Prophylaxis of Neutropenia with Mecapegfilgrastim in Patients with Hematologic Malignancies

Abstract Background: Neutropenia is a frequently reported adverse event in patients with hematologic malignancies. Prophylactic administration of long-acting granulocyte colony stimulating factor(G-CSF) had been widely applied in different solid tumors. However, the effect of long-acting G-CSF in patients with hematologic malignancies was not well studied. Methods: A multi-center, non-interventional study was conducted to explore the efficacy and safety of mecapegfilgrastim, a long-acting G-CSF, in patients with hematologic malignancies. Patients administered at least twice mecapegfilgrastim were included for statistical analysis. The baseline characteristics, effectiveness and safety results were presented. Results: Mecapegfilgrastim were administrated prophylactically in 74 patients (pts) with hematologic malignancies (Diffuse large B-cell lymphoma 34 pts, follicular lymphoma 9 pts, peripheral T-cell lymphoma 3 pts, primary mediastinal large B-cell lymphoma 3 pts, angioimmunoblastic T-cell lymphoma 3 pts, Anaplastic Large Cell Lymphoma 3 pts, classic Hodgkin's lymphoma 3 pts, other lymphomas 12 pts, other hematologic malignancies 4 pts). The median age of pts was 58 years. The ECOG performance score were 0 -2. Common chemotherapy regimens were CHOP, CHOEP, DHAP and GemOx. Rituximab, anti-PD-1 antibody, BTK inhibitors, chidamide and lenalidomide were the most administrated targeted or immunotherapeutic agents. In all 250 treatment cycles (61 chemotherapy cycles and 189 immunochemotherapy), twenty-seven pts had grade ≥3 neutropenia in 41 (16.4 %) cycles, fifteen pts had grade 4 neutropenia in 22(8.8 %) cycles, four pts experienced febrile neutropenia in 4 (1.6 %) cycles. In 61 chemo-alone treatment cycles, grade 3/4 neutropenia was reported in 10(16.4%) and, 4 (4.9 %) cycles, febrile neutropenia was recorded in 2(3.3 %) cycles. During 189 cycles of immunochemotherapy treatment, grade 3/4 neutropenia and febrile neutropenia was observed in 31(16.4%), 18(9.5 %) and 2(1.1 %) cycles, respectively. There were 5 cycles of grade 4 neutropenia occurred in 9 lenalidomide contained treatment cycles, and febrile neutropenia was reported in 1 cycle. Grade ≥ 3 neutropenia induced treatment delay (≥ 7 days) was reported in 12 cycles while dose of cytotoxic drugs were not decreased. Eleven pts developed infection including 6 pneumonia events, they were treated with antibiotics in 23 cycles. Adverse event (AE) was reported in 64(86.6 %) pts. Fourteen (18.9 %) pts were hospitalized due to AEs. Most common grade 1/2 AEs related to mecapegfilgrastim were leucocytosis (18.9%) and neutrocytosis (6.8 %). Conclusion: Mecapegfilgrastim showed promising effectiveness and reliable safety profile in pts with hematologic malignancies. Further investigation is warranted. Disclosures No relevant conflicts of interest to declare.

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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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A Phase I/II Trial of Vorinostat (SAHA) in Combination with Rituximab-CHOP in Patients with Newly Diagnosed Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG S0806

Blood ◽

10.1182/blood.v126.23.3931.3931 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3931-3931 ◽

Cited By ~ 1

Author(s):

Daniel O. Persky ◽

Hongli Li ◽

Lisa M. Rimsza ◽

Paul M. Barr ◽

Leslie L. Popplewell ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

B Cell ◽

Phase Ii ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract Background: Loss of major histocompatibility Class II antigens (MHCII) in diffuse large B-cell lymphoma (DLBCL) is associated with a decreased CD8+ tumor-infiltrating T-lymphocyte (TIL) response and poor patient survival. Transcription of the MHCII gene complex is under the control of the master transactivator, CIITA, which in part is regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor vorinostat with standard chemotherapy will enhance MHCII expression and improve patient outcome in DLBCL. Methods: SWOG S0806 was a phase I/II open label trial of vorinostat given at 400 mg po daily on days 1-9 (subsequently reduced to days 1-5) combined with Rituximab-CHOP (R-CHOP) at standard doses, given on day 3 of a 21-day cycle for 8 cycles. Eligibility criteria included having newly diagnosed advanced stage DLBCL, international prognostic index (IPI) of at least 1, and lack of known CNS involvement or HIV. Primary endpoint of phase I was to establish maximum tolerated dose (MTD) of vorinostat with standard R-CHOP. Primary endpoint of phase II was to estimate 2-year progression free survival (PFS). Translational endpoints included correlation of pre-treatment acetylation status of histones, expression of MHCII genes, and percentage of TIL to PFS; and correlation of cytokine profile to response and outcomes. Results: Phase I was open in 5 SWOG institutions and enrolled 11 patients. There were only 2 patients who had dose limiting toxicities in the first cycle - grade 3 febrile neutropenia and grade 4 hypokalemia - allowing phase II to proceed with the original vorinostat dosing of 400 mg daily days 1-9, at all SWOG institutions. However, excess rates of febrile neutropenia and sepsis were seen upon further follow up, and the study was amended to reduce the duration of vorinostat to days 1-5. A total of 72 patients were enrolled in phase II, of which 8 were ineligible and 2 withdrew consent prior to treatment. For the remaining 62 patients, median age was 64 years, 92% had stage III/IV disease, 39% B symptoms, 61% elevated LDH, 39% had more than 1 extranodal site of involvement, with IPI breakdown of 13/26/47/13/2%. Notable grade 3-4 non-hematologic toxicities included febrile neutropenia (39%), sepsis (18%), fatigue (15%), hypokalemia (11%), hyponatremia (10%), and small bowel perforation (3%). Grade 3-4 hematologic toxicities included neutropenia (60%), anemia (35%), and thrombocytopenia (35%). There was one death in phase I from sepsis and multi-organ failure at the end of 8 cycles of treatment, but no deaths from toxicity in phase II. Overall response rate was 81% (95% CI: 69-90%). With median follow-up of 24.3 months, estimate of 2-year PFS is 72% (95% CI: 58%, 81%) and of 2-year OS is 85% (95% CI: 74%, 92%). Analysis of the panel of 30 cytokines performed on matched serum specimens of 40 patients showed correlation of baseline elevated IL-2R levels with worsened PFS and OS, and correlation of decrease in Epidermal Growth Factor level with improved PFS and OS. Results of immunohistochemical stains for expression of MHCII genes and percentage of TIL will be reported at the meeting. Conclusions: The regimen of vorinostat-R-CHOP achieved 2-year PFS estimate of 72%, which is slightly more than 68% expected from R-CHOP alone per IPI adjusted historical rate, but less than an IPI adjusted target of 78% that would be sufficient to warrant further investigation. It also resulted in unexpected excess rates of febrile neutropenia and sepsis. This regimen cannot be recommended for the broad DLBCL population. Current studies are focused on finding biomarkers of response to histone deacetylase inhibitors. Disclosures Persky: Gilead Sciences, Inc: Speakers Bureau. Off Label Use: vorinostat in diffuse large B-cell lymphoma. Barr:Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

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Clinical efficacy and molecular biomarkers in a phase II study of tucidinostat plus R-CHOP in elderly patients with newly diagnosed diffuse large B-cell lymphoma

Clinical Epigenetics ◽

10.1186/s13148-020-00948-9 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Mu-Chen Zhang ◽

Ying Fang ◽

Li Wang ◽

Shu Cheng ◽

Di Fu ◽

...

Keyword(s):

Elderly Patients ◽

B Cell ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Molecular Biomarkers ◽

Newly Diagnosed ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract Background Elderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be applied to treat DLBCL. This study aimed to evaluate efficacy and safety of oral HDACI tucidinostat (formerly known as chidamide) plus R-CHOP (CR-CHOP) in elderly patients with newly diagnosed DLBCL (International Prognostic Index ≥ 2). Results Among 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. The 2-year progression survival (PFS) and overall survival (OS) rates were 68% (95% CI 52–79) and 83% (95% CI 68–91). Comparing with historical control (NCT01852435), the 2-year PFS and OS rates of double-expressor lymphoma phenotype (DEL) were improved, and negative prognostic effect of histone acetyltransferases CREBBP/EP300 mutations was also mitigated by CR-CHOP. Grade 3–4 neutropenia was reported in 171, grade 3–4 thrombocytopenia in 27, and grade 3 anemia in 11 of 283 cycles. No grade 4 non-hematological adverse event was reported. Conclusion CR-CHOP is effective and safe in elderly patients with newly diagnosed DLBCL. Relevance of DEL phenotype and molecular biomarkers on CR-CHOP response warrants further investigation in DLBCL. Trial registration ClinicalTrial.gov, NCT02753647. Registered on April 28, 2016.

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Detection of the Incidence of HBV, HCV Infection and Febrile Neutropenia Associated With CHOP With or Without Rituximab in Diffuse Large B-Cell Lymphoma–Treated Patients

Hospital Pharmacy ◽

10.1177/0018578717741394 ◽

2017 ◽

Vol 53 (3) ◽

pp. 194-197 ◽

Cited By ~ 1

Author(s):

Kashif Ali ◽

Ali Akbar Sial ◽

Mirza Tasawer Baig ◽

Nida Baig ◽

Saqib Hussain Ansari ◽

...

Keyword(s):

Hepatitis B ◽

Febrile Neutropenia ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hcv Infection ◽

Patient Records ◽

Chop Chemotherapy ◽

Large B Cell Lymphoma ◽

Large B Cell

Background: Reactivation of hepatitis B virus (HBV) and hepatitis C virus (HCV) and febrile neutropenia (FN) are common in diffuse large B-cell lymphoma (DLBCL) patients undergoing cyclophosphamide, hydroxyrubicin, Oncovin, and prednisolone (CHOP) or cyclophosphamide, hydroxyrubicin, Oncovin, prednisolone - rituximab containing (R-CHOP) chemotherapy. This ultimately leads to delaying the therapy, increasing hospital stay, and raising the pharmacoeconomic burden on patients. Aim and Objective: The aim of this study was to determine the incidence of HBV and HCV infection and febrile neutropenia in DLBCL patients treated with R-CHOP and CHOP. Methodology: This was an institutional approved study in which patient records from a private hospital, specialized in hematology and oncology (Karachi, Pakistan), were reviewed retrospectively from 2014 to 2016. Patients aged above 18 years with known diagnosis of DLBCL who underwent CHOP-21 or R-CHOP-21 chemotherapy regimen were included. Baseline blood chemistry and liver function tests along with the data regarding HBV (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [anti-HBs]), HCV (antibody anti-HCV), and febrile neutropenia were collected from patient records. Results: In total, 35 cases of DLBCL were treated during a 3-year period (ie, from 2014 to 2016), of which 16 were on CHOP-21 regimen whereas 19 were treated with R-CHOP-21. Of the 19 patients who underwent R-CHOP chemotherapy, only 2 (10%) patients were HBsAg reactive. Before commencing the second cycle, 2 (10%) patients reported to hospital with fever and had hematological (low neutrophil count) and microbiological ( Escherichia coli) proven febrile neutropenia. The incidence of HBV infection post treatment was lower in group treated with CHOP (1 patient showed HBsAg reactivity).

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Favorable Results of Rituximab in Combination with CHOP in the Front-Line Treatment of Follicular Lymphoma Grade 3.

Blood ◽

10.1182/blood.v108.11.2770.2770 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2770-2770

Author(s):

Luis Fayad ◽

Michael Overman ◽

Barbara Pro ◽

Peter McLaughlin ◽

Felipe Samaniego ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Bulky Disease ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Background: Follicular lymphoma grade 3 has a natural history that is more akin to that of diffuse large B-cell lymphoma. The addition of rituximab to standard CHOP has resulted in improved response and survival in diffuse large B-cell lymphoma. Information about outcomes in follicular lymphoma grade 3 is lacking. Methods: A single institution retrospective review of patients with follicular grade 3 lymphoma evaluated at the UTMDACC from 1999 to 2004. Patients were located from the UTMDACC lymphoma database. All patients were initially treated with R-CHOP. Results: Forty-five patients were identified: 51% male, 47% ≥60 years, and 87% follicular grade 3b. The LDH was elevated in 24%, ECOG performance status was >1 in 2%, and >1 site of extranodal involvement was present in 10%. Stage distribution was 11% stage I, 11% stage II, 42% stage III, and 36% stage IV, bulky disease (>7cm) was present in 11%, and B symptoms occurred in 13%. Beta-2 microglobulin was elevated in 57% with values >3 μg/dL in over 50%. IPI distribution was: 46% IPI Low, 38% LI, 11% IH, and 4% IPI High. Overall response rate was 100% with 96% complete responses. Relapse rate by IPI category was 24% for Low IPI, 18% for IPI LI, and 40% for IPI IH, and 100% for the two patients with High IPI. With median follow-up of 33 months, three year failure-free survival (FFS) is 73% (95% CI: 59 to 87%). One patient died (2%) with an overall survival (OS) at three years of 97% (95% CI: 93 to 100%). Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival in this group of mostly good prognosis patients. Relapses were still seen; longer follow-up is needed.

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The Efficacy of R-ICE Therapy as a Salvage Treatment for Relapse and Refractory Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.4441.4441 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4441-4441

Author(s):

Makoto Kodaira ◽

Masahiro Yokoyama ◽

Hiroaki Asai ◽

Shuhei Yamada ◽

Kyoko Ueda ◽

...

Keyword(s):

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

Salvage Treatment ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract <Background> Patients with relapsed and refractory diffuse large B-cell lymphoma are usually treated with platinum-based salvage chemotherapy. We retrospectively analyzed the efficacy of adding rituximab with ICE as a salvage treatment for relapsed and refractory diffuse large B-cell lymphoma. <Method>From November 2003 to December 2006, patients with relapsed or refractory de novo diffuse large B-cell lymphoma represented CD20 positivty who received R-ICE (rituximab375mg/m2, Ifosfamide 1200mg/m2, calboplatin 400mg/m2 and etopside100mg/m2 ), were analyzed retrospectively. <Result>23 patients (19 relapse and 4 reflactory) (M:F=14:9) (median age 69, 28–77) were included. At starting treatment, twelve patients received rituximab and 11 patients were rituximab naive. In all 23 patients, responses were 11 Complete remission (CR), and 6 partial response (PR), resulting in overall response (ORR) was 74.9%. With median follow up of 10.5 months, estimated 1yr-progression free survival (PFS) was 49% and 1yr-overall survival (OS) was 70%.In patients received rituximab, ORR was 66.7% and 5 patiets achieved CR (41.7%).In the without rituximab, ORR was 90.9% and 7 patiets achieved CR (63.6%). No statistical differences were observed in response even with retuximab pretreatment. Estimated 1yr-PFS was 23% and 70% (p=0.0752) and 1yr-OS was 59% and83% (P=0.0049),respectively. NCI-CTC grade 3/4 neutropenia and thrombocytopenia were reported 100% and 91%, For non-hematological adverse event, there were grade 3 liver dysfunction (2/23) and grade 3 arrythmia (1/23). No toxic death was reported in this study. <Conclusion> R-ICE showed promising efficacy with tolelable toxicity. Available date suggested adding rituximab to ICE is more effective for patients not received rituximab in the pretreament.

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REPOCH compared with RCHOP for the treatment of diffuse large B-cell lymphoma of activated B-cell type.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e20081 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e20081-e20081

Author(s):

Phillip Martinez-Knouse ◽

Edward Nabrinsky ◽

Anjana Chandran ◽

Timothy M. Lestingi ◽

Jacob D. Bitran

Keyword(s):

Complete Remission ◽

B Cell ◽

Retrospective Analysis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Phase Iii ◽

Cell Type ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

e20081 Background: Patients with diffuse large B-cell lymphoma of activated B-cell type (DLBCL-ABC) have a worse prognosis than patients with DLBCL of germinal center origin. Recently, a phase III randomized trial of patients with DLBCL showed no improvement in response rates or progression free survival (PFS) with REPOCH compared to RCHOP. However, the PFS reported in this study was significantly better than expected, indicating that high-risk patients, such as those with DLBCL-ABC, may have been underrepresented. The optimal treatment for patients with DLBCL-ABC remains unknown. Methods: We undertook a retrospective analysis of patients with DLBCL treated in our practice from January 1, 2015 to May 31, 2019. We then examined treatment approaches and outcomes of patients treated for DLBCL-ABC. Results: We treated 136 patients with DLBCL and identified 18 of 136 patients with DLBCL-ABC. There were 9 men and 9 women with a median age of 74 years (range 26-92 years) and a median performance status of Eastern Cooperative Oncology Group 1, (0-2). The median international prognostic index score was 3. Nine of 18 patients were treated with REPOCH, 8 with RCHOP, and one with bendamustine and rituximab (BR). The stage distribution was stage I in 2 patients, stage III in 4 patients, and stage IV in 12 patients. Of 9 patients treated with REPOCH, 9 (100%) achieved a complete remission with no relapses to date. Of 8 patients treated with RCHOP, 6 (75%) achieved a complete remission and 2 had no response and died. The one patient treated with BR failed to respond and died. The median PFS for the 8 patients treated with RCHOP was 19.5 months; whereas, the PFS in the REPOCH group had not been reached at a median follow up of 2 years. Grade 3 and 4 toxicities were more common in the RCHOP group and included cardiomyopathy in 1 patient and two episodes of neutropenic fever (one resulting in septic shock and death). There were no grade 3 or 4 toxicities in the REPOCH group. Conclusions: In this retrospective analysis, our patients with DLBCL-ABC treated with REPOCH had better overall outcomes. A prospective trial in this subset of DLBCL patients is warranted.

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Yttrium-90 Ibritumomab Tiuxetan Followed by Rituximab Maintenance as Treatment for Patients with Diffuse Large B-Cell Lymphoma Are Not Candidates for Autologous Stem Cell Transplant

Acta Haematologica ◽

10.1159/000368291 ◽

2015 ◽

Vol 133 (4) ◽

pp. 347-353 ◽

Cited By ~ 4

Author(s):

Jon E. Arnason ◽

Katarina Luptakova ◽

Jacalyn Rosenblatt ◽

Dimitrios Tzachanis ◽

David Avigan ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Cell Transplant ◽

Ibritumomab Tiuxetan ◽

Rituximab Maintenance ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Background: Not all patients with diffuse large B-cell lymphoma (DLBCL) are candidates for aggressive regimens. 90Y ibritumomab tiuxetan (90Y-IT), an anti-CD20 radionuclide-conjugated antibody, has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile. Methods: This phase II trial investigated the overall response rate (ORR), event-free survival (EFS), overall survival (OS) and toxicity of treatment with 90Y-IT (0.4 or 0.3 mCi 90Y/kg based on platelets) followed by rituximab maintenance therapy in patients with DLBCL not candidates for transplant. Results: 25 patients were enrolled. At best response 8 patients obtained a complete response (CR) and 1 a partial response (ORR 36%). Median EFS was 2.5 months and OS 8.1 months. No patient who obtained CR later relapsed systemically. Two patients were free of disease at the 61- and 100-month follow-ups; 65% had grade 3/4 thrombocytopenia, but no significant bleeding was observed. Grade 3 nonhematologic toxicity occurred in 36%. Patients who had progressed through a rituximab-containing regimen responded poorly. Conclusion: The ORR of 36% with 90Y-IT as salvage therapy for DLBCL while inferior to more aggressive regimens is significant with acceptable toxicity. For a subset of patients not candidates for salvage with autologous transplant, this treatment strategy can produce a durable, long-lasting remission.

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Statins Potentiate the Cytotoxic Effect of ABT-199 in Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.3969.3969 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3969-3969

Author(s):

David A. Fruman ◽

Jong-Hoon Scott Lee ◽

Thanh-Trang T Vo ◽

Shruti Bhatt ◽

Jonathan H. Schatz ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Lymphocytic Leukemia ◽

Lymphoma Cells ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract BCL-2 is a key pro-survival protein that is highly expressed in many leukemias and lymphomas. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2 that has demonstrated impressive responses in chronic lymphocytic leukemia (CLL) leading to FDA approval for second line treatment of patients with 17p deletion. However, other hematologic malignancies are less responsive to ABT-199 as a single agent, suggesting that combinations of targeted therapies may be required to elicit more promising responses. We have investigated the potential of combining ABT-199 with HMG-CoA reductase (HMGCR) inhibitors (statins), which have known anti-cancer potential in hematologic malignancies. Using multiple chemically distinct statin compounds, we observed profound synergistic induction of apoptosis when combined with ABT-199 in both human diffuse large B cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML) cell lines. This synergy was also seen in primary murine B lymphoma cells over-expressing MYC and BCL-2. Importantly, addition of exogenous mevalonate completely rescued cells from the combination, confirming on-target efficacy of HMGCR inhibition. Using BH3 profiling, we found that simvastatin significantly primed lymphoma cells for undergoing apoptosis (termed mitochondrial priming). Notably, the degree of priming correlated with its ability to synergize with ABT-199, suggesting that BH3 profiling may be used to predict patient responses. The combination did not synergize to kill normal human peripheral blood mononuclear cells from healthy donors, suggesting that statins may selectively prime cancer cells for apoptosis. Mechanistic studies support the hypothesis that statins synergize with ABT-199 by suppressing protein prenylation, particularly protein geranylgeranylation. In support, the addition of exogenous geranylgeranyl pyrophosphate (GGPP) completely rescued cells from the effects of simvastatin. Furthermore, selective inhibition of protein geranylgeranyl transferase (GGT) increased priming and was sufficient to recapitulate the effects of simvastatin in combination with ABT-199. Statins and GGT inhibitors increased the mitochondrial abundance of a subset of BH3-only pro-apoptotic proteins. Lastly, we have identified Rap1A de-prenylation as a marker of pharmacodynamic response to statins in vivo. Thus, this project highlights a novel combination for use in aggressive lymphomas, establishes its efficacy and tolerability using preclinical models, and provides proof-of-concept to warrant investigation of its clinical potential. Disclosures Letai: AbbVie: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

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