 11 patients had received a significantly greater (p less than 0.025) initial and average daily dose of deferoxamine, and had maintained a significantly lower (p less than 0.025) mean serum ferritin concentration over the 36 months, than the remainder of the cohort. To determine whether deferoxamine played a causative role in growth failure, growth in patients who began deferoxamine before the age 2 years was compared to that of patients who began after age 5 years, for the period between 2 and 5 years of age. Only patients begun on deferoxamine prior to age 2 years demonstrated a significant (p less than 0.01) decline in height percentile by the third year, implicating deferoxamine therapy as the cause of growth failure. We conclude that both the decline in height percentile and the bony changes observed in well-chelated patients are directly related to deferoxamine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of Residual Acute Lymphoblastic Leukemia Cells in Cultures of Bone Marrow Obtained during Remission

We used a semisolid culture assay to quantitate leukemia cells in the bone marrow of patients with childhood acute lymphoblastic leukemia (ALL). In bone marrow cultures from 40 patients with newly diagnosed disease, the colonies that developed in vitro consisted of lymphoblasts with the same surface markers and abnormal karyotype as the original diagnostic marrow specimens. We also studied marrow cultures from 13 patients in chemotherapy-induced remission; 6 of these, including 1 obtained from a patient during successful engraftment after marrow transplantation, also yielded lymphoblast colonies in culture, with the same immunologic phenotype or abnormal karyotype as the original leukemic marrow. Four of these patients, including the one who underwent marrow transplantation, relapsed within 2 to 30 months of the abnormal cultures; the other two are still in remission, one of them 30 months after diagnosis. Bone marrow cultures from eight normal controls and from the other seven patients in remission did not yield lymphoblast colonies; all seven of the latter are still in remission. This assay appears to allow detection of small numbers of residual leukemic cells. We conclude that the technique will be valuable in monitoring the efficacy of chemotherapy and allogeneic bone marrow transplantation in acute lymphoblastic leukemia, as well as in evaluating the quality of purged marrow for autologous marrow transplantation.

Management of kostmann syndrome in the g-csf era

Kostmann (1956, 1975) described an inherited haematological disorder with severe neutropenia with an absolute neutrophil count (ANC) , 0 ́2 10/l and early onset of severe bacterial infections. Most children died because of these infections, despite antibiotic treatment. Different treatment strategies for congenital neutropenia (CN) included use of steroids and lithium (Barrett et al, 1977; Hraker et al, 1977), but these treatments did not show any long-term effect on neutrophil counts. Bone marrow transplantation (BMT) was the only curative treatment option for patients with human leucocyte antigen (HLA)compatible donors (Rappeport et al, 1980). Some patients who survived infections and treatment, however, underwent malignant transformation into acute myeloid leukaemia (AML) (Gilman et al, 1970; Rosen & Kang, 1979). The availability of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in 1987 (Nagata et al, 1986; Souza et al, 1986) dramatically changed both the prognosis of CN and the quality of life for patients with CN (Bonilla et al, 1989; Welte et al, 1990). Since the establishment of the Severe Chronic Neutropenia International Registry (SCNIR) in 1994, data on 304 patients with CN have been collected to monitor the clinical course, treatment and disease outcomes in these patients. In clinical trials, . 90% of these patients responded to rHuG-CSF treatment with an increase in ANC . 1 ́0 10/l. Importantly, all responding patients required significantly fewer antibiotics and days of hospitalizations (Dale et al, 1993; Bonilla et al, 1994; Welte & Dale, 1996; Freedman, 1997; Welte & Boxer, 1997). Haematopoietic stem cell transplantation (HSCT) remains the only currently available treatment for those patients refractory to rHuG-CSF treatment that continue to have severe and life-threatening bacterial infections. Data from the SCNIR also demonstrate that for all CN patients, < 9% will develop leukaemia regardless of their treatment or response (Bonilla et al, 1994; Freedman, 1997; Welte & Boxer, 1997). The molecular and genetic basis for this disease is still largely unknown.

Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia

Summary. In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte‐macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly‐diagnosed JCML patients were investigated to characterize the disease further. In co‐cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU‐E, CFU‐GM, CFU‐Meg and CFU‐GEMM colonies. Monoclonal anti‐tumour necrosis factor alpha neutralizing antibodies (anti‐TNF‐α Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth‐promoting effect on autologous JCML cells cultured in clonogenic assays. Anti‐TNF‐α Ab and anti‐granulocyte‐macrophage colony‐stimulating factor neutralizing antibodies (anti‐GM‐CSF Ab) both reversed the stimulating effect. Recombinant GM‐CSF and recombinant TNF‐α produced a profound increase in JCML colonies when tested individually and anti‐GM‐CSF Ab reversed the TNF‐α effect. Expression studies of TNF‐α and TNF‐α receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF‐α activity was assayed in a wide variety of cell culture supernatants and in normal and patients’plasma, and only the JCML specimens showed increased TNF‐α values. Recombinant interleukin‐1 alpha (IL‐1α) also stimulated JCML colony growth, but polyclonal anti‐IL‐1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF‐α or GM‐CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF‐α and that the endogenously‐produced TNF‐α and GM‐CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL‐1α also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM‐CSF, TNF‐α or both.