ALBERT

Description: Introduction: Histone deacetylase inhibitors (HDACis) have demonstrated clinical efficacy in multiple myeloma, particularly in combination with proteasome inhibitors. CHR-3996 is a class 1 selective HDACi with potent anti-myeloma activity in vitro. Aminopeptidase inhibitors act downstream of the proteasome and prevent breakdown of proteasome generated peptides into amino acids. Synergistic cytotoxicity was observed in vitro when CHR-3996 was combined with the aminopeptidase inhibitor, tosedostat through rapid activation of NFkB followed by increased expression of the repressors IκBα, A20, CYLD, BIRC3. The MUK-three study was designed to translate these pre-clinical findings into a phase 1 clinical trial. This dose escalation study aimed to determine the maximum tolerated dose, safety and preliminary activity of CHR-3996 administered in combination with Tosedostat for patients with relapsed, refractory MM. Here we present the final study results. Methods: MUK-three was an open label multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had failed conventional treatments. Patients were permitted to meet the haematological entry criteria using growth factor and/or blood product support. During dose escalation subjects received CHR-3996 (20-40mg days1-28) and Tosedostat (0-60mg days 1-28) (Table 1) every 28 day cycle until disease progression or withdrawal. Dose limiting toxicities (DLTs) were evaluated during cycle 1 and dose escalation followed the 3+3 design. Responses were assessed using modified IMWG uniform response criteria, with the primary endpoint for the expansion phase of stable disease (SD) rate after 4 cycles of therapy. Toxicity was graded by CTCAE V4.0. Results: The trial was open to recruitment from July 2012 to December 2015. 20 patients were treated during dose escalation, including 8 at the recommended dose (RD) and 12 at dose levels (DL) 1-3. Only 1 DLT was observed at DL3 (grade 4 thrombocytopenia); however, this DL was deemed not tolerable due to the high incidence of low grade gastrointestinal toxicities. Hence the RD was determined as DL3b, CHR-3996 20mg and Tosedostat 60mg. A further 2 patients were treated at RD during dose expansion to make the required 10 patients for the protocol defined initial analysis at which point the trial closed. At the RD (n=10) median age was 63 years (range 47-73). 80% of patients had received at least 4 prior lines of therapy (median 4, range 2-9); 50% were ISS II, 30% ISS III; 4/6 patients with evaluable FISH data had 1q gain. The median time from diagnosis to treatment for the overall population was 85.3 months (27.5-198.8). The median number of cycles received was 2.5 (range 2-8) and 2 patients remain on treatment with 8 stopped due to disease progression. The 2 patients ongoing (received 5 & 9 prior lines) had their schedule adjusted to a 5 day a week dosing to further improve tolerability. Both had a clinical response (1MR, 1PR) and remained progression free at 6 months. 3/10 patients had SD after 4 cycles, the overall response rate (≥PR) was 1/10(10%) and the clinical benefit rate (≥MR) 2/10 (20%). Overall outcomes were: PR 10%, MR 10%, and SD 30%. Median time to maximum response was 1.84 months (95% CI [1.09, 8.65]). Toxicities at the RD were manageable, 30% of patients required a dose reduction. 22 serious adverse events were reported in 16 patients across all doses, mainly infections (10/22, 45.5%). The commonest grade 3-4 toxicities reported for all 22 patients were: platelet count decrease (12, 54.5%), white blood cell decreased (6, 27.2%), diarrhoea (5, 22.7%). The most frequent grade 1-2 toxicities were fatigue (15, 68.2%), nausea (14, 63.3 %), anorexia (14, 63.6%), anaemia (13, 59.1%). 1 patient withdrew due to toxicity, and there were no treatment related deaths. Conclusions: This study demonstrated that the novel combination of CHR-3996 and tosedostat was safe and tolerable in multiply relapsed, refractory myeloma patients many of which had poor bone marrow function. The recommended dose of the combination was 20mg and 60mg, respectively. Following further adjustment to an intermittent 5 day/ week dosing schedule, treatment was well tolerated and clinical benefit observed. This suggests that further evaluation of this novel combination is warranted. Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 24989786. Disclosures Williams: Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Description: BACKGROUND: With new chelation regimes such as deferasirox, there has been interest in their effects on serum creatinine, as about one third of patients show a small non-progressive increase within a few weeks of starting treatment. A question arises as to whether creatinine increases occur with other modalities of chelation therapy. The effects of deferoxamine (DFO) on serum creatinine have not been widely studied, particularly when intensive chelation regimes are used with 24 hour (h) exposure. Intensified 24h DFO for patients with high risk iron overload has been in use for selected patients for over 20 years. However, whilst factors leading to retinal and ototoxicity are well described, effects on serum creatinine are largely confined to case reports. We postulated that small increments in serum creatinine might be an inevitable effect of treatment intensification. We therefore undertook retrospectively to examine the effects on serum creatinine in patients in whom standard DFO therapy (40mg/kg as 8–10h infusions 5 days/ week) was switched to an intensive DFO monotherapy regime with 24h/day therapy. PATIENTS AND METHODS: We examined the records of 10 patients with transfusion dependent thalassaemia attending the haematology department at University College London Hospitals, between 1989 and 2008, who required an intensification of their DFO regime as a result of failure to control their iron burden with their existing regime. Nine out of the 10 patients required portacath insertion for their DFO to be delivered intravenously, the tenth patient was switched to subcutaneous DFO administered 24h/ day. The patient characteristics were as follows: 8 male and 2 female. Two had thalassaemia intermedia and the rest had thalassaemia major. Those with a portacath were commenced on warfarin as thromboprophylaxis for the portacath. Co-morbidities for the patients included splenectomy (2); diabetes (2); cardiac failure (3); arrhythmias (2). The mean dose of deferoxamine administered was 52mg/kg/24h (9 of the patients had doses between 35–60 mg/kg/24h and only 1 patient had a dose of 100 mg/kg/24h). RESULTS: The results of the study revealed a mean ferritin of 6113.2μg/L ± 1681.3 and 3910.5μg/L ± 1438.4 pre and post intensification of DFO respectively. Of the 10 patients, 6 of them displayed an increase in creatinine of over 25% of their original level on standard DFO, the other 4 also had an increase albeit a more modest one. The increase in creatinine did not correlate with the dose of DFO given. The creatinine pre-intensification showed a mean of 62.3μmol/L ± 10.19 and post intensification showed 92.3μmol/L ± 11.17. This was a statistically significant difference with a p value of 0.0016 using a paired student t test. No patient went on to develop progressive renal dysfunction and creatinine returned to baseline in all patients when the regime returned to standard therapy. CONCLUSIONS: We conclude that intensification of DFO using 24h chelation results in small increments in serum creatinine, even when doses are as low as 40–70mg/kg. The findings suggest that increments in creatinine with chelation therapy are more frequent than hitherto recognised and may be a general effect of continuous chelation therapy. These changes were reversible on returning to original intermittent DFO. While none of these patients developed permanent changes, we propose that patients who are commenced on DFO, especially at continuous intensified doses, should have their creatinine measured on a regular basis, and caution should be employed with those patients who have borderline high creatinine.

Description: DNMT3A mutations (DNMT3AMUT) are recurrent in AML. They predominate in patients with intermediate-risk (IR) cytogenetics and are often co-incident with FLT3ITD and NPM1MUT. Their prognostic impact is unclear. Most reports suggest they are associated with a worse outcome, but a large study including 1060 younger adult IR patients found that DNMT3AMUT had no significant impact on survival endpoints. Variable results have also been reported for different FLT3/NPM1 subgroups. Missense mutations at R882 in exon 23 occur in ≈65% of patients, but other missense and truncation mutations occur throughout the gene, mainly in exons 13-23. There is limited information on the prognostic impact of the different mutations, although they may have differing functional consequences. We therefore screened exons 13-23 in DNA samples from 914 younger adult AML patients (median age 43 years) with IR cytogenetics treated on UK MRC trials and evaluated outcome according to type of DNMT3Amutation. Overall, 278 mutations were detected in 272 (30%) patients; 175 (64%) had R882 missense mutations, 59 (22%) other missense mutations, 35 (13%) truncations or in-frame deletions; 3 (1%) had 2 mutations of differing types. Median R882 mutant level in 172 mutated cases was 47% (range 15-85%), consistent with a heterozygous mutation in most cells. Patients with DNMT3AMUT were significantly older than those with DNMT3A wild-type (DNMT3AWT) (P

Description: Introduction: The optimal management of relapsed/refractory lymphoma is a significant clinical challenge. Early phase clinical trials are primarily designed to assess safety but also represent options for patients with limited therapeutic choices. Outcomes for lymphoma patients on early phase trials have previously been reported as single centre cohorts or grouped analyses with other malignancies. We performed a novel meta-analysis of publically available reports of early phase trials in lymphoma and compared the outcomes with those from our early phase trials unit. Methods: The outcomes of lymphoma patients enrolled on early phase trials at a UK tertiary centre were reviewed. AEs were graded according to CTCAE v4.0 and response criteria evaluated per protocol. Patient and therapy characteristics, AEs and best clinical responses were summarised by descriptive statistics. Individual-patient survival data were analysed using Kaplan-Meier method and survival curves compared with the log-rank test. A systematic literature review was performed using EMBASE, MEDLINE and clinicaltrials.gov to identify publicly available reports of early phase clinical trials reported in 2016-2017 and data was extracted by two independent reviewers. Meta-analyses of ORRs were performed using random-effect models. Results: 50 patients were enrolled onto 9 Phase I and I/II trials between March 2012 and June 2018, Four patients participated in 2 trials, considered separate events. 5 IMPs were small molecular inhibitors, 4 immunotherapies, 4 first in human and 8 investigated as monotherapy. Diagnoses included 42 aggressive NHL (aNHL) [30 DLBCL, 3 PMBCL, 3 Richters, 1 MCL, 5 T cell], 10 indolent NHL (5 WM, 2 FL, 2 MZL, 1 CLL/SLL) and 2 HL. Median age was 54 yr (27-83), 72% male, with a median time from diagnosis of 22.5 months and median 3 prior lines of therapy (range 1-8). Patients received a median number of 2 cycles of IMP (range 1-28) over 57.5 days (IQR: 37-116). 42.6% experienced grade 3-4 toxicity and 31.5% required dose interruptions of 〉7 days. ORR and clinical benefit rate (≥SD) were 28% and 47% respectively (CR 4%, PR 24%, SD 19%). Patients were followed up for a median of 11.4 months. Median PFS and OS were 2.3 and 6.8 months respectively, with PFS and OS at 3, 6 and 12 months being 45.8%, 34.4%, 26.5% and 58.4%, 45.4% and 38.8%. Median OS was greater for those who received

Description: Background Waldenström's macroglobulinaemia (WM) is a rare non-Hodgkin B cell lymphoma. Given its rarity, information about both patient demographics and disease characteristics are limited. Treatment is indicated for symptomatic patients and treatment regimens have evolved significantly in recent years. The Rory Morrison Registry (RMR) has comprehensive patient data available for analysis. We seek to draw conclusions about UK patient demographics and disease characteristics, and evaluate how treatment practices have evolved. Methods The RMR was searched for all patients with a diagnosis of WM. Patient demographics, disease characteristic, pathology results, treatment information and survival status retrieved. Kaplan Meier and log rank analysis was performed. Results 671 patients were identified from 19 different UK centres. Median age at diagnosis was 64 years (range 27-92, figure 1). Year of diagnosis ranged from 1978 to 2019, with 7 patients diagnosed

Description: Introduction: Phase I clinical trials are primarily designed to assess the safety and toxicity of a new agent and determine the recommended dose. Such trials are challenging as patients typically have multiply relapsed/ refractory disease and have received all standard therapies. Many have a poor prognosis and would otherwise receive supportive/ palliative treatment. However, the advent of molecularly targeted therapies and immunotherapies has challenged this paradigm. The outcomes of phase 1 trials in solid tumours have been reported, but not in haematological malignancies. Here we report the phase I/II trials experience from a dedicated trials unit within a large UK Haematology centre. Methods: This was a retrospective review of patients with haematological malignancies sequentially treated in Phase I/II clinical trials at the NIHR/ UCLH Clinical Research Facility, London, UK. Patients met the relevant eligibility criteria for each study and received at least one dose of study medication. Adverse events were graded by CTCAE 4.0, response assessments as per trial protocol. Univariate and multivariate analysis was performed upon demographic, clinical and haematological/ biochemical parameters to investigate predictive markers of outcome. Kaplan Meier method was used for survival analysis and censored for those proceeding to ASCT. Results: 69 patients were enrolled onto 11 trials between March 2012 and July 2016. 6 were phase I studies (four first-in-human); 4 phase I/II studies; and one phase II study with a dose finding phase. All involved molecularly or immunologically targeted therapies. Median age was 60.3 yrs (range 32.5-80.2). The median time from diagnosis to trial treatment was 42.8 months (range 1.9-202.5). Disease types included multiple myeloma (MM) (n=41), non-Hodgkin's lymphoma (NHL) (n=16: DLBCL 12, FL 2, WM 1, MCL 1), AML (n=10) and myelofibrosis (n=2). Patients had a median of 3 (range 0-8) prior lines of therapy and 29 (42%) had at least 4 prior lines. 28/68 (41.2%) were refractory to the last treatment and 1 patient with newly diagnosed MM was enrolled. A median of 4 (range 0.3-25) cycles of treatment were completed with a median duration of treatment of 3.7 months (range: 0.2-24.4). Treatment was discontinued due to disease progression (36, 62.1%), toxicity (8, 13.8%), proceeding to ASCT (11, 19%), patient choice (2, 3.4%), completed treatment (1, 1.7%). 11 patients are on-going. Following trial discontinuation, 40 (71.4%) received further treatment (clinical trials (n=5), standard therapy (n=24), ASCT (n=11)), 2 (3.6%) were managed expectantly and 14 (25%) palliated. 17 (25%) developed grade 3-4 AEs. 30.9% had dose interruptions for 7 or more days, and 77.9% maintained their planned dose throughout. For those completing 1 or more cycle (n=61, 57 were evaluable), the clinical benefit rate (SD or more) was 68.4% (SD 5 (8.8%), MR 7 (12.3%), PR 15 (26.3%), VGPR 10 (17.5%), CR 2 (3.5%)) with an overall response rate (PR or more) of 47.4%. 18 (31.6%) were refractory to trial treatment. With a median follow-up of 9.6 months (range: 0.2-44.6), the median progression free survival (PFS) was 10.0 months (95%CI: 0.9-19.1 months). The median overall survival was 31.1 months (95%CI: 20.4-41.8) The 90 day mortality rate was 12.8%. In univariate analysis, LDH and disease types were significant for PFS and OS. However, in multivariate analysis albumin and disease type were independent predictors of OS but not PFS. Serum albumen of 〉35g/L was associated with an improved OS (HR 0.21, 95%CI 0.06-0.82, p=0.024). Age, performance status, Hb, LDH were not predictive in multivariate analysis. MM was associated with a better PFS and OS over other disease types (see table). Conclusions: These data demonstrate the wide range of PFS and OS to phase I/II studies according to disease type. Patients with MM had better outcomes and were more likely to access subsequent treatments. Most NHL patients had refractory high grade disease but still had a median OS of 17.9 months. Those with refractory AML/ myelofibrosis had a poor outcome, highlighting a clear unmet need. The PFS and OS for MM and NHL patients was encouraging. Serum albumin was predictive of OS across all disease groups. Whilst such parameters are not primary endpoints for early phase trials, these data indicate their potential clinical benefit. Stratification according to molecular profiles may further improve outcomes. Table Table. Figure Figure. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Description: In AML, the favorable prognosis associated with mutations in the CEBPA gene is restricted to those cases with double CEBPA mutations (CEBPADM), consistent with the loss of normal CEBP/alpha activity from both alleles. Current recommendations are that CEBPADM-mutated patients should not receive a stem cell transplant in first remission. In general, these cases have 2 ‘classical’ mutations, an N-terminal out-of-frame insertion/deletion that leads to loss of the full-length p42 protein and increased levels of the p30 isoform translated from an internal start site, coupled with a C-terminal in-frame insertion/deletion in the DNA binding domain (DBD) or leucine zipper domain (LZD) that interferes with DNA binding or dimerization. However, in our study of 1427 younger adult patients, 26% of mutations did not fit this classical description due to either the location or type of mutation. Furthermore, of the CEBPADM cases, 20% had a classical plus a ‘non-classical’ mutation or a homozygous non-classical mutation. It will be important to understand the functional consequences of these atypical mutations if CEBPA genotype is to be used to determine patient management. As methylation profiling has shown that CEBPADM cases form a distinct hypermethylated cluster, we investigated whether this can provide information about non-classical cases. A test set of 40 diagnostic samples were analyzed on the Illumina Infinium 27K Human Methylation Array, all normal karyotype with wild type (WT) NPM1, FLT3ITD and FLT3TKD; 10 were CEBPADM, 30 CEBPAWT. Unsupervised cluster analysis showed that the 10 CEBPADM cases clustered within a group of 16 hypermethylated cases that separated from 24 hypomethylated cases. A methylation signature was created from the 25 most-differentially methylated CpG sites between the CEBPADM and CEBPAWT cases and used to examine a validation set of 95 samples analyzed on the Illumina Infinium 450K Human Methylation Array (31 CEBPADM, 38 single-mutated CEBPA [CEBPASM], 26 CEBPAWT). This included 38 cases with non-classical mutations, 14 of them CEBPADM. On unsupervised cluster analysis, most CEBPADM cases (81%) fell in a hypermethylated group that was distinct from CEBPASM and CEBPAWT cases, with no segregation between the latter. We derived a genotype predictor by comparing the % methylation in a sample at each of the 25 CpG sites with that in the CEBPADM and CEBPAWT signatures to determine which signature the sample data most approximated. This correctly predicted 25/31 (81%) of the CEBPADM cases, including 2 with missense DBD/LZD mutations (A295P, N321S) coupled with a classic N or C mutation, 2 with homozygous classic C mutations, indicating that presence of the p30 isoform is not required for the methylation profile, and 5 with a classic N mutation coupled with a truncating mutation in the middle of the gene, consistent with the presence of the p30 isoform alone. This data was supported by functional evaluation of mutant constructs in a luciferase reporter assay to assess DNA binding and transactivation activity (TA). Classic CEBPADM constructs all had significantly lower TA than CEBPAWT (mean 12%, 27%, 15% of CEBPAWT for homozygous N, homozygous C and N+C constructs). Combination of a classic N mutation with missense DBD mutations (A295P, R297P, R300P), a LZD truncation (K313fs) or a middle region truncation (Q209fs, A238fs), all led to ≤15% activity consistent with almost complete loss of CEBP/alpha activity. Of the 6 CEBPADM cases that did not cluster as expected, 1 with classic N+C mutations had a lower mutant level (mean 28% for the 2 mutations compared to 45% for 9 other pairs with available data) and 1 had a homozygous missense LZD mutation that did not show reduced TA that could explain the discrepancy. The other 4 all had high mutant level (mean level ≥39%) and biallelic mutations as assessed by cloning, and relevant constructs showed low TA (≤19%). The reason for their misclassification is therefore not apparent, although we cannot exclude the possibility of other coincident mutations influencing methylation. These data indicate that the hypermethylated profile associated with CEBPADM cases holds true for most of the CEBPA mutations identified in patients and can be used to support predicted functional consequence of the mutations. This may be particularly useful in determining management in CEBPADM cases with non-classical mutations. Disclosures No relevant conflicts of interest to declare.

Description: Background:PQR309 is an oral balanced, pan-PI3K, mTORC1 and mTORC2 inhibitor. It is in clinical development for the treatment of solid tumors and hematologic malignancies. 1st generation mTOR inhibitors inhibit the activity of mTOR within the TORC1 complex only with activation of TORC2 proposed as a putative resistance mechanism. PI3 kinase inhibition may reduce subsequent AKT activation which can bypass some effects of mTOR inhibition. Potent antiproliferative activity of PQR309 was previously demonstrated in lymphoma cell lines in vitro and in vivo. Maximum tolerated dose (MTD) of PQR309 in solid tumours was established at 80 mg using a continuous once daily dosing schedule (OD). Methods:We performeda modified 3+3 DE of PQR309, open label phase 1 trial with expansion, to evaluate safety, pharmacokinetics (PK) and efficacy. Patients with relapsed or refractory lymphoma (any sub-type, ECOG PS of 0-1) were treated in two sequential cohorts with escalating doses of PQR309 administered on an OD dosing schedule to assess the MTD of PQR309. The starting dose of PQR309 was 60mg OD. The dose limiting toxicity (DLT) period was the first cycle of treatment, 21 days (d). PK samples were obtained at predefined time points. Clinical efficacy was evaluated according to revised Cheson criteria. In the expansion phase, patients will be treated at the MTD as defined in the DE phase of the study. Results: 15 patients were enrolled between August 2015 and March 2016 and treated with 60mg (n=8) or 80mg (n=7) of PQR309. Demographics: 5F:10M; median age 60 (range: 34-75), median number of prior systemic treatments 5 (range: 1-8). Lymphoma indications are shown in Table 1. Mean duration on therapy was 39 days (range: 3-160). One patient with follicular lymphoma remains on treatment. Grade (G)3/4 drug-related AE were seen in 3 patients treated with 60mg: 1 G4 rhabdomyolysis, 1 G4 neutropenia, 1 G3 hyperglycemia and one patient who developed G3 anorexia and G4 sepsis. Four patients treated with 80mg developed G3/4 drug-related AEs: two patients developed G3 hyperglycemia, one patient developed G3 fatigue and G3 pneumonitis. No DLT was observed. Preliminary PK showed rapid absorption (Tmax 1-2h), dose proportionality for Cmax and AUC and an estimated T1/2 of around 50 hours, consistent with PQR309 studies in solid tumours that evaluated dose levels from 10 to 150 mg PQR309. Responses observed in each patient are shown in the table below. 4 patients were non-evaluable, 3 due to disease progression requiring cessation of study drug and one requiring steroid doses exceeding protocol defined criteria, all within the 21 day DLT assessment period. Conclusion:The MTD and recommended PQR309 dose for the expansion of the study was 80mg OD, in agreement with earlier dose-finding studies in solid tumours. Adverse event patterns were consistent with those seen in studies involing solid tumours. Hyperglycemia, a predicted on-target effect of PI3K/mTOR inhibition, was observed in the majority of patients, providing evidence of pharmacodynamic effects of PQR309. PK was dose-proportional. Encouraging clinical activity including a CR was observed. The study expansion is ongoing. Disclosures Collins: Takeda: Consultancy, Honoraria, Speakers Bureau. Eyre:GSK: Honoraria; Celgene: Other: Travel, Accomodation; Gilead: Honoraria, Other: Travel, Accomodation, Speakers Bureau; Takeda: Honoraria, Other: Travel, Speakers Bureau. Ivanova:PIQUR: Employment. Schmitz:PIQUR: Employment. Dimitrijevic:PIQUR: Employment. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Introduction: Primary mediastinal B Cell Lymphoma (PMBL) is a high-grade non-hodgkin lymphoma with distinct clinical and biological features. Optimal chemotherapy for this lymphoma is not established but some centres favour more intensive regimes such as DA EPOCH-R over R-CHOP. The role of consolidation radiotherapy is yet to be clarified and whether it can be omitted in those patients with a negative end-of-treatment PET scan (EOT PET) regardless of induction chemotherapy. Furthermore, the occurrence of false positive EOT PET scans may lead to overtreatment. The aim of this study was to establish the outcomes of patients (pts) with PMBL who had been treated in a single centre. Methods: Pts diagnosed with PMBL between 2003 and 2015 in Royal Marsden Hospital were included. Data was collected from electronic patient records and PET CT images review. Survival was defined from date of diagnosis until date of death or date of last follow up. Results: Thirty-four pts were identified with characteristics as shown in the table. Median diameter of the mediastinal mass was 12cm (range 5.5 - 24cm); 25 (74%) pts had a mass of ≥ 10cm. The majority of pts received R-CHOP chemotherapy (2 had 14 day cycles, 30 had 21 day cycles), 1 R-GCVP and another R-PACEBOM. Median number of cycles of chemotherapy was 6 (range 1-8). Seven out of 32 (22%) pts received involved field radiotherapy (IFRT). EOT PET was available for 30 pts. Median time to obtaining EOT PET from completion of chemotherapy was 31 days (20-81). Twenty-three out of 30 pts had EOT PET negative disease with a Deauville score (DS) of 1-3. Twenty-one of these 23 pts did not receive IFRT. Two of these 21 pts relapsed in the mediastinum and were treated with salvage chemotherapy followed by autologous stem cell transplant (ASCT) of whom 1 died due to their lymphoma. The 2 patients who received consolidation radiotherapy remain in remission. Seven out of 30 pts had a positive EOT PET (DS 4-5); of whom 5 received IFRT. Two out of 5 patients relapsed and proceeded with further chemotherapy of whom 1 died due to treatment-related causes while the other 4 patients were alive at time of last follow-up. Two pts with a positive EOT PET did not have IFRT, 1 proceeded with salvage chemotherapy but died due to lymphoma and the other patient was followed up with serial PET scans and ultimately the residual avidity was considered to be due to thymic hyperplasia. Conclusion: Our analysis demonstrates that for the 23 patients who achieved a complete metabolic response on EOT PET the risk of relapse was low (9%) (despite that only 2 patients received consolidation radiotherapy) and only one patient (4%) died of lymphoma. Thus the majority of patients with a negative EOT PET scan following R-CHOP chemotherapy may not need consolidation radiotherapy. This finding should be taken into account when considering the risk/benefit of adding radiotherapy treatment to patients who are already in metabolic CR after chemotherapy. Consolidation radiotherapy is currently being investigated in a prospective IELSG37 trial, NCT01599559. Table. Table. Disclosures Chau: Eli-Lilly: Honoraria, Other: Advisory Board, Research Funding; Bristol Meyers Squibb: Other: Advisory Board; MSD: Other: Advisory Board; Bayer: Other: Advisory Board; Roche: Other: Advisory Board; Merck Serono: Other: Advisory Board, Research Funding; Five Prime Therapeutics: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Janssen-Cilag: Research Funding; Sanofi Oncology: Research Funding. Cunningham:Roche pharmaceuticals: Research Funding.

Description: BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive, post thymic lymphoid malignancy, with an incidence of approximately 0.1/100,000 people. T-PLL accounts for ~2% of all mature lymphocytic leukaemias in adults 〉30 years. Median overall survival (OS) ~20 months and long term remissions are infrequent. Intravenous alemtuzumab, a monoclonal antibody directed against CD52 remains the most effective treatment in T-PLL. At the Royal Marsden Hospital (RMH) we have been using alemtuzumab for T-PLL since the early 1990s. We describe our experience over the last 3 decades. METHODS: We included 174 T-PLL patients that were diagnosed or treated at RMH between 1989-2019. Immunophenotyping data was available through our hematological malignancy diagnostic service (HMDS) from 1998 onwards. Kaplan-Meier analysis was used for OS and disease free interval (DFI) RESULTS: There were 174 patients in total. Mean age at diagnosis was 61 years old (range 32-88) and M: F ratio was ~2:1 (113:61). 90 patients had reliable information on complete blood count (CBC) at diagnosis with median white blood cell count of 74 x 109/L (range 10-918), median hemoglobin 126 g/L (range 59-175) and median platelet count 116 x 109/L (range 7-513). Sufficient immunophenotyping data was available for analysis in 135/174 patients. The results showed predictably high expression of CD2, CD3, CD5, CD7, CD52 and TCRαβ. CD25 was positive in 67/135 (50%) of cases which is higher than the 18-35% seen in the current literature. CD4+/CD8- cases comprised 83/135 (61%) with CD4-/CD8+ 19/135 (14%), CD4+/CD8+ 32/135 (23%) and CD4-/CD8- 2/135 (2%). These results are summarized in table 1. Karyotyping/FISH (fluorescent in-situ hybridization) records showed a clonal result in 84 patients and of these 65/84 (77%) had an aberration of chromosome 14. These comprised 48/65 with inv(14), 6/65 t(14;14), 2/65 t(X;14), 1/65 TCL1 gene rearrangement by FISH and 8/65 with TRA/TRD involvement by FISH. Other frequent abnormalities seen were i(8)(q10) in 31/84 (39%) and complex karyotypic abnormality in 40/84 (48%). Lower frequency abnormalities seen were monosomy 11 in 8/84 (9%), monosomy 12 in 8/84 (9%), trisomy 8 in 6/84 (7%), 17p loss in 5/84 (6%) and mononsomy 13 in 4/84 (5%). Alemtuzumab was used in 116 patients, 69/116 (59%) receiving it as frontline treatment and 47/116 (41%) as salvage therapy. In 50/116 (43%) alemtuzumab was used as single agent, the remaining 66/116 (57%) receiving combination therapy, mostly pentostatin. Mean time from diagnosis to receiving alemtuzumab was 6.8 months (range 0-53 months). Overall response rate (ORR) to alemtuzumab was 94/116 (81%) with complete remission (CR) 69/116 (59%), partial remission (PR) 25/116 (22%) and no response (NR) 20/116 (17%). Alemtuzumab produced better response rates when used as frontline therapy. Table 2 summarizes these results and OS and DFI are shown in figures B and C. Allogeneic stem cell transplant (allo-SCT) was performed in 34 patients. Median OS post allo-SCT was 22 months and median DFI 31 months. Relapse rate post allo-SCT was 47%, non-relapse mortality 38% and transplant related mortality 29%. Figures D and E show OS and DFI post allo-SCT. Although relapse rates are high post allo-SCT there is a small cohort of patients who are achieving long term remission. We analysed OS by decade of diagnosis covering 3 decades 1990-1999, 2000-2009 and 2010-2019. The median OS for the whole cohort was 20.6 months with median OS of 21 months, 23 months and 19 months for each decade respectively. Results are shown in figure A. There was no statistically significant difference between the curves by log-rank analysis. DISCUSSION: Immunophenotyping results were similar to previous published data on T-PLL except for an increase in CD25 expression at 50%. Our data shows that outcomes in T-PLL have remained unchanged since the first decade of alemtuzumab usage, with no improvement in OS in the last 20 years. Despite improvements in diagnostic techniques and supportive care median OS is static at approximately 20 months. These results highlight the need for novel therapies in T-PLL. Given the rarity of T-PLL, international, multi-center, randomised trials are needed to improve outcomes. Disclosures Cross: Royal Marsden Cancer Charity: Other: MD Residency, Research Funding. Iyengar:Abbvie: Honoraria; Janssen: Honoraria. Dearden:Janssen: Honoraria; Genentech: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria.