Frank G. Keller

Preponderance of Thiopurine S-Methyltransferase Deficiency and Heterozygosity Among Patients Intolerant to Mercaptopurine or Azathioprine

PURPOSE To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group

PURPOSE The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. PATIENTS AND METHODS By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. RESULTS By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). CONCLUSION Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.

Children's Oncology Group's 2013 blueprint for research: Hodgkin lymphoma

In childhood Hodgkin lymphoma, estimated 5 years survival rates exceed 90%. Long‐term survival continues to decline from delayed toxicities. Key findings from recent Childrens Oncology Group trials include: (1) Radiotherapy selection may be based on early chemotherapy response assessed by both FDG‐PET and CT imaging, (2) A new prognostic factor score stratifies patients into risk categories; and (3) novel retrieval regimens were identified. A phase I/II trial is investigating Brentuximab vedotin (Bv) with gemcitabine in relapsed patients. A phase 3 trial will modify conventional chemotherapy and radiotherapy approaches through the addition of Bv, while incorporating translational biology to identify molecular targets. Pediatr Blood Cancer 2013; 60: 972–978.

Comparison of Allergic Reactions to Intravenous and Intramuscular Pegaspargase in Children with Acute Lymphoblastic Leukemia

Pegaspargase (PEG) is a standard component of therapy for pediatric acute lymphoblastic leukemia (ALL). Because PEG preparations are bacterially derived, they are highly immunogenic. PEG has traditionally been delivered intramuscularly (IM), but over the last several years, more PEG has been given intravenously (IV) in order to provide a less painful and more convenient means of delivery. However, there are limited data comparing allergic reactions between IV and IM PEG recipients, especially in a large cohort of patients. We reviewed the charts of pediatric ALL patients diagnosed from 2006 to 2011 who received PEG at our institution and compared the incidence, time to onset of symptoms, reaction grade, and hospitalization rate for patients who had allergic reactions to PEG. Of 318 evaluable patients, 159 received IV and 159 received IM PEG. Thirty-one (19.5%) IV patients had an allergic reaction, compared to 17 (10.7%) IM patients (P = .028). Time to onset of symptoms was ≤ 30 minutes for 26 of 27 evaluable IV patients (96.3%) versus only two of 11 evaluable IM patients (18.2%; P < .001). Four of 31 IV patients (12.9%) and six of 17 IM patients (35.5%) required hospitalization (P = .134). There is increased incidence of allergy in patients who received IV PEG compared to IM. Grade of reaction was similar between IV and IM, but allergic reactions to IV PEG had a more rapid onset. While the risk of allergy may be increased, IV delivery appears to have an acceptable safety profile for administration in ALL patients.

Safety profile of asparaginase Erwinia chrysanthemi in a large compassionate‐use trial

L‐Asparaginase is an integral component of standard chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Clinical hypersensitivity, a common reason for treatment discontinuation, has been reported in 10–30% of patients receiving Escherichia coli‐derived asparaginase. After hypersensitivity, E. coli‐derived asparaginase should be discontinued and an alternative asparaginase preparation, such as asparaginase Erwinia chrysanthemi, may be initiated. We conducted a compassionate‐use study to collect additional safety information on asparaginase Erwinia chrysanthemi and to support FDA approval of the product.

Mitoxantrone as a substitute for daunorubicin during induction in newly diagnosed lymphoblastic leukemia and lymphoma

Daunorubicin, a component of the four‐drug induction chemotherapy regimen for de novo pediatric high‐risk acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy), was unavailable in 2011 due to a national drug shortage. During this time, our institution substituted mitoxantrone 6.25 mg/m2 for daunorubicin 25 mg/m2 on induction Days 1, 8, 15, and 22. While mitoxantrone has been shown to be effective for relapsed ALL, it has not been studied in de novo pediatric ALL/LLy.

What is the best treatment for children with limited-stage Hodgkin lymphoma?

Limited-stage Hodgkin lymphoma remains a challenging problem for pediatric oncologists. Published and investigative treatment regimens represent varied approaches to balance the excellent overall and event-free survival with the substantial potential for long-term sequelae of effective treatment modalities. Regimens incorporating low-dose radiation to smaller fields and chemotherapy that limits cumulative exposure to the agents most closely associated with long-term complications have been shown to be effective for most patients. Investigative approaches to optimize overall therapy focus on identifying which patients require more or less therapy. A recent example is the use of response-based therapy as a means of limiting or omitting radiation for those with an early, rapid response to chemotherapy. Biologic markers that influence risk for treatment failure or treatment-related toxicities have been only minimally defined. This paper reviews recently published treatment regimens for children and adolescents and presents some considerations for choosing a treatment approach for individual patients.

Childhood Hodgkin International Prognostic Score (CHIPS) Predicts event-free survival in Hodgkin Lymphoma: A Report from the Children’s Oncology Group

Early response to initial chemotherapy in Hodgkin lymphoma (HL) measured by computed tomography (CT) and/or positron emission tomography (PET) after two to three cycles of chemotherapy may inform therapeutic decisions. Risk stratification at diagnosis could, however, allow earlier and potentially more efficacious treatment modifications.

Treatment of an adolescent with chronic myeloid leukemia and the T315I mutation with ponatinib

To the Editor: An important mutation in chronic myeloid leukemia (CML) is the threonine-to-isoleucine mutation at position 315 (T315I). Ponatinib is currently the only drug effective against T315I CML, but it has not been studied in children.[1] We describe a young adolescent with chronic-phase CML treated with ponatinib. A 10-year-old male was found to have a white blood cell count of 96,000mL with 1% blasts and the (9;22) (q34;q11.2) translocation. He was started on imatinib and after 6 months achieved a complete molecular response (CMR). However, at 10 months, BCR-ABL was again detected by PCR and transcript levels increased over time. At 18 months, gene sequencing identified the T315I mutation. He had no HLA-matched donors. At 24 months after his diagnosis, bone marrow FISH demonstrated t(9p;22q) in 46% of cells and the patient was started on ponatinib at the adult dose of 45mg daily (patient’s weight was >70 kg). With the start of ponatinib, BCR–ABL transcript levels dropped and after 4 months he achieved a CMR with quantification limit of 0.0063% International Standard (IS). After 18 months of ponatinib therapy, due to the reported association of ponatinib with serious thrombotic events, the dose was decreased to 15mg daily. On this decreased dose, peripheral BCR–ABL PCR has been positive only at a low level (maximum recent value 0.008% IS). He has been taking ponatinib now for over 2.8 years with no serious adverse events. At the initiation of ponatinib (age 12.1 years) the patient was Tanner stage II and he has had continued development to Tanner stage IV. However, he has had a significant decline in height velocity (Fig. 1). At last visit, TSH, FSH, LH, testosterone, and somatomedin C levels were normal. In our patient ponatinib was well tolerated and has provided excellent disease control. While the emergence of a ponatinibresistant clone is possible, follow-up of adult patients with chronic-phase CML treated with ponatinib suggests that ponatinib responses appear durable for most, and especially for patients who achieved an early landmark response.[2,3] The increasing rate of thrombotic events in patients treated with ponatinib over time is concerning for a pediatric patient who requires many years of ponatinib to maintain life-long disease control.[4] Decreasing the dose of ponatinib may minimize this risk.[5] This risk also appears to be more common in patients with preexisting cardiovascular disease.[6] Imatinib therapy has been associated with growth impairment in children with CML.[7–10] Given our patient’s growth curve, ponatinib may also impair growth; however, it is encouraging that it did not prevent pubertal development. While CML with the T315I mutation has been considered an indication for allogeneic stemcell transplant, this casedemonstrates that ponatinib may be a reasonable alternative treatment. In the future, as transplant improves and asmore is learned about the long-term efficacy and safety of ponatinib, the risk-benefit ratiomay change. Currently we believe that for children with CML and the T315I mutation, both transplant and ponatinib treatment should be considered. Robert Sheppard Nickel, MD Marla Daves, MD Frank Keller, MD Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia

Current approaches in the management of low risk Hodgkin lymphoma in children and adolescents

The outcome for children and adolescents with low risk Hodgkin lymphoma (HL) is excellent, with event‐free survival >85% and overall survival >95%. Historically, however, treatment has come at the cost of significant long‐term toxicity from chemotherapy, radiation or a combination of these. Recent treatment strategies have focused on maintaining high event‐free and overall survival while minimizing the use of therapy associated with late effects. The strategies used to achieve this vary greatly among paediatric cooperative groups and there is no one standard treatment for children with low risk HL. This review summaries recent clinical trials in paediatric low risk HL and addresses some of the important considerations when comparing trials, including differences in the definition of low risk HL, differences in outcome among histological subtypes and varying approaches to reduce or eliminate radiation therapy. Recommendations are provided for the treatment of children with low risk HL outside the setting of a clinical trial.