Myelofibrosis (MF) is the deadliest form of myeloproliferative neoplasm (MPN). The JAK inhibitor Ruxolitinib can reduce constitutional symptoms but it does not substantially improve bone marrow fibrosis. Pim1 expression is significantly elevated in MPN/MF hematopoietic progenitors. Here, we show that genetic ablation of Pim1 blocked the development of myelofibrosis induced by Jak2V617F and MPLW515L. Pharmacologic inhibition of Pim1 with a second-generation Pim kinase inhibitor TP-3654 significantly reduced leukocytosis and splenomegaly, and attenuated bone marrow fibrosis in Jak2V617F and MPLW515L mouse models of MF. Combined treatment of TP-3654 and Ruxolitinib resulted in greater reduction of spleen size, normalization of blood leukocyte counts and abrogation of bone marrow fibrosis in murine models of MF. TP-3654 treatment also preferentially inhibited Jak2V617F mutant hematopoietic progenitors in mice. Mechanistically, we show that TP-3654 treatment significantly inhibits mTORC1, MYC and TGF-β signaling in Jak2V617F mutant hematopoietic cells and diminishes the expression of fibrotic markers in the bone marrow. Collectively, our results suggest that Pim1 plays an important role in the pathogenesis of MF, and inhibition of Pim1 with TP-3654 might be useful for treatment of MF.

In 1985, a new type of peripheral T-cell lymphoma was discovered using a monoclonal antibody, Ki-1 (anti-CD30), raised against a Hodgkin lymphoma (HL) cell line. It, ultimately named anaplastic large cell lymphoma (ALCL), was characterized and found to usually contain translocation t(2;5)(p23;q35) fusing nucleophosmin (NPM) and a "new" gene, anaplastic lymphoma kinase (ALK). The NPM-ALK fusion gene results in a constitutively active ALK tyrosine kinase that drives neoplastic cell growth, in large part through activation of STAT3 and downstream signaling. ALK positive ALCL is predominantly a disease of children, adolescents, and young adults, while similar tumors in adults are ALK negative. The discovery of ALK + ALCL occurred during a time of progress in the treatment of pediatric non-Hodgkin lymphomas (NHL), and it was initially considered to have a favorable prognosis, with 60–70% event free survival compared to other pediatric NHLs for which treatment results were less favorable. Since that time, however, progress has occurred in other pediatric NHLs, but has stalled in ALCL. ALK translocations and other abnormalities have subsequently been found in a number of neoplasms including a portion of non-small cell lung cancers, and ALK tyrosine kinase inhibitors (TKIs) have been successfully used in their therapy. Tumors often develop resistance to TKIs, limiting their long-term success. TKI therapy is gradually being introduced into the treatment of ALK + ALCL in efforts to reduce toxicity of chemotherapy while preserving and increasing cure rates. Other targeted modalities are also available to aid in this quest, including the anti-CD30 antibody drug conjugate brentuximab vedotin, other immune therapies including bi-specific antibodies and immune checkpoint inhibitors, and chimeric antigen receptor T-cells (CAR-T).

To the Editor: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a histologic subtype representing 5% to 10% of HL. NLPHL is a slow growing disease that typically presents with localized peripheral disease (stage I or II) and lack of B symptoms.1–4 Traditionally, NLPHL has been treated according to protocols for classic HL, including chemotherapy and/or radiation therapy. Although patients have achieved excellent results on these protocols, long-term treatment-related toxicities and secondary malignancies occur and are not insignificant.5 Interestingly, there have been reports of cure of stages I and II disease with surgery only,6–8 but surgery as a stand alone therapy had not been formally studied. However, a recent Children’s Oncology Group (COG) study AHOD03P1 aimed to reduce the potential for longterm toxicities by minimizing exposure to chemotherapy and radiotherapy in appropriate patients with NLPHL, and to treat totally resected single node stage IA NLPHL patients with surgery alone.9 In this study, 52 of 183 eligible patients had stage IA single node, and were treated with surgery only. The 5-year overall survival was 100%, and the 5-year event-free survival was 77%, with 75% of these highly selected patients avoiding radiation and chemotherapy. It is possible that more patients could be treated with surgery alone. The purpose of this analysis was to assess the technical feasibility of extending surgery-only treatment to all children with stage IA NLPHL. From this study group we identified a subset of NLPHL patients who had stage IA disease and then eliminated those with stage IA single node only. These patients with stage IA more than single node disease then comprised the cohort. Two pediatric surgical oncologists (J.H.A., P.F.E.) independently reviewed the initial staging crosssectional imaging of this cohort. Location of disease, extent of nodal involvement, and resectability were evaluated. Concordance between the surgeons was compared, and reasons for unresectablity were noted. Goals for resectability included complete removal of all visible disease without excessive morbidity or sacrifice of adjacent structures. Among the 183 patients with NLPHL who were enrolled on AHOD03P1, 47 patients with stage IA and more than a single node were identified. There were 36 male individuals (77%) and 11 female individuals (23%). Median age was 12.3 years (range, 4.4 to 20.7 y). Eleven cases were not evaluable due to insufficient imaging available for review. Among the 36 cases that were evaluated, involved nodal locations included submandibular (1), inguinal/iliac (5), and cervical (30). The median number of nodes requiring resection was 4 (range, 1 to 15). Thirty-four cases (94%) were felt to be resectable by at least one of the surgeons. Surgeon agreement on resectability was 81% (29/36). The resectability opinion differed between surgeons in 5 cervical and 2 iliac cases. In 2 patients, both surgeons agreed that a resection should not be offered. Nine patients were determined by at least one of the surgeons to not be a candidate for surgical resection alone due to morbidity and extent of the required procedure. Previous reports have described successful surgical resection alone for patients with NLPHL with limited disease.6,7,10 Although these series provide some evidence as to the feasibility of surgery only for some patients with NLPHL, their generalizability is limited by the retrospective nature, variable clinical stages included, and lack of uniformity in the resection performed.9 AHOD03B1, the first prospective well-controlled study, used this surgery-only strategy for a clearly defined group of patients. In this cohort of stage IA, single node disease with complete resection, 75% (39/52) avoided chemotherapy and radiation therapy with 100% survival.9 The results of this study prompted further inquiry into the feasibility of whether additional patients could potentially avoid the short and long-term effects of adjuvant therapy by extending the surgery-only treatment to a broader group of NLPHL patients. This study has demonstrated that based on imaging studies, the technical feasibility of surgery for children with stage I NLPHL is excellent within the context of a clinical trial and with central radiographic review support, and could be considered for further study. Future clinical trials could incorporate a comparison of surgical resection for stage I NLPHL disease with standard chemotherapy approaches, evaluating the morbidity and outcomes of each modality.

We have previously examined the effect of crizotonib (criz) and doxorubicin (dox) on cell lines of ALK+ anaplastic large cell lymphoma (ALCL), and found that while criz induces apoptosis, the effect is antagonized by dox. We also found that criz-induced apoptosis was associated with downregulation of the cell cycle check point modulator CDK2, which is required for transition from G1 into S phase. The current experiment examined cell cycle effects of the two drugs on the ALK+ ALCL cell line Karpas 299 (K299). K299 cells were incubated with slightly less than IC50 doses of each drug, alone and in combination, and compared to untreated controls. The cells were collected after six hours, suspended with PI/RNase staining solution, and acquired using a BD LSRFortessa (BD Biosciences, San Jose, CA) cell analyzer. Cell cycle analysis data were generated using FCS Express, version 5 (DeNovo Software, Los Angeles, CA) with the MultiCycle AV DNA analysis package. Criz showed marked decrease in S phase with increase in G1 phase compared to untreated cells, whereas both dox alone and in combination with criz showed mild increase in S phase with decrease in G1 phase compared to untreated cells. Results show that criz inhibits progression through cell cycle, while dox-treated cells progress through cell cycle. Cells treated with both drugs behave similarly to those with dox alone. These findings are consistent with doxorubicin antagonism of crizotinib at the level of the cell cycle in ALK+ ALCL

Low-grade B-cell lymphomas of long bones are, to our knowledge, unreported in young people. The few cases of long bone lymphomas reported in pediatric population were of diffuse large B-cell lymphoma type. Additionally, chronic sclerosing osteomyelitis is a rare recurring bone inflammation with prominent fibrosis with unknown etiology and unknown relationship to chronic recurrent multifocal osteomyelitis of children. We report a case of a 12-year-old boy with a recent history of Lyme disease and currently on treatment who presented with intermittent knee swelling with multifocal bone lesions of bilateral lower extremities that was subsequently diagnosed with the above rare disease. The patient underwent tibial bone biopsy revealing prominent fibrosis and B-cell lymphocytosis. The B-cells labeled with immunohistochemical stains CD20 and CD79a, and were negative with CD10, CD34, and TdT. Molecular studies unveiled clonal B-cells. The atypical B-cell proliferation appears to evolve to low-grade B-cell lymphoma. Marginal zone lymphoma is an indolent disease known to occur in adult patients with established association with bacterial infections such as Helicobacter pylori in peptic ulcer disease. Although the implications of B-cell clonality in this case are unclear, B-cell proliferation associated with Helicobacter pylori is responsive to antibiotic therapy. Therefore, eradication of infection may render resolution of clonal B-cell hyperplasia. Furthermore, the bone biopsy showed very prominent fibrosis consistent with chronic sclerosing osteomyelitis. Rare reported cases of multisite osteomyelitis have been attributed to Borrelia burgdorferi, the causative organism of Lyme disease. Several Lyme disease cases demonstrate B-cell pleocytosis in the cerebrospinal fluid. Currently, there is no clear documented association of Lyme disease with sclerosing osteomyelitis and clonal B-cell proliferation or lymphoma. Hence, reporting of this peculiar case is necessary to gain an understanding of this uncommon occurrence.

Renal allograft dysfunction in the first year post-transplant has many possible causes, commonly including T-cell or antibody-mediated rejection, polyomavirus nephropathy, or recurrence of recipient’s original disease. Rarely, hematological disorders such as post-transplant lymphoproliferative disease, lymphomas or leukemia may cause early allograft dysfunction, in which case they are often donor-derived. Here we report a unique case of renal allograft involvement by donor-derived B-cell acute lymphoblastic leukemia initially diagnosed through an allograft biopsy performed for renal dysfunction. The patient was successfully treated while keeping her graft. She eventually received an allogeneic stem cell transplant and is currently in remission. This article is protected by copyright. All rights reserved.

Objectives: To assess bone marrow (BM) sampling in academic medical centers. Methods: Data from 6,374 BM samples obtained in 32 centers in 2001 and 2011, including core length (CL), were analyzed. Results: BM included a biopsy (BMB; 93%) specimen, aspirate (BMA; 92%) specimen, or both (83%). The median (SD) CL was 12 (8.5) mm, and evaluable marrow was 9 (7.6) mm. Tissue contraction due to processing was 15%. BMB specimens were longer in adults younger than 60 years men, and bilateral, staging, and baseline samples. Only 4% of BMB and 2% of BMB/BMA samples were deemed inadequate for diagnosis. BM for plasma cell dyscrasias nonphysician operators, and ancillary studies usage increased while bilateral sampling decreased over the decade. BM-related quality assurance programs are infrequent. Conclusions: CL is shorter than recommended and varies with patient age and sex, clinical circumstances and center experience While pathologists render diagnoses on most cases irrespective of CL, BMB yield improvement is desirable.

BackgroundAnaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) shows 60-70% event free survival with standard treatments. Targeted therapies are being tested for increased benefit and/or reduced toxicity, but interactions with standard agents are not well known. MethodsWe exposed four ALCL cell lines to two targeted agents, crizotinib and brentuximab vedotin, and to two standard agents, doxorubicin and vinblastine. For each agent and combination, we measured apoptosis and expression of approximately 300 previously annotated genes of interest using targeted RNA-sequencing. An aurora kinase inhibitor, alisertib, was similarly tested for gene expression effects. ResultsOnly crizotinib, alone or in combination, showed significant effects (adjusted P<0.05) on expression and apoptosis. One hundred and nine of 277 gene expressions showed crizotinib-associated differential expression, mostly downregulation, 62 associated with apoptosis, and 28 associated with both crizotinib and apoptosis. Doxorubicin was antagonistic with crizotinib on gene expression and apoptosis. Brentuximab was synergistic with crizotinib in apoptosis, and not antagonistic in gene expression. Vinblastine also appeared synergistic with crizotinib but did not achieve statistical significance. Alisertib did not show significant expression changes. ConclusionsOur data suggest that crizotinib induces apoptosis through orderly changes in cell signaling associated with ALK inhibition. Expression effects of crizotinib and associated apoptosis are antagonized by doxorubicin, but apoptosis is synergized by brentuximab vedotin and possibly vinblastine. These findings suggest that concurrent use of crizotinib and doxorubicin may be counterproductive, while the pairing of crizotinib with brentuximab (or vinblastine) may increase efficacy. Alisertib did not induce expression changes at cytotoxic dosage.

Assay of cell-free DNA in blood offers an approach to assessment of tumor DNA. We sought to determine whether Epstein-Barr virus (EBV) DNA in cell-free blood is also a good surrogate for the presence of tumor DNA in children with Hodgkin lymphoma, as it is in adults, and whether it correlates with pediatric outcomes. Pediatric patients enrolled in a Children's Oncology Group trial (AHOD0031) were studied at baseline and at 8 days after the initiation of treatment. At baseline, EBV DNA in cell-free blood correlated with the presence of EBV in tumor, and EBV DNA 8 days after the initiation of therapy predicted inferior event-free survival. EBV DNA in cell-free blood warrants further investigation as a marker of inadequate tumor response in Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL.

Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617F mutation has been detected in ∼50% cases of MF. Elevated expression of high-mobility group AT hook 2 (HMGA2) has also been frequently observed in patients with MF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617F mutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617F mutation in hematopoiesis, we transduced bone marrow cells from Jak2V617F knockin mice with lentivirus expressing Hmga2 and performed bone marrow transplantation. Expression of Hmga2 enhanced megakaryopoiesis, increased extramedullary hematopoiesis, and accelerated the development of MF in mice expressing Jak2V617F Mechanistically, the data show that expression of Hmga2 enhances the activation of transforming growth factor-β1 (TGF-β1) and Cxcl12 pathways in mice expressing Jak2V617F In addition, expression of Hmga2 causes upregulation of Fzd2, Ifi27l2a, and TGF-β receptor 2. Forced expression of Cxcl12, Fzd2, or Ifi27l2a increases megakaryocytic differentiation and proliferation in the bone marrow of Jak2V617F mice, whereas TGF-β1 or Cxcl12 stimulation induces collagen deposition in the bone marrow mesenchymal stromal cells. Together, these findings demonstrate that expression of Hmga2 cooperates with Jak2V617F in the pathogenesis of MF.

Deletion of chromosome 20q [del(20q)] is a common chromosomal abnormality associated with myeloid neoplasms including myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), MDS/MPN overlap disorders and acute myeloid leukemia (AML). The del(20q) lesion is often associated with myeloproliferative features; it is present in patients with myelofibrosis (MF) at a high frequency (24%) and thus considered to be one of the most frequent cytogenetic abnormalities in MF (Wassie et al., Br J Haematol. 2015). The del(20q) lesion can also coexist with JAK2V617F mutation in MPN/MF. However, the target tumor-suppressor gene(s) within chromosome 20q involved in the pathogenesis of MF remains unknown.

PURPOSE Children's Oncology Group study AHOD03P1 was designed to determine whether excellent outcomes can be maintained for patients with low-risk, pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) with a strategy of resection alone or minimal chemotherapy. PATIENTS AND METHODS Patients with stage IA LPHL in a single node that was completely resected were observed without further therapy; recurrences were treated with three cycles of doxorubicin/vincristine/prednisone/cyclophosphamide (AV-PC). Patients with unresected stage IA or stage IIA LPHL were treated with three cycles of AV-PC. Patients with less than a complete response (CR) to AV-PC received 21-Gy involved-field radiation therapy (IFRT). RESULTS A total of 183 eligible patients were enrolled; 178 were evaluable. Of these, 52 patients underwent complete resection of a single node. There were 13 relapses at a median of 11.5 months; 5-year event-free survival (EFS) was 77% (range, 62% to 87%). A total of 135 patients received AV-PC; 126 were treated at diagnosis and nine at relapse after surgery alone. Eleven patients receiving AV-PC had less than CR and received IFRT. Fourteen first events occurred among 135 patients (12 relapses and two second malignancies). Two relapses occurred in patients who had received IFRT. Five-year EFS was 88.8% (95% CI, 81.8% to 93.2%). Five-year EFS for the entire cohort was 85.5% (95% CI, 79.2% to 90.1%); overall survival was 100%. CONCLUSION Some 75% of highly selected pediatric patients with LPHL may be spared chemotherapy after surgical resection alone. Pediatric LPHL has excellent EFS with chemotherapy that is less intensive than standard regimens; > 90% of patients can avoid radiation therapy. The salvage rate for the few relapses is high, with 100% survival overall.

• Loss of Ezh2 inhibits erythropoiesis but increases megakaryopoiesis in Jak2V617F knock-in mice. • Loss of Ezh2 induces rapid progression to myelofibrosis in mice expressing Jak2V617F. An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera–like disease, concomitant loss of Ezh2 significantly reduced the red blood cell andhematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion ofmegakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617Fexpressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, andHmga2were transcriptionally derepressed, and theH3K27me3 levels in these gene promoterswere significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617Fmice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increasedmegakaryocytic colonies in theBMof Jak2V617Fmice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice. (Blood. 2016;127(26):3410-3423)

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.

An activating JAK2V617F mutation has been found in ∼50% patients with myelofibrosis (MF). Inactivating mutations in histone methyltransferase enhancer of zeste homolog 2 (EZH2) also have been observed in patients with MF. Interestingly, inactivating EZH2 mutations are often associated with JAK2V617F mutation in MF, although their contributions in the pathogenesis of MF remain elusive. To determine the effects of concomitant loss of EZH2 and JAK2V617F mutation in hematopoiesis, we generated Ezh2-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F alone induced a polycythemia vera-like disease, concomitant loss of Ezh2 significantly reduced the red blood cell and hematocrit parameters but increased the platelet counts in Jak2V617F knock-in mice. Flow cytometric analysis showed impairment of erythroid differentiation and expansion of megakaryocytic precursors in Ezh2-deficient Jak2V617F mice. Moreover, loss of Ezh2 enhanced the repopulation capacity of Jak2V617F-expressing hematopoietic stem cells. Histopathologic analysis revealed extensive fibrosis in the bone marrow (BM) and spleen of Ezh2-deleted Jak2V617F mice. Transplantation of BM from Ezh2-deleted Jak2V617F mice into wild-type animals resulted in even faster progression to MF. Gene expression profiling and chromatin immunoprecipitation sequence analysis revealed that S100a8, S100a9, Ifi27l2a, and Hmga2 were transcriptionally derepressed, and the H3K27me3 levels in these gene promoters were significantly reduced on Ezh2 deletion in hematopoietic progenitors of Jak2V617F mice. Furthermore, overexpression of S100a8, S100a9, Ifi27l2a, or Hmga2 significantly increased megakaryocytic colonies in the BM of Jak2V617F mice, indicating a role for these Ezh2 target genes in altered megakaryopoiesis involved in MF. Overall, our results suggest that loss of Ezh2 cooperates with Jak2V617F in the development of MF in Jak2V617F-expressing mice.

High Mobility Group AT Hook 2 (HMGA2) is a non-histone chromatin protein that regulates gene transcription and controls cell proliferation, survival and self-renewal of stem cells. HMGA2 is expressed at a low level in normal adult hematopoietic progenitors but is highly expressed in hematopoietic progenitors of patients with Myelofibrosis (MF). However, the contribution of HMGA2 to the pathogenesis of MF remains unknown.

PURPOSE:To determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m(2) to treat children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic non-Hodgkin lymphoma (L-NHL).PATIENTS AND METHODS:Patients were treated on Pediatric Oncology Group Protocol POG 9404, which included random assignment to treatment with or without dexrazoxane given as a bolus infusion immediately before every dose of doxorubicin. Cardiac effects were assessed by echocardiographic measurements of left ventricular function and structure.RESULTS:Of 573 enrolled patients, 537 were eligible, evaluable, and randomly assigned to an arm with or without dexrazoxane. The 5-year event-free survival (with standard error) did not differ between groups: 77.2% (2.7%) for the dexrazoxane group versus 76.0% (2.7%) for the doxorubicin-only group (P = .9). The frequencies of severe grade 3 or 4 hematologic toxicity, infection, CNS events, and toxic deaths were similar in both groups (P ranged from .26 to .64). Of 11 second malignancies, eight occurred in patients who received dexrazoxane (P = .17). The mean left ventricular fractional shortening, wall thickness, and thickness-to-dimension ratio z scores measured 3 years after diagnosis were worse in the doxorubicin-alone group (n = 55 per group; P ≤ .01 for all comparisons). Mean fractional shortening z scores measured 3.5 to 6.4 years after diagnosis remained diminished and were lower in the 21 patients who received doxorubicin alone than in the 31 patients who received dexrazoxane (-2.03 v -0.24; P ≤ .001).CONCLUSION:Dexrazoxane was cardioprotective and did not compromise antitumor efficacy, did not increase the frequencies of toxicities, and was not associated with a significant increase in second malignancies with this doxorubicin-containing chemotherapy regimen. We recommend dexrazoxane as a cardioprotectant for children and adolescents who have malignancies treated with anthracyclines.