Biomedical subjects

J T Sandlund

Publications and source records attributed to J T Sandlund.

At least 19 recordsLinked to original sources

PubMed2005

Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation.

To assess the prognosis of overt testicular disease at diagnosis of acute lymphoblastic leukemia, and any therapeutic role of irradiation for this involvement, we reviewed the data of 811 boys treated on St Jude studies Total X--XI (early period) and Total XII-XIV (recent period). In all, 19 boys (2.3%) had testicular disease at diagnosis. In the early period, patients with testicular leukemia had a poorer overall survival (OS) (P=0.003), event-free survival (EFS) (P=0.064), and higher cumulative incidence of relapse (P=0.041) than did other patients. During the recent period, patients with and without overt testicular leukemia did not differ in OS (P=0.257), EFS (P=0.102), or cumulative incidence of relapse (P=0.51). In a multivariate analysis, OS was lower for patients with testicular disease than for those without the involvement in the early period (P=0.047) but not in the recent one (P=0.75). Both patients who received irradiation for residual testicular disease at the end of induction subsequently died of leukemia. Of the other 17 patients who did not receive irradiation, only one developed testicular relapse in combination with bone marrow relapse. In conclusion, the prognostic impact of overt testicular disease has diminished. Irradiation appears to provide no survival advantage to this patient population.

Adolescent↗

PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗

PubMed2004

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia.

Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (+/-s.d.) CSF asparagine (0.29+/-0.63, n=9) than those who received PEG (0.77+/-0.82, n=4) (P=0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.

Antibodies↗

PubMed2004

Low-dose oral etoposide-based induction regimen for children with acute lymphoblastic leukemia in first bone marrow relapse.

We evaluated the clinical response to low-dose etoposide in relapsed acute lymphoblastic leukemia (ALL). Of the 45 patients with ALL in first bone marrow relapse enrolled on the ALL R15 protocol, 44 had received epipodophyllotoxins during frontline therapy. In the first week of remission induction therapy, patients received etoposide (50 mg/m(2) per day) administered orally as a single agent once or twice daily. On Day 8, patients started to receive dexamethasone, vincristine, and L-asparaginase. Etoposide was administered until Day 22. Two courses of consolidation therapy were followed by continuation therapy or hematopoietic stem cell transplantation. After 7 days of single-agent etoposide treatment, peripheral blast cell counts (P=0.013) and percentages of bone marrow blasts (P=0.016) were significantly reduced. In all, 38 (84.4%) attained second remission. Only time to relapse was significantly associated with outcome (P=0.025): the 5-year event-free survival estimates (+/-se) were 52.0+/-9.6% for those with late relapse and 20.0+/-8.0% for those with early relapse. We conclude that low-dose etoposide administered orally has a cytoreductive effect in relapsed ALL.

Administration, Oral↗

PubMed2003

Urolithiasis in pediatric patients with acute lymphoblastic leukemia.

We evaluated the incidence, timing, and consequences of urolithiasis in children with acute lymphoblastic leukemia (ALL). A total of 20 patients with urolithiasis were identified from 2095 patients with ALL treated at St Jude Children's Research Hospital on consecutive protocols between 1968 and 1998. For remission induction therapy, all patients received daily prednisone; continuation chemotherapy regimens differed by protocol with some including pulses of prednisone or dexamethasone and others no glucocorticoid. Patients with urolithiasis were older at diagnosis of ALL than those without urolithiasis (median age, 7.5 vs 5.0 years; P=0.03) and less likely to be black (P=0.03) than white or Hispanic, but sex and treatment era did not differ. Presenting symptoms included abdominal or flank pain, hematuria, and dysuria. All stones analyzed biochemically were calcium stones. The incidence of urolithiasis after completion of therapy was 1.8 per 10 000 person-years. Compared to this baseline rate, the relative risk of urolithiasis was 45 (P<0.01) during induction therapy, 22 (P<0.01) during continuation therapy with glucocorticoids, and 5.1 (P>0.05) during continuation therapy without glucocorticoids. Urolithiasis occurred 4.5 times more often during continuation treatment with glucocorticoids than without (P<0.05). Seven patients (35%) had recurrent urolithiasis. Patients with ALL are at risk of developing calcium renal stones during chemotherapy, especially when a glucocorticoid is included.

Adolescent↗

PubMed2002

Intensive chemotherapy with hematopoietic stem-cell support for children with recurrent or refractory NHL.

BACKGROUND: Children with refractory or recurrent NHL are generally thought to have a poor prognosis. Those with chemosensitive disease are usually considered for an intensification phase, with either autologous or allogeneic hematopoietic stem-cell transplantation (HSCT). METHODS: From 1990 to 2001 we performed 24 HSCTs in 22 children with refractory (n = 8), recurrent (n = 13), or high-risk in first CR (n = 1) NHL. Among the HSCTs, 19 were autologous and five were allogeneic. RESULTS: In two children, allogeneic HSCT was performed after failing autologous HSCT. The histologic subtypes comprised large cell, (n = 13), Burkitt's lymphoma (n = 5) and lymphoblastic (n = 4). Among the cases of primary relapse, 10 occurred during therapy and three occurred after completing initial therapy. Among the 22 children in this series, two died of transplant-related toxicity and nine died of progressive disease or relapse after transplant. Among the 11 children who are alive and disease-free, 10 had non-lymphoblastic histology and one had lymphoblastic disease; one relapsed after autologous HSCT, but was successfully salvaged with multi-agent chemotherapy and involved-field irradiation. Among the 22 initial transplanted cases, 10 of 19 children with chemosensitive disease before transplantation and one of three with chemoresistant disease are currently alive and disease-free. DISCUSSION: Intensive chemotherapy followed by hematopoietic stem-cell support is an effective strategy for children with chemosensitive recurrent non-lymphoblastic NHL.

Adolescent↗

PubMed2001

Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature.

BACKGROUND: Lactic acidosis (LA) associated with hematologic malignancies is rare, ominous, and generally occurs in adults. Its pathogenesis is poorly understood. METHODS: The authors present one case of childhood lymphoma and two cases of childhood leukemia associated with LA, and they review the available literature. Plasma concentrations of insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and tumor necrosis factor (TNF)-alpha were retrospectively measured to elucidate the pathogenesis of LA. RESULTS: Lactic acidosis has been reported to date in 28 cases of lymphoma and 25 cases of leukemia, including the authors' cases. Ongoing rapid cellular proliferation was indicated in all leukemia cases. The liver was involved in 43 of the 53 cases, and hypoglycemia was present in 20. The acidosis improved only if the disease responded to chemotherapy. Remission was achieved in only five of the reported cases. In the authors' three cases, LA was associated with altered concentrations of IGFs, IGFBPs, and TNF-alpha, although causality was not established. CONCLUSIONS: Lactic acidosis in association with hematologic malignancies carries an extremely poor prognosis. Because cancer cells have a high rate of glycolysis and produce a large quantity of lactate, this condition may result from an imbalance between lactate production and hepatic lactate utilization. The authors speculate that the IGF system is involved in the pathophysiology of LA in these patients. Only chemotherapy so far has been effective in correcting the acute acidosis in a few patients; however, it has not necessarily improved ultimate outcome.

Acidosis, Lactic↗

PubMed2001

Second malignancy after treatment of childhood non-Hodgkin lymphoma.

BACKGROUND: The objective of this report was to determine the cumulative incidence of and risk factors for second malignancy and the competing risk of death due to any other cause among patients who were treated for childhood non-Hodgkin lymphoma (NHL). METHODS: The authors retrospectively reviewed a cohort of 497 patients with NHL who were treated at St. Jude Children's Research Hospital between 1970 and 1997. RESULTS: A second malignancy developed in 16 patients (9 patients with solid tumors and 7 patients with secondary acute myeloid leukemia [AML]). This number was 10.8-fold (95% confidence interval, 6.1-16.9) higher than the 1.48 patients projected for the general population by SEER Cancer Statistics. The estimated cumulative incidence rate of second malignancy was 2.1% +/- 0.7% at 10 years after diagnosis of NHL and increased to 4.8% +/- 1.3% at 20 years after diagnosis. The cumulative incidence rate of second malignancy was least among patients with small noncleaved cell lymphoma (0.5% +/- 0.5% at 20 years), higher among patients with large cell lymphoma (5.8% +/- 3.3% at 20 years), and highest among patients with lymphoblastic lymphoma (10.9% +/- 3.6% at 20 years; P = 0.002 for overall comparison). Exposure to epipodophyllotoxins was a risk factor for the development of secondary AML (P < 0.001). The cumulative incidence rate of death due to other causes was significantly less for patients who were treated after June 1978 (19.9% +/- 2.2% at 10 years) compared with patients who were treated earlier (55.6% +/- 4.2% at 10 years; P < 0.001), whereas the risk of second malignancy was similar for these two eras. CONCLUSIONS: Survivors of childhood NHL, especially those with lymphoblastic histology, are at a greater risk of developing a second malignancy compared with the general population. The incidence rate of second malignancy has remained unchanged despite a recent decline in the risk of death related to primary NHL or earlier treatment complications.

Adolescent↗

PubMed2001

Second malignancy after treatment of childhood acute myeloid leukemia.

To investigate the cumulative incidence of second malignancy and the competing risk of death due to any other cause in patients who were treated for childhood acute myeloid leukemia (AML), we analyzed the outcomes in a cohort of 501 patients who were treated at St Jude Children's Research Hospital between 1970 and 1996. Five patients developed a second cancer (two carcinomas of the parotid gland, one non-Hodgkin's lymphoma, one supratentorial primitive neuroectodermal tumor, one acute lymphoblastic leukemia) as compared with 0.47 expected in the general population (standardized incidence ratio, 10.64; 95% confidence interval, 3.28 to 22.34). A third neoplasm (meningioma) developed in one patient. At 15 years after the diagnosis of AML, the estimated cumulative incidence of second malignancy was 1.34% +/- 0.61%, whereas the cumulative incidence of death due to any other cause was 72.96% +/- 2.14%. We concluded that although a more than 10-fold increased risk of development of cancer was found in survivors of childhood AML as compared to the general population, the risk of this late complication is small when compared to the much larger risk of death because of the primary leukemia or the early complications of its treatment. Future studies should focus on improving treatments for primary AML while preventing second malignancies.

Acute Disease↗

PubMed2001

Magnetic resonance imaging detection of avascular necrosis of the bone in children receiving intensive prednisone therapy for acute lymphoblastic leukemia or non-Hodgkin lymphoma.

The purpose of this study was to determine the frequency with which magnetic resonance (MR) imaging detects avascular necrosis of the bone (AVNB) in children with acute lymphoblastic leukemia (ALL) or advanced-stage non-Hodgkin lymphoma (NHL) who receive prednisone during remission induction, reinduction, and maintenance chemotherapy; to assess the clinical significance of these findings; and to identify factors predictive of AVNB. We prospectively obtained MR imaging of the hips and knees of 116 children who had completed at least 1 year of treatment for ALL or advanced-stage NHL on identical prednisone-containing regimens between December 1991 and October 1994. MR imaging findings of AVNB were compared with clinical outcomes, and the effect of therapeutic and patient factors on the frequency of AVNB was analyzed. The MR imaging findings of 17 of the 116 participating patients were consistent with AVNB. The most common clinical manifestation was joint pain (11 patients). Only one patient had progressive joint deterioration that necessitated surgical replacement. Only age 10 years or more at the time of the primary diagnosis was significantly associated with the development of AVNB (P = 0.004). MR imaging showed changes consistent with AVNB in approximately 15% of this patient population. However, most patients in this study who had MR imaging signs of AVNB did not experience progressive joint destruction, even with continued prednisone therapy. Therefore, the clinical usefulness of MR imaging as a screening tool for AVNB in this set of patients remains uncertain.

Adolescent↗

PubMed2001

Impact of treatment on the outcome of acute myeloid leukemia with inversion 16: a single institution's experience.

To identify treatment factors that may affect the survival of children with inv(16)(p13.1q22), we compared the outcomes of 19 patients with this genetic feature treated at our institution during two treatment eras. Nine patients were treated during era 1 (1980 to 1987), and 10 were treated during era 2 (1988 to 1996). All entered complete remission (CR) with induction therapy. Eight of the nine children treated in era 1 died, seven of relapsed leukemia. In contrast, three of 10 patients treated during era 2 have died, all of non-disease-related causes. Event-free survival (EFS) estimates were significantly higher for patients treated during era 2 than for those treated during era 1 (P = 0.03); the 6-year estimates were 70 +/- 15% (s.e.) and 11 +/- 7%, respectively. Era 2 treatment protocols differed from those of era 1 in their use of higher doses of cytarabine and etoposide during induction and consolidation chemotherapy and in their use of 2-chlorodeoxyadenosine (2-CDA). These results suggest that dose intensification of cytarabine benefits children with AML and inv(16), as is the case in adults. They also suggest that dose intensification of etoposide and addition of 2-CDA may also offer an advantage. This study underscores the dependence of the prognostic impact of cytogenetic features on the efficacy of treatment.

Acute Disease↗

PubMed2000

Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer.

Empiric oral antibiotic therapy for febrile neutropenic cancer patients has been suggested as a means to decrease hospitalization, but the safety of this approach has not been adequately studied in children. We compared continued iv antibiotic therapy with switching treatment to orally administered cefixime in a group of selected febrile neutropenic children for whom blood cultures were sterile after 48 h of incubation. Two hundred episodes of febrile neutropenia were studied (156 patients), and 100 episodes were randomized to receive each treatment. Failure to respond to therapy was defined by documented or suspected bacterial infection, recurrent fever, or discontinuation of assigned therapy for any reason before neutropenia resolved. Rates of treatment failure were similar in the oral cefixime group (28%) and in the iv antibiotic group (27%; P=1.0). Results support the safety of oral cefixime therapy for low-risk febrile neutropenic children, a therapeutic approach that would facilitate earlier outpatient management and decrease the costs of treatment.

Administration, Oral↗

PubMed2000

Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia.

The effect of traumatic lumbar puncture at the time of initial diagnostic workup on treatment outcome in children with newly diagnosed acute lymphoblastic leukemia (ALL) was investigated. The findings of the first 2 lumbar punctures performed on 546 patients with newly diagnosed ALL treated on 2 consecutive front-line studies (1984-1991) at St Jude Children's Research Hospital were retrospectively reviewed. Lumbar punctures were performed at the time of diagnosis and again for the instillation of first intrathecal chemotherapy. The event-free survival (EFS) experience for patients with 1 cerebrospinal fluid (CSF) sample contaminated with blast cells was worse than that for patients with no contaminated CSF samples (P =.026); that of patients with 2 consecutive contaminated CSF samples was particularly poor (5-year EFS = 46 +/- 9%). In a Cox multiple regression analysis, the strongest prognostic indicator was 2 consecutive contaminated CSF samples, with a hazard ratio of 2.39 (95% confidence interval, 1. 36-4.20). These data indicate that contamination of CSF with circulating leukemic blast cells during diagnostic lumbar puncture can adversely affect the treatment outcome of children with ALL and is an indication to intensify intrathecal therapy.

Adolescent↗

PubMed2000

Safety of lumbar puncture for children with acute lymphoblastic leukemia and thrombocytopenia.

CONTEXT: Patients with thrombocytopenia are at risk for spontaneous or procedure-related hemorrhage. Whether such patients can safely undergo lumbar puncture (LP) without prophylactic platelet transfusion is unknown. OBJECTIVE: To determine whether an association exists between thrombocytopenia and LP complications among children with acute lymphoblastic leukemia. DESIGN, SETTING, AND PATIENTS: Retrospective review of the records of 958 consecutive children (median age, 5.5 years) with newly diagnosed acute lymphoblastic leukemia who were treated at a pediatric cancer center between February 1984 and July 1998. INTERVENTIONS: All patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy. MAIN OUTCOME MEASURE: Serious complications of LP occurring during the remission induction and consolidation treatment periods (when thrombocytopenia is likely to occur), defined as any neurologic, infectious, or hemorrhagic problems related to the procedure, reported by platelet count at the time of the procedure. RESULTS: Of the 5223 LPs evaluated, 29 were performed at platelet counts of 10 x 10(9)/L or less, 170 at platelet counts of 11 to 20 x 10(9)/L, and 742 at platelet counts of 21 to 50 x 10(9)/L. No serious complications were encountered, regardless of the platelet count. The 95% confidence interval for the proportion of serious complications in the 199 patients with platelet counts of 20 x 10(9)/L or less was 0% to 1.75% and that for the 941 patients with platelet counts of 50 x 10(9)/L or less was 0% to 0.37%. CONCLUSIONS: In our study of children undergoing remission induction or consolidation therapy for acute lymphoblastic leukemia, serious complications of LP were not observed, regardless of platelet count. Prophylactic platelet transfusion is not necessary in children with platelet counts higher than 10 x 10(9)/L. Due to the small number of patients in our study with platelet counts of 10 x 10(9)/L or less, conclusions cannot yet be drawn for such patients. JAMA. 2000;284:2222-2224.

Adolescent↗

PubMed2000

Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system.

Epstein-Barr virus (EBV) targeted therapeutic strategies for viral associated malignant diseases have received only perfunctory consideration, first, because latent herpesviruses have been intractable to antiviral chemotherapy and, second, because the role EBV has in maintenance of the malignant cell phenotype has been uncertain. Two patients with EBV related primary central nervous system lymphoma (PCNSL) in the setting of advanced AIDS, were treated with low dose hydroxyurea based on in vitro anti-EBV activity. The responses obtained here suggest the promise of antiviral approaches in select cancers.

Adolescent↗

PubMed2000

Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia.

By using rapid flow cytometric techniques capable of detecting one leukemic cell in 10(4) normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, > or = 0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P < .001); patients with high levels of MRD at the end of the induction phase (> or = 1%) or at week 14 of continuation therapy (> or = 0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% +/- 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% +/- 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD(+) patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients. (Blood. 2000;96:2691-2696)

Adolescent↗

PubMed2000

Late effects of treatment in survivors of childhood acute myeloid leukemia.

PURPOSE: To investigate the incidence of and risk factors for late sequelae of treatment in patients who survived for more than 10 years after the diagnosis of childhood acute myeloid leukemia (AML). PATIENTS AND METHODS: Of 77 survivors (median follow-up duration, 16. 7 years), 44 (group A) had received chemotherapy, 18 (group B) had received chemotherapy and cranial irradiation, and 15 (group C) had received chemotherapy, total-body irradiation, and allogeneic bone marrow transplantation. Late complications, tobacco use, and health insurance status were assessed. RESULTS: Growth abnormalities were found in 51% of survivors, neurocognitive abnormalities in 30%, transfusion-acquired hepatitis in 28%, endocrine abnormalities in 16%, cataracts in 12%, and cardiac abnormalities in 8%. Younger age at the time of diagnosis or initiation of radiation therapy, higher dose of radiation, and treatment in groups B and C were risk factors for the development of academic difficulties and greater decrease in height Z: score. In addition, treatment in group C was a risk factor for a greater decrease in weight Z: score and the development of growth-hormone deficiency, hypothyroidism, hypogonadism, infertility, and cataracts. The estimated cumulative risk of a second malignancy at 20 years after diagnosis was 1.8% (95% confidence interval, 0.3% to 11.8%). Twenty-two patients (29%) were smokers, and 11 (14%) had no medical insurance at the time of last follow-up. CONCLUSION: Late sequelae are common in long-term survivors of childhood AML. Our findings should be useful in defining areas for surveillance of and intervention for late sequelae and in assessing the risk of individual late effects on the basis of age and history of treatment.

Acute Disease↗