The Increased Burden of Sickle Cell Disease in Italy: Findings from the Greatalys (Generating Real world Evidence Across ITALy In SCD) Study

Abstract Introduction. Sickle Cell Disease (SCD) is an evolving public health issue with a significant impact on patient survival, quality of life and costs for health systems also in Italy, a multiethnic country where epidemiology has deeply changed. We present final results from the GREATalyS study that aimed to better understand the SCD burden in Italy in terms of prevalence, clinical features, treatments and resource consumption in the clinical practice setting. Methods. Retrospective observational analysis of administrative databases for health resources consumption from a representative sample of Region/Local Health Units in Italy, covering approximately 15.3 million inhabitants. All patients with ≥1hospitalization (outside Emergency Room, ER) with main or secondary discharge diagnosis of SCD (with/without crisis) identified by ICD-9-CM codes were included between January-2010 to December-2017 (up to December 2018 for epidemiologic analysis). Prevalence of SCD in 2018 was projected to the Italian population. Patients were followed-up from the first diagnosis identified within the inclusion period (index date) to death or end of data availability. Treatments and healthcare resource consumption were evaluated on patients with at least 1 year of data availability before and after index date. SCD treatments were classified as SCD-specific, SCD-related, SCD-complication-related. Both day hospitals and ordinary hospitalizations were evaluated. Vaso-occlusive crisis (VOCs) (identified by hospitalization discharge diagnosis for SCD with crisis) and main SCD organ complications were assessed during follow-up. Mean annual healthcare resource costs were analyzed during follow-up according to the NHS perspective in terms of overall treatments, all-cause hospitalizations and out-patients services. Results. SCD prevalence in 2018 was 13 cases per 100,000 inhabitants. Prevalence projected to Italian population estimated in total 7,977 SCD patients in Italy in 2018 (of whom 1,690 and 6,287 were <18 and ≥18 years, respectively, figure 1): 1,279 were estimated with crisis, 5,894 without crisis and 804 unspecified. The study population included in the analysis comprised 1,816 patients (mean age 43.8 years, 58.4% female). Of them, 74.3% were without diagnosis of crisis, 16.1% with crisis, and 9.6% unspecified. Hematology and general medicine were the most frequent admission/discharge hospital departments for a subcohort of patients for which these data were available. During the first year of follow-up (index date included), 50.7% of patients had one all-cause hospitalization, 27.8% had 2, 10.4% had 3 and 11.1% had ≥4, in the second year 44% had at least one hospitalization, while in the third and fourth years 38.2% and 35.8%, respectively (table 1). During the available follow-up period (mean years±SD: 4.9±2.2) the average length of hospitalization stays (table 2) was around 8 days (ordinary hospitalizations) and 130 days (day hospitals). Proportion of patients with a VOC or one SCD complication was 3.7% and 15.2%, with 2 was 2.3% and 6.2% and with ≥3 was 7.7% and 12.8%, respectively. The mean annual number of SCD specific drugs was 0.6±2.7, of SCD related drugs was 3.2±4.5 and of SCD-complications-related drugs was 8.6±10.5. Antibacterials were the more frequently prescribed drugs (53-63%), followed by drugs for acid related disorders (35-48%) and antithrombotic agents (25-34%). Considering all available follow-up, mean annual number of all drugs was 14.9, of hospitalizations was 1.1 and of outpatient specialist services 5.3. Total mean annual cost per patient was €7,917 (€2,201 for prescribed drugs, €3,320 for hospitalizations, and €2,397 for outpatient specialist services, figure 2). Conclusions. This Italian real-world study may have revealed a SCD sub-population probably not noticed yet to SCD centers of reference, and still probably underestimated since ER flows were not present. Similarly, also VOC could be underestimated as only most severe episodes requiring hospitalization were captured. Proportion of patients with antithrombotic agents might be an indicator of the underlying multiorgan complications. The present data describe an SCD population with high resource utilization and heavy economic burden and warrants further efforts to increase an earlier patient identification that could lead to a timely and comprehensive treatment with less SCD-related complications. Figure 1 Figure 1. Disclosures Forni: Bluebirdbio: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Castiglioni: Novartis Farma SpA: Current Employment. Condorelli: Novartis Farma SpA: Current Employment. Valsecchi: Novartis Farma SpA: Current Employment. Premoli: Novartis Farma SpA: Current Employment. Fiocchi: Novaris Farma SpA: Current Employment.

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Fertility Rates in Young Hodgkin Lymphoma Survivors: A Danish Nationwide Cohort Study of 769 Patients

Blood ◽

10.1182/blood-2019-122642 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2841-2841

Author(s):

Andreas Kiesbye Øvlisen ◽

Lasse H. Jakobsen ◽

Kristian Hay Kragholm ◽

Martin Hutchings ◽

Henrik Frederiksen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Index Date ◽

Cox Regression ◽

Fertility Rates ◽

Grant Funding ◽

Advisory Committees ◽

First Child ◽

Funding Research

Introduction: The vast majority of young adults with Hodgkin lymphoma (HL) are cured by contemporary first line treatments. Treatment-related long-term toxicities can have a negative impact on survivorship and the risk of infertility may be particularly pertinent to young HL survivors. This study aimed to investigate the fertility rate (rate of first child after index date) over time in patients with HL compared to the matched controls. Methods: All Danish patients with HL, including classical and lymphocyte predominant HL, diagnosed in the period 2000-2015 were identified in the Danish Lymphoma Registry. Patients aged 18-40 years at diagnosis with documented complete remission after first line therapy were included. Patient data were merged with the Danish Fertility Database and the Medical Register of Births and Deaths. For each HL patient, five random Danish citizens alive at the index date of the HL patient were matched on birth date, sex, and parenthood status (categorical; with children vs without children at the index date). Follow-up was measured from 9 months post diagnosis (index date) until the time of first child, relapse, death, or censoring, whichever came first. Patients with progression/relapse within the first 9 months after diagnosis were excluded. Cumulative incidences of first living child after the index date were computed for the entire cohort and stratified on sex using the Aalen-Johansen estimator with death or relapse before first child after index date as competing events. Cox regression was used to compare the rates of first child of HL patients and matched controls by clinical subgroups and estimated for males and females separately. Results: A total of 769 HL patients were included (male:female ratio 1.2, median age 30 years) and median follow-up was 9.9 years. The mean numbers of children per person at start of follow-up were similar in patients and matched controls (female HL patients 0.64 vs matched controls 0.63 children per individual; male HL patients 0.56 vs matched controls 0.54 children per individual). At the end of follow-up, average numbers of children were higher in male and female HL patients (female HL patients 1.22 children per individual; matched control 1.14 children per individual) and males (HL patients 1.00 children per individual; matched controls 0.92 children per individual). The cumulative incidence of first child after index date in female HL patients was lower during the first three years of follow-up compared to the matched controls. However, beyond three years of follow-up the cumulative incidences of first child after index date were similar (Figure 1A). Among male HL patients the cumulative incidence of first child after index date was higher than that of the matched controls throughout the entire follow-up (Figure 1B). Overall, fertility rates were higher in HL patients (males, 36.7 per 1,000 person years; females, 41.7 per 1,000 person years) as compared to the matched controls (males, 24.2 per 1,000 person years; females, 33.0 per 1,000 person years). The Cox regression showed that both male and female patients with HL had higher fertility rates as compared to matched controls (males, HR 1.5, p-value < 0.001; females, HR 1.2, p-value = 0.012; Table 1). This was also observed in specific clinical subgroups, i.e. ages 18-30 years, CCI 0, no children prior to diagnosis, and limited stage disease. Moreover, among patients receiving 6+ cycles of chemotherapy, fertility rates were not lower than expected (Table 1). Conclusion: The fertility rates for long-term HL survivors without progression/relapse were higher than in matched controls, in particular for male HL patients. Elevated fertility rates as compared to the matched controls were observed for lower age (<30 years), limited stage disease, and for patients without children at the time of diagnosis. No clinical subgroup did significantly decrease the fertility rates. Disclosures Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Novartis: Research Funding. Frederiksen:Abbvie: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Janssen: Research Funding. Eloranta:Karolinska Institutet: Other: coordinator for a public-private real world evidence; Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence. Glimelius:Janssen Pharmaceuticals: Honoraria. Ekstroem Smedby:Janssen Cilag: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Takeda: Honoraria, Other: Grant funding, Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

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Frequency of Thrombosis Is Higher in MPN Patients Who Develop Second Cancer Than in Controls

Blood ◽

10.1182/blood-2019-127982 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4170-4170 ◽

Cited By ~ 1

Author(s):

Valerio De Stefano ◽

Arianna Ghirardi ◽

Arianna Masciulli ◽

Alessandra Carobbio ◽

Francesca Palandri ◽

...

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Board Of Directors ◽

Cumulative Incidence ◽

Odds Ratio ◽

Arterial Thrombosis ◽

Index Date ◽

Second Cancer ◽

Advisory Committees

Introduction Malignancy can be heralded by unprovoked venous thromboembolism (VTE) but also by arterial thrombosis. To date it is unknown whether this association is present also in myeloproliferative neoplasms (MPN), in which arterial thrombosis is more frequent that venous thrombosis and solid tumors are reported with an increased frequency. The MPN-K nested case-control study addressed the impact of cytoreductive drugs on the risk of developing second cancer in MPN patients (Barbui T et al, Leukemia 2019); here we re-examined the study database to evaluate the frequency and type of vascular complications in MPN patients with second cancer excluding leukemia and to establish whether arterial and venous thrombosis during follow-up after diagnosis of MPN could predict the occurrence of a second cancer. Patients and methods Cases were patients with second cancer diagnosed concurrently or subsequent to the diagnosis of MPN. Controls were MPN patients without second cancer. For each case with second cancer, up to 3 cancer-free controls were matched by each center for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. Each set consisting of one case and their matched-controls had a similar observational period (from MPN diagnosis until the index date of diagnosis for the second cancer). The study included 647 cases with second cancer (carcinoma, non-melanoma-skin cancers, hematological secondary cancer and melanoma). The most frequent category was carcinoma (n=426, 65.8%). Cases were comparable with the 1,234 matched controls for demographics, type of MPN, and exposure to potential confounders such as mutational profile, abnormal karyotype and cardiovascular risk factors. The thrombotic events of interest were ischemic stroke, transient ischemic attacks, acute coronary syndromes, peripheral arterial thrombosis, deep venous thrombosis (including thrombosis of cerebral and splanchnic veins) and pulmonary embolism. Thrombosis had to be concurrent with or in the 2 years before MPN diagnosis or occurring after MPN diagnosis. The cumulative incidence of either arterial or venous thrombosis from MPN diagnosis was estimated by the Kaplan-Meier method and was compared between cases and controls using the log-rank test. A conditional logistic regression model estimated the Odds Ratio (OR) with 95% Confidence Interval (CI) of second cancer associated with the occurrence of thrombosis before/at diagnosis of MPN and during follow-up. Other covariates were patient age, cardiovascular risk factors, the JAK2V617F mutation, and treatment during follow-up. Results Approximately 20% of either MPN cases or controls had thrombosis before MPN or at diagnosis (19.8% vs. 21.1%, respectively, p=0.462). After a median observation time from diagnosis of MPN to an index date of 4.5 years (interquartile range 1.5-8.2) in cases and 3.7 years (interquartile range 1.5-7.5) in controls, cases showed a percentage of thrombosis higher than in controls (75/647, 11.6% vs. 100/1234, 8.1%, respectively, p=0.013). Approximately one-third of thrombosis preceding cancer occurred in the 12 months before the diagnosis of second cancer (22/75, 29.3%). The excess of thrombosis in cases was due to a higher frequency of arterial thrombosis (6.2% vs. 3.7%, p=0.015), whereas no significant difference was found for venous thrombosis (5.4% vs. 4.3%, p=0.277). While the cumulative incidence of venous thrombosis over time was similar among cases and controls (p=0.864), the cumulative incidence of arterial thrombosis was higher in cases with second cancer (p=0.006) (Figure 1). The excess of arterial thrombosis after MPN diagnosis was limited to cases with carcinoma (6.8% vs 3.9%, p=0.027). In a multivariable model, arterial thrombosis during the follow-up was confirmed to be an independent predictor factor for carcinoma, with an odds ratio of 1.97 (95%CI 1.14-3.41, p=0.015). Conclusions. These findings reveal an association of arterial thrombosis with subsequent second cancer (namely carcinoma) in MPN patients. A possible biological plausibility for this link may be related to an underlying common pathogenic mechanism such as an aberrant inflammatory response consistently found in MPN. This observation may have practical implications and suggests careful clinical surveillance for early diagnosis of second cancer in MPN patients with arterial thrombosis during the follow-up. Disclosures Palandri: Novartis: Consultancy, Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Bonifacio:Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Rumi:novartis: Honoraria, Research Funding. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Lunghi:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. McMullin:Italopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

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Treatment Patterns and Outcomes in Patients with Relapsed/Refractory Follicular Lymphoma Who Received Third Line Therapy at the Christie NHS Foundation Trust in the UK

Blood ◽

10.1182/blood-2021-148490 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 5011-5011

Author(s):

Kim Linton ◽

Cristina Julian ◽

Adam Gibb ◽

Ellie White ◽

Emma-Frances Armstrong ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Index Date ◽

Treatment Patterns ◽

Advisory Committees ◽

Time Period ◽

Third Line ◽

Privately Held

Abstract Background: There are limited data on real-world treatment patterns and outcomes for follicular lymphoma (FL) in the relapsed/refractory (r/r) setting, with shorter response durations reported after each relapse (Link et al, 2019; Rivas-Delgado et al, 2019 and Batlevi et al, 2020). We examined treatment patterns for patients with FL initiating third line (3L) therapy at a single institution by time period in the post-rituximab era (2004-2010 and 2011-2020), and clinical outcomes for the overall cohort receiving therapy between 2004 and 2020. Methods: This is a retrospective, observational study of patients with FL who initiated 3L therapy between 2004 and 2020 in routine clinical practice at The Christie NHS Foundation Trust, UK. We selected patients aged ≥18 years at 3L initiation, with histologically documented FL Grade 1−3a treated with two prior lines of systemic therapy including an anti-CD20 monoclonal antibody and an alkylating agent, and at least one year of follow-up after initiating 3L therapy; follow-up ended June 2021. We excluded patients with grade 3b FL or transformation to high grade lymphoma any time before 3L treatment. Overall response rate (ORR) and complete response (CR) to 3L therapy was calculated, and overall survival (OS), progression free survival (PFS) and time to next treatment (TTNT) were estimated using the Kaplan-Meier (KM) method with 3L therapy initiation date as the index date. Results: Overall, 41 patients met all eligibility criteria; 11 and 30 patients received 3L therapy between 2004-2010 and 2011-2020, respectively. Median age at index date was 59 years and 53.7% were male; 73.2% had grade 1 or 2 FL; 78.1% had advanced stage (III/IV) FL at diagnosis. Median follow-up was 33.9 (IQR: 14.5, 63.0) months, and median time from diagnosis to 3L treatment was 60.2 (IQR: 29.4, 89.1) months. The most common regimen in 3L was rituximab plus bendamustine (R-benda) followed by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab used as a single agent (R-mono). Treatment patterns differed by time period (Table 1). R-benda was more commonly used between 2011 and 2020. The most common sequence was rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) followed by R-CHOP and R-benda (Figure 1). ORR to 3L treatment was 61.0%, CR 29.3%. Median OS, PFS and TTNT with 95% confidence interval (CI) were 70.0 (30.2-NR), 19.2 (9.5-34.7) and 11.8 (9.0-27.6) months after 3L initiation, respectively. Two- and five-year OS rates were 79% and 50%, and two-year PFS rate was 37%. Conclusions: Patients with r/r FL treated in the routine 3L setting have highly variable treatment patterns and unfavorable outcomes, representing a continued unmet medical need. This study is limited by its small size and evolving treatments, warranting a larger study of more recently treated 3L patients to evaluate the impact of modern treatment pathways and novel therapies on clinical outcomes for r/r FL. Figure 1 Figure 1. Disclosures Linton: University of Manchester: Current Employment; BeiGene: Research Funding; Hartley Taylor: Honoraria; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Julian: Genentech, Inc.: Current Employment, Current holder of stock options in a privately-held company. Gibb: The Christie NHS Foundation Trust: Current Employment; Takeda: Honoraria, Research Funding, Speakers Bureau. Li: Genesis Research: Current Employment. Liu: Genesis Research: Current Employment. Shewade: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Radford: BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company.

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Real-World Effectiveness of Voxelotor for Treating Sickle Cell Disease in the US

Blood ◽

10.1182/blood-2020-140525 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 25-25

Author(s):

Ahmar Urooj Zaidi ◽

Thokozeni Lipato ◽

Ofelia A. Alvarez ◽

Alexander Lonshteyn ◽

Derek Weycker ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Index Date ◽

Health Claims ◽

Transfusion Rate ◽

Publicly Traded ◽

Advisory Committees ◽

The Us

Background: Until late 2019, few treatments had been approved by the FDA for treating sickle cell disease (SCD). Voxelotor (Oxbryta®) is a sickle hemoglobin-polymerization inhibitor approved by the FDA in November 2019 for treatment of SCD in adults and adolescents aged ≥12 years under an accelerated approval based on results of the pivotal HOPE study. In HOPE, voxelotor increased average hemoglobin (Hb) by 1.1 g/dL from baseline in patients with 1-10 vaso-occlusive crises (VOCs) in the previous year and a Hb level between 5.5 and 10.5 g/dL who were not transfusion dependent. Of the participants on voxelotor 1500 mg, 51% had a Hb response >1.0 g/dL at week 24 (Vichinsky et al, NEJM 2019). This study sought to assess the real-world effectiveness of voxelotor based on data during the first 6 months post FDA approval. Methods: Data on medical and pharmacy claims for patients who were aged ≥12 years and receiving voxelotor from December 2019 to May 2020 were obtained from the Symphony Health claims dataset. For each patient, the date of the first voxelotor claim was defined as the "index date." Patients with at least 1 year's data prior to the index date were included in the analyses. Patients' demographic and clinical characteristics were summarized descriptively. Standardized annualized rates of transfusions and VOCs per patient per year (PPPY) prior to and after voxelotor initiation were compared. A subset of patients in the Symphony Health claims dataset had Hb lab data available. Patients with at least 1 Hb result within 30 days prior to the index date and at least 1 Hb result after the index date were included for Hb analyses. For these patients, change in Hb and the percentage of patients achieving a >1 g/dL increase in Hb were summarized. Confidence intervals and P values for changes in outcomes were based on bootstrapping. Results: As of May 31, 2020, 1275 patients from the Symphony Health claims datasets were identified who received voxelotor (40% male, mean age 35.7 years). In the year prior to voxelotor initiation, 715 (56.1%) of these patients received hydroxyurea, 121 (9.5%) received L-glutamine, 166 (13.0%) received at least 1 transfusion, 17 (1.3%) were on chronic transfusion (≥8 transfusions per year), and 681 (53.4%) had 1 or more VOCs. Mean (SD) follow-up was 64.9 (40.7) days. Among 1275 patients, 175 and 52 patients had at least 1 Hb level measurement during the 1 year prior to and after voxelotor initiation, respectively. Among the subset of patients with their Hb level tested within 30 days prior to the index date and at least 1 Hb level after index date (n=22), the baseline average Hb level was 8.0 g/dL (SD 1.4, median 7.9 g/dL, range 5.0-11.8 g/dL). Mean increase in Hb from baseline was 1.1-1.3 g/dL (Table 1) depending on the approach used to calculate Hb levels after voxelotor initiation; 55% (95% CI 32%-77%) of patients achieved a Hb increase >1 g/dL after voxelotor initiation. Among all 1275 patients, mean (SD) overall transfusion rates declined from 0.45 (1.67) PPPY pre-index to 0.31 (1.88) post-index, a change of -0.14 PPPY (P=0.005). Among 169 patients who received at least 1 transfusion in the year prior to initiation of voxelotor, the transfusion rate dropped from 3.39 (3.34) to 1.75 (4.30) PPPY, a change of -1.64 PPPY (P<0.001). Among 17 patients receiving chronic transfusions, the transfusion rate dropped from 11.29 (3.12) to 6.74 (7.37) PPPY, a change of -4.56 PPPY (P=0.013) (Table 2). After voxelotor initiation, the annualized rates of VOC were numerically reduced from 3.86 (6.69) to 3.64 (8.54) (P=0.248). To address the potential bias from the relatively short follow-up duration, similar results of transfusion and VOC rates were observed among patients with at least 30 days of follow-up or when only events within 3 months prior to index date were considered. Conclusions: Based on the first 6 months' data after the approval of voxelotor in the US, in real-world practice, voxelotor increases Hb by at least 1 g/dL, consistent with the HOPE randomized controlled trial results. Evidence suggests that transfusion rates decreased after voxelotor initiation. A favorable downward trend in VOC rates was also observed. This real-world evidence provides additional support for the use of this novel therapy in the treatment of hemolytic anemia and its associated complications in the SCD population. Further evaluation with a larger sample size and longer follow-up will help to confirm these findings. Disclosures Zaidi: Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Emmaus Life Sciences: Consultancy, Honoraria. Alvarez:Novartis: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lonshteyn:Policy Analysis Inc.: Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Weycker:Policy Analysis Inc.: Current Employment, Current equity holder in publicly-traded company; Novartis: Research Funding; Global Blood Therapeutics: Research Funding. Pham:Policy Analysis Inc.: Current Employment; Global Blood Therapeutics: Research Funding; Novartis: Research Funding. Delea:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Policy Analysis Inc.: Current Employment, Current equity holder in private company. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cong:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau; Bluebird Bio: Consultancy.

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Economic Burden of Newly Diagnosed Acute Myeloid Leukemia: A Retrospective Study Using the SEER-Medicare Database

Blood ◽

10.1182/blood-2020-136768 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-45

Author(s):

Ashley Tabah ◽

David Huggar ◽

Krystal Huey ◽

Ronda Copher ◽

Zheng-Yi Zhou ◽

...

Keyword(s):

Board Of Directors ◽

Economic Burden ◽

Research Funding ◽

Index Date ◽

Publicly Traded ◽

Advisory Committees ◽

Analysis Group ◽

Remission Period ◽

Medicare Database

Introduction: Acute myeloid leukemia (AML) poses significant economic burden on the healthcare system, particularly during induction therapy and at disease relapse. The burden associated with ongoing post-remission therapy is less clear. In patients diagnosed with AML enrolled in Medicare who received an induction therapy and achieved disease remission, we assessed the healthcare resource utilization (HCRU) and costs associated with each disease period (induction, early/late post-remission, and post-relapse). Methods: A retrospective analysis was conducted using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, comprising Medicare claims (parts A, B, and D from 2007 to 2016) and the US National Cancer Institute's SEER database (cancer diagnoses from 2007 to 2015). Identified patients had a diagnosis of AML in the SEER registry, were ≥ 65 years at the AML diagnosis date, initiated chemotherapy post-AML diagnosis (i.e. induction), and had an International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) diagnosis code for AML remission following the start of therapy. Patients were excluded if they had another blood malignancy, had received a prior hematopoietic stem cell transplant, or were enrolled in a clinical trial. Induction was defined as any therapy received from the date of first post-diagnosis chemotherapy initiation (index date) to the end of the cycle during which a patient had an ICD-9/10 code for AML remission. The 6 months prior to the index date was defined as the baseline period. Post-remission therapy was divided into an early post-remission period, which included any therapy initiated within the first 60 days (≤ 60 d) after end of induction, and a late post-remission period, which included therapy initiated more than 60 days (> 60 d) after end of induction. If specific treatment information was available, late post-remission therapy was defined by a treatment switch occurring > 60 d after end of induction. Post-remission therapy ended at the earliest of relapse or end of follow-up (i.e., death, end of eligibility, or end of available data [December 31, 2016]). The post-relapse period was from the date of first AML relapse ICD-9/10 code after remission to the end of follow-up. Baseline patient characteristics, as well as HCRU and costs (adjusted to 2019 US dollars) during the baseline, induction, post-remission, and post-relapse periods, were summarized descriptively. HCRU and costs associated with induction and post-remission therapy periods were assessed during days that were part of a treatment cycle. The average per patient per month (PPPM) HCRU and costs were reported. Duration of response (DoR) from the first remission to the earliest of relapse or death was estimated using Kaplan-Meier analysis. Results: A total of 530 patients were identified. The median age at AML diagnosis was 73 years, 53.6% of patients were male, and 80.6% were white. The median time from index date to the end of follow-up was 13.5 months. Most patients received therapy with hypomethylating agents during the AML treatment. A total of 31.9% of patients who achieved remission did not receive post-remission therapy during follow-up; for these patients, mean (median) time from end of induction to relapse or end of follow-up was 125 (23) days. A total of 63.2% of patients received chemotherapy in the early post-remission period, and 43.0% of all patients went on to receive chemotherapy in the late post-remission period. The median DoR was 5.8 months; a total of 48.9% of patients had relapsed and 80.2% had died by the end of follow-up. The mean PPPM healthcare costs were highest for induction, followed by post-relapse, early post-remission, and late post-remission periods (Table). Costs associated with the inpatient (IP) setting were the greatest contributor to PPPM costs across all periods. IP visits were most common during induction with 92.1% of patients having ≥ 1 IP visit, relative to 53.8% during baseline, 65.7% during early post-remission, 71.5% during late post-remission, and 91.1% post-relapse. Conclusions: The economic burden of relapse is approximately 1.2 and 1.6 times higher than the mean PPPM healthcare costs during early and late post-remission periods, respectively. There exists a large unmet need for therapies that will extend the duration of the post-remission period and reduce the overall economic burden of AML. Disclosures Tabah: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Huggar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Karyopharm Therapeutics: Current equity holder in publicly-traded company; FibroGen: Current equity holder in publicly-traded company. Huey:Bristol Myers Squibb: Current Employment. Copher:Bristol Myers Squibb: Current Employment. Zhou:BMS: Other: Employee of Analysis Group Inc., which received consulting fees. Zichlin:BMS: Other: Employee of Analysis Group Inc., which received consulting fees. Koenigsberg:BMS: Other: Employee of Analysis Group Inc., which received consulting fees. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Prognostic Markers in Core-Binding Factor Acute Myeloid Leukaemia

Blood ◽

10.1182/blood.v126.23.2599.2599 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2599-2599

Author(s):

Ashvind A Prabahran ◽

Mark Tacey ◽

Shaun Fleming ◽

Danielle Strong ◽

Andrew Wei ◽

...

Keyword(s):

Board Of Directors ◽

Prognostic Markers ◽

Univariate Analysis ◽

Data Availability ◽

Core Binding Factor ◽

Advisory Committees ◽

Copy Numbers ◽

Binding Factor ◽

Intermediate Dose

Abstract Introduction While core-binding factor acute myeloid leukaemia (CBF AML) as defined by t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) has a favourable prognosis, 30-40% of patients still relapse after chemotherapy. Risk factors predictive for relapse include increasing age and white cell count (WCC), poor performance status and adverse-risk cytogenetics. Rising minimal residual disease (MRD) by molecular monitoring and receptor tyrosine kinase (RTK) mutations also predict higher risk of relapse (Yin et. al., Blood 2012; Jourdan et. al., Blood 2013). Aims 1. Identify prognostic markers for CBF AML 2. Determine significance of persistent molecular positivity in complete remission (CR) post-treatment Methods We undertook a retrospective audit from 2001-2012 at 4 tertiary-level hospitals. The inclusion criteria were adult patients >18 years with de novo CBF AML treated with at least intermediate dose cytarabine. Co-variates included in univariate analysis and then multivariate analysis if predictive of overall survival (OS) and relapse-free survival (RFS) included age, WCC, sex, cytogenetics, RTK mutations (KIT and FLT3) and MRD (RUNX1-RUNX1T1 or CBFB-MYH11 bone marrow (BM) qPCR post-induction (MRD1). Univariate analysis was also performed for BM MRD after each consolidation cycle 1-4 (MRD2-5 respectively). Results 70 patients were identified (Male=39, Female=31; inv(16)=30, t(8:21)=40). The median age at diagnosis was 43 years (range 17-73). There were 2 induction deaths and 68 achieved morphological CR. OS was 70.7% and RFS was 59.1% at a median follow-up of 31.4 months. There were 16 deaths (inv(16)=9, t(8;21)=7; median OS 14.8 months; 9 from relapsed AML, 4 treatment-related complications, 2 graft-versus-host disease (GVHD) and 1 unrelated). 24 relapses (22 morphological, 2 molecular) occurred with a median RFS of 9 months (inv(16)=17, t(8;21)=7). RFS was significantly worse for inv(16) vs t(8;21) (39% vs 75%; p=0.0004). The inv(16) cohort had significantly higher median WCC of 33x109/L vs 10.5x109/L t(8;21). Univariate analysis identified age (p=0.032) and WCC>40 (p=0.002) as significant for inferior OS and RFS respectively. The impact of KIT (n=34, Pos=14, p=0.158) and FLT3 (n=27, Pos=2, p=0.152) mutations on OS/RFS were non-significant independent of CBF AML subtype. However, there were systematic differences in KIT and FLT3 data availability in the relapse vs non-relapse cohorts (Absent data: KIT 17/24(71%) vs 19/46(41%); FLT3 17/24(71%) vs 26/46(57%)). MRD analysis by qPCR at the different timepoints (MRD1=37, MRD2=24, MRD3=28, MRD4=23, MRD5=12) by < or ≥3 log reduction in comparison to pre-treatment values was not predictive of OS/RFS. On multivariate analysis excluding RTK mutations, age was the only significant predictor for OS (p=0.032) and WCC>40 for relapse (p=0.025). Standard vs intermediate/high-dose cytarabine in induction had no impact on OS/RFS but ≥3 consolidation cycles of intermediate-dose cytarabine improved OS vs ≤2 cycles (p=0.035). There was no significant difference in the median age of the cohorts receiving consolidation chemotherapy (≤2: n=37, 47 years, ≥3: n=30, 35.5 years). Median BM qPCR values increased from 0 to 11% at relapse for inv(16) at a median duration of 4.3 months (range 1-8) and 0.05 to 178% for t(8;21) at 6 months (range 5-35) respectively. Of the 43 with durable CR, 28 maintained PB or BM qPCR values of 0-0.1% or <10 copy numbers throughout follow-up for 2 years post-completion of consolidation treatment. 6 had qPCR values >0.1% or >50 copy numbers; 5 were t(8;21) achieving PCR negativity at a range of 9-24 months post-completion of consolidation. Of the 24 who relapsed, 15 proceeded to stem cell transplant (13 allograft: inv(16)=8, t(8;21)=5; 2 autograft: inv(16)). There were 6 deaths in the allograft group (inv(16)=3, t(8;21)=3) and none in the autograft group. 3 deaths were related to relapsed disease post-allograft, 2 GVHD and 1 from non-GVHD complications. Conclusions Age is a significant predictor of OS in our CBF AML cohort while WCC is more predictive of relapse risk. The significance of RTK mutations and MRD is limited by data availability. ≥3 consolidation cycles of intermediate-dose cytarabine improved OS in comparison to fewer cycles. Stable low level MRD did not predict relapse. Regular monitoring of PB and BM qPCR values post-completion of treatment is necessary for prediction of subsequent relapse. Figure 1. Figure 1. Disclosures Grigg: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Szer:Alexion Pharmaceuticals Australasia Pty Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142642 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Maria-Victoria Mateos ◽

Rohan Medhekar ◽

Istvan Majer ◽

Mehmet Turgut

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Literature Review ◽

Board Of Directors ◽

Unmet Need ◽

Publicly Traded ◽

First Line ◽

Advisory Committees ◽

Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

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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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