Non-Pegylated Liposomal Encapsulated Doxorubicin Reduces Cardiotoxicity in 1st Line Treatment of Diffuse Large B-Cell Lymphoma (DLBCL). Final Results of a Randomized Trial

Abstract Abstract 2676 Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) has improved the treatment results in DLBCL substantially. With more patients being cured from the lymphoma long term toxicity becomes an even more important issue. By replacing doxorubicin with non-pegylated liposomal encapsulated doxorubicin in the R-CHOP regimen (R-COMP) we tried to reduce the cardiotoxicity of R-CHOP in the 1st line treatment of DLBCL. We randomized 88 patients with untreated DLBCL to one of two treatment arms. R-CHOP consisted of rituximab 375 mg/sqm, cyclophosphamide 750 mg/sqm, doxorubicin 50 mg/sqm, vincristine 2 mg, each iv. day 1 and prednisolone daily po for 5 consecutive days. Six cycles of chemotherapy and 8 cycles of rituximab were planned. In the R-COMP arm doxorubicin was replaced with non-pegylated liposomal encapsulated doxorubicin 50 mg/sqm iv day 1. Forty and 39 patients were eligible in the R-COMP and R-CHOP arm, respectively. The two arms were well balanced with respect to age, smoking status, heart function, hypertension, and international prognostic index. The primary endpoint of the study was the left ventricular ejection fraction (LVEF) measured by the Simpson method at randomization, after each cycle and 8 weeks after the end of treatment. Mean and standard error were compared by the two-sample t test. Mean LVEF was significantly lower in the R-CHOP arm (62.29%) than in the R-COMP arm (63.56%) (P=.0333). Out of all LVEF measurements 10 (4.6%) vs. 31 (15.8%) were <55% in the R-COMP arm and R-CHOP arm, respectively (P<.001). The N-terminal proB-type of the natriuretic peptide (NT-proBNP) is a strong marker for heart failure. Levels of NT-proBNP began to rise in the R-CHOP arm after the 5th cycle and were significantly different after the end of treatment (median 73 pg/ml vs. 188.2 pg/ml) in the R-COMP arm and R-CHOP arm, respectively. Three (7.5%) and 12 (33.3%) patients had a NT-proBNP >450 pg/ml in the R-COMP arm and R-CHOP arm, respectively (P=.005). Side effects were lower in the R-COMP arm. We observed 26 and 40 severe adverse events in the R-COMP and R-CHOP arm, respectively (P=.029). Most of those were due to infection. The rate of grade 3 and 4 neutropenias was comparable in both arms giving evidence, that non-pegylated liposomal encapsulated doxorubicin was not under-dosed. Although the study was not powered to show differences in efficacy, we had no signal of lower efficacy. The remission rate was 97.5% (CR+CRu 75.0%) and 82.0% (CR+CRu 69.2%) with R-COMP and R-CHOP, respectively. The 3 cases progressing during treatment were in the R-CHOP arm. Clinical heart failure usually appears after several years of treatment. The difference in LVEF may translate in a lower rate of clinical heart failure with longer follow-up. Disclosures: Fridrik: Cephalon: Research Funding. Off Label Use: Non-pegylated liposomal encapsulated doxorubicin in the treatment of lymphoma. Willenbacher:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AESCA: Honoraria, Research Funding. Jaeger:Cephalon: Membership on an entity's Board of Directors or advisory committees. Greil:Cephalon: Research Funding.

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Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽

10.1182/blood-2019-122393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2898-2898

Author(s):

Vania Phuoc ◽

Leidy Isenalumhe ◽

Hayder Saeed ◽

Celeste Bello ◽

Bijal Shah ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Fdg Pet ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Are Racial Disparities in Acute Myeloid Leukemia (AML) Clinical Trial Enrollment Associated with Comorbidities and/or Organ Dysfunction?

Blood ◽

10.1182/blood-2019-129096 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 381-381

Author(s):

Abby Statler ◽

Brian P. Hobbs ◽

Tomas Radivoyevitch ◽

Sudipto Mukherjee ◽

Kimberly Bell ◽

...

Keyword(s):

Renal Function ◽

Racial Disparities ◽

Board Of Directors ◽

Organ Dysfunction ◽

Research Funding ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Eligibility Criteria ◽

Advisory Committees ◽

Laboratory Values

Background: Minority patient (pt) populations are underrepresented in clinical trials and the proportion of such pts accrued to cancer studies has decreased, specifically among African Americans (AA) (Kwiatkowski et al. Cancer 2013). If minority pt populations have higher rates of comorbidities, restrictive eligibility criteria may contribute to systematic exclusion from studies. To explore the validity of this potential bias within AML pts, we characterized the comorbidity profile and compared outcomes between AA and white pts with AML. Methods: Adult (≥18 years) AML pts who received chemotherapy at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic/renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Organ dysfunction was defined as ≥ grade 1 per the Common Terminology for Adverse Events. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariable logistic and Cox regression analyses were used to identify prognostic factors for response status per International Working Group criteria, and overall survival (OS). Kaplan-Meier method and log-rank test were used to estimate and evaluate OS, respectively. Results: Of 1,040 AML pts included, 939 (90.3%) identified as white and 101 (9.7%) as AA. Age, AML etiology, and AML risk were balanced between the two groups. Insurance coverage was different by race: AAs were more likely than whites to have Medicaid (11.9% vs. 5.1%), and less likely to have private insurance (16.8% vs. 34.6%), P<.001. Pts were treated with the following: 868 (83.5%) with intensive, cytarabine-based, and 172 (16.5%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. AA pts were just as likely as whites to receive intensive therapy (P=.68) (Table 1). AA pts presented with similar frequencies of both overall and specific comorbidities. Liver function laboratory values (AST/ALT/bilirubin) and cardiac test results (QTc/LVEF) at baseline were also similar; however, a greater proportion of AAs presented with renal dysfunction when compared to whites, as measured by creatinine (48.5% vs. 36.5%, P=.01) or creatinine clearance by Cockcroft-Gault (CrCl; 55.4% vs. 47.3%, P=.01; Table 2). With a median follow-up of 12.73 months (IQR: 4.59-43.05), the OS for the cohort was 14.75 months (range: 0.03-189.25). Median OS did not differ by race (AA vs. whites: 13.7 vs. 14.9 months, P=.89). Overall, the complete response (CR) rate was 44.2%, which also did not differ by race: (AA vs. whites: 37.6% vs. 44.9%, P=.19). When adjusting for other known predictors, in a multivariable analysis, there was no difference in OS between AAs and whites (HR=1.20, P=.16); additionally, there was no association between comorbidities/organ dysfunction and OS, with the exception of liver comorbidities (HR=2.03, P=.002) and bilirubin (>1.5 x ULN vs. normal: HR= 1.69, P=.01). Clinically insignificant creatinine (>ULN - 1.5 x ULN vs. normal: HR= 0.99, P=.97) and CrCl (84-60 ml/min vs. normal: HR=0.96, P=.69) abnormalities were not independently associated with OS. Subgroup analyses by race revealed similar results for AAs, although, there were no differences in OS based upon bilirubin. With the exception of liver comorbidities (OR= 0.17, P=.01), our analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction (similar results within the AA subgroup). Although AA were less likely to achieve a CR (AA vs. whites: OR=0.56, P=.05), there was no association between response and creatinine/CrCl abnormalities, regardless of severity. Conclusions: Within this cohort, renal function eligibility criteria may be an important barrier to enrollment, specifically within the AA population. Since there is no association between clinically insignificant renal laboratory values and OS or response, the liberalization of such criterion may be justified. Future trials that broaden the renal function eligibility criterion have the potential to accrue more diverse pt populations, which may reduce recruitment racial disparities and improve the generalizability of the trials' results. Disclosures Hobbs: Amgen: Research Funding; SimulStat Inc.: Consultancy. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Gerds:CTI Biopharma: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Imago Biosciences: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Incyte: Speakers Bureau; Jazz Pharmacutical: Research Funding; Abbvie: Consultancy; Tolero, Karyopharma: Honoraria; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

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Determinants of "Fitness" for Intensive Therapy Among Acute Myeloid Leukemia (AML) Patients

Blood ◽

10.1182/blood-2019-128853 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3836-3836

Author(s):

Abby Statler ◽

Brian P. Hobbs ◽

Tomas Radivoyevitch ◽

Caitlin Siebenaller ◽

Sudipto Mukherjee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

De Novo ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Advisory Committees ◽

Cart Analysis ◽

Cardiac Abnormalities ◽

Oncology Research ◽

Baseline Characteristics

Background: Determining which AML patients (pts) are "fit" for intensive chemotherapy (IC), both in real-world scenarios and for clinical trial eligibility (particularly as it relates to regulatory indications) is challenging. While age, AML etiology, and cardiac function have been invoked, these oversimplify the clinical assessment and recommendation for IC vs. Non-IC (NIC). We compared baseline characteristics among pts receiving IC and NIC, and evaluated associations between treatment receipt and pt characteristics. Adjusting for treatment received, pts' attributes were further evaluated for association with overall survival (OS). Methods: Adult (≥18 years) AML pts who received IC or NIC at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic and renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariate logistic and Cox regression were used to identify significant prognostic factors for treatment receipt and OS, respectively. The Kaplan-Meier method estimated distributions of OS, which were compared among pt cohorts using the log-rank test. Classification and regression tree (CART) analysis was performed to characterize the best decision process used to select pts for NIC. Results: Of 1,082 AML pts analyzed, 901 (83.2%) were treated with intensive, cytarabine-based chemotherapy, and 181 (16.8%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. As expected, baseline characteristics were significantly imbalanced between groups; pts receiving NIC were more likely to be older (P<.001), have ≥3 comorbidities (P<.001), another cancer (P=.02), myocardial (P<.001), renal (P=.006) conditions, abnormal renal (creatinine (P=.004), creatinine clearance by Cockcroft-Gault (CrCl, P<.001)), and abnormal liver function (bilirubin (P=.03)). And less likely to have de novo disease (P<.001), favorable ELN risk (P=.008), private insurance (P<.001), and mild cardiac abnormalities (QTc 450-480ms (P<.001), LVEF 50-40% (P<.001)) (Tables 1 & 2). Multivariable stepwise regression revealed independent associations with the following attributes (favoring NIC over IC): older age (OR=1.10, P<.001), etiology (prior MDS vs. de novo; OR=2.52 , P<.001), liver (bilirubin >1.5xULN vs. normal; OR=3.04, P=.02), renal (CrCl <60 ml/min vs. normal; OR=3.17, P=.002), myocardial conditions (atrial fibrillation/congestive heart failure/coronary artery disease vs. normal); OR=2.33, P=.001) and mild cardiac abnormalities (QTc 450-480ms vs. normal: OR=0.46, P=.01; LVEF 50-40% vs. normal: OR=0.33, P=.03). Clinically, in making decisions about NIC, the first step is age, followed by comorbidity. CART analyses revealed that when a comorbidity is identified, age is then re-assessed; depending upon the type of comorbidity present, various age thresholds determined NIC vs. IC. With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). OS was significantly different between groups (median OS, NIC vs. IC: 4.9 vs. 20.4 months, P<.001). In multivariate analyses controlling for treatment (IC vs. NIC), age, sex, insurance, number of comorbidities, AML etiology, and ELN risk, having another cancer (HR= 0.97, P=.78), renal (HR=1.10, P=.56) or myocardial comorbidity (HR= 0.94, P=.60) were not significantly associated with OS. Liver (bilirubin >1.5xULN: HR=1.70, P=.01), renal (creatinine >1.5xULN: HR=1.55, P=.001; CrCl<60ml/min: HR=1.37, P=.01), and cardiac dysfunction (QTc >480-500ms: HR=1.36, P=.04; LVEF 50-40%: HR=1.38, P=.04) were, however, associated with worse survival. Conclusions: Age, comorbidities, and organ dysfunction are associated with AML treatment determination. Pts who presented with cancer/renal/myocardial comorbidities and renal/liver dysfunction were more likely to receive NIC, despite the comorbid conditions not having an impact on OS. Further research needs to elucidate the extent to which NIC is the optimal treatment decision for pts exhibiting varying severities of cancer/renal/myocardial comorbidities. Disclosures Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:McGraw Hill Hematology Oncology Board Review: Other: Editor; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Advani:Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Gerds:Sierra Oncology: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Abbvie: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees.

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Initial Liver Iron Predicts Cardiac Chelation Efficacy of Deferasirox (Exjade®) Monotherapy in Chronically Transfused β-Thalassemia (β-Thal) Patients: 18- and 24-Month Data.

Blood ◽

10.1182/blood.v114.22.4069.4069 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4069-4069

Author(s):

John C. Wood ◽

Alexis A. Thompson ◽

Carole Paley ◽

Tara Glynos ◽

Barinder Kang ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Employment Equity ◽

Advisory Committees ◽

Liver Iron ◽

Cardiac Iron ◽

Equity Ownership

Abstract Abstract 4069 Poster Board III-1004 Introduction Transfused patients with β-thal major are known to experience clinical consequences of cardiac iron overload despite the widespread use of iron chelation therapy. Approximately 71% of patients will suffer cardiomyopathy, congestive heart failure (CHF) and death. Previous trials have confirmed the efficacy of deferasirox (Exjade®) in removing cardiac iron in patients with β-thal major. This ongoing study evaluates the effects of deferasirox on cardiac iron and left ventricular ejection fraction (LVEF) in patients with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. All patients have completed 18 months of therapy and we also report preliminary results from 24 months. Methods 28 patients were enrolled at four US centers. Entry criteria included MRI evidence of cardiac iron (T2* <20 ms) and normal LVEF (≥56%). Deferasirox was administered at 30–40 mg/kg/day for 18 months. Following core study completion (18 months), patients could continue treatment for an additional 6 months if their 18-month cardiac T2* was <20 ms and they demonstrated ≥25% improvement in cardiac T2* or LIC from baseline. Serum ferritin (SF) was assessed monthly. Liver iron concentration (LIC), cardiac T2* and LVEF were assessed by MRI every 6 months. Serum creatinine (SCr), biochemical and hematological status were also monitored. All results are reported as mean ± SE (range) unless otherwise stated. Baseline: All 26 evaluable patients (7 M/19 F; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4307 ± 613 ng/mL (312–12,655), cardiac T2* was 9.5 ± 0.8 ms (1.8–16.1), LIC was 20.6 ± 3.15 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.8 ± 0.8%. Results At the time of analysis, 22 and 9 patients had 18- and 24-month evaluations, respectively. Six patients discontinued the core trial due to patient decision (n=2), adverse events (AEs; n=2) or abnormal lab tests (n=2). Two of these patients died after discontinuing; the first enrolled with markedly elevated baseline cardiac iron (T2* = 1.8 ms) and died secondary to CHF. The second patient withdrew due to an AE and died 2 months later due to sepsis and multi-organ failure. 18-month results: At 18 months, 10/22 patients were on 40 mg/kg/day. The mean improvement in cardiac T2* from baseline in all patients was 2.2 ms (22%; P=0.016), with 13 patients improving, four remaining stable (T2* change <10%) and five worsening. Baseline LIC was a powerful predictor of response (Figure); cardiac T2* in 14 patients with LIC <18.5 mg Fe/g dw improved 2.2% per month, with 13/14 patients showing large improvements and one patient remaining stable. In contrast, in eight patients with LIC >18.5 mg Fe/g dw, mean T2* worsened 1.4% per month (P<0.0001); three patients remained stable and five worsened significantly. Improvements in cardiac iron were correlated with changes in LIC (r2 = 0.27, P=0.013). In general, initial T2* did not predict therapeutic response, although all three patients with T2* <6 ms increased their cardiac iron. LIC decreased 4.1 mg Fe/g dw over the study interval (P=0.003). LVEF remained stable. 24-month results: At 24 months, 7/9 patients were on 40 mg/kg/day. Relative to the 18-month time-point, 8/9 patients (89%) increased their cardiac T2*, with a mean improvement of 2.7% per month. Mean LIC, SF and LVEF were unchanged over the extension. Safety parameters from patients treated with 30–40 mg/kg/day deferasirox (n=25) were in line with previous studies at 20–30 mg/kg/day. Conclusions Deferasirox monotherapy resulted in statistically significant improvements in cardiac and hepatic iron after 18 months. Baseline LIC <18.5 mg Fe/g dw was a strong predictor of favorable response. LVEF remained stable during the study. Patients in the extension (18–24 months) improved their cardiac T2* without further improvements in LIC or SF. Deferasirox monotherapy at 30–40 mg/kg/day provides good cardiac chelation in patients with moderate cardiac and liver iron burdens. More aggressive therapy is warranted for more severe iron overload. Disclosures: Wood: Novartis: Research Funding. Thompson:Novartis: Research Funding. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Glynos:Novartis Pharmaceuticals: Employment. Kang:Novartis Pharmaceuticals: Employment, Equity Ownership. Giardina:Novartis: Research Funding, Speakers Bureau. Harmatz:Ferrokin: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Coates:Hope Pharma: Consultancy, Research Funding; Sangart Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Trial in Progress: A Multicentre, Parallel Arm, Open-Label Trial of Frontline R-CHOP/Polatuzumab Vedotin-RCHP and Glofitamab in Younger Patients with Higher Risk Diffuse Large B Cell Lymphoma (COALITION)

Blood ◽

10.1182/blood-2021-147636 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3571-3571

Author(s):

Adrian Minson ◽

Nada Hamad ◽

Costas K. Yannakou ◽

Shu Min Wong ◽

Jason P Butler ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Response Rates ◽

Line Treatment ◽

Front Line ◽

Advisory Committees

Abstract Background: R-CHOP remains a standard frontline treatment for patients with DLBCL and high-grade B-cell lymphoma (HGBL). A significant proportion of patients will have refractory disease or subsequently relapse, particularly those with high-risk features such as an elevated IPI score or rearrangements of MYC and BCL2 and/or BCL6 (double/triple hit (DH/TH)). This population remains in need of improved induction treatments that can reduce the requirement for subsequent therapies which are associated with significant toxicities and diminishing response rates. Rationale: Glofitamab is a novel full-length bispecific antibody with a unique 2:1 configuration (two CD20 binding domains and one CD3 binding domain). In combination with a single pre-dose of obinutuzumab, glofitamab has demonstrated >70% complete remission in aggressive B-cell lymphoma at the recommended target dose in a phase 1 trial (Carlo-Stella, EHA 2021). Pre-clinical studies suggest that glofitamab's activity is retained in the presence of concomitant cytotoxic and CD20 antibody therapies, making it an attractive agent for combination with R-CHOP-like induction. Polatuzumab vedotin (pola) is an antibody-drug conjugate approved for R/R DLBCL in combination with BR, and is currently in evaluation for the front-line treatment of DLBCL in combination with RCHP in a randomised trial. The safety and preliminary efficacy of glofitamab in combination with R-CHOP, or pola-RCHP as a front-line treatment for high risk DLBCL is being evaluated. Study Design and Methods: This is a parallel-arm phase Ib/II trial. Treatment consists of an initial cycle of R-CHOP, followed by 5 cycles of combination induction treatment and 2 cycles of consolidation glofitamab monotherapy. Key inclusion criteria are: age 18-65 years, a diagnosis of DLBCL or HBGL, high-risk features (IPI ≥3 or NCCN-IPI ≥4 or presence of DH/TH), treatment naïve or after 1 cycle of R-CHOP, ECOG 0-3. The primary endpoint is the safety of the combination and secondary endpoints include complete response rates at interim and end of treatment FDG-PET assessments by Lugano criteria, progression free survival and overall survival. Correlative studies assessing baseline immunologic profiles, tumour phenotype and potential resistance mechanisms are planned. Approximately 40 patients will be treated in each arm across 12-14 Australian sites. The trial commenced recruitment in July 2021 (NCT04914741). The ability to recruit prior to either cycle 1 or cycle 2 allows seamless cross-referral from non-trial sites. Figure 1 Figure 1. Disclosures Minson: Hoffman La Roche: Research Funding; Novartis: Research Funding. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Seymour: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Phase 1b Study of the Epichaperome Inhibitor PU-H71 Administered Orally with Ruxolitinib Continuation for the Treatment of Patients with Myelofibrosis

Blood ◽

10.1182/blood-2019-130310 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4178-4178 ◽

Cited By ~ 1

Author(s):

Naveen Pemmaraju ◽

Krishna Gundabolu ◽

Kristen Pettit ◽

Moshe Talpaz ◽

Nikolai A. Podoltsev ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Therapeutic Window ◽

Costal Margin ◽

Advisory Committees ◽

Phase 1B

Background: Myelofibrosis (MF) is a life-threatening disease characterized by splenomegaly, constitutional symptoms, and shortened survival. Although ruxolitinib, a JAK1/2 inhibitor, is approved for Intermediate or High-risk MF and can reduce the spleen size and improve quality of life, many patients discontinue due to loss of efficacy. In preclinical models, the activity of mutated JAK2 is tightly regulated by epichaperomes, a complex network of proteins which forms under cellular stress, such as cancer, and nucleates on heat shock protein 90 (Hsp90), which in turn assumes a specific conformation in its ATP binding domain. PU-H71 is a first-in-class inhibitor of tumor epichaperome-specific Hsp90, which potently kills cancer cells via disruption of the epichaperome and degradation of JAK2 as well as other client proteins. Prior dose-ranging studies of PU-H71 administered intravenously to patients with cancer identified a safe and tolerable dose. In this study, we assess an oral formulation of PU-H71 and evaluate the hypothesis that its cancer-specific mechanism combined with ruxolitinib may result in added clinical benefit as well as a wider therapeutic window. Methods: This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in patients with PMF, Post-PV MF, Post ET MF. Up to 24 patients who have active disease and receiving ≥3 months of ruxolitinib therapy (and on a stable dose for 8 weeks before starting therapy with PU-H71) will be enrolled. Evidence of persistent or worsening disease consisting of disease-related symptoms and splenomegaly of at least 5 cm below the costal margin as measured by physical examination are required. Additional inclusion criteria include a baseline platelet count of ≥50,000/mL and AST/ALT ≤2 x Upper Limit of Normal. Patients with a QT interval corrected using Fridericia's formula (QTcF) >480 ms (corrected) or left ventricular ejection fraction (LVEF) ≤50% are excluded. The study will employ a standard 3+3 dose escalation design beginning with 50 mg/day to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), with additional patients treated in a dose expansion cohort. Response to treatment will be assessed by the 2013 revised International Working Group-Myeloproliferative Neoplasm Research and Treatment and European Leukemia Net. Additional assessments will include symptom burden assessment using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, bone marrow histology, JAK2V617F allele burden, serum cytokine profiles, flow cytometry of peripheral blood mononuclear cells for epichaperome status, and pharmacokinetic studies. Enrollment is ongoing. Clinical trial information: NCT03935555. Disclosures Pemmaraju: abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Gundabolu:Samus Therapeutics: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Jazz pharmaceuticals: Consultancy. Pettit:Samus Therapeutics: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Podoltsev:Alexion: 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; Genentech: Research Funding; Kartos Therapeutics: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; AI Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding, Speakers Bureau. Eisenberg:Samus Therapeutics: Research Funding. Youssoufian:Samus Therapeutics: Consultancy. Duggan:Samus Therapeutics: Employment. Wallner:Samus Therapeutics: Employment. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Gilead: Research Funding; Protaganist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding.

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Phase I Trial of Carfilzomib + R-CHOP (CarR-CHOP) for Frontline Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood-2018-99-113381 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1692-1692 ◽

Cited By ~ 1

Author(s):

Brian T. Hill ◽

Robert M. Dean ◽

Deepa Jagadeesh ◽

Alex V. Mejia Garcia ◽

Brad Pohlman ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

End Of Treatment ◽

Grade 3

Abstract INTRODUCTION: R-CHOP is effective for diffuse large B-cell Lymphoma (DLBCL), but many patients (Pts) relapse or have refractory disease, likely due to inherent biologic differences in DLBCL subtype. Activated B-Cell (ABC) subtype DLBCL signals through Nuclear Factor-κ-B (NF-κB) and is more likely to display treatment failure than DLBCL arising from the germinal center (GC). Proteasome inhibitors disrupt NF-κB signaling, but randomized trials have failed to demonstrate clinical benefit of adding bortezomib to R-CHOP for the treatment of non-GC DLBCL. Carfilzomib (Car) displays superior clinical activity relative to bortezomib in plasma cell neoplasms and, while occasionally associated with cardiac events, does not have dose-limiting neuropathy. To explore the safety and efficacy of Car in upfront treatment of DLBCL, we initiated a phase I/II clinical trial of Car + R-CHOP and report the phase I results. METHODS: 24 adult (age ≥ 18) Pts with untreated de novo or transformed DLBCL, adequate organ function and performance status were enrolled. During 3 x 3 dose escalation, Car was given at 20 mg/m2 on days 1 and 2, with R-CHOP on day 2 for 6 cycles (n = 6). Due to grade 4 thrombocytopenia, the protocol was amended to administer Car at a dose (in mg/m2) of 20 on days 1 and 2 of cycle 1 with rituximab (R) on day 2 and CHOP on day 3, followed by a Car dose of 20 (n=3), 27 (n=3), 36 (n=3), 45 (n=3) and 54 (n = 6) on days 1 and 2 of cycles 2-6. All Pts received pegfilgrastim the day after CHOP and zoster prophylaxis with acyclovir x 6 months post treatment. Echocardiograms were obtained at baseline and at conclusion of therapy to assess the cardiac safety of combining Car with anthracycline. Interim response assessments with CT +/- PET were performed after cycle 3 and end-of-treatment response assessments were uniformly captured with PET. RESULTS: The median age was 57 (range 24-77) years old. 63% of patients were female. Stage at diagnosis was I-II (58%) or III-IV (32%). The majority of Pts had ECOG performance status of 0-1 (88%). B symptoms were present in 21% of Pts and 54% had an increased LDH at diagnosis. 29% had >1 extranodal site. IPI score was 0-1 (50%), 2 (21%) or 3-4 (39%). For this phase I dose escalation study, eligible Pts included primary mediastinal lymphoma (n = 1) and DLBCL of GC (n = 9), non-GC (n = 13) and unknown (n = 1) Hans algorithm subtypes. Hematologic adverse events (AEs) included 60 grade 1/2, 27 grade 3 and 16 grade 4 AEs. Grade 3/4 hematologic toxicities included neutropenia (n=14), thrombocytopenia (n = 6) anemia (n = 6), with only 4 cases of grade 3 febrile neutropenia. Grade 3/4 non-hematologic AEs were generally consistent with known R-CHOP toxicity were notable for: hypertension (n = 2), decreased ejection fraction (n =2), GI hemorrhage (n = 2) dizziness, headache, and syncope (n = 1 each), thromboembolic event (n=1), hyperglycemia (n=2), increased ALT (n=1) and nausea/vomiting (n=2). Compared to age-matched controls, end-of-treatment echocardiograms of CarR-CHOP treated Pts showed no statistically significant additional effect on ejection fraction (EF) [94.8% vs. 90.0% of pre-treatment value, respectively (P = 0.19)] after 6 cycles of treatment and there was no association of change in EF with Car dose (P = 0.61). There were no dose limiting toxicities. As of June 2018, median follow-up among surviving Pts was 16 months. There were 3 deaths during the study period, 2 from lymphoma and 1 from lung cancer. The overall response rate was 92% [75% complete remission (CR), 17% partial remission]. 18-month Kaplan Meier estimates of PFS and overall survival were 77% and 88%, respectively (Figure). There was no significant difference in CR rates or PFS for patients with GC vs. non-GC subtype (P = 0.65 and 0.61, respectively). CONCLUSION: CarR-CHOP is safe at a recommended phase II dose of 20 mg/m2 on day 1 & 2 for cycle 1 followed by 56 mg/m2 for cycles 2-6, without significant excess cardiac effects. Within the limitations of a prospective phase I clinical trial with potential patient selection bias, preliminary efficacy data suggest a high complete metabolic response rate and equivalent outcomes for patients with GC and non-GC subtype. Phase II accrual is ongoing for non-GC DLBCL only and additional correlative studies of the molecular subtype of DLBCL will be incorporated into future analysis. Disclosures Hill: Amgen: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tomlinson:Foundation Medicine: Consultancy. Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees.

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Post Relapse Survival Rates in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.4204.4204 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4204-4204 ◽

Cited By ~ 4

Author(s):

Andrew McMillan ◽

Alejandro Martín ◽

Corinne Haioun ◽

Annalisa Chiappella ◽

Alice Di Rocco ◽

...

Keyword(s):

Board Of Directors ◽

Median Survival ◽

Research Funding ◽

B Cell Lymphoma ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

Patient Age ◽

Patient Âgé

Abstract INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most frequently observed hematologic malignancy with 45,000 patients newly diagnosed globally each year. DLBCL patients can be cured if successfully treated with first line therapy, but patients who relapse face a poor prognosis. OBJECTIVES: The aim of this analysis was to assess the prognosis for patients who relapse after first line treatment and to assess the impact of patient age on outcomes through a systematic review of the literature. METHODS: A systematic review of observational and interventional studies that describe survival outcomes in DLBCL was conducted. The review included studies published internationally since 2000 that enrolled adult patients with DLBCL who had relapsed or progressed following first line treatment with rituximab. Phase I interventional studies, case reports, and studies assessing novel therapies in second line treatment were excluded. Data were collected on median overall survival (OS), and 1-yr and 5-yr survival rates. OS data were reported according to the time point from which they were calculated: from the point of relapse (studies including patients who may or may not have received second line treatment), from initiation of treatment post relapse (studies including patients who received active treatment post relapse), and from the time of autologous stem cell transplant (ASCT) post relapse. Results were further analysed by patient age. RESULTS: The search retrieved 2,275 citations, of which 28 studies met the inclusion criteria. In studies reporting OS from the time of relapse, median survival was 10 months (range 4 - 22) (Table 1). The proportions of patients alive at 1 and 5 years post relapse were on average (range) 41% (20% - 68%) and 27% (12% - 42%) respectively. The patients included in these studies were a mix of those who went on to receive a second line treatment and those who did not. In studies of patients who relapsed and received a subsequent line of treatment, median survival from the initiation of treatment post relapse was 13 months (9 - 28) and the proportions of patients alive at 1 and 5 years post second line treatment initiation were on average 60% (41% - 70%) and 30% (14% - 100%) respectively. In studies where survival was calculated from the time of ASCT post relapse, median survival was 40 months (36 - 44), while the proportions of patients alive at 1 and 5 years post ASCT were 73% (70% - 75%) and 45% respectively. The longer survival times for patients who received treatment post relapse likely reflects the better prognostic profile of patients deemed suitable for subsequent treatment versus those post relapse who may not have received second line treatment. Survival after ASCT is significantly influenced by the usual practice of selecting for transplant only patients showing chemo-responsiveness to salvage therapy. In studies that reported survival by patient age, median survival was more than twice as long for patients aged <65 years than those aged ≥65 years (24 and 10 months, respectively), and the proportions of patients alive at 5 years were 43% and 22%, respectively. CONCLUSIONS: The prognosis for patients with DLBCL who relapse is poor, with median survival of less than one year and less than half of patients who relapse still alive at one year post relapse. Despite the use of ASCT treatment, less than half of patients who met the eligibility criteria for and underwent ASCT were alive at 5 years post ASCT. Age was seen to be an important prognostic indicator in DLBCL patients who relapse, with poorer prognosis in patients aged ≥65 years than in those aged <65 years. Disclosures McMillan: Celgene: Honoraria; Roche: Honoraria. Martín:Sevier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Haioun:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chiappella:Pfizer: Speakers Bureau; Teva: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau. Di Rocco:Celgene: Honoraria. Rueda:Roche: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Mundipharma: Speakers Bureau. Palaska:Celgene: Consultancy. Davies:Pfizer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; Janssen: Honoraria; Mundipharma: Honoraria; GSK: Research Funding; Karyopharma: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.

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

Blood ◽

10.1182/blood-2019-128053 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4112-4112

Author(s):

Charline Moulin ◽

Romain Morizot ◽

Thomas Remen ◽

Hélène Augé ◽

Florian Bouclet ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Intermediate Risk ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Long Term Survivors ◽

First Line Treatment

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

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Easix As Prediction Score before CAR-T Cells Vs Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Relapsed/Refractory (r/r) Large B Cell Lymphoma (LBCL)

Blood ◽

10.1182/blood-2020-139615 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Felix Korell ◽

Thomas Luft ◽

Michael Schmitt ◽

Sascha Dietrich ◽

Anita Schmitt ◽

...

Keyword(s):

T Cells ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Tumor Board ◽

Advisory Committees ◽

Educational Activities ◽

Bulky Disease ◽

Car T Cells ◽

Car T

BACKGROUND: In a previous study we have shown that CD19-directed chimeric antigen receptor (CAR)-T cells do not appear to be inferior to alloHCT when used as standard cellular immunotherapy (CI) for patients with multiply r/r LBCL (EBMT 2020). The purpose of the present follow-up analysis was to further compare the risk profile of the 2 cohorts by applying the EASIX score (lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (109 cells per L)), and to assess if EASIX could be used as outcome predictor in patients with r/r LBCL undergoing CAR-T and alloHCT, respectively. METHODS: Eligible were all patients referred to our institution with relapsed/refractory (R/R) DLBCL and a tumor board decision recommending treatment with CAR-T cells between 07/2018 and 02/2020 and those recommending allogeneic donor search between 2004 and 2019. Patients with DLBCL transformed from CLL were excluded. EASIX was evaluated retrospectively using uni- and multivariable analyses (with regards to age, gender and number of failed therapy lines) and mortality using Cox regression analyses. RESULTS: 41 patients intended for CAR-T cells and 60 patients intended for alloHCT were included. In both cohorts nearly all patients had active disease at indication. Cohorts were comparable for sex, time from diagnosis, ZUMA1 eligibility, and PS, but CAR-T patients tended to be older (median 56 vs 51 years, p=0.093), and had more often primary refractory and bulky disease (p=0.004 and p=0.04, respectively). Median EASIX score across both cohorts was 1.50 (0.27-70.5), with significantly higher scores in the CART group both at indication (EASIX-ind; median 1.79 and 1.22 for CAR-T and alloHCT, respectively, p=0.031) and at conditioning for CI (EASIX-pre, median 2.24 vs 1.26, p=0.005). Median OS from indication was 475d for the CAR-T cohort vs 285d for the alloHCT cohort (p=0.88). On multivariate analysis, EASIX-ind was significantly associated with adverse OS if alloHCT was intended (HR per 2fold increase 1.43, 95%CI 1.08-1.90, p=0.013), but not if CAR-T was intended (HR per 2fold increase 1.16, 95%CI 0.88-1.53, p=0.3). After CI, 12-month estimates for NRM, relapse incidence, PFS, and OS for CAR-T vs alloHCT were 3% vs 21% (p=0.04), 59% vs 44% (p=0.12), 39% vs 33% (p=0.97), and 68% vs 54% (p=0.32). EASIX-pre predicted overall survival (OS) in both CAR-T (HR per 2fold increase 2.11, 95%CI 1.21-3.7, p=0.009) and alloHCT (HR per 2fold increase 3.69, 95%CI 1.54-8.31, p=0.003) cohorts. In the alloHCT group, the EASIX effect was largely driven by higher NRM risk with increasing EASIX-pre, while in the CAR-T group poorer OS with increasing EASIX-pre was largely relapse-related. CONCLUSIONS: In patients undergoing CI for r/r LBCL, EASIX measured prior to conditioning can predict mortality after both CAR-T and alloHCT. If applied already at indication for CI, the predictive capacity of EASIX is weaker and no longer significant if CAR-T is intended. Further studies for validation of this data appear to be warrantable. Disclosures Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees, Other: PI of clinical trials on letermovir; TolerogenixX Ltd: Other: Co-Founder and shareholder; Hexal: Other: Travel grants , Research Funding; Apogenix: Research Funding; Kite: Other: Travel grants, educational activities and conferences; Novartis: Other: educational activities and conferences, Research Funding. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Schmitt:Hexal: Other: Travel grants ; TolerogenixX LtD: Other: Co-founder, Part-time employee ; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grants . Dreger:Neovii: Research Funding; Roche: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau.

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