Academic literature on the topic 'D 3.5 UL 2004 C485'

Abstract Introduction: Allogeneic Stem Cell transplantation from an HLA identical sibling is considered the treatment of choice for young pts. For pts without a suitable donor, immunosupressive treatment with cyclosporine (Csa) + prednisone (Pred) + Antithymocyte globulin (ATG) is an effective alternative treatment. In 1988, as ATG supply was not regular in our country, we decided to initiate a trial using only Csa +Pred to treat SAA without a matched sibling donor. Material and Methods: All pts had the diagnosis of SAA according to established criteria (Camitta et al Blood1976; 48:63–70) and 95 pts had received previous treatment (androgens, Csa alone or steroids). Treatment: Csa: 12mg/kg/day BID from day(D)1- D8, then 7mg/kg/day BID until 1 year. After 1 year, Csa was slowly weaned (5% each month) until definitively stopped. Csa levels were maintained 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 weaned 20% each week until stopped. Prophylactic antibiotics were given according to common practice. Number of pts: 287. Period: 12/1988 to 01/2004. Age: 2-74y (Median: 22). Disease duration: 10–4015days (Median:100). Previous transfusions: 0-160UI (M:10). At diagnosis, granulocytes counts ranged from 0-3110/ul(M:540/uL) and platelet counts from 1000-53000/uL(M:11000/uL). Treatment evaluation was performed at 6weeks, 3,6 and 12 months and then yearly after. Definition of response: Type I: independence of red cells and platelets transfusions and improvement of hematological parameters (Hb>10g/dL, platelets>50.000/uL and granulocytes>1000/uL). Type II: Improvement of hematological parameters (not enough to reach the hematological counts previously specified) with or without dependence of blood transfusions. Type III: No evidence of improvement and dependence of blood transfusions. Results: Overall survival is 63% with a median follow-up of 7 y(6months- 15 years). Response to treatment: TypeI was achieved in 138pts (48%) and all but one pt is alive. These pts have a normal life, free of infections and are transfusion independent. TypeII occurred in 21 pts(7,3%) and 13 pts are alive with only 1 pt dependant of red blood cell transfusions every 45 days. TypeIII occurred in 128pts (44%) and 50 pts are still alive. Most pts responded between 3 and 6m of treatment. Response to treatment was significantly influenced by: Granulocytes at diagnosis >500/uL (p=0,0001); platelets at diagnosis >12000/ul (p=0,01); age>22y(p=0,0061) and previous transfusions < 10UI (p=0,008). Granulocytes at diagnosis >500/uL (p=0,02), platelets at diagnosis >10000/uL (p=0,01)and disease duration >45 days (p=0,02) significantly affected survival. Toxicity was tolerated and well controlled. Hypertension, gingival hypertrophy and diabetes mellitus were frequent complications. Relapse occurred in 19% (31pts) and twenty-two pts(70%) responded to a second treatment using the same drugs but 9pts became cyclosporine dependant. Clonal or malignant disease occurred in 5 pts (2AML and 3 PNH). Conclusion: This data demonstrates that Csa +Pred is an effective treatment for pts with SAA without a suitable donor. Pts may become free of infections and transfusion independent and are able to live normal lives even though their blood counts are still subnormal

Abstract Decitabine, an inhibitor of DNA methyltransferase (DNMT) enzymes, has clinical activity in myeloid malignancies, even at low doses (>1 log below the MTD) which may be optimal for demethylation rather than only cytotoxicity. We designed a two step trial for AML patients (pts) to determine: Step 1) the minimal effective pharmacologic dose (MEPD) of decitabine as a single agent (defined as lowest dose to induce reexpression of genes commonly methylated in AML in 5/6 pts treated at a single dose level) and Step 2) the MTD of the histone deacetylase inhibitor valproic acid given in combination with decitabine at this MEPD. To date, Step 1 is ongoing; decitabine alone has been administered to 14 pts at two dose levels. Pts had relapsed/refractory AML (N=8) or age>60 and ineligible/refused standard induction therapy (N=6). Pts ranged in age from 57–83 years and had received ≥ 2 prior inductions (N=6), 1 prior induction (2), or were untreated (4). 8 pts received decitabine at 15mg/m2/IV over 1 hr daily (d) for 10 consecutive d, and 6 received 20mg/m2/d on the same schedule, every 28 d. Plasma decitabine levels were analyzed by a validated LC-MS/MS method with a sensitivity of 2 ng/ml developed in our laboratory. Plasma drug concentration-time courses on d 1 and 10 achieved a mean Cmax of 93 ng/ml (N=7) and followed a two compartment infusion model. The mean short and long half-lives were 2.7 and 36.9 min, respectively, with a trend of decreasing the longer half-life on d 10. According to published bone marrow (BM) response criteria (Cheson, JCO 2003), 4/10 pts who completed two cycles of therapy responded (2 at each dose level). 3 had complete response with incomplete recovery of counts (CRi), and one achieved CR. Hematologic improvement (HI) or clinical benefit was seen in 3 additional pts: one achieved neutrophils of 2,200/uL, platelets (plts)>100,000/uL, disappearance of circulating blasts, and disappearance of BM blasts except by flow cytometry; one pt achieved plt transfusion independence (plts>100,000/uL); one pt had stabilization of disease for 6 months. Two more pts who remain on study are not yet evaluable for BM response but have already had significant HI with plts of 259,000 and 74,000/uL, respectively, after one cycle of therapy. Two pts were not evaluable for response due to death from sepsis or death related to decitabine-induced differentiation syndrome (first reported by Blum, ASH 2004), respectively. Decitabine was well tolerated, given typically as an outpatient. There were no severe non-hematologic drug related toxicities. Pts with HI or BM response required plt transfusion support when subsequent cycles were administered. At 15mg/m2/d x 10 d: 4/6 pts experienced at least 100% increase in reexpression genes commonly methylated in AML such as p15 or estrogen receptor; immunoblotting demonstrated DNMT1 protein depletion in 4/6 pts lasting 4–42 d. Clinical trial design based on achieving the MEPD is feasible in AML; we demonstrate clinical activity of low dose decitabine associated with changes in levels of the DNMT1 target and reexpression of epigenetically silenced genes. Complete PK and PD studies including gene reexpression by quantitative RT-PCR, DNMT1 protein levels by immunoblotting, and decitabine-induced promoter demethylation by COBRA/bisulfite sequencing will be presented. (NCI U01 CA 76576-05)

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: FA is an autossomal recessive syndrome that usually presents with congenital abnormalities, progressive pancytopenia and an increased risk of cancer.The first stem cell transplant for FA was performed in Latin America in 1983 and since then the BMT center from Curitiba, Brazil became a reference center for this disease. From 1983 until June 2004, 140 pts received a stem cell transplant for FA and most of them were in aplastic phase. In this study we performed a retrospective analysis of 36 patients who received an unrelated stem cell transplant for FA in our BMT center. Patients and methods: Period: 04/1996 to 06/2004, age 4 to 19 year old (median: 9y), sex: 20F/16M. Disease duration: 7 to 122 months (Median: 45), Previous transfusions: 0 to 400 (Median of 21). Aplastic phase: 35 pts. Myelodysplastic syndrome:1pt.Stem cell source : bone marrow 15 pts ( 6/6 : 12pts; 5/6 : 3pts) , cord blood : 20 pts ( 6/6: 3pts , 5/6 :8 pts and 4/6 : 9 pts) and peripheral stem cell : 1 pt ( 6/6). Preparatory regimen: 9 pts received only Cyclophosphamide (CY), 15 pts received CY + Fludarabine + Thimoglobuline, 4 pts received Fludarabine + TBI (200cGy), 4 pts received CY+ TBI ± ATG and 4 pts Fludarabine + CY. GVHD prophylaxis: Cyclosporine (Csa) + MTX: 18 pts, Csa + steroids: 14 pts and other: 4pts. All pts received prophylactic antibiotics according to common practice. Results: 13 pts are alive and well 45 to 1579 days after transplant (median 303 days). 34 pts were evaluable for engraftment (2 pts died before day 28 due to bacterial sepsis and CNS hemorrhage). Median time to reach PMN&gt; 500/uL was 21 days after transplant (+ 12 to + 57) and platelets&gt; 20.000/uL was 22, 5 days (+14 to + 49). Pts who received CY + Fludarabine + Thimoglobuline had a better survival (56%) but it did not reach statistical significance when compared to other preparatory regimens. Acute graft versus host disease (A-GVHD) occurred in 9 pts (grade III: 4 pts, grade IV: 5 pts). Three pts with grade III A-GVHD developed C-GVHD (2 were extensive and severe). VOD was diagnosed in 3 pts (moderate/severe). Mucosytis grade III- IV occurred in 16 pts. Twenty-three pts died at a median time of 58 days after transplant (7 to 226 d). All pts with primary graft failure (11) and 5 pts with only a neuthrophil engraftment died. Causes of death: 15 pts: infections or hemorrhage related to rejection; 4 pts: GVHD, 3 pts:VOD , 1 pt: P carinii and 1 pt EBV lymphoproliferative disease. Transplant related mortality (TRM) was 55% for the whole group (38% for the pts who received CY+ Fludarabine + ATG). It was also lower (35%) for the pts who received cord blood transplants but it did not reach statistical significance regarding survival rate. Conclusions: Treatment of FA pts with unrelated stem cell transplant must be directed at a more effective control of rejection and GVHD. Transplant related mortality is still very high in this group of pts. Our study shows that the use of CY + Fludarabine + Thimoglobuline may improve survival but we still need more pts and a longer follow up to confirm this data.

Abstract Abstract 2083 INTRODUCTION: The addition of chemotherapy to G-CSF for stem cell mobilization prior to autologous stem cell transplantation (ASCT) provides the potential for increased cell yield and improved mobilization outcomes relative to G-CSF alone. We have investigated the use of mid-dose VP-16 plus G-CSF in pts with lymphoma and examined whether plerixafor might be incorporated into this chemomobilization backbone in a cost-effective way for a population with inferior outcomes. METHODS: Between June 2004 and September 2010, 159 pts with lymphoma underwent ASCT following the use of VP-16 (375mg/m2 on D#1 and D#2) and G-CSF (5mcg/kg twice daily from D#3 through the final day of collection) for mobilization. 26 pts also received a dose of Rituximab (375mg/m2) on D#1. Stem cell collection was initiated when the peripheral blood CD34 cell count was more than 7 per ul. Data on costs for fixed and variable expenditures associated with mobilization and collection were calculated on an individual patient basis. Costs also included unexpected complications such as inpatient hospitalizations, antibiotic use and blood product transfusions. “Poor mobilizers” were defined as pts failing to collect 5 × 106 cells in one or two days. Univariable and multivariate logistic regression were performed to identify predictive models for poor mobilization and to identify hypothetical breakpoint scenarios for the cost-effective utilization of plerixafor. For the breakpoint scenarios, a median of 3 doses of plerixafor was assumed based on the published phase III data with plerixafor plus G-CSF. RESULTS: Of 159 pts with lymphoma, 90 (57%) were identified as “good mobilizers,” 43% were “poor mobilizers”, and 150 (94%) collected at least 2 × 10 6th/kg CD34 cells in total (83% within 4 apheresis sessions), comparing favorably to published data with G-CSF alone or G-CSF + plerixafor. 51 (32%) required PRBC or platelet transfusion, 10 (6%) were admitted to the hospital during the mobilization period, and 8(5%) required a second mobilization or bone marrow harvest. There was no increased incidence of secondary malignancies. Average costs were $14923 ($6121-$24546) for good mobilizers and $27044 ($12206-$51846) for poor mobilizers (p<0.05). The first peripheral blood CD34 count (obtained between D9-D15, with 82% of first counts obtained on D12), accurately predicted “good” vs “poor” mobilizers (c statistic 0.941, CD34 cutpoint 27/uL). Using our data, we estimated that it would not be cost effective to give plerixafor to all patients, even if 100% of patients subsequently became “good” mobilizers (net loss $15,817/pt). Instead, by reserving plerixafor for only predicted “poor” mobilizers (probability<0.5) at the time of first CD34 count, we estimated that 64% (n=49) of predicted “poor” mobilizers would need to become “good” mobilizers in order to achieve cost neutrality. CONCLUSION: VP-16 and G-CSF is a safe and effective mobilization regimen for pts with lymphoma and compares favorably to published data with G-CSF alone or G-CSF + plerixafor. Mobilization outcomes after chemomobilization might be further improved in a cost-effective way by adding plerixafor in patients predicted by the first peripheral blood CD34 count to be poor mobilizers. This will be investigated prospectively. Disclosures: Shea: Otsuka Pharmaceuticals: Research Funding.

7545 Background: Lenalidomide (Revlamid [R]) is the leading clinical compound in a new group of drugs called IMiDs. Our group demonstrated that clarithromycin (Biaxin [Bi]) augments tumor mass reduction and improves responses in patients (pts) receiving low-dose thalidomide and/or dexamethasone (D). We report the results of the combination of Bi plus R plus D (BiRD) in newly diagnosed MM. Methods: A phase II trial designed to accrue 50 pts. A 2-stage design rejects a CR rate of < 10% (alt >30%). Between Nov. 2004 and Jan. 2006, 46 pts have been accrued of which 40 pts are eligible for evaluation. R is given po at 25 mg daily on days 1–21 of a 28-day cycle. D is given po at 40 mg once weekly. Bi is given po at 500 mg bid. Pts receive low dose aspirin (ASA)(81mg) qd as thrombosis (TE) prophylaxis. Responses are defined according to modified EBMTR criteria. Analysis is by intent-to-treat. Patient Selection: Median age: 62.5 years (36–80), Male/Female 25/15, Hgb: 10.6 g/dL (7.2–15.1), Plt 234 k/uL (51–526), β2m: 3 mg/L (0.8–12.8), CRP: 0.6 mg/dL (0.12–14.2), creat: 1.1 mg/dL (0.6–3.1), albumin 3.5 g/dL (2.3–4.9). SD stage IIIa: 48%, stage IIIb: 10% and IIa: 42%. ISS stage I: 50%, stage II: 25% and stage III: 25%. Cytogenetics and FISH: trisomy 11 (10 pts), tetrasomy 11 (3 pts), del13q14 (14 pts), t (4,14) (1pt), t (11,14) (3 pts). Results: Of the 40 evaluable pts, 38 (95%) have achieved an objective response (>PR) within 3–4 months of Rx with the remaining pts continuing to respond. Seventeen pts (43%) had a >90% reduction of the initial paraprotein. Nearly one third of pts have achieved either a CR (10/40) or a nCR (2/40-continuing on Rx). CR has been confirmed in all pts by normalization of free light chain levels and ratio. The remaining 26 pts (65%) achieved a PR. Of those pts who achieved a PR, 5/26 pts (19%) had >90% reduction in the initial paraprotein. Nineteen pts have experienced grade ≥3 adverse events. Heme toxicities: anemia (11%), neutropenia (9%) and thrombocytopenia (9%). Non-heme toxicities (NHT) include TE in 7 patients (15%) 2 of them fatal. Four of the TE events were while off ASA. Other NHT include myopathy (6%), GI (4%), and mood (4%). Conclusions: BiRD therapy is a safe and highly effective primary therapy for symptomatic, treatment-naïve MM. [Table: see text]

7028 Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A prior Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also reported an encouraging response rate (Blood 109: 2999, 2007). SWOG S0919 therefore evaluated the complete remission (CR) rate in a larger number of pts with relapsed AML treated with the pravastatin dose arrived at in the Phase 1 trial. Methods: Pts were treated at SWOG institutions from Aug 2009 through Nov 2012. Pravastatin was supplied by Bristol-Meyers Squibb. The protocol was approved by each institution’s review board. Eligibility: age ≥ 18 yrs, relapsed AML, cardiac ejection fraction ≥ 45%, CR/ CR with incomplete count recovery (CRi) following most recent chemotherapy lasting ≥ 3 months, no prior hematopoietic cell transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m2/d IV Days 4-6, and cytarabine 1.5 g/m2/d continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by IWG criteria. Fifty eligible pts were to be accrued. If ≥ 21 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level = 4.8% if true CR rate = 30% and power of 90% if true CR rate = 50%). Results: The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study. Thirty-six pts with a median age of 59 yr (range 23-78) were enrolled. Seventeen pts (47%) were male and the median WBC was 2800/ uL (range 700-110,600). The median time from initial dx to registration was 18 mo (range 5-136). Relapse status: 1st: 17 pts (47%), 2nd: 15 (42%), 3rd: 2 (5.5%), and 4th: 2 (5.5%). Eighteen pts have died, 3 during treatment. The response rate was 75% (95% CI 58-88%; 20 CR, 7 CRi); and the median overall survival was 10 mo. The p-value comparing 75% to 30% (null response rate) is 3.356 x 10-8. Duration of last CR (≤ 6 months) and prior high dose cytarabine exposure did not affect response to protocol treatment. Conclusions: The CR/ CRi in this relapsed population is encouraging. We plan to evaluate the efficacy of this regimen in higher-risk patients. Clinical trial information: NCT00840177.

Introduction: JAK2 is located on chromosome 9p24 and includes 25 exons encoding a protein of about 1132 amino acids. JAK2 is one of the four Janus family non-receptor protein tyrosine kinases. JAK2V617F is by far the most prevalent mutation in BCR-ABL1-negative Myeloproliferative neoplasms (occurs in ∼95% of patients with polycythemia vera, in ∼55% with essential thrombocythemia and in ∼65% with primary myelofibrosis) 1, 2. More than 80% of hemochromatosis patients are homozygous for a C282Y mutation in HFE gene, and a smaller proportion are compound heterozygous for both the C282Y mutation and an H63D mutation3. Here we present the first case of an elderly female with concomitant diagnosis of Polycythemia Vera (PV) and hemochromatosis. To our knowledge, there is no literature about the co-existence or associations of these diseases. Case Reports: 75 year old female, former smoker with PMH of hemochromatosis and COPD with recent exacerbation, presented to the oncology clinic after hospital discharge for continuing care of her hemochromatosis requiring phlebotomy. She reports to have had multiple phlebotomies in the past fifteen years. Patient denied any history of liver disease, diabetes, arthralgia, skin pigmentation or sleep problems. Vital signs and examination were within normal limits. Her initial work up reported significantly elevated hemoglobin of 17.4gm/dl, hematocrit of 56.1%, RBC count of 6.98M/UL with MCV 80.4 fl, MCH 24.9 pg and platelet count of 673 K/UL. Peripheral smear showed normal red cell morphology and few giant platelets. Subsequently, further lab testing revealed ferritin of 25.7ng/ml. Her elevated hematocrit was further evaluated and erythropoietin was surprisingly <1mIU/ml. Genetic testing for HFE gene mutation screen was positive for homozygous C282Y mutation. Due to high suspicion for Polycythemia Vera, JAK2 mutation was also tested, which to our surprise, came back positive for JAK2 V617F point mutation. Patient is diagnosed with Polycythemia Vera and Hereditary Hemochromatosis and is recommended to start Aspirin, continue phlebotomy to maintain Hematocrit below 45% and take hydroxyurea for thrombocytosis. Discussion: It is interesting to note the co-existence of two un-related diseases. Franchini M et al analyzed 52 patients with PV for 12 HH gene mutations and found no significant association between the two conditions4. Hannuksela J et al studied C282Y and H63D mutations in 232 patients with hematological malignancies and reported no significant association5. Beaton and Adams in their review article about the myths and realities of hemochromatosis reports an elevated hemoglobin, in hemochromatosis's patient as a myth, based on their review of 634 C282Y homozygous patients at London health Science center, with mean hemoglobin of 145±13 g/L6. Our case re-iterates the importance of clinical suspicion of polycythemia Vera in a hemochromatosis patient with elevated hematocrit and undetectable erythropoietin. The coincidence is, phlebotomy is the treatment for both conditions as long as patient is fairly asymptomatic. References: 1. Ayalew Tefferi; Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1; J Cell Mol Med. 2009 Feb; 13(2): 215-237. 2. Cross NC (2011); Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2011:208-214. 3. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet1996; 13:399-408. 4. Analysis of hemochromatosis gene mutations in 52 consecutive patients with polycythemia vera. Franchini M1, de Matteis G, Federici F, Solero P, Veneri D. Hematology. 2004 Oct-Dec;9(5-6):413-4. 5. Prevalence of HFE genotypes, C282Y and H63D, in patients with hematologic disorders. Hannuksela J, Savolainen ER, Koistinen P, Parkkila S. Haematologica. 2002 Feb;87(2):131-5. 6. The myths and realities of hemochromatosis Melanie D Beaton, Paul C Adams Can J Gastroenterol. 2007 February; 21(2): 101-104. PMCID: PMC2657669 Disclosures No relevant conflicts of interest to declare.

Abstract Revlimid® (R) or lenalidomide is the leading clinical compound in a new group of drugs called IMiD®s, which have immunomodulatory properties. In contrast with thalidomide (T) R has significantly less neurological toxicity. Several phase I and II trials with R showed promising results in relapsed/refractory MM. Our group demonstrated that Bi augments tumor mass reduction and improves responses in patients (pts) receiving low-dose T and/or D. We report the initial results of a phase II trial exploring the combination of Bi plus R plus D (BiRD) in newly diagnosed MM. Methods: The trial is designed to accrue 35 pts. Thus far 28 pts have been accrued between Nov. 2004 and Aug. 2005 of which 22 pts (13 male and 9 female) are eligible for evaluation. R is given orally (po) at a dose of 25 mg daily on days 1–21 of a 28-day cycle. D is given po at a dose of 40 mg once weekly. Bi is given po at 500 mg twice daily. All pts also receive low dose aspirin (ASA)(81mg) once daily as thrombosis prophylaxis, prophylactic sulfamethoxazole/trimethoprim, and a proton pump inhibitor. Responses are defined according to the EBMTR. In addition, the category of near-CR (nCR) is defined as a CR with a positive immunofixation. A minimum of 2 cycles is required for response assessment; all pts are assessed on an intent-to-treat basis. Results: Pt characteristics are as follows: median age of 62 years (range 36–77), hemoglobin of 11.4g/dL (range 7.2–15.1), platelets of 247k/uL (range 51–526), β2m of 4.0mg/L (range 0.8–5.1), CRP of 1.0mg/dL (range 0.3–8.4), creatinine of 1.3mg/dL (range 0.5–3.1), albumin of 3.6g/dL (range 2.3–4.9), and calcium of 8.9mg/dL (range 6.9–11.2). Conventional cytogenetics was normal in all pts; FISH abnormalities are as follows: trisomy 11 (2 pts), tetrasomy 11 (1 pt), del13q14(5 pts), t(4,14)(1pt), t(11,14)(2 pts). 52% of the pts are stage IIIa, 13% are stage IIIb, 35% are stage IIa. Responses are summarized in the table below. Of the 22 evaluable pts, 21(95%) have achieved an objective response (&gt;PR) within 1–2 months of Rx with the remaining pt continues to respond. Nearly one third of pts have achieved either a CR(6/22) or a nCR(1/22-continuing on Rx). The remaining 14 pts(63%) achieved a PR. Of those pts who achieved a PR, 6/14 pts(43%) had &gt;90% reduction in the initial paraprotein, while 12/14 pts(86%) had &gt;75% decrement. 5 pts are now off study (3 pts in CR going to PBSCT and 2 due to toxicities). So far 15 pts have experienced grade ≥3 adverse events. These include, anemia(4.5%), neutropenia(4.5%), thrombocytopenia(4.5%), increased liver enzymes(4.5%), anxiety(4.5%), insomnia(9%), tremors(4.5%), hyperglycemia(4.5%), syncope(4.5%), Stevens Johnson’s(4.5%) and colonic perforation(4.5%). DVT occurred in 3(13.6%) patients, all off ASA, of which 2 (9%) had an associated PE, one of whom died. No grade 4 toxicities have been otherwise observed. Three pts have undergone successful stem cell harvest of which one has undergone transplantation with melphalan 200. Engraftment was successful by day 12. Conclusions: BiRD is highly effective and safe in the initial Rx of MM. Stem cell harvest is not impaired after BiRD induction. Supported in part by the LLS SCOR grant and K23CA109260-01 Response Evaluation # of Pts % Total 22 100 Overall Response 21 95 CR 6 27.3 n-CR 1 4.5 PR 14 63.6 SD 1 4.5

Introdução: Com a evolução da microcirurgia ao longo dos anos o Retalho Anterolateral da Coxa vem se tornando uma das principais opções para reconstruções na cabeça, pescoço, tronco e extremidades devido sua versatilidade e confiabilidade. Objetivo: Descrever dados de um hospital terciário referência em trauma na reconstrução de extremidades com o Retalho Anterolateral da Coxa. Método: Este é um estudo retrospectivo de 18 retalhos Anterolateral da Coxa microcirúrgicos realizados entre Março de 2016 e Outubro de 2019 em pacientes de todas as idades, na reconstrução de membros, onde se observou dados referentes ao paciente: idade, sexo, membro acometido, tempo entre a lesão e a confecção do retalho; ao intraoperatório: anatomia dos vasos perfurantes, tempo cirúrgico total, vasos receptores utilizados; e informações do pós-operatório: número de cirurgias relacionadas ao retalho, necessidade de reabordagem e número de perdas. Foram excluídos pacientes que perderam seguimento ou que apresentaram dados do prontuário incompletos. Realizou-se estatística descritiva e cruzamento de algumas variáveis utilizando o teste t-Student. Resultados: Nas reconstruções houve predomínio de pacientes do sexo masculino (72%), em idade produtiva, de etiologia traumática e nos membros inferiores. O tempo médio até a reconstrução foi de 21 dias e o tempo cirúrgico foi de 384 minutos. O paciente permaneceu, em média, 39 dias internado. Dos 18 retalhos, 3 evoluíram com necrose, 2 por trombose arterial e 1 por infecção. 6 retalhos necessitaram de reaborgadem de emergência, 3 por sangramento, 2 por congestão e 1 por infecção. Foram realizadas uma média de 3 cirurgias até a alta. Foram identificadas 15 perfurantes miocutâneas (83%) e 3 septocutâneas (17%). A análise do sucesso do retalho em relação ao tempo cirúrgico e dos dias até a cirurgia não mostrou significância estatística, assim como a necessidade de reabordagem em relação ao tempo cirúrgico. Conclusão: O retalho Anterolateral da Coxa mostrou-se confiável, além de apresentar diversas vantagens como: por ser retirado com uma grande ilha de pele, apresentar pedículo longo, vasos de bom calibre, não necessitar de mudança de decúbito e apresentar baixa morbidade da área doadora.Descritores: Retalho Miocutâneo; Microcirurgia; Hospitais Especializados.ReferênciasDaniel RK, Taylor GI. Distant transfer of an island flap by microvascular anastomoses. A clinical technique. Plast Reconstr Surg. 1973;52(2):111-17.Ninkovic M, Voigt S, Dornseifer U, Lorenz S, Ninkovic M. Microsurgical advances in extremity salvage. Clin Plast Surg. 2012;39(4):491-505.Tamimy MS, Rashid M, Ehtesham-ul-Haq, Aman S, Aslam A, Ahmed RS. 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Plast Reconstr Surg. 1998; 102(5):1517-23Spindler N, Al-Benna S, Ring A, Homann H, Steinsträsser L, Steinau HU et al. Free anterolateral thigh flaps for upper extremity soft tissue reconstruction. GMS Interdiscip Plast Reconstr Surg DGPW. 2015;4:Doc05.Kimura N, Satoh K, Hasumi T, Ostuka T. Clinical application of the free thin anterolateral thigh flap in 31 consecutive patients. Plast Reconstr Surg. 2001;108(5):1197-210.Collins J, Ayeni O, Thoma A. A systematic review of anterolateral thigh flap donor site morbidity. Can J Plast Surg. 2012;20(1):17-23.Kuo YR, Jeng SF, Kuo MH, Huang MN, Liu YT, Chiang YC et al. Free anterolateral thigh flap for extremity reconstruction: Clinical experience and functional assessment of donor site. Plast Reconstr Surg. 2001;107(7):1766-71Novak CB, Lipa JE, Noria S, Allison K, Neligan PC, Gilbert RW. Comparison of anterolateral thigh and radial forearm free flap donor site morbidity. Microsurgery. 2007;27(8):651-54.Pagano M, Gauvreau K. 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