Long-term Remission In Patients Research Articles

Characterization of Patients with Multiple Myeloma in Long- Term Remission

INTRODUCTIONMultiple Myeloma is still considered an incurable disease despite the development of new therapy options. However, there is a small fraction of patients achieving a long- term remission (LTR) after induction therapy followed by high dose chemotherapy and autologous stem cell transplantation (ASCT). Such patients that are still in complete remission or experience an indolent disease course over many years after high dose therapy are referred to as functionally cured. To date, it is still unclear which patients experience a long term disease control. METHODSWe have screened our Myeloma register for patients that experienced a LTR over 7 years after high dose chemotherapy followed by ASCT. Characteristics of patients that fit to these criteria have been analyzed in detail. The current disease state was evaluated according to the IMWG criteria. Using the Next Generation Flow technique from Cytognos, bone marrow samples from the patients were examined for minimal residual disease (MRD, sensitivity <10-5). To further characterize the bone marrow environment of myeloma patients in LTR, we currently perform a quantitative analysis of the lymphocyte compartment in peripheral blood and bone marrow using flow cytometry. Moreover, bone marrow mononuclear cells are currently being characterized using the single cell RNA sequencing approach by 10X Genomics. RESULTSWe have identified 24 living patients with ongoing remission from 7 till 17 years after high dose therapy and autologous stem cell transplantation. Patients' characteristics are summarized in Table 1. Unexpectedly, 10 patients had a poor prognosis score at first diagnosis (6 patients with ISS score II and 4 patients with ISS score III). Furthermore, the average tumor burden, determined by plasma cell infiltration of bone marrow at initial diagnosis, was remarkably high with 49.5 %. 4 patients had high risk cytogenetics (3 patients with TP53/del17p and 1 patient with t(4;14)).Regarding the depth of response, the 24 patients were subdivided into 3 groups (Table 2). 9 of 24 patients had a detectable monoclonal protein in serum with an indolent disease course. 15 of 24 patients had no detectable monoclonal protein in serum. Of note, MRD assessment of the bone marrow by Next Generation Flow revealed MRD positivity in 4 of 15 patients. Preliminary data using flow cytometry and single cell RNA sequencing suggest a unique immunological profile of the different patient cohorts in LTR. CONCLUSIONPatients with multiple myeloma in LTR can be subdivided into 3 groups: patients with detectable monoclonal protein but indolent disease course, patients in Flow MRD negative complete remission and patients in Flow MRD positive remission. A deep analysis of patients' peripheral blood and bone marrow by flow cytometry and single cell RNA sequencing is currently being performed focusing on the immunological signature of the different patient cohorts. Preliminary results suggest a unique immunophenotype which is possibly associated to long- term disease control. Data will be presented at the meeting. [Display omitted] DisclosuresKriegsmann:BMS: Research Funding; Celgene: Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Durie:Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Goldschmidt:Takeda: Consultancy, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria.

Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study

The combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease; however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial. In our single-centre, phase 2, single-arm trial in the USA, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Eligible patients had newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, a left ventricular ejection fraction above 50%, and adequate hepatic and renal function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher levels were believed to be due to leukaemia at the discretion of the investigator). Patients received eight cycles of 21 days, alternating between two drug combinations: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine. Ponatinib was given orally at 45 mg per day for the first 14 days of cycle 1 then continuously at 45 mg per day for the subsequent cycles. After 37 patients were treated, the protocol was amended to reduce the dose of ponatinib to 30 mg per day at cycle 2, with further reduction to 15 mg once a complete molecular response (defined as absence of quantifiable BCR-ABL1 transcripts) was achieved. Patients in complete remission received maintenance with ponatinib daily (30 mg or 15 mg) indefinitely, and with vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 2 years. The primary endpoint was 3-year event-free survival in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424982, and is ongoing and still enrolling patients. 76 patients with a median age of 47 years (IQR 39-61) were enrolled and treated between Nov 19, 2011, and April 4, 2018. The 3-year event-free survival was 70% (95% CI 56-80). The most common grade 3 or 4 adverse events were infection (n=65, 86%), increased transaminases (n=24, 32%), increased bilirubin (n=13, 17%), pancreatitis (n=13, 17%), hypertension (n=12, 16%), bleeding (n=10, 13%), and skin rash (n=9, 12%). Six patients died while still on study treatment. Three patients (4%) died from infection and one (1%) from haemorrhage. Two patients died from myocardial infarction related to early ponatinib use; neither death occurred after protocol revision. The combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. This regimen could represent a new standard of care for this population. A randomised, phase 3 study to evaluate the efficacy of this combination compared with chemotherapy plus earlier-generation tyrosine-kinase inhibitors is warranted. Takeda Oncology.

Subcutaneous immunotherapy induces alterations in monocytes and dendritic cells homeostasis in allergic rhinitis patients

BackgroundSpecific subcutaneous immunotherapy (SCIT) can achieve long-term remission in patients with allergic rhinitis (AR) through complex and still unknown mechanisms. The aim of this study is to evaluate the effect of SCIT over CD16+ and CD16− monocytes, myeloid (mDCs) and plasmacytoid dendritic cells (pDCs) in patients with AR, comparatively to pharmacological standard treatment (non-SIT).MethodsThe relative frequency and absolute number of monocytes and DC subsets, the frequency of these cells producing TNFα after in vitro stimulation with Dermatophagoides pteronyssinus (Dpt) extract, and the expression levels of receptor-bound IgE or IgG were assessed by flow cytometry, in peripheral blood samples from 23 healthy individuals (HG) and 43 participants with AR mono-sensitized to Dpt; 10 with non-SIT treatment and 33 under SCIT, just before (SCIT-T0) and 4 h after administration (SCIT-T4). Moreover, IFNα mRNA expression was evaluated in purified pDCs, by qRT-PCR.ResultsAfter SCIT administration we observed a strong decrease of circulating pDCs, although accompanied by higher levels of IFNα mRNA expression, and an increase of circulating CD16+ monocytes. AR participants under SCIT exhibited a higher expression of receptor-bound IgE in all cell populations that expressed the high affinity receptor for IgE (FcεRI) and a higher frequency of CD16+ monocytes producing TNFα. Conversely, we observed a decrease in the frequency of mDCs producing TNFα in AR under SCIT, similar to the observed in the control group.ConclusionsSCIT seems to induce numeric, phenotypic, and functional changes in circulating monocytes and dendritic cells, contributing at least in part to the well described immunological alterations induced by this type of immunotherapy.

Pre-surgical medical treatment, a major prognostic factor for long-term remission in acromegaly.

To determine whether pre-surgical medical treatment (PSMT) using long-acting Somatostatin analogues in acromegaly may improve long-term surgical outcome and to determine decision making criteria. This retrospective study included 110 consecutive patients newly diagnosed with acromegaly, who underwent surgery in a reference center (Marseille, France). The mean long-term follow-up period was 51.4 ± 36.5 (median 39.4) months. Sixty-four patients received PSMT during 3-18 (median 5) months before pituitary surgery. Remission was defined at early (3 months) evaluation and at last follow-up by GH nadir after oral glucose tolerance test < 0.4µg/L and normal IGF-1. Pretreated and non-pretreated groups were comparable for the main confounding factors except for higher IGF-1at diagnosis in PSMT patients. Remission rates were significantly different in pretreated or not pretreated groups (61.1% vs. 36.6%, respectively at long-term evaluation). In multivariate analysis, PSMT was significantly linked to 3 months (p < 0.01) and long-term remission (p < 0.01). Duration of PSMT was not significantly different in cured or non-cured patients, at both evaluation times. PSMT appeared to be more beneficial for patients with an invasive tumor. No patient with a tumor greater than 18mm or mean GH level exceeding 35ng/mL at diagnosis was cured by surgery alone (vs. 8 and 9 patients in the pretreated group, respectively). Patients with PSMT showed more transient mild hyponatremia after surgery. PSMT significantly improved short and long-term remission in patients with acromegaly, independent of its duration, especially in invasive adenomas.

Predictive and therapeutic biomarkers in chimeric antigen receptor T-cell therapy: A clinical perspective.

The adoptive transfer of genetically engineered T cells modified to express a chimeric antigen receptor (CAR) has shown remarkable activity and induces long-term remissions in patients with advanced hematologic malignancies. To date, little is known about predictive indicators of therapeutic efficacy or serious toxicity after CAR T-cell therapy in clinical practice. Biomarkers are not only potentially able to inform physicians and researchers of immunotherapy targets in particular but could also be used to monitor the effectiveness of treatments and to predict incidence of side effects in some circumstances. Identification of new biomarkers can therefore not only contribute to the development of new therapeutic and prognostic strategies for CAR T-cell therapy for cancer but also help to generate improved clinical practices for early recognition and minimization of adverse effects while preserving the antitumor activity of the CAR T cells. Herein, we will consider a variety of predictive and therapeutic biomarkers in CAR T-cell therapy and the state of current understanding of their clinical utility. The incorporation of biomarker studies in CAR T-cell clinical trials and practice will help to realize the potential clinical benefit of biomarker-guided therapy.

The USP8 mutational status may predict long-term remission in patients with Cushing's disease.

Almost half of the cases of Cushing's disease (CD) tumours carry recurrent activating somatic mutations in the ubiquitin-specific protease eight gene (USP8). The USP8 mutational status could predict remission in patients with CD, so our objective was to correlate the presence of somatic USP8 mutations with the rate of recurrence after transsphenoidal surgery (TSS) retrospectively. Biochemical, radiological and clinical data were retrospectively assessed in 48 patients. USP8 mutational status was determined from corticotroph tumour samples. Association between USP8 mutational status, remission and recurrence was investigated. Patients with Cushing's disease from a single-centre cohort who underwent TSS between 1991 and 2012. Long-term remission and recurrence rate after TSS with at least 6months follow-up. Biochemical, radiological and clinical data, including sex, age at diagnosis, tumour size and pre-operative hormonal levels. USP8 mutational status. Patients with USP8 mutant corticotroph tumours (18 of 48; 37%) were diagnosed significantly earlier (mean±SD 46±10years vs 53±11years; P=0.028) and presented with higher pre-operative 24-hour urinary-free cortisol levels (median IQR μg/24hours 1174.0, 1184.5 vs 480.0, 405.3; P=0.045). The incidence of recurrence in a 10-year follow-up was significantly higher in patients with USP8 mutant tumours after the initial remission (58% vs 18% P=0.026). Recurrence appeared significantly earlier in these patients (months 70, 44-97 95% CI vs 102, 86-119 95% CI; P=0.019). Recurrence appears to be more frequent and earlier after TSS in patients with USP8 mutant corticotroph tumours.

Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia

AbstractClonal hematopoiesis by hematopoietic stem progenitor cells (HSPCs) that lack an HLA class I allele (HLA− HSPCs) is common in patients with acquired aplastic anemia (AA); however, it remains unknown whether the cytotoxic T lymphocyte (CTL) attack that allows for survival of HLA− HSPCs is directed at nonmutated HSPCs or HSPCs with somatic mutations or how escaped HLA− HSPC clones support sustained hematopoiesis. We investigated the presence of somatic mutations in HLA− granulocytes obtained from 15 AA patients in long-term remission (median, 13 years; range, 2-30 years). Targeted sequencing of HLA− granulocytes revealed somatic mutations (DNMT3A, n = 2; TET2, ZRSR2, and CBL, n = 1) in 3 elderly patients between 79 and 92 years of age, but not in 12 other patients aged 27 to 74 years (median, 51.5 years). The chronological and clonogenic analyses of the 3 cases revealed that ZRSR2 mutation in 1 case, which occurred in an HLA− HSPC with a DNMT3A mutation, was the only mutation associated with expansion of the HSPC clone. Whole-exome sequencing of the sorted HLA− granulocytes confirmed the absence of any driver mutations in 5 patients who had a particularly large loss of heterozygosity in chromosome 6p (6pLOH) clone size. Flow–fluorescence in situ hybridization analyses of sorted HLA+ and HLA− granulocytes showed no telomere attrition in HLA− granulocytes. The findings suggest that HLA− HSPC clones that escape CTL attack are essentially free from somatic mutations related to myeloid malignancies and are able to support long-term clonal hematopoiesis without developing driver mutations in AA patients unless HLA loss occurs in HSPCs with somatic mutations.

LONG-TERM REMISSION OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION WITH AS-NEEDED ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY.

To determine the presenting characteristics of patients with neovascular age-related macular degeneration with long-term remission (LTR), which was defined as the absence of intraretinal/subretinal fluid, or hemorrhage, and absence of leakage on fluorescein angiography for longer than 6 months while on as-needed antivascular endothelial growth factor treatment. The presenting characteristics of patients with LTR were compared with a control group including 32 eyes of 28 age-, gender-, and ethnicity-matched patients who did not achieve LTR. Seventy-four percent of patients in the LTR group had Type 1 choroidal neovascular membrane and 18.5% had retinal angiomatous proliferation. In the control group, 28 eyes had Type 1 choroidal neovascular membrane (87.5%), and none of the patients had retinal angiomatous proliferation; overall, there was a significant difference in lesion types between the 2 groups (P = 0.036). Eyes with LTR at presentation had significantly thinner subfoveal choroidal thickness (147 vs. 178 μm, P = 0.04). There was more intraretinal fluid and less subretinal fluid at the presentation in the remission group (59.3% intraretinal fluid and 11.1% subretinal fluid) compared with the control group (28.1% intraretinal fluid and 34.4% subretinal fluid, P = 0.03). The presence of retinal angiomatous proliferation, thinner choroidal thickness, more intraretinal fluid, and less subretinal fluid at presentation were associated with LTR in patients receiving as-needed treatment for age-related macular degeneration.

ФАКТОРЫ ФОРМИРОВАНИЯ ДЛИТЕЛЬНЫХ РЕМИССИЙ У БОЛЬНЫХ АЛКОГОЛЬНОЙ ЗАВИСИМОСТЬЮ

Alcohol dependence syndrome is the important modern medico-social issues. In recent years, the problem of achieving&#x0D; remission with alcohol dependence has been given great attention, both in Russia and abroad. The duration, persistence&#x0D; and quality of remission are the indicators of effectiveness of alcohol dependence therapy. The possibility of an objective&#x0D; prediction of the outcome of ongoing therapy, the duration of remissions and the likelihood of relapses of alcohol depend-&#x0D; ence are urgent needs. Despite a large number of scientific studies, there is no single idea of the factors influencing the&#x0D; formation of remissions in patients with alcoholic dependence syndrome. The article presents the modern view on the&#x0D; terms and stages of the remissions formation in alcohol dependence syndrome, clinical-psychopathologic structure of&#x0D; remissions. Diagnostic assessment of the remissions is examined according to the current classifications of ICD-10 and&#x0D; DSM-V. Biological, personal, social and therapeutic factors of the formation of long-term remissions in patients with&#x0D; alcohol dependence are analyzed. Comorbid affective disorders, in particular, depressive and anxiety-phobic disorders,&#x0D; cerebral pathology (traumatic, hypertonic, vertebrogenic genesis), nicotine dependence, are attributed to factors in-&#x0D; fluencing the stability of the clinical picture of remission and causing a high risk of recurrence. Modern approaches to&#x0D; the prognosis of remission in alcohol dependence on the basis of a complex biopsychosocial approach are presented.

Topical Tacrolimus 0.03% for Maintenance Therapy in Steroid-Dependent, Recurrent Phlyctenular Keratoconjunctivitis.

To evaluate the efficacy of topical tacrolimus 0.03% as steroid-free maintenance therapy in young patients with severe, recurrent phlyctenular keratoconjunctivitis (PKC). The medical records of 6 eyes of 5 patients (4 children and 1 young adult) with recurrent, steroid-dependent PKC were reviewed. The patients were treated with combined application of topical steroids and tacrolimus 0.03% in the active phase and maintained on topical tacrolimus alone after remission. The clinical signs, symptoms, and visual acuities resolved in all patients after 25.2 ± 16.9 days of combined treatment with steroids and tacrolimus. After disease remission, the patients were maintained on topical tacrolimus 0.03% once daily alone for 8.4 ± 4.7 months, and no recurrence occurred during 10.6 ± 1.9 months of follow-up. Tacrolimus was successfully discontinued in 2 patients without further recurrence. There were no ocular side effects related to the use of topical tacrolimus. Topical tacrolimus 0.03% was effective in maintaining long-term remission in patients with recurrent, steroid-dependent PKC.

Long-term remission of hormone receptor-positive/HER2-positive metastatic breast cancer due to combined treatment with everolimus/trastuzumab/exemestane: A case report.

The present case report describes a postmenopausal patient with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer, who experienced progression of disease in bilateral lungs, lymph nodes and the liver under previous endocrine therapy and trastuzumab. Following the failure of two lines of endocrine-based treatment, the patient was administered the combined treatment of everolimus, trastuzumab and exemestane following surgical resection of the liver metastasis. A durable partial remission was achieved, which has continued for >27 months. This prominent clinical outcome in this patient demonstrates that the combined administration of endocrine therapy, trastuzumab and everolimus is clinically effective, and may induce long-term remission in patients with HR+/HER2+ metastatic breast cancer.

Surgical outcomes in patients with Cushing's disease: the Cleveland clinic experience.

Transsphenoidal surgery (TSS) to resect a pituitary adenoma is considered first-line treatment for patients with Cushing's disease (CD). Early, post-operative remission rates >80% are expected for patients with a microadenoma (≤ 10mm) visible on magnetic resonance (MR) imaging. To report surgical outcomes and predictors of remission in a specialist center for patients with CD. Clinical data was obtained from a prospective CD database in addition to review of all electronic medical, laboratory and surgical patient records. Patients who underwent their first TSS by one neurosurgeon between 2004 and 2013, and had a minimum 1 year follow up, were evaluated. One hundred and one consecutive patients with CD (73F, 28M) underwent TSS. Median (range) age and follow-up were 47 (15-87) and 4.33 (1-9.8) years, respectively. At surgery, 74 (73.2%) patients had a microadenoma, 27 a macroadenoma; six of the latter patients had a planned, subtotal resection to control neurological signs due to mass effect. Initial remission rates were: microadenoma, 89% (66/74); macroadenoma, 63% (17/27); and 81% (17/21) in those macroadenomas where complete surgical removal was anticipated. Initial non-remission occurred in 18 patients, ten macro- and eight microadenoma; six of 18 had residual disease on most recent follow up. Six (2 macro, 4 micro) of the 83 patients with initial remission have had late (>12 months) recurrence of hypercortisolism that required either repeat TSS or adjunctive therapy, three of whom have persistent hypercortisolism. Macroadenoma (p = 0.003) and tumor invasion beyond the pituitary and sella (p < 0.001) were associated with failure to obtain remission with the initial TSS and greater likelihood of late recurrence. Patients in whom no lesion was seen on neuroimaging had rates of initial remission (21/25 or 84%) and a similar late recurrence rate of 4% (1/25) in comparison with those with MR-visible microadenomas (3/49, or 6%). A team-based approach, in a specialized pituitary center, can lead to initial and durable, long-term remission in patients with CD. The presence of a macroadenoma and tumor extension beyond the pituitary and sella were predictive of initial non-remission as well as risk of late recurrence.

P473 How to monitor the withdrawal of maintenance treatment with azathioprine in IBD patients with deep remission: results from a prospective study on multiple non invasive tests

Background: There is uncertainty regarding the optimal duration of maintenance treatment with azathioprine (AZA) in Crohn's disease (CD) and ulcerative colitis (UC), with some studies suggesting durations up to 4–5 years and others supporting long-term indefinite use. More recent guidelines state that for patients in long term remission, cessation of treatment may be considered in the absence of objective signs of inflammation, but no data are available on how to monitor these patients after AZA withdrawal. Methods: A prospective observational study was performed on consecutive patients with CD or UC who stopped their maintenance treatment with AZA while being in steroid-free, deep remission, defined as normal clinical and endoscopic indexes, normal C-reactive protein (CRP) and normal fecal calprotectin. After AZA withdrawal, all patients received maintenance treatment with salicylates. Every 3 months, blood samples were collected for standard biochemical tests (including CRP, full blood count and protein electrophoresis), as well as stool samples for fecal calprotectin dosage. Bowel ultrasonography and ileocolonoscopy were performed every 6 and 12 months, respectively, as well as in case of clinical relapse. Multiple logistic regression and Cox proportional-hazards models were used to assess the predictors of disease relapse. Results: 41 patients (23 males, median age 45 years) who stopped AZA after median 7 years (range 5–14) were enrolled. After a mean follow-up of 24 months (range 5–48), 19 patients (46%; 7/19 CD, 12/22 UC) relapsed, within median 13 months (range 2–35). Predictors of clinical relapse at the time of AZA withdrawal were female gender (p=0.045) and age ≤45 years (p=0.035) only for UC. Fecal calprotectin was the only predictor of clinical relapse during the non invasive monitoring performed after AZA withdrawal, both in UC (p=0.019) and in CD (p=0.017). Moreover, fecal calprotectin was positive in all patients with UC and in 57% of CD patients at the time of relapse. Conclusions: Up to half of patients with IBD relapses after AZA withdrawal at different times. Fecal calprotectin can predict subsequent clinical relapse after AZA withdrawal. This can be useful in the non invasive monitoring of patients to detect preclinical relapse and to early correct our therapeutic strategy after AZA withdrawal. Prospective randomized studies are needed to validate such strategy.

Antibody-Based Cancer Therapy: Successful Agents and Novel Approaches.

Since their discovery, antibodies have been viewed as ideal candidates or "magic bullets" for use in targeted therapy in the fields of cancer, autoimmunity, and chronic inflammatory disorders. A wave of antibody-dedicated research followed, which resulted in the clinical approval of a first generation of monoclonal antibodies for cancer therapy such as rituximab (1997) and cetuximab (2004), and infliximab (2002) for the treatment of autoimmune diseases. More recently, the development of antibodies that prevent checkpoint-mediated inhibition of T cell responses invigorated the field of cancer immunotherapy. Such antibodies induced unprecedented long-term remissions in patients with advanced stage malignancies, most notably melanoma and lung cancer, that do not respond to conventional therapies. In this review, we will recapitulate the development of antibody-based therapy, and detail recent advances and new functions, particularly in the field of cancer immunotherapy. With the advent of recombinant DNA engineering, a number of rationally designed molecular formats of antibodies and antibody-derived agents have become available, and we will discuss various molecular formats including antibodies with improved effector functions, bispecific antibodies, antibody-drug conjugates, antibody-cytokine fusion proteins, and T cells genetically modified with chimeric antigen receptors. With these exciting advances, new antibody-based treatment options will likely enter clinical practice and pave the way toward more successful control of malignant diseases.

New Targeted Treatments for Cutaneous T-cell Lymphomas.

Cutaneous T-cell lymphomas (CTCLs) represent a group of rare and heterogeneous diseases that are very difficult to treat at advanced stages. The development of monoclonal antibodies is a new hope for the treatment of these diseases. Alemtuzumab (Campath) is a humanized IgG1 kappa monoclonal antibody specific for CD52, an antigen expressed by most T and B lymphocytes. Alemtuzumab may frequently induce long-term remissions in patients with Sezary syndrome but high-dose treatments lead to severe cytopenia, immune depletion, and opportunistic infections. This treatment is less efficient in mycosis fungoides (MF). Brentuximab vedotin is a chimeric anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E, a cytotoxic antitubulin agent. Brentuximab vedotin is a very interesting new treatment for advanced tumor MF, Sezary syndrome, and primary cutaneous CD30+ lymphoproliferative disorders. The main limiting adverse event is neurosensitive peripheral neuropathy. Mogamulizumab is a humanized anti-C-C chemokine receptor Type 4 monoclonal antibody with a defucosylated Fc region leading to increased antibody-dependent cellular cytotoxicity. Mogamulizumab is very efficient on aggressive peripheral T-cell lymphomas, particularly adult T-cell leukemia/lymphoma and CTCLs, especially on the blood component of tumor cells. The main limiting events are related to the concomitant depletion of regulatory T-cells. IPH4102 is a humanized monoclonal antibody that targets the immune receptor KIR3DL2/CD158k. Preclinical results with this antibody offer proofs of concept for the clinical development of IPH4102 to treat patients with advanced CTCL.

Factors predicting the outcomes of removal of corticotropinom in Cushing's disease

Обоснование. Болезнь Иценко–Кушинга (БИК) – тяжелое многосимптомное заболевание гипоталамо-гипофизарно-надпочечниковой системы. Причиной заболевания является наличие аденомы гипофиза (кортикотропиномы). Увеличение секреции адренокортикотропного гормона (АКТГ) аденомой гипофиза приводит к повышенной секреции кортизола корой надпочечников и развитию тотального эндогенного гиперкортицизма. Золотым стандартом лечения данного заболевания является хирургическое удаление кортикотропиномы. Однако аденомэктомия не во всех случаях бывает эффективной, и примерно в 20% случаев после проведенного радикального лечения не удается достичь ремиссии заболевания и возникает рецидив.&#x0D; Цель. Целью нашей работы являлась оценка факторов, оказывающих влияние на результат аденомэктомии у пациентов с болезнью Иценко–Кушинга, и выявление предикторов рецидива.&#x0D; Методы. В исследование было включено 84 пациента (80 женщин и 4 мужчин) в возрасте от 18 до 58 лет с БИК до и после трансназальной аденомэктомии. Период наблюдения от 3 до 15 лет, начиная с 2001 г. (в среднем 9,0 лет). Была проведена ретроспективная оценка клинических и гормональных факторов (АКТГ и кортизола) до операции и через 1–3 и 8–13 дней после операции.&#x0D; Результаты. У 54 (64,3%) из 84 пациентов с БИК после проведенной трансназальной аденомэктомии развилась ремиссия заболевания. Оперативное лечение было неэффективно у 30 (35,7%) пациентов, и им была проведена повторная аденомэктомия. По данным МРТ головного мозга, среди пациентов с ремиссией заболевания чаще встречались микроаденомы гипофиза (54%) по сравнению с пациентами, у которых операция оказалась неэффективна, а на МРТ чаще встречались макроаденомы (63%). У всех больных с БИК независимо от исхода нейрохирургической операции наблюдалось достоверное снижение уровня кортизола и АКТГ в раннем послеоперационном периоде.&#x0D; Заключение. Показателями эффективности аденомэктомии и длительной ремиссии у пациентов с БИК являются уровень утреннего кортизола менее 100 нмоль/л и уровень АКТГ менее 10,0 пг/мл на ранних сроках после операции (1–13-й дни). Наличие надпочечниковой недостаточности после аденомэктомии является предиктором эффективности операции, но не исключает вероятности развития рецидива.

Outcomes of Autologous Stem Cell Transplantation in Elderly Mexican Patients

IntroductionAutologous hematopoietic stem cell transplantation (ASCT) is a treatment option for long-term remission in patients with multiple myeloma and recurrent non-Hodgkin´s lymphoma (NHL).The eligibility for ASCT is based on a risk-benefit assesssment of the disease, age has not been considered an exclusion criteria for ASCT where treatment related mortality are relatively low. The treatment-related morbidity is associated with toxicity of condition regimen and infections associated with the degree of immune deficiency. Outcome in elderly patients with multiple myeloma and recurrence of Hodgkin´s lymphomas with chemosensitive illness in ≥ 60 years patients undergo ASCT are limited and contradictory. For this reason the aims of the present study was to reviewed to identify patient with multiple myeloma and non-Hodgkin lymphoma undergoing ASCT at 60 or greater and describe the clinical data and outcome.Method:This work was a retrospective transversal study, 24 patients older than 60 years was enrolled and all of them were undergo ASCT al Instituto Nacional de Cancerologia, Mexico from 2005 to 2015.We assessed previous comorbidities, treatment lines, response prior to transplantation, treatment response, relapse free-survived and global survival, it was considered from the transplantation day until last visit at the hospital.ResultsTwenty-four patients were assessed, all were ≥60 years at the transplant moment. 16 of them had diagnostic of multiple myeloma and 8 with Non-Hodgkin’s lymphoma (NHL). For the multiple myeloma group the median of age was 66 years (60-70 years), the 81% was male. At the transplant moment, two people in that group had hypertension, one had diagnosis of Diabetes Mellitus Diabetes II and the another did not have any other illness. At the transplant moment 62.5% of the patients had been treated with only one line treatment and 37.5% had been received two treatment lines. On the other hand, at the transplant moment 50% of the patients had completed response, 12% had partial response, 31.26% had very good partial responses and 6.25% had illness progression.Multiple myeloma patient was conditioned with melphalan 200mg/m2 in 95%. Neutrophils recovery was at 12 days. Fourty-three percent of the patient required transfusion. Neutropenic fever was presented in 43% of the patient. Fifty percent got completed response after ASCT and 20% with progression disease. Relapse disease was in 31% and mortality was 6.25%, there was not mortality associated with the process and 44% is alive without illness (Table 1). In patients with multiple myeloma the OS at two year was 100% and at three years 86%; for NHL patients OS at one year was 67% and at two years 33%. .For the NHL group the median of age was 67 years (61-72 years), the 50% was male, one person in that group had HTA at transplant moment, another one had diagnosis of MDII, another one had rheumatology disease and another one had long disease, and the other four did not have any other diseases. At the transplant moment 37.5% of the patients had been treated with only one line treatment, 37.5% had been received two treatment lines and 25% had been received three treatment lines. On the other hand, at the transplant moment 87.5% of the patients had completed response and 12.5% had partial response.NHL patients were conditioned with PEAM (cisplatin, etoposide, cytosine arabinoside and melphalan) 25%, Rituximab-PEAM in 62.5% and one patient with fludarabine with cyclophosphamide (FLUCY). Neutrophils recovery was at 12 days. Fourty-three percent of the patient required transfusion. Neutropenic fever was presented in 43% of the patient. Fifty percent got completed response after ASCT and 20% with progression disease. Relapse disease was in 31% and mortality was 6.25%, there was not mortality associated with the process and 44% is alive without illness (Table 1)For lymphoma, the relapse-free survival at one year 48.6%. For patients with multiple myeloma, the free illness survival at one year was 85.7%, at two years 77.9% and at four year 58.4%.ConclusionAutologous stem cell transplantion in older people is a good option for treatment without mortality asociated at process. The complications like neutropenic fever and transfusional requirement are similar with younger patients. In our population, age is not a limit to offer a treatment with high dose of chemotherapy and autologous. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Stratified Intense-Dose- Yttrium-90 Ibritumumab Tiuxetan (90YIT ) with Bendamustine+Fludarabine Nonmyeloablative Conditioning for Allogeneic Stem Cell Transplantation in b-Cell Malignancies

Background: Nonmyeloablative allogeneic transplantation has the potential to induce long-term remissions in patients with relapsed lymphoma. However, a non-intense conditioning regimen enhances the risk of early relapse. Anti-CD20 antibody radioimmunotherapy (90YIT) delivers radiation dose not only to the tumor cells that bind the antibody but also to inaccessible neighboring cells as a result of the cross-fire effect. Thus, we hypothesized that the addition of escalated 90YIT dose to the recently published bendamustine+fludarabine conditioning regimen (Khouri et al. Blood 2014) would facilitate early cytoreduction in such patients and promote improved long-term disease control by the allogeneic graft. Organ doses from a 90YIT weight-based activity prescription (mCi/kg) vary considerably, which justifies a dosimetry-based strategy for mCi/kg escalation.Methods and patients: On days -22 and -14, rituximab was given at 250 mg/m2 preceding 111In ibritumumab and 90YIT administration, respectively. Organ dosimetric assessment was performed based on serial 111In ibritumumab whole body scanning (0, 4, 24, 72 and 144 hours) , to select from among five 90YIT mCi/kg prescriptions (0.5, 0.75, 1, 1.25 or 1.5) that would result in an estimated 10 - 12 Gy dose to the liver, lungs or kidneys. Organ dose was corrected for patient-specific mass, based on a CT volume estimate times 1.03 g/cc for liver and kidneys, and a variable specific gravity for lungs (Simon, J Clin Monit Comput, 2000). Bendamustine 130 mg/m2 plus 30 mg/m2 of fludarabine IV were given daily on days -5 to - 3 prior to transplantation. Tacrolimus and mini-methotrexate (Mycophenolate mofetil in case of cord blood transplantation) were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving an unrelated donor transplant.Results: Twenty patients were studied. The median age was 58 years (range, 37-71). Lymphoma histologies included: indolent (n=8, 40%), diffuse large cell (n=6; 30%), double-hit (n=2; 10%) and mantle cell (n= 4, 20%). The median number of prior chemotherapies received was 4 (range, 2-7). At study entry, 8 patients (40%) were in complete remission following salvage therapy, 7 (35%) were in partial response, and 5 (25%) had refractory disease. Six of 16 (37.5%) patients tested were PET+. Dosimetry: The most exposed organ was either liver (16 patients) or lungs (4 patients). The distribution among the five 90YIT mCi/kg prescriptions (smallest to largest) was 2, 4, 12, 1 and 1, with a mean of 0.94 ± 0.23 mCi/kg. If all twenty patients were treated at 1 mCi/kg (the most common prescription), the 20 Gy limit employed for 90YIT clinical trials prior to approval would have been exceeded in only one patient for the liver (22.9 Gy) or lungs (20.9 Gy). The maximum liver and lung doses at 0.75 mCi/kg would have been 17.2 and 15.7 Gy, respectively. Transplant outcomes: Fifteen patients (75%) received their transplants from unrelated donors (including 1 mismatched and 2 cord blood), and only 5 (25%) from HLA-compatible siblings. The median number of CD34+ cells infused was 6.2 × 106/kg. Neutrophil counts recovered to > 0.5 × 109/L after a median of 12 days (range, 0-24 days). Platelet counts recovered to > 20 × 109/L after a median of 19 days (range, 9-30 days). By day 30, median donor myeloid and T-cells were 100% (range, 98-100). The cumulative incidence of acute grade 2-4 GVHD and chronic extensive GVHD were 25% (5% for acute grade 3-4) and 32%, respectively. Treatment-related mortality (TRM) rates at day 100 and 1 year after transplantation were 0% and 10%, respectively. The 2 cord blood transplants engrafted with 100% donor cells and none had GVHD. With a median follow-up duration of 14 months (range, 3-34 months), the overall survival and progression-free survival rates were 85% and 70%, respectively. No significant difference in survival or TRM could be detected by age, donor type, histology, disease status, PET status or number of prior therapies.Conclusions: Our results indicate that dose-intense 90YIT combined with fludarabine and bendamustine is a well-tolerated nonmyeloablative allogeneic conditioning for lymphoid malignancies, with promising results of engraftment, GVHD and survival. Our stratified 90YIT prescription results suggest that future studies with a fixed dose of 1 mCi/kg level without dosimetry would have an acceptable radiation risk to vital organs in this setting. DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Efficacy of Adoptive Immunotherapy By Donor Lymphocyte Infusions after Allogeneic Stem Cell Transplantation from Related an Unrelated Donors: A Single Center Retrospective Analysis

Introduction: Allogeneic stem cell transplantation (alloSCT) has become an integral part in the therapy of patients with malignancies of the lympho-hematopoietic system. One of the main reasons for treatment failure after alloSCT is relapse of the underlying disease, which, in the majority of cases, is associated with a poor prognosis. Adoptive immunotherapy by the use of donor lymphocyte infusions (DLI) was shown to be effective in this setting. However, the conditions and the optimal timing of DLI administration for prophylaxis or treatment of (impending) relapse remains controversial.Patients and Methods: We retrospectively analyzed 160 consecutive patients (median age: 48 (range: 17-69) years) who received DLI after previous alloSCT performed at our center between 1998 and 2014. Indications for alloSCT were: acute myeloid leukemia (AML) (N=68), acute lymphoblastic leukemia (ALL) (N=49), myelodysplastic syndrome/myeloproliferative neoplasia (MDS/MPN) (N=26), or myeloma/lymphoma (N=17). The disease risk index (DRI) was low (N=1), intermediate (N=101), high (N=43), or very high (N=6) (unknown: N=9). Comorbidities, as specified by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), were low (N=38), intermediate (N=79), or high (N=38) (unknown: N=5). In N=71 patients a 10/10 human leukocyte antigen (HLA) matched-related donor was chosen, whereas N=89 patients were transplanted from an unrelated donor, either matched (N=73) or mismatched (N=16). Conditioning was either myeloablative (MAC) (N=71) or reduced-intensity (RIC) (N=89). The median interval from alloSCT to first DLI was 7.1 (range: 1.0-93.2) months. Indication for DLI was prophylactic (e.g. high-risk of relapse or active disease at the time of alloSCT) (N=28), pre-emptive (e.g. persistent or increasing mixed chimerism/molecular relapse) (N=86), or hematologic relapse (N=46). Pre-treatment before DLI was none/cessation of immunosuppression (N=129), lymphodepleting chemotherapy (N=16), or other (N=15). The median number of DLI units given was 2 (range: 1 - 6) and the median cumulative CD3+ cell dose/kg body weight given was 1.1 x 10E7 (range: 5.0 - 16.0 x 10E7).Results: The median follow-up of all patients from day of alloSCT was 37.3 (range: 3.0 - 202.6) months, whereas the median follow-up from day of first DLI administration was 21.2 (range: 0.3 - 200.5) months. Overall survival (OS) of the entire cohort at 1, 3, and 5 years after alloSCT was 80.5%, 63.8%, and 57.7%. Calculated from the day of first DLI OS at the same time points was 68.8%, 61.0%, and 55.8%. At five years after alloSCT OS in the group of patients with AML or ALL was significantly lower as compared to patients with MDS/MPN or myeloma/lymphoma, i.e. 52.0% versus 66.2% (p=0.043). Furthermore, OS in the group of patients receiving pre-emptive DLI was virtually identical to patients who received prophylactic DLI, i.e. 70.4% versus 69.8% at 5 years. In contrast, patients with hematologic relapse prior to DLI had an inferior outcome, i.e. an OS of 23.3% at 5 years. In addition to indication for DLI administration, i.e. prophylactic or pre-emptive versus therapeutic, the occurrence of chronic graft-versus-host disease (cGvHD) was the strongest predictor for outcome, i.e. long-term survival.Conclusions: Taken together, our data indicate that adoptive immunotherapy by the use of DLI is capable of inducing long-term remissions in patients after alloSCT. As pre-emptive and prophylactic treatment yielded virtually identical results, latter may be reserved for selected patients with (very) unfavorable disease characteristics, e.g. AML or ALL with active disease at the time of transplant. The optimal type of pre-treatment needs to be determined by investigating larger patient cohorts. DisclosuresNo relevant conflicts of interest to declare.

Erratum to: Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: a cross-sectional study.

Increasing numbers of patients (up to 40 %) with rheumatoid arthritis (RA) achieve remission, yet it remains to be elucidated whether this also normalizes their cardiovascular risk. Short-term treatment with TNF inhibitors lowers arterial wall inflammation, but not to levels of healthy controls. We investigated whether RA patients in long-term remission are characterized by normalized inflammatory activity of the arterial wall and if this is dependent on type of medication used (TNF-inhibitor versus nonbiological disease-modifying antirheumatic drugs (DMARDs)). Arterial wall inflammation, bone marrow and splenic activity (index of progenitor cell activity) was assessed with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in RA patients in remission (disease activity score (DAS28) 6 months) and healthy controls. We performed ex vivo characterization of monocytes using flow cytometry and a transendothelial migration assay. Overall, arterial wall inflammation was comparable in RA patients (n = 23) in long-term remission and controls (n = 17). However, RA subjects using current anti-TNF therapy (n = 13, disease activity score 1.98[1.8–2.2]) have an almost 1.2-fold higher 18F-FDG uptake in the arterial wall compared to those using DMARDs (but with previous anti-TNF therapy) (n = 10, disease activity score 2.24[1.3–2.5]), which seemed to be predominantly explained by longer duration of their rheumatic disease in a multivariate linear regression analysis. This coincided with increased expression of pro-adhesive (CCR2) and migratory (CD11c, CD18) surface markers on monocytes and a concomitant increased migratory capacity. Finally, we found increased activity in bone marrow and spleen in RA patients using anti-TNF therapy compared to those with DMARDs and controls. A subset of patients with RA in clinical remission have activated monocytes and increased inflammation in the arterial wall, despite the use of potent TNF blocking therapies. In these subjects, RA disease duration was the most important contributor to the level of arterial wall inflammation. This increased inflammatory state implies higher cardiovascular risk in these patients, who thus may require more stringent CV risk management.