Publications by authors named "Monika L Metzger"

90 Publications

Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies.

Cancer 2021 Feb 17. Epub 2021 Feb 17.

Children's Hospital Los Angeles, Los Angeles, California.

Background: A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies.

Methods: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m /d) in combination with clofarabine (40 mg/m ), etoposide (100 mg/m ), and dexamethasone (8 mg/m ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5.

Results: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m /d, 6 were treated at the dose level of 40 mg/m /d, and 4 were treated at the dose level of 60 mg/m /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years.

Conclusions: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509).

Lay Summary: Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.
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http://dx.doi.org/10.1002/cncr.33465DOI Listing
February 2021

Catalyzing Childhood Cancer Care in Peru After One Year of the Global Initiative for Childhood Cancer.

JCO Glob Oncol 2021 Feb;7:187-189

Unit of Noncommunicable Diseases, Department of Noncommunicable Diseases and Mental Health, Pan American Health Organization, Washington, DC.

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http://dx.doi.org/10.1200/GO.20.00601DOI Listing
February 2021

Prognostic factors affecting survival in children and adolescents with HIV and Hodgkin lymphoma in South Africa.

Leuk Lymphoma 2020 Dec 7:1-14. Epub 2020 Dec 7.

St Jude Children's Research Hospital, University of Tennessee Health Sciences Center, Memphis, TN, USA.

South African children with Hodgkin lymphoma (HL) and human immunodeficiency virus (HIV) have low 5-year overall survival (OS) rates. In this retrospective multicenter study, 271 South African pediatric patients with HL were studied to determine OS and prognostic factors in those with HIV and HL. Univariate risk factor analysis was performed to analyze prognostic factors. The 29 HIV-infected patients were younger ( = .021), more likely to present with wasting (0.0573), stunting (0.0332), and Stage IV disease ( = .000) than HIV-uninfected patients. The 5- and 10-year OS of HIV-infected patients of 49% and 45% 84% and 79%, respectively for HIV-uninfected patients ( = .0001) appeared to be associated with hypoalbuminemia (<20 g/dL) and CD4 percentage of <15%. Causes of death in the HIV-infected group included disease progression (6/14), infection (4/14), unknown (3/14), and second malignancy (1/14). HIV-infected pediatric patients with HL experience increased mortality due to post-therapy opportunistic and nosocomial infections.
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http://dx.doi.org/10.1080/10428194.2020.1852472DOI Listing
December 2020

Nodular lymphocyte predominant Hodgkin lymphoma: executive summary of the American radium society appropriate use criteria.

Leuk Lymphoma 2020 Dec 4:1-14. Epub 2020 Dec 4.

University of Rochester Medical Center, Rochester, NY, USA.

This guideline for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) by the American Radium Society was developed by a multidisciplinary expert panel of medical, pediatric, and radiation oncologists convened to formulate guidelines for evaluation and treatment. The guideline development was based on an in-depth literature review and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of the recommendations by the panel. Given the scarcity of compelling data for strong recommendations for a rare lymphoma that has been shown to be more indolent than classical Hodgkin lymphoma, in instances where evidence is not available or equivocal, expert opinion guided the recommendations. Four clinical variants exemplify common scenarios and represent the consensus recommendations for patients with nodular lymphocyte Hodgkin lymphoma. A summary of the available published literature is also presented.
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http://dx.doi.org/10.1080/10428194.2020.1852559DOI Listing
December 2020

Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia.

Blood 2021 Jan;137(3):364-373

Department of Pharmaceutical Sciences and.

There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.
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http://dx.doi.org/10.1182/blood.2020006164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819760PMC
January 2021

Expert consensus statements for Waldeyer's ring involvement in pediatric Hodgkin lymphoma: The staging, evaluation, and response criteria harmonization (SEARCH) for childhood, adolescent, and young adult Hodgkin lymphoma (CAYAHL) group.

Pediatr Blood Cancer 2020 09 16;67(9):e28361. Epub 2020 Jul 16.

Division of Haematology/Oncology, Department of Paediatrics, SickKids Hospital and University of Toronto, Toronto, Canada.

Waldeyer's ring (WR) involvement in pediatric Hodgkin lymphoma (HL) is extremely rare and criteria for determining involvement and response to treatment are unclear. The international Staging, Evaluation, and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) Group performed a systematic review of the literature in search of involvement or response criteria, or evidence to support specific criteria. Only 166 cases of HL with WR involvement were reported in the literature, 7 of which were pediatric. To date no standardized diagnostic or response assessment criteria are available. Given the paucity of evidence, using a modified Delphi survey technique, expert consensus statements were developed by the SEARCH group to allow for a more consistent definition of disease and response evaluation related to this rare site of involvement among pediatric oncologists. The available evidence and expert consensus statements are summarized.
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http://dx.doi.org/10.1002/pbc.28361DOI Listing
September 2020

Liver involvement in pediatric Hodgkin lymphoma: A systematic review by an international collaboration on Staging Evaluation and Response Criteria Harmonization (SEARCH) for Children, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL).

Pediatr Blood Cancer 2020 08 3;67(8):e28365. Epub 2020 Jun 3.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

Hepatic involvement in Hodgkin lymphoma (HL) is uncommon (∼5% of patients) but always implies stage IV disease. Accurate staging is mandatory for making the appropriate risk assignment and treatment decisions. The Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) international working group conducted a systematic literature review of liver involvement in HL patients with the aim to propose a universally acceptable definition for liver involvement in pediatric HL. Thirty-three articles describing 6985 pediatric and adult HL patients were reviewed, of which 539 (7.7%) mentioned liver involvement. The literature did not provide a uniform definition of hepatic involvement and we propose consensus criteria derived from the EuroNet and Children's Oncology Group protocols, where liver involvement is defined as any hepatic lesion on computed tomography scan that correlates with F-FDG uptake greater than background liver. A clear definition of liver lesions is necessary to consistently identify liver involvement and compare its impact on outcomes among protocols worldwide.
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http://dx.doi.org/10.1002/pbc.28365DOI Listing
August 2020

Whole-joint magnetic resonance imaging to assess osteonecrosis in pediatric patients with acute lymphoblastic lymphoma.

Pediatr Blood Cancer 2020 08 30;67(8):e28336. Epub 2020 May 30.

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

Background: Osteonecrosis is a debilitating complication in children and adolescents with acute lymphoblastic leukemia or acute lymphoblastic lymphoma (LLy). An objective screening test to identify patients at risk for symptomatic, extensive joint involvement will help manage osteonecrosis.

Methods: We performed a prospective, longitudinal pilot study with whole-joint magnetic resonance imaging (MRI) of shoulders, elbows, hips, knees, ankles, and hindfeet to evaluate the incidence and timing of osteonecrosis involving multiple joints in 15 patients with LLy aged 9-21 years at diagnosis.

Results: Osteonecrosis affecting ≥30% of the epiphysis occurred in eight of 15 patients, with a high prevalence in hips (12 of 26 examined [46%]) and knees (10 of 26 [38%]) post reinduction I and in shoulders (seven of 20 [35%]) post reinduction II. Most osteonecrotic hips and knees with ≥30% epiphyseal involvement became symptomatic and/or underwent surgery (100% and 82%, respectively). All eight patients with ≥30% epiphyseal involvement had multijoint involvement. Seven of these patients had hip or knee osteonecrosis by the end of remission induction, and only these patients developed osteonecrosis that became symptomatic and/or underwent surgery in their hips, knees, shoulders, ankles, and/or feet; all of these joints were associated with epiphyseal abnormalities on post reinduction I imaging.

Conclusions: MRI screening in adolescent patients with LLy revealed osteonecrosis in multiple joints. Initial screening with hip and knee MRI at the end of induction may identify susceptible patients who could benefit from referrals to subspecialties, more extensive follow-up imaging of other joints, and early medical and surgical interventions.
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http://dx.doi.org/10.1002/pbc.28336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391358PMC
August 2020

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

The association of mediastinal mass in the formation of thrombi in pediatric patients with non-lymphoblastic lymphomas.

Pediatr Blood Cancer 2020 02 17;67(2):e28057. Epub 2019 Nov 17.

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

Background: Children diagnosed with cancer are at a significantly higher risk of developing a thrombotic event (TE) compared with the general population. The rarity of these events makes it difficult to discern the specific risk factors; however, age, sex, presence of central venous lines, inherited thrombophilia, and mediastinal mass may play a role. The primary aim of this study is to identify prognostic characteristics of children diagnosed with non-lymphoblastic lymphomas associated with a greater risk of developing a TE early on in their disease, with an increased focus on mediastinal mass characteristics.

Methods: Retrospective chart review of pediatric patients diagnosed with non-lymphoblastic lymphoma between 2004 and 2014 at St. Jude Children's Research Hospital.

Results: TE occurred in 8.5% (n = 28/330) of individuals at a median of 21 days from the diagnosis of a non-lymphoblastic lymphoma, with 60% of TEs occurring within 30 days of diagnosis. Of the variables evaluated, only presence of a peripherally inserted central catheter (odds ratio [OR]: 3.14 [95% CI: 1.24-7.98; P = 0.02]) and degree of superior vena cava (SVC) compression of > 25% increased the odds of developing a TE (OR: 2.2 [95% CI: 1.01-4.93; P = 0.048]).

Conclusion: Pediatric patients with non-lymphoblastic lymphoma are at increased risk of developing TEs. In contrast to previous studies, the presence of a mediastinal mass alone was not associated with a higher risk of TE, but individuals with a mediastinal mass with 25% or greater degree of SVC compression were more likely to develop a TE. This finding highlights a high-risk group of children who may benefit from prophylactic anticoagulation.
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http://dx.doi.org/10.1002/pbc.28057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233458PMC
February 2020

Leydig Cell Function in Male Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study.

J Clin Oncol 2019 11 26;37(32):3018-3031. Epub 2019 Sep 26.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes.

Patients And Methods: In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality.

Results: The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes.

Conclusion: Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.
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http://dx.doi.org/10.1200/JCO.19.00738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839908PMC
November 2019

Brentuximab vedotin as consolidation after hematopoietic cell transplant for relapsed Hodgkin lymphoma in pediatric patients.

Pediatr Blood Cancer 2019 12 20;66(12):e27962. Epub 2019 Aug 20.

Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.

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http://dx.doi.org/10.1002/pbc.27962DOI Listing
December 2019

Late Health Outcomes After Contemporary Lymphome Malin de Burkitt Therapy for Mature B-Cell Non-Hodgkin Lymphoma: A Report From the Childhood Cancer Survivor Study.

J Clin Oncol 2019 10 8;37(28):2556-2570. Epub 2019 Jul 8.

St Jude Children's Research Hospital, Memphis, TN.

Purpose: The widely used, risk-based Lymphome Malin de Burkitt (LMB) chemotherapy regimen has improved survival rates for children with mature B-cell non-Hodgkin lymphoma (NHL); however, associated late effects remain understudied. We assessed late health outcomes after LMB treatment in the Childhood Cancer Survivor Study.

Patients And Methods: Multivariable regression models compared chronic health conditions, health status, and socioeconomic and neurocognitive outcomes between survivors of NHL treated with the LMB regimen (n = 126), survivors of NHL treated with non-LMB regimens (n = 444), and siblings (n = 1,029).

Results: LMB survivors were a median age of 10.2 years (range, 2.5 to 20.5 years) at diagnosis and 24.0 years (range, 10.3 to 35.3 years) at evaluation. Compared with siblings, LMB survivors were at increased risk for adverse health outcomes. However, survivors of NHL treated with LMB and non-LMB regimens did not differ with regard to risk of having any chronic health conditions, impaired health status, neurocognitive deficits, or poorer socioeconomic outcomes. Increased risk for the following specific neurologic conditions was observed in LMB survivors compared with non-LMB survivors: epilepsy (relative risk [RR], 15.2; 95% CI, 3.1 to 73.4); balance problems (RR, 8.9; 95% CI, 2.3 to 34.8); tremors (RR, 7.5; 95% CI, 1.9 to 29.9); weakness in legs (RR, 8.1; 95% CI, 2.5 to 26.4); severe headaches (RR, 3.2; 95% CI, 1.6 to 6.3); and prolonged arm, leg, or back pain (RR, 4.0; 95% CI, 2.2 to 7.1). The survivors from the group C LMB risk group (n = 50) were at the highest risk for these conditions; however, except for worse functional status (odds ratio, 2.7; 95% CI, 1.2 to 5.8), they were not at increased risk for other adverse health status or socioeconomic outcomes compared with non-LMB survivors.

Conclusion: Survivors treated with LMB and non-LMB regimens are largely comparable in late health outcomes except for excess neurotoxicity among LMB survivors. These data inform treatment efforts seeking to optimize disease control while minimizing toxicity.
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http://dx.doi.org/10.1200/JCO.19.00525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001792PMC
October 2019

Treatment patterns and disease outcomes for pediatric patients with refractory or recurrent Hodgkin lymphoma treated with curative-intent salvage radiotherapy.

Radiother Oncol 2019 05 5;134:89-95. Epub 2019 Feb 5.

Department of Radiation Oncology, St. Jude Children's Hospital, Memphis, United States.

Background And Purpose: The use of radiotherapy (RT) for pediatric patients with Hodgkin lymphoma (HL) experiencing disease progression or recurrence (15%) is controversial. We report treatment patterns and outcomes for pediatric patients with refractory/recurrent HL (rrHL) treated with curative-intent RT.

Materials And Methods: Forty-six patients with rrHL treated with salvage RT at our institution were identified. All received risk-adapted, response-based frontline therapy and were retrieved with cytoreductive regimens followed by RT to failure sites, with or without autologous hematopoietic cell transplantation (AHCT). Cumulative incidence (CIN) of local failure (LF) and survival were estimated after salvage RT and regression models determined predictors of LF after salvage RT.

Results: RT was administered as part of frontline therapy in 70% of patients, omitted for early response assessment in 13%, or deferred for primary progression in 17%. AHCT was omitted in 20% of patients. Median initial and salvage dose/site were 25.5 Gy and 30.6 Gy, respectively. Eight patients experienced progression. Two died without progression (median follow-up from salvage RT = 3.8 years). The 5-year CIN of LF after salvage RT was 17.7% (95% confidence interval [CI], 8.2-30.2%). The 5-year freedom from subsequent treatment failure and overall survival (OS) was 80.1% (95% CI, 69.2-92.6%) and 88.5% (95% CI, 79.5-98.6%), respectively. Inadequate response to salvage systemic therapy (p = 0.048) and male sex (p = 0.049) were significantly associated with LF after salvage RT.

Conclusion: rrHL is responsive to salvage RT, with low LF rates after moderate doses. OS is excellent, despite refractory disease. Initial salvage therapy response predicts subsequent LF.
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http://dx.doi.org/10.1016/j.radonc.2019.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478442PMC
May 2019

Epidemiology, outcome, targeted agents and immunotherapy in adolescent and young adult non-Hodgkin and Hodgkin lymphoma.

Br J Haematol 2019 06 6;185(6):1142-1157. Epub 2019 Feb 6.

Pädiatrische Hämatologie und Onkologie, Justus-Liebig-Universität Gießen and Medical Faculty of the Martin-Luther University of Halle, Germany.

The epidemiology, outcome and targeted immunotherapy in adolescent and young adult non-Hodgkin and Hodgkin lymphoma were discussed during the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma September 26th-29th 2018 in Rotterdam, the Netherlands. This review summarizes some of those presentations, as well as other current and novel antibody therapy, immune check-point inhibitors, chimeric antigen receptor T cells, cancer vaccines and cytotoxic T lymphocyte therapy.
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http://dx.doi.org/10.1111/bjh.15789DOI Listing
June 2019

Outcome of pediatric non-Hodgkin lymphoma in Central America: A report of the Association of Pediatric Hematology Oncology of Central America (AHOPCA).

Pediatr Blood Cancer 2019 05 24;66(5):e27621. Epub 2019 Jan 24.

Department of Oncology, Leukemia/Lymphoma Division, and Global Pediatric Medicine Program, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Treating B-non-Hodgkin lymphoma (B-NHL) in lower-income countries is challenging because of imprecise diagnosis, the increased risk of fatal toxicity associated with advanced disease at presentation, and limited supportive care.

Procedure: Central American patients with newly diagnosed stage I or II B-NHL received a modified Berlin-Frankfurt-Münster (BFM) regimen including a prephase (prednisone, cyclophosphamide) followed by A/B/A courses (A: cytarabine, dexamethasone, etoposide, ifosfamide, methotrexate, and intrathecal therapy; B: cyclophosphamide, dexamethasone, doxorubicin, methotrexate, and intrathecal therapy). Those with stage III or IV NHL received additional courses (B/A/B), intensified for stage IV disease by additional vincristine and methotrexate doses. Patients in poor condition received a second prephase treatment before their chemotherapy courses.

Results: Between March 2004 and June 2016, of 405 patients with B-NHL, 386 (109 females) were eligible for treatment. Immunohistochemistry was performed in 177 cases (47.4%) and characterized the disease as mature B-cell lymphoma. Stage distribution was as follows: I/II, 31 (8.1%); III, 252 (65.3%); IV, 93 (24.1%); 10 (2.6%) not available. The 3-year overall survival was 70% for the whole group (86% for stages I/II, 75% for stage III, 58% for stage IV). Events included death during induction (34 patients, 8.8%), relapse/progression (46, 11.9%), death in remission (9, 2.3%), second malignancy (1, 0.26%), and death of unknown cause (1, 0.26%). Twenty-three (6%) patients abandoned or refused therapy.

Conclusions: Approximately 70% of children with B-NHL from Central America experienced long-term, disease-free survival with a modified BFM schedule. Toxic death and relapse/resistant disease were the main reasons for treatment failure.
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http://dx.doi.org/10.1002/pbc.27621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428601PMC
May 2019

Global Access to Essential Medicines for Childhood Cancer: A Cross-Sectional Survey.

J Glob Oncol 2018 12;4:1-11

Phillip Cohen, Children's Hospital of Philadelphia, Philadelphia, PA; Phillip Cohen, Centre for Global Health, Trinity College Dublin, Dublin, Ireland; and Paola Friedrich, Catherine Lam, Sima Jeha, Monika L. Metzger, Ibraham Qaddoumi, Paula Naidu, Lane Faughnan, Carlos Rodriguez-Galindo, and Nickhill Bhakta, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Global data mapping access to essential chemotherapeutics for pediatric cancer are scarce. We report a survey of international pediatric cancer care providers' access to these medicines.

Methods: A Web-based survey was sent to pediatric oncologists registered on the Cure4Kids Web portal. We queried chemotherapeutics in the WHO Essential Medicines List for Children, from which the average proportional availability was summarized as each country's access score. In addition, we examined availability of drug packages defined by the WHO-sanctioned Expert Committee for eight pediatric cancers. We undertook a sensitivity analysis investigating how regimen access would change if the cytotoxics specified in recent agreements between the Clinton Health Access Initiative, American Cancer Society, and pharmaceutical companies were universally available.

Results: There were significant ( P < .001) differences in the median access scores between World Bank income groups, and 42.9% of respondents from low-income and lower middle-income countries reported suboptimal access scores. Our disease-based analysis revealed that 42.1% of patients in low-income and lower middle-income countries lacked full access to chemotherapy packages. Guaranteed availability of the cytotoxics specified in the Clinton Health Access Initiative/American Cancer Society agreements was projected to increase this regimen-based access by 1.6%, although including four additional chemotherapeutics would further increase coverage by 13.9%.

Conclusion: This study is the first, to our knowledge, to assess worldwide variation in practical access to pediatric chemotherapy. Although mapping the proportion of available chemotherapeutics is informative, we also developed a meaningful estimate of access using disease-specific drug packages. These data provide an important baseline for continued monitoring and can aid in planning adaptive treatment guidelines that consider the trade-offs between access and outcomes.
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http://dx.doi.org/10.1200/JGO.18.00150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010437PMC
December 2018

Severe Progressive Mycobacterium avium Complex Infection Associated With Brentuximab Vedotin Therapy.

J Pediatric Infect Dis Soc 2019 09;8(4):371-373

Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee.

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http://dx.doi.org/10.1093/jpids/piy109DOI Listing
September 2019

Improving Immunohistochemistry Capability for Pediatric Cancer Care in the Central American and Caribbean Region: A Report From the AHOPCA Pathology Working Group.

J Glob Oncol 2018 09;4:1-9

Teresa Santiago, Caleb Hayes, Carlos Rodriguez-Galindo, and Monika L. Metzger, St Jude Children's Research Hospital, Memphis, TN; Ana Concepción Polanco, Hospital Nacional de Niños Benjamín Bloom, San Salvador, El Salvador; Lisa Miranda, Hospital Nacional de Niños "Dr. Carlos Sáenz Herrera," San José, Costa Rica; Argelia Aybar, MediPath, Santiago City; Belkis Gomero, Hospital Infantil Dr. Robert Reid Cabral, Santo Domingo, Dominican Republic; Elizabeth Orellana, Francisco Marroquín Medical School, Guatemala City, Guatemala; Fabienne Anglade, Laboratory Regional Stephen at Pilar Robert, Mirebelais, Haiti; Mázlova Luxely Toledo González, Hospital Escuela-Universitario, Tegucigalpa, Honduras; Eduviges Ruiz, Hospital Infantil Manuel de Jesus Rivera "La Mascota," Managua, Nicaragua; Moisés Espino-Durán, Hospital del Niño Dr. José Renán Esquivel, Panama City, Panama.

Accessibility to immunohistochemistry (IHC) is invaluable to proper diagnosis and treatment of pediatric patients with malignant neoplasms. Whereas IHC is widely available in anatomic pathology laboratories in high-income countries, access to it in anatomic pathology laboratories of low- and middle-income countries remains a struggle, with many limitations. To advance the quality of the pathology service offered to children with cancer in areas with limited resources, a 5-day pathology training workshop was offered to pathologists and histotechnologists from various countries of the Central American and Caribbean region. An initial assessment of the workshop participants' current laboratory capacities was performed, and a regional training center was selected. Didactic and hands-on activities were offered, and review and evaluation of the IHC slides produced during the training course were compared with original slides from the participants' sites. This model of intensive 5-day training appears to be effective and can potentially be used in other budget-constrained regions. Moreover, it can serve as a continuing education activity for pathologists and histotechnologists, and as part of validations and quality improvement projects to build capacity and develop IHC assay proficiency in low- and middle-income countries.
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http://dx.doi.org/10.1200/JGO.17.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223474PMC
September 2018

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

The management of Hodgkin lymphoma in adolescents and young adults: burden of disease or burden of choice?

Blood 2018 07 12;132(4):376-384. Epub 2018 Jun 12.

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

Adolescents and young adults (AYAs) comprise the largest age group affected by Hodgkin lymphoma (HL). Despite excellent overall survival of AYA patients with HL due to advances in treatment regimens, therapy-associated late effects continue to be a concern in HL survivors, especially for younger patients who have decades of life remaining. Since the first clinical trial for HL with chemotherapy in 1964, subsequent protocols have attempted to reduce chemotherapy-induced toxicities and yet maintain high overall survival rates. Today, new analytic methods applied to data from survivorship cohorts, such as the recently described cumulative burden of disease metric, can be used to inform changes for future protocols. Although pediatric and adult trial consortia have followed this process, the AYA population, an age cohort split between pediatric and adult health care services, faces many barriers to care and is the least likely to be enrolled in clinical trials. AYA patients with HL theoretically have a choice to be treated in pediatric or adult protocols when presented with these options. Recent efforts by the National Clinical Trials Network, the Children's Oncology Group, and others have been made to ensure that the burden of choice for the AYA population is not greater than the burden of disease.
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http://dx.doi.org/10.1182/blood-2018-01-778548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071556PMC
July 2018

A framework to develop adapted treatment regimens to manage pediatric cancer in low- and middle-income countries: The Pediatric Oncology in Developing Countries (PODC) Committee of the International Pediatric Oncology Society (SIOP).

Pediatr Blood Cancer 2017 12;64 Suppl 5

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

Many children with cancer in low- and middle-income countries are treated in hospitals lacking key infrastructure, including diagnostic capabilities, imaging modalities, treatment components, supportive care, and personnel. Childhood cancer treatment regimens adapted to local conditions provide an opportunity to cure as many children as possible with the available resources, while working to improve services and supportive care. This paper from the Adapted Treatment Regimens Working Group of the Pediatric Oncology in Developing Countries committee of the International Society of Pediatric Oncology outlines the design, development, implementation, and evaluation of adapted regimens and specifies levels of services needed to deliver them.
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http://dx.doi.org/10.1002/pbc.26879DOI Listing
December 2017

Bone mineral density in children with acute lymphoblastic leukemia.

Cancer 2018 03 19;124(5):1025-1035. Epub 2017 Dec 19.

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

Background: Children with acute lymphoblastic leukemia (ALL) can develop reduced bone mineral density (BMD). However, data from patients who received treatment on a frontline regimen without cranial irradiation are limited, and no genome-wide analysis has been reported.

Methods: Lumbar BMD was evaluated by quantitative computed tomography at diagnosis, after 120 weeks of continuation therapy, and after 2 years off therapy in pediatric patients with ALL (ages 2-18 years at diagnosis) who were treated on the St. Jude Total XV Protocol. Clinical, pharmacokinetic, and genetic risk factors associated with decreased BMD Z-scores were evaluated.

Results: The median BMD Z-score in 363 patients was 0.06 at diagnosis, declined to -1.08 at week 120, but partly recovered to -0.72 after 2 years off therapy; BMD in patients with low BMD Z-scores at diagnosis remained low after therapy. Older age (≥10 years vs 2-9.9 years at diagnosis; P < .001), a higher BMD Z-score at diagnosis (P = .001), and a greater area under the plasma drug concentration-time curve for dexamethasone in weeks 7 and 8 of continuation therapy (P = .001) were associated with a greater decrease in BMD Z-score from diagnosis to week 120. Single-nucleotide polymorphisms in 2 genes important in osteogenesis and bone mineralization (COL11A1 [reference single-nucleotide polymorphism rs2622849]; P = 2.39 × 10 ] and NELL1 [rs11025915]; P = 4.07 × 10 ]) were associated with a decreased BMD Z-score. NELL1 (P = .003) also was associated with a greater dexamethasone area under the plasma drug concentration-time curve.

Conclusions: BMD Z-scores decreased during therapy, especially in patients who had clinical, pharmacokinetic, and genetic risk factors. Early recognition of BMD changes and strategies to optimize bone health are essential. Cancer 2018;124:1025-35. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821586PMC
March 2018

Genetics of pleiotropic effects of dexamethasone.

Pharmacogenet Genomics 2017 08;27(8):294-302

Departments of aPharmaceutical Sciences bBiostatistics cOncology dComprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

Objectives: Glucocorticoids such as dexamethasone have pleiotropic effects, including desired antileukemic, anti-inflammatory, or immunosuppressive effects, and undesired metabolic or toxic effects. The most serious adverse effects of dexamethasone among patients with acute lymphoblastic leukemia are osteonecrosis and thrombosis. To identify inherited genomic variation involved in these severe adverse effects, we carried out genome-wide association studies (GWAS) by analyzing 14 pleiotropic glucocorticoid phenotypes in 391 patients with acute lymphoblastic leukemia.

Patients And Methods: We used the Projection Onto the Most Interesting Statistical Evidence integrative analysis technique to identify genetic variants associated with pleiotropic dexamethasone phenotypes, stratifying for age, sex, race, and treatment, and compared the results with conventional single-phenotype GWAS. The phenotypes were osteonecrosis, central nervous system toxicity, hyperglycemia, hypokalemia, thrombosis, dexamethasone exposure, BMI, growth trajectory, and levels of cortisol, albumin, and asparaginase antibodies, and changes in cholesterol, triglycerides, and low-density lipoproteins after dexamethasone.

Results: The integrative analysis identified more pleiotropic single nucleotide polymorphism variants (P=1.46×10(-215), and these variants were more likely to be in gene-regulatory regions (P=1.22×10(-6)) than traditional single-phenotype GWAS. The integrative analysis yielded genomic variants (rs2243057 and rs6453253) in F2RL1, a receptor that functions in hemostasis, thrombosis, and inflammation, which were associated with pleiotropic effects, including osteonecrosis and thrombosis, and were in regulatory gene regions.

Conclusion: The integrative pleiotropic analysis identified risk variants for osteonecrosis and thrombosis not identified by single-phenotype analysis that may have importance for patients with underlying sensitivity to multiple dexamethasone adverse effects.
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http://dx.doi.org/10.1097/FPC.0000000000000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523978PMC
August 2017

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

ACR Appropriateness Criteria® Recurrent Hodgkin Lymphoma.

Oncology (Williston Park) 2016 12;30(12):1099-103, 1106-8

This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decision-making associated with the management of recurrent Hodgkin lymphoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440297PMC
December 2016

Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma.

Cancer Chemother Pharmacol 2016 Dec 11;78(6):1217-1223. Epub 2016 Nov 11.

Pharmaceutical Sciences, St. Jude Children's Research Hospital, The University of Tennessee Health Science Center, Memphis, TN, USA.

Purpose: Because of the observed success of phase I/II trials, the novel anti-CD30 agent brentuximab vedotin is now being evaluated as a frontline agent in the high-risk pediatric Hodgkin lymphoma trial HLHR13. The objectives of this study were to evaluate the pharmacokinetic variability during weekly dosing of 1.2 mg/kg of brentuximab vedotin, determine factors that may explain this variability, compare our drug exposure with published data, and evaluate toxicity of brentuximab vedotin in the pediatric population.

Methods: Brentuximab vedotin, MMAE and anti-therapeutic antibody levels were measured in the serum samples of 16 pediatric patients with Hodgkin lymphoma. A compartmental pharmacokinetic model was fit to the data by using nonlinear mixed-effects modeling.

Results: Clearance and volume of brentuximab vedotin were significantly correlated with weight (p < .001), which was responsible for over 60% of the parameters inter-individual variability. Clearance and volume were higher in boys compared to girls (p = 0.08 and p = 0.03, respectively). Brentuximab vedotin's AUC and C were lower in our pediatric study than those reported in adult studies (25 and 11%, respectively). Toxicity was comparable to that of the standard-of-care backbone using vincristine instead of brentuximab vedotin. The sera of all 16 patients remained negative for anti-therapeutic antibodies during and at the end of therapy.

Conclusions: As in previous studies, weight continues to be the most significant factor explaining brentuximab vedotin's pharmacokinetic variability in pediatric patients. Exposure to weekly dosing appears to be safe and tolerable in pediatric patients.
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http://dx.doi.org/10.1007/s00280-016-3180-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206991PMC
December 2016

ACR Appropriateness Criteria® Hodgkin Lymphoma-Favorable Prognosis Stage I and II.

Am J Clin Oncol 2016 12;39(6):535-544

*University of Rochester Medical Center, Rochester †††Memorial Sloan Kettering Cancer Center, American Society of Clinical Oncology, New York, NY †Stanford Cancer Center, American Society of Clinical Oncology, Stanford ‡University of Southern California Keck School of Medicine, Los Angeles, CA §University of Texas MD Anderson Cancer Center, Houston ¶University of Texas Health Science Center at San Antonio, San Antonio, TX ∥Emory University, American Society of Clinical Oncology, Atlanta, GA #University of Florida Proton Therapy Institute, Jacksonville **University of Florida, Gainesville, FL ††St. Jude Children's Research Hospital, American Society of Clinical Oncology, Memphis, TN ‡‡University of Pennsylvania Health System, Philadelphia, PA §§Yale University School of Medicine, New Haven, CT ∥∥Richard L. Roudebush VA Medical Center, Indiana University School of Medicine, Indianapolis, IN ¶¶The University of Chicago, American Society of Hematology, Chicago, IL ##Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, MD ***Massachusetts General Hospital, Boston, MA.

This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy.
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http://dx.doi.org/10.1097/COC.0000000000000331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433865PMC
December 2016

Comparison of C-Methionine and F-FDG PET/CT for Staging and Follow-up of Pediatric Lymphoma.

J Nucl Med 2017 Mar 8;58(3):419-424. Epub 2016 Sep 8.

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

Methionine transport across plasma membranes occurs via the large amino acid transporter, which is overexpressed in malignant cells, leading to tracer accumulation within tumors. We investigated the uptake of C-methionine (C-MET) in children and young adults with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and compared the biodistribution of C-MET PET/CT with that of F-FDG PET/CT. Conducted under an investigational new drug authorization, we prospectively enrolled patients with newly diagnosed HL ( = 19) and NHL ( = 2) onto the Institutional Review Board-approved investigation of C-MET PET/CT. After a minimum 4-h fast, patients received 740 MBq/1.7 m (maximum, 740 MBq [20 mCi/1.7 m; maximum, 20 mCi]) of C-methionine intravenously. PET/CT was performed 5 min after injection from the vertex to thighs at 3 min per bed position. In a separate session, patients received 5.5 MBq/kg (maximum, 485 MBq [0.15 mCi/kg; maximum, 12 mCi]) of F-FDG with imaging initiated approximately 1 h after radiopharmaceutical administration. All studies were reviewed by consensus of 2 senior imaging specialists. The presence of metabolic activity on baseline studies was compared among 17 nodal groups. Eighteen patients (11 male; median age, 15.2 y; age range, 9.5-22.6 y) comprised the study cohort. All had paired C-MET PET/CT and F-FDG PET/CT studies at diagnosis. At baseline, 3 nodal groups demonstrating discordant metabolic activity by both F-FDG PET/CT and C-MET PET/CT were Waldeyer's ring, paraaortic region, and the liver. All others were found to have concordant metabolic activity. Normal intense C-MET uptake in the pancreas and liver reduced sensitivity for disease detection in these regions. At follow-up, 14 of 15 study pairs had concordant results. C-MET uptake is elevated in most regions involved with lymphoma at diagnosis and follow-up. Its utility in the abdomen is limited by uptake in normal structures.
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http://dx.doi.org/10.2967/jnumed.116.178640DOI Listing
March 2017