Lack Of Complete Remission Research Articles

Novel Causal Inference Method Estimates Treatment Effects of Contemporary Drugs in a Global Cohort of Patients with Relapsed and Refractory Mature T-Cell and NK-Cell Neoplasms

There is no universal approach to treat patients with relapsed and refractory (RR) mature T-cell and NK-cell neoplasms (TNKL). While participation in a clinical trial is favored, appropriate options are often unavailable. Thus, outside of a trial, physicians may rely on real world evidence when making a treatment choice. We hypothesized that innovative causal predictive models that utilize existing clinical information could estimate comparative efficacy of various treatments and support clinical decision making. As the first step, we built a large global cohort of 925 patients with RR TNKL diagnosed between Jan 2010 and Dec 2020 representing 9 countries. Eligible patients received either a single agent (SA) such as an epigenetic modifier, small molecule inhibitor, brentuximab vedotin (BV) among others, or platinum-, gemcitabine-, ifosfamide-based cytotoxic chemotherapy (CC) in the second line setting. Patients were followed from lymphoma diagnosis, or first retreatment start date to death or lost to follow-up. Thirteen covariates [relapsed/refractory state, with refractory defined as lack of complete remission (CR) to first line therapy, country Japan, age >50 years, histological subtype AITL, IPI, PIT score, response to 1 st line treatment, 2 nd line treatment (SA or CC), response to 2 nd line treatment, autologous stem cell transplantation (Auto-SCT), response to ASCT, allogeneic stem cell transplantation (Allo-SCT), response to Allo-SCT] were identified to have an independent prognostic effect on overall survival (OS). Based on measures of Brier score (BS) and Concordance index (CI), eight of them were selected for multivariate Cox regression model. We observed comparable performance of the Cox models utilizing these 8 covariates (CI: 0.755; BS:0.174) versus 5 of these 8 covariates (CI:0.744; BS:0.186). Hence 5 covariates were utilized for further OS analyses. We found that multivariate Cox outperforms other traditional models including random survival forest and gradient boosted (Table 1). Since data under consideration is observational and not derived from a clinical trial, there may be several (unobserved) confounders leading to bias in the outcomes, which are not adjusted for by these traditional approaches. We introduce a novel causal method, Synthetic Intervention (SI), which adjusts for such biases. For comparative evaluation of SI with multivariate Cox, due to data requirement for SI, we chose only two covariates [response to 1 st line stratified as CR, partial remission (PR), stable disease (SD) and progressive disease (PD) and administration of second line treatment (SA or CC)] (Table 1). We found that SI outperforms multivariate Cox. Further, despite heterogeneity in OS across the 8 cohorts, the median OS prediction of SI was comparable to actual median OS for each cohort, thus highlighting robustness of SI (Figure 1). All the performance evaluations were done using 60:40 train: test split, repeated 500 times. We confirmed previous reports that relapsed patients had superior OS compared to primary refractory patients across common histologies: PTCL-NOS (p<.0001), AITL (p=.036), ENKTCL (p=.027), and ALK- ALCL (p=.001). Those who received SA at first retreatment had superior OS compared to those treated with CC in AITL (p<.0005) and ALK- ALCL (p=.036) and comparable OS in PTCL-NOS, ENKTCL, and ALK+ ALCL. In ALK- ALCL, those treated with BV had superior OS compared to CC (p=.027). Patients with AITL treated with small molecule inhibitors (SMI) had greater OS compared to those treated with CC (p<.0005) and epigenetic modifiers (EM) (p=.001), with the most common SMIs including alisertib, duvelusib, cerdulatinib, and cyclosporine. Those who responded to EM and BV (CR+PR+SD) had superior OS compared to non-responders (PD) in PTCL-NOS (p=.004) and ALK- ALCL (p<0.0005). Among patients who underwent SCT after second line therapy, those bridged with SA had comparable OS to CC in PTCL-NOS and an improved trend (p=.073) in AITL. In summary, we have characterized the largest global cohort of RR patients with TNKL in the era of contemporary therapies. As a causal analysis method, SI demonstrates the causal effect superiority of SA over CC in terms of survival outcomes for patients who responded differently to their 1st line treatment. Moreover, it achieves prediction accuracy comparable to, if not better than, Cox regressions, one of the most widely used methods in survival analysis.

Prognostic Role of Red Cell Distribution Width (RDW) in Patients with Diffuse Large B-cell Lymphoma.

Several A number of prognostic blood markers related tofor Diffuse Large B-Cell Lymphoma (DLBCL) have been identified, most of which are costly and not easily availableaccessible. Although the relationship between the prognostic role of RDW and some cancers has been well established, the role it of RDW plays in DLBCL patients is unclear still questionable and requires more investigations. All patients diagnosed with DLBCL who had referred to Imam Reza Hospital, during were included in this retrospective cohort study. Based onRegarding their RDW, the subjects were divided into two groups of normal (RDW ≤14.6%) and elevated RDW (RDW > 14.6%) RDW, and the outcomes were investigated. One hundred fifty patients with DLBCL were included in this study. The results showed a significant relationship between the RDW values of the DLBCL patients and stage frequency distribution, relapse, mortality, and complete remission (P value<0.05). It was also found out that elevated RDW > 14.6% was associated with the risk of relapse (OR=2.50, P value<0.05), mortality (OR=3.59, P value<0.01), and lack of complete remission (OR=0.115, P value< 0.01). The results of the survival analysis indicated that the subjects with higher RDWs had a lower median survival rate than those with low RDWs. In addition, the mortality risk for the individuals with RDW > 14.6% was 2.44 times that of those with RDW≤14.6% (HR=2.44, P value<0.05). The results of this study well indicated that as an independent prognostic factor, RDW was associated with the stage of DLBCL patients, failure to achieve complete remission, disease relapse, and patient mortality. However, further studies are would be needed to realize determine the role of RDW in DLBCL patients.

Primary extranodal diffuse large B-cell lymphoma in the rituximab era: a single center, retrospective analysis

ABSTRACT Objectives To analyse the clinical characteristics and therapeutic response of Chinese patients with primary extranodal diffuse large B-cell lymphoma DLBCL (PE-DLBCL). Methods We analysed the clinical features and outcomes of 197 patients who were newly diagnosed with PE-DLBCL between January 2015 and December 2020. Results The gastrointestinal tract showed the highest rate of involvement (34%), followed by the central nervous system (CNS) and intraocular system (31.5%). The 3-year overall survival (OS) rate was 81% for the entire group and 79% for those with CNS and vitreoretinal involvement. Ann Arbour stage, lactate dehydrogenase level, International Prognostic Index > 2, and complete remission (CR) were significantly related to the survival of patients with PE-DLBCL. The lack of CR was the only independent adverse prognostic factor for OS. Conclusion The clinical outcomes of patients with PE-DLBCL at our centre were encouraging, especially for patients with CNS and vitreoretinal involvement.

Pathological and Evolutive Correlations in Steroid Resistant Nephrotic Syndrome in Children

BackgroundNephrotic syndrome (NS) is the term used for the association of edema and massive proteinuria. From a therapeutic point of view, it is important to distinguish between primitive and secondary kidney damage. The clinical evolution, prognosis and therapeutic response in the NS in children are directly determined by the anatomopathological aspect. Steroid resistant nephrotic syndrome was diagnosed in patients with idiopathic NS based on lack of complete remission despite treatment with steroids.PurposeTo analyse the anatomopathological aspects of steroid resistant nephrotic syndrome (SRNS) and their correlation with evolution.Materials and MethodsWe made a retrospective study with the aim to analyze the anatomo-pathological aspects and their correlations with evolution in 68 cases of steroid resistant nephrotic syndrome (SRNS) hospitalized in the Pediatric Nephrology Department in Iaşi, Romania. We defined SRNS in all cases without response to corticosteroids after the first month of therapy. For all the cases selected, the period of follow-up was the minimal 6 months.Results and DiscussionsA 36% case of nephrotic syndrome was corticoresistant, with the mean age at onset of patients with SRNS being 9.18 years, compared to KDIGO studies in which the corticosteroid resistance is 10–20%. Renal biopsy was performed in 80.88% children with SRNS and was allowed the evaluation of the activity and chronicity index. Total remission was obtained in 44.01% children with SRNS. The correlation of the anatomopathological aspects with the evolution is not statistically significant (p = 0.76), observing different therapeutic responses to all the analyzed histological types.ConclusionAlmost half of NS in children are cortico resistant. Remission was obtained in 44% of cases of SRNS. Predicting the response to long-term treatment in SRNS is difficult using only renal biopsy; it is necessary to introduce genetic molecular analyses to establish a judicious therapeutic attitude.

Comparison of Mobilized Peripheral Blood Stem Cells Versus Unmanipulated Bone Marrow Haploidentical Transplantation Using Post-Transplant Cyclophosphamide: A Retrospective Study of SFGM-TC in 176 Patients

IntroductionThe administration of high dose cyclophosphamide post-transplant (HD-Cy) has improved the outcome of patients who receive an unmanipulated haploidentical graft. The modalities described by the group of Baltimore originally associated a non myeloablative conditioning regimen and the use of a T cell replete bone marrow (BM) graft. Nevertheless, mobilized peripheral blood (PB) is increasingly used as it is more convenient. A very recent report from the United States showed a lower rate of graft versus host disease (GVHD) with BM but an increased risk of relapse in leukemic patients, as compared to PB, leading to a similar overall survival (OS). We report the French experience of haploidentical transplantation using HD-Cy and unmanipulated BM or PB, with a particular interest on the contents of the grafts.Patients and methodsOne hundred seventy-six patients with hematologic malignancy received a haploidentical transplant in 21 French centers from May 2012 to December 2015. We compared the outcome of patients who received a BM graft (n=89) with those receiving a PB graft (N=87). Median age at transplant was 44 year-old (2.5-72). One hundred thirteen (64%) patients had myeloid disease, 19 (11%) had acute lymphoblastic leukemia and 44 (25%) had lymphoid neoplasm. Prophylaxis of GVHD consisted in anticalcineurin and mycophenolate in 94% of the cases. All patients received HD-CY post-transplant (100 mg per kg total dose).ResultsThe 2 groups were comparable for age, disease status at transplant, type of conditioning regimen (RIC 71% and 80% for BM and PB respectively; p=0.16), recipient cytomegalovirus (CMV) seropositive status, ABO mismatch. PB recipients were more likely to receive antithymocyte globulin (ATG) (N=19 vs 0) and to have a higher disease risk index (DRI). The number of CD34+ and CD3+ infused cells was higher in PB grafts (median 2.64x106 CD34/Kg and 26 x106 CD3/Kg for BM and 6.03x106 CD34/Kg and 191 x106 CD3/Kg for PB. Median follow up was 281 days (6-1851).In univariate analysis, the rate of patients who recovered neutrophils and platelet (>50G/L) were similar in both groups (91% and 75% vs 96% and 75% for BM vs PB respectively). However, median time to neutrophil engraftment was significantly longer in BM than in PB group (20 days (13-59) vs 18 days (13-45) respectively, p=0.004). Median time to platelet recovery was not significantly different (30 days (17-250) vs 24 days (13-52) in BM and PB, p=0.14). Patients who recovered neutrophils received a graft which contained more CD3+ cells than patients who did not (p=0.007).At one year, OS, progression free survival (PFS) and relapse were similar in the 2 groups (OS = 64% vs 53% (p=0.1), PFS= 53% vs 46 % (p=0.17) and relapse rate 28% vs 34% (p=0.19) in BM and PB respectively). Acute GVHD II-IV or III-IV and chronic GVHD were similar in both groups (aGVHD II-IV= 18% vs 28% (p=0.09) and aGVHD III-IV = 7% vs 9% (p=0.48), cGVHD=13% vs 15% (p=0.6) in BM and PB respectively), resulting in a similar GVHD-free relapse-free survival (GRFS) at 1 year (48% vs 37% (p=0.09)). Interestingly, the number of infused CD3+ cells/Kg impacted the incidence of acute GVHD II-IV (p=0.049).High DRI and the lack of complete remission at transplant had a significant pejorative effect on OS, PFS, relapse, GRFS and platelet recovery. CMV seropositive recipients had a worse GRFS (p=0.045).ConclusionIn this retrospective study the use of PB instead of BM does not significantly impact the outcome of patients who received a haploidentical unmanipulated graft for a malignant disease with HD-CY. PB graft contained more CD3+ and CD34+ cells than BM and were associated with a faster neutrophils recovery. A higher number of CD3+ cells increased the risk of acute GVHD II-IV in univariate analysis, without significant effect on GRFS. Prospective randomized studies are needed to evaluate the effect of PB vs BM in haploidentical settings. DisclosuresPeffault De Latour:Pfizer: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Multi-Autoantibody Signature and Clinical Outcome in Membranous Nephropathy.

Patients with membranous nephropathy can have circulating autoantibodies against membrane-bound (phospholipase A2 receptor 1 [PLA2R1] and thrombospondin type-1 domain containing 7A [THSD7A]) and intracellular (aldose reductase, SOD2, and α-enolase) podocyte autoantigens. We studied their combined association with clinical outcomes. Serum levels of anti-PLA2R1, anti-THSD7A, anti-aldose reductase, anti-SOD2, and anti-α-enolase autoantibodies were determined in 285 patients at diagnosis and during follow-up using standardized and homemade assays. An eGFR>60 ml/min per 1.73 m2 and remission of proteinuria (<0.3/<3.5 g per d) after 12 months were the outcomes of interest. At diagnosis, 182 (64%), eight (3%), and 95 (33%) patients were anti-PLA2R1+, anti-THSD7A+, and double negative, respectively. The prevalence of a detectable antibody to at least one intracellular antigen was similarly distributed in patients who were anti-PLA2R1+ (n=118, 65%) and double negative (n=64, 67%). Positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase antibodies and higher titers at diagnosis were associated with poor clinical outcome independently to each other. Combined positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase was associated with highest risk of poor outcome (odds ratio, 5.5; 95% confidence interval, 1.2 to 24; P=0.01). In Kaplan-Meier analysis, patients who were anti-PLA2R1+/anti-SOD2+ or anti-PLA2R1+/anti-α-enolase+ had lower eGFR at 12 months compared with patients who were anti-PLA2R1+/anti-SOD2- or anti-α-enolase-. Predictive tests (net reclassification index and area under the curve-receiver-operating characteristic analysis) showed that combined assessment of antibodies improved classification of outcome in 22%-34% of cases for partial remission of proteinuria and maintenance of normal eGFR. For patients with nephrotic syndrome at diagnosis, anti-SOD2 positivity and high anti-PLA2R1 titer were associated with a lack of complete remission. Patients who were anti-PLA2R1-/anti-intracellular antigens- had the lowest proteinuria and the highest eGFR at diagnosis and the lowest risk of lower eGFR at 12 months. Epitope spreading was present in 81% of patients who were anti-PLA2R1+ and was associated with increased positivity for intracellular antigens and poor eGFR at diagnosis and 12 months. Combined serological analysis of autoantibodies targeting membrane-bound and intracellular autoantigens identifies patients with poor clinical outcomes.

Molecular Mechanisms Mediating Relapse Following Ivosidenib Monotherapy in Patients with IDH1-Mutant Relapsed or Refractory Acute Myeloid Leukemia

Molecular Mechanisms Mediating Relapse Following Ivosidenib Monotherapy in Patients with IDH1-Mutant Relapsed or Refractory Acute Myeloid Leukemia

Developmental Plasticity of Acute Myeloid Leukemia Mediates Resistance to Venetoclax-Based Therapy

Developmental Plasticity of Acute Myeloid Leukemia Mediates Resistance to Venetoclax-Based Therapy

Outcome of allogeneic hematopoietic cell transplantation in patients with adult T-cell leukemia.

Adult T‐cell leukemia/lymphoma (ATL) is an aggressive peripheral T‐cell neoplasm, and the outcome of patients with ATL after chemotherapy is poor. Allogeneic hematopoietic stem‐cell transplantation (allo‐HSCT) is a curative treatment modality for ATL, and four factors, namely, age > 50 years, male recipient, lack of complete remission at transplantation, and transplantation of cord blood, were previously shown to be associated with poor survival. We retrospectively analyzed the outcome of 21 patients with ATL who had undergone allo‐HSCT at our hospital during a 3‐year period. Of 21 patients, all had at least one of the above risk factors, and 18 had two or more. With a median follow‐up of 19.7 months for living patients, the 1‐ and 2‐year overall survival (OS) rates after transplantation were 34% and 27%, respectively. All relapse/progression events occurred within 1 year after allo‐HSCT, and the cumulative incidence of relapse/progression at 1 year after allo‐HSCT was 46.9%. The 100‐day and 1‐year nonrelapse mortality (NRM) rates were 19% and 42%, respectively. No significant difference in OS was observed between myeloablative and reduced‐intensity conditioning regimens. The 3‐year OS (27%) of ATL patients who received allo‐HSCT and who had at least one adverse factor was somewhat poorer than the 3‐year OS of 33% identified in a nationwide study of allo‐HSCT in ATL patients in Japan. The high relapse/progression and NRM rates are major problems to be solved to achieve better outcome.

Children with Steroid-Resistant Nephrotic Syndrome: A Single -Center Experience.

Background:Nephrotic syndrome (NS) is one of the most frequent glomerular diseases among children. While most of the children with primary NS respond to steroid treatment, 10 to 20% of the patients are steroid-resistant, and the best therapy for such cases has never been defined.Objective:The present study aimed to evaluate steroid-resistant nephrotic syndrome (SRNS) patients.Materials and methods:Our research included 50 children (56% female and 44% male) with NS. NS was defined as the presence of edema, massive proteinuria, hypoalbuminemia and hyperlipidemia. Patients with NS were treated according to international protocol. SRNS was diagnosed in patients with idiopathic NS based on lack of complete remission despite treatment with steroids. Renal biopsy was performed in 22 patients with SRNS at the Pediatric Clinic II of the University Clinical Center in Sarajevo (UCCS). Histopathologic analyzes of renal biopsy were performed at the Department of Pathology, University Clinical Center in Tuzla (UCCT). Patients with SRNS, after kidney biopsy were treated with nonsteroidal immunosuppressant’s.Results:Eight (36.4%) of the 22 patients who had undergone renal biopsies had minimal change disease (MCNS) and seven (31.8%) had focal segmental glomerulosclerosis (FSGS). The immunosuppressive drugs used in SRNS were Cyclosporine (CsA), Cyclophosphamide (CYC), Mycophenolat mofetil (MMF) and Rituximab (RTX). Three patients (13.6%) did not respond to any treatment and had developed end - stage renal disease (ESRD).Conclusion:With current treatments, some children will ultimately achieve a sustained remission with one of the second line or third line of the proposed drugs. Patients with refractory NS will go to progression towards ESRD. The rapid development of molecular genetics will give a new contribution to the pathogenesis and treatment of this disease.

Impact of Donor-Recipient Histocompatibility and CMV-Mismatch on Outcome of Allogeneic Stem Cell Transplantation for AML and MDS: A Retrospective Registry Study of the German Stem Cell Transplant Registry (DRST) of the German Working Group for Blood and Marrow Transplantation (DAG-KBT)

IntroductionAllogeneic stem cell transplantation (allo-SCT) is a curative treatment for several hematological diseases. Donor-recipient histo-incompatibility is associated with poorer outcome. Transplant outcome of CMV positive patients is reported to be poorer, if the unrelated donor is CMV negative (CMV-mismatch). Recent developments in transplant strategies including high resolution HLA-typing, toxicity-reduced conditioning regimens, CMV-monitoring, and improved supportive care have made transplants from HLA- as well as CMV- mismatched unrelated donors more feasible. We present a retrospective registry analysis from a large, and recent cohort of patients transplanted under these conditions.Patients and methods:We report data from adult recipients of allo-SCT treated between 2005 and 2013 in 10 transplant centers across Germany. Inclusion criteria were: 1.) consecutive patients from each center with AML or MDS as reported to the German Stem Cell Transplant Registry (DRST), 2) age >/= 18 years, 3) availability of high-resolution typing for HLA-A, -B, C, DRB1 and DQB1 in case of unrelated donor. Patients with ex-vivo T cell depletion were excluded.3215 patients with AML (n = 2648) or MDS (n = 567) were included in the study. Donors were matched related (MRD, n =872), matched unrelated (MUD, n = 1553) or mismatched unrelated (9/10 MMUD, n= 620; 8/10 MMUD n = 137; <8/10 MMUD n = 33). Remission status at transplant was CR (49%), not in CR (40%) or untreated (11%). The vast majority of patients (96%) received peripheral blood stem cell grafts. Conditioning was reduced intensity (51%) or myeloablative (49%) according to EBMT criteria. ATG (56%) or alemtuzumab (8%) were used for in vivo T cell depletion. Median patient age was 56 (18-79) years. Median donor age was 38 (12-80) years. Median follow-up was 54 months (34-81 months). Primary endpoint was overall survival (OS) at 3 years.Results:Kaplan-Meier estimates for OS at 3 years was similar after transplants from MRD = 55% (95%CI 51-59%) compared to MUD = 53% (95%CI 51-59%), p = 0.26. OS at 3 years was worse for 9/10 MMUD with 45% (95% CI 41-49%, p<0.001), for 8/10 MMUD with 35% (95% CI: 27%-43%, p < 0.001) and for <8/10 MMUD with 29% (95% CI 13%-45%, p = 0.005) (figure 1).In recipients of unrelated donor transplants, multivariate cox regression analysis revealed significant negative impact of increasing patient age, increasing donor age, sex-mismatch (male patient/female donor), CMV-mismatch (patient pos/ donor neg), diagnosis of AML or sAML compared to MDS, lack of complete remission at transplant, abnormal cytogenetics and HLA-mismatching (table 1a).In a subgroup analysis restricted to patients transplanted from unrelated donors after myeloablative conditioning and T cell depletion, 3 years OS was better after 10/10 MUD: 60% (55-65%) compared to 9/10 MMUD: 49% (41-57%), p = 0.02. This was also true after reduced intensity conditioning and T cell depletion with ATG, with 3 year OS after 10/10 MUD: 49% (45-53) compared to 9/10 MMUD: 37% (31-43%), p = 0.001. Excluding HLA-DQB1-mismatches and HLA-C0303/0304-mismatches from the 9/10 MMUD group did not significantly alter results.Acknowledging the negative impact of both HLA and CMV-mismatching, we sought to determine which of these two parameters is of higher relevance for donor selection. For this purpose subgroup analyses were performed including only CMV-positive patients who received transplants from an unrelated donor (10/10 MUD or 9/10 MMUD). HLA-DQB1-mismatches and HLA-C0303/0304-mismatches were excluded. For this subgroup of n = 1167 patients multivariate cox regression analysis revealed better outcome after 10/10 MUD from CMV neg. donors compared to 9/10 MMUD from a CMV pos. donors (RR: 1.31, p = 0.04, table 1b and figure 2). Restricting the analysis only to patients who received T cell depletion with ATG did not significantly alter these findings.Conclusions:In this large multicenter cohort of recently transplanted patients, we find similar survival outcomes for matched related and fully matched unrelated donor transplants. We confirm the negative impact of HLA-mismatching on survival outcome, irrespective of conditioning intensity. Our results show that though CMV-mismatching is associated with poorer outcome, its relevance is secondary to HLA-mismatching.Acknowledgments:This work was supported by a research grant of the DKMS-Stiftung to FA and WB. [Display omitted] [Display omitted] [Display omitted] DisclosuresStelljes:Pfizer: Consultancy. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Omega – 3 fatty acids in schizophrenia – part I: importance in the pathophysiology of schizophrenia

Abstract Despite the increasing offer of antipsychotic drugs, the effectiveness of pharmacotherapy in schizophrenia is still unsatisfactory. Drug resistance, lack of complete remission and the increasing risk of metabolic complications are the reasons why the new forms of therapy in schizophrenia among which unsaturated essential fatty acids omega 3 (EFAs ω-3) affecting the proper functioning of nervous system, are mentioned, are being looked for. Fatty acids represent 50-60% of the dry weight of the brain and diet is one of the factors that influence the value of each of the fat fractions in the neuron membranes. Patients with schizophrenia tend to have irregular nutritional status concerning essential fatty acids ω-3, which might result from metabolic disorders or irregular consumption of fatty acids. Apart from being a review of the literature on this subject, this very paper characterizes essential fatty acids ω-3, their metabolism, the most important sources in the diet and the opinions of experts in the field about the recommended intake. It pays attention to the role of essential fatty acids in both the structure and functioning of the central nervous system is, as well as their role in the pathophysiology of schizophrenia, with particular emphasis on the membrane concept by David Horrobin. The assessment of the errors in consumption and metabolism of essential fatty acids are described as well. The evidence was found both in epidemiological and modeling studies. It supports the participation of EFAs in etiopathogenesis and pathophysiology of schizophrenia. Further research is needed, both observational and interventional, as to the role of essential fatty acids ω-3 in the functioning of the CNS as well as the development and course of schizophrenia.

Mucocutaneous lupus erythematosus in dogs (21 cases)

The diagnosis of dogs with chronic juxtamucosal erosive lesions and histopathology typical of cutaneous lupus erythematosus (CLE) is unclear. We report herein 21 dogs with mucocutaneous erosive lesions and lupus-specific histopathology that we propose to be affected with mucocutaneous lupus erythematosus (MCLE), another variant of chronic CLE. Inclusion criteria were the presence of the following: (i) a >2 month history of chronic or recurrent skin lesions; (ii) erosions or ulcers predominating at mucosae or mucocutaneous junctions; (iii) microscopic lesions of CLE (i.e. a lymphocyte-rich interface dermatitis with basal keratinocyte damage); and (iv) a lack of complete remission following antimicrobials. Clinical questionnaires and skin biopsies were reviewed. Direct immunofluorescence and antinuclear antibody serology were performed whenever possible. More than half of the 21 dogs were German shepherds or their crosses. The disease affected mostly dogs in their mid-adulthood and there was an over-representation of females. Erosions and ulcers predominated at genital/perigenital and anal/perianal areas, with a lower frequency of involvement of periocular, perioral and perinasal regions. In these dogs, there were no clinical signs suggestive of an associated systemic lupus erythematosus. Microscopic lesions were specific for CLE, but they were patchy and often infected with bacteria. The most common immunological finding was focal IgG deposition at the basement membrane zone. Lesions responded to varying interventions, but oral glucocorticoids led to a shorter time to complete remission. Relapses were common upon treatment tapering. These observations support MCLE being another variant of canine CLE.

Cytochrome P450 2B6*5 Increases Relapse after Cyclophosphamide-Containing Conditioning and Autologous Transplantation for Lymphoma

Cyclophosphamide (Cy) is a prodrug that depends on bioactivation by hepatic cytochrome P450 (CYP) enzymes for its cytotoxicity. We evaluated the influence of single nucleotide polymorphisms (SNPs) of CYP enzymes on the efficacy of autologous hematopoietic cell transplantation (HCT) for lymphoma. SNPs of 22 genes were analyzed in 93 patients with Hodgkin (n = 52) and non-Hodgkin lymphoma (n = 41) treated with high-dose Cy followed by autologous HCT between 2004 and 2012. Preparative regimens contained Cy (120 mg/kg) combined with carmustine/etoposide (n = 61) or Cy (6000 mg/m2) with total body irradiation (n = 32). Lack of complete remission as measured by pretransplant positron emission tomography was the sole clinical factor associated with increased risk of relapse (HR, 2.1). In genomic analysis, we identified a single SNP (rs3211371) in exon 9 (C > T) of the CYP2B6 gene (allele designation 2B6*5) that significantly impacted patient outcomes. After adjusting for disease status and conditioning regimen, patients with the CYP2B6*1/*5 genotype had a higher 2-year relapse rate (HR, 3.3; 95% CI, 1.6 to 6.5; P = .041) and decreased overall survival (HR, 13.5; 95% CI, 3.5 to 51.9; P = .008) than patients with the wild-type allele. Two-year progression-free survival for patients with 2 hypofunctional CYP2B6 variant genotypes (*5 and *6) was only 11% (95% CI, 1% to 39%) compared with 67% (95% CI, 55% to 77%) for patients with the wild-type CYP2B6*1 allele in exon 9. Our results suggest that CYP2B6 SNPs influence the efficacy of high-dose Cy and significantly reduce the success of autologous HCT for lymphoma patients with the CYP2B6*5 variant.

Randomized Study of Liposomal Cytarabine and Daunorubicin (CPX-351) for Adults with Untreated High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) at High Risk of Treatment-Related Mortality

Background: Because of the concern for therapeutic resistance and excessive toxicity or even treatment-related mortality (TRM), many medically unfit patients do not receive AML-directed therapy, although evidence suggests that outcomes are improved if essentially all of these patients are offered some form of chemotherapy rather than given supportive care only. Here, we evaluated the potential value of attenuated doses of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in medically unfit patients with newly diagnosed AML or high-risk MDS (≥10% blasts). In earlier trials, CPX-351 appeared to afford superior outcomes in high-risk AML patients with a wide therapeutic window suggesting that reduced dose treatment may be helpful in this population.Methods: Patients aged ≥18 years with untreated AML or high-risk MDS were eligible if they had a TRM score of ≥13.1, corresponding to an expected TRM (i.e. death within 28 days of treatment initiation) of 31% with standard induction chemotherapy. Bilirubin was to be <2.0 mg/ml because of hepatic excretion of CPX-351, and active infection was an exclusion criterion. Patients were randomly assigned 1:1 to receive CPX-351 at either 32 or 64 units/m2 per dose (previous phase 1 investigations established a maximum tolerated dose of 101 units/m2 per dose) on days 1, 3, and 5 for up to 4 identical induction/re-induction courses. Patients achieving either complete remission (CR) or CR with incomplete platelet count recovery (CRp) could receive up to 4 courses of post-remission treatment with CPX-351 using the same dose on days 1 and 3 only. The primary goal of the study was to estimate whether either the 32 or 64 units/m2 doses were likely to improve TRM rates while keeping the CR rate comparable to historic controls. Specifically, a Bayesian design was used to monitor both response (CR) and toxicity (TRM), with early stopping if the posterior probability was <0.10 that the true TRM rate was <15% (vs. the historical = 31%) or if the posterior probability was >0.90 that the true CR rate with CPX-351 was <30% (historical = 30%).Results: 23 patients, median age 71.1 (range: 53.1-91.1) years, with a median TRM score of 25.7 (range: 13.7-90.0) and a median ECOG performance status of 2 (range: 1-3), were enrolled. Cytogenetic risk was favorable in 1, intermediate in 8, and adverse in 14 (including 3 with insufficient culture growth for analysis), with 9 patients having a monosomal karyotype. 13 patients had secondary disease. Overall, study patients received a median of 1 (range, 1-3) cycles of induction therapy. Among the first 9 patients randomized to 64 unit/m2, 1 CR, 1CRp, and 3 deaths by day 28 occurred. The deaths were due to overwhelming infection in patients presenting with TRM scores of 14.5, 44.4, and 57.9. Because of these 3 deaths, accrual to the 64 units/m2 arm stopped. The 9 patients given 64 units/m2 might have, by chance, been more unfavorable than the large number of historical pts. (n =2,238) used to derive the TRM score. We addressed this possibility by summing the TRM scores in these 9 patients, thus calculating the number of expected deaths by day 28 had these patients received historical treatments, principally 3+7 or higher doses of cytarabine. The number of expected deaths was 3.0, the same as the number observed. Because it met neither the early stopping bound for TRM or lack of CR, the 32 units/m2arm has continued accrual. 14 patients have been enrolled (including 3 who were enrolled without randomization after the higher-dose arm closed). 2 CRs (14.3%) were observed, and 4 patients died early; deaths were related to overwhelming infection in 1 (TRM score of 23.7), and early disease progression in 3 (TRM scores of 23.7, 33.3, and 90.0).Conclusion: This study illustrates the challenge of balancing therapeutic resistance and disease/treatment-related complications in medically unfit adults with AML. Within the constraints of historical controls and an experience limited to 9 patients at the higher dose level, our data suggest that at 64 units/m2, CPX 351 is relatively unlikely to decrease TRM to 15% (from ~30% historically) and increase CR rate to 40% (from ~30% historically) in patients at high risk of TRM. These results present the first attempt at identifying and treating medically unfit patients with CPX-351 and suggest that further adjustments in eligibility and CPX-351 dosing to maximize efficacy and reduce early leukemia-related deaths are needed. DisclosuresOff Label Use: CPX-351 currently has investigational drug status. Louie:Celator Pharmaceuticals, Inc: Employment.

Combined Epigenetic and Immunotherapy For Newly Diagnosed Mantle Cell Lymphoma: Correlative Studies Suggest The Importance Of Enhanced ADCC, Mechanisms of Resistance and Cyclin D1 Nuclear Localization Genotype

Previously, we reported that epigenetic therapy with cladribine, SAHA, and rituximab (SCR) for newly diagnosed mantle cell lymphoma was remarkably effective, with 100% overall response rate, 85-90% CR rate, and durable responses( Hasanali, AACR,2013 LBA140). Over 40 patients now have been enrolled with all patients completing therapy. Final response and CR rates will be reported at the meeting. This abstract will focus on the correlative studies performed as part of this trial.Cladribine, a purine analog with reported epigenetic activity was shown here by HELP assays to inhibit DNA methylation in vivo in 6 patients with leukemic MCL. Similar activity was also observed in two MCL and two CLL patients treated with cladribine without vorinostat off trial, suggesting cladribine is a DNA hypomethylating agent. Due to cladribine's ability to inhibit the enzyme SAH hydrolase and thus inhibit the donation of methyl groups by S-adenosyl methionine (SAM), we assayed the ability of cladibine to inhibit histone methylation in vitro by Western blot analysis and in vitro assays of histone methyltransferase (HMT) activity on H3lys9 and H3lys27. Both assays demonstrated inhibition of methylated histones (Western) and HMT activity using MCL cell cells and nuclear extract at concentrations of cladribine in the 10-20 um range, higher than the in vivo concentration of 10-20 nm. These observations could be due to the lack of sensitivity of these assays, and more sensitive assays are in development.Studies to help elucidate the mechanism of action of synergy of epigenetic drugs with the monoclonal antibody rituximab were performed. Using cells from patients with leukemic MCL treated with SCR, we assayed for characteristic changes of apoptosis using Western blotting and TUNEL assays. None were detected. We were unable to observe complement mediated cytoxicity in vitro using human serum and rituximab with added cladribine or vorinostat. With ADCC being the primary mechanism of presumed combined epigenetic and rituximab synergy, we investigated ADCC further. CD137 transcriptional upregulation was seen in several but not all treated patients, and some patients showed up regulation of perforin and granzyme mRNA by QRTPCR. An NK cell line, NKL, showed transcriptional upregulation of CD137 after treatment with cladribine and vorinostat.A polymorphism at an intron-exon junction effects the nuclear localization of cyclin D1 by removing a nuclear export signal. Although there is published evidence supporting the role of nuclear cyclin D1 in increased oncogenesis, the role of this polymorphism in MCL remains controversial. Samples from peripheral blood of patients on trial were genotyped at the cyclin D1 locus as AA, AG, or GG, with the A allele being the loss of function allele. The presence of the A allele strongly correlated with the blastic phenotype and the lack of complete remission after SCR therapy, with both being statistically significant (table 1). Immunofluorescent studies with cyclin D1 antibodies showed nuclear and cytoplasmic localization as predicted in patients with the AA and GG genotypes (Fig 1). The heterozygotes are under investigation and will be reported. [Display omitted] [Display omitted] The mechanism of resistance to SCR was studied in a patient with blastic, leukemic MCL. A 63 male achieved complete remission after two cycles of SCR. Subsequently, he developed neurologic symptoms and was found to have CNS disease. At autopsy, CD20+ disease was found in his CNS and CD20- disease was found systemically. A cell line was established from his peripheral blood that showed significantly reduced levels of CD20 mRNA. Treatment of these cells with a variety of epigenetic drugs was unable to upregulate CD20 mRNA. These cells have been in continuous culture for over 1 year and continue to show diminished levels of CD20 mRNA and protein. Epigenetic changes at the promoter are being studied by chromatin immunoprecipation (ChiP) assays. Disclosures:No relevant conflicts of interest to declare.

The Revised International Prognostic Scoring System (IPSS-R) Predicts Posttransplantation Outcome Of Patients With Myelodysplastic Syndrome Receiving Allogeneic Stem Cell Transplantation: A Basis For Clinical Decision Making

BackgroundThe only curative treatment for patients with myelodysplastic syndrome (MDS) is allogeneic stem cell transplantation (allo-SCT). Decision to transplant is currently based on the International Prognostic Scoring System (IPSS), which has limitations. Recently, a revised IPSS (IPSS-R) has been developed (Blood. 2012;120:2454-2465). AimTo identify predictive factors for transplantation outcome, we studied 519 patients with MDS or acute myeloid leukemia (AML) evolving from MDS who received allo-SCT and were reported to the GITMO registry between 2000 and 2010. Results 1Posttransplantation outcome according to cytogenetics. Cytogenetic abnormalities were classified according to MDS Cytogenetic Scoring System (MCSS) criteria. Four groups of patients with different overall survival (5-year OS ranging from 48% to 15%, P=.003) and probability of relapse (P=.001) after transplantation were identified. In a multivariate model, MCSS significantly affected OS (HR 1.29, P=.001) and probability of relapse (HR 1.40, P<.001). Monosomal karyotype (MK) was found in 76 patients (15%) and was associated with a dismal outcome after allo-SCT (5-year OS 10%; 5-year cumulative incidence of relapse 49%). MK maintained a significant effect on OS and probability of relapse in patients stratified according to MCSS (P<.001 and P=.001, respectively). Results 2Posttransplantation outcome according to degree of peripheral blood cytopenia and percentage of marrow blasts. No significant effect of neutrophil and platelet count on posttransplantation outcome was noticed. The 5-year OS was 51%, 40% and 33% in patients with hemoglobin >10g/dl, between 8-10 g/dl and <8 g/dl, respectively (P=.001). The 5-year incidence of non-relapse mortality (NRM) was 29%, 37% and 44%, respectively (P=.003). The impact of hemoglobin level on posttransplantation outcome was maintained in a multivariate model (OS: HR 1.37, P=.002; NRM: HR 1.41, P=.009). Marrow blast count as stratified according to IPSS-R criteria significantly predict the probability of relapse (P=.005). ResultsPosttransplantation outcome of patients stratified according to IPSS-R. Patients were then classified according to IPSS-R criteria: 59 patients had a low risk (11%), 89 patients (17%) an intermediate risk, 207 (40%) a high risk, and 164 (32%) a very high risk. Five-year OS was 71%, 58%, 39% and 23%, respectively (Figure 1, P=.001). 5-year cumulative incidence of relapse was 4%, 12%, 23% and 39%, respectively (P=<.001). Compared with the IPSS-based stratification, the IPSS-R risk group would have changed for 65% of patients, 59% of which would have been assigned to a less favourable prognostic group. By applying the Akaike criterion, IPSS-R was more likely to capture prognostic information in this patient setting with respect to IPSS, especially in early stage disease (i.e., low and intermediate-1 IPSS risks). [Display omitted] We analyzed the prognostic effect of IPSS-R score by a multivariate model. The IPSS-R score significantly affected OS (HR 1.41, P<.001) and probability of relapse (HR 1.81 P<.001) in MDS patients. The effect of IPSS-R on posttransplantation outcome was maintained also when including MDS/AML as well as when stratifying patients according to type of conditioning (P form .006 to <.001).Recipient age (≥50 years) and presence of comorbidity (high risk according to HCT-CI score) were significant risk factors for increased NRM (HR 1.79, P=.02 and HR 1.83 P=.017, respectively), while MK and lack of complete remission after induction chemotherapy showed an independent effect on relapse risk (HR 2.23, P=.001 and HR 1.94, P=.001, respectively). According to the presence of these additional risk factors, the cumulative incidence of NRM among different IPSS-R categories ranged from 13% to 52% in patients receiving standard conditioning (P<.001), and from 9% to 42% in patients receiving reduced-intensity conditioning (P<.001), while the cumulative incidence of relapse ranged from 4% to 39% (P<.001) and from 5% to 57% (P<.001), respectively. ConclusionsThis study clearly shows that IPSS-R allows a reliable prediction of posttransplantation outcome in MDS patients. Allo-SCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages. Disclosures:Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

Efficacy and Relative Costs Of Re-Induction Chemotherapy With Clofarabine and Cytarabine For Adults With AML

IntroductionChemotherapy for adults with Acute Myeloid Leukemia (AML) has undergone little change in 30 years. Unfortunately, many patients relapse following an initial response to chemotherapy, and there is no standard salvage chemotherapy regimen in AML. There have been no randomized trials comparing various intensive re-induction regimens (i.e., MEC – Mitoxantrone/cytarabine/etoposide; FLAG-Ida – Fludarabine/cytarabine/idarubicin/g-csf; CLAG – cladribine/cytarabine/g-csf), and reported rates of complete remission (CR) with these regimens range from 25-60%. The only potentially curative therapy for relapsed AML is an allogeneic stem cell transplant (SCT), and SCT outcomes are improved for patients in second CR compared to those transplanted with refractory disease. Clofarabine is a second-generation purine analog, inhibiting ribonucleotide reductase and DNA polymerase. The CLASSIC I trial randomized older patients with relapsed/refractory AML to either clofarabine/cytarabine to low-dose cytarabine, with improved CR (35%) and event-free survival and no significant difference in overall survival. Single arm clinical trials with a combination of clofarabine and cytarabine report CR rates of 25-60% in the setting of relapsed AML. Our institution has treated patients with relapsed or refractory AML with the clofarabine/cytarabine regimen off clinical trial from September, 2011, to January, 2013. Here, we report the outcomes in the context of chemotherapy drug costs (Table 1). MethodsWe conducted a retrospective chart review of 20 consecutive adult patients with AML treated at the University of Kansas Medical Center from September, 2011 to January, 2013, with the combination of clofarabine (40mg/m2/day days 1-5) followed 4 hours later by cytarabine (1g/m2/day days 1-5). Data collected included age, sex, AML cytogenetics, number of prior therapies, remission rates, toxicities, number of patients proceeding on to stem cell transplant and length of hospitalization. ResultsThe median age was 67 years (range 34-74) with a male predominance (12/20 patients) and average of 2 prior therapies (range 1-3). Cytogenetics at diagnosis are available for 18 patients: 11 with poor risk; 6 with intermediate risk; 1 with favorable risk (normal cytogenetics, NPM1 mutated). We observed a 30% CR rate, with 5/6 patients in CR going on to SCT (one patient who achieved CR had evidence of leukemia recurrence at evaluation for planned SCT). The average length of stay was 33 days (5-70). Three patients had short hospitalizations (less than 14 days) or outpatient administration of chemotherapy and all three required re-admission for neutropenic fever and /or sepsis. Seven patients underwent SCT following clofarabine and cytarabine re-induction: 5 in CR and 2 with active disease at the time of SCT. Six patients received an allogeneic SCT at our institution, 5 in CR and 1 with active disease; 1 patient received SCT at another institution. One patient had relapse of AML following SCT in CR2 at day 128 post-SCT. The other 4 patients in CR at time of SCT remain alive without relapse at 215, 293, 608 and 647 days after clofarabine/cytarabine. The patient who was transplanted with active leukemia died 113 days after clofarabine/cytarabine. One patient who did not achieve CR but had a decrease in blast percentage continues to receive decitabine monthly and is alive after 14 doses at the time of this writing despite lack of CR. DiscussionOur single institution experience with clofarabine/cytarabine for refractory or relapsed AML a CR rate of 30%, consistent with published literature. It also allowed 5 patients to receive SCT in CR2, and of those, 4 remain alive and in remission; one additional patient remains alive although with residual leukemia. However, length of hospitalization was 33 days and there is significant underlying drug cost disparity. The regimen of clofarabine and cytarabine is effective in inducing CR in adult patients with relapsed and refractory AML, albeit at a higher drug-specific cost than other regimens.Table 1Drug and vial sizeCost/vialTypical re-induction dose for 2m2 patientCost/re-induction courseCladribine 10mg$46010mg × 5 days$2300Clofarabine 20mg$300780mg × 5 days$60,140Cytarabine 1000mg$262000mg × 5 days$260Etoposide 100mg$12200mg × 5 days$120Fludarabine 50mg$12160mg × 5 days$1210Mitoxantrone 20mg$16916mg × 5 days$676 Disclosures:No relevant conflicts of interest to declare.

Premature cardiovascular mortality in lymphoma patients treated with (R)-CHOP regimen — A national multicenter study

BackgroundPremature cardiovascular mortality related to chemotherapy and occurred in lymphoma survivors before disease progression is one of significant clinical failure of modern hematology. The aim of this retrospective analysis was to evaluate early cardiovascular mortality and its predictors in patients treated with the (R)-CHOP regimen. MethodsThe study assessed 610 patients: 581 patients were treated with non-liposomal doxorubicin (cumulative dose of 337±96mg/m2), and 29 patients with liposomal non-pegylated doxorubicin (cumulative dose of 237±126mg/m2). Their present status, history of cardiovascular diseases and associated risk factors were recorded. ResultsThe analysis identified 93 deaths (15.5%): 51 cases (55%) related to lymphoma disease progression and 28 (30%) to cardiovascular complications. Multivariate Cox analysis revealed history of previous heart diseases (HR=4.71; CI: 3.82–5.6; p<0.001), ECG rhythm abnormalities related to chemotherapy (HR=4,78; CI: 3.63–5.92; p=0,01), and lack of complete remission (HR=2.73; CI: 1.78–3.66; p=0.03), as the independent predictors for cardiovascular death. Neither decreased LVEF nor increasing cumulative dose of anthracyclines had a significant predictive value for cardiovascular prognosis. ConclusionsThe study indicated that cardiovascular mortality in lymphoma patients treated with (R)-CHOP regimen is relatively high and ECG monitoring may be the most effective in cardiological risk assessment. The unfavorable outcome depended on lack of complete remission that seems to be a consequence of patients' individual susceptibility for cardiac events, which should become a purpose of further trials.

CD34+ Marker As Prognostic Factor in Chronic Lymphoid Leukemia

AbstractAbstract 4591From 2008 to date we marked all Chronic Lymphocytic Leukemia (CLL) with monoclonal CD34. The authors consider presence of said marker on the CLL cell membrane is a prognostic added factor to positivity for CD38 and ZAP70. CLL frequency is lower in countries with mixed races, compared with Europe and North America. In Venezuela is 5.4% (Luigi De Salvo personal communication) where I have never diagnosed a CLL case in a pure Venezuelan Indian. Similar reports are documented from Japan and China, provided racial genetics. Since 2008 to date we studied 28 patients for CLL: male 18 and female 10 with CD34-labeled. All patients presented lymphadenopathy, splenomegaly, and hypogammaglobulinemia. Flow cytometry revealed: HLA-Dr (33–100%), CD19 (44–100%), CD20 (28–95%), CD23 (63–100%), CD19 + CD5 (44–100%), CD23 + CD5 (28–100%) and CD19 + CD23 (28–100%) ZAP-70 (31–97%) and CD38 (12–75%). Of 28 patients studied, 21 individual CD34+ presented a variability of 10–99%. All had diffuse bone marrow infiltration, anemia and a white cell count range of 20.000–325,000/dl, with more than 80% lymphocytes of mature appearance. All patients presented discrete thrombocytopenia 70,000–120,000 plt/ml and responded well to standard treatment with Fludara + Rituximab. We believe presence of CD34 antigen on the cell membrane is an added risk factor for patients with CLL, producing an increased angiogenesis, and infiltration of organs and bone marrow by the leukemia cell. Lack of complete remission or negativity of Minimal Residual Disease may be CD34-linked. Disclosures:No relevant conflicts of interest to declare.