Phase 2 Randomized Trial Comparing 6 Cycles of Standard RCHOP Chemotherapy Vs 6 Cycles of Brcap (bortezomib, rituximab, cyclophosphamide, adriamicine and prednisone) As First Line Treatment in Young Patients with Poor Prognosis Diffuse Large B-Cell Lymphoma (DLBCL): Interim Analysis

Abstract Background: survival of young patients with high IPI DLBCL treated with RCHOP chemotherapy needs to be improved. In this poor risk population the combination of RCHOP with new drugs is an attractive approach, along with performing an early evaluation with PET/CT after 2 to 4 cycles and change induction therapy if a complete response is not achieved. Bortezomib has been combined with RCHOP [1]. We present preliminary data of patients treated in a clinical trial comparing 6 cycles of RCHOP vs 6 cycles of BRCAP, a modified RCHOP regimen changing vincristine by bortezomib at a dose of 1.3 mg/m2 sc days 1, 8, and 15 of every 21 days cycle (NCT01848132). Methods: patients younger than 70 yrs diagnosed of DLBCL with aIPI 2-3 or aIPI 1 with elevated beta2microglobulin were eligible. The main objective was to evaluate the proportion of patients who survives free of event at 2 years. Central pathology review was performed in all cases, and samples were classified as GC vs non-GC subtypes by IHC (Hans algorithm). PET/CTs were performed at diagnosis, after 2, 4 and 6 cycles (PET2, PET4 , and PET6), and were reviewed by at least 3 experts of a central panel at real time. Response was analyzed following the visual method with the Deauville scale, and for PET2 and PET4 the semiquantitative method was used. Patients with persistent disease after 4 cycles were considered a failure of therapy and were dropped out from the trial. Results: data from the first 76 patients were analyzed. Diagnosis of DLBCL was confirmed in all except 3 pts, 36 pts were treated in the experimental arm and 37 in the control arm. Median age was 58.2 yo (range 23-70), 37 (50.7%) were males. Characteristics at diagnosis were: non-GC subtype 18/46 (39.1%), C-myc expression 35/43 (81.4%), bcl2 expression 43/49 (87.7%), double expression cmyc/bcl2 30/42 (71%), stage III-IV 64 (87.6%), ≥2 extranodal locations 27 (42.2%), ECOG 2-3 24 (33%), elevated LDH 43 (62.3%), elevated beta 2 microglobulin 47 (75.8%), aIPI 2: 42 (57.5%), aIPI 3: 21 (28.8%). Among 160 cycles of BRCAP chemotherapy, 5 (3.1%) on day 8, and 22 (13.7%) on day 15, were given without bortezomib due to a neutrophil count below 0.5 /L. The most common toxicities are shown in table 1 without significant differences between both arms. Twenty-one (32.8%) out of 64 patients had a positive PET2. Fifteen (26.8%) out of 56 patients who have finished the 4 cycles had a positive PET4 according to central review and were withdrawn of the trial. Table 1. Episodes of treatment-related adverse events Control arm: RCHOP n=166 Experimental arm: BRCAP n=160 Any grade Grade 3-4 Any grade Grade 3-4 Anemia 6 0 22 9 ( 5.6%) Neutropenia 31 26 (15.6%) 47 37 (23.1%) Thrombocytopenia 9 4 ( 2.4%) 16 5 ( 3.1%) Febrile neutropenia - 6 ( 3.6%) - 10 ( 6.2%) Fever 8 1 ( 0.6%) 8 0 Infection 4 1 ( 0.6%) 7 1 ( 0.6%) Nausea/vomiting 12 0 19 0 Peripheral neuropathy 7 1 ( 0.6%) 7 1 ( 0.6%) Diarrhea 4 0 8 0 Constipation 7 0 4 0 Hepatotoxicity 6 0 6 0 Conclusions: BRCAP regimen with bortezomib sc d1, 8, and 15 is feasible. Its main toxicity is hematological, and some patients cannot receive some doses of bortezomib due to neutropenia. Grade 3-4 non-hematological toxicity is rare, including peripheral neuropathy, and do not differ from RCHOP toxicity. 1.Ruan J et al, JCO 2011;29:690-7 Disclosures Sancho: CELLTRION, Inc.: Research Funding. Lopez-Guillermo:Roche, Celgene, Mundipharma, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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New Era in Chronic Lymphocytic Leukemia: Consequences of the Arrival of New Drugs

Blood ◽

10.1182/blood-2021-150195 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4696-4696

Author(s):

Jorge Labrador ◽

Covadonga Garcia Diaz ◽

Beatriz Cuevas ◽

Maria Victoria Cuevas ◽

Rodolfo Alvarez ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Statistical Significance ◽

Young Patients ◽

Complete Response ◽

Cell Receptor ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

New Drugs ◽

First Line

Abstract Introduction In the last decade, the incorporation of anti-CD20 monoclonal antibodies (MoAb) (rituximab, obinutuzumab), bendamustine, B-cell receptor inhibitors (ibrutinib) and Bcl-2 antagonists (venetoclax) have changed the paradigm of chronic lymphocytic leukemia (CLL) treatment, improving overall survival (OS). Methods We conducted a retrospective observational study of patients diagnosed with CLL between 2003 and 2016 at our center to evaluate: i) the influence of date of diagnosis, before or after 2010; ii) having received new drugs (MoAb or target therapies) in first line or not. Results A total of 182 patients were evaluated: 104 men (57%) and 78 women (43%); median age 74 years (39 - 97), 132 patients were >65 years (72.5%). At diagnosis, 135 (74%), 19 (10%), 15 (8%), 4 (2%) and 9 (5%) were diagnosed as stages 0, I, II, II, III and IV of the Rai classification. While 154 (84%) 15 (8%) and 14 (8%) were classified as Binet's stages A, B and C. Regarding the presence of comorbidities, the median CIRS scale score was 4 (0 - 15). 71 patients (39%) were diagnosed before 2010 and 111 (61%) from 2010 onwards. With a median follow-up of 76 months (range, 20-212), 77/182 (42%) patients had received ≥1 line(s) of treatment: 1: 53%, 2: 26%, 3: 8%, ≥4: 13%. 20 patients (26%) received the first line of treatment before 2010, and 56 (74%) from 2010 onwards. Half of the patients received new drugs in 1st line (n=39), 92% of them from 2010 onwards. 32 patients (41.5%) achieved complete response after 1st line, and 24 (31%) at least a partial response. The median OS of patients diagnosed before 2010 was 66 months (35.32 - 96.68) vs 143 months (95% CI 90.5 - 195.5) (p=0.032) as of 2010. In those ≤ 65 years median OS has not been reached, being 80.5% at 10 years: 65% for those diagnosed before 2010 and 97% after 2010, p=0.036. The median OS of patients > 65 years was 6 years (95% CI 4.17 - 7.83), and increased from 82 months for those diagnosed before 2010, to 110 months in those diagnosed after 2010, p=0.744. Patients treated with new drugs in 1st line increased the median OS from 76 months and 13% at 10 years to a median not reached and OS of 77% at 10 years, p=0.000. This difference was more evident in those ≤ 65 years: 20% vs 100% at 10 years (p=0.012), while it was not statistically significant for those > 65 years (11% vs 50% at 10 years, p=0.181) (Figure 1). However, in a multivariate model including age, sex, CIRS>6 and year of diagnosis (before or after 2010), treatment with new drugs retained statistical significance (HR 0.414; 95% CI 0.183 - 0.935) along with age ≤ 65 years (HR 0.256; 95% CI 0.085 - 0.771) and CIRS ≤ 6 (HR 0.247; 95% CI 0.111 - 0.551). Conclusions In our experience, the introduction of new drugs in the first line has led to an increase in OS, especially in young patients. Figure 1 Figure 1. Disclosures Gonzalez-Lopez: Grifols: Other: Advisory board honoraria; Sobi: Other: Advisory board honoraria; Amgen: Other: Advisory board and speakers honoraria, Research Funding; Novartis: Other: Advisoryboard and speakers honoraria, Research Funding.

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A Phase I Study of Romidepsin, Gemcitabine, Dexamethasone and Cisplatin Combination Therapy in the Treatment of Peripheral T-Cell and Diffuse Large B-Cell Lymphoma: Canadian Cancer Trials Group Study LY.15

Blood ◽

10.1182/blood.v128.22.4162.4162 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4162-4162 ◽

Cited By ~ 2

Author(s):

Tony Reiman ◽

Kerry J. Savage ◽

Michael Crump ◽

Matthew Cheung ◽

David A. MacDonald ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hematological Toxicity ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract Background: The outcome of peripheral T-cell lymphomas (PTCLs) remains poor and improved therapies are needed. Retrospective data suggest that integration of anthracyclines in the primary therapy may not impact outcome, providing the rationale to explore alternative regimens. Histone deacetylase inhibitors appear to have a class effect in PTCLs andromidepsin monotherapy demonstrates activity in a proportion of patients with relapsed/refractory PTCLs and can induce durable remissions. Gemcitabine is reported to be a highly active agent in PTCL, and the GDP (gemcitabine, dexamethasone, cisplatin) regimen has become a standard chemotherapy backbone for relapsed aggressive lymphomas (Crump, JCO 2014). We investigated the feasibility, safety and efficacy of GDP combined with romidepsin in a phase I dose escalation trial. Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) were also included. Methods: Patients with relapsed/refractory PTCL or DLBCL, PS 0-2, with measurable disease and who had received one or two prior lines of systemic therapy, were treated with standard doses of GDP (gemcitabine, 1000 mg/m2 d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 d1) every 21 days, plus escalating doses of romidepsin (6, 8, 10 and 12 mg/m2) on days 1 and 8 to a maximum of 6 cycles in a standard 3+3 design. After the first 4 patients were enrolled, based on the observed pattern of thrombocytopenia, the treatment schedule was modified so that gemcitabine and romidepsin were given on days 1 and 15 and cycles extended to every 28 days. Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles and defined as requiring platelet transfusion for bleeding, grade 3 hematological toxicity lasting >10 days, grade 4 hematological toxicity lasting >7 days, febrile neutropenia, or grade 3-4 non-hematological toxicity attributable to romidepsin. Responses were as per Cheson, JCO 2007 excluding PET scans. Results: 20 eligible patients (PTCL n=10; DLBCL n=10) were enrolled between 10/2013 and 01/2016 and treated with GDP plus romidepsin. The main PTCL subtype was PTCL, not otherwise specified (50%). Median age was 65 years (24-74); 9 were female; ECOG performance status was 0 (n=2), 1 (n=13), or 2 (n=5). Number of prior therapies was 1 (n=17) or 2 (n=3). 17 (85%) patients received >90% of the planned dose each cycle. The median number of cycles was 2 (range, 1-6); one patient is still on therapy. The reasons for treatment discontinuation were lymphoma progression (n=10), toxicity (n=2), proceeding to autologous stem cell transplant (ASCT, n=3), intercurrent illness (n=1), or completion of 6 cycles (n=3). On the 21-day schedule at 6 mg/m2 romidepsin, there were 3 DLTs among four patients (2 with grade 3-4 thrombocytopenia, 1 venous thromboembolic event). On the 28-day schedule, there were no DLTs observed in the three patients treated at each of the 6, 8 or 10 mg/m2 dose levels. At 12 mg/m2 there were 4 observed grade 3 DLTs among six evaluable patients (hypotension, acute kidney injury, anorexia, thrombocytopenia >10 days). Notable toxicities during any cycle were: febrile neutropenia (n=2); grade 3-4 thrombocytopenia (n=9); grade 3-4 neutropenia (n=4); and grade 3-4 anemia (n=4); grade 2 atrial fibrillation (n=2); grade 2 QTc prolongation (n=1); grade 1 sinus tachycardia (n=1); grade 2-3 infections (n=16); grade 1-3 cutaneous toxicity (n=9); grade 1-3 thromboembolic events (n=2); TIA (n=2) or stroke (n=1). One patient died after cycle 1 due to sepsis. 7 other patients have died of progressive lymphoma. The overall response rate was 9/20 (45%), all were partial remissions (PR), 3 had stable disease (SD), 4 had progressive disease (PD), and 4 were not objectively evaluable. Of the responders, 5 had PTCL and 4 had DLBCL. Four patients went on to ASCT. With a median follow-up of 5.8 months, the median duration of response was 2.8 months and median PFS is 2.2 months. For all patients, the 1 year PFS was 6% and 1 year OS was 43% Discussion: Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 given on a day 1, 15 every 28 days schedule. Thrombocytopenia prohibits this combination on a 21-day schedule. Toxicity is otherwise acceptable and as expected. Further study at the recommended dose and schedule would be required to properly define the activity of this regimen in PTCLs and DLBCL. Disclosures Reiman: Celgene: Honoraria, Research Funding. Buckstein:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kuruvilla:Merck & Co., Inc.: Consultancy, Honoraria. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

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Treatment for frail elderly patients with diffuse large B-cell lymphoma (DLBCL): A single center experience.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18505 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18505-e18505

Author(s):

Pascal Chaïbi ◽

Amale Chebib ◽

Elodie Baudry ◽

Elise Cotto ◽

Francois Piette ◽

...

Keyword(s):

Performance Status ◽

Dose Intensity ◽

B Cell Lymphoma ◽

Complete Response ◽

Median Number ◽

Oral Route ◽

Common Side Effect ◽

Hematological Toxicity ◽

Single Center Experience ◽

Grade 3

e18505 Background: DLBCL occurs frequently in elderly pts and recent studies demonstrated that immunochemotherapy with R-mini-CHOP could be a safe and effective treatment for selected pts over 80 years Methods: Since 2008, R-mini-CHOP has been the treatment proposed for elderly pts with DLBCL referred to our oncogeriatric unit, irrespectively of their performance status (PS). We reviewed data of elderly pts treated for DLBCL at our institution from January 2008 to June 2011. Results: 74 pts (50 women, 24 men) were treated for DLBCL. Median age was 85 years (range 71–97), 84 % of pts ≥ 80 years and 16 % of pts ≥ 90 years. 68 pts (92%) had at least one comorbidity. Median number of daily medicines was 4 (range 0 – 12), irrespectively of treatments for DLBCL. Malnutrition was diagnosed in 49 pts. 50 pts (67,5 %) had a poor PS (> 2). Age-adjusted International Pronostic Index (aaIPI) was 0-1 in 9 pts, 2 in 28 pts and 3 in 35 pts. 61 pts were treated with mini-CHOP (cyclophosphamide: 400 mg/m2 D1; doxorubicine: 25 mg/m2 D1; vincristine: 1 mg total dose D1 and prednisolone 40 mg/m2 by oral route from D1 to D5) plus rituximab (375 mg/m2 D1) every 21 days for 6 cycles. Doxorubicine was replaced by etoposide (150 mg/m2 D1) for 5 pts because of cardiac dysfunction. 8 pts received reduced dose intensity chemotherapy ( without doxorubicine) for the 2 first cycles because of high risk toxicity. Prophylaxis of neutropenia with GCSF was systematic. Median survival was 11 months. 21 pts died during treatment, because of progressive disease (13) or treatment toxicity (6). Complete response (CR) was observed in 44 pts (59,5 %). With a median follow-up of 18 months, 11 relapses were observed. In our population study, aaIPI appears highly predictive of CR, with a CR Rate of 87,5 %, 75 % and 43% respectively for pts with aaIPI 0 - 1, 2 and 3.Hematological toxicity was the most common side effect. Grade 3–4 neutropenia was observed in 28% of the pts and grade 3–4 thrombocytopenia in 12%. 14 pts (19%) experienced at least one episode of febrile neutropenia. Conclusions: In unselected elderly pts with DLBCL, immunochemotherapy with R-mini-CHOP can be effective, but with significant toxicity, even using systematic G-CSF prophylaxis. Prognosis remains poor for pts with aaIPI 3

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A Phase I/II Trial of Lenalidomide and RCHOP (R2CHOP) in Patients with Newly Diagnosed Diffuse Large B -Cell (DLBCL) and Follicular Grade 3 Lymphoma.

Blood ◽

10.1182/blood.v114.22.1669.1669 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1669-1669 ◽

Cited By ~ 4

Author(s):

Grzegorz S. Nowakowski ◽

Betsy LaPlant ◽

Thomas Habermann ◽

David J Inwards ◽

Patrick L Johnston ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Dose Escalation ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hematological Toxicity ◽

Newly Diagnosed ◽

Chop Chemotherapy ◽

Grade 3

Abstract Abstract 1669 Poster Board I-695 Background The addition of rituximab to chemotherapy significantly improved the results of therapy in aggressive non-Hodgkin's B cell lymphoma (NHL). However, significant number of the patients relapse following initial therapy. Lenalidomide was shown to have significant single agent activity in relapsed aggressive B cell lymphoma (J Clin Oncol 26:4952-7, 2008) however the safety in combination with standard first line immunochemotherapy is unknown. We initiated a phase I/II trial of R2-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone rituximab and lenalidomide) to establish the safety and efficacy of this therapy in the treatment of patients with newly diagnosed aggressive B cell NHL. Herein, we report the results of phase I portion of this study. Methods A phase I study was designed to define the maximum tolerated dose (MTD) of lenalidomide administered on days 1-10 with R-CHOP chemotherapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50mg/m2, vincristine 1.4 mg/m2, all on day 1, prednisone 100 mg/m2 days 1-5 of 21 day cycle) utilizing 3+3 dose escalation design. Lenalidomide dose escalation levels were 15 mg, 20 mg and 25 mg. All patients received 6 mg pegfilgrastim injection on day 2. Dose limiting toxicity (DLT) was defined as any grade 3 or more non-hematological toxicity or a hematological toxicity requiring a delay of the next cycle of chemotherapy due to cytopenia. The latter criterion was to ensure maintenance of the dose intensity and schedule of RCHOP; a potentially curative therapy in this setting. Eligible patients were adults newly diagnosed with CD20 positive diffuse large cell or follicular grade III B cell lymphoma, ECOG PS 0-2 and good organ function. There was no upper age restriction to participate in this study. Results Twelve patients were enrolled in phase I of this study. The median age was 69 years (range, 49-82) and 58% (7/12) of patients were males. Ten patients (83%) had DLBCL and two (17%) patients had follicular grade 3B lymphoma. International prognostic index was intermediate, high- intermediate and high in 6, 4 and 2 patients respectively. Patients distribution by lenalidomide dose was: 3 patients received 15 mg/day, 3 received 20 mg/day and 6 received 25 mg/day on days 1-10. Non-hematological toxicities included: grade 3 toxicity - neuropathy in one patient (8.3%), grade 2 toxicities were: infection in 17% (2/12) patients (skin in one patient, otitis media, and urinary tract infection in one patient); nausea 8% (1/12), rash 8% (1/12) and alopecia 41% (5/12). The most common toxicity to R2-CHOP was myelosuppresion. Grade 3 and 4 neutropenia occurred in 17% (2/12) and 41% (5/12) of patients, respectively. The neutropenia was of short duration, and no patients developed neutropenic complications. Grade 3 thrombocytopenia was seen in 8% (1/12). Most importantly, there were no delays in chemotherapy due to cytopenias. No DLT was seen. The 25 mg/day days 1-10 dose of lenalidomide was taken forward to an ongoing phase 2 trial. Conclusion Lenalidomide at a dose of 25 mg/day for days 1- 10 combined with R-CHOP chemotherapy is well tolerated. The addition of lenalidomide did not affect hematological recovery and did not result in treatment delays. This dose and schedule is now being evaluated in the phase II part of the trial. Disclosures Zent: Genentech, Bayer, Genzyme, Novartis: Research Funding. Witzig:Novartis: Research Funding.

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Melphalan, Thalidomide and Prednisone (MPT) Combined with Oral Panobinostat In Patients with Relapsed/Refractory MM: a Phase I-II Study

Blood ◽

10.1182/blood.v116.21.3019.3019 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3019-3019 ◽

Cited By ~ 3

Author(s):

Massimo Offidani ◽

Federica Cavallo ◽

Claudia Polloni ◽

Anna Marina Liberati ◽

Stelvio Ballanti ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Research Funding ◽

Haematological Toxicity ◽

Study Drug ◽

New Drugs ◽

Hematological Toxicity ◽

Synergistic Activity ◽

Histone Proteins ◽

Grade 3

Abstract Abstract 3019 Background: Panobinostat (LBH-589) is a pan-deacetilase inhibitor that targets histone proteins increasing tumor suppressor gene activities leading to cell-cycle and differentiation arrest besides to target non-histone proteins such as HSP90, aggressomes, p53, HIF-1a, and a-tubulin somehow promoting cell death. Panobinostat, combined with steroids and/or immunomodulatory drugs, demonstrated additive/synergistic activity in Multiple Myeloma (MM) and ability to overcome previous chemoresistance. Several combination studies with Panobinostat plus novel drugs are now ongoing in MM. Methods: This is a multicenter, open-label, phase I-II study exploring the combination of a standard therapy such as MPT (Melphalan 0.18 mg/kg per os for 4 days, Prednisone 1.5 mg/kg per os for 4 days, Thalidomide 50 mg/day continuously) with Panobinostat 15 mg p.o. thrice weekly for 3 weeks in a 28-day cycle to assess safety profile and activity of this combination in patients with relapsed/refractory MM having adequate performance status and haematological, cardiac, liver and neurological functions. The study was designed according to the Briant and Day method that plans a “dose-escalation phase” to determine both the MTD and the activity of the study drug and an “expansion-phase” in which the MTD of the study drug is used to further assess its safety and efficacy. Despite in the first phase of this study 19 patients were planned according to the study design, protocol was amended after 13 patients had been enrolled since more than 50% grade 3–4 toxicity occurred although response criteria were met. Therefore, Panobinostat was reduced to 10 mg p.o. thrice weekly for 3 weeks in a 28-day cycle whereas the dose of drugs of the MPT combination was not modified. Toxicity and response were assessed according to CTC version 4 and IMWG criteria, respectively. Results: As of February 2010, 24 patients were enrolled in this study. Median age was 71.5 years (range 40–81 years) and 12 patients (50%) had ISS 2–3 score. Patients had received a median of 2 prior therapies (range 1–6) and 5 (21%) three or more prior lines of therapy. Sixteen (73%), 13 (54%), 18 (75%), 11 (46%) and 9 (37.5%) patients had been previously treated with ASCT, thalidomide, bortezomib, lenalidomide and all 3 new-drugs, respectively. Seven patients (29%) were refractory to the last therapy. Twelve patients (50%) had a disease history longer than 5 years. In the first 13 patients treated with Panobinostat 15 mg, grade 3–4 thrombocytopenia and neutropenia occurred in 6 (46%) and 9 patients (69%), respectively. Moreover, 4 patients (31%) developed non-hematological adverse events such as fatigue, constipation, infection and arrythmia. In the group of 11 patients treated with Panobinostat 10 mg, grade 3–4 thrombocytopenia decreased to 18% (2 patients) but neutropenia was still high (8 patients: 72.5%). Three patients (27%) had grade 3–4 non-hematological toxicity (one fatigue and two constipation). No patients had QTcF prolongation or severe neuropathy. Dose adjustment was necessary in 9 patients (37.5%, all due to hematological toxicity) while 6 patients (25%) interrupted the protocol because of side effects (5 due to no resolution of grade 3–4 hematological toxicity within 4 weeks and one due to atrial fibrillation). One patient (4%) died on study due to sepsis during prolonged neutropenia. Response ≥ PR were observed in 12 patients (50%) including 4 VGPR and 8 PR. Additionally, 2 patients had MR and 8 SD. Only 2 patients progressed during treatment. There was no difference between the two cohorts of patients (Panobinostat 15 mg and Panobinostat 10 mg) in terms of response ≥ PR (54% vs 45.5%) or disease progression (7.5% vs 9%). Notably, response was obtained also in 2/7 patients (28%) who progressed during bortezomib or IMIDs. Conclusions: This study suggests that MPT-Panobinostat combination has an encouraging anti-myeloma activity since responses were still seen in patients with advanced stage or resistant to new drugs diseases. Different schedules of Panobinostat/melphalan should be explored to reduce haematological toxicity. Disclosures: Offidani: Celgene: Honoraria. Off Label Use: Panobinostat in relapsed/refractory multiple myeloma. Cavallo:Celgene: Honoraria. Polloni:Celgene: Honoraria. Ballanti:Celgene: Honoraria. Catarini:Celgene: Honoraria. Alesiani:Celgene: Honoraria. Corvatta:Celgene: Honoraria. Gentili:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Research Funding. Leoni:Celgene: Honoraria. Palumbo:Celgene: Honoraria, Research Funding.

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Icans Prophylaxis with Simvastatin and Intrathecal Dexamethasone in Adults Receiving Axicabtagene Ciloleucel (Axi-Cel) Treatment

Blood ◽

10.1182/blood-2021-149607 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1744-1744

Author(s):

Joseph Maakaron ◽

Emily Stene ◽

Megan Bruns ◽

Todd E. DeFor ◽

Najla H El Jurdi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiovascular Health ◽

B Cell Lymphoma ◽

Patient Characteristics ◽

Complete Response ◽

Clinical Syndrome ◽

Advisory Committees ◽

Cytokine Analysis ◽

Grade 3

Abstract Background Axi-cel is approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma since 2017 and has demonstrated efficacy and durability but with significant side effects, namely cytokine release syndrome (CRS) and neurotoxicity (ICANS). In patients receiving axi-cel for aggressive lymphomas, any grade ICANS occurs at a rate of 50% and grade 3/4 occurs about 35% of the time. The mechanism underlying ICANS remains unclear. The current working hypothesis is that endothelial injury caused by the disease and lymphodepleting chemotherapy leads to breakdown of the blood-brain-barrier. Following activation of axi-cel, cytokines are trafficked into the central nervous system leading to local production of cytokines and the clinical syndrome observed. ICANS is treated with systemic steroids with good CNS penetration. Statins have been shown to stabilize the endothelium and have anti-inflammatory effects. We are currently evaluating the safety and feasibility of administering simvastatin to stabilize the endothelium in addition to dexamethasone delivered intrathecally to prevent the occurrence and decrease the severity of neurotoxicity. Methods: This is a feasibility study combining simvastatin 40 mg orally, daily, starting at least 5 days prior to apheresis in addition to dexamethasone delivered intrathecally on days -1, +6, +13 in relation to axi-cel. A schema of the trial is presented in figure 1. This is registered on Clinicaltrials.gov number (NCT04514029). Results: We have accrued 6/20 planned patients with r/r DLBCL who received axi-cel per institutional guidelines. One passed away prior to apheresis due to disease progression and was non-evaluable. Table 1 shows the patient characteristics. With a median follow up of 123 days (50-245), all patients achieved a complete response and remained alive. Table 2 summarizes the feasibility, safety, and dose-density received out of prescribed. None of the 5 patients had grade 3 or 4 ICANS and only 1 patient had grade 1 neurotoxicity (Table 3). A cytokine analysis and markers of endothelial and neuronal activation is underway. Discussion: In a preliminary analysis, simvastatin and intrathecal dexamethasone appears to be feasible to administer, safe and efficacious in a population of patients receiving axi-cel for relapsed and refractory DLBCL. There appears to be a signal in abrogating neurotoxicity without any effect on the efficacy of axi-cel. This will allow for a safer delivery of axi-cel and improve access to this treatment. This study is ongoing. Figure 1 Figure 1. Disclosures Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Miller: Wugen: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. OffLabel Disclosure: Simvastatin is an HMG-CoA reductase inhibitor approved for hyperlipidemia and cardiovascular health.

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Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Blood ◽

10.1182/blood-2018-11-880526 ◽

2019 ◽

Vol 133 (18) ◽

pp. 1964-1976 ◽

Cited By ~ 38

Author(s):

Andrew D. Zelenetz ◽

Gilles Salles ◽

Kylie D. Mason ◽

Carla Casulo ◽

Steven Le Gouill ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Phase 2 ◽

Non Hodgkin Lymphoma ◽

Phase 1B ◽

Grade 3

Abstract Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

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A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2020-143095 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Daniel Guy ◽

Marcus Watkins ◽

Fei Wan ◽

Nancy L. Bartlett ◽

Amanda F Cashen ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Complete Response ◽

High Dose ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3 ◽

Stem Cell Collection

Introduction The management of younger fit patients with mantle cell lymphoma (MCL) varies widely with no consensus on an optimal induction therapy. To date, the treatments with the longest progression-free survival incorporate a chemotherapy backbone that includes high dose cytarabine, followed by consolidation with an autologous stem-cell transplantation (ASCT) (Hermine et al. Lancet 2016, Eskelund et al. Br J Haematol 2016). Recent data showed that a regimen of bendamustine/rituximab followed by cytarabine/rituximab achieved high complete response rates with high minimal residual disease (MRD) negativity (Merryman RW et al. Blood Adv 2020). We hypothesized that adding the Bruton tyrosine kinase inhibitor acalabrutinib to the same chemotherapeutic backbone would be safe and increase complete response rates as well as minimal residual disease (MRD) negativity pre-transplant, and potentially improve clinical outcomes. Methods We conducted a single arm, single institution pilot study registered at clinicaltrials.gov (NCT03623373). Patients with untreated MCL, who were between ages 18-70 and were candidates for ASCT, were eligible. Patients received six 28-day cycles of treatment. Cycles 1-3 consisted of bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2 on day 1 and acalabrutinib 100mg BID on days 1 through 28. Cycles 4-6 consisted of rituximab 375 mg/m2 on day 1, cytarabine 2 g/m2 (1.5 g/m2 if age>60) q12 hours on days 1 and 2, and acalabrutinib 100mg BID on days 1 through 7 and 22 through 28. Restaging PET/CT and response assessment based on the Lugano classification were obtained following cycles 3 and 6. After cycle 6 patients underwent leukapheresis and stem-cell collection as preparation for ASCT. Blood for MRD status was collected after cycles 2, 4 and 6 and will be evaluated using the ClonoSeq assay (Adaptive Biotechnologies). The primary objective was to determine the stem cell mobilization success rate. Secondary objectives included safety and tolerability, overall response rate (ORR), pre-transplant complete response rate (CR), and the MRD negativity rate during and after completion of therapy. Results The trial enrolled 14 patients from December 2018 to February 2020. One patient withdrew consent prior to start of treatment and another was found to have an undiagnosed adenocarcinoma shortly after starting MCL treatment. Both are excluded from the analysis. The median age was 57 years (range 52-66). 11 patients were males (92%), all patients had an ECOG performance status of 0-1. 11 patients (92%) presented with stage IV disease. The mean MCL International Prognostic Index (MIPI) score was 6.3 (25% high-risk, 42% intermediate-risk and 33% low-risk). Of the 12 patients who began treatment, 9 completed all 6 cycles. Three patients did not complete therapy due to: insurance issues (n = 1), and thrombocytopenia (n = 2) following cycle 5 and 4. The side effect profile showed expected hematologic toxicities with grade 3-4 cytopenias in all patients, mostly during cytarabine cycles. In total, 100% of patients developed grade 3-4 thrombocytopenia and 83% of patients developed grade 3-4 neutropenia. Three episodes of febrile neutropenia were observed. One patient had a grade 3 transaminase increase, and one patient had grade 3 diarrhea. No bleeding events or treatment related deaths occurred. The remainder of the side effects were low grade and the treatment was generally well tolerated. Of the 12 evaluable patients, 10 responded (ORR 83%) with 9 achieving CR (75%). One patient achieved PR prior to being removed from the study due to thrombocytopenia and then achieved CR off study. Two patients experienced PD during induction. With a median follow up of 9 months, no responding patients have relapsed. The median CD34+ stem cell collection was 3.84x106 cells/kg (range 2.77 - 5.9). MRD results will be presented at the meeting. Conclusions This is the first study attempting to combine BTK inhibition with a high dose cytarabine containing regimen. The addition of acalabrutinib to a regimen of bendamustine/rituximab followed by cytarabine/rituximab appears to be safe. The R-ABC combination will be further tested in the recently activated intergroup trial EA4181. Disclosures Bartlett: Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy. Fehniger:ImmunityBio: Research Funding; HCW Biologics: Research Funding; Kiadis: Consultancy; Nkarta: Consultancy; Indapta: Consultancy; Wugen: Consultancy; Orca Biosystems: Consultancy; Compass Therapeutics: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; EUSA: Consultancy; WuGen: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy.

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Phase II Study of Thalidomide in Escalating Doses for Follicular (F-NHL) and Small Lymphocytic Lymphoma (Sll): CALGB Study 50002.

Blood ◽

10.1182/blood.v104.11.3284.3284 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3284-3284 ◽

Cited By ~ 4

Author(s):

David L. Grinblatt ◽

Jeffrey Johnson ◽

Donna Niedzwicki ◽

David A. Rizzieri ◽

Nancy Bartlett ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Adverse Events ◽

Phase Ii ◽

Performance Status ◽

Sensory Neuropathy ◽

Complete Response ◽

Lymph Node Biopsy ◽

Prior Therapy ◽

Median Daily Dose ◽

Grade 3

Abstract Background: Thalidomide has marked activity in both untreated and heavily pretreated myeloma. Its activity in part is believed to be due to inhibition of bFGF and VEGF induced angiogenesis. Elevated levels of bFGF in serum and urine have correlated with decreased survival in lymphoma possibly through up-regulation of BCL-2. Methods: 25 patients (pts) with previously treated F-NHL and SLL were registered and treated on this multi-institutional study from July 2001–April 2004 to evaluate the efficacy and safety of oral thalidomide in this patient group. Pts had B-cell SLL (7: 36.8%), F-NHL grade 1 (7: 36.8%), grade 2 (3: 15.8%) and grade 3 (2: 10.1%) NHL. Pts were eligible for entry with up to 3 prior chemotherapy (CT) and 2 immunotherapy (IT) regimens provided performance status was ≥ 1. Pts with new onset of B-symptoms, rising LDH, rapid tumor growth or greater than one year from initial diagnosis were required to undergo repeat lymph node biopsy to exclude recent transformation. Pts with CNS involvement, prior peripheral neuropathy >gr 1, HIV+, and pregnant or nursing women were also excluded. Pts were required to have Cr <2 x ULN, AST/ALT <2.5 x ULN and an ANC > 750. Median age at study entry was 60 years (36–87). Prior therapy was evaluated in 20 pts and 17/20 had received multi-agent CT while 12/20 pts received prior IT. Thalidomide was initiated at a dose of 200 mg daily and escalated by 100 mg daily every 1–2 weeks as tolerated with a maximal dose of 800 mg/d. If ≥ gr 2 peripheral neuropathy or ≥ gr 3 somnolence or mood changes occurred, the dose was held for one week and restarted at 50% of the prior daily dosage. Results: The median daily dose was 400 mg (range 50–800 mg). There was 1 complete response (CRu-residual abnormality) in a pt with SLL and one partial response in a pt with F-NHL grade 1 (ORR 8%: 95%CI: 1–26%). 16 pts had progressive disease during therapy and 2 died of disease soon after stopping therapy due to adverse events. One patient continues on therapy without progression of disease to date. The remaining 4 pts were taken off of therapy prior to the first 3 month evaluation. The reason for withdrawal was pt refusal (2) and adverse events (2). The median event free survival was 2.6 months (95% CI:1.4–4.4 mos) with a median overall survival of 23.3 months. Toxicity information on 24/25 pts revealed 4 (17%) with grade 4 neutropenia with 1/4 febrile as well. The most common grade 3 toxicities were anemia (13%), dyspnea (13%), fatigue (8%) and neurologic toxicities consisting of somnolence, dizziness, depression and anxiety (21%). Peripheral sensory neuropathy was reported as gr 2 in 8% and gr 3 in 8%. However, 38% of pts were reported as experiencing gr 2 fatigue. There were no grade 5 toxicities. Conclusion: These phase II trial results in a pretreated pt population demonstrate that, despite an acceptable toxicity profile, thalidomide has only minimal efficacy in F- NHL and SLL.

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The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽

10.1182/blood.v114.22.1661.1661 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1661-1661 ◽

Cited By ~ 6

Author(s):

Brad S Kahl ◽

Hailun Li ◽

Mitchell R Smith ◽

Randy D. Gascoyne ◽

Elisabeth Paietta ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Complete Response Rate ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

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