The CLL-international prognostic index (CLL-IPI) predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL

The utility of the chronic lymphocytic leukemia - international prognostic index (CLL-IPI) in predicting outcomes of individuals with Rai 0 stage CLL and monoclonal B-cell lymphocytosis (MBL) is unclear. We identified 969 individuals (415 MBL and 554 Rai 0 CLL; median age=64 years, 65% men) seen at Mayo Clinic between 1/1/2001 and 10/1/2018, and ascertained time to first therapy (TTFT) and overall survival (OS). After a median follow up of 7 years, the risk of disease progression needing therapy was 2.9%/year for MBL (median=not reached) and 5%/year for Rai 0 CLL (median=10.4 years). Among patients with low, intermediate and high/very high risk CLL-IPI risk groups, the estimated 5-year risk of TTFT was 13.5%, 30%, and 58%, respectively, p<0.0001 (c-statistic=0.69); and the estimated 5-year OS was 96.3%, 91.5%, and 76%, respectively, p<0.0001 (c-statistic:0.65). In a multivariable analysis of absolute B-cell count with individual factors of the CLL-IPI, the absolute B-cell count was associated with shorter TTFT (hazard ratio [HR] for each 10 x 109/L increase: 1.31; p<0.0001), and shorter OS (HR: 1.1; p=0.02). The OS of the entire cohort was similar to age- and sex-matched general population of Minnesota (p=0.17), although Rai 0 CLL patients with high and very high risk CLL-IPI score had significantly shorter OS (p=0.01, and p=0.0001, respectively). The results of this study demonstrate the ability of CLL-IPI to predict time from diagnosis to first treatment (an endpoint not impacted by therapy) in a large cohort of patients whose only manifestation of disease is a circulating clonal lymphocyte population.

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Cause of death in patients with newly diagnosed chronic lymphocytic leukemia (CLL) stratified by the CLL-International Prognostic Index (CLL-IPI).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8026 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8026-8026

Author(s):

Yucai Wang ◽

Sara J Achenbach ◽

Kari G. Rabe ◽

Tait D. Shanafelt ◽

Timothy Call ◽

...

Keyword(s):

High Risk ◽

Cause Of Death ◽

Risk Group ◽

International Prognostic Index ◽

Prognostic Index ◽

Lymphocytic Leukemia ◽

Intermediate Risk ◽

Newly Diagnosed ◽

Second Malignancies ◽

Very High

8026 Background: CLL progression and CLL-related complications (infections and second malignancies) were the leading cause of death (COD) in a prospective cohort of CLL patients (Strati, BJH 2017). The CLL-IPI integrates major clinical and molecular prognostic factors and stratifies patients into 4 risk groups with distinct prognosis. It is unknown if COD differs according to CLL-IPI risk group in patients with newly diagnosed CLL. Methods: Patients diagnosed with CLL between 1/2000-12/2019 and seen within 1 year of diagnosis were identified from the Mayo Clinic CLL database. Cumulative incidences of cause-specific death were analyzed using Gray’s test, with deaths from different causes treated as competing events and deaths from unknown causes excluded. Results: 1276 patients were included in this study. The median age at diagnosis was 63 years (range 24-92), and 880 (69%) were male. Based on CLL-IPI score, 449 (35%) had low risk disease, 443 (35%) had intermediate risk disease, and 384 (30%) had high/very high risk disease. Median follow-up time for the study was 6 years; 286 deaths occurred. The COD was CLL progression in 99 (35%), infection in 16 (6%), second malignancy in 47 (16%), CLL-unrelated in 59 (21%), and unknown in 65 (23%) patients. The rates of death due to CLL progression were higher (17.3% at 5 years; 30.3% at 10 years) than the rates due to CLL-related complications (5.7% at 5 years; 12.9% at 10 years) or due to CLL-unrelated causes (8.6% at 5 years; 16.9% at 10 years) in the CLL-IPI high/very high risk group, but not the CLL-IPI low or intermediate risk group (Table). A higher CLL-IPI risk group was associated with a higher rate of death due to CLL progression ( P < 0.001), as well as a higher rate of death due to CLL-related complications ( P = 0.013), and CLL-unrelated causes ( P < 0.001). Conclusions: Causes of death in newly diagnosed CLL patients differ according to their CLL-IPI risk group. In patients with high/very high risk CLL, improving CLL disease control with novel agents seems justified. In patients with low/intermediate risk CLL, there should be increased efforts to reverse immune dysfunction to reduce infections and second malignancies. [Table: see text]

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Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL

Blood ◽

10.1182/blood-2018-07-862862 ◽

2019 ◽

Vol 133 (9) ◽

pp. 919-926 ◽

Cited By ~ 19

Author(s):

Magdalena Klanova ◽

Laurie H. Sehn ◽

Isabelle Bence-Bruckler ◽

Federica Cavallo ◽

Jie Jin ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Cell Of Origin ◽

Cns Relapse ◽

Relapse Prediction ◽

Expression Status ◽

Dual Expression

Abstract Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS–International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.

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Bendamustine and rituximab as induction therapy in both transplant-eligible and -ineligible patients with mantle cell lymphoma

Blood Advances ◽

10.1182/bloodadvances.2020002068 ◽

2020 ◽

Vol 4 (15) ◽

pp. 3486-3494

Author(s):

Diego Villa ◽

Laurie H. Sehn ◽

Kerry J. Savage ◽

Cynthia L. Toze ◽

Kevin Song ◽

...

Keyword(s):

High Risk ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

First Line ◽

Ki 67 ◽

Historical Cohort ◽

Entire Cohort ◽

Mantle Cell

Abstract Rituximab-containing chemotherapy regimens constitute standard first-line therapy for mantle cell lymphoma (MCL). Since June 2013, 190 patients ≥18 years of age with MCL in British Columbia have been treated with bendamustine and rituximab (BR). The overall response rate to BR was 88% (54% complete response). Of these, 61 of 89 patients (69%) aged ≤65 years received autologous stem cell transplantation and 141 of 190 patients (74%) from the entire cohort received maintenance rituximab. Twenty-three patients (12%) had progressive disease, associated with high risk per the Mantle Cell Lymphoma International Prognostic Index (MIPI), Ki-67 ≥50%, and blastoid/pleomorphic histology. Outcomes were compared with a historical cohort of 248 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; January 2003 to May 2013). Treatment with BR was associated with significant improvements in progression-free survival (PFS), but not overall survival (OS), compared with R-CHOP in the whole cohort (3-year PFS, 66% BR vs 51% R-CHOP, P = .003; 3-year OS, 73% BR vs 66% R-CHOP, P = .054) and in those >65 years of age (3-year PFS, 56% BR vs 35% R-CHOP, P = .001; 3-year OS, 64% BR vs 55% R-CHOP, P = .063). Outcomes in transplanted patients were not statistically significantly different compared with R-CHOP (3-year PFS, 85% BR vs 76% R-CHOP, P = .135; 3-year OS, 90% BR vs 88% R-CHOP, P = .305), although in multivariate analyses, treatment with BR was associated with improved PFS (hazard ratio, 0.40 [95% confidence interval, 0.17-0.94]; P = .036) but not OS. BR is an effective first-line option for most patients with MCL, however, outcomes are suboptimal for those with high-risk features and further studies integrating novel agents are warranted.

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Risk Adjusted Management of Newly Diagnosed High and Intermediate FLIPI Follicular Lymphoma Using (90)Y Ibritumomab Tiuxetan

Blood ◽

10.1182/blood.v128.22.1794.1794 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1794-1794

Author(s):

Neil L Berinstein ◽

Nancy M Pennell ◽

Rashmi Weerasinghe ◽

Matthew C. Cheung ◽

Eugenia Piliotis ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

B Cell ◽

International Prognostic Index ◽

Prognostic Index ◽

Newly Diagnosed ◽

Ibritumomab Tiuxetan ◽

Cell Counts ◽

Post Therapy

Abstract Background: Although the natural history of follicular lymphoma is indolent with a median overall survival of about 12-15 years, the disease is heterogeneous. The 5 and 10 year overall survival (OS) of low, intermediate and high risk FLIPI is 91%, 78% and 53% and 71%, 51% and 36% using standard rituximab-based treatment. 5-year progression-free survival (PFS) is 80%, 70% and 48% respectively. Methods: Based upon this we conducted an investigator-initiated single-centre Phase II trial of intensified therapy with CHOP-R followed by (90)Y ibritumomab tiuxetan consolidation and 24 months of rituximab maintenance as treatment for patients with intermediate and high-risk newly diagnosed symptomatic follicular lymphoma. 33 patients were enrolled. Results: The addition of (90)Y ibritumomab tiuxetan was well tolerated but resulted in asymptomatic grade 3 or 4 thrombocytopenia and neutropenia in11-36% and 10-24% of patients between weeks 2-8 post (90) Y. After 9 years of follow-up (median follow-up 61 months) the 0S for intermediate and high risk FLIPI was 95% and 78%. The 5 year PFS was 79% and 64% for intermediate and high risk FLIPI, respectively. Responses at three months post consolidation were as follows: 3/33 (9%) achieved CR, 25/33(76%), achieved CRU, 1/33(3%) had PR, and 1/33(3%) had PD. Three patients did not receive (90)Y ibritumomab tiuxetan due to disease progression 2/33(6%), or death 1/33(3%). Of 19 patients who had a molecular marker for their lymphoma, 18 (95%) achieved molecular remissions in peripheral blood with CHOP-R therapy. Nine (47%) of these patients have been recently assessed for MRD and remain in molecular remission. The therapy resulted in decreased levels of IgG, IgM and IgA below the lower normal level in 33%, 40% and 23% of patients respectively post therapy. These levels did not recover in most of these patients. B cells were depleted to undetectable levels during therapy including rituximab maintenance. In 18 evaluable patients only 11 recovered normal B cell counts post maintenance rituximab. There was no correlation between normal B-cell recovery and Ig levels. Many patients with low or no B cell counts had normal IgG levels, whereas some patients who regained normal B cell counts were still unable to reach normal Ig levels. No patient developed human anti-mouse antibody. Immunity to measles, mumps, or rubella was retained post therapy. Patients did not have significant infections or opportunistic infections (although 2 developed Grade 1 shingles post (90)Y ibritumomab tiuxetan) and none required IVIG. Conclusions: We conclude that this intensified regimen is highly active in cyto-reducing lymphoma in high and intermediate risk FLIPI follicular lymphoma patients. The toxicity is tolerable although a significant percentage of patients will end up with persistent asymptomatic reductions in B cells and serum Ig. Only randomized trials will determine whether this regimen enhances outcome over standard of care in this higher risk follicular lymphoma population. References: 1.Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Nooka AK, Nabhan C, Zhou X, Taylor MD, Byrtek M, Miller TP, Friedberg JW, Zelenetz AD, Link BK, Cerhan JR, Dillon H, Sinha R, Shenoy PJ, Levy D, Dawson K, Hirata JH, Flowers CR. Ann Oncol. 2013 Feb;24(2):441-8. doi: 10.1093/annonc/mds429. Epub 2012 Oct 5 2.Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting. van de Schans SA, Steyerberg EW, Nijziel MR, Creemers GJ, Janssen-Heijnen ML, van Spronsen DJ. Ann Oncol. 2009 Oct;20(10):1697-702. doi: 10.1093/annonc/mdp053. Epub 2009 Jun 23. PMID: 19549712 Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding.

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BAL is a novel risk-related gene in diffuse large B-cell lymphomas that enhances cellular migration

Blood ◽

10.1182/blood.v96.13.4328.h8004328_4328_4334 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4328-4334

Author(s):

Ricardo C. T. Aguiar ◽

Yoshihiro Yakushijin ◽

Samir Kharbanda ◽

Ravi Salgia ◽

Jonathan A. Fletcher ◽

...

Keyword(s):

Cell Migration ◽

High Risk ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Cellular Migration ◽

Cell Phenotype ◽

Large B Cell

Clinical risk factor models such as the International Prognostic Index are used to identify diffuse large B-cell lymphoma (DLB-CL) patients with different risks of death from their diseases. To elucidate the molecular bases for these observed clinical differences in outcome, differential display was used to identify a novel gene, termed BAL (B-aggressivelymphoma), which is expressed at significantly higher levels in fatal high-risk DLB-CLs than in cured low-risk tumors. The major BAL complementary DNA encodes a previously uncharacterized 88-kd nuclear protein with a duplicated N-terminal domain homologous to the nonhistone portion of histone-macroH2A and a C-terminal alpha-helical region with 2 short coiled-coil domains. Of note, the BAL N-terminus and secondary structure resemble those of a recently identified human protein, KIAA1268. In addition, bothBAL and KIAA1268 map to chromosome 3q21, further suggesting that these genes belong to a newly identified family. BAL is expressed at increased levels in DLB-CL cell lines with an activated peripheral B cell, rather than a germinal center B cell, phenotype. This observation and the characteristic dissemination of high risk DLB-CLs prompted studies regarding the role of BAL in B-cell migration. In classical transwell assays, stable BAL-overexpressing B-cell lymphoma transfectants had significantly higher rates of migration than vector-only transfectants, indicating that the risk-related BAL gene promotes malignant B-cell migration.

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CHOP-R + bortezomib as initial therapy for diffuse large B-cell lymphoma (DLBCL)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8031 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8031-8031 ◽

Cited By ~ 11

Author(s):

J. P. Leonard ◽

R. R. Furman ◽

Y. K. Cheung ◽

J. M. Vose ◽

P. W. Glynn ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

B Cell ◽

International Prognostic Index ◽

Elevated Serum ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Serum Lactate Dehydrogenase ◽

Hematologic Toxicity ◽

Combination Regimen

8031 Background: Bortezomib is a proteasome inhibitor with anti-tumor activity in B cell malignancies. These effects, which may relate to NF-kappaB associated pathways, could sensitize tumor cells to standard chemotherapy-based regimens and enhance efficacy. We report findings of a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL patients (accrual of the MCL cohort of this study remains ongoing). Methods: Patients with previously untreated DLBCL (n=40) received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n=8) or 1.3 mg/m2 (Arm 2, n=28 including phase I and all phase II) on days 1 and 4 of each cycle Results: Median age (n=40) was 58 years (range 21–86), thirty-five subjects (88%) had stage III/IV disease at study entry, and 29 (73%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 16 subjects (40%) and 3–5 in 19 subjects (48%). Median follow-up is 21 months (range 9 - 35 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 22 subjects (55%), with 45% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity included thrombocytopenia (15%) and leukopenia (15%). Four subjects (3 over age 75 and all with high risk IPI) died prior to first response assessment. Intent to treat (ITT) overall response rate (n=40) is 90% with 68% CR/CRu. For the evaluable subset (n=36), ORR was 100% with CR/CRu 75%. Kaplan-Meier estimate (n=40) of 2-year progression-free survival is 72%. Of all 19 enrolled (ITT) patients in the high-intermediate or high-risk IPI groups, 14 (74%) were alive without progression at last assessment. Correlation of outcome with cell of origin type (activated B cell vs germinal center) is ongoing. Conclusions: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Efficacy findings with this combination regimen in newly-diagnosed DLBCL are encouraging and warrant further study. No significant financial relationships to disclose.

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A comprehensive prognostic index for patients with CLL.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7015 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7015-7015

Author(s):

Natali Pflug ◽

Jasmin Bahlo ◽

Tait D. Shanafelt ◽

Barbara Eichhorst ◽

Manuela Bergmann ◽

...

Keyword(s):

High Risk ◽

Risk Score ◽

Mayo Clinic ◽

External Validation ◽

Prognostic Index ◽

Observation Time ◽

Clinical Staging ◽

Newly Diagnosed ◽

C Statistic ◽

Very High

7015 Background: Besides clinical staging, a number of biomarkers predicting OS in CLL have been identified. The multiplicity of markers, limited information on their independent value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We developed an integrated prognostic index using the database of the German CLL Study Group (GCLLSG), which was subsequently validated in a cohort of untreated CLL patients (pts) from the Mayo Clinic. Methods: The analysis was based on a dataset collected between 1997 and 2006 in 3 GCLLSG phase III trials. The external validation was performed on a series of newly diagnosed CLL pts managed at Mayo Clinic. Results: The GCLLSG dataset (1,948 physically fit pts at early and advanced stage; median age: 60 yr (range 30-81); median observation time 63.4 mo) was used as a training dataset. 7 parameters were identified as independent predictors for OS: sex, age, ECOG status, del 17p, del 11q, IGHV mutation status, thymidine kinase and β2-microglobulin. By using a weighted grading a prognostic index was derived separating four different pts groups: low risk (score 0 - 2), intermediate risk (score 3-5), high risk (score 6-10) and very high risk (score 11-14) with significant different OS rates (95.2%, 86.9%, 67.7% and 18.7% OS after 5 yr for the low, intermediate, high and very high risk group respectively (p<0.001). This prognostic index was validated in a cohort of 676 newly diagnosed, untreated pts from the Mayo Clinic (median age 61.5 yr (range 32 - 89); median observation time 47.0 mo). The 4 risk groups were reproduced with 98.3%, 95.4%, 75.4% and 10.8% OS after 5 yr. The prognostic index predicts OS independent of Rai/Binet stage and provides accurate estimations regarding time to first treatment (TTF). C-statistic is 0.75. Conclusions: Using a multi-step process including external validation, we developed a comprehensive prognostic index combining clinical, serum, and molecular information into a single risk score for pts with untreated CLL. The prognostic index provides more accurate prediction of both TTF and OS. To our knowledge it is the first prognostic model in CLL to reach the C-statistic threshold (c > 0.70) necessary to have utility at the level of the individual.

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Risk and Clinical Implications of Transformation of Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.3260 ◽

2007 ◽

Vol 25 (17) ◽

pp. 2426-2433 ◽

Cited By ~ 258

Author(s):

Silvia Montoto ◽

Andrew John Davies ◽

Janet Matthews ◽

Maria Calaminici ◽

Andrew J. Norton ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Advanced Stage ◽

Large B Cell Lymphoma ◽

Large B Cell

Purpose To study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in patients with follicular lymphoma (FL). Patients and Methods From 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomew's Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%. Results The risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P = .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P = .04) scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P = .008). Older age (P = .005), low hemoglobin level (P = .03), high lactate dehydrogenase (P < .0001), and high-risk FLIPI (P = .01) or IPI (P = .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P < .0001) and a shorter survival from progression (P < .0001) than did those in whom it was not diagnosed. Conclusion Advanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival. There may be a subgroup of patients in whom HT does not occur.

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Randomized, phase III study of early intervention with venetoclax and obinutuzumab versus delayed therapy with venetoclax and obinutuzumab in newly diagnosed asymptomatic high-risk patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): EVOLVE CLL/SLL study (SWOG S1925, NCT#04269902).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps7567 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS7567-TPS7567

Author(s):

Deborah Marie Stephens ◽

Anna Moseley ◽

Brian T. Hill ◽

John M. Pagel ◽

Mazyar Shadman ◽

...

Keyword(s):

Early Intervention ◽

High Risk ◽

International Prognostic Index ◽

Prognostic Index ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Free Survival ◽

High Risk Patients ◽

Asymptomatic Patients ◽

Risk Patients

TPS7567 Background: Currently, asymptomatic patients with CLL/SLL are observed without treatment until development of symptoms or cytopenias. Historically, early intervention studies with chemoimmunotherapy have not resulted in an overall survival (OS) benefit and have resulted in toxicity. The introduction of targeted therapies, such as venetoclax and obinutuzumab (VO), have provided tolerable/efficacious options for CLL patients. In the CLL14 study, symptomatic CLL patients receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more minimal residual disease-undetectable (MRDu)] compared with those receiving chlorambucil and obinutuzumab (Fischer 2019). The CLL-International Prognostic Index (CLL-IPI; Table) is a validated prognostic model to predict which patients are highest risk for a shorter time to first therapy and shorter OS. We aim to use VO as early intervention in asymptomatic, high-risk patients with CLL to potentially lengthen OS and thus alter the natural history of the disease. Methods: On 12/14/20, we activated the S1925 study for adult patients with CLL or SLL, who were diagnosed within 12 months of enrollment. Eligible patients have a CLL-IPI score ≥ 4 (Table) or complex cytogenetics (≥3 cytogenetic abnormalities) and do not meet any criteria for initiation of treatment by the International Working Group for CLL (IWCLL; Hallek 2018) guidelines. Enrolled patients are randomized in a 2:1 manner to early versus delayed (at the time IWCLL indication for treatment is met) therapy with VO. VO is administered for a fixed duration of 12 months as previously described (Fischer 2019). The primary endpoint is OS. We hypothesize that early intervention with VO will improve the rate of 6-year OS from 60% to 80%. This design requires 222 eligible patients for 88% power (2-sided α=0.05) for the primary comparison. To allow for 10% ineligibility, we will enroll 247 patients. Estimated accrual time is 4 years. Secondary endpoints include: rates of response, PFS, and relapse-free survival; safety; time to 2nd CLL-directed therapy; and quality of life (FACT-Leukemia total score). The primary translational objective is to evaluate the prognostic association between OS and peripheral blood MRD status at 15 months after treatment initiation by flow cytometry. Additional exploratory objectives include the association of other clinical outcomes, baseline prognostic factors, and IWCLL-defined response with MRD status at multiple timepoints. Currently, enrollment is open. Clinical trial information: NCT04269902. [Table: see text]

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The t(14;18) Is Associated with Germinal Center Phenotype Subset of the Diffuse Large B-Cell Lymphoma Patients in Egypt.

Blood ◽

10.1182/blood.v110.11.4124.4124 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4124-4124

Author(s):

Hasan A. Abdel-Ghaffar ◽

Sherin M. Abdel-Aziz ◽

Doaa A. Shahin ◽

Ezzat S. Sobki Board ◽

Nadia I. Attwan ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Germinal Center ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Biological Variables ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is a generic term for clinically and biologically heterogeneous group of tumors. Identification of high risk patients at presentation will allow effective trials of treatment. Therefore, t(14;18) detection using interphase Florescence in Situ Hybridization (FISH) and Biomed multiplex polymerase chain reaction (PCR) was done on formalin fixed paraffin embedded lymph node archives from pathology department, National Cancer Institute, Cairo, Egypt. Diagnosis were confirmed by pathological review using the diagnostic criteria defined in the revised European-American Classification of Lymphoid Neoplasm / WHO classification. The study was carried out on 26 patients with lymph screen CD 19 +/ CD 5 - / CD 10 ± correlating t(14;18) with the immunophenotypic biological variables, Immunohistochemistry, and the standardized international prognostic index (IPI) with a median follow up for 5 years. Comparison of FISH and PCR techniques showed identical specificity with advantageous sensitivity of FISH over the PCR. Nine patients out of eleven with t(14;18) were associated with Germinal Center (GC) phenotype (CD10+ /Bcl-6 +). However, Only two out of fifteen with non GC phenotype(CD10- /Bcl-6 -) were associated t(14;18). The mean 5 years survival time of patients with t(14;18) was significantly lower (31.18 ± 3.06 month) compared to those without translocation (54.32 ± 2.54 month) (P=0.001). Interestingly, patients with t(14;18) showed Bcl-2 positive (100%) compared to 46.6% in patient without t(14;18) (P=0.004). There is a significant correlation between t(14;18) and the clinicopathological risk criteria of IPI(P=0.01). In our study we demonstrated a detection of t(14;18) by FISH was found to be superior to PCR. The high risk group of GC phenotype together with Bcl-2 expression were associated with t(14;18) and could be used to tailor treatment.

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