Prognostic Impact of Hematopoietic Recovery After Fludarabine, IV Busulfan and Antithymocyte Globulins (FB2 regimen) Reduced-Intensity Conditioning Regimen (RIC) Allogeneic Stem Cell Transplantation (allo-SCT)

Abstract Abstract 4483 Introduction: RIC regimens are increasingly used prior to allo-SCT. The FB2 regimen (Fludarabine 120–150 mg/m2 + IV Busulfan 6.4 mg/Kg + ATG Thymoglobuline 5mg/Kg) is currently the most widely used RIC regimen in many European centres. This retrospective analysis aimed to assess the hematopoietic and immune recovery in a homogeneously treated cohort of 53 patients (males: n=33; median age: 59 years (range: 22–70)) who received the FB2 regimen between January 2007 and October 2010 in our department. Patients and Methods: Diagnoses were as follow: AML n=23; ALL n=1; biphenotypic leukemia n=1; lymphoma n=16; myelodysplastic syndrome n=9; multiple myeloma n=3. Nineteen patients (36%) had received a prior autologous SCT. The majority of patients (n=40, 75.5%) were transplanted in complete remission. Thirty patients received a graft from a matched sibling donor (56.5%). All patients, but one (who received unmanipulated bone marrow) received G-CSF-mobilized PBSCs. GVHD prophylaxis consisted of cyclosporine (CsA) alone in patients transplanted with an HLA-identical sibling, and CsA+ mycophenolate mofetyl in other cases. None of the patients received G-CSF during aplasia following transplant while nine patients received erythropoietin before day+100. Results: Engraftment was achieved in 96% of patients (n=51). Median times for neutrophils (n=51) and platelets (n=22) recovery were 17 days (range: 0–39) and 10 days (range: 4–186), respectively. The majority of patients (n=31, 58%) did not receive platelet support during aplasia. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 30% and 15%, respectively, while overall incidence of chronic extensive GVHD was 33%. With a median follow-up of 19 months (range: 2–53), the 2-year OS, DFS, relapse incidence, and NRM were 63%, 59.5%, 35% and 6%, respectively. In univariate analysis, when regarding pre-transplant factors associated with outcome, the only factor correlated with a significantly higher 2-year OS and DFS was a higher total circulating lymphocytes count at transplant (> 730/mm3) (OS: 81.5% vs 43.2%, p=0.01; DFS: 73.2% vs 45.5%, p=0.03). Regarding post-transplant factors, we found that higher recovery of leukocytes (>5000/mm3) (2-year OS: 78% vs 46%, p=0.007; 2-year DFS: 70% vs 48%, p=0.08), neutrophils (>3230/mm3) (2-year OS: 76% vs 50%, p=0.02; 2-year DFS: 67.5% vs 52.0%, p=0.09), and monocytes (>590/mm3) (2-year OS: 80% vs 47%, p=0.004; 2-year DFS: 75% vs 42%, p=0.007) at day+30 post-transplant were the most significant factors associated with outcome. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm3; HR 0.22; 95%CI: 0.08–0.63, p=0.005; and HR: 0.29; 95%CI: 0.12–0.71, p=0.006, respectively) and a higher monocytes count at day+30 post-transplant (>590/mm3) (HR: 0.24; 95%CI: 0.08–0.66, p=0.006; and HR: 0.28; 95%CI: 0.11– 0.68, p=0.005; respectively). Conclusion: These results suggest that hematopoietic status and recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT. Disclosures: No relevant conflicts of interest to declare.

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Minimal Residual Disease (MRD) By Either Flow Cytometry or Cytogenetics Prior to an Allogeneic Hematopoietic Cell Transplant (allo-HCT) Predicts Poor Acute Myeloid Leukemia (AML) Outcomes

Blood ◽

10.1182/blood.v126.23.3221.3221 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3221-3221

Author(s):

Lakshmikanth Katragadda ◽

Maxim Norkin ◽

Myron Chang ◽

Yunfeng Dai ◽

Jan S Moreb ◽

...

Keyword(s):

Flow Cytometry ◽

Complete Remission ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Cox Proportional Hazards Model ◽

Cell Transplant ◽

Poor Risk ◽

The Impact ◽

Count Recovery

Abstract Introduction: Persistent AML is a known risk factor for poor outcomes after allo-HCT. The impact of MRD in patients who achieve complete remission (CR) or CR with incomplete count recovery (CRi) has been less well studied. Methods: We retrospectively reviewed the records of AML patients who underwent allo-HCT in morphological remission (<5% myeloblasts and normal marrow cellularity) with or without blood count recovery between January, 2000 and January, 2014. Data was collected for variables known to impact the prognosis of AML patients (Table 1). MRD was defined as evidence of abnormalities associated with AML by either flow cytometry, cytogenetics or Fluorescence in situ hybridization (FISH). The impact of MRD identified at the time of allo-HCT on cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) was assessed in MRD+ and MRD- patients. Results: A total of 166 eligible patients were identified. The median follow-up among living patients is 46 months (range, 13-103).Thirty seven (22%) patients had evidence of MRD (13 by flow cytometry only, 17 by cytogenetics/FISH only and 7 by both). MRD was more common in patients with poor risk karyotype at diagnosis and CRi at the time of allo-HCT (Table 1). PFS (P= 0.0016), OS (P=0.002), and CIR (P=0.02) were all significantly worse in MRD+ patients (Figures 1& 2). In univariate analysis, MRD+ patients, assessed by flow cytometry had worse PFS (P=0.0216) and OS (P=0.0314) compared to MRD- patients. Similarly patients with evidence of MRD+ by cytogenetics/FISH had worse PFS (P=0.007) and OS (P=0.0031). In a multivariate cox proportional hazards model 1) any MRD positivity prior to allo-HCT, 2) poor-risk karyotype at diagnosis, and 3) CRi at allo-HCT independently predicted significantly poor PFS and OS. Only poor-risk karyotype was associated with a significant increase in CIR, while MRD positivity showed a trend towards higher CIR. Conclusion: MRD positivity prior to HCT by either flow cytometry or by cytogenetics/FISH independently predicts adverse AML outcomes. Table 1. Comparison of pre-transplant variables Covariate Label MRD + (N=37) MRD - (N=129) P-Value Age(years) < 40 8 (21%) 20 (16%) 0.708 40 - 59 20 (53%) 69 (54%) ≥ 60 10 (26%) 39 (30%) Karyotype risk Favorable/ Intermediate 19 (53%) 95 (74%) 0.011 Poor 18 (47%) 33 (26%) Timing of Allo-HCT 1st remission (CR1) 28 (74%) 97 (76%) 0.792 > CR1 10 (26%) 31 (24%) Allo-HCT after1st relapse(>CR1): duration of CR1 > 12 mo 31 (82%) 113 (88%) 0.285 ≤ 12 mo 7 (18%) 15 (12%) Secondary AML No 23 (60%) 78 (61%) 0.964 Yes 15 (40%) 50 (39%) Complete remission vs CRi CR 28 (74%) 110 (86%) 0.077 CRi 10 (26%) 18 (14%) Conditioning Regimen Ablative 24 (63%) 72 (56%) 0.449 Other 14 (37%) 56 (44%) Donor Type Matched sibling donor 12 (32%) 42 (33%) 0.887 Other 26 (68%) 86 (67%) Female donor: male recipient (FDMR) Other 28 (80%) 91 (78%) 0.844 FDMR 7 (20%) 25 (22%) Disclosures No relevant conflicts of interest to declare.

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Immunophenotypic Response After Allografting In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3371.3371 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3371-3371 ◽

Cited By ~ 1

Author(s):

Luisa Giaccone ◽

Lucia Brunello ◽

Roberto Passera ◽

Moreno Festuccia ◽

Milena Gilestro ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Flow Cytometry ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Conditioning Regimen ◽

First Line ◽

Significant Difference ◽

The Impact

Abstract Background Minimal residual disease (MRD) by multiparameter flow-cytometry recently showed a promising role in predicting outcomes in patients with multiple myeloma. However, data on immunophenotypic response (IR) after allografting are lacking. Aim To evaluate the impact of IR and compare it to conventional complete remission (CR) following allografting in myeloma patients. Methods Sixty-six consecutive patients, median age 54 years (35-66), who underwent an allograft between January 2000 and December 2011 with a follow-up of at least 3 months were included. Disease response was evaluated by serum and urine electrophoresis, and bone marrow aspirate at baseline, 3, 6, 12, 18, 24 months after transplant and yearly thereafter. Skeletal survey or MRI were performed yearly or as clinically indicated (overt relapse or complaints of bone pain). Bone marrow aspirates had to contain at least 13000 cells/µL for flow-cytometry studies and IR was defined as absence of monoclonal plasma-cells detected by 4 or 6-colour staining with the following antibodies: CD38, CD138, CD56, CD19, CD45, cyKappa, cyLambda. CR was defined according to standard criteria (Durie et al, Leukemia 2006; 20:1467-73). Results Conditioning regimen was non-myeloablative 2Gy TBI-based in 55 patients, reduced intensity (fludarabine-melphalan-based) in 10 and myeloablative in 1 patient. Post-grafting immunosuppression consisted of cyclosporine with mycophenolate mofetil or methotrexate. Donors were HLA identical siblings in 58 patients and unrelated in 8. Only 1 patient received bone marrow as source of stem cells. Thirty-five/66 (53%) received the allograft as part of the first line treatment, whereas the remaining 31/66, (47%) were transplanted at relapse. At the time of transplant, 5/66 were both in IR and CR, 16 were only in IR and 4 patients were only in clinical CR. All 21 patients in IR at the time of transplant maintained it, while 26/45 (58%) entered IR after the allograft. Among patients surviving at least 3 months, overall treatment related mortality was 10.6% at 3 years. After a median follow-up of 69 months (range 19-147), the incidence of acute and chronic graft-versus-host disease was 45.6% and 49.3% without significant difference between responsive and non-responsive patients. At follow-up, overall, 24 patients achieved CR and IR (CR/IR group), 21 achieved IR but not CR because of persistence of urine/serum M-component (noCR/IR group), and 21 did not achieve either CR or IR (noCR/noIR group). Interestingly, none achieved CR without IR. Median overall survival (OS) and event-free survival (EFS) in patients who achieved IR were 96 and 55 months versus 36 and 7 months in those who did not (p<0.001). Median OS and EFS were not reached and 59 months in the CR/IR group, 77 and 15 months in the noCR/IR, and 30 and 5 months in the noCR/noIR respectively (p<0.001 for both EFS and OS-fig.1). In univariate analysis, being in the CR/IR group was the only significant predictor for prolonged OS and EFS (p<0.001). Of note, cumulative incidence of extra-medullary disease at first relapse after the allograft was 4% in the CR/IR, 32% in the noCR/IR and 15% in the noCR/noIR groups respectively (p<0.001). Receiving the allograft as first line therapy or later during the disease course did not significantly impact on OS and EFS. Conclusion The achievement of IR confers a favorable impact on OS and EFS after allografting. A higher incidence of extra-medullary in the noCR/IR group (some 30% of our patient cohort) may suggest that myeloma cells escape immune control outside the bone marrow. In this group, imaging studies such as positron emission tomography may clinically be indicated during follow-up to detect early relapse. Disclosures: No relevant conflicts of interest to declare.

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Post-Transplant Cyclophosphamide (PTCY) Vs Anti-Thymoglobulin (ATG) As Part of the Gvhd Prophylaxis for Fludarabine/Clofarabine/Busulfan Reduced Intensity Conditioning (RIC) in Allogeneic Stem Cell Transplantation (allo-SCT): Influence on Early Immune Reconstitution

Blood ◽

10.1182/blood.v126.23.1955.1955 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1955-1955

Author(s):

Christelle Retiere ◽

Catherine Willem ◽

Thierry Guillaume ◽

Henri Vié ◽

Laetitia Gautrot-Rolland ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Immune Reconstitution ◽

Conditioning Regimen ◽

Immune Recovery ◽

Post Transplant ◽

Gvhd Prophylaxis ◽

The Impact

Abstract Introduction: The influence of PTCY on early immune reconstitution after allo-SCT has been poorly studied so far, especially in comparison to standard use of ATG as GVHD prophylaxis. Patients and Methods: A prospective study was conducted at the CHU of Nantes with the aim to compare early immune recovery between patients receiving PTCY or ATG as GVHD prophylaxis after a RIC allo-SCT. Secondary objectives were to study the impact of 1 vs 2 days of PTCY (CY1 vs CY2) or ATG (A1 vs A2), and of fludarabine (Flu) vs clofarabine (Clo) as part of the RIC regimen. As such, 3 RIC regimens were considered in both groups: FluCY2 (Baltimore regimen, Luznic, BBMT 2008), FluCY1, CloCY2 (where Clo replaces Flu), on one hand, and FluB2A2, CloB2A2, CloB2A1 (Chevallier, Haematologica, 2014), on the other hand. FluCY2 and FluB2A2 are currently standard of care RIC regimens for patients with haplo-identical and matched donors, respectively. Five patients had to be included in each RIC subgroup, depending on the type of disease and donor (/): FB2A2 (lymphoid/matched); FluCY2 (lymphoid/haplo); CloB2A2 or CloB2A1 (myeloid/matched); CloCY2 (myeloid/haplo), FluCY1 (myeloid or lymphoid/matched). The source of graft was peripheral blood stem cells for all cases. Blood samples were collected before starting the conditioning regimen then 3 times per week from day +0 until day+30, and at days +60 and +90. The following cell subsets were studied: a/b and g/d CD3+, CD8+ and regulatory (Tregs) T cells, B and NK cells and monocytes. The median percentage (%) compared to total lymphocytes was considered for all lymphocytes subsets between days 0-30. Thereafter, median absolute numbers (AN)/mm3 were considered for samples collected at days +30, +60 and +90. The study was approved by the IRB of the CHU of Nantes and all patients provided informed consent. Results: Between August 2014 and May 2015, thirty patients were included, including 15 in both groups and 5 in each RIC subgroups. Median age was 61 years. There were more patients with active disease at transplant (47% vs 7%) and more haplo-identical donors (67% vs 0%) in the PTCY group. All patients engrafted and were alive at day +90. However, 1 PTCY patient with T-ALL relapsed before day+100. Within the first month post-transplant, PTCY group had a significantly higher median % of a/b T cells (69.1 vs 18.9, p<0.0001) and Tregs (3.46 vs 0.45, p<0.0001) while ATG group had higher median % of NK (23 vs 2.57, p<0.0001) and B-cells (0.88 vs 0.43, p=0.0002). Between day+30 and day+90, ATG group had significant higher median counts of a/b T cells at days +60 (1316 vs 79.6, p=0.0001) and +90 (795.8 vs 151.6, p=0.03); g/d T cells at day+60 (27.6 vs 1.26, p=0.002); CD8 T cells at day+60 (735 vs 29.6, p=0.008); NK cells at day+30 (203.7 vs 89, p=0.04) and monocytes at days +30 (455.5 vs 221.7, p=0.009) and +60 (832.5 vs 247.2, p=0.004). Compared to the standard FluCY2 regimen, although not significant, FluCY1 was associated with higher median %, between days 0-30 of g/d T cells (2.32 vs 0.8) and higher median AN of g/d T cells at days +30 (9.2 vs 1.02) and +60 (9.22 vs 1.05), of B cells at days +30 (0.4 vs 0.14) and +60 (1.6 vs 0.39) and of NK cells at day+30 (213.9 vs 82.7). Compared to the standard FB2A2 regimen, although not always significant, CloB2A1 was associated with higher median % between days 0-30 of Tregs (0.97 vs 0.25, p=0.002) and higher median AN of g/d T cells at day+30 (6.8 vs 2), B cells at days +30 (2.35 vs 0) and +60 (43.7 vs 0.19), NK cells at day +30 (288 vs 62.1) and Tregs at days +30 (4.3 vs 0.2), +60 (8.8 vs 1.14) and +90 (8.96 vs 3.45). Compared to the standard FB2A2 regimen, although not always significant, CloB2A2 was associated with higher median % between days 0-30 of a/b T cells (28.87 vs 3.78, p=0.01) and B cells (0.76 vs 0.5, p=0.02) and higher median AN of a/b T cells at days +30 (324.3 vs 125.8) and +90 (1594 vs 604.3), of g/d T cells at day +30 (7.35 vs 2), of CD8 + T cells at days +30 (209.7 vs 38.9) and +90 (1211.7 vs 504.6), of B cells at day +30 ( 1.41 vs 0), of NK cells at days +30 (303 vs 62.1), +60 (514.5 vs 225.7) and +90 (647 vs 102.8, p=0.03) and of monocytes at days +30 (688.9 vs 257.4, p=0.03) and +90 (2157.4 vs 611.2). Conclusion: Strong differences exist in term of early immune recovery when using PTCY or ATG as part of the GHVD prophylaxis for RIC allo-SCT. Dose or drug modifications within the standard RIC regimen in both groups may be envisaged to favor some cell population recoveries after allo-SCT in order to increase outcome in patients. Disclosures No relevant conflicts of interest to declare.

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Pretransplatation PET as Major Prognostic Discriminant in IGEV (ifosfamide, gemcitabine, vinorelbine and prednisone) Treated Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL).

Blood ◽

10.1182/blood.v114.22.3707.3707 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3707-3707

Author(s):

Rita Mazza ◽

Stefano Luminari ◽

Massimo Magagnoli ◽

Michele Spina ◽

Teodoro Chisesi ◽

...

Keyword(s):

Complete Remission ◽

Fdg Pet ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Disease Status ◽

Response To Therapy ◽

High Dose ◽

Bulky Disease ◽

The Impact

Abstract Abstract 3707 Poster Board III-643 Introduction response to salvage chemotherapy prior to high–dose therapy (HDT) is of major prognostic concern in relapsed/refractory HL. FDG-PET is able to distinguish between persistent disease and fibrosis/necrosis and has thus become the mainstay to define clinical response in this setting (Cheson et al, JCO 2007). The value of FDG-PET in this subset of patient is less well established. IGEV chemotherapy has shown very encouraging results as induction therapy in refractory/relapsed HL (Santoro et al, Haematologica 2007). Aims to retrospectively evaluate the predictive value of PET in pts with relapsed/refractory HL receiving IGEV and HDT. Methods seventy-two multicentric cases with refractory/relapsed HL who had completed IGEV x 4 courses and HDT between 01/98 and 05/07 were reviewed. FDG-PET evaluation was performed before HDT and, according to revised Cheson criteria, complete remission (CR) was defined as negative FDG-PET, independently from the presence of residual masses at CT scan. Univariate analysis was performed considering FDG-PET as well as other usually evaluated prognostic factors. Results patient characteristics: M/F 30/42, median age 33 (range 16-71), Nodular sclerosis 61 (85%), refractory 28 (39%), relapsed 44 (61%), one previous regimen 60 (83%), B symptoms 18 (25%), bulky disease 7 (10%), extranodal disease 32 (44%), previous radiotherapy 39 (54%). After induction, 36 pts (50%) received single (with BEAM as conditioning regimen ), and 36 (50%) tandem HDT (with melphalan as first and BEAM as second conditioning). After IGEV, on the basis of PET 47 pts (65%) were classified as complete remission (CR), 21 (29%) as partial remission (PR) and 4 (6%) did not respond. Ten of the 47 PET negative pts, and 18 of the 25 PET positive pts relapsed. With a median follow up 48 months, the 3-year PFS was 80% vs 25% for patient with negative vs positive PET respectively (HR 5.7 no CR vs CR - CI 95%: 2.6-12.4). The 3-year overall survival (OS) was 91% vs 56 % for patient with negative vs positive PET respectively (HR 7.8 no CR vs CR CI 95%: 2.6-23.7). In univariate analysis, factors influencing the probability of achieving CR to IGEV were disease status (refractory vs relapse) (p.096) and bulky disease at IGEV (p .088). Factor significantly associated with PFS and OS are reported in table. In multivariate analysis only response to therapy, as defined by pre-transplant PET result, maintained significance as prognostic indicator for both PFS (HR 5.7) and OS (HR 7.8). Conclusions these data in homogeneously treated pts with refractory/relapsed HL underline the crucial prognostic relevance of pre-transplant FDG-PET, even overwhelming the impact of disease status at progression. FDG-PET driven trials are highly recommended in this subset of patients. Disclosures: No relevant conflicts of interest to declare.

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DNTM3A Mutations and Prognosis in Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v128.22.1988.1988 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1988-1988

Author(s):

Mrinal M Patnaik ◽

Terra L. Lasho ◽

Christy Finke ◽

Matthew T Howard ◽

Curtis A. Hanson ◽

...

Keyword(s):

Conflicts Of Interest ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Gene Mutations ◽

Chronic Myelomonocytic Leukemia ◽

World Health ◽

Prognostic Impact ◽

Wild Type ◽

The Impact ◽

Myelomonocytic Leukemia

Abstract Background : DNMT3A mutations result in epigenetic dysregulation and impart a negative prognostic impact in acute myeloid leukemia and myelodysplastic syndromes. In chronic myelomonocytic leukemia (CMML), DNMT3A mutations are seen in 2-5% of patients. In a large Groupe Français des Myélodysplasies (GFM) study (n=312), DNMT3A mutations were seen in 2% and were not included in further survival analyses (Itzykson JCO 2013). In a prior Mayo Clinic study (n=175), DNMT3A mutations were seen in 5% (n=9) and on univariate, but not multivariate analysis (Patnaik Blood C J 2016), were associated with shortened over-all survival (OS). We carried out this study on a larger CMML cohort (n=261), with more (n=15) informative cases to assess the impact of DNMT3A mutations. Methods : 261 patients with World Health Organization (WHO)-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. The 2016 WHO diagnostic criteria were used. Results: Among the 261 study patients, 65% were males and median age was 70 years (range, 28-91). 154 (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations (LT) were documented. Mutational frequencies ≥4% were encountered in; TET2 45%, ASXL1 45%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, DNMT3A 6%, U2AF1 6%, SF3B1 5%, ZRSR2 4%, Tp53 4%, and IDH2 4%. i) DNTM3A mutated CMML: phenotypic and molecular correlates DNMT3A mutations were seen in 15 (6%) patients; 64% male with a median age of 64 years. DNMT3A amino acid substitutions included; R882H 50%, R882C 29%, R910P 7%, R598* 7% and R320* 7%. The median variant allele frequency burden was 45%. Concurrent gene mutations were detected in; TET2 43%, ASXL1 21%, SF3B1 21%, U2AF1 14%, RUNX1 14%, SETBP1 14%, NRAS 14%, SRSF2 7%, JAK2 7% and Tp53 7%. There was no difference between DNMT3A mutated and wild-type patients in terms of age and gender distribution, hemoglobin level, leukocyte, monocyte (AMC), and platelet counts, peripheral blood (PB) or BM blast content. Concurrent gene mutations were equally distributed with the exception for a higher prevalence of SF3B1 (p=0.003) and a lower prevalence of SRSF2 (p=0.004) mutations in DNMT3A mutated CMML. Four (29%) patients underwent leukemic transformation. ii) Impact on OS and leukemia-free survival (LFS): Median survival for the entire cohort (n=261) was 24 months. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wild-type (median 27 months) patients (p=0.0007; HR 2.9, 95% CI 1.5-5.7; Figure 1A). Other variables of significance, in univariate analysis, included lower hemoglobin (p=0.002), higher leukocyte count (p=0.0009), higher AMC (p=0.0012), PB blast % (p=0.001), circulating immature myeloid cells (IMC, p=0.01), BM blast % (p=0.045), abnormal karyotype (p=0.02), and ASXL1 (p=0.01) mutations. Survival was also adversely affected by the presence of either (n=133) or both (n=3) ASXL1/DNMT3A mutations (0=0.007, Figure 1B). In multivariable analysis (MVA) excluding ASXL1 and DNMT3A mutations, hemoglobin (p=0.03), IMC (p=0.013) and AMC (p=0.02) retained significance. When ASXL1 mutations were added to the MVA, ASXL1 (p=0.01) mutations, AMC (p=0.012) and IMC (p=0.03) retained significance. Similarly, when only DNMT3A mutations were added to the MVA, DNMT3A (p=0.003) mutations, IMC (p=0.01) and AMC (p=0.02) retained significance. When both DNMT3A and ASXL1 mutations were added to the MVA, only DNMT3A (p<0.0001) and ASXL1 (p=0.004) mutations remained significant. DNMT3A mutations predicted shortened OS, independent of the ASXL1 inclusive GFM model (p<0.0001) and Mayo Molecular Model (p=0.002). DNMT3A mutations (p=0.0018), along with low hemoglobin levels (p=0.003) independently predicted for a shorter LFS. Conclusions: DNMT3A mutations are seen in ~5% of patients with CMML and impart a negative prognostic impact on both OS and LFS. This finding warrants inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models. Disclosures No relevant conflicts of interest to declare.

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Impact of Previous Invasive Fungal Infections on the Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cells

Blood ◽

10.1182/blood.v128.22.5748.5748 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5748-5748

Author(s):

Gaetano Maffongelli ◽

Laura Cudillo ◽

Fabio Di Piazza ◽

...

Keyword(s):

Conflicts Of Interest ◽

Fungal Infections ◽

Conditioning Regimen ◽

P Value ◽

Period Range ◽

European Organization ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Post Transplant ◽

The Impact

Abstract Introduction: Outcome in allogeneic HSCT varies widely depending on disease type, stage, stem cell source, HLA-matched status and conditioning regimen. IFI is a possible complication of HSCT and a prior IFI increases the patient's risk for transplant related mortality due to the possibility of reactivation of the fungal infection. This study aimed to evaluate the impact of a previous IFI history on transplant outcome Methods: We retrospectively collected the clinical data of patients considered eligible for allogeneic HSCT during 2014 at the Rome Transplant Network (RTN), a JACIE accredited metropolitan transplant program established in Rome since 2006. The observation of patients was continued until 31 December 2015. The diagnosis of IFI were defined as possible, probable and proven as established by European Organization for Research and treatment of Cancer. Results: Twenty-one (37%) out of 57 eligible patients had an IFI episode before transplant: 6 of the episodes were proven, 4 probable and 11 possible. Overall, 10 (47%) pneumonia, 4 (19%) gastroenteritis, 3 sinusitis, 2 candida sepsis, 1 meningitis and 1 cutaneous abscess were registered. Five out of 21 patients (23%) died before HSCT versus 2 of 36 patients (5%) without previous documented IFI, [OR 5.31 95% CI 0.93- 30.40 , p value 0.06 Fisher Test], . A larger percentage of patients with past IFI waited HSCT over 6 months from the date of eligibility in comparison with those without previous IFI [43% vs 30% ; OR 1.87 95% CI 0.54-6.40 , p value 0.5 Yates test]; Sixteen (57%) out of 28 dead patients in the pre-transplant period have had a previous IFI episode vs 5(17%) out of patients alive [OR 6.4, 95% CI 1.89-21.68, p value: 0.004 Yates Test]. In the post-transplant period, only 6% of patients with a past IFI, experienced an engraftment in a time of < 15 days, vs 30% of patients without past IFI [OR 4.86 CI 95% 0,5-43,2, p value 0,2 Yates test]. In the post-transplant period, a IFI was diagnosed in 13 (26%) patients; ten (76%) out of 13 patients had a past IFI versus 9 (24%) of the patients without IFI.. [OR 7.87, CI 95% 1,8-34,2, p value 0,005 Yates test].Among the dead HSCT patients, those who had a previous IFI had a lower median survival [160 days (range 22- 480)] compared to patients without a previous IFI who died [196.5 days period (range 20-820)]. Conclusions: A previous IFI episode in the pre transplant period slow the accessibility to the transplant, adversely affects the engraftment, and is significantly associated with increased post-transplant mortality Disclosures No relevant conflicts of interest to declare.

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Lymphocyte:Monocyte Ratio At The Start Of Conditioning Regimen Is Associated With Survival Post-Autologous Stem Cell Transplantation (ASCT) For Lymphoma and Myeloma

Blood ◽

10.1182/blood.v122.21.3327.3327 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3327-3327

Author(s):

Guilherme Fleury Perini ◽

Alessandro de Moura Almeida ◽

Erika MM Costa ◽

Joyce E Hyppolito ◽

Fabio Rodrigues Kerbauy ◽

...

Keyword(s):

Stem Cell ◽

Lymphocyte Count ◽

Hodgkin’S Lymphoma ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Hodgkin's Lymphoma ◽

Prognostic Impact ◽

Monocyte Count ◽

Cox Analysis

Abstract Introduction Several studies have suggested that an increased peripheral blood absolute lymphocyte count (ALC) at day 15 after ASCT is associated with improved survival and decreased relapse rate. Recently, the ratio of ALC to the absolute monocyte count (AMC) (Lymphocyte:Monocyte Ratio; LMR) has been described as a strong prognostic factor at time of diagnosis in patients with various lymphoid malignancies. In most reports, a LMR cut-off value of less than 1.1 indicates patients who have a worse outcome. Objective To evaluate the prognostic impact of the LMR at start of conditioning regimen and at day 15 post ASCT in patients with a diagnosis of lymphoma and myeloma Methods We retrospectively reviewed the medical records of 121 adult patients with a diagnosis of lymphoma or myeloma who underwent ASCT at Hospital Israelita Albert Einstein from January, 2005 to July, 2012. Lymphocyte count was registered at the 15th day after SCT and lymphopenia was defined as an ALC< 500 at this time point. The LMR was calculated considering the ALC and AMC at baseline (start of conditioning regimen) and at day 15 post-ASCT. Overall survival (OS) was estimated from the time of transplant until death, with surviving patients censored at last follow-up. Variables entered into the multivariate Cox analysis were those with a p-value <0.10 in the univariate analysis. Statistical analysis was performed with STATA (v11.0) and alfa error was defined as 5%. Results The majority of patients were male (69%) and the median age was 58 years old (range: 3–76). Peripheral stem cell harvest was the main source of cells (61%). Diagnosis included multiple myeloma (49%), non-Hodgkin’s lymphoma (45%) and Hodgkin’s lymphoma (6%). The median LMR at start of conditioning regimen was 0.60, while at day 15 it was 1.75. Seventy-three percent of patients at start of conditioning had a LMR <1.1, while the same percentage at day 15 was 25%. Considering LMR cut-off at 1.1, an increased LMR value at baseline was associated with improved survival (HR 0.44; p=0.03), while it was not predictive at day 15 (HR=0.99; p=0.99). At 2 years, the OS was 48% for patients with a LMR<1.1 at start of conditioning regimen versus 76% for those patients with a LMR ≥1.1 (p=0.03 by logrank). In a multivariate Cox analysis considering age, sex, diagnosis, day 15 lymphopenia and baseline LMR, baseline LMR remained an independent variable associated with survival (HR=0.40, p=0.044), while day15 lymphopenia had no prognostic value (HR=0.80. p=0.56). Conclusion In our cohort of patients, the presence of an increased LMR at baseline before start of conditioning regimen identified a subgroup of patients who had a very good outcome. These results should be validated in other cohorts. Strategies to improve outcome for patients who present with decreased LMR and a better understanding of the role of LMR should be the focus of future studies. Disclosures: No relevant conflicts of interest to declare.

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Influence of CD34+ and CD3+ Graft Content on Gvhd Development after Haploidentical Allogeneic Transplantation with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood.v126.23.3131.3131 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3131-3131

Author(s):

Mariana Bastos-Oreiro ◽

Pascual Balsalobre ◽

Diana Champ ◽

Juan Churruca ◽

Maria Jesus Pascual ◽

...

Keyword(s):

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Patient Characteristics ◽

Allogeneic Transplantation ◽

Hematologic Malignancies ◽

Post Transplant ◽

Cell Dose ◽

The Impact

Abstract Introduction: CD34+ and CD3+ cell dose in peripheral blood stem cell (PBSC) graft have been related with increased incidence of graft versus host disease (GVHD) in some transplant settings. Our aim in this study was to evaluate the impact of CD34+ and CD3+ cells graft composition on GVHD incidence in the setting of haploidentical transplant (haplo-HSCT) with post-transplant cyclophosphamide (PT-Cy), in a multicenter analysis. Materials (or patients) and methods: We retrospectively evaluated 175 patients with hematologic malignancies who were treated with a haplo-HSCT from 2011 to 2014 with PBSC in GETH centers. All patients received Busulfan-Fludarabine as conditioning regimen and GVHD prophylaxis was performed with PT-Cy (50 mg/kg on days +3 and +4) and a calcineurin inhibitor plus mycophenolate from day +5. We analyzed the impact of CD34+ and CD3+ cell doses (low vs. high with cut-off at the median value, and the 25-75 percentiles) on the development of acute and chronic graft versus receptor disease. Death before GVHD development was considered as a competitive event. The analysis was adjusted for conditioning intensity. STATA software was used for data analysis Results: We analyzed 175 patients. Patient characteristics are resumed in table 1. Median CD34+ and CD3+ cell dose was 5.31x10e6/kg (p 25-75: 4.31-6.1) and 2.07x10e8/kg (p25-75: 1.19-2.94), respectively. Cumulative incidences of grade II-IV acute GVHD and all grades chronic GVHD was 32.6% and 30% respectively. The median follow-up was 12.3 months (r:6-46). No difference in terms of GVHD (acute and chronic), was found between low and high CD34+ cell doses. However, if we focus on T cells, high doses of CD3+, for values above the median, have been has been associated with increased incidence of acute GVHD II-IV (day 150: 47% vs 26% p=0.01, figure 2), as well as cGVHD (30 month: 39% vs 16%, p= 0.01 figure 1). If we focus the analyses regarding the intensity of conditioning regimen, the influence of CD3+ doses remains for the group of reduced-intensity conditioning (RIC) (aGVHD, day 150: 54% vs 24%, p=0.003; cGVHD, 30 month: 47% vs 16%, p=0.006 figure 2), but lost for patients who receive myeloablative intensity (aGVHD, day 150: 33% vs 33% p=0-8; cGVHD, 30 month: 21% vs 16%, p=0.81) Conclusion: In our series, in the setting of haplo-HSCT with Pt-Cy, the highest dose of lymphocytes was associated with a higher incidence of aGHVD II-IV and cGV HD, especially for the RIC procedures. Disclosures No relevant conflicts of interest to declare.

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POS1234 IMPACT OF THE CHANGE IN ADMINISTRATION ROUTE OF TOCILIZUMAB AND ABATACEPT, DUE TO THE COVID-19 LOCKDOWN ON DISEASE ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3126 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 900.1-900

Author(s):

L. Diebold ◽

T. Wirth ◽

V. Pradel ◽

N. Balandraud ◽

E. Fockens ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Physical Activity ◽

Disease Activity ◽

Univariate Analysis ◽

Route Of Administration ◽

Anxiety And Depression ◽

Administration Route ◽

Factors Associated ◽

The Impact

Background:Among therapeutics used to treat rheumatoid arthritis (RA), Tocilizumab (TCZ) and Abatacept (ABA) are both biologic agents that can be delivered subcutaneously (SC) or intravenously (IV). During the first COVID-19 lockdown in France, all patients treated with IV TCZ or IV ABA were offered the option to switch to SC administration.Objectives:The primary aim was to assess the impact of changing the route of administration on the disease activity. The second aim was to assess whether the return to IV route at the patient’s request was associated with disease activity variation, flares, anxiety, depression and low physical activity during the lockdown.Methods:We conducted a prospective monocentric observational study. Eligibility criteria: Adult ≥ 18 years old, RA treated with IV TCZ or IV ABA with a stable dose ≥3 months, change in administration route (from IV to SC) between March 16, 2020, and April 17, 2020. The following data were collected at baseline and 6 months later (M6): demographics, RA characteristics, treatment, history of previous SC treatment, disease activity (DAS28), self-administered questionnaires on flares, RA life repercussions, physical activity, anxiety and depression (FLARE, RAID, Ricci &Gagnon, HAD).The primary outcome was the proportion of patients with a DAS28 variation>1.2 at M6. Analyses: Chi2-test for quantitative variables and Mann-Whitney test for qualitative variables. Factors associated with return to IV route identification was performed with univariate and multivariate analysis.Results:Among the 84 patients who were offered to switch their treatment route of administration, 13 refused to change their treatment. Among the 71 who switched (48 TCZ, 23 ABA), 58 had a M6 follow-up visit (13 lost of follow-up) and DAS28 was available for 49 patients at M6. Main baseline characteristics: female 81%, mean age 62.7, mean disease duration: 16.0, ACPA positive: 72.4%, mean DAS28: 2.01, previously treated with SC TCZ or ABA: 17%.At M6, the mean DAS28 variation was 0.18 ± 0.15. Ten (12.2%) patients had a DAS28 worsening>1.2 (ABA: 5/17 [29.4%] and TCZ: 5/32 [15.6%], p= 0.152) and 19 patients (32.8%) had a DAS28 worsening>0.6 (ABA: 11/17 [64.7%] and TCZ: 8/32 [25.0%], p= 0.007).At M6, 41 patients (77.4%) were back to IV route (26 TCZ, 15 ABA) at their request. The proportion of patients with a DAS28 worsening>1.2 and>0.6 in the groups return to IV versus SC maintenance were 22.5%, 42.5% versus 11.1% and 22.2% (p=0.4), respectively. The univariate analysis identified the following factors associated with the return to IV route: HAD depression score (12 vs 41, p=0.009), HAS anxiety score (12 vs 41, p=0.047) and corticosteroid use (70% vs 100%, p=0.021), in the SC maintenance vs return to IV, respectively.Conclusion:The change of administration route of TCZ and ABA during the first COVID-19 lockdown was infrequently associated with a worsening of RA disease. However, the great majority of the patients (77.4%) request to return to IV route, even without disease activity worsening. This nocebo effect was associated with higher anxiety and depression scores.Disclosure of Interests:None declared

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600. Decreased Hospital Readmission After Programmatic Strengthening of an Outpatient Parenteral Antimicrobial Therapy (OPAT) Program

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.794 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S362-S363

Author(s):

Gaurav Agnihotri ◽

Alan E Gross ◽

Minji Seok ◽

Cheng Yu Yen ◽

Farah Khan ◽

...

Keyword(s):

Hospital Readmission ◽

Multinomial Logistic Regression ◽

Univariate Analysis ◽

Tertiary Care ◽

Intervention Group ◽

Care Hospital ◽

Full Time ◽

Post Intervention ◽

Before And After ◽

The Impact

Abstract Background Although it is recommended that an OPAT program should be managed by a formal OPAT team that supports the treating physician, many OPAT programs face challenges in obtaining necessary program staff (i.e nurses or pharmacists) due to limited data examining the impact of a dedicated OPAT team on patient outcomes. Our objective was to compare OPAT-related readmission rates among patients receiving OPAT before and after the implementation of a strengthened OPAT program. Methods This retrospective quasi-experiment compared adult patients discharged on intravenous (IV) antibiotics from the University of Illinois Hospital before and after implementation of programmatic changes to strengthen the OPAT program. Data from our previous study were used as the pre-intervention group (1/1/2012 to 8/1/2013), where only individual infectious disease (ID) physicians coordinated OPAT. Post-intervention (10/1/2017 to 1/1/2019), a dedicated OPAT nurse provided full time support to the treating ID physicians through care coordination, utilization of protocols for lab monitoring and management, and enhanced documentation. Factors associated with readmission for OPAT-related problems at a significance level of p< 0.1 in univariate analysis were eligible for testing in a forward stepwise multinomial logistic regression to identify independent predictors of readmission. Results Demographics, antimicrobial indications, and OPAT administration location of the 428 patients pre- and post-intervention are listed in Table 1. After implementation of the strengthened OPAT program, the readmission rate due to OPAT-related complications decreased from 17.8% (13/73) to 6.5% (23/355) (p=0.001). OPAT-related readmission reasons included: infection recurrence/progression (56%), adverse drug reaction (28%), or line-associated issues (17%). Independent predictors of hospital readmission due to OPAT-related problems are listed in Table 2. Table 1. OPAT Patient Demographics and Factors Pre- and Post-intervention Table 2. Factors independently associated with hospital readmission in OPAT patients Conclusion An OPAT program with dedicated staff at a large academic tertiary care hospital was independently associated with decreased risk for readmission, which provides critical evidence to substantiate additional resources being dedicated to OPAT by health systems in the future. Disclosures All Authors: No reported disclosures

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