Second Malignancies Following Treatment of Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era

Abstract Background: Since continuous treatment with tyrosine kinase inhibitors (TKIs) has dramatically improved the survival of patients with chronic myeloid leukemia (CML), it is of interest to examine the possible risk of long-term adverse events. Previous studies have presented conflicting results regarding risk of second malignancies. Our aim was to examine the development of second malignancies (except acute myeloid or lymphoblastic leukemia, myelodysplastic syndromes or non-melanoma skin cancer) in CML chronic phase patients diagnosed after the introduction of TKI treatment. Materials and methods: We studied the development of second malignancies in 868 patients diagnosed with CML in chronic phase 2002 to 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. Each patient was followed from the time of CML diagnosis until death from any cause, date of allogeneic hematopoietic stem cell transplantation (SCT) or end of study on December 31, 2011, whichever came first. SCT was used as an endpoint because of the well established increased risk of second malignancies after this procedure. Standardized Incidence Ratios (SIR) were calculated to assess the risk of a second malignancy by dividing the number of observed second malignancies with the number of expected malignancies in the Swedish population, using data from the Swedish Cancer Register. The expected numbers of malignancies were determined by dividing the CML population according to 5-year age groups, sex, region of residence (6 regions) and calendar year. The number of person-years in each stratum was multiplied with the incidence of malignancies or deaths found in the corresponding strata in the general population. Results: With a median follow-up of 3.7 (range 0-9.9) years, 65 (7.5%) patients developed 75 second cancers (non-hematologic), 49 of these of invasive type. Compared to expected rates in the background population matched by age, sex, region of residence (6 regions) and calendar year, the risk of second malignancies was significantly higher in the CML cohort, with a Standardized Incidence Ratio (SIR) of 1.5 (95 % CI 1.13-1.99). SIR before and after the second year following diagnosis of CML was 1.6 (95 % CI 1.004-2.38) and 1.5 (95 % CI 0.98-2.11), respectively. Looking at CML subpopulations, the increased risk of developing a second malignancy reached statistical significance for females (SIR: 1.8; 95 % CI 1.18-1.99), but not for males (SIR: 1.3; 95 % CI 0.85-1.91), and for patients above 60 years of age at diagnosis (SIR: 1.5; 95 % CI 1.05–1.96). Assessment of risk by cancer type was hampered by small numbers. However, the data at hand indicate an increased risk for gastrointestinal cancer (SIR: 3.0; 95 % CI 1.60-5.16), as well as nose and throat cancer (SIR: 37.1; 95 % CI 7.46-108.40), table 1. Conclusions: Utilizing large, population-based registries with data accumulated during the TKI era, our results indicate that CML patients, compared to the normal control population, are at an 50% increased risk of developing a second malignancy. Similar SIR before and after the second year following the diagnosis of CML may indicate that these findings are linked to the CML disease itself, rather than to the TKI treatment. Further studies and longer follow-up seem however warranted. Physicians caring for CML patients should be aware of signs and symptoms of other malignancies in this patient population. Table 1 Standardized Incidence Ratios for second malignancies (excluding cases of non-melanoma skin cancer, AML, ALL and MDS) among 868 Swedish CML patients diagnosed between 2002 and 2011. Total follow up time 3293 person-years (median 3.7 years). Variable Observed Expected SIR (Observed/Expected) 95 % CI for SIR Overall 52 34 1.5 1.13–1.99 Men 26 20 1.3 0.85–1.91 Women 26 14 1.8 1.18–2.66 Age <60 years 10 5 1.9 0.89–3.42 Age ³ 60 years 42 28 1.5 1.05–1.96 Second cancer type Prostate 14 8 1.8 0.96–2.94 Gastrointestinal 13 4 3.0 1.60–5.16 Gynecological 4 1 3.6 0.98–9.30 Nose and Throat 3 0,1 37.1 7.46-108.40 Lung 2 2,7 0.7 0.08-2.67 Breast 4 4,2 0.98 0.26-2.45 Disclosures Björkholm: Novartis: Research Funding; Shire: Research Funding; Merck: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Akinon: Honoraria; Nordic Nanovector: Honoraria. Richter:Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Själander:Novartis: Honoraria.

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Increased Risk of Cardiovascular Events Associated with TKI Treatment in Chronic Phase Chronic Myeloid Leukemia. Data from Swedish Population-Based Registries

Blood ◽

10.1182/blood.v124.21.3134.3134 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3134-3134 ◽

Cited By ~ 2

Author(s):

Torsten Dahlén ◽

Gustaf Edgren ◽

Martin Höglund ◽

Mats Lambe ◽

Magnus Björkholm ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Events ◽

Research Funding ◽

Chronic Phase ◽

Population Based ◽

Swedish Population ◽

2Nd Generation ◽

Increased Risk ◽

Tki Treatment

Abstract Introduction: The introduction of continuous tyrosine kinase inhibitor (TKI) treatment has dramatically improved progression-free survival for chronic phase chronic myeloid leukaemia (CML) patients. This success, however, has put the issue of long-term drug toxicity and safety into focus. Recent data from clinical studies have indicated an increased risk of cardiovascular events (CVE), including peripheral arterial occlusive disease, in CML patients receiving treatment with the TKIs nilotinib or ponatinib, as compared to imatinib (Giles et al, Leukemia 2013; Kim et al, Leukemia 2013; Cortes et al, New England Journal of Medicine 2013; FDA communication 2013). This study used data retrieved from Swedish population-based registries to estimate the frequency of CVE in CML patients, particularly those treated with imatinib and the 2nd generation TKIs nilotinib and dasatinib. Methods: We identified all incident cases between 2002 and 2012 in the Nationwide Swedish CML register. All patients who were in blast crisis or accelerated phase at time of diagnosis were excluded. All patients were followed untill death, emigration or 31st December 2012. For all CML patients a comparison cohort was established, matched to be of the same age and sex as the CML cohort, with 5 control subjects per CML patient. By means of record linkage with the nationwide Swedish patient register both cohorts were followed for the occurrence of adverse cardiovascular outcomes. Two sets of relative risks (expressed as incidence rate ratios; IRRs) of cardiovascular and venous thromboembolic disease were computed. In a first step CML patients were compared to the control population. In a second step, restricted to CML patients ever treated with TKIs, CML patients on different TKI treatments were compared. Patients could be treated with several TKIs during their follow-up, and events would only be attributable to the TKI used during the time period. Both analyses were adjusted for age, sex and calendar period. The second analysis was also adjusted for Sokal risk score. Results: A total of 896 CML patients were included and followed during a median of 4.2 years (Table I). The main outcome data are presented in Table II. A total of 23 venous thrombotic events (VTE) and 60 arterial thrombotic events were detected in the CML patient cohort during follow-up. Compared with the general population, this corresponded to significantly increased risks. In particular, deep venous thrombosis and “other arterial thromboses” were more common among CML patients (IRR 2.41 95% CI 1.29-4.52 and IRR 3.50 95% CI 1.36-9.04, respectively). Assessing risks associated with particular TKIs, we noted that treatment with any of the 2nd generation TKIs nilotinib or dasatinib, as compared to imatinib, was associated with a significantly increased occurrence of myocardial infarction (IRR 2.98 95% CI 1.05-8.49 and IRR 2.89 95% CI 1.20-7.00, respectively). Notably, there were no differences in the occurrence of CVE between the different patient groups before CML diagnosis. Conclusion: These data, derived from a large population-based Swedish cohort, provide evidence of an increased risk of both venous and arterial thrombotic events among CML patients and that patients on 2nd generation TKIs, as compared to imatinib, may be at increased risk of myocardial infarction. Further analyses will assess whether these differences may reflect patient selection and characterstics, rather than drug-related factors. Meanwhile, risk factors for CVE should be observed and considered in the TKI treatment of CML. Figure 1 Figure 1. Figure 2 Figure 2. * Footnote: the number of events may not add up because of occurrence of more than one type of vascular event in one subject. The number of events in the analysis within the CML cohort is lower than in the comparison with the general population because of exclusion of patients who were never treated with TKIs in the former analysis. Disclosures Björkholm: Novartis: Research Funding; Shire: Research Funding; Merck: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Akinon: Honoraria; Nordic Nanovector: Honoraria. Själander:Novartis: Honoraria. Richter:Ariad: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria.

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Incidence of second and secondary malignancies in patients with CLL: A single institution experience.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6568 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6568-6568 ◽

Cited By ~ 1

Author(s):

Samir Dalia ◽

Julio C. Chavez ◽

Gelenis Domingo ◽

Estrella M. Carballido ◽

Paibel I. Aguayo-Hiraldo ◽

...

Keyword(s):

Solid Tumor ◽

Light Exposure ◽

Lymphocytic Leukemia ◽

Myelogenous Leukemia ◽

Cancer Center ◽

Secondary Malignancy ◽

Cancer Type ◽

Second Malignancy ◽

Second Malignancies ◽

Increased Risk

6568 Background: Patients with chronic lymphocytic leukemia (CLL) have a higher incidence of second malignancies than the general population with one study showing the risk at 2.2 times the general popualtion. The increased incidence is thought to be due to immunosupression which results in decreased cell surveillance and proliferation of malignant cells. Our study aims to present the rate of second malignancies by cancer type in patients with CLL at our institution. Methods: The Moffitt Cancer Center Total Cancer Care (TCC) database was used to identify patients who had a diagnosis of CLL between January 1993-December 2009. Individual charts were reviewed to confirm the diagnosis of CLL, collect demographic data, and to assess for the presence of a second malignancy under an IRB approved protocol. A second malignancy was defined as another malignancy or transformation of CLL reported in the medical record. Second malignancy data was placed in three categories; skin cancers, solid tumor malignancy, and hematologic malignancy. Results: 546 CLL patients were included in the study. Median age was 62.5 years. 84 (43%) were Stage 0 and 62 (32%) were Stage 1 RAI at diagnosis indicating earlier disease. 266 (49%) patients had a second or secondary malignancy. A total of 304 cancers were identified. 14% of patients had more than one malignancy. Melanoma was identified in 44 (16.5%) patients and non-melanoma skin cancer was identified in 54 (20%). Lung cancer was identified as the most frequent solid tumor malignancy with 36 (13.5%) cases, followed by prostate (35), breast (21), colorectal (15), and bladder (14). 10 patients had a Richter’s transformation of their CLL. 26 patients developed either myelodysplastic syndrome or acute myelogenous leukemia. Conclusions: Second malignancies are frequent in CLL patients. Immunosupression, increased UV light exposure, longer life expectancy in low risk CLL, and tertiary cancer center referral bias are likely reasons for these increased rates. Further research is needed to identify the precise mechanism which cause patients with CLL to have higher rates of second malignancies and to identify if there is an increased risk of a specific type of malignancy in patients with CLL.

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Incidence and Risk Factors for Second Malignancies after Transplant in Long Term Survivors of Allogeneic Haematopoietic Stem Cell Transplant: A Single Centre Experience

Blood ◽

10.1182/blood-2018-99-114229 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3417-3417

Author(s):

Mohammed Snober ◽

Richard Syzdlo ◽

Jane Apperley ◽

Aristeidis Chaidos ◽

Edward Kanfer ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Haematopoietic Stem Cell ◽

Cell Transplant ◽

Second Malignancy ◽

Second Malignancies ◽

Additional Information ◽

Increased Risk ◽

High Index Of Suspicion

Abstract Second malignancies are well recognised complications of haematopoietic stem cell transplantation (HCT). The incidence increases with time after HCT with no evidence of plateau with follow up times of 15-20 years. In this study we have investigated patients over a 37-year period to include all patients transplanted at The Hammersmith hospital since 1979 who survived a minimum of two years after transplant. We aimed to describe the post-transplant malignancies (PTM) that occurred and calculate the cumulative incidence with time. Methods Data was gathered through internal databases and supplemented with case notes with all patients giving consent for their data to be used in clinical studies. Additional information on patients who had died at the time of analysis included review of death certificates for evidence of a second malignancy. If a patient had not been seen within 5 years evidence of death was sought on the NHS Spine and if apparently still alive, the date of last follow up was taken as follow up time. Second malignancies included second solid neoplasms (SSN), non-melanoma skin cancer (NMSC) and leukemias/lymphomas. These were recorded and categorised in accordance with the international classification of disease for oncology (ICD-O). Results 697 patients survived a minimum of two years after HCT between 1979-2018, 60% of whom were male. Follow up was prolonged with 20% of our 2-year survivors followed up for more than 20 years. The majority of patient (80%) were aged between 20-50 at time of HCT. (median age 35.6y, range 4-69) with only 7 patients < 10 y at HCT. The most frequent diagnoses were CML (n=463) or AML (n=103). The majority of patients (n=538, 77%) had received TBI, and the most frequently used conditioning was Cyclo-TBI (479 patients, 69%). At the time of analysis, 222 patients had died and of the remaining 475, 107 were lost to follow up. We identified 97 PTM in 87 patients a median of 14.2 years post HCT (range 0.8-35.9 years). These included 58 cases of SSN, 28 cases of NMSC and 11 cases of leukemia or lymphoma. The most frequent SSN were breast (n=12), tongue (n=7), colorectal (n=6), melanoma (n=5), bladder (n=4), thyroid (n=3) and oesophagus (n=3). Of 28 patients with NMSC, 19 developed one or more BCC and 9 developed SCC. The cumulative incidence of PTMs did not plateau with time. Cumulative incidences were as follows with 95% confidence intervals (CI) in parentheses: 4.9% (3.3-7.3) at 10 years, 12.2% (9.1-16.2) at 15 years, 22.5% (17.6-28.9) at 20 years, 39% (30.3-48.4) at 25 years and 53% (41.6-64.1) at 30 years. These data reflected the substantial increases in the CI of SSN and NMSC between these time points. For SSN the cumulative incidence increased from 3% (1.8-5) at 10 years to 37.9% (27.4-49.6) at 30 years; for NMSC the cumulative incidence increased from 1.3% (0.6-2.7) at 10 years 16.6% (9.2-28.2) at 30 years. In multivariate analyses older age (>50) at time of transplant was associated with significantly increased (p<0.01) risk of PTM with a relative risk (RR) of 4.53 (2.1-9.6). On subgroup analysis this was only relevant to SSN where the RR was 5.17 (2.2-12.1). Patient/donor sex combinations other than male patient/male donor were also at increased risk of PTM, RR 1.797 (1.1-2.9), p=0.033, and again this was only significant for SSN (RR 2.11, 1.13-3.93). Discussion and conclusions In this predominantly adult study, the cumulative incidence of SSN and NMSC increased substantially with time after HCT beyond a 10-year follow-up period. The risk was increased in patients who were >50 at time of HCT. Prolonged expert follow-up with a high index of suspicion for second malignancy in these patients is recommended to facilitate early diagnosis. Disclosures Apperley: Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Milojkovic:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

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Risk of secondary cancers after breast conserving therapy in Japan.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.3_suppl.256 ◽

2016 ◽

Vol 34 (3_suppl) ◽

pp. 256-256

Author(s):

Kenshiro Shiraishi ◽

Tomohiro Shinozaki

Keyword(s):

Cumulative Incidence ◽

Breast Conserving Therapy ◽

National Registry ◽

Cancer Type ◽

Secondary Malignancies ◽

Second Malignancies ◽

Secondary Cancers ◽

Kaplan Meier ◽

Increased Risk

256 Background: There is a growing body of evidence that vast majority of patients with early breast cancer who underwent breast conserving therapy (BCT) live their longer ‘cancer survivor’ lives through modern sophisticated treatment. Accordingly, second malignancies after BCT are on the rise, which are sticky dilemmas accompanied by additional anxiety and need for further medical care. Investigation of secondary malignancies should be made the first priority in Japan as the world's top country for longevity. Methods: In order to investigate the second malignancies after BCT, a cohort study was conducted based on our database from 1982 to mid-2015. Actuarial rates of second malignancies, overall (OS) and cause-specific survival (CSS), were calculated by using the Kaplan-Meier method. We calculated standardized incidence ratios (SIR) for each cancer type corresponding to the national registry. Results: 1,557 patients (49.5%) were followed-up for more than 10 years. At a median follow-up of 113 months, 180 patients had developed a second malignancy. The increases in risk were for leukemia (SIR: 3.89 (1.76–6.84)) and ovarian cancer (SIR: 3.65 (2.26–5.38)). Trends toward increased risk was seen in reno-ureteral cancer (SIR: 2.25 (0.96–4.08)) and endometrial cancer (SIR: 1.59 (0.92–2.43)) though it was not statistically significant. No increased risk was observed for other gastrointestinal and genitourinary cancer, malignant melanoma, lymphoma, thyroid or head and neck cancer. Overall 10-year cumulative incidence of OS was 93.3%, and overall 10-year cumulative incidence of CSS was 95.0%. Overall 10-year incidence of secondary cancer was 5.9%. A total number of secondary malignancies within 10 years was 157 and this number explained 84.4% of all cases observed during follow-up. Secondary cancers continued to occur afterward, and cumulative incidence at 15- and 20-years were 8.4% , and 9.6%, respectively. Conclusions: Secondary cancers after BCT continue to arise as long as patients survive. Given its nature of life-threatening to cancer survivors, attending care team must pay persistent attention to secondary malignancies especially in Japan with the longest life-span.

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Advanced Age at Transplant Increases the Risk of Second Solid Malignancy (SSM) after Haematopoetic Stem Cell Transplantation (HSCT)

Blood ◽

10.1182/blood.v124.21.3952.3952 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3952-3952

Author(s):

John Murray ◽

John Chadwick ◽

Adrian Bloor ◽

Jim Cavet ◽

Mike Dennis ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Second Malignancy ◽

Single Centre ◽

Solid Malignancy ◽

Increased Risk ◽

Cell Transplants ◽

Long Term Survivors

Abstract Introduction: It is increasingly important to understand the long term risk associated with transplantation because the number of long term survivors is steadily growing. In comparison to other long term risks following transplantation like infertility, cataracts, endocrine dysfunction, etc. the risk of second malignancy is likely to be associated with increased risk of mortality and hence significant impact on survival outcomes. This retrospective, single centre analysis was undertaken to evaluate the risk of second solid malignancy in patients undergoing HSCT. Methods: From February 1973 to November 2013, 1983 patients (median age: 45yr., range: 14-76 yr.; M: 1259, F: 724) received stem cell transplants for haematological malignancies (Ac. Leuk: 507, Chr. Leuk: 97, lymphoma:645, myeloma:621, solid tumours:113). Donor was allogeneic (n=528) or autologous (n=1455) and conditioning was with (n=556) or without TBI (n=1427). Donor was sibling (n=302), matched unrelated (n=220) or cord blood (n=6). Source of stem cell was marrow (n=322), PBSC (n=1627), both (n=28) or cord blood (n=6). GVH prophylaxis included Campath in 203 cases. Of all the patients 1774 received single transplant but 209 received more than one transplant. Data was analysed as of 01/12/2013 using competing risk models with death as the competing event. Patients who developed second haematological malignacy were not included in this analysis. Results: Patient follow-up was more than 10 years in 382 cases (19%), between 5 to 10 years in 328 (17%), 1 to 5 years in 667 (34%) and less than 1 year in 606 cases (31%). Second solid malignancy developed in 70 patients with the incidence of 1% at 5yr (95% CI: 0.5-1.6), 2.2% at 10 yr (95% CI: 1.6-3.3), 4.8% at 15yr (95% CI: 3.6-6.8) and 8% (95% CI: 5.9-10.5) at 20 years. Site of second malignancy was brain (n=2), breast (n=15), cervix (n=3), GIT (n=11), genitourinary (n=9), lung (n=3), skin (n=17), head & neck (n=7), thyroid (n=3) and non EBV related lymphoma (n=3). In univariate analysis 10 yr. probability of developing SSM was not influenced by gender, stage of disease, primary diagnosis, type of HSCT, use of TBI, cranial top-up radiation, type of donor or year of transplant. It was significantly higher with use of PBSC (1.4% vs. 2.6%, p=0.02) and age above 65yr. (1.5% vs. 11%, p=0.001). In multi-variate analysis age above 65yr. (RR: 1.8, 95% CI: 1.1-2.9, p=0.02) and PBSC (RR: 9.4, 95% CI: 1-99, p=0.05) were independently associated with increased risk of SMN. 19 patients have died due to SSM (27%) and survival was significantly shorter with gastrointestinal, genitourinary and lung cancers. Conclusion: This single centre analysis shows that the risk of developing SSM increases with advancing age, longer follow-up and the survival is poor. Long term survivors of stem cell transplants need follow-up probably for life in speciality clinics. Continued vigilance, avoidance of known carcinogens and life style changes are strongly recommended. Disclosures Bloor: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavet:Novartis: Research Funding; BMS: Research Funding.

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Age over 55 Years at Diagnosis Increases Risk of Second Malignancies after Auto-Transplantation for Hodgkin's Lymphoma Patients

Blood ◽

10.1182/blood.v126.23.3186.3186 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3186-3186

Author(s):

Sai Ravi Pingali ◽

Rima Saliba ◽

Paolo Anderlini ◽

Chitra M. Hosing ◽

Issa F. Khouri ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Age At Diagnosis ◽

Hodgkin's Lymphoma ◽

Second Malignancy ◽

Secondary Malignancies ◽

Second Malignancies ◽

Advisory Committees

Abstract Introduction: Age at diagnosis is of prognostic value in Hodgkin's lymphoma (HL) patients. However, there is paucity of data on the impact of age on outcomes of autologous hematopoietic transplantation (auto-HCT) for patients with relapsed and refractory HL. We studied impact of age at diagnosis on long-term outcomes of patients with HL undergoing auto-HCT. Patients and Methods: All consecutive patients with relapsed/refractory HL who underwent auto-HCT at our center between January 1996 and December 2010 were included. Baseline patient and disease characteristics were collected. As HL has bimodal peak incidence betweenages of 15 and 34 years and over age of 50 to 55 years, we stratified patients into 3 groups: > 55, 26 to 55 years, and ≤ 25 year age groups. We compared overall survival (OS), progression free survival (PFS), relapse rate and rates of secondary malignancies between these groups. As the outcomes were similar between ≤ 25 and 26 to 55 years groups, subsequent analysis of these two groups was done together as ≤ 55 years vs. > 55 years groups. Baseline patient and disease-related characteristics were compared using the chi-square test for categorical variables and Mann Whitney's rank-sum test for continuous variables. Actuarial OS was estimated using the Kaplan-Meier method. Prognostic factors for OS, disease progression and non-relapse mortality (NRM) were assessed on univariate and multivariate analyses using Cox proportional hazards regression analysis. Results: 30 (9.7%) patients were > 55, 168 (54.1%) patients were between 26 to 55, and 112 (36.1%) were ≤ 25 years of age. At a median follow-up of 80 months, patients > 55 were at significantly higher risk for mortality with hazard ratio (HR) of 2.3 (95% CI, 1.3-4.2; P = 0.007) compared to patients ≤25 years of age. There was no difference in mortality when between age 26 to 55 years and ≤ 25 years group (HR 1.0; 95% CI, 0.6-1.6; P = 0.9). Risk for progression was similar between the 3 groups, with HRs of 1.3 (95% CI, 0.7-1.5; P = 0.5) and 1.2 (95% CI, 0.8-1.8; P = 0.3) for > 55 group and 26 to 55 groups, respectively compared to ≤ 25 years group (Table 1). Patients > 55 years at diagnosis had significantly higher incidence of secondary malignancies mostly MDS/AML(30% vs. 8%; P<0.001) than patients ≤ 55 years (Figures 1) leading to higher NRM. Prior radiation therapy, time from initial diagnosis to transplant and number of prior therapies did not impact risk for second malignancies. Conclusion: Patients >55 years at diagnosis who receive auto-HCT for relapsed/refractory HL experience higher mortality from secondary malignancies. Table 1. Outcomes of Auto-HCT at Median Follow-Up of 80 Months Outcomes Entire Cohort > 55 yearsN = 30 ≤ 55 yearsN = 280 P value OS 65% (59-71) 27% (9-49) 69% (63-74) 0.003 PFS 54% (48-60) 31% (12-53) 56% (50-62) 0.2 CI of progression 41% (26-64) 52% (36-75) 37% (32-44) 0.7 CI of NRM 8% (5-12) 33% (16-65) 5% (3-9) 0.001 CI of second malignancy 11% (7-16) 30% (16-57) 8% (5-14) < 0.001 CI of second malignancy excluding skin cancers 9% (6-13) 22% (10-49) 7% (4-12) 0.003 SHAPE P=0.001 P <0.001 Figure 1. A-CI of second malignancies & 1B-CI of NRM Figure 1. A-CI of second malignancies & 1B-CI of NRM Disclosures Fanale: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.

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Predictors of Response Duration and Survival with Second-Line Bosutinib Therapy in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Prior Imatinib

Blood ◽

10.1182/blood.v126.23.4041.4041 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4041-4041

Author(s):

Jorge E. Cortes ◽

Tim H. Brümmendorf ◽

Hagop M. Kantarjian ◽

Dong-Wook Kim ◽

Philippe Schafhausen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Second Line ◽

Advisory Committees ◽

Imatinib Resistance ◽

Increased Risk

Abstract Bosutinib (BOS), a Src/Abl tyrosine kinase inhibitor (TKI), is approved for adults with Philadelphia chromosome-positive (Ph+) CML that is resistant/intolerant to prior therapy. In this retrospective analysis, baseline and on-treatment characteristics of chronic phase (CP) CML pts receiving second-line BOS following imatinib resistance (IM-R) or intolerance (IM-I) in an ongoing open-label, phase 1/2 study and a long-term extension study were examined to identify potential predictors of duration of major cytogenetic response (MCyR), overall survival (OS), and progression-free survival (PFS), using a backward-elimination multivariate Cox regression model. A total of 284 (IM-R, n=195; IM-I, n=89) pts who received BOS starting at 500 mg/d were included in this analysis. Median (range) age was 53 (18‒91) y; time from CML diagnosis was 3.7 (0.1‒15.1) y; treatment duration was 25.6 (0.2‒106.7) mo; follow-up duration was 53.7 (0.5‒106.8) mo. For the last enrolled patient, time from first BOS dose was ≥6 y. After ≥6 y of follow-up, median MCyR duration and OS were not yet reached. Kaplan-Meier estimated probability of maintaining MCyR at 6 y was 71%, OS rate was 83%, and cumulative incidence of on-treatment disease progression or death was 21%. Several factors were identified as predictive of MCyR duration, OS or PFS, including baseline Ph+ ratio ≥95% vs ≤35% and MCyR by week 12, which were significant predictors of all 3. Other significant predictors of decreased OS included: age ≥65, BOS-sensitive mutations vs no mutations and higher peripheral blood (PB) blasts at baseline (all P ≤0.031; Table). Other significant predictors of decreased PFS included: higher PB blasts and no dose reduction to 400 mg/d due to AEs (all P ≤0.025; Table). Prior IM response or resistance did not predict long-term outcomes, nor did any treatment-emergent adverse events examined except for abnormal liver function test (LFT), which was predictive of increased OS. In conclusion, pts with CP CML resistant/intolerant to IM treated with BOS were identified as having an increased risk of poorer outcomes if they had the following characteristics: baseline Ph+ ratio ≥95% vs ≤35%, higher PB blasts at baseline or no MCyR by week 12. Having a better understanding of factors that may be predictive of long-term patient outcomes with TKI therapies may aid healthcare providers in the future selection of optimal treatment regimens for pts with Ph+ CML. Disclosures Cortes: ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Brümmendorf:Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent: Patents & Royalties: Patent on the use of imatinib and hypusination inhibitors. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Nadanaciva:Pfizer Inc: Employment. Bardy-Bouxin:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Other: Stock Ownership. Leip:Pfizer Inc: Employment. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gambacorti-Passerini:Pfizer: Consultancy, Research Funding; BMS: Consultancy.

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Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Blood ◽

10.1182/blood-2019-124489 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5470-5470

Author(s):

Julie E Chang ◽

Vaishalee P. Kenkre ◽

Christopher D. Fletcher ◽

Aric C. Hall ◽

Natalie Scott Callander ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Maintenance Therapy ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Second Malignancies ◽

Front Line ◽

First Line ◽

11Q Deletion ◽

Line Chemotherapy

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

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Cardiac Morbidity in Adolescents and Young Adult Survivors of Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-136454 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Kristin C. Marr ◽

Jonathan Simkin ◽

Andrea C. Lo ◽

Joseph M. Connors ◽

Alina S. Gerrie ◽

...

Keyword(s):

Cumulative Incidence ◽

Research Funding ◽

Index Date ◽

Population Based ◽

Stage Disease ◽

Increased Risk ◽

Matched Case ◽

Cv Disease ◽

Relapsed Disease

INTRODUCTION Adolescents and young adult (AYA) survivors of Hodgkin lymphoma (HL) are potentially at increased risk of cardiovascular (CV) disease due to anthracycline exposure, in addition to use of mediastinal radiotherapy (RT). Although the risk has been well described in the pediatric age-group, the impact in the AYA population has been less well characterized. Capturing the incidence of these late effects is challenging given that events can occur more than a decade after therapy completion. Using population-based administrative data, we evaluated the incidence of CV disease (combined heart failure (HF) and ischemic heart disease (IHD)) in a cohort of AYA survivors treated for classical HL (cHL) using ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) or equivalent chemotherapy. METHODS Patients with cHL aged 16-39 years (y), diagnosed between 1992-2013 and treated with an ABVD or equivalent therapy, were identified in the BC Cancer Lymphoid Cancer Database. Patients must have survived to an Index Date defined as 2 y from most recent HL event (primary diagnosis or if applicable, most recent relapse) and have had a minimum follow-up of 1 y beyond their Index Date. Patients were excluded if they had history of prior malignancy or HIV positivity. Limited stage disease was defined as stage IA, IB or IIA and absence of bulky disease (≥10cm); all others had advanced stage disease. Cases were linked with population-based databases of BC Cancer Registry; BC Radiation Oncology Database; and BC Ministry of Health (MOH) Chronic Disease Registry (CDR) that captures all BC residents registered with medical service plan coverage during the study period. The outcome variables, including HF and IHD, were defined by the BC MOH CDR using Standardized Case Definitions. To focus on late onset CV complications, only events that occurred after the Index Date were included in the analysis. A 10:1 individually-matched control population was identified from the CDR based on age, sex, and health authority region on the Index Date of the matched case. Controls were excluded if they had a pre-existing malignancy, HF, or IHD prior to the study window. Individual outcomes were collected from the Index Date of the matched case until December 31, 2015 or until an individual was censored due to loss to follow-up or death. Kaplan Meier (K-M) methodology and log-rank test was used to estimate cumulative incidence. A competing risk regression analysis was used to evaluate relative risk (RR) and p-values less than 0.05 were considered significant. RESULTS With a median follow-up time of 11 y (range 3-24 y) from most recent HL event, 764 AYA 2-y survivors were identified, aged 20 to 61 y (median 38 y) at the end of study period. The proportion of limited and advanced stage disease was 34.2% and 65.6%, respectively; and 49.9% were male. Eighty-eight patients (11.5%) had relapsed disease; eighty-six (11.3%) underwent high dose chemotherapy and autologous stem cell transplantation as part of their salvage therapy. In total, 268 patients (36.4%) were treated with mediastinal RT for primary therapy or for relapsed disease. Fifty-three percent received cumulative anthracycline dose ≥300 mg/m2. Survivors had a 3-fold increased risk of CV disease relative to controls (p<0.0001). The onset of CV disease in survivors occurred at median of 11.7 y after most recent treatment (range 2.2-19.2 y), and at a median age of 44.3 y (range 21 - 58 y). At 15 y, the estimated cumulative incidence of CV disease was 6.3% in survivors compared to 2.3% in controls (Figure A). In the 496 survivors that received chemotherapy only, the incidence of CV disease at 15 y was 4.6% vs 2.3% in controls, and those that received anthracyclines and mediastinal RT had significantly higher incidence at 8.6% (Figure B). The increase in risk was greatest for a diagnosis of HF (RR 6.92, p<0.0001): at 15 y, the cumulative incidence of HF was 2.2% vs 0.6% in controls. The RR of IHD was 2.63 (p<0.0001) with incidence of 5.1% in cases compared to 1.8% in controls. CONCLUSION Similar to the pediatric population, AYA cHL survivors are at increased risk of both HF and IHD after completion of treatment. The majority of patients had received ABVD alone and had a lower incidence of CV disease at 15 y when compared to those that received treatment that included mediastinal RT. These results will inform counseling regarding risk factor modification and aid in the development of surveillance guidelines for AYA survivors. Disclosures Gerrie: Sandoz: Consultancy; Roche: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding. Villa:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AZ: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria. Scott:NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding. Sehn:AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Chugai: Consultancy, Honoraria. Savage:BeiGene: Other: Steering Committee; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria.

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Sequence of Second Generation Tyrosine Kinase Inhibitors (TKIs) in the Treatment of Patients with Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukaemia - Real World Experience in the UK

Blood ◽

10.1182/blood-2019-122893 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3434-3434

Author(s):

Jenny Byrne ◽

Joanne Ewing ◽

Adam J. Mead ◽

Heather Oakervee ◽

Gavin Campbell ◽

...

Keyword(s):

Real World ◽

Research Funding ◽

Kinase Inhibitors ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Educational Support ◽

Third Line ◽

The Uk ◽

Observation Period

Background: The prognosis of patients with chronic-phase myeloid leukaemia (CML) has drastically improved with the introduction of tyrosine kinase inhibitors (TKIs). During the period of this study, availability of treatment options in the UK were limited and determined by the date reimbursement was granted and when restrictions on the use of individual licensed TKIs were removed. Currently, imatinib, nilotinib and dasatinib are reimbursed for 1st line treatment (1L) with bosutinib and ponatinib reimbursed for 2nd line or subsequent lines of treatment. Aims: The primary aim was to determine the sequence of 2nd generation (2G) TKIs (nilotinib, dasatinib, bosutinib) in patients with chronic-phase Philadelphia chromosome-positive (Ph+) CML who had received their 3rd and subsequent lines of TKIs in a real world UK setting. Methods: A multi-centre, retrospective, chart review was undertaken in the UK from November 2018 to July 2019. To be included, patients had to be aged ≥18 with chronic phase Ph+ CML who had started a third line of TKI treatment between June 2013 and February 2018. Patients were excluded if they had >3-month gap in treatment before progression or relapse, or were treated with a 2G TKI within an interventional clinical study during third line treatment. At each line, molecular responses, cytogenetic responses, duration of therapy and reasons for stopping were recorded until the date of last hospital follow-up or death. Overall survival was determined from date of initiation of 3rd or 4th line TKI therapy until death by any cause. Results: An interim analysis was undertaken for 65 patients from 11 sites. Median age at diagnosis was 53.0 years. 50.8% were male and 49.2% were female. Of these 65 patients, 48 patients were still being treated at the end of observation (29 patients in 3rd, 18 in 4th and 1 in 5th line). Patient demographics are typical of CML populations. Throughout the study, imatinib was 1L treatment of choice for the majority of patients (57/65; 88%) and this held true (21/22; 95%) even when nilotinib and dasatinib were reimbursed for use 1L. Nilotinib was most commonly prescribed in 2L (42/65; 56%), reflecting the greater availability of this drug during the study period. Dasatinib and bosutinib constituted 22% and 4% respectively of 2L treatments. The most frequent sequencing pathway observed was I1-N2-D3 (Table 1, Fig. 1). 19 other pathways at low frequencies were observed across 39 patients. 97% of patients (63/65) achieved an optimal response at any time as defined by the 2013 ELN guidelines (Table 2) during the observation period. Of the 31 (48%) patients who were resistant to 1L, 24 (37%) achieved a response in 2L and of the 7 (10.7%) patients who were resistant to 1L and 2L, 5 (7.7%) achieved a response in 3L. At the end of the observation period, only 2 (3%) patients never achieved a response. In 3L: 29 (45%) patients are still ongoing, 4 died, 3 were lost to follow up and 3 underwent transplantation. In 4L: 18 (69%) are still ongoing, 3 died, and 3 underwent transplantation. Median overall survival for L3 was 21 months and 12 months in L4. In all lines of treatment, the main cause of switching away from imatinib was lack of efficacy (61%), and for all 2G TKIs the main cause was intolerance (66%). During the period when only imatinib was available in 1L, median duration of 1L treatment was longer at 26 months for patients failing to respond vs 9 months when nilotinib and dasatinib were also available. Conclusions: In this UK real-world study, for patients requiring 3 or more lines of treatment, sequencing of TKIs may have been determined by drug reimbursement. As availability of TKIs increased, time to switch therapy decreased for all patients, suggesting that clinicians were following guidelines and switching treatments more readily. However, initial 1L prescribing behaviour has not changed in this observation period despite better access to 2G TKI, and there appears to be a trend of physicians preferring to repeat 2G TKIs treatment sequences that yield a favourable outcome. Disclosures Byrne: Ariad/Incyte: Honoraria, Speakers Bureau. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . Mead:Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy; CTI: Honoraria, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding. Oakervee:Novartis: Honoraria; Pfizer: Honoraria; Bristol Myers-Squibb: Honoraria. Campbell:Novartis: Consultancy, Other: Educational support; Takeda: Consultancy, Other: Educational support; Bristol Myers-Squibb: Other: Educational support; Roche: Other: Educational support; Celgene: Other: Educational support. Amott:Celgene: Other: Meeting attendance sponsorship . Goringe:Novartis: Consultancy, Other: Speaker. Heartin:Celgene: Other: Speaker's fees; Janssen: Other: Speaker's fees; Takeda: Other: Speaker's fees; Alexion: Other: Speaker's fees; Novartis: Other: Speaker's fees. Dimitriadou:Celgene: Other: Meeting attendance sponsorship . Arami:Takeda: Other: Meeting attendance sponsorship ; Gilead: Other: Meeting attendance sponsorship ; Roche: Other: Meeting attendance sponsorship ; Celgene: Other: Meeting attendance sponsorship . Neelakantan:Novartis: Honoraria; Celgene: Honoraria. Frewin:Novartis: Consultancy, Other: Meeting attendance sponsorship ; AbbVie: Other: Meeting attendance sponsorship . Pillai:Celgene: Honoraria. De Lavallade:BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte biosciences: Honoraria, Research Funding, Speakers Bureau. Cross:Novartis: Consultancy, Research Funding; Incyte: Consultancy. Thompson:Incyte: Employment.

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