Publications by authors named "Richard A Drachtman"

22 Publications

  • Page 1 of 1

Definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma: A report from the International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH).

Pediatr Blood Cancer 2020 04 22;67(4):e28142. Epub 2019 Dec 22.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: The International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH) seeks to provide a universally acceptable definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma.

Procedure: A comprehensive literature search was performed using PubMed and Google Scholar with the search terms "Hodgkin lymphoma," "osseous lesions," "bony involvement," and "pediatric." Publications reviewed included case reports, retrospective analyses, and literature reviews. Each was evaluated for study design, number of participants, median age and age range at diagnosis, percentage of pediatric patients, criteria of interest definition, diagnostic tools, study objectives, and level of evidence. The final definition was based on the available data and consensus of the SEARCH working group.

Results: Twenty-five papers specifically addressing cortical bone involvement in Hodgkin lymphoma met the inclusion criteria. Eighteen papers were case reports with literature reviews; the remainder were observational cohort studies. Of these, 14 included pediatric patients (aged 0-21 years). The criteria for cortical bone involvement were not clearly defined in any paper, often varied within a study, and were inconsistent between publications.

Conclusions: The SEARCH group for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) proposes the following criteria as defining cortical bone involvement: any cortical bone biopsy-proven lesion; a positive bony window lesion on computer tomography (CT), with an FDG-PET positive correlate in a patient with biopsy-proven Hodgkin lymphoma, if there is no other typical skeletal pathology; auspicious skeletal lesions on FDG-PET or magnetic resonance imaging should be confirmed by CT or Tc-99m scan to distinguish cortical lesions from bone marrow involvement. Nodal masses that extend into bone with bony destruction are considered extranodal extension or "E" lesions and do not represent metastatic or stage IV disease.
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http://dx.doi.org/10.1002/pbc.28142DOI Listing
April 2020

An Isolated Testicular Relapse of Burkitt's Lymphoma.

Glob Pediatr Health 2019 30;6:2333794X19872427. Epub 2019 Aug 30.

Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

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http://dx.doi.org/10.1177/2333794X19872427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719464PMC
August 2019

Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1-2 trial.

Lancet Oncol 2018 09 16;19(9):1229-1238. Epub 2018 Aug 16.

Department of Pediatric Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA.

Background: Patients with primary refractory Hodgkin's lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkin's lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkin's lymphoma or early relapse.

Methods: In this Children's Oncology Group, multicentre, single-arm, phase 1-2 trial, we recruited patients with Hodgkin's lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662.

Findings: Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m. 24 (57%) of 42 evaluable patients (95% CI 41-72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51-80]). The most common grade 3-4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths.

Interpretation: Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials.

Funding: National Institutes of Health and the St. Baldrick's Foundation.
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http://dx.doi.org/10.1016/S1470-2045(18)30426-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487196PMC
September 2018

Significance of pleural effusion at diagnosis in pediatric Hodgkin lymphoma: a report from Children's Oncology Group protocol AHOD0031.

Pediatr Radiol 2018 11 16;48(12):1736-1744. Epub 2018 Jul 16.

Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY, USA.

Background: Pleural effusion at presentation in Hodgkin lymphoma has been associated with inferior outcome but has not been systematically evaluated.

Objective: To determine whether pleural effusion at presentation in children with Hodgkin lymphoma is a primary indicator of poor prognosis or secondary to associated factors.

Materials And Methods: Children's Oncology Group (COG) AHOD0031, a randomized, response-based, centrally reviewed protocol, enrolled 1,712 eligible patients <22 years of age with initial presentation of intermediate risk, biopsy-proven Hodgkin lymphoma; 1,423 had available imaging for retrospective review. We coded effusions as fluid-only or with associated pleural nodule or adjacent lung or bone involvement and correlated this with disease stage, tumor response, large mediastinal adenopathy, and mass effect on the superior vena cava (SVC) and left innominate vein. We recorded change in size and character of effusions post-chemotherapy.

Results: Pleural effusions were present in 217, with 204 having fluid-only and 13 having associated solid components. Patients with effusions were more likely to have large mediastinal adenopathy (P<0.0001), be slow early responders (P<0.0001) and have higher relapse rate (P<0.0001). Vascular compression was not significantly correlated with pleural effusion. Of 121 patients with adequate [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT imaging, no FDG PET avidity was seen in any pleural effusion but was present in solid components. The side of the pleural effusion in those with moderate or large effusions was highly associated with the side of large mediastinal adenopathy (P<0.0001). Statistical analysis indicates that pleural effusion is an independent risk factor for poorer response and relapse.

Conclusion: Pleural effusion in Hodgkin lymphoma is an important independent poor prognostic indicator for response and relapse.
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http://dx.doi.org/10.1007/s00247-018-4197-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208959PMC
November 2018

Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement.

Pediatr Blood Cancer 2017 Jul 18;64(7). Epub 2017 Jan 18.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence-based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.
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http://dx.doi.org/10.1002/pbc.26421DOI Listing
July 2017

A Stroke Mimic: Methotrexate-induced Neurotoxicity in the Emergency Department.

J Emerg Med 2017 Apr 13;52(4):559-561. Epub 2017 Jan 13.

Department of Pediatrics, Children's Specialized Hospital, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey; Department of Pediatric Emergency Medicine, Bristol-Myers Squibb Children's Hospital, New Brunswick, New Jersey.

Background: Acute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia. The treatment of ALL involves multimodality therapy, and methotrexate (MTX) remains a mainstay of treatment. A complication of MTX therapy includes acute, subacute, and chronic neurotoxocity. Signs and symptoms may range from headaches, dizziness, and mood disorders to seizures and stroke-like symptoms.

Case Report: An 18-year-old woman with a history of ALL presented to the emergency department with acute onset of right-sided facial paralysis, right upper extremity flaccid paralysis, and right lower extremity weakness after receiving MTX therapy 3 days earlier. Diagnostic studies were unremarkable and the patient was treated with oral dextromethorphan for presumed MTX-induced neurotoxicity. The patient's symptoms began to improve within hours and she was discharged home within 48 hours with no neurologic deficits. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of this complication of MTX therapy given the sensitivity in regards to time with respect to cerebral vascular accidents. An awareness of this complication in the setting of the appropriate history and physical examination can lead to an accurate diagnosis and intervention and the avoidance of administering thrombolytics.
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http://dx.doi.org/10.1016/j.jemermed.2016.11.016DOI Listing
April 2017

Long-term outcomes for children with acute lymphoblastic leukemia (ALL) treated on The Cancer Institute of New Jersey ALL trial (CINJALL).

Leuk Lymphoma 2016 10 16;57(10):2275-80. Epub 2016 Feb 16.

b Department of Pediatrics , Albert Einstein College of Medicine , Bronx , NY , USA ;

The Cancer Institute of New Jersey Acute Lymphoblastic Leukemia trial (CINJALL) employed a post-induction regimen centered on intensive oral antimetabolite therapy, with no intravenous methotrexate (MTX). Fifty-eight patients enrolled between 2001 and 2005. A high rate of induction death (n = 3) or induction failure (n = 1) was observed. Among those who entered remission, five-year DFS is 80 ± 8.9% for those at standard risk of relapse and 76 ± 7.8% for high-risk patients, with median follow up over six years. The estimated cumulative incidence of testicular relapse among boys was elevated (13 ± 7.2%) compared to the rate observed on contemporary protocols. We conclude that post-induction therapy using intensive oral antimetabolites for children with acute lymphoblastic leukemia (ALL) can result in overall long-term DFS comparable to that observed among children treated with regimens including intravenous MTX. However, an increased risk of late extramedullary relapse among boys was observed, supporting the prevailing opinion that high-dose MTX improves outcome for children with ALL.
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http://dx.doi.org/10.3109/10428194.2016.1141406DOI Listing
October 2016

Asparaginase Erwinia chrysanthemi as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia who have developed hypersensitivity to E. coli-derived asparaginase.

Expert Rev Hematol 2016 Mar 19;9(3):227-34. Epub 2016 Feb 19.

b Pediatic Hematology/Oncology , Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School , New Brunswick , NJ , USA.

Asparaginase has been a mainstay of therapy in the treatment of acute lymphoblastic leukemia since the 1970s. There are two major preparations available and FDA approved in the United States today, one derived from Escherichia coli and the other from Erwinia chrysanthemi. Erwinia asparaginase is antigenically distinct from and has a considerably shorter biological half-life than E coli asparaginase. Erwinia asparaginase has been used in cases of hypersensitivity to E. coli-derived asparaginases, which has been reported in up to 30% of patients. While PEG asparaginase is increasingly used in front-line therapy for ALL, hypersensitivity still occurs with this preparation, and a change to a non-cross-reactive preparation may be necessary.
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http://dx.doi.org/10.1586/17474086.2016.1142370DOI Listing
March 2016

Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli-Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia.

Pediatr Blood Cancer 2016 Feb 16;63(2):228-33. Epub 2015 Sep 16.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.

Background: Erwinia asparaginase is antigenically distinct from E.coli-derived asparaginase and may be used after E.coli-derived asparaginase hypersensitivity. In a single-arm, multicenter study, we evaluated nadir serum asparaginase activity (NSAA) and toxicity with intravenously administered asparaginase Erwinia chrysanthemi (IV-Erwinia) in children and adolescents with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma with hypersensitivity to E.coli-derived asparaginase.

Patients And Methods: Between 2012 and 2013, 30 patients (age 1-17 years) enrolled from 10 centers. Patients received IV-Erwinia, 25,000 IU/m(2)/dose on Monday/Wednesday/Friday, for 2 consecutive-weeks (6 doses = 1 cycle) for each dose of pegaspargase remaining in the original treatment plan. The primary objective was to determine the proportion of patients achieving NSAA ≥ 0.1 IU/ml 48 hr after dose 5 in Cycle 1. Secondary objectives included determining the proportion achieving NSAA ≥ 0.1 IU/ml 72 hr after Cycle 1 dose 6, and the frequency of asparaginase-related toxicities.

Results: Twenty-six patients completed Cycle 1; 24 were evaluable for NSAA assessment. In Cycle 1, NSAA ≥ 0.10 IU/ml was detected in 83% of patients (95% confidence interval [CI], 63-95%) 48 hr post-dose 5 (mean ± SD; 0.32 IU/ml ± 0.23), and in 43% (95% CI, 22-66%) 72 hr post-dose 6 (mean ± SD; 0.089 IU/ml ± 0.072). For all 30 patients over all cycles, hypersensitivity/infusional reactions with IV-Erwinia occurred in 37%, pancreatitis 7%, and thrombosis 3%.

Conclusions: IV-Erwinia administration in children/adolescents appeared feasible and tolerable. A therapeutically-effective NSAA (≥ 0.10 IU/ml) was achieved in most patients at 48 hr, but in fewer than half 72 hr post-dosing, suggesting that monitoring NSAA levels and/or every 48 hr dosing may be indicated.
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http://dx.doi.org/10.1002/pbc.25757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715717PMC
February 2016

A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study.

Br J Haematol 2015 Jul 1;170(1):118-22. Epub 2015 Apr 1.

Department of Pediatrics, MD Anderson Cancer Center, Houston, TX, USA.

A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59-83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61-95%; p = 0.32). Although not statistically different, results suggest IVB may be a promising combination.
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http://dx.doi.org/10.1111/bjh.13388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478135PMC
July 2015

Stratification of treatment intensity in relapsed pediatric Hodgkin lymphoma.

Pediatr Blood Cancer 2014 Apr 8;61(4):579-86. Epub 2013 Nov 8.

Division of Pediatric Hematology and Oncology, Midwest Children's Cancer Center, Milwaukee, Wisconsin.

Risk-adapted, response-based therapies for pediatric Hodgkin lymphoma have resulted in 5-year survival exceeding 90%. Although high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) are considered standard for most patients with relapsed or refractory Hodgkin lymphoma, a subset of children with low risk relapse do not require AHSCT for cure. Currently there are no widely accepted criteria defining who should receive standard dose chemotherapy and/or radiotherapy, nor is there a standardized treatment regimen. We propose a risk-stratified, response-based algorithm for children with relapsed or refractory Hodgkin lymphoma that is based on a critical appraisal of published outcomes and prognostic factors.
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http://dx.doi.org/10.1002/pbc.24851DOI Listing
April 2014

Early [¹⁸F]fluorodeoxyglucose positron emission tomography-based response evaluation after treatment with gemcitabine and vinorelbine for refractory Hodgkin disease: a children's oncology group report.

Pediatr Hematol Oncol 2010 Nov;27(8):650-7

Children's Oncology Group, Arcadia, California, USA.

The International Harmonization Project defined complete response (CR) after treatment for Hodgkin disease (HD) by absence of fluorodeoxyglucose avidity, regardless of the size of residual masses. Residual avidity after initial treatment is known to predict inferior survival. In the setting of retrieval therapy, early positron emission tomography (PET) scans may improve assessment of treatment efficacy. Retrospective analysis after 2 cycles of gemcitabine and vinorelbine for refractory HD revealed 6 CR among 13 patients by PET and 1 CR in 13 by computed tomography (CT). No relationship between PET response and event-free or overall survival could be discerned, presumably because of the heterogeneity of subsequent therapies.
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http://dx.doi.org/10.3109/08880018.2010.504250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083978PMC
November 2010

Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin's disease: a children's oncology group report.

J Clin Oncol 2009 Mar 17;27(9):1456-61. Epub 2009 Feb 17.

Children's Oncology Group, Arcadia, CA, USA.

Purpose: The Children's Oncology Group conducted this phase II study to assess the efficacy and toxicity of gemcitabine and vinorelbine (GV) in pediatric patients with heavily pretreated relapsed/refractory Hodgkin's disease. Both agents have significant single-agent response rates in this setting.

Methods: GV was given on days 1 and 8 of each 21-day treatment cycle: vinorelbine 25 mg/m(2)/dose administered via intravenous (IV) push before gemcitabine 1,000 mg/m(2)/dose IV over 100 minutes. Any patients who demonstrated a measurable response (complete response [CR], very good partial response [VGPR], or partial response [PR]) were considered to have experienced a response to GV. Response was evaluated after every two cycles. A two-stage minimax rule was used to test the null hypothesis that the response rate is
Results: Thirty eligible patients with a median age of 17.7 years (range, 10.7 to 29.4 years) were enrolled. All patients had received at least two prior chemotherapy regimens, and 17 patients had undergone prior autologous stem-cell transplantation. Hematologic toxicity was predominant in all treatment cycles. Nonhematologic grade 3 to 4 toxicity, including elevated hepatic enzymes and hyperbilirubinemia, was less common. Pericardial and pleural effusions developed in one patient after cycles 4 and 5 of GV, consistent with gemcitabine-induced radiation recall. There were no toxic deaths. Measurable responses were seen in 19 (76%) of 25 assessable patients (95% exact binomial CI, 55% to 91%), including six CRs, 11 VGPRs, and two PRs.

Conclusion: GV is an effective and well-tolerated reinduction regimen for children with relapsed or refractory Hodgkin's disease.
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http://dx.doi.org/10.1200/JCO.2008.20.3778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668553PMC
March 2009

Cord Compression due to Extramedullary Hematopoiesis in an Adolescent with Known Beta Thalassemia Major.

J Radiol Case Rep 2009 1;3(1):17-22. Epub 2009 Jan 1.

Department of Radiology, UMDNJ - Robert Wood Johnson Medical School, New Brunswick, NJ.

We describe a 16 year-old male with β thalassemia major and gait disturbances that had not been given blood transfusions due to a severe childhood transfusion reaction. Thoracic spine MRI demonstrated hematopoietic marrow throughout the spine and epidural masses causing cord compression consistent with extramedullary hematopoiesis (EMH). After treatment with steroids, radiotherapy and monitored blood transfusions, the patient demonstrated significant improvement of his paraspinal lesions and near complete resolution of his neurological symptoms. While EMH causing cord compression in adolescents is rare in the current era of bone marrow transplantation or chronic transfusions, it should be considered when thalassemia major patients present with neurological deficits. The well defined imaging features of EMH can play a central role in its diagnosis and management, especially because surgical and / or radiotherapeutic intervention are often considered in cases of failed medical treatment.
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http://dx.doi.org/10.3941/jrcr.v3i1.83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303263PMC
September 2012

Deep venous thrombosis in adolescents due to anatomic causes.

Pediatr Blood Cancer 2008 Jul;51(1):125-8

Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.

Aberrant or anomalous anatomy is an under appreciated risk for venous thromboembolic events (VTE). Five adolescents with VTE and predisposing anatomic abnormalities are presented. In three cases, knowledge of the underlying anatomic abnormalities resulted in changes in treatment and management. In two other cases, failure to consider or correct the underlying defect resulted in recurrent thrombosis or post-thrombotic complications. Few case reports are found in the pediatric literature, but a MEDLINE search across all age groups suggests these anomalies are frequently found when appropriate radiological imaging is obtained.
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http://dx.doi.org/10.1002/pbc.21486DOI Listing
July 2008

Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia.

Cancer Chemother Pharmacol 2008 Jun 2;62(1):65-75. Epub 2007 Sep 2.

Pediatric Hematology/Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School/UMDNJ, 195 Little Albany Street, New Brunswick, NJ 08901, USA.

Purpose: Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients' blasts. This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL.

Experimental Design: Patients at high risk of relapse were non-randomly assigned to therapy including oral aminopterin 4 mg/m(2), in two doses 12 h apart, in place of methotrexate 100 mg/m(2) in four divided doses.

Results: Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase.

Conclusions: Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of aminopterin and methotrexate in therapy for patients with ALL.
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http://dx.doi.org/10.1007/s00280-007-0576-7DOI Listing
June 2008

Phase II trial of oral aminopterin for adults and children with refractory acute leukemia.

Clin Cancer Res 2005 Nov;11(22):8089-96

Department of Pediatric Oncology, The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, USA.

Purpose: To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro.

Experimental Design: Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro.

Results: Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed.

Conclusions: Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-0355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906753PMC
November 2005

Low molecular weight heparin in the treatment of venous and arterial thromboses in the premature infant.

Pediatrics 2004 Sep;114(3):703-7

Division of Pediatric Hematology, Bristol Myers Squibb Children's Hospital at Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, USA.

Objective: Thrombosis in the preterm newborn is a growing problem, a result of improved survival of the smallest and sickest infants. Treatment with low molecular weight heparin (LMWH) has potential advantages, including predictable pharmacokinetics, subcutaneous administration, and minimal monitoring. However, studies with LMWH in term infants demonstrate the need for higher doses as compared with older children and adults. Physiologic differences suggest the need for gestational age-appropriate treatment strategies. Because of the relatively small numbers of infants affected each year, large-scale prospective studies have not been feasible. With the goal of establishing treatment guidelines within our own institution, we reviewed retrospectively our experience with LMWH for the treatment of thrombosis in the preterm infant.

Methods: Medical and pharmacy records of the intensive care nursery were used to identify preterm infants with venous and arterial thrombosis. Chart documentation, orders, pharmacy records, and radiologic studies were used to develop a retrospective database to assess efficacy and safety of the treatment. Main outcome measures were the dose of LMWH required for therapeutic levels, anti-factor Xa levels achieved, bleeding complications, resolution of thrombosis, additional thromboembolic events, and death from all causes.

Results: Ten preterm infants (mean gestational age: 26 weeks) who were treated with LMWH were identified. Mean patient weight at diagnosis of thrombosis was 1215 g (range: 565-1950 g). All 10 patients had either a current or recent history of a central venous or arterial catheter. Mean starting dose of enoxaparin was 1.25 mg/kg per 12 hours (range: 0.8-2 mg/kg). Therapeutic anti-factor Xa levels were achieved in only 5 patients. Mean time to therapeutic range was 33 days (range: 14-63 days). The mean dose of enoxaparin required to achieve therapeutic levels was 2.27 mg/kg per 12 hours (dose range: 2.0-3.5 mg/kg per 12 hours). Clot resolution was observed in all but 2 patients, both of whom died of complications of their thromboembolic events. No bleeding events that necessitated a change in treatment strategy occurred.

Conclusions: Higher doses of LMWH are required in the preterm infant as compared with the healthy term neonate. Once therapeutic levels are achieved, continued regular monitoring and dose adjustments are required to maintain anticoagulation in therapeutic range.
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http://dx.doi.org/10.1542/peds.2004-0178DOI Listing
September 2004

Thrombosis and gangrene in a patient with sickle cell disease and dactylitis.

J Pediatr 2003 Apr;142(4):449

Division of Pediatric Hematology and Oncology, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.

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http://dx.doi.org/10.1067/mpd.2003.102DOI Listing
April 2003

Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity.

Pediatr Hematol Oncol 2002 Jul-Aug;19(5):319-27

Cancer Institute of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08816, USA.

Methotrexate-induced neurotoxicity (MTX-Ntox) is a frequent complication of methotrexate (MTX) therapy for patients with both malignant and inflammatory diseases. MTX-Ntox can occur after intrathecal MTX or after low-, intermediate-, or high-dose systemic administration. Symptoms can present in the acute, subacute, or late setting form, and can range from affective disorders, malaise, and headaches, to somnolence, focal neurologic deficits, and seizures. While the pathogenesis of MTX-Ntox is likely multifactorial, one potential biochemical pathway leading from MTX to neurotoxicity involves the folate dependent remethylation of homocysteine (Hcy). MTX therapy is known to cause elevations of both plasma and CSF Hcy. Hcy is directly toxic to vascular endothelium and it and its metabolites are excitatory agonists of the N-methyl-D-aspartate (NMDA) receptor. Competitive or noncompetitive antagonists might afford protection from or reversal of MTX-Ntox. Using high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, the authors measured CSF Hcy in sequential patients with severe subacute MTX-Ntox. CSF Hcy was higher in these patients (n = 9, median = 0.93 microM) than in asymptomatic patients (n = 11, median 0.2 microM, p < .01). Five patients with severe subacute MTX-Ntox (most with dysarthria and/or hemiplegia) were treated with 1-2 mg/kg oral dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-1-aspartate (NMDA) receptor. All five had resolution of symptoms. These data provide additional clinical support for elevated CSF Hcy in the induction of MTX-Ntox through activation of the NMDA-receptor. These data provide support for a placebo-controlled clinical trial to examine the ability of DM to prevent or alleviate MTX-Ntox.
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http://dx.doi.org/10.1080/08880010290057336DOI Listing
December 2002