Four-Fold Increased Mortality from Sars-Cov-2 Infection in Patients with Hematologic Versus Non-Hematologic Malignancies Treated at the Largest Tertiary COVID-19 Center in Chicago/Rush University Medical Center (March 1, 2020-December 31,2020)

Abstract N.K.Y., P.C., & P.R.Y. contributed equally to this study Introduction: Many studies have concluded that active cancer patients infected with SARS-CoV-2 have a more complicated infection course and worse outcomes compared to the general patient population hospitalized with COVID-19. However, little evidence exists whether having a history of cancer plays a significant role in these observations. Patients with hematologic malignancy (HM) might have worse prognosis among all cancer patients but the reason remains unclear. Our objective is to evaluate outcomes and severity of COVID-19 in patients with Hematological Malignancy (HM) versus Solid-tumors (ST) in different clinical settings and also compare these outcomes within the group of patients with hematological malignancies. Methods: This retrospective study examines risk factors and outcomes of COVID-19 in patients with a history of cancer and laboratory-confirmed COVID-19 diagnosis between March 1 st, 2020, and December 31 st, 2020, at Rush University Medical Center, one of the largest COVID-19 tertiary care hospitals in Chicago. Baseline characteristics, malignancy type and types of cancer treatment within the last 30 days were recorded. Measures of COVID-19 severity included hospital admission versus outpatient care, use of oxygen, intensive care unit (ICU) admission, and mechanical ventilation. The primary outcome was death. Statistical analysis was conducted using optimal discriminant analysis, a non-parametric exact machine-learning algorithm which identifies the relationship between independent and dependent variables that maximizes model predictive accuracy adjusted to remove the effect of chance. Analysis was performed separately for each attribute using the entire sample ("training" analysis), then one-sample jackknife analysis was conducted to estimate cross-generalizability of findings using the model to classify an independent random sample. Results: 378 total patients with a history of cancer tested positive for COVID-19 within the time frame of the study. Of these, 294 (78%) patients had ST malignancy and 84 (22%) patients had HM. Characteristics and outcomes are summarized in Table 1. ST patients were marginally older than HM patients (p<0.025). A significantly greater proportion of HM patients were male (p<0.0023). HM and ST patients did not differ with respect to percentage receiving active cancer treatment (p<0.81). Compared to ST patients, more HM patients had received corticosteroids in the 30 days prior to COVID-19 diagnosis (p<0.017), had higher rates of hospitalization (p<0.0013) and ICU requirement (p<0.0001) with a significantly longer length of ICU stay (p<0.0036). Compared to ST patients, HM patients also required oxygen (p<0.002) and mechanical ventilation (p<0.0005) more often and had a 3.88-fold statistically higher death rate (OR 3.88 [95% CI 1.62-9.29] p<0.003). Patients with HM are categorized by disease subtype and summarized in Table 2. The case fatality rate from COVID-19 was 33.3% for patients with myeloproliferative neoplasms/myelodysplastic syndromes (MPN/MDS), 21.4% for patients with chronic lymphocytic leukemia (CLL), 13.6% for patients with non-Hodgkin lymphoma, 10.5% for patients with plasma cell neoplasms, and 4.5% for patients with acute leukemia. When looking at outcomes, CLL had the highest percentage of patients requiring hospital admission, oxygen, and ICU admission, and MPN/MDS had the highest percentage of patients requiring mechanical ventilation. Conclusions: Patients with hematologic malignancies had more severe COVID-19 illness and hospitalization rates and a 3.88-fold higher rate of death than patients with solid tumors. The comparable proportion of patients on anti-cancer therapy despite differences in survival suggests that being on anti-cancer therapy is less important than the underlying diagnosis of HM versus ST as a determinant of poor outcomes. Clinicians should closely monitor and initiate early COVID-19 treatments for all patients with HM and COVID-19. Because HM are highly heterogenous group of cancers, it is important to look at subtypes in greater detail. Numerous patient-level, disease-specific, and therapy-related factors may impact outcomes of COVID-19 among patients with HM, and we are currently analyzing additional data to better understand the factors which make this disease group more susceptible to severe infection. Figure 1 Figure 1. Disclosures Kuzel: Sanofi-Genzyme Genomic Health Tempus laboratories Bristol Meyers Squibb: Honoraria; Genomic Health: Membership on an entity's Board of Directors or advisory committees; Exelixis: Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other; Curio Science: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen Corp: Membership on an entity's Board of Directors or advisory committees; CVS: Membership on an entity's Board of Directors or advisory committees; Tempus Laboratories: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data Monitoring Committee Membership; Amgen: Other: Data Monitoring Committee Membership; SeaGen: Other: Data Monitoring Committee Membership; Medpace: Other: Data Monitoring Committee Membership.

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Safety and Efficacy of Tenalisib Given in Combination with Romidepsin in Patients with Relapsed/Refractory T-Cell Lymphoma: Final Results from a Phase I/II Open Label Multi-Center Study

Blood ◽

10.1182/blood-2021-145851 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1365-1365

Author(s):

Swaminathan P Iyer ◽

Auris Huen ◽

Weiyun Z. Ai ◽

Deepa Jagadeesh ◽

Mary Jo Lechowicz ◽

...

Keyword(s):

Family Member ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Data Monitoring Committee ◽

Data Monitoring ◽

Open Label ◽

Advisory Committees ◽

Monitoring Committee ◽

Committee Membership

Abstract Background: Tenalisib (RP6530), a highly selective PI3K δ/γ and SIK3 inhibitor has shown promising activity as a single agent in T Cell lymphoma (TCL) and a differentiated safety profile (Huen A et al., Cancers,2020). In vitro studies in TCL cell lines showed synergistic activity when tenalisib was combined with romidepsin. A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics, and efficacy in patients with relapsed/refractory (R/R) TCL peripheral (PTCL) and cutaneous T cell lymphoma (CTCL) (NCT03770000). Methods: This was a multi-center, open label study. We performed a Phase I, 3+3 dose escalation study to determine the MTD/recommended Phase II dose (RP2D), and a dose expansion study in both the subtypes separately (PTCL and CTCL). Patients received tenalisib at doses ranging from 400-800 mg BID (fasting), orally in combination with romidepsin at doses ranging from 12-14 mg/m 2, intravenously, given on Days 1,8 and 15 of a 28-day cycle. Results: Thirty-three patients (16 PTCL and 17 CTCL) who received more than 1 prior therapy were enrolled in the study; 9 in dose escalation and 24 in dose expansion. Of the 33 patients, 64% were refractory to their last therapy. The median number of prior therapies was 3. Most patients (67%) had stage III/IV disease at time of enrolment. No dose limiting toxicity (DLT) was reported during dose escalation; tenalisib 800 mg BID with romidepsin 14 mg/m 2 (given on Days 1, 8, and 15) was chosen as the RP2D. The most frequent treatment emergent adverse events (TEAEs) were nausea (All: 73% and ≥G3:0%), thrombocytopenia (All:57% and ≥G3:21%), fatigue (All: 54% and ≥G3:6%), AST elevation (All:33% and ≥G3:6%) ALT elevation (All:27% and ≥G3:18%), neutropenia (All: 27% and ≥G3:15%), vomiting (All:27% and ≥G3:0%), decreased appetite (All: 27% and ≥G3:0%). There were no unexpected TEAEs. Among CTCL patients, five related TEAEs led to drug discontinuation were sepsis, ALT elevation, GGT elevation, rash, and dysgeusia. None of the PTCL patients discontinued the study drug due to related TEAEs. Incidences of TEAEs leading to drug interruption (72%) and dose reduction (45%) of any the drugs in the combination were similar in PTCL and CTCL groups. Based on C max and AUC, dose proportional exposure of tenalisib was observed from doses 400-800 mg BID. Co-administration of romidepsin with tenalisib did not significantly alter the PK of either agent. Of the 33 patients enrolled, 27 (12 PTCL and 15 CTCL) who received at least 1 dose of study drug and provided at least 1 post-baseline efficacy assessment were considered evaluable for efficacy as per protocol. The overall response rate (ORR) was of 63%; 7 (26%) patients achieved CR and 10 (37%) patients had PR (Table 1). The median duration of response (DoR) was 5.03 months (range: 2.16 months-Not Reached). In twelve evaluable PTCL patients, the ORR was 75% with 6 CR (50%) and 3 PR (25%). Among 15 evaluable CTCL patients, 8 responded with an ORR of 53.3%, 1 CR (6.7%) and 7 PR (46.7%). The median DoR was 5.03 (range: 2.16 months-Not Reached) for PTCL and 3.8 months (1.9-18.86) for CTCL. Three of the six (50%) PTCL patients with CR were bridged to transplant. Six patients who benefitted with the treatment and completed the protocol were enrolled in an open-label compassionate medication study after Cycle 7 and are being followed up. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising anti-tumor activity in patients with R/R TCL. Based on these encouraging results, further development of this combination in PTCL patients in being planned. Figure 1 Figure 1. Disclosures Huen: Rhizen: Research Funding; Elorac: Research Funding; Kyowa Kirin: Research Funding; Tillium: Research Funding; Innate: Research Funding; Galderma: Research Funding; Miragen: Research Funding. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Kuzel: Cardinal Health: Membership on an entity's Board of Directors or advisory committees; Exelixis: Membership on an entity's Board of Directors or advisory committees; Genomic Health: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme Genomic Health Tempus laboratories Bristol Meyers Squibb: Honoraria; Abbvie: Other; Curio Science: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen Corp: Membership on an entity's Board of Directors or advisory committees; CVS: Membership on an entity's Board of Directors or advisory committees; Tempus Laboratories: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data Monitoring Committee Membership; Amgen: Other: Data Monitoring Committee Membership; SeaGen: Other: Data Monitoring Committee Membership; Medpace: Other: Data Monitoring Committee Membership.

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French National Retrospective Cohort of Hairy-Cell Leukemias: Risk of Second Malignancies after 10 Years of Follow-up

Blood ◽

10.1182/blood-2019-127560 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1537-1537

Author(s):

Jérôme Paillassa ◽

Edouard Cornet ◽

Stephanie Noel ◽

Cecile Tomowiak ◽

Aline Schmidt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Retrospective Cohort ◽

Hematological Malignancies ◽

Hematological Malignancy ◽

Solid Cancer ◽

Advisory Committees ◽

History Of ◽

History Of Cancer

Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p < 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p < 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. 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. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.

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Heterozygous CTC1 Variants in Acquired Bone Marrow Failure

Blood ◽

10.1182/blood-2018-99-115193 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3866-3866

Author(s):

Wenyi Shen ◽

Cassandra M. Hirsch ◽

Bartlomiej P. Przychodzen ◽

Reda Z. Mahfouz ◽

Tomas Radivoyevitch ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Germ Line ◽

Index Case ◽

Bone Marrow Failure ◽

Compound Heterozygous ◽

Advisory Committees ◽

Tier 1 ◽

History Of ◽

History Of Cancer

Abstract Germ line (GL) alterations of telomerase machinery genes may lead to inherited telomeropathies, but recent analysis of large control populations revealed that some of the previously assumed pathologic variants are present in comparable frequencies in healthy individuals. Pathogenic telomerase gene variants can be found, but are rare in idiopathic aplastic anemia (AA) and are associated with excessive telomere attrition. Previously, in a cohort of patients with MDS, pathogenic germ line variants of telomerase genes were very extremely rare. Recently a patient with bone marrow failure and liver cirrhosis presented with a biallelic CTC1 gene mutation. CTC1 is a member of the CTC complex, located on Chr 17p13.1, and critical for telomere replication. GL alterations of this gene were found to cause inherited disease, including Coats plus (CP), dyskeratosis congenital (DC) and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) in a compound heterozygous manner. Our patient (age 28) had compound heterozygous CTC1 germline mutations (p.Lys242Leufs*41 and p.Cys985del) resulting in early childhood presentation of DC, subsequent severe AA at the age of 19, and a significant shortening of telomeres. Both parents as confirmed CTC1 variant carriers showed normal blood counts. Based on this index case and literature reports, manifest CTC1 diseases follow a recessive trait, however, but it is possible that heterozygous carriers may indeed have also an increased, albeit attenuated risk of BMF leading to a later manifestation or incomplete penetrance. To test this possible scenario we screened a cohort of acquired BMF (n=538) with AA/PNH (172), MDS/AML (n=366), with deep NGS of all coding regions of CTC1. In total, we identified 10 heterozygous CTC1 variants in 10 unrelated patients (8 AA/PNH and 2 MDS); 4/10 variants (1 stop gain R1202X and 3 frameshift deletions D405fs, P999fs, E454fs) were fulfilled the criteria of Tier-1 lesions and were found in AA/PNH patients (4/172, 2.3%), The remaining 6 missense variants were of uncertain significance or likely benign(Tier-2), 2 of which (H1092G and E1136K) were found in a compound heterozygous configuration in a AA/PNH patient. K438N, as a novel missense variant, was recurrently present in 2 MDS pts. Given the expected frequency of the CTC1 variants found in controls (104/33370, 0.3%), CTC1 variants appear to be enriched in AA/PNH subgroup (p<0.001). Of note is that none of the carriers of pathogenic CTC1 mutations showed any physical signs of inherited congenital BMF syndromes or any family history of leukemia, BMF and any other cancers. Interestingly, patients with sAA/PNH syndrome and biallelic CTC1 variant eventually evolved to MDS, while the other monoallelic CTC1 carriers showed stable disease and responsed to immunosuppression. Flow cytometric telomere length measurement (adjusted for age) showed a markedly shortened telomere in the index case, as well as 1 SAA case carrying biallelic CTC1 variants and 1 AA case with co-concurrent POT1 and CTC1 variants when compared with age matched controls. A significant difference was seen when comparing telomere length between CTC1 variants carriers and age-matched normal controls, while no difference was seen among CTC1 variants carriers, AA/PNH group without any variants. Because of the curious co-incidence of heterozygous CTC1 variants and AA/PNH, we further analyzed this subgroup for the presence of other telomerase gene mutations, 11/172 Tier-1 variants, while 6 Tier-1 GLVs detected in MDS. Most frequent SNVs were found in POT1 with 5/172 (3%) in AA/PNH and 3/366 (0.8%) in MDS/AML. Notably, in one AA/PNH patient POT1 stop gain variant (Q364X) was co-concurrent with CTC1 heterozygous frame shift deletion (P999fs). The enrichment of variants in TELO-related genes in AA/PNH subgroup was found in comparison to MDS/AML (p<.01) and ExAC database controls (p<.01). Further clinical phenotype analysis indicated that 3 AA/PNH cases harboring POT1, TINF2 and TERT Tier-1 variants had family history of cancer. Family history of cancer was also found in a MDS patient with a TINF2 variant. In sum, our results indicate that heterozygous CTC1 variants were associated with otherwise typical AA with clonal outgrowth of PNH clone and the presence of this variant does not seem to preclude response to immunosuppression. Disclosures Maciejewski: Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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TP53 Mutations in Myeloid Neoplasm Patients with and without Significant Personal and Family History of Cancer

Blood ◽

10.1182/blood-2018-99-115562 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2270-2270

Author(s):

Sophia Colombari Figueroa ◽

Bhumika J. Patel ◽

Shimoli Vipul Barot ◽

Teodora Kuzmanovic ◽

Aziz Nazha ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Tp53 Mutation ◽

Degree Relative ◽

Advisory Committees ◽

Tp53 Mutations ◽

Family History Of Cancer ◽

Common Diagnosis ◽

History Of ◽

History Of Cancer

Abstract Background: Next generation sequencing (NGS) of bone marrow or peripheral blood is increasingly being used in the upfront evaluation of patients with a new diagnosis of myeloid neoplasm (MN). This testing identifies salient mutations that are relevant in the biology of MN. Information obtained from NGS can inform patients and their family members about potential predisposition to current and future cancer diagnosis. Informing patients of the utility of NGS testing with regard to detection of GL risk as well as its current use in detection of somatic mutations is important. Additional relevant family history data can be combined in the clinical context of patient's personal oncologic history with the presence of a variant allele frequency (VAF) >30%-50% to enhance the prediction of GL predisposition. However, there is not a current consensus/guideline for further evaluation for possible GL predisposition for MN patients in the era of NGS results. Methods: At our institution, we identified 401 patients with the diagnosis of MN who were sequenced by NGS from 2012-2017. We performed a retrospective review of this panel of patients to identify specific characteristics that may warrant further GL testing. Among these, we focused our study on MN patients that harbored a TP53 mutation (N=66), although future work will include patients with other mutations including but not limited to genes such as RUNX1, GATA2, and ETV6 which are also known to be associated with GL predisposition to MN. We collected demographic information, specific diagnosis, personal history of cancer and corresponding treatment, family history of cancer in first and second degree relatives as well as cytogenetic abnormalities. The location, variant allele frequency (VAF), mutation type, and significance for each TP53 mutation was annotated. Additional mutations in any of the 36 other disease-relevant genes such as ASXL1, BCOR, JAK2 were also fully annotated. Results: In our cohort of 66 patients, 27 were females and 39 were males. AML/ALL was the most common diagnosis (32/66; 48.5%) followed by 31.8% (21/66) with MDS, 13.6% (9/66) with MPN, and 6% (4/66) with MPN/MDS. Clinically, of the 19 (30%) patients with prior history of cancer, 13 had treatment with chemotherapy and/or radiation. Forty-four (67%) patients had family history of cancer, with 41 including a first degree relative and 9 including a second degree relative. Breast cancer was the most common diagnosis among those with family history of cancer (12/44). We further examined the characteristics of the TP53 mutations in our cohort. We identified that 48/66 (72.7%) cases had a single TP53 mutation of which 43 had a VAF >30% and 41 had a variant of known significance. Among the 18/66 (27.3%) cases with two TP53 mutations, 7 had a VAF >30% and all 18 had a variant of known significance. Only 1 case had a third TP53 mutation, which was a variant of known significance and had a VAF >30%. Additionally, at least one other co-mutation in a relevant gene was seen in 44% patients (29/66). Of these, the most common were DNMT3A (n=9), JAK2 (n=5), TET2 (n=5), with 3 each of BCORL1, IDH2 and NOTCH1. In terms of cytogenetics, samples were available for 60 patients of which only 4 (6.7%) had normal cytogenetics. Of those with abnormal cytogenetics, 49/56 (87.5%) had complex cytogenetics, 38/56 (67.9%) had deletion of chromosome 5q (del (5q)) and 21/56 (37.5%) had deletion of chromosome 17p (del (17p13.1)), all conferring adverse risk according to the 2017 European LeukemiaNet recommendations. Conclusion: Despite the widespread use and availability of NGS, patients may not have clarity on the possible implications of these test results. Our cohort demonstrates that there is a significant number of MN cases that warrant further annotation to determine GL versus somatic contributions. Further identification and follow up of the GL patients will offer clarity on how these genetic risks predict future outcomes. This cohort represents work that is a stepping stone for design and justification of a future prospective study that will propose and validate criteria for GL evaluation in patients with hematological neoplasms. Disclosures Nazha: MEI: Consultancy. Gerds:Apexx Oncology: Consultancy; Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Carraway:Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Agios: Consultancy, 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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Data Monitoring Committees: Current issues

Clinical Trials ◽

10.1177/1740774518764855 ◽

2018 ◽

Vol 15 (4) ◽

pp. 321-328 ◽

Cited By ~ 15

Author(s):

Thomas R Fleming ◽

Susan S Ellenberg ◽

David L DeMets

Keyword(s):

Best Practices ◽

Safety Data ◽

Data Monitoring Committee ◽

Data Monitoring ◽

Marketing Approval ◽

Definitive Evidence ◽

Trial Conduct ◽

Risks And Benefits ◽

Monitoring Committee ◽

Study Participants

Maintaining confidentiality of emerging data and ensuring the independence of Data Monitoring Committees are best practices of considerable importance to the ability of these committees to achieve their mission of safeguarding the interests of study participants and enhancing the integrity and credibility of clinical trials. Even with the wide recognition of these principles, there are circumstances where confidentiality issues remain challenging, controversial or inconsistently addressed. First, consider settings where a clinical trial’s interim data could provide the evidence regulatory authorities require for decisions about marketing approval, yet where such a trial would be continued post-approval to provide more definitive evidence about principal safety and/or efficacy outcomes. In such settings, data informative about the longer term objectives of the trial should remain confidential until pre-specified criteria for trial completion have been met. Second, for those other than Data Monitoring Committee members, access to safety and efficacy outcomes during trial conduct, even when presented as data pooled across treatment arms, should be on a limited “need to know” basis relating to the ability to carry out ethical or scientific responsibilities in the conduct of the trial. Third, Data Monitoring Committee members should have access to unblinded efficacy and safety data throughout the trial to enable timely and informed judgments about risks and benefits. Fourth, it should be recognized that a mediator potentially could be useful in rare settings where the Data Monitoring Committee would have serious ethical or scientific concerns about the sponsor’s dissemination or lack of dissemination of information. Data Monitoring Committee Contract Agreements, Indemnification Agreements and Charters should be developed in a manner to protect Data Monitoring Committee members and their independence, in order to enhance the Data Monitoring Committee’s ability to effectively address their mission.

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Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽

10.1182/blood-2019-128807 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3433-3433

Author(s):

Caitlin Siebenaller ◽

Madeline Waldron ◽

Kelly Gaffney ◽

Brian P. Hobbs ◽

Ran Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Smoking Status ◽

Consolidation Therapy ◽

Peripheral Vascular ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

History Of ◽

Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

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BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood-2020-138838 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Austin Kulasekararaj ◽

Jacques Le Roux Malherbe ◽

Andrew McDonald ◽

Melanie Cornpropst ◽

Phil Collis ◽

...

Keyword(s):

South Africa ◽

Board Of Directors ◽

Research Funding ◽

Total Bilirubin ◽

Proof Of Concept ◽

Advisory Committees ◽

Clone Size ◽

The Past ◽

History Of ◽

Pre Treatment

INTRODUCTION: PNH, a rare, chronic, life-threatening disease, is characterized by hemolytic anemia due to uncontrolled activity of the complement alternative pathway (AP), bone marrow failure, and thrombosis. Inhibition of C5 by intravenously administered eculizumab and ravulizumab reduces intravascular hemolysis, but PNH red blood cells (RBCs) become opsonized and susceptible to extravascular hemolysis (Risitano et al, Blood 2009). Only approximately half of PNH patients become transfusion independent with eculizumab treatment (Hillmen et al, NEJM 2006). BCX9930 is a potent, selective, orally administered inhibitor of complement factor D. Inhibition of factor D may prevent both intravascular and extravascular hemolysis in PNH. In healthy subjects, BCX9930 showed linear pharmacokinetics and dose-related AP suppression, and was safe and generally well-tolerated over a wide dose range. Here we describe safety and laboratory data establishing proof-of-concept for BCX9930 monotherapy in PNH patients in Study BCX9930-101 (NCT04330534). METHODS: Ongoing Study BCX9930-101 includes an open-label, dose-ranging evaluation of BCX9930 in PNH subjects who may either be naïve to C5 inhibitors (and receive BCX9930 as monotherapy) or have an incomplete treatment response to eculizumab or ravulizumab (with BCX9930 added to existing treatment). Up to 4 sequential cohorts each use a forced titration design for the first 28 days (Figure 1). Subjects enrolled in South Africa can participate in an individualized 48-week extension if they derive benefit at Day 28. Clinical benefit from BCX9930 is evaluated using laboratory monitoring and symptom assessment. Safety and tolerability are evaluated via clinical and laboratory monitoring, causality of adverse events is assessed by investigators, and the study is overseen by an independent Data Monitoring Committee. Data from Cohort 1 through 28 days is reported; data from the extension and subsequent cohorts will be subsequently summarized as available. RESULTS: To date, four C5 inhibitor naïve PNH subjects in South Africa have enrolled in Cohort 1. These subjects had PNH for a median of 4.5 years; 2 subjects had a history of transfusions in the past year; 1 subject each had a history of aplastic anemia or major thrombosis. Pre-treatment lactate dehydrogenase (LDH), total bilirubin, hemoglobin (Hb), reticulocyte count, and RBC PNH Type III clone size ranged from 3.7-11.1 × ULN, 0.61-3.3 mg/dL, 6.1-11.6 g/dL, 0.13-0.29 × 106/µL, and 41.4%-88.6% respectively. Treatment over 28 days with 50 mg twice daily (BID; Days 1-14) and 100 mg BID (Days 15-28) of BCX9930 produced dose-dependent, clinically meaningful improvements across hemolysis biomarkers (Figure 2). Decreases were observed in LDH (4/4), reticulocytes (4/4), and total bilirubin (2/2 subjects with elevated pre-treatment values). Increases were observed in Hb (3/4) and PNH RBC clone size (4/4). One subject showed an initial response to BCX9930 50 mg BID, followed by worsening indicators of hemolysis temporally associated with an upper respiratory tract infection (URTI; onset on Day 7). With an increase in dose to 100 mg BID and resolution of the URTI, LDH and reticulocytes fell and Hb rose. All four subjects reported one or more PNH-associated symptoms, including hemoglobinuria, jaundice, fatigue, erectile dysfunction, headache and abdominal pain, prior to enrollment. With the exception of one subject with persistent hemoglobinuria, all symptoms resolved by Day 28 on BCX9930. Three subjects experienced moderate headache that resolved in < 3 days after initiating BCX9930. One subject developed a rash during treatment with amoxicillin for an URTI; the rash resolved while continuing BCX9930 dosing. One subject on concomitant chronic corticosteroids and azathioprine had an unrelated fatal serious adverse event of disseminated varicella during the study extension. Based on review of safety data, Cohort 2 opened at doses of 200 mg BID and 400 mg BID and, in the 3 subjects who continued into the extension, the dose was titrated to ≥ 200 mg BID. CONCLUSIONS: Oral BCX9930 elicited rapid changes in laboratory parameters indicative of reduced hemolysis and clinical benefit and was safe and generally well-tolerated over a 28-day dosing interval. These interim results establish proof of concept for monotherapy with BCX9930 in the treatment of C5-inhibitor naïve PNH patients and support evaluation of higher doses. Disclosures Kulasekararaj: Alexion:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Ra Pharma:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;BioCryst Pharmaceuticals, Inc.:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Apellis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.Malherbe:Key Oncologics:Honoraria, Other: Conference sponsor;Novartis:Other: Conference sponsor;Astellas:Honoraria, Other: Conference sponsor;Takeda:Consultancy;Acino:Honoraria;Shire:Other: Conference sponsor;BioCryst Pharmaceuticals, Inc.:Consultancy;Janssen:Consultancy, Honoraria, Other: Conference sponsor;Roche:Honoraria, Other: Conference sponsor.McDonald:venetoclax advisory board in South Africa (in CLL context):Consultancy;Alberts Cellular Therapy:Current Employment.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Collis:BioCryst Pharmaceuticals, Inc.:Current Employment.Davidson:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Tower:BioCryst Pharmaceuticals, Inc.:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Risitano:Alexion:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Alnylam:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;Achillion:Membership on an entity's Board of Directors or advisory committees;Apellis:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Biocryst:Membership on an entity's Board of Directors or advisory committees;RA pharma:Research Funding;Amyndas:Consultancy;Samsung:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;Jazz:Speakers Bureau.

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Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry

Blood ◽

10.1182/blood-2021-153560 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2188-2188

Author(s):

Louis Terriou ◽

Christopher J. Patriquin ◽

Morag Griffin ◽

Jong Wook Lee ◽

Philippe Gustovic ◽

...

Keyword(s):

Rare Disease ◽

Board Of Directors ◽

Survival Probability ◽

Advisory Committees ◽

Term Survival ◽

Treatment Status ◽

History Of ◽

Baseline Characteristics

Abstract Background Eculizumab, the first C5 inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH), transformed PNH treatment by improving survival to that of an age- and sex- matched general population. Previous analyses demonstrating the survival benefit of eculizumab in patients with PNH leveraged historical data and were limited by small patient numbers and short follow-up durations; few evaluated survival of patients receiving eculizumab compared with untreated patients. The objective of the current analysis was to describe the baseline characteristics and overall survival of a large international cohort of eculizumab-treated patients compared with a contemporaneous untreated cohort using data from the prospective, observational International PNH Registry (NCT01374360). Methods Data from patients enrolled in the Registry after March 16, 2007 with complete information for birth date, sex, enrollment date, and treatment status were included (database cut-off, April 12, 2021). Ever-treated patients were those who received eculizumab for a minimum treatment period of 35 days while enrolled in the Registry; never-treated patients did not receive eculizumab at any time before or during Registry participation. Univariate and multivariate analyses were performed using a Cox proportional hazards that incorporated the following parameters at baseline as covariates: treatment status, presence of high disease activity (HDA), age, sex, history of bone marrow failure (BMF), history of thrombotic events (TE), transfusion dependence, and estimated glomerular filtration rate ≤60 mL/min/1.73 m 2. HDA was defined as lactate dehydrogenase (LDH) ratio ≥1.5 × upper limit of normal (ULN) and ≥1 of the following: history of major adverse vascular events (including TE); anemia (hemoglobin <10 g/dL), or physician-documented abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction at any time before and including baseline. Baseline was defined as the date of eculizumab treatment initiation (ever-treated patients) or date of Registry enrollment (never-treated patients). Survival time was analyzed using a left-truncation approach that mapped time in patients' survival based on disease start date, defined as the earliest date of first-reported PNH diagnosis, PNH symptom, or first consistent flow cytometry result. Results Baseline characteristics of the 4627 patients included in the analysis (mean [SD] age at disease start, 40.2 [18.71] years; 53% female; 75% white) were comparable between the ever-treated and never-treated groups (n=1892 and n=2735, respectively). Compared with never-treated patients, more ever-treated patients had LDH ≥1.5 × ULN (90% vs 35%), and fewer had <10% PNH granulocytes (3% vs 57%) or history of BMF (45% vs 76%). The univariate Cox proportional hazard ratio (HR) for mortality in ever-treated vs never-treated patients was 0.48 (95% CI, 0.39-0.60; P<0.0001), indicating a 52% increase in survival in the treated group (Table). Among ever-treated patients, those with HDA at baseline experienced the largest reduction in mortality risk (HR [95% CI], 0.46 [0.33-0.64]; n=174); however, decreased mortality was also evident in ever-treated patients without HDA (HR, 0.65 [0.39-1.10]; n=212) or with unknown HDA status (HR, 0.50 [0.32-0.76; n=120) at baseline. Overall survival probability by treatment status was consistently greater in ever-treated vs never-treated patients through 20 years of follow-up; survival probability at 20 years was 82% (ever-treated) vs 69% (never-treated). Although long-term survival probability was greatest throughout follow-up in ever-treated patients with HDA at baseline, increased survival among ever-treated patients was evident in all 3 HDA status groups (Figure). Conclusion In this analysis of Registry data, treatment with the C5 inhibitor eculizumab improved patient survival compared with a never-treated cohort at a comparable time point in their disease course. Covariates were assessed at baseline only and competing risks and time on treatment were not controlled for, which are potential limitations. Survival benefits conferred by eculizumab treatment were observed regardless of HDA status at baseline, were more pronounced in treated patients with HDA vs those without HDA, and were maintained through 2 decades of real-world follow-up. Figure 1 Figure 1. Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin: Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Biocryst: Honoraria; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease: Current Employment. Szer: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Chronic Lymphocytic Leukemia in Kuwait

Blood ◽

10.1182/blood-2019-127234 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5467-5467

Author(s):

Salem Alshemmari ◽

Ramesh Pandita ◽

Abdulaziz Hamadah ◽

Ahmad Alhuraiji

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Mutational Analysis ◽

Staging System ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Western Countries ◽

Mutational Status ◽

Study Results ◽

History Of

Background :Chronic lymphocytic leukemia (CLL) is common malignancy in Western countries. However, little known about this disease entity in our area. This study exploring the biology in out patients' population. Method:Patients with confirmed CLL under IGHV and TP53 mutational analysis at presentation or during follow up. We also integrated other clinical and biological parameter in this study. Results: A total of 137 cases were analyzed, median age 61 years (range:34-89); 30% of the cases age was<55 years at presentation. There was 108 males vs. 29 females M:F ratio 3.7. Two patients gave a family history of CLL, while 1 patient gave a history of other lymphoproliferative disorders. Binet staging system available in 134 cases, A: 109 (81.3%), B: 12 (9%), C:13 (9.7%). B2 macroglobulin elevated in 40/112 (36%) cases and 10/103 (10%) had M-spike. CD38 positivity reported in 37/112 (33%) of cases. Cytogenetics data evaluable in 85 cases: isolated del(13q): 35%, isolated trisomy 12 (16.5%), del(11q) (4.5%), del(17p)(2.4%). IGHV mutational status mutated vs unmutated: 40% vs 60%. Cases with available treatment information on 132 cases. Fifty cases required treatment due to disease progression. First line treatment Bendamustine-Rituximab (BR) 3 cases, Fludarabine Cyclophosphamide Rituximab (FCR) 30 cases and Chlorambucil with anti-CD 20 antibody 6 cases. At the time of review, 3 cases on ibrutinib (2 in 3rdline and 1 case in the 4thline). Conclusion: This is the first study to shed light on CLL in our area. There are biological differences between our patients' population and the western countries. Disclosures Pandita: Novartis: 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, 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; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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