OBJECTIVE To determine the frequency, risk factors, and outcomes for vancomycin-resistant Enterococcus (VRE) colonization and infection in patients with newly diagnosed acute leukemia. DESIGN Retrospective clinical study with VRE molecular strain typing. SETTING A regional referral center for acute leukemia. PATIENTS Two hundred fourteen consecutive patients with newly diagnosed acute leukemia between 2006 and 2012. METHODS All patients had a culture of first stool and weekly surveillance for VRE. Clinical data were abstracted from the Intermountain Healthcare electronic data warehouse. VRE molecular typing was performed utilizing the semi-automated DiversiLab System. RESULTS The rate of VRE colonization was directly proportional to length of stay and was higher in patients with acute lymphoblastic leukemia. Risk factors associated with colonization include administration of corticosteroids (P=0.004) and carbapenems (P=0.009). Neither a colonized prior room occupant nor an increased unit colonization pressure affected colonization risk. Colonized patients with acute myelogenous leukemia had an increased risk of VRE bloodstream infection (BSI, P=0.002). Other risk factors for VRE BSI include severe neutropenia (P=0.04) and diarrhea (P=0.008). Fifty-eight percent of BSI isolates were identical or related by molecular typing. Eighty-nine percent of bloodstream isolates were identical or related to stool isolates identified by surveillance cultures. VRE BSI was associated with increased costs (P=0.0003) and possibly mortality. CONCLUSIONS VRE colonization has important consequences for patients with acute myelogenous leukemia undergoing induction therapy. For febrile neutropenic patients with acute myelogenous leukemia, use of empirical antibiotic regimens that avoid carbapenems and include VRE coverage may be helpful in decreasing the risks associated with VRE BSI.

Background: Current chemotherapy regimens in children with ALL produce disease-free survival (DFS) rates of greater than 80%. In contrast, adults with ALL have a much poorer prognosis, with DFS rates of 30-40%. Recent prospective studies suggest that young adults may have superior outcomes when treated with intensive pediatric regimens. We recently reported a 4-yr DFS and overall survival (OS) of 69% (n=78 who achieved CR) and 67% (n=92), respectively (DeAngelo et al. Leukemia 2015) using a native E. coliasparaginase based regimen. This phase II successor trial was performed to determine if a pediatric regimen using pegylated-asparaginase (peg-asp) could be feasibly administered to adults. Methods: Patients (pts) between 18-50 yrs with de novo ALL were eligible. The primary objective of this study was to determine the feasibility of a single dose of peg-asp during induction and of delivering peg-asp every 2 wks during a 30 wk consolidation period. The therapeutic backbone of this protocol was based on the very high-risk arm of the DFCI Childhood ALL Consortium Protocol 05-01. Pts received induction chemotherapy, which included doxorubicin, prednisone, vincristine, pegylated-asparaginase (peg-asp), and triple intrathecal therapy. Consolidation I consisted of a course of high-dose methotrexate, followed by a BFM-like intensification and a course of high-dose cytarabine, etoposide and dexamethasone. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of eight 3-wk courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 wks of IV peg-asp initially dosed at 2500 IU/m2every 2 wks. Continuation therapy consisted of 3 wk courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 yrs from complete remission (CR). Imatinib at 600 mg/d was administered to those pts who were Philadelphia chromosome (Ph) positive. Results: Of 112 pts enrolled, 110 were eligible. The first 65 pts were treated with the initial study design of IV peg-asp during induction and peg-asp every two wks for 15 doses during consolidation. However, due to the high frequency of asparaginase toxicities mainly hyperbilirubinemia, peg-asp was replaced with native E. coli asp at a dose of 25,000 IU/m2 IM during induction and the dose and frequency peg-asp was decreased to 2000 IU/m2 every 3 wks during the consolidation phase in the subsequent 45 pts. The median age was 32 yrs, (range, 18-50), 61% were male, 82% had B-lineage phenotype, and 21 were Ph positive. The CR rate after 4 wks was 89%. 70 pts had the opportunity to receive peg-asp intensification therapy (42 at the 2500 IU/m2 every 2 wks schedule and 28 on the 2000 IU/m2 every 3 wk schedule). Of the 42, 18 pts (43%; 80% CI, 32-54%) on the 2 wk schedule completed at least 13 of 15 doses of peg-asp (26 wks) and 22 of 28 pts (79%; 80% CI, 65-88%) on the 3 wk schedule completed at least 8 of 10 doses of peg-asp, which met the feasibility endpoint (lower bound CI > 60%). The median asp levels post the induction dose of peg-asp were 0.025, 0.78, 0.28, 0.10, at baseline, 7, 11 and 25 days and >0.20 for each consolidation time point for both the 2 and 3 wk cohorts. Two deaths occurred during induction therapy (sepsis; CNS hemorrhage). Post-induction four pts developed pancreatitis, 14 pts had an allergic reaction to the asp, 12 pts developed osteonecrosis, 2 had a bone fracture, 13 pts had thrombosis/embolism and 32 pts had a grade 3-4 neutropenic infection. With a median follow-up time of 39 mos, the estimated 3-yr DFS is 73% for those who achieved a CR (n=90) and the estimated 3-yr OS is 75%. Conclusions: The administration of a dose intensified pediatric regimen with peg-asp to adults with ALL is feasible. However, the dose and schedule of peg-asp that is well-tolerated in adults is lower and less frequent as compared to that of pediatric pts. Although the DFS and OS are high for an adult cohort, longer follow up is needed. Pediatric-like therapies, including those using intensive peg-asp, are tolerable in young adults with ALL and represent a major therapeutic advance. Table 1. Outcome Summary n 3-yr % OS [95% CI] n 3-yr % DFS [95% CI] All Pts./CR Pts. 110 75 [66-82] 90 73 [62-81] Immunophenotype B cell 90 74 [64-82] 72 70 [58-80] T cell 20 78 [52-91] 18 83 [57-94] Ph- 89 80 [70-87] 78 75 [63-84] Figure 1. Figure 1. Disclosures DeAngelo: Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Storring:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Stone:Pfizer: Consultancy; Juno: Consultancy; AROG: Consultancy; Amgen: Consultancy; Agios: Consultancy; Celator: Consultancy; Novartis: Research Funding; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Merck: Consultancy; Roche/Genetech: Consultancy.

Summary:Relapse is the major cause of treatment failure after allogeneic transplantation of children with juvenile myelomonocytic leukemia (JMML), and the role of post-transplant immunomodulation is poorly understood. We report a 12-month-old child with JMML relapsed after unrelated marrow transplantation who received cytoreduction followed by donor lymphocyte infusion (DLI) with improvement, and after addition of interferon-alpha (IFN) achieved complete donor chimerism. He was weaned from IFN and has maintained complete remission for 19 months. This is the first published report of a patient with non-monosomy-7 JMML responding to post-transplant immunomodulation and suggests a role for DLI plus IFN in these patients. Juvenile myelomonocytic leukemia (JMML) is a rare pediatric malignancy, which presents in infancy or early childhood with myeloproliferative features and hepatosplenomegally. Monosomy-7 occurs in one-quarter of these patients, and although JMML with monosomy-7 may progress more slowly, long-term outcome is the same as non-monosomy-7 JMML (10-year overall survival 6%). 1 Hematopoietic cell transplantation has led to improved outcome, with reports of 2-to 4-year overall survival varying from 24% (NMDP) to 54% (Japanese data). 2,3 The major cause of failure is relapse, with rates as high as 58% at 2 years. 2 In spite of the well-documented efficacy of post transplant immunomodulation in other disorders, published work suggesting a graft-versus-leukemia (GVL) effect of post-transplant donor lymphocyte infusion (DLI) or intereferon in JMML is limited, and responding patients have all had monosomy-7 JMML. [4][5][6] We describe a patient who relapsed early after unrelated allogeneic bone marrow transplantation for non-monosomy-7 JMML in whom DLI induced a partial response, and the addition of interferon-alpha (IFN) likely contributed to attaining and sustaining a prolonged complete remission. This observation suggests a role for post-transplant immunotherapy approaches in non-monosomy-7 JMML. Clinical historyThe patient presented at age 6 months with hepatosplenomegally, thrombocytopenia, and GI bleeding. Initial WBC was 42.8  10 9 /l and marrow assessment showed JMML (based on the International JMML Working Group criteria). 1 Cytogenetics were normal. The patient underwent a splenectomy followed by two courses of cytoreductive chemotherapy with flu/ara-C (fludarabine 30 mg/m 2 /day  5 days and cytosine arabinoside 2 g/m 2 / day  5 days), resulting in pathologic complete remission.The patient then underwent allogeneic stem cell transplant utilizing a preparative regimen of TBI (total 1200 cGy), cyclophosphamide (60 mg/kg  2), and ATG (total 75 mg/kg). Bone marrow from a 6/6 matched unrelated donor was infused with a dose of 12  10 6 CD34 þ cells/kg. GVHD prophylaxis consisted of cyclosporin and short-course methotrexate. Stage 3 skin (overall grade II, Glucksberg) acute GVHD was noted just after engraftment, but resolved with topical therapy. Day þ 100 whole blood chimerism by VNTR analysis was 90% d...

BACKGROUND Outcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi‐agent approach derived from a Dana‐Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752). METHODS The primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase. Imatinib was incorporated for Philadelphia chromosome–positive disease. After induction, the first consolidation incorporated clofarabine. Patients in remission could proceed to allogeneic hematopoietic cell transplantation (HCT) after induction and consolidation I. Those not receiving HCT went on to receive central nervous system, consolidation II, and continuation phases of treatment. RESULTS Thirty patients were enrolled: 19 achieved a complete remission (CR) after induction and 1 achieved CR after consolidation I for a CR rate of 67%. Sixteen patients underwent HCT. The proportion surviving at 1 year was 63%, and this met the primary endpoint. The 2‐year OS rate was 52% (n = 30), and the 2‐year disease‐free survival rate was 52% for patients achieving CR (n = 20). There was no survival advantage among those undergoing HCT. Therapy‐related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing. CONCLUSIONS Intensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016;122:2379–2388. © 2016 American Cancer Society.

Malignant infantile osteopetrosis (MIOP), a rare genetic disorder of the osteoclast, is fatal without hematopoietic stem cell transplantation. Primary pulmonary hypertension (PPH), a rare progressive disorder of the pulmonary circulation, is predominantly fatal in the absence of successful therapy. A clinical association between these two disorders has not been recognized and a pathophysiologic link between osteoclast function and pulmonary vascular pressure as a rationale for such an association is not readily apparent. Here, we report five infants with MIOP, without cardiac abnormalities, who were found to have PPH after undergoing stem cell transplantation. We suggest that PPH may be linked to a specific variant of MIOP and recognizing the potential for pulmonary hypertension in children with MIOP may lead to a more rapid diagnosis and life-saving intervention.