Journal articles on the topic 'D 3.5 UL 2008 N134'

590 Background: CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2) is an option for adjuvant therapy for patients with low risk early stage breast cancer. DD regimens as predicted by mathematical models of cancer growth and treatment response are superior. We previously demonstrated the safety of DD EC (epirubicin/cyclophosphamide) followed by paclitaxel at 10–11 day (d) intervals. We investigated the feasibility of administering DD adjuvant CMF every 14 d and then every 10–11 d in a 2-stage phase II trial. Methods: An initial cohort (A) was treated q 14 d with PEG-filgrastim (Neulasta) support. A second cohort (B) was treated every 10–11 d with filgrastim/Neupogen x 5 d and then, based on feasibility, modified (cohort C) to use 7 d filgrastim. The primary end point was feasibility defined as having ANC > 1.5 x 103/uL on day 1 of planned treatment for all 8 cycles with no grade 3 or higher non-hematologic toxicity. All three cohorts were tested using a Simon's two-stage optimal design with type I and type II errors set at 10%. This design would effectively discriminate between true tolerability (as protocol-defined) rates of< 60% and> 80%. Cohort A: 38 pts with early stage breast cancer were accrued from 3/2008 though 6/2008. Cohort B: 7 pts were accrued from June 2008 through August 2008. Cohort C: Is still open with 16 pts accrued from August 2008 through December 5, 2008. Results: Median age 51: range 38 to 78. Cohort A: 29/38 pts completed 8 cycles of CMF. The regimen was considered feasible. 2 other pts completed 7 cycles and were withdrawn for depression and grade 2 transaminitis. The 7 other pts completed between 1 and 6 cycles of CMF were withdrawn as follows: 3 personal, 1 (grade 3) bone pain, 2 allergy unrelated to CMF, and 1 seizure. Cohort B: 7 pts were accrued. 6 out of 7 pts could not complete 8 cycles of chemotherapy secondary to neutropenia and 1 secondary to grade 3 ALT elevation. Cohort C: Accrual has not been completed. 16 pts are currently enrolled. Conclusions: Dose dense adjuvant CMF is feasible at 14 d intervals with PEG-filgrastim support. Adjuvant CMF every 10–11 days with filgrastim given for 5 days beginning day 2 is not feasible. Accrual is ongoing for CMF at 10–11 days with filgrastim x 7 days. Updated results will be available for Cohort C. [Table: see text]

Abstract Background: Hematopoietic stem cell release is regulated by the sympathetic nervous system through the β (3) adrenergic receptor [Mendez-Ferrer et al. Nature 2008]. Peripheral sympathetic nerve neurons express the G-CSF receptor and stimulation of peripheral sympathetic nerve neurons with G-CSF reduced norepinephrine (NE) reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability [Lucas et al Blood 2012]. Based on preclinical data, we investigated the NE reuptake inhibitor desipramine in HSC mobilization. Despite augmentation with Plerixafor (CXCR4 inhibitor), 20% of all patients fail to mobilize 6*10^6 CD34 cells/kg in myeloma and the collection rate with G-CSF alone is 51.1% [Diperiso et al Blood 2012]. The cost of upfront plerixafor is $9,081 per patient while desipramine costs $40. We undertook a feasibility study of adult patients with MM undergoing autologous transplantation (ASCT) to study safety and efficacy of mobilization with desipramine and G-CSF. Patients & Methods: From 2013- 2014, 10 patients between the ages of 18-70, eligible for ASCT were enrolled. Desipramine 100mg daily was administered for 7 days, starting 4 days prior to starting G-CSF (D-3) and continue along with G-CSF for a total of 7 days. CBC and CD34 counts were determined on Day+5. If CD34 counts were > 10/ul, stem cell collection was commenced and if < 10/ul, plerixafor was added as salvage therapy. The endpoints were safety and efficacy in mobilizing CD34 cells for ASCT in patients with multiple myeloma. This trial was registered at clinicaltrials.gov as NCT01899326. Results Six of ten patients enrolled completed the protocol and underwent stem cell transplantation. Reasons for not completing were 1. Lack of insurance coverage 2. Non-compliance with study treatment 3. Disease relapse prior to ASCT. Five patients did not have any grade 3 or 4 adverse events and 1 had disease-related Grade 4 hypercalcemia and Grade 2 AKI at the time of stem cell mobilization. No patients had significant treatment related adverse effects. All 6 patients who completed the protocol achieved the target collection of 5*10^6 CD34 cells/kg. Four patients achieved 6*10^6 CD34 cells/kg or more and the remaining 2 patients achieved 5.52 and 5.92 *10^6 CD34 cells/kg respectively. Among the 6 patients, 2 patients received salvage plerixafor. The median time to achieve WBC >1000/ul, ANC >500/ul and platelets>20k was 11.5, 11, 13.5 days Table 1. Age Ind. Regimne Disease status P PB CD34/ul CD34 collected *10^6 / kg Total CD34/kg collected Engraftment (Days to) Adverse effects from desipramine D1 D2 D3 D4 D2 D3 D4 ANC >0.5 Platelets> 20k G1,G2 G3,G4 1 62 Free λ VRD VGPR N 45.8 66.0 7.01 7.01 12 13 none none 2 50 Free λ VRD VGPR N 88.0 143.5 12.22 12.22 12 12 none none 3 58 IgA VCD VGPR N 38.0 67.7 31.6 4.22 2.75 6.97 13 17 none none 4 70 IgAκ VRD VGPR Y 2.40 40.2 16.6 4.31 1.61 5.92 12 14 none none 5 56 IgGκ VCD VGPR Y 8.70 11.9 37.1 19.4 1.33 4.57 1.61 7.51 11 12 none none 6 70 IgGλ VD RD Relapse N 76.2 97.1 5.54 5.54 11 20 AKI hypercalcemia P-Plerixafor; V-Velcade; R-Lenalidomide; D-Dexamethasone; C-Cyclophosphamide Conclusions Overall G-CSF + Desipramine combination appears to be safe, well tolerated and shows signs of efficacy. G-CSF and desipramine was successful in 4/6 (66%) and all achieved the stem cell collection in 2 days or less. Desipramine, GCSF and Plerixafor was successful in all (6/6) patients to achieve a target of 5*10^6 CD34 cells/kg. The mean number of CD34 cells collected in the desipramine+ G-CSF mobilisers was 7.24*10^6 CD34 cells/kg which, based on historical data, is higher than what would be expected with G-CSF alone even though 3/4 of these patients had lenalidomide as induction therapy. Based on these results, a phase II clinical study evaluating the efficacy of G-CSF with desipramine with or without salvage plerixafor in multiple myeloma and lymphoma will be initiated. Disclosures Barta: Seattle Genetics: Research Funding.

Abstract Abstract 2065 Poster Board II-42 Background: Hypomethylating agents have significant clinical activity in myelodysplastic syndromes (MDS) and AML. In AML, we recently demonstrated a novel epigenetic mechanism of action for the proteasome inhibitor bortezomib (Liu, Blood 2008). Bortezomib induced hypomethylation of leukemic cells in vitro and in vivo via depletion of the Sp1/NF-kB transcriptional activation complex on the DNA methyltransferase 1 (DNMT1) gene promoter, which results in down-regulation of DNMT1 mRNA and enzyme, DNA hypomethylation and re-expression of otherwise hypermethylated target genes. Based on this preclinical work, we designed a phase I dose escalation study of 5-azacytidine (AZA) in combination with bortezomib in AML. Methods: Adults with relapsed or refractory AML by WHO criteria and preserved organ function with ECOG ≤2 were eligible. Previous decitabine or AZA was permitted. Patients received AZA at 75mg/m2 IV daily for days (d) 1-7. Bortezomib was gradually dose escalated–dose level 1 (DL 1): 0.7mg/m2 by IV push given immediately after AZA on d 2 and 5; DL 2: 0.7mg/m2 on d 2, 5, 9, and 12; DL 3: 1.0mg/m2 on d 2, 5, 9, and 12; and DL 4: 1.3mg/m2 on d 2, 5, 9, and 12. Cycles were repeated every 28 d, regardless of count recovery or response at least until 3 cycles were administered. Responses were graded by International Working Group criteria for AML (Cheson, JCO 2003). Bortezomib was discontinued after 3 cycles if no objective response of complete remission (CR), CR with incomplete count recovery (CRi), or partial remission (PR) was achieved, but AZA could be continued beyond this timepoint in the absence of disease progression. For responding patients, 12 or more cycles of therapy were permitted. Dose limiting toxicities (DLT) were assigned for cycle 1 of therapy. Given the high likelihood of infection in this population regardless of therapy, infection was not considered a DLT. Six additional patients were treated at the recommended phase 2 dose (RP2D). Results: 23 patients were enrolled with a median age of 65 years (range, 42-81) and had received a median of 2 prior inductions (range, 1-5). Median presenting WBC was 3,700/uL (500-59,100/uL); median BM blast was 26% (2-93%). 14 patients were refractory to last therapy received, including 4 with primary refractory AML. 9 patients had relapsed disease; all but 2 of these had prior CR duration <1 year. Patients received a median of 2 cycles of study therapy (range, 1-12+ cycles). Dose escalation was halted once the target bortezomib dose was reached; the RP2D was AZA at 75mg/m2 d 1-7 plus bortezomib 1.3mg/m2 d, 2, 5, 9, 12. Though no toxicities were considered to be DLT in this study, infection and/or febrile neutropenia were universal. Death within 8 weeks occurred in 5 patients (22%) due to pneumonia (1), sepsis (1), or progressive disease (3). Two patients had discontinuation of bortezomib after 2 cycles due to Grade 3 neuropathy; only 1 patient received bortezomib beyond 3 cycles. In 3 patients without objective response (and with no progression), AZA alone was continued after 3 cycles of combination therapy; each reported a subjective improvement in fatigue without bortezomib. Overall, the objective response rate was 26% (6/23). Responses were as follows: 3- CR, 2- CRi, and 1-PR. One CRi patient (in cytogenetic remission also) who discontinued study treatment after 2 cycles due to unrelated trauma subsequently had complete count recovery, but a repeat marrow examination was not performed. Three patients went on to allogeneic transplantation due to response achieved. Response followed the typical pattern of azanucleoside activity, requiring more than one cycle of therapy; the median number of cycles to initial response was 2 (range, 1-5). 5/6 responders had response to combination therapy; one patient responded following 5 cycles of treatment, the last 2 cycles with AZA as a single agent. Conclusions: The combination of 5-azacytidine and bortezomib is well tolerated and active in this cohort of relapsed or refractory AML patients. Additional studies to further elucidate the role of proteasome inhibition as a mediator of hypomethylating activity in AML are warranted. Correlatives studies are ongoing. Disclosures: Blum: Celgene: Research Funding.

Background: Allogeneic stem cell transplantation (AlloSCT) from an HLA-matched sibling donor is the only known curative therapy in patients with high-risk SCD (Talano/Cairo, EJH, 2015). Unfortunately only about 15% of high risk patients with SCD have an HLA-matched unaffected sibling donor. T cell depletion has been employed to reduce AGVHD e.g., CD3/CD19 cell depletion (Barfiled RC, et al, Cytotherapy, 2004), αβ T-cell/CD19 cell depletion (Locatelli F, et al, Blood, 2017), CD34+ positive selection (Aversa F, et al, NEJM, 1998). MUD transplantation in high-risk SCD recipients has shown unexpectedly high rates of CGVHD (Shenoy et al, Blood, 2016). We reported a very low incidence of acute and chronic GVHD in pediatric recipients receiving CD34 enriched HPC products with PB MNC addback with 2 x 105 CD3/kg from MUD donors (Geyer/Cairo et al, BJH, 2012). Furthermore, rapid NK cell reconstitution after AlloSCT is associated with a significant improvement in 1yr OS (Pical-Izard, BBMT, 2015; Dunbar et al, Hematologica, 2008). Recently, we reported promising results for high-risk SCD patients at 1 year follow-up after FHI CD34 enriched/PBMNC with addback AlloSCT with the probability of 1-year overall survival (OS) n=17; 88.2% (CI95: 60.6-96.9) (Talano/Cairo, ASH, 2017), expanding the donor pool and hopefully improving outcomes for high-risk patients with SCD. Objective: To investigate donor chimerism, immune cell reconstitution and NK cell function in high-risk patients with SCD following AlloSCT using FHI CD34 enrichment/PBMNC (2 x 105 CD3/kg) addback. Methods: Twenty-one eligible SCD patients (2-<21 yrs) were enrolled. Nineteen patients received hydroxyurea, azathioprine, fludarabine, busulfan, thiotepa, cyclophosphamide, R-ATG, and TLI followed by FHI AlloSCT to date (Talano/Cairo, ASH, 2017). CD34 cells were enriched using the CliniMACS® system, kindly provided by Miltenyi Biotec, with a target dose of 10 x 106 CD34+ cells/kg with a PBMNC addback dose of 2x10*5 CD3/kg in the final product. Whole blood and RBC chimerism (estimated using CD71 to isolate an eythroid lineage-enriched fraction) were determined by STR. Immune cell and subset reconstitution was assessed by flow cytometry as previously described (Geyer/Cairo et al. BJH, 2012). NK function was determined by cytotoxic activity against K562 tumor targets at 10:1 E:T ratio by europium release assay and intracellular LAMP-1 (CD107a) and granzyme B expression by flow cytometry as previously described (Chu/Cairo et al, Can Imm Res, 2015). Results: There was 100% engraftment of neutrophils and platelets. The median day post-HISCT to neutrophil and platelet engraftment was +9 and +19, respectively. Whole blood donor chimerism (mean±SEM) at 1-year, 2-year, and 3-year post-HISCT was 97±1%, 97±1%, 97±1%, respectively (Fig.1). Donor chimerism for CD71+ RBCs (mean±SEM) at 1-year, 2-year, 3-year post-HISCT was 97±2%, 98±1%, 98±1%, respectively (Fig.1). Immune reconstitution of CD3, CD4, CD8, and CD19 was evaluated. The time to recovery of minimally normal levels post-HISCT of CD3 (800 cells/ul), CD4 (400 cells/ul), CD8 (200 cells/ul), and CD19 (200 cells/ul), was approximately 365, 365, 270, and 60 days post-HISCT (Fig.2), respectively. Probability of Grade II-IV AGVHD, CGVHD and 1 year EFS/OS was 6.2%, 6.7% and 90%, respectively. NK reconstitution was rapid and peaked at d+30 (36±9%, 2710cells/ml). NK cytotoxicity against K562 at a E:T=10:1 peaked at d+30 (26±3%) and d+180 (28±3%) vs at pre-t (16±2%) (p<0.01) (Fig. 3A). Consistent with increased NK cytotoxicity, CD56dimCD3- subset was increased at d+30 vs pre- HISCT (p<0.05). The NK activation marker, CD107a peaked at d+30 (38±9%) and d+180 (41±6%) (Fig.3B). More over, reconstituted NK cells expressed higher level of activating receptors NKp46 (24±9%), NKG2D (32±9%) and KIR2DS (8±3%) and inhibitory receptors NKG2A (33±9%), CD94 (28±9%) and KIR2DL2/3 (11±2%) at d+30 compared to other time points. Conclusion: Despite a 5 log depletion of T cells, the PBMNC addback (fixed at 2 x 105 CD3/kg) facilitated rapid donor chimerism and immune reconstitution with a low probability of Grade II-IV AGVHD. The rapid NK reconstitution may have in part contributed to the excellent 1yr OS in the FHI study. (Supported by FDA R01FD004090 (MSC)). Disclosures Cairo: Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau; Osuka: Research Funding; Miltenyi: Other: MTA.

Abstract Introduction Ruxolitinib is a selective JAK 1/2 inhibitor, which shows an excellent treatment outcome in myelofibrosis (MF) patients. Main side effect of JAK 1/2 inhibitors is an increased risk of infection. JAK1/2 inhibition may interfere with the differentiation of interferon-γ (IFN-γ) producing Th1 cells and IFN-γ is a key cytokine involved in protective immunity against Mycobacterium tuberculosis(TB). During COMPORT-II trial, a case of disseminated TB with ruxolitinib was reported. Here, we analyze the efficacy and safety of ruxolitinib in Korean MF patients and report cases of TB lymphadenitis during the treatment. Methods Forty-nine patients diagnosed with PMF, PPV-MF or PET-MF have been enrolled and at this time twenty patients are evaluable (median age; 63 years, 37-80). Starting dose of ruxolitinib was determined based on each patient’s baseline platelet count (20 mg bid/d for a baseline platelet more than 200,000/µL, 15 mg bid/d for 100,000-200,000/uL). To determine the efficacy of ruxolitinib, we serially assessed the spleen size by palpation, myelofibrosis symptom assessment using MFSAF and BM examination with JAK2V617Fmutation allele burden. Among 20 evaluable patients, 16 assessed IFN-γ release assays (IGRAs, quantiFERON-TB Gold test) before starting ruxolitinib. Results Of total twenty patients, 12 (60.0%), 3 (15.0%) and 5 (25.0%) were PMF, PPV-MF and PET-MF, respectively. By DIPSS, 13 (65.0%) was Int-2 risk, 3 (15.0%) and 4 (20.0%) were Int-1 and high risk. Eleven patients started with 20 mg bid/d (median baseline platelet: 302,000/uL, 206,000-814,000) and nine were 15 mg bid/d (median; 139,000/uL, 100,000-194,000). Median baseline total symptom score (TSS) was 12 (1-36) and palpable spleen length was 19 cm (1-30). JAK2V617Fmutation was positive in 13 (65.0%) patients (median allele burden; 87.1%, 26.2-93.7). Median time of ruxolitinib exposure was 2.0 ms. (0.8-6.2). Two patients increased TSS following ruxolitinib treatment, however, median maximal reduction in TSS was above 90.9% (27.8-100) and 64.7% of patients showed more than 50% reduction of TSS with ruxolitinib. In an aspect of spleen length, all except two patients showed decreased palpable spleen length. Median maximal reduction in spleen length was 70.2% (0-100) and 72.2% of patients showed more than 35% reduction in spleen length with ruxolitinib. Three patients (15.0%) experienced gr. 3/4 thrombocytopenia and one (5.0%) gr. 3 neutropenia. Among patients who assessed pre-treatment IGRAs, only one revealed positive IGRAs. Since there was no evidence of active TB in symptom and radiologic examination, he was diagnosed as latent TB infection (LTBI) and started 9 ms.-isoniazid (INH) treatment. He had a huge hepatosplenomegaly combined with large amount of ascites which needed frequent paracentesis, hence, we started ruxolitinib with INH treatment. He showed no evidence of active TB and achieved negative IGRAs result on 5 ms. of ruxolitinib treatment. On 1 m. and 5 ms. of ruxolirinib treatment, two patients developed pyrexia and neck masses which were diagnosed as TB lymphadenitis. All of them had no previous history of TB and showed negative results in pre-treatment IGRAs and radiologic examinations. First patient discontinued ruxolitinib by herself and eventually died of MF progression 2 ms. later. Second patient continued ruxolitinib treatment with TB medication and there was no evidence of active TB or MF progression on 5 ms. of ruxolitinib treatment. Conclusions Ruxolitinib was generally well tolerated and showed an excellent treatment outcome in Korean MF patients. By 2008 WHO report, intermediate burden of TB cases exist in Korea, hence, TB is still endemic in Korea. According to 2011 Korean Guidelines for TB, LTBI should be treated in patients receiving immunosupressive agents including TNF-α inhibitors. Although further prospective investigations on the incidence of TB with JAK 1/2 inhibitors in TB endemic countries are warranted, it seems to be reasonable to check the possibility of LTBI before starting JAK 1/2 inhibitors. LTBI confirmed patients receiving JAK 1/2 inhibitors may be deemed a high risk of active TB and consider LTBI treatment. Furthermore, it is necessary to use a caution for active TB infection during the treatment of JAK 1/2 inhibitors in such countries. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2234 Introduction/Background: Immunosuppressive therapy is the best alternative for patients with severe aplastic anemia (SAA) without matched sibling donor or with age > 40 years. Since 1988, an alternative protocol was developed with cyclosporine (CSA) and prednisone (PRED) due to irregularity in distribution of anti-thymocyte globulin (ATG) in Brazil. This study aims to show the results of this treatment on the quality of response, overall survival and development of clonal evolution. Materials and methods: 384 patients diagnosed with SAA (Camitta and Bacigalupo criteria) were evaluable by medical records review from 12/1988 to 12/2008. The immunosuppressive therapy consisted of CSA: 12mg/kg/day BID from day (D)1- D8, then 7mg/kg/day BID until 1 year. After that CSA was progressively tapered (5% each month) and ultimately stopped usually by two years. CSA levels were kept between 200–400ng/ml. PRED: 2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on PRED dose was tapered 20% each week. Sulfamethoxazole-trimethoprim and fluconazole were used for prophylaxis against Pneumocystis jiroveci (P carinni) and fungal diseases, respectively. Treatment response was defined as Table 1. Treatment evaluation was performed at 6 weeks, 3, 6 and 12 months and then yearly. At diagnosis: median age was 21 years (2-75), disease duration 95 days (2-4749), and median number of transfusions were 12 (0-200). Etiology was idiopathic in 78%. In peripheral blood, median hemoglobin was 7.4g/dL, granulocytes 580/uL, platelets 12.000/uL and reticulocyte 0.5% (corrected value). 60% of the patients had not been treated previously. Results: Overall survival was 61% ± 3 with a median follow-up of 7 years (range: 2 months - 23 years). Response to treatment: 51% had some degree of response, with good quality of life and transfusions independent (143 patients with complete response and 53 partial response). 36 patients had no response and there were 96 deaths. Fifty six patients have lost follow-up. Most patients achieved response between 3 and 6 months of therapy. In multivariate analysis the number of neutrophils ≥ 200/uL (p = 0.009), platelets ≥ 12.000/uL (p = 0.018), reticulocyte ≥ 0.5% (p <0.001) and starting treatment after 1997 (p = 0.002) had an impact on overall survival. Patients with 15 or more previous transfusions (p = 0.006) and age ≥ 40 years (p = 0.003) had lower survival. Overall survival was 63% ± 4 and 42% ± 6 for for patients with severe disease and very severe aplastic anemia (p <0.001). The subgroup analysis of patients under 10 years old had similar results. Among patients with response, thirty-four remained dependent of CSA. Cumulative incidence of relapse was 28% ± 4 within a median of 4.4 years. Hypertension, gingival hypertrophy and diabetes mellitus were common, but easily controlled. The rate of clonal evolution among this cohort was 7.81% (16 patients developed Paroxysmal Nocturnal Hemoglobinuria, 9 Myelodysplastic Syndrome and 5 Acute Myeloid Leukemia). Conclusion: This study, with a long follow-up, has demonstrated that the overall survival using CSA and PRED is similar to that reported with ATG therapy. Even patients with partial responses had achieved good quality of life, free from transfusions and infections. Survival was influenced by the neutrophils, platelet counts, reticulocyte, number of transfusions, age at diagnosis, and therapy started after 1997. The incidence of clonal evolution was lower when compared to reported trials with ATG + CSA. Disclosures: Oliveira: Alexion: Speakers Bureau. Funke: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pasquini: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Abstract 3293 Background: The hypomethylating agent decitabine has significant activity in AML. We previously demonstrated a novel epigenetic mechanism of action for the proteasome inhibitor bortezomib in AML cells (Liu, Blood 2008). Bortezomib induced hypomethylation of leukemic cells in vitro and in vivo via disruption of the Sp1/NF-kB transcriptional activation complex on the DNA methyltransferase 1 (DNMT1) gene promoter, which resulted in down-regulation of DNMT1 mRNA and protein levels, DNA hypomethylation, and re-expression of otherwise hypermethylated target genes. Based on this, we designed a phase 1 dose escalation trial of decitabine in combination with bortezomib. Methods: Adults with high risk AML who had preserved organ function and ECOG ≤2 were eligible. High risk AML included relapsed/refractory AML or age>60 years with previously untreated disease (if ineligible for or refused standard induction therapy). Patients received decitabine at 20mg/m2 IV daily for days (d) 1–10 of 28 d cycles with dose modification in subsequent cycles based on response and myelosuppression. Bortezomib (given immediately after decitabine) was gradually dose escalated in standard 3+3 fashion from 0.7mg/m2 on d 5 and 8 to the target dose of 1.3mg/m2 on d 5, 8, 12, and 15. Cycles were repeated every 28 d, regardless of count recovery. The plan was to administer 3 cycles if possible before discontinuation due to lack of response. For responding pts, therapy was continued indefinitely. Six additional pts were treated at the recommended phase 2 dose. Dose limiting toxicities (DLT) were assigned for cycle 1 of therapy. Given the high likelihood of infection in this population regardless of therapy, infection was not considered a DLT unless toxicity exceeded that expected with conventional therapy. Results: 19 pts were enrolled with a median age of 69 years (range, 32–83). 12 pts were age>70. 10 pts were previously untreated. Median presenting WBC count was 3,900/uL (range, 1,300-69,200/uL); median bone marrow blast was 34%. Patients received a median of 2 cycles of therapy (range, 1–14 cycles). Two pts received combination therapy beyond 3 cycles of treatment; one received combination for 8 cycles, then decitabine alone for 6 additional cycles, and the other received combination for 4 cycles, then decitabine alone for 6 additional cycles. Dose escalation was halted once the target bortezomib dose was reached; the MTD was decitabine at 20mg/m2 d 1–10 plus bortezomib 1.3mg/m2 d 5, 8, 12, and 15. One DLT of death due to sepsis occurred in dose level 3. Febrile neutropenia and infectious complications were frequent. Death within 8 weeks occurred in 4 pts (21%). Neuropathy attributable to bortezomib, though not meeting DLT criteria, was problematic with repetitive cycles of administration. Specifically, two pts had Grade 3 neuropathy requiring discontinuation of treatment. Responses occurred in 4/10 previously untreated pts: 3 had complete remission (CR) and one had CR with incomplete blood count recovery (CRi). One 84 year old pt with complex karyotype discontinued therapy after one cycle due to fatigue with persistent disease (non-responder). Notably, the pt subsequently had complete count recovery and lived for 14 months with no additional treatment, refusing further marrow evaluation of response. Response durations for the 3 CR were as follows: 12 months, 9 months, and the last patient died in CR after 10 months response duration due to unrelated and preexisting cardiac disease. The CRi lasted 3 months before relapse. Responses occurred in 2/9 relapsed/refractory pts. Both had CRi. Response duration for one patient was only 2 months. The other had allogeneic transplant in first remission 22 months ago before recently expiring in remission with transplant-related complications. In 3/6 responders with abnormal karyotype, two achieved cytogenetic CR. Conclusions: The combination of decitabine and bortezomib was reasonably well tolerated and active in high risk AML. Neuropathy beyond cycle 1 limited prolonged exposure to both agents. Given recent data suggesting equivalent efficacy with weekly dosing of bortezomib in multidrug treatments for myeloma, modification of the bortezomib schedule may facilitate more prolonged exposure to the combination. A phase 2 study of this combination is being planned, with bortezomib modification as noted. Correlative studies are ongoing. NCI U01 CA 76576, NIH/NCI K23CA120708. Disclosures: Blum: Celgene: Research Funding. Off Label Use: decitabine and bortezomib in AML.

Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Abstract 4443 Introduction: Various chemotherapeutic agents particularly cyclophosphamide (CY) are utilized in combination with growth factors in an attempt to increase the number of stem cells available for collection in the peripheral blood. Plerixafor (P) is a reversible antagonist of CXCR4 and interrupts its interaction with SDF-1. This results in a rapid release of hematopoietic stem cells from the marrow to the circulation. Recent pivotal phase III trial data has established the efficacy of P in combination with G-CSF (G) in patients who had failed prior attempts at stem cell collection. However, there is limited data about the utility of plerixafor in patients who are being mobilized with chemotherapy and G. Method: In this single institution study of uniformly treated patients we describe our experience with the use of P as a salvage option in patients who fail to optimally mobilize CD34+ cells (>5 × 106 CD34+ cells/kg). Patients received CY (3-4 g/m2) followed by GCSF (10 mcg/kg) from day 1 to day 10. Thirteen patients (6 NHL, 4 MM, 2 Hodgkin lymphoma, 1 Ewings sarcoma) received salvage P from 2008–2010. Their outcomes were compared with 10 matched, historic controls mobilized with (CY n=8; CY + etoposide n=1; CY + topotecan n=1) plus G-CSF (10mcg/kg/d) identified from our institutional database. Data was collected on mobilization and transplant outcomes and analyzed utilizing SPSS version 13.0. Patients receiving P were closely matched to historic controls (CY+G). Result: Both groups were similar with regards to age, gender, disease type, prior therapies and performance status (p>0.05 for all). Patients in the P arm received a median of 2.5 doses (range 1–8). The mean CD34+ count was 21.5cells/ul in the P arm and 32.5 cells/ul in the CY+G arm (p=0.2). Similarly, no significant difference was observed in the average number of apheresis sessions in the P vs. CY+G arms (4.2 vs. 4.4, p=0.8) or the total number of CD34+ stem cells collected (4.0×106/kg vs. 3.9×106/kg, p=0.9). However, 7 out of the 13 patients who received P did have an increase of >10 CD34+ cells/ul in their peripheral blood. Utilizing a cut-off of 5×106 CD34+/kg, 3 (23%) patients in the P arm and 3 (30%) patients in the CY+G arm had a successful harvest. Three NHL patients required >4 doses of P, but all eventually collected >2 × 106 CD34+ cells/kg. Neutrophil and platelet engraftment dynamics were similar in both groups of patients. Median time to neutrophil engraftment was 10 days for both groups, p=0.8, and to platelet engraftment was 22 days vs. 20.5 days, p=0.1, respectively for P vs. CY+G. Conclusion: Our limited single-center retrospective case-controlled outcomes data, suggests that when compared with CY+G, the addition of P as a salvage agent does not significantly improve mobilization outcomes. Further evaluation is needed to combine P with CY+G in terms of optimal timing and potentially dosing of chemotherapy agents utilized. We suggest that the combination P+G would provide better potential outcomes such as improved collection and less hospitalization and reduce the use of chemo-mobilization prior to an Autologous Hematopoietic Stem Cell Transplant. Disclosures: No relevant conflicts of interest to declare.

I ntroduction : Paroxysmal nocturnal hemoglobinuria (PNH) often presents as hemolysis and/or bone marrow failure. Flow cytometric testing can accurately detect PNH. However, the long term studies on PNH clone size and how it relates to clinical course are few. We sought to understand how PNH clone size correlates with clinical course over time and the impacts on clone size with different treatments. Here we report long term clone size monitoring and clinical data of 57 patients with PNH in a single intuition. Methods : High sensitivity PNH flow cytometry (0.01% limit of detection) was performed with FLAER-FITC, CD64-PE, CD14-ECD, CD15-PC5, CD24-AA7500, CD45-KO for neutrophils & monocytes; CD59-PE and CD235a-AA750 for RBCs. Retrospective analysis was done in the positive PNH cases from 2008-2019 at OHSU. Total 173 cases for 57 patients; including 27 females and 30 males, 52 adults and 5 pediatrics, with a mean age of 45 (range 9-78). We also reviewed results of serum LDH, bone marrow biopsies and molecular/cytogenetics of these patients. Among of these patients, 18 patients (11 females and 7 males, mean age 49.33, age range 29-73) with long term (at least over 4 years) follow-up have more than 3 PNH tests. Besides PNH clone on RBC and PMN, we also reviewed results of WBC count (x103/ul), Hb (g/dL), PLT (x103/ul) serum LDH (U/L), bone marrow biopsy reports and molecular/cytogenetics findings in these patients. Results: Among 57 patients, there are 30 aplastic anemia (AA) patients (53.63%), 7 AA patients progressing to PNH (AA&PNH, 12.28%), 5 myelodysplastic syndromes (MDS, 8.77%), 12 PNH patients (21.05%), 1 pancytopenia, 1 autoimmune disease, 1 thrombosis. The diagnosis of AA and MDS were confirmed by bone marrow biopsy and molecular/cytogenetics. Significantly higher levels of all PNH clones were observed in PNH and AA/ PNH, compared to AA (all P &lt;0.001) and MDS (all P&lt;0.05) shown in Figure A-D. LDH was higher in PNH and AA/PNH than AA and MDS groups (P&lt;0.001, Figure E). LDH demonstrated positive correlation with PNH clone size in RBC-type-III, neutrophils and monocytes (all P&lt;0.0001, R= 0.4447, 0.5469, 0.5711, respectively, Figure F). No correlation was observed between LDH and RBC-type-II. Long term (4-11 years ) follow up include 18 patients were divided into 4 groups: 5 AA treated with immunosuppressant only, 5 AA treated with immunosuppressants and/or eltrombopag, 5 classic PNH or AA that progressed to PNH treated with immunosuppressants and/or eculizumab, and 3 PNH with observation and supplements only. The study showed immunosuppression only has lowest PNH clone size for both RBC and WBC (Figure G-H). As for the Hb and WBC count, there were no statistics differences among 4 groups (Figure I-J). Decreased PLT was detected in eltrombopag group (Figure K). Significantly, increased LDH was observed in the observation/supplement group (Figure L). Interestingly, all these 3 patients without special treatment have high PNH clones and LDH from diagnosis to now over 10 years. Despite receiving basic supportive care, the patients' clinical courses have been stable with only supplementation of vitamin B12 and Folic Acid. Conclusions : Positive PNH test was most frequently seen in AA patients. AA has lower PNH clone size and LDH than those of PNH patients or AA progressed to PNH patients. For all patients, PNH population showed positive correlation with LDH. Our study suggest that it is necessary to follow PNH clone size, as this may impact the decision of when to start therapy with what agents. Figure Disclosures No relevant conflicts of interest to declare.

TPS6635 Background: FLT3-ITD AML are associated with poor prognosis. We identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 2008; Borthakur G., Haematologica, 2010). FLT3-ITD is associated with overexpression of chemokine receptor CXCR4 and we found increased in vivo activity of S combined with CXCR4 inhibitor Plerixafor (P) and G-CSF (G) (Zeng Z et.al. Blood 2009). Here we report first data testing this concept in patients with R/R FLT3-ITD AML. Methods: G (10 ug/kg) and P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400-600mg), S on d 1 - 28(one cycle). G/P was held when blasts > 5x104/uL. CD34, 38, 123, CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were measured by flow cytometry. Results: 10 patients have been treated so far : 2 achieved CRp, 4 PR and 4 failed (NR), for an overall response rate of 6/10; 3/6 responders and 4/4 NR were previously treated with FLT3 inhibitors. 4/10 pts. developed hyperleukocytosis (and missed 1 to 5 doses of G/P), 6 skin rash and 3 hypertension. Analysis of cells mobilized in 22 cycles revealed a 29-fold increase in WBC, 41-fold in absolute blasts, 77-fold in granulocytes. Increase in circulating stem/progenitor cells was as follows: CD34+: 231-fold, CD34+/38- : 90-, CD34+/38-/123+(LSC) : 148-, CXCR4+: 139-, VLA-4+ : 68- and CD44+: 82-fold. Increase in LSC was correlated with baseline blasts and VLA4, not with CXCR4. FISH confirmed mobilization of leukemic cells. Increased levels of pERK and pAKT were observed in mobilized cells. Conclusion: The combination of G-CSF+Plerixafor appears superior in increasing circulating leukemic blasts and stem/progenitor cells in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast increase 2.1-fold; Uy et al. Blood, in press). Treatment resulted in 2/10 CRp and 4/10 PRs. Mobilized stem/progenitor cells displayed increased MAPK/AKT signaling and increased CXCR4 expression. This is the first clinical report of G-CSF/Plerixafor for the “mobilization” of AML cells, aimed at removing them from their protective bone marrow microenvironment. The initial results are providing proof-of–principle of this concept.

Abstract Abstract 142 FLT3-ITD AML are associated with poor prognosis. Our group identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 2008; Borthakur G., Haematologica, 2010). FLT3-ITD is also associated with overexpression of the chemokine receptor CXCR4. Utilizing preclinical in vitro and in vivo models we determined increased activity of S when combined with CXCR4 inhibitor Plerixafor (P) and G-CSF (G) (Zeng Z et.al. Blood 2009). Here we report clinical and translational data testing this concept in patients with R/R FLT3-ITD AML. Clinical trial: G (10 ug/kg) and P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400–600mg) on d 1 – 28(one cycle). G/P was held when blasts exceeded 5×104/uL. Cell populations expressing CD34, 38, 123, CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were assessed at baseline and at multiple time points during treatment by flow cytometry of up to 10 parameters and by flow cytometric mass spec using CyTOF. Results: 13 patients have been treated so far; responses are as follows: 1 CR, 3 CRp, 6 PR and 4 failed (NR), for an overall response rate of 10/13 (77%); One patients achieved 2 CRp. Six/13 patients, including 3/6 responders and 3/4 NR were previously treated with and considered refractory to FLT3 inhibitors. Four patients had additional D835 mutations: 2 failed and 2 achieved PRs, none of the CR/p patients carried this mutation. Side effects included hyperleukocytosis in 3/10 pts.(who missed 1 to 5 doses of G/P), skin rash (5 pts.), hand foot syndrome (3 pts.) hypertension (7 patients), diarrhea (10 pts.), nausea (8 pts.), headache (6 pts.), muscle weakness (3 pts.) and anorexia (5 pts.). Analysis of cells mobilized in 22 treatment cycles revealed massive mobilization: a 29-fold increase in WBC, 41-fold in absolute blasts and 77-fold in granulocytes. Increases in the numbers of circulating stem/progenitor cells: CD34+: 231-fold, CD34+/38-: 90-, CD34+/38-/123+(LSC): 148-, CXCR4+: 139-, VLA-4+: 68- and CD44+: 82-fold. Increase in circulating LSC was positively correlated with baseline blasts and VLA4 levels, but not with baseline CXCR4. Serial FISH analyses confirmed the preferential mobilization of leukemic vs. non-leukemic cells and 10-color flow cytometry demonstrated altered levels of pERK and pAKT but not of pSTAT3 in mobilized cells. Surprisingly, CXCR4 levels in mobilized cells were increased. CyTOF analysis of up to 29 parameters documented mobilization of primitive LSC. Conclusions: The combination of G-CSF+Plerixafor appears superior in increasing the number of circulating leukemic blasts and stem/progenitor cells in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast increase 2.1-fold; Uy et al. Blood, 2012). Treatment resulted in 4/13 CR and CRp and 6/13 PRs, for an overall response rate of 77%. Mobilized stem/progenitor cells displayed altered MAPK/AKT signaling and increased CXCR4 expression. This is the first clinical study of G-CSF/Plerixafor for the “mobilization” of AML cells, aimed at removing them from their protective bone marrow microenvironment and the initial results are providing proof-of–concept and encouraging clinical responses. Disclosures: Off Label Use: Clofarabine in AML. Burger:Pharmacyclics: Consultancy, Research Funding. Kantarjian:Genzyme: Research Funding.

Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and the Medical Research Counsel, United Kingdom, and supported in part by Public Health Service Grants CA180820, CA180794, CA180790, CA189859, CA180853, CA180791, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Late relapse in acute leukemia is considered a relatively rare event. Patients with acute myeloid leukemia (AML) are often considered cured of the disease at 3 years, but information regarding adult acute lymphoblastic leukemia (ALL) patients is scarce. Data are presented from one of the largest prospective adult ALL studies, the MRC UKALLXII/ECOG E2993, to evaluate the rate and characteristics of late relapse in ALL. For this purpose, late relapse was defined, arbitrarily, as relapse 3 years post achievement of complete remission (CR) and very late relapse was defined as relapse > 5 years from CR. Methods: The UKALLXII/ECOG E2993 was an international ALL trial conducted jointly by the MRC in the United Kingdom and ECOG in the United States. All patients received identical induction therapy, followed by central nervous system prophylaxis. Patients with a sibling donor (or a matched unrelated donor in Philadelophia-chromosome-positive ALL) were assigned to receive an allogeneic hematopoietic stem cell transplant (HSCT); all others were randomized to undergo an autologous transplant or protracted standard consolidation/ maintenance therapy. The study accrued 2109 patients from 1993 to 2008. Following relapse, patients were followed for survival. For this report only patients registered before the tyrosine kinase inhibitors era are included in the analysis. Results: 1518 study patients were eligible for this analysis, 1208 (79.6%) Philadelphia-chromosome negative (Ph-neg) and 267 (17.5%) Philadelphia-chromosome positive (Ph-pos). 1381 (91%) of the patients achieved CR; 93% of the Ph-neg and 82% of the Ph-pos. 572 patients (37.7%) underwent allogeneic HSCT. The median duration of follow-up of patients who achieved CR was 10 years. Among the 1381 patients who achieved CR, 626 (45.3%) had a documented relapse; 566 (90.4%) relapsed within 3 years of CR and 60 (9.6%) relapsed beyond 3 years ('late relapse') (Figure 1). Among these 60 patients, 18(2.9%) relapsed after 5 years ('very late relapse'). Table. Patients n CR All relapses Relapses< 3 years Relapses≥ 3 years Relapses≥ 5 years All patients 1518 1381 (91%) 626 (45.3%) 566 (90.4%) 60 (9.6%) 18 (2.9%) Ph-neg 1208 (79.6%) 1123 (93%) 485 (40.1%) 429 (88.5%) 56 (11.5%) 17 (3.5%) Ph-pos 268 (17.5%) 219 (82%) 124 (56.6%) 122 (98.4%) 2 (1.6%) 1 (0.8%) Relapse beyond 3 years occurred in 4.3% of all who achieved CR, in 5% of Ph-neg and 0.01% of Ph-pos patients. Among the 60 late relapses, the median time to relapse was 46 months. 61.7% of the late-relapse patients were males, median age was 32 years, 88.3% were B-lineage ALL and the median white cell count at diagnosis was 6000/ul. 56.7% were in cytogenetic standard risk, 8.3% at high risk and the data of 35% are unknown. The median survival for the late relapse patients was longer than for those who relapsed within 3 years. The overall survival (OS) of the 56 Ph-neg patients who relapsed beyond 3 years is shown in Fig 2. Table.Relapse > 3 yearsRelapse > 3 yearsMedian survival from relapse (months)5.411.23-year OS from relapse6.5%29%5-year OS from relapse5.6%19% Conclusions: Late relapses in adults with Ph-neg ALL are not uncommon. About 10% of relapses occur beyond 3 years and 4.3% of all ALL patients who achieved a CR can expect to have a late relapse. These data are in contrast to AML where only 1% of patients relapse beyond 3 years (Watts JM et al, 2014). Most of the late relapse patients were at standard risk and appeared to have a relatively favorable outcome post relapse. Patients with ALL, particularly those who are Ph-neg, cannot be considered as cured at 3 years and need to be closely followed. Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Disclosures Rowe: Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Douer:Gilead: Consultancy.

Abstract Abstract 2555 High hyperdiploidy is present in 30% of children with acute lymphocytic leukemia (ALL), and is associated with a favorable prognosis. We evaluated pts with newly diagnosed ALL treated on SWOG trials S9400 (1995–2000) and S0333 (2005–2010) to determine the prevalence and prognostic impact of hyperdiploidy in adults with ALL. Additionally, we examined the prognostic impact of hypodiploidy, a feature typically associated with a poor prognosis in children. Methods: One-hundred and eighty-five pts treated on S9400 and S0333 with successful cytogenetic (CG) analysis were included. The treatment regimens were: S9400 [Induction: Daunorubicin (D), vincristine (V), prednisone (P), PEG-asparaginase (PEG); Consolidation: Cytoxan (Cy), cytarabine (AraC), 6-mercaptopurine (6MP), intrathecal methotrexate (IT Mtx). Consolidation was followed by allogeneic stem cell transplant or maintenance chemotherapy] and S0333: Double Induction Chemotherapy [Induction 1: D, V, P, PEG; Induction 2: high dose AraC, mitoxantrone, decadron. Consolidation: Cy, AraC, 6MP, Mtx; consolidation was followed by maintenance therapy]. Karyotypes were centrally reviewed and clonal abnormalities described according to ISCN (2009). Hyperdiploidy was defined as: low hyperdiploidy [47–49 chromosomes (cs)], high hyperdiploidy (51–65 cs), near triploidy (66–79 cs), and near tetraploidy (84–100 cs). Hypodiploidy was defined as: near haploidy (25–29 cs), low hypodiploidy (31–39 cs), and high hypodiploidy (42–45 cs). When more than one cell line was present, ploidy was assigned by the most complex clonal karyotype. Hypodiploidy and hyperdiploidy were analyzed as prognostic factors for complete response (CR) rate and residual disease (RD) by logistic regression and chi-square tests; and for overall survival (OS) and relapse-free survival (RFS) by proportional hazards. Multivariable analyses were stratified by study and using the baseline variables: age, WBC, lineage, and CG risk. Results: The median age was 32 yrs (range 17–64), and median WBC at diagnosis 17.2 K/uL (range 0.6–396.6). CG risk was ascribed by (Pullarket V et al. Blood 2008; 111: 2563). Forty-five pts (24%) had normal CG, and 73 (39%) had poor risk CG. Fourteen pts (8%) had hypodiploidy (2: low hypodiploidy; 12: high hypodiploidy). Fifty-three pts (29%) had hyperdiploidy [40: low hyperdiploidy, 10: high hyperdiploidy (5%), 3: near tetraploidy or tetraploidy (2%)]. The CR rate for all pts was 72%; with a median RFS of 15 mos (95% CI: 12–29 mos) and median OS of 28 mos (95% CI: 21–36 mos). There was no significant association with ploidy status and age, WBC, or lineage. However, there was an increased prevalence of the t(9;22) in the high hypodiploidy group compared to the normal/pseudo diploidy group (p=0.049). Neither hypodiploidy nor hyperdiploidy were predictive of CR or RD; although pts with hypodiploidy had a higher rate of RD (p=0.062). The 2 pts with low hypodiploidy had very poor outcomes (1 had RD and died after 11 mos; the other relapsed after 3 mos from CR and died 4 mos after study registration). There were no statistically significant differences in OS, CR rate, or RFS between the ploidy groups even after adjusting for baseline characteristics in multivariate analysis. Surprisingly, when excluding pts with poor risk CG there was still a trend towards a worse RFS (29 vs. 32 months, p=0.20) and OS (40 vs. 68 mos, p=0.29) in pts with hyperdiploidy compared to normal/pseudodiploidy. In addition, the 3 pts in the high hyperdiploidy group without poor risk CG had poor OS (median 23 mos). Conclusions: The prevalence of high hyperdiploidy is much lower in adults with ALL, compared to children. The prevalence of hypodiploidy and near tetraploidy/tetraploidy is comparable to that seen in children with ALL. Hypodiploidy and high hyperdiploidy were not prognostic factors for outcome in this group of patients. Given the low prevalence of these abnormalities, it is possible that larger numbers of pts may be needed to detect such a difference. The poor outcomes of pts with low hypodiploidy are consistent with findings by Moorman et al. (Blood 2006; 109: 3189). However, in contrast to Moorman's results, there was no evidence of an association of hyperdiploidy with age/WBC, and there was a trend towards a worse prognosis in this subset of patients. This suggests that the biology and prognosis of high hyperdiploidy may be affected more by WBC and age in the adult population. Disclosures: No relevant conflicts of interest to declare.

Background: Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (alloHCT) to prevent graft versus host-disease (GVHD) and graft rejection. In the T-cell replete setting, post-HCT rATG exposure is variable with high exposures resulting in delayed CD4+immune reconstitution (CD4+IR) and higher mortality. The goal of this study was to estimate the rATG exposure in pediatric and adult recipients of ex vivo T-cell depleted CD34+ selected alloHCT and correlate it with outcomes to determine the optimal exposure. Methods: We performed a retrospective analysis of patients who underwent their first myeloablative-conditioned ex vivo CD34+ selected alloHCT between 2008 and 2018. Post-HCT rATG exposure was estimated as area under the curve (AUC) (mg*d/L) using a validated population pharmacokinetic (PK) model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+IR, defined as CD4+&gt;50/uL at two consecutive measures within 100 days of HCT, non-relapse mortality (NRM), overall survival (OS), GVHD, and relapse. We evaluated the association between post-HCT rATG exposures and CD4+IR using a smoothed effect to define the optimal post-HCT rATG exposure. We subsequently analyzed outcomes in 3 post-HCT rATG exposure groups, &lt;30 mg*d/L, 30-55 mg*d/L, and &gt;=55 mg*d/L. Cox proportional hazard models and multi-state competing risk models were used for analyses. Results: Of 554 patients included, 239 (43%) were female, median age at HCT was 49 (range 0.2 to 73) years and 425 (76.7%) received matched donor transplant, while 129 (23.3%) patients received mismatched donor HCT. In this cohort of patients, 515 (93%) underwent alloHCT for hematologic malignancies - leukemia: 356 (64.3%), myelodysplastic syndrome: 122 (22%), and other hematological malignancies: 37 (6.7%) while 39 (7%) underwent alloHCT for non-malignant indications. Total Body Irradiation based conditioning regimen was administered in 177 (32%) patients. Among all 554 patients, 540 (97%) attained engraftment. Median post-HCT rATG exposure was 47mg*d/L (range 0 - 101 mg*d/L). A decreasing post-HCT AUC (optimum &lt;30 mg*d/L) was associated with higher probability of CD4+IR (p&lt; 0.0001, Figure 1a); lower NRM (p=0.03, Figure 1b) and improved OS (p=0.05, Figure 1c). Patients who attained CD4+IR earlier had lower rates of NRM (p&lt;0.0001, Figure 1d). On further assessing rATG exposure post allo-HCT by three cut -off levels (&lt;30mg*d/L, 30-55 mg*d/L and &gt;=55 mg*d/L), time to CD4+IR varied depending on the ATG exposure (Figure 1e). In multivariable cox models, post-HCT rATG exposure &gt;=55 mg*d/L was associated with an increased risk of NRM as compared to the lower exposure of &lt;30 mg*d/L (HR: 4.11, CI: 1.52, 11.2, Figure 1f), and inferior OS (HR: 2.03, CI: 1.03,4.00, Figure 1g). In addition, post-HCT rATG exposure &gt;=55 mg*d/L was associated with a higher risk of acute GVHD (HR: 2.28, CI: 1.01, 5.16, Figure 1h). In patients with hematologic malignancies, post-HCT rATG exposure was not associated with relapse (HR: 0.73, CI: 0.31,1.7). In the entire cohort of 554 patients, 9 (1.6%) patients had graft rejection: 1 primary rejection in the post-HCT ATG exposure &lt;30mg*d/L group, 6 secondary rejections in the post-HCT ATG exposure of 30-55 mg*d/L group and 2 secondary rejections in the post-HCT ATG exposure &gt;=55mg*d/L group. Among all patients, 204 (37%) died secondary to reasons such as relapse of disease: 73 (36%), infection: 51 (25%), GVHD: 40 (20%), toxicity/organ failure: 29 (14%) and other causes: 11 (5%). Conclusions: In a large cohort of patients who underwent ex vivo CD34+ selected alloHCT, higher post-HCT rATG exposure led to higher NRM, a paradoxical increase in GVHD, and lower OS driven by poorer CD4+ IR. The increased rates of GVHD with higher post-HCT exposure may be related to increased infections in these cohorts, though this needs to be explored further. Individualizing rATG dosing by PK targeting to a low post-HCT rATG exposure may improve outcomes. We intend to validate these results in a forthcoming prospective clinical trial. Figure 1 Disclosures Scordo: McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Curran:Celgene: Research Funding; Novartis: Consultancy, Research Funding; Mesoblast: Consultancy. Kernan:Amgen: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. O'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties: EBV-specific T-cell bank, Research Funding. Prockop:Mesoblast, Inc,: Consultancy, Honoraria, Research Funding; Atara: Research Funding; Jasper: Research Funding. Scaradavou:Excellthera: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Giralt:OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; KITE: Consultancy; MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boelens:Bluebird Bio: Consultancy; Advanced Clinical: Consultancy; Race Oncology: Consultancy; Bluerock: Consultancy; Omeros: Consultancy; Avrobio: Consultancy; Takeda: Consultancy.

<p><strong>Guest editors: Joanne Lehrer (Université du Québec en Outaouais), Christine Massing (University of Regina), Scott Hughes (Mount Royal University), and Alaina Roach O’Keefe (University of Prince Edward Island)</strong></p><p>Not only is professional learning conceptualised as critical for increasing educational quality and enhancing children’s learning and developmental outcomes (e.g. Lazarri et al., 2013; Munton et al., 2002; Penn, 2009; Vandenbroeck et al., 2016), but specific elements of professional learning (in both initial and continuing education, or preservice and in-service learning) have been identified as essential to transforming early childhood educators’ and preschool teachers’ professional identities and practice. For example, critical and supported reflection (Thomas &amp; Packer, 2013), learning experiences that target entire teams (Vangrieken, Dochy, &amp; Raes, 2016), collaborative and empowering practice (Helterbran &amp; Fennimore, 2004), and competent leadership (Colmer et al., 2008) have all been found to be effective means of supporting professional learning.</p><p>While there appears to be consensus in the literature around <em>what</em> needs to be done, and even around <em>how</em> it should be done, numerous constraints prevent the implementation and maintenance of sustainable and transformational professional learning in ECEC. Vandenbroeck and colleagues (2016) go beyond the focus on individuals and childcare teams, identifying two further levels necessary for competent systems of professional learning: partnerships between local early childhood programs and social, cultural, and educational institutions (such as colleges and universities); and governance regarding vision, finance, and monitoring. In the Canadian context, the Canadian Child Care Federation has also stressed the importance of a system-wide strategy to strengthen the child care workforce (CCCF, 2016). However, early childhood services in Canada are under the purview of the provincial and territorial governments and, therefore, the conditions, regulations, certification requirements, curriculum documents, and educational systems vary widely from jurisdiction to jurisdiction. The educational requirements for certification, for example, may include no formal training (in NWT and Nunavut), one entry-level short course, one-year certificates, or two-year diplomas. This complicates efforts to define who the early childhood professional is and what opportunities are constitutive of professional learning (Prochner, Cleghorn, Kirova, &amp; Massing, 2016). While these disparities within the field may impede the development of a cohesive strategy, Campbell et al. (2016) recently asserted that much can be learned from sharing and appreciating the rich diversity of approaches to professional learning both within and across provinces and territories. In addition, examples from other countries serve to broaden the discussion and expand our understanding of what is possible (Vandenboreock et al., 2016).</p><p>This special issue, then, is dedicated to sharing stories of hope and coordinated action, linking theory with practice. We seek Canadian and international submissions related to professional learning practices that extend beyond individual programs, showcasing partnerships and community mobilization efforts within and across various settings for young children (child care, Kindergarten, drop-in centres, etc.) in relation to philosophical, practical, critical, transformative, personal, and/or hopeful themes. Each submission will respond to one or more of the key questions, including, but not limited to:</p><ul><li>How can professional learning be conceptualised?</li><li>How do we build and maintain effective partnerships to foster professional learning?</li><li>What strategies for transformative community mobilization might be shared?</li><li>How can innovative strategies be applied on a wider scale?</li><li>How might taken-for-granted professional learning and evaluation practice be disrupted?</li><li>What story about professional learning do you need (or want) to tell?</li><li>How has your community been transformed through a particular activity, event, or practice?</li><li>How might the lives and futures of children be positively shaped by engagement in partnerships and mobilization?</li><li>Where might we be in 5, 10, or 15 years through such endeavours?</li></ul><p>We welcome submissions in multiple formats, including research articles, theoretical papers, multimedia pieces, art work, book reviews, and so forth. These may be submitted in English, French, or in any Canadian Indigenous language. </p><p>Submissions are due August 1, 2017 and should be submitted as per <a href="http://journals.uvic.ca/index.php/jcs/about/submissions#onlineSubmissions">Journal of Childhood Studies submission guidelines. </a></p><p><strong><br /></strong></p><p> </p><p>References</p><p>Campbell, C., Osmond-Johnson, P., Faubert, B., Zeichner, K., Hobbs-Johnson, A. with S. Brown, P. DaCosta, A. Hales, L. Kuehn, J. Sohn, &amp; K. Steffensen (2016). <em>The state of educators’ professional learning in Canada</em>. Oxford, OH: Learning Forward.</p><p>Canadian Child Care Foundation [CCCF], (2016). <em>An Early Learning and Child Care Framework for Canada’s Children</em>. Retrieved from: http://www.cccf-fcsge.ca/wp-content/uploads/CCCF_Framework-ENG.pdf</p><p>Colmer, K., Waniganayake, M. &amp; Field, L. (2014). Leading professional learning in early childhood centres: who are the educational leaders<em>?, Australasian Journal of Early Childhood</em>, 39(4), 103-113.</p><p>Helterbran, V.R. &amp; Fennimore, B.S. (2004). Early childhood professional development: Building from a base of teacher investigation. <em>Early Childhood Education Journal, 31</em>(4), 267-271.</p><p>Lazarri, A., Picchio, M., &amp; Musatti, T. (2013). Sustaining ECEC quality through continuing professional development: systemic approaches to practitioners’ professionalization in the Italian context. <em>Early Years: An International Research Journal, 33</em>(2), 133-145.</p><p>Munton, T., Mooney, A., Moss, P., Petrie, P., Calrk, A., Woolner, J. et al., (2002). <em>Research on ratios, group size, and staff qualifications and training in early years and childcare settings</em>. London: University of London.</p><p>Penn, H. (2009). <em>Early childhood education and care: Key lessons from research for policy makers</em>. Brussels: Nesse.</p><p>Prochner, L., Cleghorn, A., Kirova, A., &amp; Massing, C. (2016). <em>Teacher education in diverse settings: Making space for intersecting worldviews</em>. Rotterdam, The Netherlands: Sense Publishers.</p><p>Thomas, S., &amp; Packer, D. S. (2013). A Reflective Teaching Road Map for Pre-service and Novice Early Childhood Educators. <em>International Journal of Early Childhood Special Education</em>, <em>5</em>(1), 1-14.</p><p>Vandenbroeck, M., Peeters, J., Urban, M. &amp; Lazzari, A. (2016). Introduction. In M. Vandenbroeck, M. Urban &amp; J. Peeters (Eds.) <em>Pathways to Professionalism in Early Childhood Education and Care</em>, (pp. 1-14). London: Routledge.</p><p>Vangrieken, K., Dochy, F., &amp; Raes, E. (2016). Team learning in teacher teams: team entitativity as a bridge between teams-in-theory and teams-in-practice. <em>European Journal Of Psychology Of Education - EJPE (Springer Science &amp; Business Media B.V.)</em>, <em>31</em>(3), 275-298. doi:10.1007/s10212-015-0279-0</p>

<p><strong>Rédacteurs invités: Joanne Lehrer (Université du Québec en Outaouais), Christine Massing (Université de Regina), Scott Hughes (Université Mount Royal), Alaina Roach O’Keefe (Université de l’Île-du-Prince-Édouard)</strong></p><p><strong></strong>Non seulement l’apprentissage professionnel est-il considéré comme essentiel à l’amélioration de la qualité éducative et comme soutien à l’apprentissage et au développement des enfants (par exemple, Lazarri <em>et al.</em>, 2013, Vandenbroeck <em>et al</em>., 2016), mais certains éléments de la formation initiale et continue ont été identifiés comme critiques pour transformer les identités professionnelles et la pratique des éducatrices (en SGÉ) et des enseignantes (au préscolaire). Par exemple, la réflexion critique et soutenue (Thomas et Packer, 2013), les expériences d’apprentissage ciblant des équipes entières (Vangrieken <em>et al</em>, 2016), les pratiques collaboratives qui visent le pouvoir d’agir des praticiennes (Helterbran et Fennimore, 2004) et la direction (Dolmer <em>et al., </em>2008) sont toutes considérées comme des moyens efficaces afin de soutenir l’apprentissage professionnel.</p><p>Bien qu’il semble y avoir consensus dans les écrits sur <em>ce qui doit être fait</em>, et même sur <em>la façon dont cela devrait être fait</em>, de nombreuses contraintes empêchent la mise en œuvre et le maintien d’un système d’apprentissage professionnel durable et transformationnel en éducation à la petite enfance. Vandenbroeck et ses collaborateurs (2016) vont au-delà de l’accent mis sur les individus et les équipes en identifiant deux autres niveaux nécessaires pour des systèmes compétents d’apprentissage professionnel : des partenariats entre les programmes locaux de l’éducation à la petite enfance et les institutions sociales, culturelles et éducatives (collèges et universités); et la gouvernance en matière de vision, de finances et de suivi. Dans le contexte canadien, la <em>Fédération canadienne des services de garde à l’enfance</em> a également souligné l’importance d’une stratégie cohérente visant à renforcer la main-d’œuvre en services de garde éducatifs (CCCF, 2016). Toutefois, l’éducation à la petite enfance au Canada relève des gouvernements provinciaux et territoriaux. Par conséquent, les conditions, les règlements, les exigences de certification, les programmes et les systèmes d’éducation varient considérablement d’une province ou d’un territoire à l’autre. Les exigences en matière d’éducation pour la qualification, par exemple, peuvent comprendre une formation non formelle (dans les Territoires du Nord-Ouest et au Nunavut), une formation de courte durée, un certificat d’un an ou un diplôme de deux ans. Cela complique les efforts pour définir qui est le professionnel de la petite enfance et quelles sont les possibilités constitutives de l’apprentissage professionnel (Prochner <em>et al</em>., 2016). Bien que ces disparités puissent entraver l’élaboration d’une stratégie cohérente, Campbell et ses collaborateurs (2016) ont récemment affirmé que l’on pourrait approfondir les apprentissages, en partageant et en appréciant la riche diversité des approches en matière d’apprentissage professionnel, à la fois au sein des provinces et des territoires et intra provinces et territoires. De plus, des exemples provenant d’autres pays permettraient d’élargir la discussion et d’élargir notre compréhension des possibilités (Vandenboreock <em>et al</em>., 2016).</p><p>Ce numéro spécial est donc consacré aux partages d’histoires d’espoir et d’actions concertées, reliant la théorie à la pratique. Nous attendons des propositions canadiennes et internationales liées aux pratiques d’apprentissage professionnel qui s’étendent au-delà des programmes individuels, mettant en vedette des partenariats et des efforts de mobilisation communautaire à l’intérieur et à travers différents contextes éducatifs liés à la petite enfance (Centres de la Petite Enfance, maternelle, halte-garderie, etc.) et en lien avec diverses thématiques : philosophiques, pratiques, critiques, transformatrices, personnelles et d’espoir. Chaque soumission répondra à une ou à plusieurs des questions clés, y compris, mais sans s’y limiter à :</p><ul><li>Comment conceptualiser l’apprentissage professionnel en éducation à la petite enfance?</li><li>Comment établir et maintenir des partenariats efficaces pour favoriser l’apprentissage professionnel?</li><li>Quelles stratégies de mobilisation communautaire transformatrice pourraient être partagées?</li><li>Comment les stratégies novatrices peuvent-elles être appliquées à une plus grande échelle?</li><li>Comment les pratiques d’évaluation et d’apprentissage professionnelles peuvent-elles être perturbées?</li><li>Quelle histoire de l’apprentissage professionnel avez-vous besoin de (ou voulez-vous) raconter?</li><li>Comment votre communauté a-t-elle été transformée par une activité, une pratique ou un évènement ou particuliers?</li><li>Comment la vie et l’avenir des enfants peuvent-ils être façonnés positivement par l’engagement dans les partenariats et la mobilisation?</li><li>Où pourrions-nous être dans 5, 10 ou 15 ans?</li></ul><p>Nous accepterons des soumissions dans des formats multiples, y compris des articles de recherche, des articles théoriques, des pièces multimédias, des œuvres d’art, des recensions de livres, etc. Ils peuvent être présentés en anglais, en français ou dans toute langue autochtone canadienne reconnue.</p><p>La date limite pour les soumissions est fixée au 1^er aout 2017.</p><p> </p><p>References</p><p>Campbell, C., Osmond-Johnson, P., Faubert, B., Zeichner, K., Hobbs-Johnson, A. with S. Brown, P. DaCosta, A. Hales, L. Kuehn, J. Sohn, &amp; K. Steffensen (2016). <em>The state of educators’ professional learning in Canada</em>. Oxford, OH: Learning Forward.</p><p>Canadian Child Care Foundation [CCCF], (2016). <em>An Early Learning and Child Care Framework for Canada’s Children</em>. Retrieved from: http://www.cccf-fcsge.ca/wp-content/uploads/CCCF_Framework-ENG.pdf</p><p>Colmer, K., Waniganayake, M. &amp; Field, L. (2014). Leading professional learning in early childhood centres: who are the educational leaders<em>?, Australasian Journal of Early Childhood</em>, 39(4), 103-113.</p><p>Helterbran, V.R. &amp; Fennimore, B.S. (2004). Early childhood professional development: Building from a base of teacher investigation. <em>Early Childhood Education Journal, 31</em>(4), 267-271.</p><p>Lazarri, A., Picchio, M., &amp; Musatti, T. (2013). Sustaining ECEC quality through continuing professional development: systemic approaches to practitioners’ professionalization in the Italian context. <em>Early Years: An International Research Journal, 33</em>(2), 133-145.</p><p>Munton, T., Mooney, A., Moss, P., Petrie, P., Calrk, A., Woolner, J. et al., (2002). <em>Research on ratios, group size, and staff qualifications and training in early years and childcare settings</em>. London: University of London.</p><p>Penn, H. (2009). <em>Early childhood education and care: Key lessons from research for policy makers</em>. Brussels: Nesse.</p><p>Prochner, L., Cleghorn, A., Kirova, A., &amp; Massing, C. (2016). <em>Teacher education in diverse settings: Making space for intersecting worldviews</em>. Rotterdam, The Netherlands: Sense Publishers.</p><p>Thomas, S., &amp; Packer, D. S. (2013). A Reflective Teaching Road Map for Pre-service and Novice Early Childhood Educators. <em>International Journal of Early Childhood Special Education</em>, <em>5</em>(1), 1-14.</p><p>Vandenbroeck, M., Peeters, J., Urban, M. &amp; Lazzari, A. (2016). Introduction. In M. Vandenbroeck, M. Urban &amp; J. Peeters (Eds.) <em>Pathways to Professionalism in Early Childhood Education and Care</em>, (pp. 1-14). London: Routledge.</p><p>Vangrieken, K., Dochy, F., &amp; Raes, E. (2016). Team learning in teacher teams: team entitativity as a bridge between teams-in-theory and teams-in-practice. <em>European Journal Of Psychology Of Education - EJPE (Springer Science &amp; Business Media B.V.)</em>, <em>31</em>(3), 275-298. doi:10.1007/s10212-015-0279-0</p>

<table id="announcementDescription" width="100%"><tbody><tr><td><p><strong>Guest editors: Joanne Lehrer (Université du Québec en Outaouais), Christine Massing (University of Regina), Scott Hughes (Mount Royal University), and Alaina Roach O’Keefe (University of Prince Edward Island)</strong></p><p>Not only is professional learning conceptualised as critical for increasing educational quality and enhancing children’s learning and developmental outcomes (e.g. Lazarri et al., 2013; Munton et al., 2002; Penn, 2009; Vandenbroeck et al., 2016), but specific elements of professional learning (in both initial and continuing education, or preservice and in-service learning) have been identified as essential to transforming early childhood educators’ and preschool teachers’ professional identities and practice. For example, critical and supported reflection (Thomas &amp; Packer, 2013), learning experiences that target entire teams (Vangrieken, Dochy, &amp; Raes, 2016), collaborative and empowering practice (Helterbran &amp; Fennimore, 2004), and competent leadership (Colmer et al., 2008) have all been found to be effective means of supporting professional learning.</p><p>While there appears to be consensus in the literature around <em>what</em> needs to be done, and even around <em>how</em> it should be done, numerous constraints prevent the implementation and maintenance of sustainable and transformational professional learning in ECEC. Vandenbroeck and colleagues (2016) go beyond the focus on individuals and childcare teams, identifying two further levels necessary for competent systems of professional learning: partnerships between local early childhood programs and social, cultural, and educational institutions (such as colleges and universities); and governance regarding vision, finance, and monitoring. In the Canadian context, the Canadian Child Care Federation has also stressed the importance of a system-wide strategy to strengthen the child care workforce (CCCF, 2016). However, early childhood services in Canada are under the purview of the provincial and territorial governments and, therefore, the conditions, regulations, certification requirements, curriculum documents, and educational systems vary widely from jurisdiction to jurisdiction. The educational requirements for certification, for example, may include no formal training (in NWT and Nunavut), one entry-level short course, one-year certificates, or two-year diplomas. This complicates efforts to define who the early childhood professional is and what opportunities are constitutive of professional learning (Prochner, Cleghorn, Kirova, &amp; Massing, 2016). While these disparities within the field may impede the development of a cohesive strategy, Campbell et al. (2016) recently asserted that much can be learned from sharing and appreciating the rich diversity of approaches to professional learning both within and across provinces and territories. In addition, examples from other countries serve to broaden the discussion and expand our understanding of what is possible (Vandenboreock et al., 2016).</p><p>This special issue, then, is dedicated to sharing stories of hope and coordinated action, linking theory with practice. We seek Canadian and international submissions related to professional learning practices that extend beyond individual programs, showcasing partnerships and community mobilization efforts within and across various settings for young children (child care, Kindergarten, drop-in centres, etc.) in relation to philosophical, practical, critical, transformative, personal, and/or hopeful themes. Each submission will respond to one or more of the key questions, including, but not limited to:</p><ul><li>How can professional learning be conceptualised?</li><li>How do we build and maintain effective partnerships to foster professional learning?</li><li>What strategies for transformative community mobilization might be shared?</li><li>How can innovative strategies be applied on a wider scale?</li><li>How might taken-for-granted professional learning and evaluation practice be disrupted?</li><li>What story about professional learning do you need (or want) to tell?</li><li>How has your community been transformed through a particular activity, event, or practice?</li><li>How might the lives and futures of children be positively shaped by engagement in partnerships and mobilization?</li><li>Where might we be in 5, 10, or 15 years through such endeavours?</li></ul><p>We welcome submissions in multiple formats, including research articles, theoretical papers, multimedia pieces, art work, book reviews, and so forth. These may be submitted in English, French, or in any Canadian Indigenous language. </p><p><span>Submissions are due August 1, 2017</span> and should be submitted as per <a href="http://journals.uvic.ca/index.php/jcs/about/submissions#onlineSubmissions">Journal of Childhood Studies submission guidelines. </a></p><p><strong><br /></strong></p><p> </p><p>References</p><p>Campbell, C., Osmond-Johnson, P., Faubert, B., Zeichner, K., Hobbs-Johnson, A. with S. Brown, P. DaCosta, A. Hales, L. Kuehn, J. Sohn, &amp; K. Steffensen (2016). <em>The state of educators’ professional learning in Canada</em>. Oxford, OH: Learning Forward.</p><p>Canadian Child Care Foundation [CCCF], (2016). <em>An Early Learning and Child Care Framework for Canada’s Children</em>. Retrieved from: http://www.cccf-fcsge.ca/wp-content/uploads/CCCF_Framework-ENG.pdf</p><p>Colmer, K., Waniganayake, M. &amp; Field, L. (2014). Leading professional learning in early childhood centres: who are the educational leaders<em>?, Australasian Journal of Early Childhood</em>, 39(4), 103-113.</p><p>Helterbran, V.R. &amp; Fennimore, B.S. (2004). Early childhood professional development: Building from a base of teacher investigation. <em>Early Childhood Education Journal, 31</em>(4), 267-271.</p><p>Lazarri, A., Picchio, M., &amp; Musatti, T. (2013). Sustaining ECEC quality through continuing professional development: systemic approaches to practitioners’ professionalization in the Italian context. <em>Early Years: An International Research Journal, 33</em>(2), 133-145.</p><p>Munton, T., Mooney, A., Moss, P., Petrie, P., Calrk, A., Woolner, J. et al., (2002). <em>Research on ratios, group size, and staff qualifications and training in early years and childcare settings</em>. London: University of London.</p><p>Penn, H. (2009). <em>Early childhood education and care: Key lessons from research for policy makers</em>. Brussels: Nesse.</p><p>Prochner, L., Cleghorn, A., Kirova, A., &amp; Massing, C. (2016). <em>Teacher education in diverse settings: Making space for intersecting worldviews</em>. Rotterdam, The Netherlands: Sense Publishers.</p><p>Thomas, S., &amp; Packer, D. S. (2013). A Reflective Teaching Road Map for Pre-service and Novice Early Childhood Educators. <em>International Journal of Early Childhood Special Education</em>, <em>5</em>(1), 1-14.</p><p>Vandenbroeck, M., Peeters, J., Urban, M. &amp; Lazzari, A. (2016). Introduction. In M. Vandenbroeck, M. Urban &amp; J. Peeters (Eds.) <em>Pathways to Professionalism in Early Childhood Education and Care</em>, (pp. 1-14). London: Routledge.</p><p>Vangrieken, K., Dochy, F., &amp; Raes, E. (2016). Team learning in teacher teams: team entitativity as a bridge between teams-in-theory and teams-in-practice. <em>European Journal Of Psychology Of Education - EJPE (Springer Science &amp; Business Media B.V.)</em>, <em>31</em>(3), 275-298. doi:10.1007/s10212-015-0279-0</p></td></tr></tbody></table>