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

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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Prevalence and Risk Predictive Factors of Comorbid Malignancies in Patients with Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.1900.1900 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1900-1900

Author(s):

Tong-Yoon Kim ◽

Sung-Eun Lee ◽

Soo-Hyun Kim ◽

Soo-Young Choi ◽

Eun-Jung Jang ◽

...

Keyword(s):

Board Of Directors ◽

Medical Records ◽

Myeloid Leukemia ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Advisory Committees ◽

History Of

Abstract Introduction: As chronic myeloid leukemia (CML) patents are generally diagnosed at old age and live longer by active use of BCR-ABL1 tyrosine kinase inhibitors (TKIs), the occurrence of other malignancy (OM) is becoming a critical issue as a long-term comorbidity. An increased rate of OM has been reported in myeloproliferative disorders and long-term TKI treatment may induce OM in CML. To explore exact prevalence and characteristics of OM, we reviewed medical records of CML patients and compared with those of age-matched Korean population. Methods: The medical records of 1,469 CML patients who diagnosed between January 2000 and December 2014 were reviewed using Korean data-set of Asia CML Registry (ACR). With a cut-off date of July 2016, age-standardized prevalence rates (A-SPR) of OM (except benign tumors and other leukemias) were analyzed and compared with that of general population in Korea Central Cancer Registry (KCCR). In addition, we analyzed cumulative incidence rate of OM and various risk factors. Results: The median duration of follow-up was 84 (1-197) months, and 96 CML patients had at least one OM. Forty three patients had a history of OM before a median 69 (1-161) months of CML diagnosis and 53 patients developed OM after a median 53 (range; 0.2-172) months of CML diagnosis. The OM included 32 thyroid cancers, 19 colorectal cancers, 16 stomach cancers, 9 breast cancers, 4 gynecological cancers (3 cervical cancers and 1 uterine endometrial cancers), 3 lymphoma (2 non-Hodgkin's lymphoma and 1 Hodgkin's lymphoma), 3 biliary cancer, 3 skin cancers, 3 prostate cancers, 2 lung cancer, 2 tongue cancer, 2 liver cancer, 2 esophageal cancer, 1 pancreatic cancer, and 1 bladder cancer.A-SPR of OM was 1.7 times higher in CML patients. Hodgkin's lymphoma (8.7 times), thyroid cancer (2.6 times), biliary cancer (2.6 times), colorectal cancer (2 times), non-Hodgkin's lymphoma (1.8 times), cervical cancer (1.8 times), and breast cancer (1.6 times) had a higher A-SPR. On the other hands, skin cancer (3.3 times), lung cancer (2 times), and liver cancer (2 times) were lower than that of general population. With 53 patients who had OM after CML diagnosis, we analyzed the cumulative incidence. The risk of OM was increased over the follow-up period (2.7% at 7 years) Univariate analysis revealed that patients who were more than 37 years old at CML diagnosis (4.3% vs. 0.4%, p<0.001) and who had family history of cancer (8.2% vs. 2.3%, p=0.002) were associated with a higher OM. After adjusting for factors, multivariate analysis showed that older age (HR of 4.19, P<0.001) and family history (HR of 3.17, P=0.001) were independently associated with increased risk. There was no difference in 7-year overall survival (OS) between patients with OM (n=96) and without OM (n=1,373) (84.9% vs. 86.9%, p=0.573). However advanced cancer stages (stage 3 and 4) of OM significantly affected poor OS ( 88.3% vs. 65.6% P=0.0406). Conclusion: Although comorbid malignancies did not significantly affect CML survival, poor survival in advanced stages and the high risk of other cancers warn the need of systematic screening in long-term CML survivors. In addition, the specific cancer types with a significantly higher A-SPR should be considered for further studies including genetic mechanisms. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Incidence and Mortality of Second Malignancies In 559 Patients with Chronic Myeloid Leukemia (CML) Treated with Imatinib Frontline: Data From the GIMEMA CML Working Party

Blood ◽

10.1182/blood.v116.21.2281.2281 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2281-2281

Author(s):

Gabriele Gugliotta ◽

Fausto Castagnetti ◽

Francesca Palandri ◽

Massimo Breccia ◽

Francesco Cavazzini ◽

...

Keyword(s):

Urinary Tract ◽

Board Of Directors ◽

Research Funding ◽

Working Party ◽

Second Malignancy ◽

Second Malignancies ◽

Advisory Committees ◽

Tract Cancer ◽

Urinary Tract Cancer ◽

Risk Patients

Abstract Abstract 2281 Introduction. Imatinib is the standard of care for CML in early chronic phase. Until now, even in stable complete molecular response, discontinuation of imatinib is not recommended, and imatinib remains a life-saving drug to be taken chronically. Long term side effects, including the incidence of second malignancies, represent a potential relevant issue. Roy et al (Leukemia 2005) reported an unexpected incidence of second neoplasms in patients treated with imatinib after interferon (6/189 patients, 3.2%; urinary tract cancer: 4/6). In contrast, an analysis performed by Novartis Pharma (Pilot et al, Leukemia 2006) on 9518 patients treated with imatinib (including pre-treated patients) did not provided evidence for an increased overall incidence of second malignancies. According to epidemiologic data (Registro Tumori) in Italy, the annual incidence of neoplasms varies from 1%, in the range of age between 50 and 69 years, to 3% for patients over 70 years. AIM. To evaluate the incidence of second malignancies in CML patients treated with imatinib frontline. METHODS. Overall, 559 patients have been enrolled in 3 concurrent clinical studies of the GIMEMA CML Working Party: CML/021, Imatinib 800 mg in intermediate Sokal risk patients (Clin Trials Gov. NCT00514488); CML/022, Imatinib 400 mg vs 800 mg in high Sokal risk patients (Clin Trials Gov. NCT00510926); CML/023, observational, Imatinib 400 mg. We evaluated the incidence of II malignancy notified as severe adverse events reported by the GIMEMA clinical Centers. RESULTS. The median age at the diagnosis of CML was 52 (extr.18 – 84) years; 308 patients (55%) were ≥ 50 years. The median follow-up is currently 60 months. Eighteen patients (3.2%) developed a second malignancy at a median time of 20 months (extremes 2 – 52) from the start of imatinib therapy (Table 1); 4 of these malignancies (2 colon cancer and 2 NHL) were diagnosed within 6 months. All patients were older than 50 years (median 64, extremes 50 – 79) at the diagnosis of the second malignancy. Fifteen out of the 559 (2.7%) patients died due to second neoplasm progression. CONCLUSION. In this multicentre nation-wide experience of CML patients treated with imatinib frontline, the incidence of life-threatening or requiring hospitalization secondary neoplasms (severe adverse events), seems not to be superior to the observed incidence of neoplasm in the Italian national population. In particular, in contrast to what previously reported, no increased incidence of urinary tract cancer was observed. Disclosures: Gugliotta: Novartis: Honoraria. Castagnetti: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Martinelli: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Pane: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Saglio: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baccarani: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

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Mortality and Morbidity in 15-Year Survivors of Stem Cell Transplants for Haematological Malignancy

Blood ◽

10.1182/blood.v126.23.4348.4348 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4348-4348

Author(s):

Jack Stuart ◽

Richard Szydlo ◽

Jane F. Apperley ◽

Jeannie Todd ◽

Nina Salooja

Keyword(s):

Board Of Directors ◽

Causes Of Death ◽

Population Data ◽

Lipid Lowering ◽

Second Malignancy ◽

Second Malignancies ◽

Advisory Committees ◽

Mortality And Morbidity ◽

The Uk

Abstract Introduction: Haemopoietic stem cell transplantation (SCT) is a potentially curative treatment for haematological disease. Relapse, second malignancies, cardiovascular events, infection and GVHD-related disease are all established causes of death in the first 10 years post-SCT. Significant morbidity has also been described including cardiac risk factors, cardiovascular disease, malignancy, endocrinopathies and infertility. Although many of these complications are well documented in the first 5-15 years of follow-up, few studies have addressed mortality and morbidity in patients surviving longer than 15 years. Methods: In this single centre study, the causes of death and cumulative burden of morbidity were investigated for patients who survived a minimum of 15 years after allogeneic SCT. Survival status was verified by a) confirming recent attendance in clinic b) review of National Health Service data which records mortality statistics for patients registered with a family doctor (GP) in the UK. Causes of death were sought from hospital records, GP records or death certificates. Data on second malignancies (excluding non-melanoma skin cancer) and cardiac disease were documented from patient notes. Use of medication at 15, 20, 25 and 30 years was collected as a surrogate indicator of the cumulative burden and nature of morbidity. Results: 178 patients were identified who were known to be alive and in the UK 15 years post-SCT. The median follow up from this point was 7.4 years (range 0-20). The majority (170/178) received TBI conditioning with a median dose of 12Gy (range 10-14.4). The median age 15 years post-SCT was 48 years (range 20-74). Original disease was CML in 152 (85.4%) and acute leukaemia in 18 (10.1%). Probabilities of survival at 20, 25 and 30 years post-SCT were 90.0% (CI 85.4-94.6), 79.5% (72.2-86.7) and 73.5% (63.9-83.1). 32/178 (20%) of the 15-year survivors died, at a median of 19.1 years (range 15.1-30.6) post-SCT. Causes of death were available for 26/32 (81%) patients: eleven were due to infection, ten attributed to second malignancy, 2 cardiac, 2 respiratory and 1 was due to acute pancreatitis. Of infective deaths, 9 were from pneumonia and 8/9 of these were associated with underlying lung disease, organ failure or immune suppression. No patient died from primary disease relapse. Second malignancies affected 35/178 (20%) patients with 9 developing them prior to 15 years. The probabilites of having a second malignancy at 15, 20, 25 and 30 years post-SCT were 5.6% (95% CI 2.2-9.0), 17.6% (11.0-23.2), 29.1% (18.9-39.3) and 42.7% (26.1-59.3). Seven patients developed multiple second malignancies. From a total of 43 malignancies the most common tumour sites were breast (n=8) and oral cavity (n=5). Development of second malignancy was associated with significantly reduced survival compared to patients who did not have a second malignancy (p=0.001). Cardiovascular disease affected 14.7% of patients with cumulative incidences of 5.7% (1.7-9.7), 8.2% (3.2-13.2) and 22.3% (12.1-32.5) by 15, 20 and 25 years post-SCT respectively. Fifteen years post SCT, the use of anti-hypertensive. lipid lowering medication and (in women) anti-platelet agents were higher than the use in the gender matched normal population (Table 1). Use of these drugs increased significantly further (p<0.05) between 15 and 30 years to 38.5%, 48.7% and 15.4% respectively. Conclusion: Our data indicate that deaths after 15 years in this group of patient are most frequently due to second malignancy or else pneumonia in a setting of post-transplant complications. There were no deaths due to relapse. The burden of morbidity increased substantially between 15 and 30 years and this warrants lifelong specialist follow up. Table 1. comparison of medication use between study group and age matched population statistics from *HSCIC (UK Health and Social Care Information Centre, Use of prescribed Medicines 2013) 15years post SCT Age matched population data* 25 years post SCT Age matched population data* MALE PATIENTS Median age (range) 47.4 years (29-74)n=100 51.1 years (39-65) n=25 Lipid lowering drugs 15% 11% 52.6% 11% Anti-hypertensive agents 30% 12% 36.8% 12% Anti-platelet agents 5% 4% 15.8% 4% FEMALE PATIENTS Median age (range 48.2 years (20-73) n=78 56.2 years (31-75) n=33 Lipid lowering drugs 23.3% 6% 42.9% 17% Anti-hypertensive agents 35% 10% 42.9% 22% Anti-platelet agents 5% 2% 14.3% 6% Disclosures Apperley: BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Introducing a Predictive Score for Successful Treatment Free Remission in Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood-2019-131500 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 26-26 ◽

Cited By ~ 4

Author(s):

Simone Claudiani ◽

Silvia Metelli ◽

Rafiee Kamvar ◽

Richard Szydlo ◽

Afzal Khan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cox Model ◽

Univariate Analysis ◽

Age At Diagnosis ◽

Predictive Score ◽

Rank Test ◽

Advisory Committees ◽

Tki Resistance

Background: Treatment free remission (TFR) is now a realistic goal of treatment for CML. Approximately 50% of patients (pts) who discontinue tyrosine kinase inhibitors (TKI) after achieving deep molecular responses (DMR) are able to remain off treatment without losing major molecular response (MR3). Data from the largest available TKI stopping trial, EURO-SKI, showed that the most important variable associated with prolonged TFR is the duration of DMR. However, to date no clinical tool exists to guide clinicians and patients in predicting the likelihood of success of TFR attempt. Methods: We performed a retrospective analysis of clinical data from 172 pts with CML in whom treatment was discontinued in 6 hospital centres in order to identify factors associated with TFR. Data analysis started with a training set (TS) derived from pts treated at a single centre which was then validated on a validation set (VS) derived from the 5 other centres. Eligibility criteria included diagnosis of CML in chronic phase, a minimum duration of treatment with TKI of 3 years and discontinuation of TKI after achievement of confirmed ≥MR4. Patients diagnosed in accelerated phase CML and/or who underwent prior allogeneic stem cell transplant were excluded. Kaplan-Meier method was used for univariate analysis, with log-rank test for group comparison. A Cox proportional hazards model was employed with the purpose of choosing the most influential prognostic predictors on the probability of TFR in MR3 (pTFR3) and TFR in MR4 (pTFR4) on the TS. Variables with a p-value ≤0.1 entered in the multivariate analysis (MVA). Proportional hazard assumptions were tested for the final model. A prognostic TFR score was built from the combination of the predictors identified by the Cox model and validated on the VS. Results: The TS included 118 pts, while the VS 54 pts (Table 1). In the TS, the 2-year pTFR3 was 67.4% (95% CI 66.5-68.3%) and the 2-y pTFR4 was 56.8% (95% CI, 55.9-57.7%). The median time to MR3 loss was 3.8 months (range 1-31), and for MR4 loss was 3.2 months (range 0.8-24.5). After loss of MR4, the 1-year probability of MR3 loss was 77% (95% CI, 70.8-73.2%). However, 10 pts (8.5%) resumed TKI after MR4 loss and were not evaluable for time to loss of MR3. In univariate analysis, the variables most significantly associated with higher pTFR3 and pTFR4 were age at diagnosis >40 years (p=0.029 and p=0.002), absence of previous TKI resistance (p=0.003 and p= 0.068), longer duration of MR4 (p=0.003 and p<0.0001) and ≥MR4.5 at stopping (p=0.026 and p= 0.004). Variables entered into the MVA were age at diagnosis, BCR-ABL1 transcript type, Sokal score, dose of TKI at stopping, previous TKI resistance, duration of MR4 at stopping, depth of response at stopping. The Cox model suggested the inclusion of the following variables, for both pTFR3 and pTFR4: duration of MR4, previous TKI resistance, age at diagnosis and transcript type. Using these variables we developed a predictive score (Figure 1a), which was able to identify a good risk population (2-y pTFR3 81.8%, 2-y pTFR4 80%); intermediate (66.6% and 61.5%) and poor risk (42.3% and 30.8%) (overall log-rank test p=0.00092 and p <0.0001 for pTFR3 and pTFR4, respectively)(Figure 1b). The score was tested on the VS of 54 pts. In this population, the overall 2-y pTFR3 and pTFR4 were 61.3% (95% CI, 59.8-62.7%) and 42.6% (95% CI, 41.2-44%), respectively. Despite the small sample size, our score was still able to predict different 2-y TFR probabilities (Figure 1c) in the three risk groups. Of the pts who lost MR3 in the TS (n=39), 37 regained ≥MR3 after resuming TKI; 1 patient did not restart TKI and died from an unrelated cause; 1 patient had only 2 months follow-up after TKI resumption. In the VS, 15 of 21 pts losing MR3 achieved ≥MR3 again after TKI resumption; 3 pts had a follow-up <3 months after MR3 loss, 2 were lost to follow-up and 1 had not yet re-gained MR3 6 months after restarting TKI. In both cohorts no case of disease progression had occurred at last follow-up. Conclusions:This retrospective study confirms the safety of TFR attempt and identifies variables strongly associated with prolonged TFR. The resulting predictive score presented here, if validated in larger patient cohorts, might help in tailoring the choice of TKI discontinuation to the individual patient. Also, most pts who lose MR4 inevitably lose MR3, suggesting the importance of a more intense monitoring strategy in this subgroup. Disclosures Claudiani: Pfizer: Honoraria; Incyte: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Rothwell:Incyte: Speakers Bureau; Novartis: Honoraria, Other: advisory board; Pfizer: Speakers Bureau. Copland:Incyte: 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, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Clark:Ariad/Incyte: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Milojkovic:BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Apperley:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Differences in Quality of Life Between Bendamustine Plus Rituximab Compared with Standard First-Line Treatments in Patients with Previously Untreated Advanced Indolent Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.155.155 ◽

2012 ◽

Vol 120 (21) ◽

pp. 155-155 ◽

Cited By ~ 2

Author(s):

John M. Burke ◽

Richard H. Van der Jagt ◽

Brad S. Kahl ◽

Peter Wood ◽

Tim E. Hawkins ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Final Visit ◽

Advisory Committees ◽

Non Hodgkin's Lymphoma ◽

Pharmaceutical Industries

Abstract Abstract 155 Background Bendamustine is a unique alkylating agent, active as monotherapy and in combination with rituximab for relapsed and refractory indolent non-Hodgkin's lymphoma (NHL). This study compared efficacy and safety of bendamustine-rituximab (BR) with standard treatment regimens of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in first-line treatment of patients with indolent NHL or mantle cell lymphoma (MCL). The primary objective was to determine whether the complete response rate for BR was noninferior to R-CHOP/R-CVP (presented separately). The present analysis reports results for quality of life (QOL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). Methods Previously untreated patients with indolent NHL or MCL were randomized to receive BR (bendamustine 90 mg/m2/day on days 1 and 2; rituximab 375 mg/m2 on day 1 of each 28-day cycle) or R-CHOP/R-CVP (rituximab 375 mg/m2 and vincristine 1.4 mg/m2 (up to maximum 2 mg) on day 1 and prednisone at 100 mg on days 1–5 (of a 21-day cycle), plus either [1] cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 or [2] cyclophosphamide 750 mg/m2 or 1000 mg/m2(investigator choice) on day 1. QLQ-C30 was administered at screening (baseline); after cycles 1, 3, 6, 8; and at the end-of-treatment visit. Linear transformation to standardize raw scores was performed. The QLQ-C30 is composed of 5 multi-item functional scales, 1 global health status (GHS)/QOL scale, 3 symptom scales, and 6 single-item measures; all scores could range from 0 to 100. Rising scores for functional scales and GHS/QOL indicate improvement. Rising scores for symptom scales/single items indicate worsening. GHS/QOL score change at last QLQ-C30 administration postbaseline was interpreted using analysis of covariance. Data from the last observation (end-of-treatment visit) were analyzed. Results The 447 enrolled patients were randomly assigned to 1 of the 2 treatments; 224 to BR (NHL n=187, MCL n=36, missing n=1) and 223 to R-CHOP/R-CVP (NHL n=184, MCL n=38, missing n=1). Treatment groups were well matched for demographic and clinical characteristics. Among all randomized patients, mean change in GHS/QOL score from baseline to final visit was significantly higher (indicating relative improvement) for patients treated with BR than those treated with R-CHOP/R-CVP (3.6 vs −5.1 respectively, P=0.0005). For patients with indolent NHL, mean change in GHS/QOL score by final visit was significantly higher in patients treated with BR than those receiving R-CHOP/R-CVP (2.1 vs −6.3, respectively, P=0.0021); in patients with MCL, mean change in GHS/QOL score was numerically higher in the BR group, but the difference was not statistically significant (10.9 vs 1.6, P=0.0654). All randomized patients receiving BR showed greater improvement in QLQ-C30 Emotional Functioning (from baseline to final visit), compared with patients receiving R-CHOP/R-CVP. Mean change from baseline scores (± SEM) for QLQ-C30 for Cognitive, Physical, Role, and Social Functioning scales of the QLQ-C30 decreased (signifying deteriorating effect) in both treatment groups, with patients treated with BR deteriorating less than patients treated with R-CHOP/R-CVP (Figure). For symptom scales/item measures, patients treated with BR showed larger reductions in mean scores from elevated baseline levels (signifying greater improvement), compared with R-CHOP/R-CVP for Appetite Loss (−2.9 for BR vs −1.1 for R-CHOP/R-CVP), Pain (−5.6 vs −1.7), and Constipation (−0.7 vs 1.8). For symptom scales/item measures of Dyspnea, Fatigue, and Financial Difficulties, both treatments showed deteriorating effects, with BR showing less than R-CHOP/R-CVP: Dyspnea (0.8 vs 4.8), Fatigue (0.5 vs 7.2), and Financial Difficulties (0.9 vs 1.3). Patients receiving R-CHOP/R-CVP had larger reductions in mean scores for Insomnia (−2.1 for BR vs −6.7 for R-CHOP/R-CVP), Diarrhea (0.5 vs −1.3), and Nausea and Vomiting (1.8 vs 0.9). Conclusions In this study, BR significantly improved GHS/QOL, compared with R-CHOP/R-CVP treatment, in previously untreated patients with indolent NHL or MCL. In addition, BR provided improved patient QOL scores for most aspects of functioning and symptoms, as measured by the QLQ-C30. Support: Teva Pharmaceutical Industries Ltd. Disclosures: Burke: Spectrum Pharmaceuticals: Consultancy. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Van der Jagt:Celgene: Consultancy, Research Funding, Sponsorship Other; Novartis: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Roche: Consultancy, Sponsorship, Sponsorship Other; Teva: Consultancy, Research Funding; Incyte: Research Funding; Xanthus: Research Funding; Bristol-Myers Squibb: Consultancy. Kahl:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. MacDonald:Lundbeck: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Teva Pharmaceutical Industries Ltd.: Employment. Munteanu:Teva Pharmaceutical Industries Ltd.: Employment. Clementi:Teva Pharmaceutical Industries Ltd.: Employment. Chen:Teva Pharmaceutical Industries Ltd.: Employment. Flinn:Teva: Research Funding.

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Abexinostat (S78454/PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients

Blood ◽

10.1182/blood.v120.21.3643.3643 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3643-3643 ◽

Cited By ~ 2

Author(s):

Franck Morschhauser ◽

Louis Terriou ◽

Bertrand Coiffier ◽

Gilles Salles ◽

Ioana Kloos ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Abstract Abstract 3643 Background. Abexinostat is a new hydroxymate-based pan-HDAC inhibitor of class I and II that induces apoptosis and cell cycle arrest in various human tumor cell lines and inhibits tumor growth in several lymphoma xenograft models. Aim. The primary objective of the Phase I was to assess the safety profile and to determine the recommended Phase 2 dose (RP2D) as well as the optimal administration schedule of abexinostat in patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia. The secondary objectives included assessment of pharmacokinetic and pharmacodynamic profiles and preliminary antitumor activity. Methods. Eligibility criteria included ECOG ≤ 1 and adequate hematological, renal and hepatic functions. This study used a 3+3 cohort expansion design to reach the RP2D. Three different 3-week schedules of abexinostat were tested: schedule 1 (S1) with 14 days of treatment (day 1 – day 14); schedule 2 (S2) with 10 days of treatment (day 1 – day 5 and day 8 – day 12); schedule 3 (S3) with 12 days of treatment (day 1 – day 4, day 8 – day 11 and day 15 – day 18). The schedules were evaluated at different dose levels of abexinostat b.i.d. (4 h apart): S1 at 30 mg/m2, and all 3 schedules at both 45 mg/m2 and 60 mg/m2. The following were considered DLTs if they occurred in cycle 1: ≥ grade 3 non-hematologic toxicity, prolongation of QTc interval and febrile neutropenia; grade 4 neutropenia or thrombocytopenia; and next cycle postponed by > 1 week. Results. A total of 35 patients were included. The median age was 61 (21–83). The sex ratio M/F was 22/13. The median number of prior therapies was 5 (2–11). Lymphoma subtypes were Hodgkin's lymphoma (HL) (n=11), follicular lymphoma (FL) (n=7), diffuse large B-cell lymphoma (DLBCL) (n=6), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) (n=4), marginal zone B-cell lymphoma (MZL) (n=3), mantle cell lymphoma (MCL) (n=3) and peripheral T-cell lymphoma (n=1). One DLT (thrombocytopenia) was observed in S2 at 45 mg/m2. At 60 mg/m2, 2 DLTs were observed in each schedule: thrombocytopenia in S1 and S2 (2 each), thrombocytopenia and febrile neutropenia (1 each) in S3. Grade 3 and 4 toxicities were exclusively hematologic: thrombocytopenia (G3: 31.4% patients, G4: 25.7% patients), neutropenia (G3: 11.4% patients, G4: 5.7% patients), febrile neutropenia (G3: 2.9% patients, G4: 2.9% patients), anemia (G3: 2.9% patients, G4: 2.9% patients) and leukopenia (G3: 2.9% patients). The other frequent drug-related adverse events were grade 1 and 2: asthenia (34.3% patients), gastro-intestinal disorders (60% patients) and dry skin (17.1% patients). No prolonged QTc intervals were observed in any schedule. A dose reduction occurred in 28.6% patients in S1, 33.3% in S2 and 37.5% in S3. S1 was selected for Phase 2 since it allowed a full week for platelets recovery, a longer drug exposure than S2 and a safety profile similar to the 2 other schedules. Cmax was reached after each administration with median tmax between 0.5 h and 1 h for each schedule and at each dose level. The median apparent terminal elimination half-life was around 4 h. These results are consistent with the limited accumulation of abexinostat with these dose regimens. There is no evidence of time dependent pharmacokinetics. No correlations have been demonstrated so far between histones H3 acetylation in peripheral blood mononuclear cells and PK parameters or clinical activity. Eight out of 29 (27.5%) evaluable patients achieved objective response: 2 complete responses (2 FL) and 6 partial responses (1 FL, 1 CLL, 1 MZL and 3 HL). At the time of data cut off, all but 1 (HL) responses were ongoing between cycle 6 and cycle 22 (median 13.5 cycles). One stable disease (1 MZL) was observed and was still ongoing after cycle 9. Nineteen patients withdrew for progressive disease, including 9 patients who withdrew after at least 2 cycles (4 HL, 2 DLBCL, 1 MCL, 1 MZL and 1 FL). Conclusion. Abexinostat is well tolerated and demonstrates promising durable responses (including CRs) in indolent lymphomas and Hodgkin's lymphoma patients. Enrollment in the Phase II part of the study is ongoing following S1 (3-week cycles – 14 days of treatment) at the RP2D (45 mg/m2b.i.d.). Disclosures: Terriou: Servier: Honoraria; Pfizer: Consultancy; Amgen: Honoraria; GSK: Honoraria. Coiffier:Servier: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kloos:Institut de recherches internationales Servier: Employment. Tavernier:Institut de recherches internationales Servier: Employment. Depil:Institut de recherches Internationales Servier: Employment. Ribrag:Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding.

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Results of the Primary Analysis of Complement A+B: A Phase III Study of Ofatumumab in Combination with Bendamustine Versus Bendamustine Alone in Patients with Indolent Non-Hodgkin's Lymphoma That Is Unresponsive Following Rituximab or Rituximab-Containing Regimen

Blood ◽

10.1182/blood-2018-99-114484 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 450-450

Author(s):

Mathias J Rummel ◽

Ann Janssens ◽

David MacDonald ◽

Mary-Margaret Keating ◽

Jan Zaucha ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Response Rates ◽

Hodgkin's Lymphoma ◽

Phase Iii ◽

Primary Analysis ◽

Advisory Committees ◽

Non Hodgkin's Lymphoma ◽

Grade 3

Abstract Background: Despite a variety of treatment options, indolent non-Hodgkin's lymphoma (iNHL) remains a largely incurable disease with patients experiencing multiple relapses. Both rituximab (RTX) and bendamustine (Benda) are used as single agents for the treatment of relapsed/refractory iNHL. When given in combination to patients with relapsed iNHL, high response rates were observed (Rummel, 2016). Ofatumumab (OFA) is a human, anti-CD20 type-I antibody that binds a distinct epitope from RTX. A phase I/II study showed that OFA has activity in patients with follicular lymphoma (FL) who relapsed after RTX-containing therapy (Hagenbeek, 2008). Based on these experiences, COMPLEMENT A+B evaluated if OFA+Benda would improve progression-free survival (PFS) compared to Benda alone in unresponsive or progressive iNHL after RTX or RTX-containing regimen. Methods: This phase III, open-label, randomized, global, multi-center study enrolled adult patients (≥18 years) with CD20+ small lymphocytic, marginal zone, lymphophasmacytic and Grades 1-3A FL who had either stable disease after or disease progression during or within 6 months of RTX or RTX-containing regimen. Patients were randomized (1:1) to receive either OFA+Benda or Benda. Benda (90 mg/m2 in OFA+Benda arm and 120 mg/m2 in Bendaarm) was given on Days 1 and 2 every 21 days for up to 8 cycles. OFA (1000 mg) was given on Day 1 of Benda cycles and then every 28 days for a total of 12 doses. The primary endpoint was PFS as assessed by an independent review committee (IRC). Key secondary endpoints included PFS in patients with FL, overall response rates (ORR) and overall survival (OS) in all patients and in patients with FL which were tested hierarchically if the prior endpoint was statistically significant. Results: Overall, 346 patients were enrolled (173 in each arm) in 85 centers across 15 countries. Baseline characteristics were similar between the 2 arms. Median (range) age was 62 (21-87) years, majority were males (59%) and 69% had FL. Ann Arbor Stage IVA was common (OFA+Benda: 43%; Benda: 42%). Median duration of follow up was 61.1 months. Median treatment duration was longer in the OFA+Benda arm (OFA+Benda: 260 days; Benda: 135 days). Median (range) number of prior RTX therapy was 1 (1-8). In the OFA+Benda arm, 58% and 65% completed treatment with OFA and Benda, respectively, whereas in the Benda arm, 43% completed treatment. The main reason for premature discontinuation of OFA treatment in OFA+Benda arm was adverse events (AEs), 14%. The main reason for premature treatment discontinuation of Benda was AEs (OFA+Benda: 17%; Benda: 27%). Primary analysis was performed after 217 IRC-assessed PFS events occurred. In the OFA+Benda and Benda arms, 61% and 65% of patients, respectively, had PFS events (Figure 1). Median IRC-assessed PFS was 16.7 months in the OFA+Benda arm and 13.8 months in the Benda arm (hazard ratio [HR]=0.82, 95% confidence interval [CI] [0.62, 1.07]; p=0.1390). Similar results were seen in patients with FL where the median IRC-assessed PFS was similar in FL patients - 16.6 months in the OFA+Benda arm and 12.1 months in the Benda arm (HR=0.76, 95% CI [0.55,1.06]; p=0.1076) (Figure 2). IRC-assessed ORR was similar in both arms (OFA+Benda: 73%; Benda: 75%; difference in ORR [95% C]: -1.2% [-10.4%, 8.1]; p=0.8003). Median OS was 58.2 months and 51.8 months in the OFA+Benda and Benda arms, respectively (HR=0.89, 95% CI [0.63, 1.25]; p=0.4968). Frequencies of deaths (OFA+Benda: 38%; Benda: 41%) and on-treatment deaths (OFA+Benda: 7%; Benda: 9%) were similar in both arms. The main cause of death during the study was disease under study (OFA+Benda: 20%; Benda: 15%). Overall, 73% of patients in the OFA+Benda arm and 80% in the Benda arm experienced a ≥ Grade 3 AE. The most common ≥ Grade 3 AEs were neutropenia, thrombocytopenia, anemia, and leukopenia (Table 1). Conclusions: No significant improvement in PFS was seen with OFA+Benda as compared with Benda alone for patients with RTX-refractory iNHL. The safety profile for OFA was consistent with prior experience. The difference in outcomes compared to those in the GADOLIN trial (Sehn, 2016) could be due to the differences in drug exposure as patients in the GADOLIN study received maintenance anti-CD 20 therapy for up to 2 years; in the patient population as approximately 80% had FL in GADOLIN versus 69% in COMPLEMENT A+B; and in the mechanism of action of type-1 versus type-2 monoclonal antibody. Disclosures Rummel: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Eisai: Honoraria. Janssens:Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. MacDonald:Roche Canada: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Merck: Honoraria. Keating:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davis:Novartis: Employment. Lasher:Novartis: Employment. Lobe:Novartis: Employment. Izquierdo:Novartis: Employment, Equity Ownership. Friedberg:Bayer: Honoraria.

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R-CHOP, Followed by High Dose Therapy and Autologous Stem Cell Rescue (HDT/ASCR), and R-Hypercvad Have Equivalent Progression-Free Survival and Are Superior to R-CHOP Alone in Younger Patients with Mantle Cell Lymphoma: a Comparative Effectiveness Analysis From the National Comprehensive Cancer Network (NCCN) Non-Hodgkin's Lymphoma Outcomes Database Project.

Blood ◽

10.1182/blood.v114.22.403.403 ◽

2009 ◽

Vol 114 (22) ◽

pp. 403-403 ◽

Cited By ~ 8

Author(s):

Ann LaCasce ◽

Jonathan L. Vandergrift ◽

Maria A. Rodriguez ◽

Allison L. Crosby ◽

Eva M. Lepisto ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

Hodgkin's Lymphoma ◽

Advisory Committees ◽

Non Hodgkin's Lymphoma ◽

Mantle Cell

Abstract Abstract 403 Background: Mantle Cell Lymphoma (MCL) is an uncommon histology of non-Hodgkin's lymphoma (NHL) with an unfavorable prognosis for which optimal initial therapy has not been clearly defined. Despite a number of single center studies and uncontrolled trials examining first-line therapy options in MCL, no randomized clinical trials or observational studies have directly compared initial therapeutic options in a single cohort of patients. The role of aggressive induction therapy versus sequential standard chemotherapy remains uncertain, particularly in younger patients. We therefore used the NCCN NHL Outcomes Database to compare R-HyperCVAD, R-CHOP followed by HDT/ASCR and R-CHOP alone as first-line therapy. Our endpoints were progression-free survival (PFS) and overall survival (OS). Methods: The NCCN Non-Hodgkin's Lymphoma Outcomes Database is a prospective cohort study collecting comprehensive clinical, treatment, and outcome data for patients seen at 7 participating NCCN centers. Overall, 229 patients <65 years old with newly diagnosed MCL presented at NCCN institutions between August 2000 and February 2009. Patients were excluded if they (1) were enrolled in clinical trial (n=27), (2) did not receive Rituximab therapy (n=27), (3) did not receive either R-HyperCVAD or R-CHOP induction therapy (n=10), or (4) received both R-CHOP and R-HyperCVAD as induction (n=9). Induction therapy was determined as the initial chemo-immunotherapy received within 180 days of diagnosis. HDT/ASCR consolidation was defined as a transplant after achieving remission. In the R-CHOP+ HDT/ASCR group, ASCR was initiated within 100 days of induction therapy for 90% of patients. The maximum time from induction to ASCR was 172 days. In total, 156 patients were included in the final analysis. Median follow-up was 30 months. Results: Overall, 28 (18%) patients received R-CHOP alone, 29 (19%) received R-CHOP+HDT/ASCR, and 99 (63%) received R-HyperCVAD. No significant differences were observed between therapy groups with regards to co-morbidity (p=0.419), ECOG performance status (p=0.216), B symptoms (p=0.685), bulky disease (p=0.647), IPI risk group (p=0.247), or bone marrow involvement (p=0.651). No difference in PFS (p=0.546) was observed between the R-HyperCVAD and R-CHOP+HDT/ASCR arm (figure 1a). R-CHOP without consolidation had significantly poorer PFS than both R-HyperCVAD (p=0.001) and R-CHOP+HDT/ASCR (p=0.001). No significant differences in OS were observed between the three groups. However, there was a strong trend favoring R-HyperCVAD over R-CHOP (p=0.082, figure 1b). Conclusion: R-CHOP was inferior to both R-HyperCVAD and R-CHOP+HDT/ASCR, which had equal PFS and OS in patients with de novo mantle cell lymphoma. Even with these aggressive induction regimens in younger patient populations, the median PFS in these cohorts was only 3 years. Future trials should focus on incorporating novel agents rather than comparing efficacy of current suboptimal regimens. Disclosures: Czuczman: NCCN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nademanee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blayney:American Society of Clinical Oncology: Membership on an entity's Board of Directors or advisory committees; BlueCross Blue Shield of Michigan: Research Funding; NCCN: Honoraria; University of Michigan Health System: Employment. Friedberg:Genentech: Membership on an entity's Board of Directors or advisory committees.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Clinical and Biological Characteristics and Outcomes of Richter Transformation : A French Multicenter Study from the Filo Group

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

Introduction: About 2 to 10% of patients (pts) diagnosed with Chronic Lymphocytic Leukemia (CLL) develop diffuse large B-cell lymphoma (DLBCL, so-called Richter transformation (RT)) over long-term follow-up. The outcomes of pts with RT are variable and poorly understood and there is no consensus on the best therapeutic approach. The aim of this study was to analyze the clinical characteristics, outcomes and factors predictive of survival in a large series of RT from the French Innovative Leukemia Organization (FILO). Methods: Biopsy-confirmed RT (limited to DLBCL and excluding Hodgkin lymphoma) diagnosed from 2001 to 2018 were identified from eight FILO centers. Clinical and biological characteristics of CLL and RT at diagnosis, including cytogenetics, clonal relation with the pre-existing CLL, Epstein-Barr virus (EBV) status, cell of origin (COO) analyzed by immunohistochemistry and RT score (Tsimberidou AM et al, J Clin Oncol, 2006) were analyzed as well as treatment and outcomes. Overall survivals (OS) were defined as time from CLL and RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analyses were performed with SAS version 9.4. Results: A total of 70 CLL pts who developed RT were identified. The median age at CLL diagnosis was 62 years old (range 35-82), and 50 (71.4 %) were male. The median time to transformation was 5.5 years (range 0 to 22 years), with 12 simultaneous diagnosis of CLL and RT. Prior to RT, 20 (29%) pts had not been treated for CLL, 50 received one (n=21) or more (n= 29) line of treatment ; 6 pts had received a novel agent (ibrutinib, idelalisib or venetoclax). The median age at RT diagnosis was 68 years old (range 42-88). All biopsies were centrally reviewed; 38/58 pts (66%) had elevated LDH (>1.5N) ; 35/65 pts (54 %) had bulky disease (≥ 5 cm); 10/54 (18.5%) pts had del(17p) or TP53 mutation ; 9/42 pts (21%) had a complex karyotype (at least 3 abnormalities). The CLL and RT were clonally related in 27/27 (100%) tested pts. COO by Hans algorithm was non germinal center B cell-like (GCB) in 26/28 pts (93%). EBV was positive or detected in 5/40 (12.5%) pts. The median of Ki67 positivity was 70% (range 30% to 100%). The RT score (based at RT diagnosis on ECOG performance status 2-4, LDH >1.5 x normal, platelets<100 x 109/L, tumor size >5 cm and >1 prior therapy for CLL) was : low risk in 17 pts (31%), low-intermediate risk in 10 pts (19%), high-intermediate risk in 14 pts (25%) and high risk in 14 pts (25%). The most common first-line treatment of RT was immunochemotherapy (n=57, 87%) including R-CHOP-like regimen (n=48, 73%). Autologous or allogeneic transplantation was performed for 7 pts (11%). Response to first-line treatment was complete or partial response in 26 pts (40%), and stable disease or progression in 39 pts (60%). After a median follow-up of 8 years, 51/64 pts (80%) have died. The main causes of death were progressive DLBCL (n=36, 71%), infection (n=8, 16%) or progressive CLL (n=2, 4%). The median OS of the cohort from CLL and RT diagnosis (Figure 1) were 7.8 years and 9.5 months, respectively. In univariate analysis, patients with TP53 disruption at CLL stage, low platelets count, elevated LDH, elevated beta2-microglobulin, high ECOG score, high RT score, EBV positivity and absence of response to first-line RT treatment had worse OS. The ECOG score, platelets count and TP53 disruption remain significant in multivariate Cox-regression. Last, we compared the clinical and biological parameters of two Richter groups defined as: (i) short-term survivors (<12 months, n = 34) and (ii) long-term survivors (>48 months, n = 18). Long survival was significantly associated with elevated platelets count, low LDH, low ECOG, low RT score and response to RT first-line treatment. Discussion: The clinical outcomes of RT patients is poor and novel treatment options are needed. However, a group of long-term survivors was identified, characterized by elevated platelets count, low LDH, low ECOG, low RT score and response to immunochemotherapy. Disclosures Leblond: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Cymbalista:Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; Sunesis: Research Funding; Roche: Research Funding; Abbvie: Honoraria. Guièze:Abbvie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Roche: Honoraria. Broseus:Janssen: Honoraria; Gilead: Honoraria; Novartis: Research Funding. Feugier:gilead: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

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