Bendamustine-Rituximab Does Not Improve Survival over Rituximab Monotherapy for Older Patients with Nodal or Splenic Marginal Zone Lymphoma

Background: Nodal and splenic marginal zone lymphomas (NMZL/SMZL) are rare, usually disseminated, and typically diagnosed in older patients (median age 69 years). They are increasingly treated with first-line bendamustine/rituximab (BR) based on phase 3 trials that pooled various B-cell indolent lymphomas (Rummel et al., Lancet 2013). However, NMZL and SMZL have unique biology and clinical course. In this context, without histology-specific evidence, the risk/benefit ratio of BR over single-agent rituximab (R) in SMZL/NMZL is uncertain. Our objective was to examine treatment patterns, and to compare survival and toxicity outcomes of BR versus (vs.) R, using population-based data. Methods: Using Medicare claims linked to cancer registry data covering ~34% of the US population (SEER-Medicare), we identified all SMZL/NMZL patients age ≥65 who received 1st line R or BR between 2009-2016 (after approval of bendamustine) and had complete Medicare records. We used a propensity score to generate "pseudo-randomized" cohorts (pooled, including NMZL and SMZL, and histology -specific for NMZL and SMZL), balancing patient and disease characteristics: age, sex, race, comorbidities (including kidney disease and heart failure), performance status, lymphoma stage, B symptoms, prior splenectomy, anemia (including autoimmune hemolytic), transfusions, hospitalizations, and time from diagnosis to therapy. In the balanced pseudo-randomized cohorts, we compared event-free survival (EFS, defined as 2nd line chemotherapy, splenectomy, hospice, or death) and overall survival (OS) from the start of therapy, risk of major toxicities (hospitalization, transfusions), and inflation-adjusted Medicare spending. Outcome models report hazard ratios (HR) or risk ratios (RR) with 95% confidence intervals (95%CI), and marginal means for costs. Results: Among 1,315 patients (901 with NMZL and 414 with SMZL), median age was 78 years [y], and there were 52% women. About half of patients received first-line R every year, but the proportion treated with BR increased from 4% in 2009 to 23% in 2016 (Fig. A). In the pooled NMZL/SMZL cohort of patients receiving BR or R (N=926), those treated with BR were on average younger, more likely to have NMZL, stage 2-4 lymphoma, and B symptoms. With median follow-up 3.8 y, median EFS was 4.3 y (95%CI, 3.5-5.1) for NMZL, and 4.5 y (95%CI, 3.8-6.5) for SMZL. Median OS was 5.7 y (95%CI, 4.9-6.7) in NMZL, and 5.2 y (95%CI, 4.4-6.7) in SMZL. After balancing the confounders, there was no significant difference in either EFS (HR for BR, 1.00; 95%CI, 0.76-1.30, P=.98) or OS (HR, 1.14; 95%CI, 0.85-1.53; P=.38). Toxicities were higher with BR, including hospitalizations (RR, 1.46; 95%CI, 1.14-1.87; P=.003) and transfusions (RR, 2.35; 95%CI, 1.55-3.56; P<.001). Mean Medicare spending within 1 year from diagnosis was higher after BR (mean $83,480) than R (mean $53,776; P<.001). A sensitivity analysis showed that >50% of BR patients would need to have an unobserved risk factor doubling their mortality to explain lack of OS benefit. We then fitted separate propensity score models in NMZL and SMZL. In the comparative NMZL cohort (N=609), 434 patients (71%) received R, and 175 (29%) received BR. We observed no significant difference in either EFS (HR for BR, 0.93; 95%CI, 0.68-1.29; P=.67; Fig. B) or OS (HR, 1.16; 95%CI, 0.82-1.63; P=.40), whereas toxicities and costs were consistently higher with BR. In the comparative SMZL cohort (N=317), 272 patients (86%) received R, and 45 (14%) received BR. Again, there was no significant difference in EFS (HR for BR, 0.84; 95%CI, 0.46-1.53; P=.56; Fig. C) or OS (HR, 0.92; 95%CI, 0.46-1.83; P=.80). Results for toxicities and costs were again consistent. Conclusions: Among older patients with SMZL and NMZL treated in the community, the use of first-line BR is increasing. However, in this large observational study, BR was not associated with any significant EFS or OS benefit over single-agent R, while it increased toxicities and costs. Without a formal randomized histology-specific study, single-agent R may offer a favorable risk/benefit ratio as a first-line therapy for older NMZL/SMZL patients at average risk, reserving BR for those with compelling clinical circumstances. Our results may however be affected by bias due to unobserved confounding, and may not be applicable to younger patients. Disclosures Olszewski: Adaptive Biotechnologies: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding. OffLabel Disclosure: Rituximab with bendamustine is off-label for marginal zone lymphoma

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Comparative Effectiveness of Lenalidomide, Bortezomib, and Their Combinations As First-Line Treatment of Older Patients with Myeloma

Blood ◽

10.1182/blood-2019-121992 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3155-3155 ◽

Cited By ~ 1

Author(s):

Peter Barth ◽

Smith Giri ◽

John L. Reagan ◽

Adam J Olszewski

Keyword(s):

Propensity Score ◽

Renal Disease ◽

Older Patients ◽

Research Funding ◽

Medicare Beneficiaries ◽

First Line ◽

Medicare Claims ◽

First Line Therapy ◽

Line Therapy ◽

Significant Difference

Background: In the S0777 phase 3 trial (Durie et al., Lancet. 2017), the lenalidomide, bortezomib, and dexamethasone (RVD) triplet showed survival advantage over lenalidomide/dexamethasone (RD) as initial therapy for myeloma. However, older transplant-ineligible patients often receive doublet regimens (RD or bortezomib/dexamethasone [VD]), or VD plus cyclophosphamide (VCD). In this setting, RVD has not been directly compared with doublets, or RD compared with VD, leaving an important gap in evidence. Our objective was to compare these regimens based on real-life data from older patients receiving first-line therapy for myeloma in the United States (US), using a causal inference approach. Methods: We identified Medicare beneficiaries with myeloma receiving first-line RD, VD, RVD, or VCD in 2007-2015, using Medicare claims linked to data from cancer registry (SEER-Medicare) covering ~35% of the US population, with successful linkage of >95% individuals aged 65 or over. Patients had to have complete Medicare claims, including outpatient prescriptions (Part D), and we excluded cases with amyloidosis or end-stage renal disease. We used propensity score analysis to generate pseudo-randomized cohorts balancing multiple baseline factors, including socio-economic and performance status, time from diagnosis, presence of baseline hypercalcemia, renal disease, anemia, neuropathy, venous thromboembolism (VTE), and other comorbidities. In each comparative analysis, we fitted a separate propensity score, aiming at confounder balance measured by standardized difference of means <0.10. After generating adequately balanced cohorts to minimize indication bias, we analyzed two survival endpoints (measured from start of first-line therapy): event-free survival (EFS, defined as start of a 2nd-line agent, hospice enrollment, or death, censored in case of an autologous transplant) and overall survival (OS), reporting hazard ratios (HR) with 95% confidence intervals (CI). We also compared select identifiable toxicities occurring within 6 months of starting therapy: hospitalization, anemia, neuropathy, and VTE, reporting relative risk (RR), as well as cumulative incidence function (CIF) for secondary solid tumors, reporting subhazard ratio (SHR). Results: We identified 6,076 eligible myeloma patients receiving first-line therapy between 2007 and 2015. Median age was 76 years [y], and there were 50% women. Between 2007 and 2015, the proportion of Medicare beneficiaries receiving RD increased from 18% to 25% (total N = 1,541; Fig. A), VD from 17% to 26% (N = 1,672), and RVD from 1% to 26% (N = 891). Median EFS in the study population was 0.88 y (95%CI, 0.83-0.93), and median OS was 2.7 y (95%CI, 2.6-2.8 y). Lenalidomide was dosed at 25mg in 58%. Bortezomib was dosed weekly in 57%. Detailed results of comparative models are shown in the Table. In the analysis of RVD versus (vs.) doublets, RVD showed better EFS (median 1.7 vs 0.8y; Fig. B) and OS (median 3.4 vs 2.7y). RVD resulted in higher rates of hospitalization (RR, 1.17; 95%CI 1.03-1.32), anemia (RR, 1.16; 95%CI 1.09-1.23), and neuropathy (RR, 1.49; 95%CI, 1.14-1.96), but no increased risk of VTE (RR, 1.06; 95%CI, 0.79-1.44). A higher proportion of patients treated with RVD underwent consolidative transplant (26% vs 6%). There was no significant difference in the risk of secondary cancers. Consistent findings were observed in the more specific comparison of RVD vs. RD (Table). In the analysis of RD vs. VD, RD demonstrated better EFS (median 1.0 vs 0.6y; Fig. C) and marginally better OS (median 2.7 vs 2.3y). RD resulted in more frequent VTE (RR, 1.44; 95%CI, 1.13-1.83), but less neuropathy (RR, 0.39; 95%CI, 0.29-0.53), without significant difference in hospitalization (RR, 0.96; 95%CI, 0.87-1.06) or anemia (RR, 0.95; 95%CI, 0.89-1.00). In the comparison of VCD vs. VD, there were no significant differences in EFS (Fig. D), OS, or observed toxicities. Conclusions: In this large, population-based study, first-line RVD shows EFS and OS advantage for older patients with myeloma who can tolerate higher potential short-term toxicity. RVD (or "RVD-lite" to minimize toxicity) should be the preferred regimen, but it is applied in only a minority of Medicare beneficiaries. For patients not eligible for the RVD triplet, an unexpected advantage of RD over VD was observed, suggesting that RD may be the preferred doublet. VCD appears to offer no benefit over the VD doublet. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding.

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Clonal B-Cell Lymphocytosis with Marginal Zone Features and Splenic Marginal Zone Lymphoma Share a Similar Cytogenetic and Mutational Profile

Blood ◽

10.1182/blood.v128.22.2962.2962 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2962-2962

Author(s):

Paul Legendre ◽

Olivier Kosmider ◽

Coralie Derrieux ◽

Nicolas Chapuis ◽

Isabelle Radford-Weiss ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Marginal Zone ◽

Univariate Analysis ◽

Marginal Zone Lymphoma ◽

Fish Analysis ◽

Splenic Marginal Zone Lymphoma ◽

First Line ◽

Significant Difference ◽

First Line Treatment

Abstract Introduction: Clonal B-cell lymphocytosis with marginal zone features (CBL-MZ) is a non-CLL type B-cell monoclonal lymphocytosis that has been recently recognized in the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Whether CBL-MZ corresponds to the early stage of splenic marginal zone lymphoma (SMZL) is not clearly defined. The aim of the study was to compare CBL-MZ and SMZL in patients diagnosed during the same period in two French university hospitals. Methods: We performed a retrospective study including all consecutive patients with a diagnosis of CBL-MZ or SMZL between 2010 and 2014. For the purpose of the present study, all CBL-MZ and SMZL were reclassified according to the 2016 WHO classification. Patient and disease characteristics comprised clinical data, immunophenotyping of lymphocytes by flow cytometry, cytogenetic studies (G-banding and TP53 FISH) and targeted gene sequencing (TP53, NOTCH2 and MYD88). We assessed progression-free survival (PFS), lymphoma-specific survival (LSS), overall survival (OS) and cumulative incidence of histologic transformation. Results: Forty-one patients were diagnosed with CBL-MZ (n=15) or SMZL (n=26) on consensus review. None had HCV infection. Median age was 74 years (range 43-93). At diagnosis, B symptoms (7% vs 46%, p=0.009), elevated lactate dehydrogenase (13% vs 50%, p=0.023) and elevated β2-microglobulin (50% vs 93%, p=0.039) were significantly more frequent in SMZL patients. HPLL score A was more frequent in patient with CBL-MZ (93% vs 58%, p=0.003). On lymphocyte immunophenotyping, CD23 was expressed only in SMZL (0% vs 38%, p=0.015). Aberrant karyotype was displayed in 5/7 CBL-MZ and 15/18 of SMZL (p=0.591). Fourteen patients (56%; 2 CBL-MZ and 12 SMZL, p=0.177) had at least 3 chromosomal abnormalities and were considered to have a complex karyotype. There was no significant difference between CBL-MZ and SMZL for the frequency of detection of +3, +12, +18, del(7q) or 14q alterations. A chromosome 17p abnormality or monosomy 17 was seen in 12/25 patients (48%) without significant difference between CBL-MZ and SMZL, and was confirmed in 11/11 cases by TP53 FISH analysis (one patient had an isochromosome 17q and TP53 FISH was not done). In 11 other patients, no TP53 deletion was detected by FISH. In the 2 remaining patients (one normal karyotype and one abnormal karyotype without abnormal 17p) there was no more material for FISH analysis. TP53 mutation was present in 1/15 (7%) CBL-MZ and 6/22 (27%) SMZL (p=0.161), NOTCH2 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0,632) and MYD88 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0.632). After a median follow-up of 47 months (CBL-MZ, 52 months; SMZL, 46 months, p=0.771), no CBL-MZ patients had event (progression, histologic transformation or death) or started treatment, whereas 24/26 (92%) SMZL patients started a first-line treatment (chemotherapy in 62%, rituximab in 42% and/or splenectomy in 39%). Twelve SMZL patients (50% of treated patients) relapsed or progressed after the first-line treatment. Among them, 6 had histologic transformation, either in diffuse large B-cell lymphoma (DLBCL, n=5) or Hodgkin lymphoma (HL, n=1). Finally, 5 SMZL patients died (3 of DLBCL, 1 of HL, 1 of SMZL). Overall, 4-year PFS was 100% and 31% (95% CI, 13% to 49%) for CBL-MZ and SMZL, respectively (p=0.002); 4-year LSS was 100% and 77% (95% CI, 61% to 93%) for CBL-MZ and SMZL, respectively (p=0.26); and 4-year OS was 100% and 71% (95% CI, 54% to 88%) for CBL-MZ and SMZL, respectively (p=0.25). Clinical, laboratory, cytogenetic and molecular features were subjected to univariate analyses to evaluate their impact on PFS, LSS, OS and histologic transformation in SMZL patients. In univariate analysis for PFS, only NOTCH2 mutations and TP53 inactivation (i.e. del(17p) or TP53 mutations) predicted poorer PFS, but in multivariate analysis NOTCH2 mutations were the sole factor significantly affecting PFS rates (p=0.041). For LSS, OS and histologic transformation, no prognostic factor was identified in univariate analysis. Conclusions: Our data suggest that CBL-MZ and SMZL share a similar cytogenetic and mutational profile. These findings suggest the possible involvement of a common oncogenic mechanism in the development of these lymphoid neoplasms. Disclosures Hermine: Novartis: Research Funding; Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Research Funding.

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Stratification Approach for Splenic Marginal Zone Lymphoma Based on Hemoglobin, Platelet Count, High LDH and Extrahilar Lymphadenopathy: The HPLL/ABC System

Blood ◽

10.1182/blood.v118.21.1583.1583 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1583-1583 ◽

Cited By ~ 1

Author(s):

Carlos Montalban ◽

Victor Abraira ◽

Luca Arcaini ◽

Eva Domingo-Domenech ◽

Pablo Guisado-Vasco ◽

...

Keyword(s):

Cancer Research ◽

Platelet Count ◽

Research Funding ◽

Marginal Zone ◽

Risk Groups ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

Training Set ◽

Conditioning Treatment ◽

Significant Difference

Abstract Abstract 1583 Splenic Marginal Zone Lymphoma (SMZL) is a distinct lymphoma included in the WHO 2008 classification. Ann Arbor staging system is not adequate to stratify SMZL patients into risk groups, as blood and bone marrow are usually involved. Further, there are neither established criteria for starting treatment nor gold standard treatment. Herein we report an international retrospective study on 593 SMZL patients aimed to identify which factors could influence starting treatment and which could allow stratify risk categories. Logistic regression was used to identify the factors that have conditioned treatment in the whole series and Cox regression for factors influencing Lymphoma Specific Survival (LSS) in a training set of 336 patients. The variables used were age, hemoglobin level and platelet count (as continuous variables) and sex, low albumin serum level (<3 gr/dl), high LDH and β2microglobulin, serum monoclonal component, DAT positivity, active autoimmune anemia, HCV positivity, lymphadenopathy (other than in hepatic and splenic hila) and extranodal involvement. The final model for LSS was used to produce a prognostic index (PI) and allowed to divide the patients in three risk groups applying cutpoints at the 20th and 80th centiles in patients with events. The resulting stratification was validated in another set of 227 patients. Also, the stratification was compared with the Interguppo Italiano Linfomi (IIL) score in the set of 450 patients in whom the required data were available, using the extension net reclassification improvement (NRI). Hemoglobin (p=0.000), extrahilar lymphadenopathy (p=0.000), and HCV positivity (p=0.001), were the factors independently conditioning treatment. Untreated patients had a significant longer LSS than treated patients (p=0.000). In the treated group there were no differences in LSS according to the type of therapy (splenectomy, chemotherapy, rituximab or their combinations) (Figure A). The low number of rituximab treated patients (n=39) precluded statistically reliable conclusions. In the training set, haemoglobin (p=0.003), platelet count (p=0.043), high LDH (p=0.011) and extrahilar lymphadenopathy (p=0.020) were the factors independently influencing LSS. The resulting PI was: 0.6 × platelet count (in hundreds of thousands/mm3) + 0.2 × hemoglobin (g/dl) − 1 × high LDH (1 when LDH above normal, 0 when normal) – 0.75 × extrahilar lymphadenopathy (1 when present, 0 when absent). Applying the cut points a low, intermediate and high risk groups with significantly different 5 year LSS of 0.94, 0.78 and 0.67, respectively, were identified (Figure B). In the validation set the system also separated 3 groups with significant different 5 year LSS of 0.96, 0.88 and 0.44, respectively. This stratification was named HPLL after the determinant factors (H emoglobin, P latelet count, high L DH, L ymphadenopathy) and the resulting risk groups HPLLA, HPLLB and HPLLC. In the comparison HPLL/ABC system separated 3 groups with significantly different LSS, whereas in the IIL score there was no significant difference between the low and intermediate risk groups (p=0,102). Using as reclassification calibration statistics the Hosmer-Lemeshow test, HPLL/ABC (χ2 =1.48; p=0.475) showed a better fit than the IIL score (χ2= 3.339; p=0.118) indicating that HPLL/ABC discriminated better the risk groups. In this large SMZL series, haemoglobin, extrahilar lymphadenopathy and HCV positivity were the factors independently conditioning treatment. The combination of hemoglobin, platelet count, high LDH and extrahilar lymphadenopathy stratify the patients in three groups with significantly different outcome. This system may be helpful to select risk-tailored treatment approaches. Disclosures: Montalban: Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding. Mollejo:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding. Piris:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.

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Outcomes In Splenic Marginal Zone Lymphoma: Analysis Of 108 Patients Treated In British Columbia (BC)

Blood ◽

10.1182/blood.v122.21.4369.4369 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4369-4369

Author(s):

Katharine He Xing ◽

Amrit Kahlon ◽

Joseph M. Connors ◽

Brian Skinnider ◽

Randy D. Gascoyne ◽

...

Keyword(s):

British Columbia ◽

Hepatitis C ◽

Research Funding ◽

Marginal Zone ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Transformation Rate ◽

Splenic Marginal Zone Lymphoma ◽

First Line

Abstract Introduction Splenic marginal zone lymphoma (SMZL) is uncommon and accounts for less than 1% of all non-Hodgkin lymphomas. The optimal treatment for SMZL is unknown. We describe the outcome of 108 patients with SMZL treated in British Columbia. Methods All patients with SMZL diagnosed between 1985 and June 2012 were identified in the BC Cancer Agency Centre for Lymphoid Cancer and Lymphoma Pathology Databases. Overall survival (OS) was measured from time of diagnosis to death or last follow-up. Progression-free survival (PFS) was measured from the date of diagnosis to the date of lymphoma recurrence or transformation, or death. Time to transformation (TTT) was calculated from date of diagnosis to date of transformation to aggressive lymphoma. Results 108 patients were identified with a diagnosis of SMZL. Baseline patient characteristics: median age 67 years (range 30-88), male 41%, stage IV 98%, B symptoms 17%, performance status ≥2 22%, splenomegaly 93%, bone marrow involvement 93%, peripheral blood involvement 87%. Hepatitis C serology was positive in 5 of 60 patients with available data. As initial treatment, 53 underwent splenectomy (10 with chemotherapy), 38 chemotherapy alone (21 with a rituximab-containing regimen), 2 received antiviral therapy for hepatitis C, and 15 were observed. Of the 43 patients who had splenectomy alone, 9 subsequently received chemotherapy upon progression, 1 had excision for a soft tissue mass, and 4 transformed to diffuse large B cell lymphoma (DLBCL). Of the 38 who received chemotherapy first line, 6 subsequently received combined chemotherapy and splenectomy, 1 splenectomy alone, 4 chemotherapy alone, and 7 transformed to DLBCL. Neither of the 2 patients who received antivirals had further progression. With a median follow-up of 7 years (range 3 months to 18 years) for living patients, the 5 and 10 year OS were 65% and 48%, respectively. The 5 and 10 year PFS were 38% and 18%, respectively. The 5 year OS for patients who had a splenectomy as their first-line therapy compared to other treatments was 76% vs 53% (p=0.01); and the 5 year OS for patients who received chemotherapy alone as first-line compared to other treatments was 52% vs 72% (p=0.04). There was no difference in outcomes between those treated with rituximab containing chemotherapy as first line compared to other treatments (p=0.65). The 5 and 10 year PFS after first-line splenectomy were 52% and 18%, respectively. A total of 14 patients transformed to DLBCL with a median TTT of 3.2 years (range 6 months to 11.9 years). The 5, 10, 15 year rates of transformation were 9%, 21% and 35%, respectively. Conclusions Splenectomy remains a reasonable treatment option for patients with SMZL. Patients selected for splenectomy as initial management of symptomatic disease experience improved outcomes. The transformation rate in SMZL is similar to that of other indolent lymphomas. Disclosures: Connors: F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Skinnider:Roche Canada: Research Funding. Gascoyne:Roche Canada: Research Funding. Sehn:Roche Canada: Research Funding. Savage:Roche Canada: Research Funding. Slack:Roche Canada: Research Funding. Shenkier:Roche Canada: Research Funding. Klasa:Roche Canada: Research Funding. Gerrie:Roche Canada: Research Funding. Villa:Roche Canada: Research Funding.

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Comparative Effectiveness of Rituximab-Based Immunochemotherapy in Waldenstrom's Macroglobulinemia (WM)

Blood ◽

10.1182/blood.v128.22.2986.2986 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2986-2986 ◽

Cited By ~ 1

Author(s):

Adam J Olszewski ◽

Steven P Treon ◽

Jorge J Castillo

Keyword(s):

Clinical Trials ◽

Comparative Effectiveness ◽

Research Funding ◽

Randomized Clinical Trials ◽

Single Agent ◽

The United States ◽

Population Based ◽

First Line ◽

Prophylactic Measures ◽

Significant Difference

Abstract Background: Waldenström macroglobulinemia (WM) is difficult to study in randomized clinical trials because of its rarity, and higher incidence among older patients (pts). The most recent published trial focusing on WM (Leblond et al., J Clin Oncol 2013) compared chlorambucil with fludarabine-treatments no longer in common use. Recent data (Olszewski et al., Oncologist 2016) show that over 80% of WM pts in the United States are now treated with rituximab (R) alone or in combination with chemotherapy, although the effect of R on overall survival (OS) in WM has not been shown in clinical trials (Buske et al., Leukemia, 2009). Our objective was to provide comparative evidence of therapeutic efficacy for R-based immunochemotherapy in WM by applying causal inference methods to population-based, observational data. Methods: Using Medicare claims from 1999-2013, linked to the Surveillance, Epidemiology and End Results registry data, we identified WM patients (pts) >65 years old, who initiated first-line chemotherapy with or without R, with purine analogues (PUR, fludarabine or cladribine) and/or classic alkylating agents (ALK, chlorambucil or cyclophosphamide). Pts receiving both fludarabine and cyclophosphamide were grouped as PUR. Factors associated with treatment selection were studied in multivariable mixed-effects logistic models. We then conducted 3 separate comparative analyses: 1) regimens with R versus without R, 2) R monotherapy versus combination immunochemotherapy, and 3) PUR- versus ALK-based regimens. In each case, we balanced baseline characteristics (age, sex, race, socioeconomic status, comorbidities, performance status, time from diagnosis), and indicators of WM severity previously validated to correlate with OS (anemia, transfusions, plasmapheresis) using propensity score analysis, to minimize indication bias and simulate a randomized experiment. We then compared OS and select adverse events within 90 days of treatment (hospitalization, transfusion, or plasmapheresis) using survival or log-binomial models weighted by inverse probability of treatment (IPT), reporting hazard ratio (HR) or relative risk (RR) with 95% confidence intervals (CI). Results: Among 1,310 pts (median age 78 years, 43% women), 54% received first-line R monotherapy, 12% R+PUR, 12% R+ALK, 14% PUR-(without R)- and 8% ALK-(without R)-based regimen. Receipt of R was more likely among pts with metropolitan residence, diagnosis after 2003, and baseline neuropathy, and significantly varied by treating physician (intra-class correlation, 45%, CI 25-66%, P<.0001). Unadjusted 5-year OS was 42.0% (CI, 36.1-47.8) for chemotherapy without R, 51.9% (CI, 46.0-57.6) for chemotherapy with R, and 50.6% (CI, 46.4-54.7) for R alone. In each comparative analysis, we achieved adequate balance of confounding variables using propensity scores. In the IPT-weighted outcome models, OS was significantly better for pts who received R as part of their therapy compared with those who did not (HR, 0.77; CI, 0.64-0.93; P=.0058; Fig. A), without difference in the studied toxicities. Within 3 months of starting therapy, there was an overall 20.4% frequency of transfusion, 9.6% of hospitalization, and 4.4% of plasmapheresis. The RR for plasmapheresis after R-based regimen was 1.09 (CI, 0.63-1.90, P=.76). There was no significant difference in OS between pts receiving R alone or in combination with chemotherapy (HR, 0.90, CI, 0.74-1.08, P=.25, Fig. B), but the risk of transfusions (RR, 0.71; CI, 0.56-0.88; P=.002) and hospitalizations (RR, 0.52; CI, 0.34-0.79; P=.002) was lower after single-agent R. Furthermore, there was no evident difference between PUR- or ALK-based regimens in OS (HR, 1.13, CI, 0.90-1.42, P=.30, Fig. C), or in the studied toxicities. Conclusions: This population-based, comparative effectiveness study provides evidence of OS benefit of R (as monotherapy or combination immunochemotherapy) for Medicare beneficiaries (>65 years old) with WM. Toxicity of single-agent R was lower compared with combination regimens, without a difference in survival, thus confirming its utility as a treatment option for older pts who do not have a strong indication for cytotoxic therapy. Acknowledging likely pre-selection on the basis of (unrecorded) IgM levels, and possible uncaptured prophylactic measures, R-based therapy did not appear to result in a higher risk of plasmapheresis or hospitalization. Figure Figure. Disclosures Olszewski: TG Therapeutics: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy. Treon:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy. Castillo:Janssen: Honoraria; Millennium: Research Funding; Pharmacyclics: Honoraria; Abbvie: Research Funding; Otsuka: Consultancy; Biogen: Consultancy.

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Does Hispanic Origin Affect the Repartition and Outcome of Marginal Zone Lymphoma?

Blood ◽

10.1182/blood-2020-136220 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-12

Author(s):

Lakene Raissa Djoufack Djoumessi ◽

Snegha Ananth ◽

Michael E Auster ◽

Joel E Michalek ◽

Qianqian Liu ◽

...

Keyword(s):

Overall Survival ◽

Median Survival ◽

Survival Probability ◽

Research Funding ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Age At Diagnosis ◽

Poverty Index ◽

Hispanic Origin ◽

Significant Difference

BACKGROUND Marginal zone lymphoma (MZL) is a rare indolent lymphoma that represents about 7% of all Non-Hodgkin's lymphoma (NHL). MZL is divided into 3 subtypes with different repartition based on primary anatomical site: 60% extra-nodal (EMZL), 32% nodal (NMZL), and 9% Splenic (SMZL) (CA Cancer J Clin, PMID: 27618563). While asymptomatic MZL is often left untreated, there are no clear guidelines regarding the first-line treatment of each subtype (Future Oncol, PMID: 29260925). Although the survival rate of MZL is superior to other NHL with a 5-year survival of 83-91%, cancer remains a leading cause of death among Hispanics (CA Cancer J Clin, PMID: 7618563; Natl Vital Stat Rep, PMID: 32501203). Our study aimed at establishing the impact of Hispanic origin on the repartition and outcomes of MZL. METHODS: Data from the Texas Cancer Registry were utilized including adult patients diagnosed with NHL between 2006-2016. The third edition of the International Classification of Diseases for Oncology (ICD-O-3) was used to select patients diagnosed with MZL and all patient information was de-identified. Standard demographic information and outcomes were obtained and summarized in tables. The significance of variance of categorical outcomes by ethnicity was calculated using Fisher's Exact test or T-test (statistical significance of 5%). Survival time was calculated from the date of primary diagnosis to date of death. Kaplan-Meier curves were used for survival distributions and the significance of variation in median survival with ethnicity was assessed with log-rank testing. RESULTS AND DISCUSSION Of the 43166 total cases of NHL, 3529 (8.2%) were MZL, of which 82%(n=2867) were Non-Hispanics (NH) and 18%(n=662) were Hispanics (H). When comparing the number of cases among each subtype of MZL in H vs NH, there were 408 vs 1570 cases of EMZL, 174 vs 1022 cases of NMZL, and 38 vs 275cases of SMZL respectively. The median age at diagnosis was 63.2 for H and 66.7 for NH. Younger age at diagnosis was noted in H compared to NH for EMZL (60.4 vs 65, p<0.001) and NMZL (64.4 vs 66.7, p=0.004). There was no statistical difference between genders. About 51.6% of H was in the 20-100% poverty index bracket compared to 20.1% in NH (p< 0.0001). The most prevalent insurance type was Medicare in both groups (H: 37%, NH: 47.2%) and the uninsured rate was higher in H (12.4 vs 3.2 p<0.02). Most individuals regardless of their ethnicity lived in the metro area (87%), non-border area (85%). EMZL was more prevalent in H (61% vs 54%, p=0.001) whereas NMZL (26,2% vs 35,6%, p=0.0005) and SMZL (5.7% vs 9.5% p=0.002) where more prevalent in NH. Regarding systemic treatment, there was no statistically significant difference between the two groups irrespective of MZL subtype; patients were treated with single or multiple agent chemotherapy as it follows: NMZL 34% H vs 27% NH, EMZL 16% H vs 15.5 NH, SMZL 24% H vs 25% NH. Beam radiation was more frequent in H for both EMZL (20% vs 14.6% p=0.031) and NMZL (3.4% vs 0.2%, p=0.02). Median survival in years was very similar in H vs NH (EMZL: 9 vs 9.3; NMZL: 7.6 vs 7.6; SMZL: 7.3 vs 8.3). Furthermore, there was no statistically significant difference in the overall survival probability for the 10-year follow up period (EMZL: p=0.46, NMZL: p=0.69; and SMZL: p=0.74). Demographics and results are summarized in Table 1. CONCLUSION Despite differences in demographics, poverty index, insurance coverage, and prevalence of each subtype of MZL in H compared to NH, there was no statistically significant difference in overall survival probability. These findings also suggest that the complex correlation between MZL biology, ethnicity and oncologic care can serve as the equalizer of disparities that lead to long term balanced outcomes. More in depth studies are needed to further clarify. Disclosures Diaz Duque: ADCT Therapeutics: Research Funding; Molecular Templates: Research Funding; AstraZeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Seattle Genetics: Speakers Bureau; Verastem: Speakers Bureau; AbbVie: Speakers Bureau.

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Under-Treatment of Older Patients with Newly Diagnosed Epithelial Ovarian Cancer Remains an Issue

Cancers ◽

10.3390/cancers13050952 ◽

2021 ◽

Vol 13 (5) ◽

pp. 952

Author(s):

Lucy Dumas ◽

Rebecca Bowen ◽

John Butler ◽

Susana Banerjee

Keyword(s):

Ovarian Cancer ◽

Older Women ◽

Older Patients ◽

Single Agent ◽

Eastern Cooperative Oncology Group ◽

Standard Of Care ◽

First Line ◽

Care Treatment ◽

Platinum Based Chemotherapy ◽

Standard Of Care Treatment

Older women with ovarian cancer have disproportionately poorer survival outcomes than their younger counterparts and receive less treatment. In order to understand where the gaps lie in the treatment of older patients, studies incorporating more detailed assessment of baseline characteristics and treatment delivery beyond the scope of most cancer registries are required. We aimed to assess the proportion of women over the age of 65 who are offered and receive standard of care for first-line ovarian cancer at two UK NHS Cancer Centres over a 5-year period (December 2009 to August 2015). Standard of care treatment was defined as a combination of cytoreductive surgery and if indicated platinum-based chemotherapy (combination or single-agent). Sixty-five percent of patients aged 65 and above received standard of care treatment. Increasing age was associated with lower rates of receiving standard of care (35% > 80 years old versus 78% of 65–69-year-olds, p = 0.000). Older women were less likely to complete the planned chemotherapy course (p = 0.034). The oldest women continue to receive lower rates of standard care compared to younger women. Once adjusted for Federation of Gynaecology and Obstetrics (FIGO) stage, Eastern Cooperative Oncology Group (ECOG) performance status and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Optimisation of vulnerable patients utilising a comprehensive geriatric assessment and directed interventions to facilitate the delivery of standard of care treatment could help narrow the survival discrepancy between the oldest patients and their younger counterparts.

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Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Blood ◽

10.1182/blood-2019-124330 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 179-179

Author(s):

Jessica K. Altman ◽

Tsila Zuckerman ◽

Olga Frankfurt ◽

Selina M. Luger ◽

Dale L. Bixby ◽

...

Keyword(s):

Board Of Directors ◽

Standard Therapy ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Prior Exposure ◽

Efficacy And Safety ◽

First Line ◽

Advisory Committees ◽

Ongoing Phase

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

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Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-136370 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Brian T. Hill ◽

Deepa Jagadeesh ◽

Alex V. Mejia Garcia ◽

Robert M. Dean ◽

Omer N. Koc ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Marginal Zone ◽

Proteasome Inhibitors ◽

Marginal Zone Lymphoma ◽

Aggressive Lymphoma ◽

Advisory Committees ◽

Frontline Treatment

INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

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Dramatic Response with Single-Agent Ibrutinib in Multiply Relapsed Marginal Zone Lymphoma with MYD88L265P Mutation

Case Reports in Oncology ◽

10.1159/000480292 ◽

2017 ◽

Vol 10 (3) ◽

pp. 813-818 ◽

Cited By ~ 2

Author(s):

Ryan C. Lynch ◽

Ranjana H. Advani

Keyword(s):

B Cell ◽

Signaling Pathway ◽

Marginal Zone ◽

Single Agent ◽

Cell Receptor ◽

Marginal Zone Lymphoma ◽

B Cell Receptor ◽

Receptor Signaling Pathway ◽

B Cell Receptor Signaling ◽

Cell Receptor Signaling

The B-cell receptor signaling pathway is important in the lymphomagenesis of many lymphomas, including marginal zone lymphoma (MZL). Herein we describe a case of extranodal MZL refractory to multiple lines of therapy. The presence of an IgM paraprotein prompted further evaluation, and the patient was found to have an MYD88L265P mutation. Treatment with ibrutinib led to a dramatic response with prompt resolution of symptoms and significant improvement in measurable sites of disease. The excellent response to ibrutinib in our patient with MYD88L265P-mutated refractory MZL supports a biological rationale for its use.

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