PubMed Health⌕ Search

Biomedical subjects

Franklin O Smith

Publications and source records attributed to Franklin O Smith.

At least 19 recordsLinked to original sources
PubMed2007

The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review.

Clinical research examining the role of hematopoietic stem cell transplantation (SCT) in the therapy of acute myeloid leukemia (AML) in children is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented in the table entitled "Summary of Treatment Recommendations Made by the Expert Panel for Pediatric Acute Myeloid Leukemia" and were reached unanimously by a panel of experts in AML. The identified priority areas of needed future research in pediatric AML include: What is the role of risk group stratification, including the role of cytogenetics, in selection of patients for allogeneic SCT, especially those in first CR? What is the appropriate timing and use of alternative donor SCT, given that matched unrelated donor SCT appears to yield outcomes equivalent to matched related donor SCT? What is the role of reduced intensity SCT (including the use of fludarabine-based preparative regimens) and/or other immunomodulatory approaches to maximize the graft-versus-leukemic effect? and What is the role of biologically targeted agents (ie, tyrosine kinase inhibitors, farnesyl transferase inhibitors, Flt-3 inhibitors, etc) in the treatment of AML, including induction, consolidation, conditioning regimens, and after SCT?

Acute Disease↗
PubMed2007

Stem cell collection and gene transfer in Fanconi anemia.

Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive bone marrow failure (BMF), congenital anomalies, and a predisposition to malignancy. Successful gene transfer into hematopoietic stem cells (HSCs) could reverse BMF in this disease. We developed clinical trials to determine whether a sufficient number of CD34(+) stem cells could be collected for gene modification and to evaluate the safety and efficacy of HSC-corrective gene transfer in FA genotype A (FANCA) patients. Here, we report that FA patients have significant depletion of their BM CD34(+) cell compartment even before severe pancytopenia is present. However, oncoretroviral-mediated ex vivo gene transfer was efficient in clinical scale in FA-A cells, leading to reversal of the cellular phenotype in a significant percentage of CD34(+) cells. Re-infusion of gene-corrected products in two patients was safe and well tolerated and accompanied by transient improvements in hemoglobin and platelet counts. Gene correction was transient, likely owing to the low dose of gene-corrected cells infused. Our early experience shows that stem cell collection is well tolerated in FA patients and suggests that collection be considered as early as possible in patients who are potential candidates for future gene transfer trials.

Adolescent↗
PubMed2006

Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961.

To assess the impact of minimally differentiated acute myeloid leukemia (AML-M0) morphology in children, we analyzed 2 sequential Children's Cancer Group AML clinical trials. We compared presenting characteristics and outcomes of 82 CCG-2891 and CCG-2961 patients with de novo, non-Down syndrome (DS) AML-M0 with those of 1620 patients with non-M0 AML, and of 10 CCG-2891 patients with DS-associated AML-M0 with those of 179 with DS-associated non-M0 AML. Morphology and cytogenetics were centrally reviewed. The non-DS AML-M0 children had a lower white blood cell (WBC) count (P = .001) than their non-M0 counterparts and a higher incidence of chromosome 5 deletions (P = .002), nonconstitutional trisomy 21 (P = .027), and hypodiploidy (P = .002). Outcome analyses considering all children with non-DS AML demonstrated no significant differences between M0 and non-M0 patients. Analyses restricted to intensive-timing CCG-2891 and CCG-2961 demonstrated comparable complete response (CR) rates (79% and 78%) between non-DS M0 and non-M0 patients. Overall survival (OS) from diagnosis (38% +/- 14% versus 51% +/- 3%; P = .160) was not significantly different between the 2 groups. OS from end of induction (45% +/- 17% versus 63% +/- 3%; P = .038), event-free survival (EFS; 23% +/- 11% versus 41% +/- 3%; P = .018), and disease-free survival (DFS; 31% +/- 14% versus 52% +/- 3%; P = .009) were inferior in the M0 group. There was no significant outcome difference between DS-associated AML-M0 and non-M0 children. This study suggests that intensively treated non-DS-associated AML-M0 children have an inferior outcome compared with children with non-M0 AML.

Adolescent↗
PubMed2006

End points to establish the efficacy of new agents in the treatment of acute leukemia.

Federal regulations provide 2 pathways for approval of new agents for the treatment of acute leukemia, regular and accelerated approval. Regular approval requires evidence of clinical benefit, which is generally defined as either prolongation of life or improved quality of life, or an effect on an end point established as a surrogate for clinical benefit. Accelerated approval can be obtained based on demonstration of an effect on a surrogate measure "reasonably likely" to predict clinical benefit, but requires demonstration of clinical benefit after approval as well. The acute leukemias are a heterogeneous and relatively uncommon group of diseases. The design and execution of prospective randomized clinical trials demonstrating prolongation of life or improved quality of life for patients with these disorders can be difficult and costly and require lengthy follow-up. Thus, the development of novel trial design and inclusion of validated surrogate markers for clinical benefit are needed. To explore some of the issues pertinent to the choice of end points for drug approval in acute leukemia, the Food and Drug Administration invited the American Society of Hematology to participate in the organization and conduct of a joint workshop. In this report, we present the results of that effort.

Acute Disease↗
PubMed2006

Exposure to medical test irradiation and acute leukemia among children with Down syndrome: a report from the Children's Oncology Group.

OBJECTIVE: The etiology of acute childhood leukemia is not well understood, particularly among children with Down syndrome, in whom a 10- to 20-fold increased risk of leukemogenesis has been reported compared with children without Down syndrome. We explored the association between medical test irradiation, a postulated leukemogenic agent, and acute leukemia among children with Down syndrome. PATIENTS AND METHODS: Children with Down syndrome (controls) were frequency matched on age to children with Down syndrome and leukemia (cases) diagnosed at ages 0 to 19 years during the period 1997-2002 at participating Children's Oncology Group institutions in North America. Telephone interviews were completed with mothers of 158 cases (n = 97 acute lymphoblastic leukemia and n = 61 acute myeloid leukemia) and 173 controls. Paternal interviews were completed with 275 fathers and 40 mothers serving as surrogates. Three irradiation exposure periods were examined: preconception, in utero, and postnatal. Multivariate unconditional logistic regression models were constructed to evaluate the associations of interest, resulting in odds ratios and 95% confidence intervals. RESULTS: There was little evidence that maternal or paternal preconception irradiation exposure, intrauterine exposure, or postnatal exposure contributes to leukemogenesis in children with Down syndrome. Overall, no evidence for an effect of any periconceptional exposure was observed. Similar results were observed among acute lymphoblastic leukemia and acute myeloid leukemia cases analyzed separately. CONCLUSIONS: This was the first study, to our knowledge, to examine such an association among this unique patient population. The results do not provide evidence of a positive association between ionizing radiation exposure and acute leukemia among children with Down syndrome. The absence of an association should be encouraging for concerned parents of children with Down syndrome who undergo a series of diagnostic radiographs in the course of their standard care.

Adolescent↗
PubMed2006

Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group.

Infant acute lymphoblastic leukemia (ALL) has a poor therapeutic outcome despite attempts to treat it based on prognostic factor-guided therapy. This is the first cooperative group trial characterizing all infants at the molecular level for MLL/11q23 rearrangement. All infants enrolled on Children's Cancer Group (CCG) 1953 were tested for MLL rearrangement by Southern blot and the 11q23 translocation partner was identified (4;11, 9;11, 11;19, or "other") by reverse-transcriptase polymerase chain reaction (PCR). One hundred fifteen infants were enrolled; overall event-free survival (EFS) was 41.7% (SD = 9.2%) and overall survival (OS) was 44.8% at 5 years. Five-year EFS for MLL-rearranged cases was 33.6% and for MLL-nonrearranged cases was 60.3%. The difference in EFS between the 3 major MLL rearrangements did not reach statistical significance. Multivariate Cox regression analyses showed a rank order of significance for negative impact on prognosis of CD10 negativity, age younger than 6 months, and MLL rearrangement, in that order. Toxicity was the most frequent cause of death. Relapse as a first event in CCG 1953 was later (median, 295 days) compared with CCG 1883 historic control (median, 207 days). MLL/11q23 rearrangement, CD10 expression, and age are important prognostic factors in infant ALL, but molecular 11q23 translocation partners do not predict outcome.

Age Factors↗
PubMed2006

Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children's Oncology Group.

We evaluated differences in outcome by ethnicity among children with acute myeloid leukemia (AML). We analyzed 791 children in the CCG 2891 trial and confirmed positive findings in 850 children in the CCG 2961 trial. Hispanic and black children treated with chemotherapy in CCG 2891 had significantly inferior overall survival (OS) from study entry compared with white children (37%+/- 9% vs 48%+/- 4% [P = .016] and 34% +/- 10% vs 48% +/- 4%, [P = .007], respectively). Significantly fewer black children had related donors. Analyses of CCG 2961 confirmed that black children had significantly decreased OS rates compared with white children (45% +/- 12% vs 60% +/- 4%; P = .007) The difference in OS rates between Hispanic and white children approached statistical significance (51% +/- 8% vs 60% +/- 4%; P = .065) Only 7.5% of black children on CCG 2961 had an available family donor. In conclusion, Hispanic and black children with AML have worse survival than white children. Access to chemotherapy, differences in supportive care or leukemia phenotype, and reduced compliance are unlikely explanations for this difference because therapy was given intravenously according to CCG protocols. Fewer black children than expected had an available family marrow donor.

Acute Disease↗
PubMed2005

Periconceptional vitamin useand leukemia risk in children with Down syndrome: a Children's Oncology Group study.

BACKGROUND: Periconceptional vitamin supplementation reduces the risk of neural tube defects, and possibly may reduce the risk of certain childhood malignancies, including acute lymphoblastic leukemia (ALL). Because children with Down syndrome (DS) experience a 20-fold higher risk of leukemia than the general population, the authors evaluated whether periconceptional vitamin supplementation reduced the risk of leukemia in children with DS. METHODS: From 1997 to 2002, 158 children ages birth-18 years with DS and acute leukemia (n = 61 children with acute myeloid leukemia [AML] and n = 97 children with ALL) were enrolled through the Children's Oncology Group in North America. Children with DS alone (n = 173) were identified through the cases' pediatric clinics and frequency matched to cases on age. Mothers of cases and controls completed a telephone interview that included questions regarding vitamin supplement use in the periconceptional period and after knowledge of pregnancy. RESULTS: A decreased risk of leukemia was observed with vitamin supplementation in the periconceptional period (odds ratio [OR] = 0.63; 95% confidence interval [95% CI], 0.39-1.00). When stratified by leukemia type, the reduced risk was observed for ALL (OR = 0.51; 95% CI, 0.30-0.89), but not for AML (OR = 0.92; 95% CI, 0.48-1.76). Compared with vitamin use in the periconceptional period, use only after knowledge of pregnancy was associated with an increased risk of leukemia (OR = 1.61; 95% CI, 1.00-2.58). This was observed for both ALL and AML. CONCLUSIONS: These data added to a growing body of evidence that suggests that periconceptional vitamin use may be protective in the development of certain childhood cancers.

Adolescent↗
PubMed2005

Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia.

This open-label, dose-escalation study evaluated the safety and efficacy of single-agent gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted chemotherapeutic agent, for pediatric patients with multiple relapsed or primary refractory acute myeloid leukemia (AML). Twenty-nine children 1 to 16 years of age (relapsed disease, 19; refractory disease, 10) received gemtuzumab ozogamicin ranging from 6 to 9 mg/m2 per dose for 2 doses (separated by 2 weeks) infused over 2 hours. All patients had anticipated myelosuppression. Other toxicities included grade 3/4 hyperbilirubinemia (7%) and elevated hepatic transaminase levels (21%); the incidence of grade 3/4 mucositis (3%) or sepsis (24%) was relatively low. One patient treated at 9 mg/m2 developed veno-occlusive disease (VOD) of the liver and defined the dose-limiting toxicity. Thirteen patients underwent hematopoietic stem-cell transplantation less than 3.5 months after the last dose of gemtuzumab ozogamicin; 6 (40%) developed VOD. Eight of 29 (28%) patients achieved overall remission. Remissions were comparable in patients with refractory (30%) and relapsed (26%) disease. Mean multidrug resistance-protein-mediated drug efflux was significantly lower in the leukemic blasts of patients achieving remission (P < .005). Gemtuzumab ozogamicin was relatively well tolerated at 6 mg/m2 for 2 doses and was equally effective in patients with refractory and relapsed disease. Further studies in combination with standard induction therapy for childhood AML are warranted.

Acute Disease↗
PubMed2005

Mortality in overweight and underweight children with acute myeloid leukemia.

CONTEXT: Current treatment for acute myeloid leukemia (AML) in children cures about half the patients. Of the other half, most succumb to leukemia, but 5% to 15% die of treatment-related complications. Overweight children with AML seem to experience excess life-threatening and fatal toxicity. Nothing is known about how weight affects outcomes in pediatric AML. OBJECTIVE: To compare survival rates in children with AML who at diagnosis are underweight (body mass index [BMI] < or =10th percentile), overweight (BMI > or =95th percentile), or middleweight (BMI = 11th-94th percentiles). DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of BMI and survival in 768 children and young adults aged 1 to 20 years enrolled in Children's Cancer Group-2961, an international cooperative group phase 3 trial for previously untreated AML conducted August 30, 1996, through December 4, 2002. Data were collected through January 9, 2004, with a median follow-up of 31 months (range, 0-78 months). MAIN OUTCOME MEASURES: Hazard ratios (HRs) for survival and treatment-related mortality. RESULTS: Eighty-four of 768 patients (10.9%) were underweight and 114 (14.8%) were overweight. After adjustment for potentially confounding variables of age, race, leukocyte count, cytogenetics, and bone marrow transplantation, compared with middleweight patients, underweight patients were less likely to survive (HR, 1.85; 95% confidence interval [CI], 1.19-2.87; P = .006) and more likely to experience treatment-related mortality (HR, 2.66; 95% CI, 1.38-5.11; P = .003). Similarly, overweight patients were less likely to survive (HR, 1.88; 95% CI, 1.25-2.83; P = .002) and more likely to have treatment-related mortality (HR, 3.49; 95% CI, 1.99-6.10; P<.001) than middleweight patients. Infections incurred during the first 2 courses of chemotherapy caused most treatment-related deaths. CONCLUSION: Treatment-related complications significantly reduce survival in overweight and underweight children with AML.

Adolescent↗
PubMed2004

Pilot study of idarubicin-based intensive-timing induction therapy for children with previously untreated acute myeloid leukemia: Children's Cancer Group Study 2941.

PURPOSE: Randomized comparisons of idarubicin (IDA) with daunorubicin (DNR) show that in adults with acute myeloid leukemia (AML), IDA achieves higher remission rates and longer remission durations. In Children's Cancer Group Pilot Study CCG-2941, we assessed toxicity and feasibility of substituting 4 mg of DNR with 1 mg of IDA in intensive-timing daunorubicin-based induction therapy (DNR/DNR) used in CCG-2891. PATIENTS AND METHODS: On days 1 through 3 and 10 through 14, patients received two courses of dexamethasone, cytarabine, 6-thioguanine, etoposide, and IDA (IDA/IDA). After enrollment of 65 patients, toxicity prompted replacement of IDA with DNR (IDA/DNR) on days 10 through 14 for the remaining 28 patients. Outcomes were compared with those of intensive timing in CCG-2891. RESULTS: Treatment-related mortality after two courses of induction was not significantly different among the three regimens: 14% with IDA/IDA, 7% with IDA/DNR, and 9% with DNR/DNR. In course 1 of CCG-2941 IDA/IDA, 11% of patients withdrew compared with 1.5% in CCG-2891 (P <.001) and 5% in CCG-2941 IDA/DNR (P = not significant). Compared with CCG-2891 DNR/DRN, CCG-2941 IDA/IDA increased days in hospital (43 v 36 days; P =.007), mean duration of course 1 by a week (P =.002), and risk of grade 3 or 4 hyperbilirubinemia (18% v 5%; P =.02). Toxicity of IDA/DNR was not different from that of DNR/DNR in CCG-2891. The mean day 7 marrow blast percentage was 11.4% in CCG-2941 versus 21.1% in CCG-2891 (P =.004). Remission induction, survival, and event-free survival rates were not significantly different from those of CCG-2891. CONCLUSION: In CCG-2941, excessive toxicity and withdrawals outweighed potential benefits of early response with IDA.

Acute Disease↗
PubMed2003

Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891.

PURPOSE: To determine the outcome of children with Down syndrome (DS) and acute myeloid leukemia (AML) receiving standard timing chemotherapy without bone marrow transplantation (BMT), with determination of prognostic factors. PATIENTS AND METHODS: Children with DS and newly diagnosed AML or myelodysplasia were prospectively enrolled on Children's Cancer Group study 2891 (N = 161) and treated uniformly with four standard timing induction courses of dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER) followed by intensively timed high-dose cytarabine. RESULTS: Children with DS were significantly younger at diagnosis than those without (median age, 1.8 v 7.5 years, respectively; P <.001), with more megakaryocytic leukemia (70% v 6%; P <.001). Higher complete remission rates (91%) were achieved in children with DS than among those without DS (75%; P <.001). Equivalent grade 3 to 4 toxicity (29% v 30%; P =.84) was seen, though children with DS had greater pulmonary toxicity (P <.01) during induction and mucositis during intensification (P =.12). Children with DS had significantly better 8-year event-free survival (EFS; 77% v 21% standard and 40% intensive induction; P <.0001). Multivariate analysis in children with DS revealed that only age at diagnosis of 2 years or older was a risk factor for greater relapse risk (odds ratio, 4.9; P =.006) and worse survival. Children between ages 0 to 2 years (n = 94) had a 6-year EFS of 86%; those from 2 to 4 years (n = 58), 70%; and those older than 4 years (n = 9), 28%. Remission failures were the primary reason for worse 6-year EFSs (1% in those 0 to 2 years v 14% if >2 years; P =.002). CONCLUSION: Outcome for children with DS and AML is excellent with standard induction therapy, but declines with increasing age.

Acute Disease↗
PubMed2003

Telomerase activity is prognostic in pediatric patients with acute myeloid leukemia: comparison with adult acute myeloid leukemia.

BACKGROUND: Significantly elevated telomerase activity (TA) has been found in samples from patients with almost all malignant hematologic diseases. The impact of elevated TA on the course of pediatric patients with acute myeloid leukemia (P-AML) is unknown. METHODS: Using a modified polymerase chain reaction-based, telomeric repeat-amplification protocol assay, the authors measured TA in bone marrow samples from 40 patients with P-AML and, for comparison, in 65 adult patients with AML (A-AML), excluding patients with French-American-British M3 disease. The results were correlated with patient characteristics and survival. RESULTS: TA in patients with P-AML was significantly lower compared with TA in patients with A-AML (P = 0.005). Patients who had P-AML with low TA had a projected 5-year survival rate of 88%, whereas patients who had P-AML with high TA had a projected 5-year survival rate of 43% (P = 0.009). Conversely, patients who had A-AML with very high TA (upper quartile) had significantly longer survival compared with patients who had A-AML with lower TA (P = 0.03). There was no correlation between complete remission rate or disease free survival and TA in P-AML or A-AML. In the A-AML group, when patients were separated by cytogenetic findings (poor prognosis vs. others), it was found that TA was significantly lower in patients with a poor prognosis, but the prognostic value of TA was not independent of cytogenetic status. CONCLUSIONS: The current results suggest, that for patients with P-AML, bone marrow TA is a highly significant prognostic factor.

Acute Disease↗
PubMed2003

Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia.

Acute myelocytic leukemia (AML) is a heterogeneous disease that accounts for nearly a quarter of the pediatric leukemias. Despite near myeloablative therapy, half of patients relapse and die from their disease. Identification of patients at high risk of relapse early in the course of treatment may allow for treatment modification to improve their outcome. In addition, patients at lower risk of relapse may benefit from treatment de-escalation, sparing them adverse side effects. This review describes prognostic factors that play a major role in the outcome of children with AML and their potential use for treatment stratification in pediatric AML trials.

Acute Disease↗
PubMed2003

A theoretically optimized method for cord blood stem cell cryopreservation.

The objective of this study was to develop an optimal cryopreservation method for human umbilical cord blood hematopoietic progenitor cells as evidenced by improved retention of in vivo engraftment ability and multilineage differentiation. An extended understanding of the osmometric/permeability characteristics of cord blood stem cells was accomplished by measuring permeability of the cryoprotectant dimethyl sulfoxide (DMSO) at below-ambient temperatures (10 degrees and 3 degrees C). These data were combined with previously published osmotic and permeability data and the water-NaCl-DMSO phase diagram in conjunction with a mathematical model to determine an optimal initial DMSO concentration, cooling rate, and liquid nitrogen plunging temperature. Cells cryopreserved with the theoretically optimized procedure were then compared with cells frozen using standard methods for the ability to engraft in irradiated NOD/SCID mice. The optimal procedure was determined to include a 0.7 molal (approximately 5%) DMSO concentration at a cooling rate of 4 degrees C/min, and a plunging temperature of -44 degrees C. The optimized protocol resulted in significantly higher engraftment of human CD45(+) cells (17.2 +/- 1.6% vs. 8.4 +/- 1.6%), CD19(+) B lymphocytes (11.3 +/- 1.2% vs. 5.8 +/- 1.2%), and CD34(+) cells (1.9 +/- 0.09% vs. 0.6 +/- 0.09%) compared to cells frozen using a standard method. Engraftment of CD33(+) cells was not significantly different (4.0 +/- 0.3 vs. 3.2 +/- 0.6, respectively). This study demonstrated that the use of a theoretically determined optimal cryopreservation method is superior to standard methods for maintaining UCB PCBs with multilineage repopulation potential in NOD/SCID mice.

Antigens, CD↗
PubMed2003

Update in childhood acute myeloid leukemia: recent developments in the molecular basis of disease and novel therapies.

Childhood acute myeloid leukemia is a heterogeneous group of disorders that remains challenging to treat. There are multiple common genetic alterations in childhood acute myeloid leukemia. These include chromosomal translocations affecting RUNX1-CBFbeta, RARalpha, and MLL. There are known activating mutations in the genes for the receptor tyrosine kinases FLT3, KIT, and FMS. As these abnormalities are better understood, they are providing important insights into the pathogenesis of disease as well as information about prognosis. Although intensive chemotherapy remains the mainstay of acute myeloid leukemia therapy, long-term cure rates with chemotherapy alone remain approximately 50%, creating an urgent need for better therapies. Multiple avenues are being explored in the design of new treatments for pediatric acute myeloid leukemia. Targeted therapies include targeted antibody therapy; inhibitors of FLT3, KIT, and farnesyltransferase; diphtheria toxin conjugated to the granulocyte-macrophage colony-stimulating factor; and antisense oligonucleotides. Another area of interest is chromatin remodeling and differentiation therapy, including agents such as all- retinoic acid, arsenic trioxide, and inhibitors of DNA methylation and histone deacetylation. There are also ongoing trials of antiangiogenesis agents. Another avenue for novel therapies is immunotherapy with agents such as interleukin-2 and tumor vaccines. This article reviews recent advances in understanding of the molecular basis for childhood acute myeloid leukemia and the design of novel therapies for the treatment of childhood acute myeloid leukemia.

Acute Disease↗