Longer Remission Research Articles

Asymmetrical Fc Engineering Greatly Enhances Antibody-dependent Cellular Cytotoxicity (ADCC) Effector Function and Stability of the Modified Antibodies

Antibody-dependent cellular cytotoxicity (ADCC) is mediated through the engagement of the Fc segment of antibodies with Fcγ receptors (FcγRs) on immune cells upon binding of tumor or viral antigen. The co-crystal structure of FcγRIII in complex with Fc revealed that Fc binds to FcγRIII asymmetrically with two Fc chains contacting separate regions of the FcγRIII by utilizing different residues. To fully explore this asymmetrical nature of the Fc-FcγR interaction, we screened more than 9,000 individual clones in Fc heterodimer format in which different mutations were introduced at the same position of two Fc chains using a high throughput competition AlphaLISA® assay. To this end, we have identified a panel of novel Fc variants with significant binding improvement to FcγRIIIA (both Phe-158 and Val-158 allotypes), increased ADCC activity in vitro, and strong tumor growth inhibition in mice xenograft human tumor models. Compared with previously identified Fc variants in conventional IgG format, Fc heterodimers with asymmetrical mutations can achieve similar or superior potency in ADCC-mediated tumor cell killing and demonstrate improved stability in the CH2 domain. Fc heterodimers also allow more selectivity toward activating FcγRIIA than inhibitory FcγRIIB. Afucosylation of Fc variants further increases the affinity of Fc to FcγRIIIA, leading to much higher ADCC activity. The discovery of these Fc variants will potentially open up new opportunities of building the next generation of therapeutic antibodies with enhanced ADCC effector function for the treatment of cancers and infectious diseases.

Evolution of targeted phototherapy for psoriasis

Psoriasis is a major inflammatory disorder in the dermatological field. Phototherapy is effective and safe for psoriasis vulgaris. Narrow-band ultraviolet (UV) B and psoralen plus UVA are known to be the common modality as conventional non-targeted phototherapy. Non-targeted phototherapy making unnecessary irradiation to the unaffected skin may cause long-term adverse effects of UV. Targeted phototherapies with advantages, for example, higher dosages for lesional skin, a rapid clearing and longer remission rates, have been developed. Targeted phototherapies are preferably used for childhood, palmoplantar psoriasis, scalp and nail psoriasis as well as refractory lesions remained after whole-body UV therapy. Light sources of targeted phototherapy include broad-band UVB, narrow-band UVB, 308-nm excimer laser and light, 307-nm excimer light and 312-nm flat-type fluorescent lamp. This comprehensive review focuses recent evolution of target phototherapy for the treatment of psosriasis.

Alloreactive T Cell Clonotypes Identified By In Vitro Mixed Lymphoid Reaction and High-Throughput Sequencing Exhibit Increased Frequency In Peripheral Blood Samples From Patients Following Allogeneic Hematopoietic Cell Transplantation For Chronic Lymphocytic Leukemia

IntroductionAllogeneic hematopoietic cell transplantation (allo-HCT) provides long-term immunologic disease control for a substantial portion of patients with hematologic malignancies. Chronic lymphocytic leukemia (CLL) is sensitive to graft-versus-leukemia (GVL) effects as evidenced by responses to reduced-intensity conditioning (RIC) allo-HCT, and to donor lymphocyte infusions (DLI) for post-HCT relapse. To identify potential alloreactive (AR)/GVL T cells, we performed in vitro mixed lymphocyte reactions (MLRs) between recipient CLL cells and donor T cells derived from blood apheresis products acquired for DLI. Responder and non-responder T cell populations from MLRs and recipient post-HCT blood samples underwent T cell receptor beta (TCRB) high-throughput sequencing (HTS). The prevalence of candidate AR/GVL TCRB clonotypes at various times following HCT was quantified and correlated with CLL disease burden and graft-versus-host disease (GVHD). MethodsCLL cells isolated from cryopreserved PBMC aliquots of 7 patients who experienced post-HCT relapse were pre-stimulated in vitro for 72 hours with CpG oligodeoxynucleotides in X-VIVO 15 supplemented with IL-4, IL-7, BAFF, and GM-CSF. Upregulation of CD80, CD86, CD40L, MHCI, and/or MHCII was confirmed by flow cytometry. Donor T cells were isolated from cryopreserved DLI using pan-T cell isolation beads (Miltenyi), labeled with CFSE, and incubated with CpG-stimulated CLL cells for 7 days. Upon the conclusion of the MLR incubation, T cell populations were sorted into rapid responders (RR; CFSEdim), slow responders (SR; CFSEbrightCD69pos) and non-responders (NR; CFSEbrightCD69neg) and RNA was isolated from each cell population. RNA was then amplified and TCRB sequenced using the LymphoSIGHT platform (Sequenta). PBMC samples collected and cryopreserved pre-HCT and regularly following HCT and DLI were also subjected to TCRB-HTS. ResultsRR cells comprised 11.5 +/- 9.2% of MLR T cells, whereas SR were 4.2 +/- 3.5% and NR were 84.3 +/- 10.1% (Fig 1A). RR, SR, and NR populations demonstrated clonotypic exclusion with a mean 4.4% +/- 5.5% coincidence between populations (Fig 1B). TCRB diversity in the RR population was more restricted compared with diversity in the SR and NR populations, with the mean number of clonotypes comprising the top 50th percentile of total TCRB reads being 11.8 +/- 6.5%, 17.7 +/- 8.5%, and 20.2 +/- 1.8% of unique reads, respectively (p<0.01). Candidate AR/GVL TCRB clonotypes, specified as those enriched in MLR-responder populations compared to pre-stimulation samples, were validated by comparison with pre-stimulation frequency-matched clonotypes. The mean frequency of AR/GVL TCRB clonotypes in blood samples post-HCT were 10- to 100-fold greater than control clonotypes, depending on the patient (Fig 1C). AR/GVL T cells were present within the post-HCT PBMC TCRB repertoires at mean frequencies of 5x10-4 at day +90 rising to 2x10-3 by day +360 post-HCT in 3/4 patients experiencing at least 2 year remissions post-HCT. In patients experiencing early relapse (within 1yr post-HCT), no candidate AR/GVL clonotypes were identified in 1/3 patients and 2/3 exhibited AR/GVL clonotypes at roughly one log lower frequencies (mean 8x10-5 at day +90 and 4x10-4 at day 360) than those with longer remissions (Fig 1D). One patient who experienced fatal post-DLI steroid-refractory GVHD exhibited striking changes in AR/GVL clonotype prevalence following DLI (Fig 1D). [Display omitted] ConclusionsIn vitro MLR between donor T cells and CpG-stimulated CLL cells selects clonotypically distinct T cell populations with an oligoclonal RR population. Persistence of adoptively transferred candidate AR/GVL clones identified by MLR appears to correlate with likelihood of maintaining clinical remission beyond 2 years in CLL patients undergoing RIC allo-HCT. Failure to adoptively transfer AR/GVL clonotypes may be associated with early treatment failure. Disclosures:Klinger:Sequenta, Inc.: Employment, Research Funding. Moorhead:Sequenta, Inc.: Employment, Research Funding. Zheng:Sequenta, Inc.: Employment, Research Funding. Faham:Sequenta Inc.: Employment, Stockholder Other.

Maintenance Therapy with Immunomodulatory Drugs after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials

BackgroundAlthough high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) has been confirmed to result in longer remission time than conventional chemotherapy, multiple myeloma (MM) remains incurable. Post-ASCT maintenance is considered as a strategy for obtaining durable remissions and preventing tumor progression. Randomized controlled trials (RCTs) studying maintenance therapy with immunomodulatory drugs (IMiDs) after ASCT have shown some valuable survival improvements. This meta-analysis of RCTs therefore assesses the effect of post-ASCT IMiDs maintenance on MM patients.MethodsWe performed a meta-analysis to evaluate the impact of IMiDs (thalidomide or lenalidomide) as post-ASCT maintenance therapy on the survival of newly diagnosed MM patients. The outcomes for this meta-analysis were progression-free survival (PFS) and overall survival (OS).ResultsEight RCTs enrolling 3514 patients were included for analysis. An obvious improvement in Os (hazard ratio [HR] 0.75) and a significant PFS advantage (HR 0.58) with post-ASCT IMiDs maintenance was revealed. Thalidomide maintenance after ASCT can result in significant benefit in Os (HR 0.72), particularly combined with corticosteroids (HR 0.66).ConclusionsMM patients after ASCT have a significant overall survival benefit with IMiDs maintenance. IMiDs maintenance was justified for MM patients who received HDT with ASCT.

Pimecrolimus vs. tacrolimus for the topical treatment of unresponsive oral erosive lichen planus: a 8 week randomized double‐blind controlled study

Oral lichen planus (OLP) is a chronic inflammatory disease, affecting nearly 1-2% of the population; Proposed therapies are usually symptomatic and numerous drugs have been used, but recently, it has been published that there is insufficient evidence to support the effectiveness of any specific treatment as being superior. To the best of our knowledge, direct evaluation of the efficacy of topically applied pimecrolimus and tacrolimus in the treatment of atrophic-erosive OLP, refractory to topical steroids, is still lacking. To assess the efficacy and safety of topical calcineurin inhibitors for unresponsive OLP. An 8 week randomized, double-blind controlled trial, followed by a 6 month follow-up period. Patients were treated with either pimecrolimus 1% cream or tacrolimus 0.1% ointment, both mixed with an equivalent amount of 4% hydroxyethyl cellulose gel. The medications were to be applied twice daily for 2 months. Each patient was examined at the beginning of therapy, and then every 2 weeks during the treatment and every 3 months of follow-up. Main outcome measures were: (i) to compare the effectiveness of topically applied pimecrolimus and tacrolimus; (ii) to evaluate which is more cost-effective; (iii) to determine which drug is faster in reducing signs and symptoms and (iv) which gives the longest remission. Thirty patients were involved in the study. Both drugs were effective at inducing clinical improvement, with no statistical difference. Pimecrolimus creams revealed a significantly better stability of the therapeutic effectiveness (P = 0.031). Both medications would currently appear to be a treatment of choice for patients with unresponsive atrophic-erosive OLP. Pimecrolimus seemed to be more effective in providing long-term resolution of signs and symptoms. Future efforts are however needed to obtain more objective evidence of the benefit of these medications in the treatment of immunologically mediated oral mucosal lesion.

Omega 3 fatty acids in psychiatry

Omega-3 long-chain polyunsaturated fatty acids (?-3 LC-PUFAs) are thought to be important for normal dopaminergic, glutamatergic and serotonergic neurotransmission. Depression is less prevalent in societies with high fish consumption, and depressed patients have significantly lower red blood cell ?-3 levels. Studies with ?-3 supplementation have led to controversial results. A significantly longer remission of bipolar symptomatology has been confirmed from a high-dose DHA and EPA mixture. Greater seafood consumption per capita has been connected with a lower prevalence of bipolar spectrum disorders. Reduced levels of ?-6 and ?-3 PUFAs were found in patients with schizophrenia.

The Natural History of Myeloma Patients Who Relapse Early After High Dose Therapy.

AbstractAbstract 3125The median progression free survival (PFS) for younger, fitter patients with multiple myeloma is between 3 and 4 years, however some patients respond very poorly and relapse within a year of autologous transplantation. These patients then go on to receive relapse chemotherapy often with novel agents and, surprisingly, some have a longer remission with second line therapy. The prognostic factors which describe such patients are not well understood, and identifying and treating these patients remains a challenge. To characterise these patients further and describe prognostic markers, we have utilised 2 datasets (1081 patients) comprising 619 patients from the Myeloma IX trial and 462 patients from the Royal Marsden database (RMH). All patients were initially treated with high dose melphalan and peripheral blood stem cell support. Patients were then divided into two groups: early relapse (<12 months from transplant) or late relapse (>12 months after transplant or disease free at last follow up).The Myeloma IX trial consisted of 147 patients (23.7%) in the early relapse group compared to 472 patients (76.3%) in the late relapse group, with a median PFS1 of 7.6 vs. 27.8 months (P<0.001) and OS of 28 vs. 68.8 months (P<0.001), respectively. A similar pattern was seen in the RMH database, where the early relapse group consisted of 86 patients (18.6%) compared to 376 patients (81.4%) in the late relapse group, and with a median PFS of 6.3 vs. 38.6 months (P<0.001) and OS of 31.9 vs. 117.9 months (P<0.001), respectively.In order to describe prognostic factors for early relapse after autologous transplant, we utilized the Myeloma IX dataset, and show that a low Hb, a low platelet count, a low serum albumin, ß2M ≥5.5 mg/L, an ISS Stage III combined with adverse cytogenetics such as t(4;14) and 1q21+ at time of diagnosis predict for an early relapse (<12 months after transplant). In addition, we used Affymetrix gene expression profiling (GEP) to identify significant genes associated with early relapse. A distinct GEP signature containing 38 genes was identified as being associated with early relapse after transplantation, among which 10 genes were on chromosome X.We then used the Royal Marsden dataset to investigate the clinical outcome for patients who relapsed early following second line treatment. To do this, we divided the early relapse group (<12 months from transplant) into two groups: patients with a longer second remission than first remission (47 patients, group A) and patients with a shorter second remission than first remission (39 patients, group B). The median PFS after second line therapy between the two groups was 11.7 vs. 1.8 months (P<0.001) and the median OS was 51.5 vs. 23.0 months (P<0.001), respectively. Univariate analysis showed that a low Hb, a low platelet count, a high ß2M and an ISS stage III at time of second line therapy and no maintenance therapy after second line treatment predicted for a shorter second remission. Failure to achieve a response at the time of first transplant or post second line therapy was highly correlated with a shorter second remission and very aggressive disease outcomes. Multivariate analysis confirmed that failure to achieve a response after second line therapy was the only significant factor correlated with a shorter second remission, and poor survival.Taken together, our data demonstrates that approximately 20% of patients undergoing HDT will have a short remission. High ISS stage, adverse cytogenetics and failure to achieve a response to chemotherapy can be used to identify this group. In addition GEP signature can also identify such patients. About 45% of these early relapse patients will go on to have a very poor outcome, but 55% can be rescued with novel agents. Important aspects to consider in treating these patients are: careful assessment of the bone marrow reserve, the use of a non-cross reacting agent for second line treatment, an early assessment of response to therapy and incorporating novel agent maintenance therapy. Paying attention to these factors will hopefully prolong progression free survival, overall survival and in the end, quality of life in this poor prognosis group. Disclosures:Davies:Celgene, Johnson & Johnson, Onyx, Novartis: Honoraria, Speakers Bureau; Merck: Speakers Bureau.

Stem cell transplantation for multiple myeloma: current and future status

High-dose melphalan with autologous stem cell support has been an integral part of myeloma therapy for more than 25 years either as salvage therapy or as consolidation of an initial remission. Although multiple phase III trials have demonstrated that this therapy results in higher response rates and longer remission duration than conventional chemotherapy the use of thalidomide, lenalidomide and bortezomib as induction therapy have limited the clinical relevance of these trials. In this manuscript, we will summarize the results of ongoing and recently published clinical trials and describe how they have impacted current transplant recommendations, and their relevance to the treatment of myeloma patients in developing countries.

Adoptive Immunotherapy with Cytokine-Induced Killer Cells for Patients with Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Cell Transplantation

Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of exvivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 × 10(7) CD3(+) cells/kg (n = 4), 5 × 10(7) CD3(+) cells/kg (n = 6), and 1 × 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated invitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations.

Hairy cell leukemia: current therapies and future directions

Evaluation of: Zinzani PL, Pellegrini C, Stefoni V et al. Hairy cell leukemia: evaluation of the long-term outcome in 121 patients. Cancer 116(20), 4788–4792 (2010).Hairy cell leukemia is a rare disease for which there are multiple treatment options. Purine nucleoside analogs (cladribine and pentostatin) are generally used for front-line treatment. Other active agents include interferon, rituximab and, although rarely, splenectomy. In the series published by Zinzani et al. in Cancer, the authors conclude that initial treatment for hairy cell leukemia should be maximized since these patients generally enjoy the highest complete response rates and the longest remission durations, and subsequent lines of therapy have lower response rates and more frequent relapses. However, evolving immunohistochemical and molecular diagnostic techniques, as well as criteria for evaluating response to therapy and clinical trials investigating chemoimmunotherapy, may result in clinicians re-evaluating how patients are treated in the front-line and when treatment should be initiated for relapsed patients.

Issues of management of Epidermolysis bullosa in Georgia

As of today there are no radical methods of treatment of epidermolysis bullosa (EB) as well as other genetically determined diseases. This accounts for the acuteness of the problem of providing adequate care for such patients. The Georgian Foundation for Genetic and Rare Diseases (GeRaD), a self-help organisation of people personally affected by rare diseases in Georgia, observed 3 patients, age 1.5, 2, and 3.5 years. The first 2 patients were diagnosed with dystrophic polydysplastic form of EB, while the third one had a simple generalised epydermolytic form. All patients were received in various clinics and with various level of success some pathogenetic (steroids, erythromycin, tocopherol acetate, retinoids), symptomatic, and local treatment. All of them had reached periods of remission of various lengths. It should be noted that the longest remission was achieved, contrary to the opinion of many authoritative dermatologists, as a result of treatment with Phenytoin. The families of the patients, despite notable therapeutic success, faced care and nutrition related problems caused by the lack of information about the disease that affected their children. We tried to solve these problems by addressing the Institute of Dermatology and Venereology. During 6 months in the frame of the activities of the nursing for patients with severe dermatoses the doctors and nurses of the Institute provided free treatment for our patients and information for their parents about actual issues of living with EB (care, nutrition, prevention of opportunistic infections, etc.). According to the parents’ evaluations, the quality of life of their children significantly improved due to our activities. This example of successful collaboration between a State medical institution and an NGO in the sphere of providing care for patients with rare diseases may serve as one of the preconditions for creation of the optimal model of management of rare diseases in Georgia.

Self‐administered, subcutaneous alemtuzumab to treat residual disease in patients with chronic lymphocytic leukemia

Alemtuzumab is highly effective at treating chronic lymphocytic leukemia (CLL) in bone marrow, which is the usual site of residual disease after fludarabine-based treatment. Eliminating residual disease potentially is associated with longer remission and overall survival. The authors of this report evaluated the ability of subcutaneous alemtuzumab to treat residual disease. Patients in partial remission (PR), nodular PR (nPR), or complete remission (CR) who had disease in bone marrow established by 2-color flow cytometry analysis were enrolled and received alemtuzumab 30 mg subcutaneously 3 times weekly for 4 weeks, and patients had the option to self-administer alemtuzumab. Responders were patients in PR who converted to an nPR or a CR, patients in nPR who converted to a CR, and patients in CR who had no evidence of disease on 2-color flow cytometry analysis after treatment. There were 31 patients enrolled, of whom 29 were evaluable, and there were 23 responders (4 of 4 patients who achieved a CR, 8 of 9 patients who achieved an nPR, and 11 of 16 patients who achieved a PR. Nonresponders had significantly lower plasma alemtuzumab levels at the end of treatment. Furthermore, higher plasma alemtuzumab levels at the end of treatment were correlated with a longer response duration. Compared with the results from an historic group that received intravenous alemtuzumab for residual disease, there was a trend toward a higher response rate but a shorter response duration with subcutaneous alemtuzumab. The current results demonstrated that self-administered, subcutaneous alemtuzumab was safe and active for residual disease and that plasma alemtuzumab levels and real-time minimal residual disease evaluation are important endpoints to monitor in future alemtuzumab consolidation trials.

Clinical course of guttate psoriasis: Long‐term follow‐up study

Guttate psoriasis, known to have a better prognosis than other types of psoriasis, shows rapid involution and longer remission, but its clinical course has barely been studied. The aim of this study was to determine the clinical course and to compare the clinical and laboratory features of guttate psoriasis. This is a retrospective study of 26 patients with guttate psoriasis. The patients were divided into two groups; the good one with complete remission and long remission for at least 1 year (group A) and the poor one with incomplete remission and progression into chronic plaque psoriasis (group B). Among 36 patients, 22 patients (61.1%) were group A and 14 patients (38.9%) were group B. In group A, most of the skin lesions disappeared within 8 months. In group B, two patients without proper treatment progressed to plaque psoriasis. The onset age was younger and more frequent upper respiratory infection and high anti-streptolysin O (ASO) titer were found in group A, but family history of psoriasis was more common in group B. Patients had two distingushable clinical courses: rapid involuting course with long-term remission and chronic course without remission. There was a tendency toward younger age of onset with elevated ASO titer in patients with rapid involuting course.

Sustained, Durable Responses with Alemtuzumab in Refractory Angioimmunoblastic T-Cell Lymphoma.

Abstract 2730 Poster Board II-706 Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype representing 2% of Non-Hodgkin's Lymphoma characterized by lymphadenopathy, hepatosplenomegaly, anemia, hypergammaglobulinemia and immune dysfunction. Prognosis is poor with a median survival of less than 36 months. There is no standard treatment for AITL. Most patients initially respond to treatment, but relapse within short time intervals. Alemtuzumab is a humanized monoclonal antibody that binds to CD52 antigen, a cell surface glycoprotein with high expression on T-cells. We report three patients with refractory AITL, with confirmed T-cell receptor gene rearrangements, who achieved sustained, durable responses with alemtuzumab. The table below lists the treatment regimens, duration of remissions and complications for all 3 cases. Infectious and autoimmune complications were effectively treated in all.PatientPrevious Treatment (Response duration, months)Alemtuzumab (Response duration)InfectionsAutoimmune manifestationsACHOP (10) Cytoxan-P (1) Gemzar-P (1)24 monthsCMVBCHOPE (10) ICE (0) Gemcitabine-P followed by Cyclosporine maintenance (1)&gt;24 monthsAspergillusAgranulocytosis Autoimmune hemolytic anemiaCCHOP (1)&gt;14 monthsCMV Legionella Patient A was a 73 year-old female who presented with lymphadenopathy and biopsy proven AITL. Her longest remission was 10 months following CHOP. She was started on alemtuzumab 30 mg 3 times per week for 4 weeks in June 2007 after relapsing. Her only complication from treatment was CMV infection. She remained in remission until June 2009 when she relapsed in her liver and colon. She was treated with alemtuzumab and prednisone for 2 weeks, but developed neutropenic fever, CMV and died July 2009. Patient B is a 73 year-old male with a history of ITP who presented in July 2005 with fevers, lymphadenopathy and anemia, and biopsy proven AITL. His longest remission was 10 months with CHOPE. In June 2007, the patient was treated with alemtuzumab for 7 weeks after relapsing. Treatment complications included Aspergillus pneumonia, agranulocytosis and autoimmune hemolytic anemia. He achieved a complete response as evidenced by PET/CT scan. He remains in remission 2 years later. Patient C is a 62 year-old woman with a history of MGUS who presented in 2007 with rapidly growing lymphadenopathy and a biopsy that revealed AITL. She never achieved a sustained remission with chemotherapy. June 2008, the patient was treated with alemtuzumab for 6 weeks, complicated by CMV and Legionella pneumonia. She remains in remission now over 14 months. Here we have shown remarkable success with short courses of alemtuzumab. Three patients remained disease free for an average of 21 months; two remissions are on-going. This report demonstrates sustained responses for patients with AITL, suggesting that alemtuzumab is a valid and rational treatment choice in heavily pretreated patients. We propose using anti-CD52 therapy as consolidation after primary response to conventional chemotherapy in patients with AITL. Disclosures: Off Label Use: Alemtuzumab is not licensed for use in Angioimmunoblastic T-cell Lymphoma.

Topical clobetasol in the treatment of atrophic‐erosive oral lichen planus: a randomized controlled trial to compare two preparations with different concentrations

Oral lichen planus (OLP) is a chronic inflammatory disease that can be painful, mainly in the atrophic and erosive forms. Numerous drugs have been used with dissimilar results, but most treatments are empirical and do not have adequate control groups or correct study designs. However, to date, the most commonly employed and useful agents for the treatment of LP are topical corticosteroids. A randomized, double-blind, placebo-controlled trial has been designed to compare the efficacy and safety of two different formulations of clobetasol, a very potent topical steroid, in the topical management of OLP and to evaluate which gives the longest remission from signs and symptoms. Thirty-five consecutive patients were divided into two groups: the first received clobetasol propionate 0.025% and the second was given clobetasol propionate 0.05%. Both drugs were placed in 4% hydroxyethyl cellulose bioadhesive gel. Anti-mycotic prophylaxis was also added. After the end of therapy, patients received a 2-month follow-up. In all, 14 of the 15 clobetasol 0.025% patients (93%) and 13 of the 15 clobetasol 0.05% patients (87%), had symptoms improvement after 2 months of therapy (P = 0.001 in both groups). Also, 13 of the 15 clobetasol 0.025% patients (87%) and 11 of the 15 clobetasol 0.05% patients (73%) had clinical improvement after 2 months of therapy (P < 0.05 in both groups). No statistical differences were found in comparing the two different formulations. A larger concentration of the active molecules cannot further improve the therapeutic findings or optimize the obtained results in a significant manner.

Advances in the treatment of metastatic colorectal carcinoma

Background. In most cases, metastatic colorectal cancer is incurable; however, the prognosis and survival of these patients have significantly improved in the last 6 years. A few years back, the only efficient drug for colorectal carcinoma, 5-fluoruracil, yielded the mean survival of 10 months, whereas today, the survival rates of 20 months or more may be obtained by using new cytostatics. In the last six years, five new drugs were registered for the treatment of metastatic colorectal cancer. These are three cytostatics (capecitabine, irinotecan, oxaliplatin) and two target drugs (cetuximab and bevacizumab). Conclusions. A combined treatment assures a better quality of life, and longer remissions and overall survival. The combination of cytostatics and target drugs improves particularly the mean survival rate, which may be longer than 30 months. These combinations of drugs used together with surgical treatment of lung and liver metastases may result in complete remission. An important research achievement of this year is the determination of KRAS mutations. The KRAS gene is the first biomarker that predicts how well patients will respond to certain combination of treatment.

The Duration of Clinical Remission of Photochemotherapy and Narrow-Band UV-B Phototherapy in the Treatment of Psoriasis: A Retrospective Study

PUVA and UVB-NB phototherapy have an established role in the treatment of moderate-to-severe psoriasis. Even though psoriasis patients often require continuous treatments, inadequate attention is devoted to the duration of remission after the treatment. The purpose of this retrospective study is to assess which phototherapeutic regimen induces a longer remission. Twenty patients with psoriasis were included: 10 patients received PUVA and 10 patients received UVB-NB. We consider as a cycle the therapeutic period needed to reach clinical remission. The comparison between the average number of days in remission revealed that PUVA induces a longer remission period than UVB-NB: PUVA 386 days (ds +/- 321), UVB-NB 298 days (ds +/- 257). Although the difference of the duration of remission is not statistically significant, a trend is seen and patients treated with PUVA remain clear for a period about 88 days longer than that of patients treated with UVB-NB. The differences in the duration of remission of psoriasis therapies must be considered in planning a patients course of treatment.

Mit der HIV-Infektion assoziierte maligne Lymphome

The course of disease in 119 HIV-infected patients (117 men, 2 women; median age 38.5 years) with malignant tumours other than Kaposi's sarcoma was analyzed in a multi-centre retrospective study. This was conducted to obtain initial information concerning the incidence, clinical features and results of therapy in HIV-associated neoplasms, especially malignant lymphomas. The most frequent tumour was malignant non-Hodgkin's lymphoma (98 patients, 82.5%), seven patients had Hodgkin's disease, five had solid tumours, four a polyclonal lymphoproliferative syndrome, three an acute lymphocytic leukaemia, and two had other lymphoproliferative diseases. 58% of the non-Hodgkin's lymphomas occurred in patients with marked immunodeficiency, 85% were high grade malignancies and 47% had primary extranodal disease. 56% of primary nodal lymphomas also had visceral spread (Stage IV). Lymphoblastic non-Hodgkin's lymphoma was more common in patients with favourable immunological status, presented less frequently with primary extranodal disease, was diagnosed earlier than other non-Hodgkin's lymphomas, and appeared to carry a better prognosis. 78 out of the 98 patients with non-Hodgkin's lymphoma had been treated, 66 with cytotoxics. The median survival time was 6 months. Longer remission periods, of at least 12 months, were seen in ten of the 78 patients (13%). Despite the overall poor prognosis and the pre-existing immune defect, palliative (chemo-)therapeutic measures are both justified and promising, and may also result in life-prolonging remissions.

Repeat Treatment with Iodine-131-Rituximab Is Safe and Effective in Patients with Relapsed Indolent B-Cell Non-Hodgkin Lymphoma (NHL) Who Had Previously Responded to This Therapy.

Aims. A recent multi-center phase II trial of I131 rituximab treatment for patients (pts) with relapsed or refractory indolent B-cell NHL demonstrated an overall response rate (ORR) of 76%, with 53% attaining a complete response (CR) or CR unconfirmed (CRu). Small series suggest re-treatment with murine anti-CD20 radio-immunotherapy (Bexxarä, Zevalinä) may be safe and effective. Humanized antibodies have a longer half-life than murine antibodies, potentially prolonging bone marrow radio-isotope exposure, potentially leading to cumulative myelo-suppression on re-treatment. We therefore retrospectively analysed data from two institutions on the safety and efficacy of re-treatment with 131I-rituximab in pts with relapsed or refractory indolent CD20 positive B-cell NHL.Methods. All pts who had been treated with two or more episodes of 131I-rituximab were identified from the institutional databases from January 2000 to July 2007. Pts received two unlabeled doses of rituximab 375mg/m2 and individualized 131-I-rituximab doses estimated to deliver a whole-body radiation absorbed dose of 0.75 Gy. Pts were monitored with weekly full blood counts until 12 wks post-therapy or recovery from nadir levels, and thyroid function was routinely monitored at follow-up visits. Following treatment, the severity and duration of cytopenias was noted, as was the development of myelodysplasia (MDS) and acute myeloid leukemia (AML), as well as elevated thyroid stimulating hormone (TSH) and/or a low free thyroxine (T4). We compared the response duration following first and second treatments and haematological toxicity.Results. Sixteen pts [follicular (15), mantle cell (1)] who had previously responded to RIT were re-treated with I131 rituximab [median inter-treatment interval 19 months (9–54)]. There were no grade 3/4 adverse reactions during re-treatment infusion with 131I-rituximab, and in particular no anaphylaxis occurred. There was an ORR of 88%, with a 56% CR rate and by Kaplan-Meier analysis 36% of all retreated pts were estimated to be progression-free at 12 months. Six pts had longer remissions with the second treatment than their first. The time to progression post second treatment (median 11 months) was not significantly different from the first treatment (median 14 months; P=0.89). Rates of Grade 3/4 hematologic toxicity were neutropenia 29% and thrombocytopenia 27% respectively, and did not differ from first treatment (both 25%). There were no infectious complications requiring hospital admission and only one patient required packed cell transfusion. Three pts have subsequently required thyroxine supplementation, but no cases of thyroid cancer have occurred. AML was diagnosed in one pt at 28 months, although this patient had previously been treated with chlorambucil, and had a mild macrocytosis consistent with an early MDS prior to their first RIT. No cases of MDS were seen.Conclusions. Re-treatment with 131I-rituximab is an efficacious and safe option for pts who have responded previously to 131I-rituximab. Myelo-suppression was unchanged from first exposure. Durable responses may be achieved despite modest TTP following the initial treatment.

Mild-to-moderate ulcerative colitis: your role in patient compliance and health care costs.

Ulcerative colitis (UC) is a chronic relapsing disease necessitating lifelong treatment. Most patients present with mild-to-moderate disease characterized by alternating periods of remission and clinical relapse. Continued disease progression and relapse of UC over time are associated with an increased risk of colorectal cancer (CRC). To discuss the latest treatment options for mild-to-moderate UC, to review the current data involving the economics of UC, and to demonstrate the relationship between treatment adherence, clinical relapse, inflammation severity, CRC risk, and treatment outcomes. One of the main goals of therapy in UC is to induce and maintain a long-lasting remission of disease to reduce or avoid the high personal and financial costs of relapse. In recent studies, researchers have demonstrated a link between increased colonic inflammation and CRC risk, highlighting the importance of preventing relapse, which can lead to costly surgical procedures and hospital stays and thus increase the cost of treatment 2- to 20-fold. The risk of disease relapse is affected by several factors, of which the most prominent is nonadherence to maintenance therapy. Nonadherence to therapy can be associated with several other factors, including forgetfulness, male sex, complicated dosing regimens, treatment delivery methods (oral vs. rectal), and pill burden. In the treatment of mild-to-moderate UC, 5-aminosalicyclic acid (5-ASA) is the standard first-line therapy and the treatment of choice for maintaining remission of disease. Novel formulations of 5-ASA and newly devised high-dose 5-ASA regimens offer more options for the treatment of UC and thus may lead to improved treatment adherence, longer remission, and improved patient well-being. Periods of remission during UC treatment must be aggressively maintained to prevent relapse and decrease the risk of an unfavorable outcome. By controlling the risks and conditions that lead to therapeutic nonadherence and relapse among patients with UC, clinicians can increase the likelihood of long-term remission and ensure favorable long-term outcomes.