ALBERT

Description: Background: A histologic finding of large cell transformation (LCT) in Mycosis fungoides (MF) is often associated with an aggressive clinical course and inferior prognosis (Arulogun et al. Blood 2008). In patients (pts) with advanced MF (stage IIB-IV), LCT has been established as an independent prognostic factor (Scarisbrick et al. JCO 2015). Although CD30 expression is observed more frequently in MF with LCT vs without LCT, a wide range of CD30 expression levels is observed in LCT lesions and the level of expression lacks prognostic value for MF (Vergier et al. Blood. 2000). The ALCANZA study (NCT01578499) demonstrated significantly better rates of objective response lasting ≥4 months (ORR4) (∆43.8%; p

Description: Introduction: MAVORIC was an open-label, multicenter, randomized phase 3 study evaluating the safety and efficacy of mogamulizumab (moga) compared to vorinostat (vori) in patients with mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least one prior course of systemic therapy (NCT01728805). Primary results have been reported (Kim et al. Lancet Oncol 2018) and were based on a data cutoff date of December 31, 2016. The primary endpoint was progression-free survival (PFS); patients in the moga treatment arm experienced significantly longer PFS compared to patients in the vori treatment arm (median 7.7 months vs 3.1 months; p

Description: Previous cytogenetic studies of primary cutaneous T-cell lymphoma (CTCL) were based on limited numbers of patients and seldom showed consistent nonrandom chromosomal abnormalities. In this study, 54 tumor DNA samples from patients with CTCL were analyzed for loss of heterozygosity on 10q. Allelic loss was identified in 10 samples, all of which were from the 44 patients with mycosis fungoides (10/44 patients; 23%). Of the patients with allelic loss, 3 were among the 29 patients with early-stage myosis fungoides (T1 or T2) (3/29 patients; 10%), whereas the other 7 were among the 15 patients with advanced cutaneous disease (T3 or T4) (7/15 patients; 47%). The overlapping region of deletion was between 10q23 and 10q24. In addition, microsatellite instability (MSI) was present in 13 of the 54 samples (24%), 12 from patients with mycosis fungoides and 1 from a patient with Sezary syndrome. There was also an association between MSI and disease progression in patients with mycosis fungoides, with 6 of 15 (40%) patients with MSI having advanced cutaneous disease and only 6 of 29 (21%) having early-stage disease. Samples with allelic loss on 10q were analyzed for abnormalities of the tumor suppressor genePTEN (10q23.3). No tumor-specific mutations were detected, but homozygous deletion was found in 2 patients. Thus, we found loss of heterozygosity on 10q and MSI in advanced cutaneous stages of mycosis fungoides. These findings indicate that a tumor suppressor gene or genes in this region may be associated with disease progression. Furthermore, abnormalities of PTEN may be important in the pathogenesis of mycosis fungoides, but our data imply that this gene is rarely inactivated by small deletions or point mutations.

Description: Erythrodermic cutaneous T-cell lymphoma (CTCL) includes patients with erythrodermic mycosis fungoides who may or may not exhibit blood involvement and Sézary syndrome and in whom hematological involvement is, by definition, present at diagnosis. These patients were stratified into 5 hematologic stages (H0-H4) by measuring blood tumor burden, and these data were correlated with survival. The study identified 57 patients: 3 had no evidence of hematologic involvement (H0), 8 had a peripheral blood T-cell clone detected by polymerase chain reaction (PCR) analysis of the T-cell receptor gene and less than 5% Sézary cells on peripheral blood smear (H1), and 14 had either a T-cell clone detected by Southern blot analysis or PCR positivity with more than 5% circulating Sézary cells (H2). Twenty-four patients had absolute Sézary counts of more than 1 × 109 cells per liter (H3), and 8 patients had counts in excess of 10 × 109 cells per liter (H4). The disease-specific death rate was higher with increasing hematologic stage, after correcting for age at diagnosis. A univariate analysis of 30 patients with defined lymph node stage found hematologic stage (P = .045) and lymph node stage (P = .013) but not age (P = .136) to be poor prognostic indicators of survival. Multivariate analysis identified only lymph node stage to be prognostically important, although likelihood ratio tests indicated that hematologic stage provides additional information (P = .035). Increasing tumor burden in blood and lymph nodes of patients with erythrodermic CTCL was associated with a worse prognosis.The data imply that a hematologic staging system could complement existing tumor-node-metastasis staging criteria in erythrodermic CTCL.

Description: Abstract 3452 Extracorporeal photopheresis (ECP) has become a recognised treatment for steroid refractory chronic Graft versus Host Disease (cGvHD) but the optimal frequency and duration of treatment has yet to be established. We report on a large cohort of 75 patients who commenced ECP treatment for cGvHD from 01/01/2005 to 31/12/2009 at St Thomas' Hospital, London. Patients were initially treated with a bimonthly regimen of 2 ECP treatments on consecutive days (one cycle) which was subsequently tapered to a monthly regimen depending on response. Patients were reviewed pre-treatment and at 3 monthly intervals. Immunosuppression was tapered at the discretion of the referring transplant centre. Data were collected from the unit's GvHD database which had ethical approval. The median age of patients at time of commencing ECP was 43 years (16-67 years). 30 were female and 45 were male. Patients had undergone allogeneic transplant (22 – unrelated donor, 53 – sibling/related donor) at 13 referral centres. Underlying diagnoses were acute leukaemia (31), lymphoma (16), chronic leukaemias (16), myeloma (6) and other (6). The median time from transplant to commencing ECP was 2 years (6 months to 10 years). 16 patients had developed GvHD following donor lymphocyte infusion. 27 had denovo cGvHD and 18 had progressive disease. 72 patients had cutaneous disease. 38 had sclerodermoid disease and 32 had lichenoid disease (1 - both types, 1 - unknown). 37 patients had oral disease. Other organs involved included liver (17), eyes (12), gut (4), tongue (1), joint (1), genitalia (1). 29 had one organ involved, 26 had two, 17 had three and 3 had four organs involved. At the start of ECP, 64 patients were on immunosuppressive drugs (prednisolone – 56, cyclosporine – 36, mycophenolate mofetil – 26 and other (tacrolimus, rituximab, azathioprine, pentostatin, methotrexate) – 18). 10 patients were on a single agent, 38 were on 2, 14 were on 3 and 2 were on 4 agents. The median dose of prednisolone was 25mg (5mg-135mg). 52 patients had completed ECP at time of analysis. 23 were receiving ongoing treatment but had received at least 6 months of ECP. The median duration of treatment in those that had completed ECP was 330 days (42-987). The median number of ECP cycles received was 15 (1.5-32 cycles). 46 patients had reduced the frequency of ECP to monthly. The median time to reduction in treatment was 206 days (74-571 days). Reduction of immunosuppression at 6 months was used as a global measure of response to ECP as many patients had multiorgan involvement and response in organs may vary. Assessment of cGVHD symptoms and signs was also documented in 62/75 patients. 51 patients had a partial improvement, 8 patients had a complete improvement and 3 patients had no improvement. 49/64 patients on immunosuppression were reassessed and 37/49 (76%) had a dose reduction. 37/45 (82%) had decreased their steroid dose (10 stopped completely and 18 had ≥ 50% reduction). 3 patients' doses were stable and 5 had increased. The median dose was 10mg (3-30mg). 4 patients on other immunosuppressive drugs remained on a stable dose. The remaining patients had died (5), completed 〈 6 months treatment (6) or dosage data were missing (4). Of the 11 patients not on immunosuppression at start of ECP, 3 had recommenced steroids and 8 remained on no systemic immunosuppression. All patients were included in the survival analysis including those who had completed 〈 6 months of treatment. Overall survival at 2.5 years from the start of ECP was 73%. This study reports the largest series of patients receiving bimonthly ECP treatment for cGvHD. We confirm that ECP is highly effective in steroid refractory chronic cGvHD with 76% of patients successfully reducing immunosuppression within 6 months. Further randomised studies are required to assess the optimal ECP treatment schedule and to rationalise the reduction in immunosuppression. Disclosures: Dignan: Therakos (Johnson and Johnson): Honoraria, Research Funding. Off Label Use: The extracorporeal administration of UVADEX (methoxsalen) sterile solution was used with the THERAKOS UVARXTS system in this study for the treatment of patients with chronic graft versus host disease. Scarisbrick:Therakos (Johnson and Johnson): Honoraria, Speakers Bureau.

Description: Background Cutaneous T cell lymphoma (CTCL) is a chronic disease that negatively impacts quality of life (QoL) and, in advanced stages, has poor prognosis. Current systemic therapies rarely provide reliable and durable responses, and to date, no systemic agent has shown outcomes superior to standard-of-care therapy such as methotrexate (MTX) or bexarotene (Bex). CD30-directed antibody-drug conjugate brentuximab vedotin (BV) has demonstrated marked clinical activity in two phase 2 single-arm trials in CTCL with overall response rates (ORR) of about 70%. These results led to ALCANZA, a randomized, open-label, multicenter phase 3 trial of the efficacy and safety of BV vs physician's choice (PC) of MTX or Bex, in previously treated patients with CD30-expressing CTCL (NCT01578499). This is the first reported randomized phase 3 trial testing a new agent against standard-of-care therapy in CTCL. Methods Adults with CD30-expressing (≥10% of infiltrate by central review) mycosis fungoides (MF) who received ≥1 prior systemic therapy or primary cutaneous anaplastic large cell lymphoma (pcALCL) who received ≥1 prior systemic therapy or radiotherapy were enrolled. Patients were stratified by diagnosis and randomized 1:1 to receive BV 1.8 mg/kg IV, once every 3 weeks, or PC of either MTX 5-50 mg PO, once weekly, or Bex 300 mg/m² (target dose) PO, once daily, for up to 16 three-week cycles, until disease progression or unacceptable toxicity. Primary endpoint was ORR4, defined as ORR lasting ≥4 months, an endpoint that captures response rate and duration as a single measurement. ORR4 was determined by independent review of global response using the ISCL/EORTC consensus guidelines. Global response is a composite of skin evaluation (modified severity weighted assessment tool), radiographic assessment, and Sézary cell enumeration. Key secondary endpoints were CR rate, PFS, and symptom burden measured by the symptom domain of the Skindex-29 QoL tool. Sample size was calculated to provide 90% power to detect a 30% improvement in ORR4. Treatment-emergent adverse events (AEs) were evaluated according to NCI CTCAE v4.03. Results 131 patients were randomized with 128 patients in the intent-to-treat population (97 MF, 31 pcALCL; 3 excluded for insufficient CD30 expression) and assigned to BV (n=64) or PC (n=64). Baseline characteristics were generally balanced between arms with the exception of more patients with extracutaneous disease in the BV arm (Table). In BV vs PC arms, respectively, median age was 62 (22-83) vs 58 (22-83) years; ECOG performance status 0-1 was 95% vs 97%. Patients in each arm had a median of 2 prior systemic therapies. At a median follow-up of 17.5 months, ORR4 (primary endpoint) and PFS strongly favored BV vs PC with ORR4 of 56% vs 13% (p

Description: Background: Cutaneous T cell lymphoma (CTCL) is a rare/orphan disease. Mycosis fungoides (MF) and Sézary syndrome (SS) are the major subtypes. Most patients with MF present in early stages (IA-IIA) with a good prognosis. However a third present in advanced stages (IIB-IVB) with a median survival of 1-5yrs. Clinical management is stage-based; however there is wide range of outcome within clinical stages. Currently, we lack evidence based prognostic information for further stratification that can optimize clinical management or be applied in therapeutic trials. Published prognostic studies in MF/SS have largely been single centre. A retrospective study from the UK & a US site proposed a potential prognostic model for MF/SS (Benton et al Eur J Cancer 2013;49:2859-68) but is limited in power and lacking standardised definitions. Due to the small numbers of patients presenting with advanced stage disease only a large collaboration would power a study to determine prognostic parameters with international relevance. Towards this aim, we have established an international collaborative alliance, the Cutaneous Lymphoma International Consortium (CLIC), to acts as an efficient conduit where well-defined parameters and end-points are used to design studies. This retrospective CLIC study tests selected prognostic parameters against survival in advanced stages of MF/SS in order to determine power and identify prognostic markers that impact globally and may be used in future prospective studies to establish an international prognostic index. Methods: We reviewed the literature of prognostic markers in MF/SS and identified 11 candidate clinical, pathological, and laboratory parameters; 1) stage, 2) age, 3) male sex, 4) modified skin weighted assessment tool score (MSWAT), histological features of 5) folliculotropism, 6) CD30 positivity, 7) proliferation index (%Ki-67 staining) & 8) large cell transformation(LCT), 9) leucocyte/lymphocyte count, 10) LDH & 11) identical T-cell clone in blood & skin. Data were collected on patients presenting with advanced stages of MF/SS (IIB-IVB) diagnosed after the new staging system [Olsen et al. Blood. 2007;110:1713-22]. Results: Twenty-five international sites (16 EU, 6 US, 1 Australian, 1 Asian, 1 South American) identified 1249 MF/SS patients presenting with advanced stage disease since 2007. Patients with complete staging and outcome data (91% 1147 patients) were included in the analyses. MSWAT was not tested due to incompleteness of data (26%). Data completeness for the other 9 prognostic variables ranged from 38-100%. Median survival for this advanced stage cohort was 65 months with 2 and 5 year survival of 79% and 53%, respectively. The median survival for Stage IIB and III was not reached (restricted mean survival was 63 months in both stage IIB & III), median survival for stage IVA was 47 months and 44 months in stage IVB (Fig 1). In univariate analysis 4/9 variables were significantly associated with decreased survival including age〉60 years (data 100% complete, p60, LDH & LCT were associated with a worse survival in stage IIB, in stage III only age & LDH and in stage IVA LDH & a raised leucocyte count were significant. Conclusion: This study has proven the ability of the CLIC to work cohesively, as the first large-scale international collaboration in CTCL. The current staging system shows similar survival in stage IIB and III disease (Fig 1) highlighting the need for further refinement within these stages. Our analysis found age〉60yrs & LDH are independent prognostic parameters with potential relevance in advanced stages of MF/SS. This study has highlighted the need for prospective data collection due the intrinsic flaws of retrospective analysis including missing data, lack of standard definitions rendering some data unusable and potential bias in more complete data in aggressive subtypes. Future prospective studies with well-defined criteria and more complete data collection will be required to better identify parameters of prognostic significance and to test their utility towards building a prognostic index model. Fig 1 Kaplan Meier Survival Curves According to Stage Fig 1. Kaplan Meier Survival Curves According to Stage Disclosures No relevant conflicts of interest to declare.

Description: Aims: Patients with the cutaneous T-cell lymphoma subtypes mycosis fungoides (MF) and Sézary syndrome (SS) often require multiple lines and types of systemic therapy. The phase 3 MAVORIC study (NCT01728805) showed that mogamulizumab (MOGA), a monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), is superior to vorinostat (VORI) in median progression-free survival (PFS; 7.7 vs 3.1 months, P

Description: Data were analyzed from 23 patients with Sézary syndrome (defined by erythroderma, more than 10% circulating atypical mononuclear cells, and peripheral blood T-cell clone) undergoing monthly extracorporeal photopheresis as the sole therapy for up to 1 year. The cohort showed a significant reduction of skin scores during treatment (P = .001). Thirteen patients (57%) achieved a reduction in skin score greater than 25% from baseline at 3, 6, 9, or 12 months (responders). Reduction in skin score correlated with reduction in the Sézary cell count as a percentage of total white cell count (P = .03). Responders and nonresponders were compared. None of the measured parameters was significantly different between the 2 groups. It was assessed whether any of the baseline parameters predicted outcome. A higher baseline lymphocyte count was significantly associated with a decrease in skin score at 6 months (P 

Description: Donor lymphocyte infusions (DLI) are frequently used following haemopoietic stem cell transplant (HSCT) in patients with a high risk of relapse. Limited data are available on the characteristics of GVHD in this setting. The aim of this study is to investigate the NIH type, severity, treatment and response rates of GVHD following DLI. Consecutive patients receiving DLI at 4 transplantation centres in the UK were identified since 2006. Data were collected retrospectively to include diagnosis, date of transplant, dates and doses of DLI, onset of GVHD, treatment of GVHD, follow up (FU) and outcome. 58 patients were identified having received DLI. The mean age at HSCT was 55yrs (median 45, range 20-70). Haematological malignancies were AML in 22, MDS in 9, CML in 7, myeloma in 5, CLL in 5, NHL in 3 and other in 7. 33 received matched related and 25 unrelated donor transplants. The reason cited for DLI was pre-emptive (mixed chimerism) in 30, therapeutic in 28 (relapse in 18, molecular relapse in 6, cytogenetic abnormality in 3 and consolidation in 1). DLI was given at a mean of 14 months after HSCT (median 7, range 1-65). DLI dose ranged from 1x105–1x107 CD3+ cellskg-1. The number of doses ranged from 1-8, mean 2.3, median 2. 43 patients had GVHD after DLI (acute in 16, chronic in 26 and overlap in1). In aGVHD skin was the most common organ involved in 13/16 patients, followed by liver in 7, and gut in 6. 9/16 had single organ involvement (7 skin only, 2 liver only). 3 patients had skin and gut and 4 skin, gut and liver. In 6 patients this was severe (grade III-IV aGVHD). Of the 27 with cGVHD the most common organ involved in decreasing order was skin (n=20), oral (n=16), liver (n=9), eye (n=6), gut (n=4) and lung (n=1). 9 patients had single organ involvement (skin only in 6, oral 2, eye 1). 12 patients had 2, 2 had 3, 2 had 4 and 2 had five organs involved. 8 patients had cGVHD recorded as severe. The mean time between first DLI doses and development of aGVHD was 2 months (median 1, range 1-5 months) and 5.7months (median 3, range 1-28) in cGVHD. First treatment of aGVHD was oral prednisolone in all 16 patients: first treatment response was CR in 4/16, relapse in 4 and progressive GVHD in 8. 5 died (2 from relapse, 2 from aGVHD and 1 from pneumonia). 5 with progressive GVHD received a 2nd line therapy (ECP in 3, tacrolimus in 1 & MMF in 1). 2 patients had a CR, 1 patient relapsed and died, 1 has ongoing mild GVHD and the other had 3rd line therapy with ECP and a PR. The 1st treatment in cGVHD was oral prednisolone in 16/27 (prednisolone alone in 12, plus CyA in 2, tacrolimus in 1, MMF in 1). 9 received topical steroids only, 1 received MMF and 1 rituximab. 16/27 patients had a CR to first line therapy, 1 died of severe lung GVHD and 1 relapsed. 9 received a 2nd line therapy (ECP in 4, MMF in 3, imatinib in 1 and infliximab in 1). 1 had CR, 7 had PR and 1 relapsed. 4 had a 3rd line therapy (ECP in 2 and MMF in 2) of which 1 had CR and 3 PR. I further patient had a 4th therapy with ECP and a PR. Of 8 patients with severe cGVHD 1 had 1 therapy (and died), 4 had 2, 2 had 3 and 1 had 4 therapies: 7/8 are alive, 4 in remission with GVHD, 2 in remission without GVHD and 1 relapsed. Mean FU for cohort is 51.7 months (median 45, range 5-124) post HSCT. 35 are in remission, 11 of whom are receiving treatment for GVHD (4 with severe cGVHD). 18 patients relapsed (7 are receiving treatment and 11 died). In total 16/58 died and causes were relapse (11), severe GVHD (3, 2x aGVHD,1x cGVHD), ruptured aortic aneurysm (1) and pneumonia (1). 7/30 (23%) patients receiving DLI for mixed chimerism died compared to 9/18 (50%) receiving DLI for relapse. Overall survival in those developing aGVHD and cGVHD was 63% and 74% respectively compared to 12/15 (80%) in those without GVHD. Death from relapse was similar in those with and without GVHD post DLI at 20% and 26% respectively and death rates in those with severe GVHD do not appear higher. We report on 58 patients receiving DLI after HSCT. 74% developed GVHD which was severe in 24%. In the majority of patients developing GVHD after DLI successful treatment may be achieved with increased immunosuppression. 39% of patients received second line therapy for GVHD most commonly ECP. 21% received a third line therapy. 16/58 patients have died (28%) including 3 (5%) of GVHD. The most common cause of death was relapse in 19%. In summary patients develop both aGVHD and cGVHD post DLI and may require consecutive therapies but mortality from GVHD is infrequent. Disclosures: No relevant conflicts of interest to declare.