Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis.

Children's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). "Rapid early responders" (RERs) had a negative PET1 (PET1-); "slow early responders" (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as "within the PET1+ site" or "initially involved but outside the PET1+ site." Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Bartonella henselae Infection and Lymphadenopathy in a Patient With T Cell Acute Lymphoblastic Leukemia.

Patients undergoing therapy for T cell acute lymphoblastic leukemia are at risk of infections during their treatment course. Cat scratch disease caused by Bartonella hensalae can masquerade as leukemic relapse and cause systemic infection. Obtaining a thorough exposure history may aid clinicians in making the diagnosis.

A single-center retrospective review of pediatric cases of progressive transformation of germinal centers.

BACKGROUND: Progressive transformation of germinal centers (PTGC) is a rare diagnosis characterized by asymptomatic lymph node enlargement. It has previously been associated with lymphoma, autoimmune conditions, and lymphoproliferative diseases in small pediatric case series. PROCEDURES: We conducted a single-center retrospective review of pediatric cases of PTGC diagnosed at our institution by hematopathologists from 2000 to 2020. RESULTS: We identified 57 primary cases and three recurrent cases of PTGC. Laboratory and imaging evaluations were obtained inconsistently. Nine patients (16%) saw a pediatric hematology/oncology (PHO) specialist prior to diagnosis, and 21 (37%) had follow-up with PHO after diagnosis. CONCLUSIONS: Patients with PTGC had similar age and involved lymph node sites to those from previous case series. Fewer patients underwent recurrent lymph node biopsy than previously described. PTGC has been linked to certain types of lymphoma, although never definitively associated with lymphoma. Follow-up with a PHO provider is indicated to ensure that close surveillance is performed.

Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation Rescues Marrow Failure From Acute Leukemia Therapy in a Patient With Previously Undiagnosed Ligase IV Syndrome.

Patients with DNA double-strand breakage repair disorders are at increased risk of malignancy which is often difficult to treat given underlying sensitivity to chemotherapy and radiotherapy, lending an important role to hematopoietic stem cell transplantation. The choice of conditioning regimen used must balance reducing risk of rejection with minimizing excessive toxicity from myeloablative chemotherapy or ionizing radiation. We describe successful engraftment following a nonmyeloablative hematopoietic stem cell transplantation in a patient with Ligase IV syndrome and numerous pretransplant complications including malignancy, cardiac failure, and secondary hemophagocytic lymphohistiocytosis. Congruent with prior reports, a reduced intensity regimen appears efficacious in Ligase IV syndrome patients.

Experience with ponatinib in paediatric patients with leukaemia.

Ponatinib has proven to be effective in adults with Philadelphia chromosome-positive leukaemias, but data in paediatrics are scarce. Among paediatric patients with chronic myeloid leukaemia (n = 9) or acute lymphoblastic leukaemia (n = 12) treated with varying doses of ponatinib in 13 centres, 71% showed a decrease in disease burden after a median of three months. Ponatinib was well tolerated, with grade 3 toxicities occurring in 29% of patients. Toxicities were similar to those reported in adults, with the exception of arterial thrombotic events, which were not observed. Ponatinib has a favourable safety profile in this paediatric cohort, but dose-finding studies are needed.

Very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor.

Involvement of the pituitary gland by leukemic infiltration is exceedingly rare. Here, we describe a very late recurrence of B-cell acute lymphoblastic leukemia masquerading as a pituitary tumor and review the literature for previously reported cases. Our female patient presented 13 years after completion of therapy for B-ALL with headache, amenorrhea, galactorrhea and a pituitary mass. Subsequent studies revealed recurrence of her leukemia, and the pituitary lesion resolved after induction chemotherapy. Our case highlights the importance of considering leukemic infiltrate in the differential diagnosis of pituitary mass, particularly in a patient with a history of hematologic malignancy, sparing unnecessary surgical intervention and informing endocrine evaluation. In addition, the case also highlights difficulties with characterizing this recurrence as a very late relapse or clonal evolution of the original leukemia.

The association of age, literacy, and race on completing patient-reported outcome measures in pediatric oncology.

PURPOSE: Age is often used to determine when children can begin completing patient-reported outcome (PRO) instruments or transition to adult instruments. This study's purpose was to determine relationships between literacy, age, and race and their influence on a child's ability to understand and complete a PRO instrument. METHODS: The Wide Range Achievement Test was used to evaluate literacy in children and young adults with cancer, participating in a cognitive interview for the Pediatric PRO-CTCAE instrument. 140 participants (7-20 years) were recruited from 8 sites. Logistic regression and multivariable liner regression were used to examine relationships among key variables. RESULTS: Higher literacy scores were significantly associated with fewer PRO-CTCAE items being identified as "hard to understand" (p = 0.017). Literacy scores increased with age, but older participants were more likely to fall behind expected reading levels compared with US norms. A 1-year increase in age was associated with a 19% increase in the likelihood for being below the expected WRAT word reading score (OR 1.19; 95% CI 1.06-1.33, p = 0.003). No associations were found between race and literacy. CONCLUSIONS: Wide variations in literacy were noted across age groups. All participants were able to complete the Pediatric PRO-CTCAE, although most 7 year olds (63%) required reading assistance. Those with lower literacy skills were able to understand items suggesting that multiple factors may be involved in comprehension (developmental stage, concentration, vocabulary, or prior health experiences). Risk for falling below expected literacy levels increased with age implying a need for literacy consideration for cancer patients.

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group AHOD0431 study evaluated a response-directed treatment paradigm in which minimal initial chemotherapy and low-dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low-dose radiation salvage regimen was received by those who had a protocol-defined, low-risk recurrence. METHODS: Patients younger than 21 years who had stage IA or IIA nonbulky disease were eligible. The treatment strategy was evaluated by determining the proportion that received minimal chemotherapy alone, the proportion that had a first or second remission without the receipt of high-dose chemotherapy/stem cell rescue or higher dose involved-field radiation therapy (>21 grays), and overall survival. RESULTS: In total, 278 patients were eligible. At 4 years, 49.0% had received minimal chemotherapy and no radiation, 88.8% were in remission without receiving high-dose chemotherapy with stem cell rescue or >21 grays of involved-field radiation therapy, and the overall survival rate was 99.6%. Patients who had mixed cellularity histology had a 4-year event-free survival (EFS) rate of 95.2%, which was significantly better than the 75.8% EFS for those who had nodular sclerosis histology (P = .008). A red blood cell sedimentation rate ≤20 mm/hour and a negative fluorodeoxyglucose-positron emission tomography scan after 1 cycle of chemotherapy (PET1) were associated with a favorable EFS outcome. The study was closed early when the receipt of radiation therapy exceeded the predefined monitoring boundary. CONCLUSIONS: This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.

Incidence and outcomes of lymphoid malignancies in adolescent and young adult patients in the United States.

Lymphoma incidence and survival in adolescent and young adult (AYA, defined as 15-39 years of age) and adult patients (>39 years) were assessed using Surveillance, Epidemiology, and End Results (SEER) data. From 2000 to 2014, 431 721 lymphoma cases were reported to SEER, 9% in AYA patients. In the AYA group, the highest age-adjusted incidence rate was for classical Hodgkin lymphoma [HL; 3·4 per 100 000 person-years; 95% confidence interval (CI), 3·38-3·49] followed by diffuse large B cell lymphoma (DLBCL; 1·56, 95% CI, 1·53-1·60) and for adults, it was plasma cell neoplasms (14·17, 95% CI, 14·07-14·27), DLBCL (13·86, 95% CI, 13·76-13·96) and chronic lymphocytic leukaemia (CLL; 13·19, 95% CI, 13·09-13·29). HL comprised 42% of lymphoma cases for AYAs, but only 4% in adults. The occurrence of DLBCL among AYAs and adults was similar, 18% and 20%, respectively. Twenty-eight percent of AYAs compared with 9% of adults presented with stage II disease, and 21% of AYAs compared with 10% of adults had B-symptoms. Extranodal disease was less common (33%) in AYAs than adults (59%). Overall, AYA patients with lymphoma have better 2- and 5-year relative survival rates (RSRs) compared to adults. When restricted to HL and DLBCL, RSR of AYA patients exceeds adult RSR.

Early-stage Hodgkin lymphoma in the modern era: simulation modelling to delineate long-term patient outcomes.

We developed a novel simulation model integrating multiple data sets to project long-term outcomes with contemporary therapy for early-stage Hodgkin lymphoma (ESHL), namely combined modality therapy (CMT) versus chemotherapy alone (CA) via 18 F-fluorodeoxyglucose positron emission tomography response-adaption. The model incorporated 3-year progression-free survival (PFS), probability of cure with/without relapse, frequency of severe late effects (LEs), and 35-year probability of LEs. Furthermore, we generated estimates for quality-adjusted life years (QALYs) and unadjusted survival (life years, LY) and used model projections to compare outcomes for CMTversusCA for two index patients. Patient 1: a 25-year-old male with favourable ESHL (stage IA); Patient 2: a 25-year-old female with unfavourable ESHL (stage IIB). Sensitivity analyses assessed the impact of alternative assumptions for LE probabilities. For Patient 1, CMT was superior to CA (CMT incremental gain = 0·11 QALYs, 0·21 LYs). For Patient 2, CA was superior to CMT (CA incremental gain = 0·37 QALYs, 0·92 LYs). For Patient 1, the advantage of CMT changed minimally when the proportion of severe LEs was reduced from 20% to 5% (0·15 QALYs, 0·43 LYs), whereas increasing the severity proportion for Patient 2's LEs from 20% to 80% enhanced the advantage of CA (1·1 QALYs, 6·5 LYs). Collectively, this detailed simulation model quantified the long-term impact that varied host factors and alternative contemporary treatments have in ESHL.

A variant c-KIT mutation, D816H, fundamental to the sequential development of an ovarian mixed germ cell tumor and systemic mastocytosis with chronic myelomonocytic leukemia.

An activating point mutation of the c-KIT tyrosine kinase receptor gene, D816H, has been described in germ cell tumors (GCTs). We report an adolescent diagnosed with an ovarian mixed GCT and systemic mastocytosis with chronic myelomonocytic leukemia (SM-CMML). The teratoma and dysgerminoma differed by copy number aberrations via single nucleotide polymorphism (SNP) microarray, but were inclusive of the same c-KIT D816H point mutation (c.2446G>C) also identified in blood and bone marrow mast cells. These findings indicate not only a clonal origin of the GCT and hematologic malignancy, but also suggest a rare KIT mutation may be playing a fundamental role in malignancy development.

Utility of peripheral blood immunophenotyping by flow cytometry in the diagnosis of pediatric acute leukemia.

BACKGROUND: Childhood acute leukemia is traditionally diagnosed from a bone marrow aspirate (BMA). New-onset acute leukemia patients do not always have visible circulating blasts in the peripheral blood (PB) at diagnosis. While the role of bone marrow flow cytometry for the diagnosis of acute leukemia is well established, the utility of PB flow cytometry (PBFC) is unknown. We performed a single-institution retrospective analysis to compare PBFC versus BMA in establishing or excluding a diagnosis of childhood acute leukemia. PROCEDURE: We retrospectively identified 485 PBFC samples with concurrent BMA from 2008 to 2013. Results of four-color flow cytometry for immunophenotypic characterization of leukemic versus nonclonal disease were characterized. Sensitivity and specificity were calculated among patients without a known diagnosis or prior therapy. RESULTS: Among 485 samples eligible for analysis, 120 had negative PBFC and BMA, 359 had positive PBFC and BMA, 3 had negative PBFC and positive BMA, and 3 had positive PBFC and negative BMA. There were small but significant differences in sensitivity (100 vs. 93.8%; P = 0.002) and positive predictive value (100 vs. 93.8%; P = 0.002) favoring BMA over PBFC among those demonstrating absence of circulating morphologic blasts. CONCLUSION: PBFC has high sensitivity and specificity for the diagnosis of childhood acute leukemia. The predictive value of PBFC remains high for patients without visible circulating blasts and may enhance the diagnostic process for determining the indications for marrow testing.

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

BACKGROUND: 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. PATIENTS AND METHODS: We developed a predictive model for event-free survival (EFS) in pediatric/adolescent HL using clinical data known at diagnosis from 1103 intermediate-risk HL patients treated on Children's Oncology Group protocol AHOD0031 with doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy and radiation. Independent predictors of EFS were identified and used to develop and validate a prognostic score (Childhood Hodgkin International Prognostic Score [CHIPS]). A training cohort was randomly selected to include approximately half of the overall cohort, with the remainder forming the validation cohort. RESULTS: Stage 4 disease, large mediastinal mass, albumin (<3.5), and fever were independent predictors of EFS that were each assigned one point in the CHIPS.  Four-year EFS was 93.1% for patients with CHIPS = 0, 88.5% for patients with CHIPS = 1, 77.6% for patients with CHIPS = 2, and 69.2% for patients with CHIPS = 3. CONCLUSIONS: CHIPS was highly predictive of EFS, identifying a subset (with CHIPS 2 or 3) that comprises 27% of intermediate-risk patients who have a 4-year EFS of <80% and who may benefit from early therapeutic augmentation.  Furthermore, CHIPS identified higher risk patients who were not identified by early PET or CT response. CHIPS is a robust and inexpensive approach to predicting risk in patients with intermediate-risk HL that may improve ability to tailor therapy to risk factors known at diagnosis.

Maintenance Treatment With Low-Dose Mercaptopurine in Combination With Allopurinol in Children With Acute Lymphoblastic Leukemia and Mercaptopurine-Induced Pancreatitis.

Mercaptopurine (6-mercaptopurine, 6MP) is a mainstay of curative therapy in childhood acute lymphoblastic leukemia (ALL), and contributes to its 90% overall survival rate. We present two patients with ALL who suffered with severe pancreatitis secondary to 6MP. Through the use of allopurinol in conjunction with reduced dose 6MP, we were able to continue 6MP without further pancreatitis. This report contributes to the small body of literature on 6MP associated pancreatitis in childhood ALL and describes a novel approach to continued use of 6MP during therapy.

Early T-Cell Precursor Acute Lymphoblastic Leukemia in an Infant With an NRAS Q61R Mutation and Clinical Features of Juvenile Myelomonocytic Leukemia.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-acute lymphoblastic leukemia (T-ALL) arising from a primitive precursor. We present a unique case of an infant with ETP-ALL with a missense NRAS mutation in codon 61 (c.182A>G, p.Q61R). The patient also had a minor population of non-ETP T-ALL blasts and clinical features typically associated with juvenile myelomonocytic leukemia (JMML), namely, absolute monocytosis, splenomegaly, and elevated hemoglobin F. The treatment was initiated with chemotherapy, followed by cord blood transplantation. The patient achieved remission, but unfortunately died from transplant-related complications. This case highlights an NRAS mutation in ETP-ALL with JMML-like phenotype.

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.