Dose-Dense Chemoimmunotherapy and Early Central Nervous System Prophylaxis For High-Risk Diffuse Large B-Cell Lymphoma. –Preliminary Results From a Nordic Phase II Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 849-849 ◽  
Author(s):  
Sirpa Leppa ◽  
Anne Maria Tierens ◽  
Judit Jorgensen ◽  
Mats Jerkeman ◽  
Magnus Bjorkholm ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Progression Rate ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Dose Dense ◽  
Large B Cell

Abstract Background Despite the advent of rituximab (R)-based chemoimmunotherapy, outcome for patients with high-risk diffuse large B-cell lymphoma (DLBCL) continues to be suboptimal, and the risk of central nervous system (CNS) progression is high. In a previous Nordic phase II study with dose-dense chemoimmunotherapy followed by systemic CNS prophylaxis, the CNS progression rate was lower than expected (4.5%), but all events occurred within 6 months after initiation of therapy (Holte et al., Ann Oncol 2013). Hence, in the present study, systemic CNS prophylaxis was moved to the beginning of therapy and CNS targeted therapy was further intensified by adding intrathecally administered liposomal AraC. Methods Inclusion criteria are age 18-65 years, primary DLBCL or grade 3B follicular lymphoma without clinical or radiological signs of CNS disease and cytology negative cerebrospinal fluid (CSF), age adjusted IPI 2-3, WHO performance score ≤3, and/or site specific risk factors for CNS recurrence. Treatment consists of two courses of high dose (HD)-Mtx in combination with R-CHOP14, four courses of R-CHOEP14 and a course of HD-AraC with R. In addition, liposomal AraC is administered intrathecally in courses 1, 3 and 5. All courses are administered with support of pegfilgastrim. Indications for radiotherapy are bulky masses at diagnosis and localized PET positive residual disease not eligible for biopsy. Primary endpoints are failure-free survival at 3 years, and CNS progression rate at 18 months. A secondary aim is to elucidate if CSF cytology negative/flow cytometry (FC) positive cases carry an increased risk of CNS progression with the present regimen. Results Of the accrued 84 patients by July 22, 2013, 70 had a complete set of baseline data. Median age was 55 years (range 20-64). The majority presented with DLBCL (96%), advanced-stage disease (94%), elevated LDH (94%), B-symptoms (67%), and 49% with >1 extranodal site. Seven CSF-samples were FC positive. Data on toxicity, response and relapse rates were registered for 45 patients. One toxic death due to pneumonia was reported. Grade 4 hematological toxicity and infections were observed in 78% and 11% of the patients, grade 3-4 mucositis and gastrointestinal toxicity in 27% and 42%, and grade 3 arachnoiditis in 2.2% of the patients. CR, CRu, PR and PD rates at the end of chemoimmunotherapy were 69.0%, 14.3%, 14.3% and 2.4 %, respectively. After a median follow up time of 19 months, four patients have relapsed, two of whom with fatal CNS manifestations. Conclusions Preliminary results indicate highly satisfactory response rates and reasonable toxicity despite intensive therapy. HD-Mtx in combination with R-CHOP in the beginning of therapy and further intensification of treatment with CNS targeted liposomal AraC seem feasible and safe. ClinicalTrials.gov Identifier: NCT01325194 Disclosures: Leppa: Amgen: Research Funding; Mundipharma: Honoraria, Research Funding. Holte:Mundipharma: Honoraria, Research Funding; Amgen: Research Funding.

R-CHOEP-14 × 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade 3 with Age Adjusted IPI Score 2–3: Final Results of a Nordic Lymphoma Group Phase 2 Study Including 156 Patients Aged 18–65 Years.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2805-2805 ◽  
Author(s):  
Harald Holte ◽  
Sirpa Leppä ◽  
Magnus Bjorkholm ◽  
Øystein Fluge ◽  
Sirkku Jyrkkiö ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Residual Masses ◽  
Grade 3 ◽  
Large B Cell

Abstract Abstract 2805 CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods: From October 2004 to June 2008 patients were included in a phase II study. Inclusion criteria: 1) Age 18–65 years. 2) Newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade III. 3) No clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture. 4) No HIV infection. 5) WHO performance score 0–3. 6) Adequate organ functions. Schedule: Six courses of R-CHOEP14. Pegfilgrastim 6 mg sc. day four of each cycle. One course of high dose cytarabine 12 g/m2 (6 g/m2 for patients 60–65 years). One course of high dose methtrexate 3 g/m2 (1 g/m2 for patients 60–65 years). Biopsy and/or 18FDG PET/CT imaging of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results. Demographic data:.156 eligible patients were included (97 males). Median age: 54 years (range 20–64). Histology: DLBCL: 145, FL grade 3: 12 (three patients no data). Age adjusted IPI score: 2: 117; 3: 39. Stage III-IV: 150 patients. LDH elevated: 151 patients. Performance status 2–3: 51 patients. B-symptoms were registered in 97 patients, more than one extranodal site in 42 and bulky lesions (≥ 10 cm) in 68. Median observation time for patients alive at last follow up was 36 months. Toxicity: Three toxic deaths are registered, one large bowel perforation, one fulminant hepatic necrosis and one septic shock. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Radiotherapy was given to 16% of the patients. Response: Response rates at end of therapy: CR/CRu: 69%, PR: 22%, SD: 1%, PD: 4.5%. Seventeen patients (7%) were not treated according to protocol, either due to lack of response (6 patients) or due to toxicity (eleven patients). The majority of the PR patients were considered to have residual masses and not viable tumour tissue. Survival: Three year overall survival was 80% (95% CI +/− 6.5%) and three year treatment failure free time 67% (95% CI +/−8.0%). CNS events: Seven patients had a CNS relapse, all but one were isolated (4 intracerebral, 3 meningeal). All CNS relapses occurred within 6 months after inclusion. Conclusions: The results are promising with a low three year treatment failure rate, a low toxic death rate and fewer CNS events than expected. The CNS events might be further reduced by earlier CNS prophylaxis. The study was supported by an unrestricted grant from Amgen Disclosures: Holte: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. LeppÃ: Roche: Honoraria. Bjorkholm:Roche: Research Funding. Jyrkkiö:Roche: Honoraria. Kolstad:Roche: Honoraria; Amgen: Honoraria. Fosså:Roche: Honoraria. φstenstad:Roche: Honoraria; Amgen: Honoraria. Eriksson:Amgen: Research Funding.

scholarly journals Young High Risk Patients with MYC/BCL2 Double Hit Lymphoma, BCL2+ and/or Germinal Centre B-Cell like Diffuse Large B-Cell Lymphoma Benefit from Dose-Dense Chemoimmunotherapy Including Early CNS Prophylaxis: Analysis of Data from the Nordic Lymphoma Group CRY-04 and Chic Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2955-2955 ◽  
Author(s):  
Sirpa Leppa ◽  
Judit Jørgensen ◽  
Leo Meriranta ◽  
Klaus Beiske ◽  
Jan M.A. Delabie ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Dose Dense ◽  
In The Beginning ◽  
Large B Cell

Abstract Background. Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two Nordic trials including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these trials to compare clinical outcome and biological prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) versus at the end (CRY-04) of therapy. Patients and methods. In CRY-04 study, patients were treated with six courses of R-CHOEP14 followed by HD-Mtx and HD-Ara-C. In CHIC trial, treatment started with two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP-14 and one course of R-HD-AraC. In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. For the correlative studies, formalin fixed paraffin embedded pretreatment tumor samples were analyzed by fluorescent in situ hybridization for BCL2 and c-MYC breakpoints and by immunochemistry for CD10, BCL6, MUM1, MYC and BCL2 expression. Germinal center B-cell-like (GCB)/non-GCB) subclassification was performed according to Hans algorithm. Results. Among 303 patients enrolled in the trials (CRY-04, n=160 and CHIC, n=143), 295 (CRY-04, n=154 and CHIC, n=139) were evaluable for baseline characteristics and outcome. Median age (54 and 56 years, p=0.222), male/female ratio, stage, and aaIPI scores were comparable in the two cohorts. CHIC regimen improved outcome over CRY-04; the findings included 4-year estimates of PFS (81% vs 66%, p=0.003), OS (83% and 79%, p=ns) and cumulative incidence rates of CNS progression (2.4% and 5.0%, p=ns). Treatment with the CHIC regimen reduced the risk of systemic progression (aaIPI adjusted RR=0.489, 95%CI 0.308-0.777, p=0.002). PFS benefit with CHIC over CRY-04 was observed across pre-specified subgroups, and particularly in patients less than 60 years old (p=0.008). In the entire study population, dual protein expression (DPE) of BCL2 and MYC was the only parameter to be significantly correlated with a worse PFS (4-y PFS 77% vs 50%, p=0.024; RR=2.300, 95% CI 1.088-4.860, p=0.029). Neither any single immunohistochemical marker nor the GCB/non-GCB subtype or MYC/BCL2-translocations significantly affected outcome. However, when treatment interaction was tested, MYC/BCL2 double hit status (DHL; 13%) predicted poor outcome among patients treated with CRY-04 regimen compared with patients who received CHIC regimen (4-y PFS; 38% vs 78%, p=0.086). GCB subtype and BCL2 positivity were also associated with better outcome in the CHIC cohort (4 y PFS; 63% vs 84%, p=0.011 and 61% vs 80%, p=0.007, respectively), whereas there were no significant survival differences between these regimens among the patients with non-GCB subtype, BCL2 negative DLBCL or DPE lymphomas. Conclusions. Our results derived from trial data with homogenous treatment support the use of HD-Mtx in the beginning rather than at the end of therapy. The survival benefit related to CHIC regimen over CRY-04 is due to better systemic control of the disease, and at least partly linked to improved survival among patients with GCB subtype, BCL2 positivity and DHL. Disclosures Leppa: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bayer: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding.

scholarly journals An Open-Label Phase II Study of Buparlisib (BKM120) in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma or Follicular Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1718-1718 ◽  
Author(s):  
Anas Younes ◽  
Gilles Salles ◽  
R. Gregory Bociek ◽  
Giovanni Martinelli ◽  
Dolores Caballero ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Grade 3 ◽  
Large B Cell

Abstract Background: Non-Hodgkin's lymphoma (NHL), which includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), is associated with a high unmet need in the relapsed and refractory setting. The PI3K/AKT/mTOR pathway has been shown to play a key role in the pathogenesis of NHL. Overexpression of PIK3CD (encoding the PI3Kd isoform) is common in B-cell malignancies and is therefore widely viewed as a therapeutic target in NHL. PIK3CA and PIK3CB are also expressed in B-cell malignancies, with PIK3CA overexpression seen particularly at relapse, thereby justifying exploration of pan-PI3K inhibitors in the relapsed or refractory setting. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor which has demonstrated activity in patients with solid tumors as well as in in vitro and in vivo models of hematologic malignancies. Methods: The primary objective of this Phase II study (NCT01693614) was to evaluate the efficacy of buparlisib in three parallel cohorts of adult patients with relapsed or refractory DLBCL, FL, or MCL. Secondary objectives were to evaluate safety and tolerability, progression-free survival, duration of response, and overall survival. Inclusion criteria were: patients with relapsed or refractory disease who have received at least one prior line of therapy; at least one measurable nodal lesion (≥2 cm); ECOG performance status ≤2; and adequate bone marrow and organ function. Patients with DLBCL must have received, or be ineligible for, autologous or allogeneic stem cell transplant. All patients received single-agent buparlisib 100 mg orally QD continuously until progression, intolerance, or patient withdrawal. Tumor response was evaluated by investigators per standard criteria (Cheson, 2007). Results: At data cut-off (June 19, 2014), 64 patients had been enrolled; 26 DLBCL, 24 FL, and 14 MCL. Here, results are presented for the DLBCL cohort only. Updated results from the DLBCL cohort including biomarker analyses and results for the FL cohort will be presented at the meeting. The MCL cohort is currently enrolling. For the DLBCL cohort, median age (range) was 63.5 (28–81) years and 69% were male. The median (range) number of prior therapy regimens was 3 (1–12). Specific prior therapies included: rituximab (n=25, 96%) and bendamustine/carmustine (n=8, 31%); all patients had received prior anthracycline and an alkylating agent (e.g. cyclophosphamide), and 6 (23%) patients had undergone prior stem cell transplantation. The most common (≥15%) AEs (all grades) regardless of causality were hyperglycemia and nausea (39% each), depression (31%), anxiety and fatigue (23% each), vomiting and diarrhea (19% each), and abdominal pain (15%). Alanine transaminase or aspartate transaminase elevations were rare (4% each, with no Grade 3/4 AEs). The most common (>5%) Grade 3/4 AEs regardless of causality were hyperglycemia (23%), and nausea, depression, anxiety, urinary tract infection, and neutropenia (8% each). Six (23%) patients discontinued therapy due to AEs (potentially treatment-related). Seven on-treatment deaths were reported: 6 were disease-related and 1 was suspected to be treatment-related (unexplained death following a gastrointestinal [GI] bleed in a patient with massive GI lymphoma involvement). Overall response rate was 12% (95% CI = 2.4, 30.2) with 3 responses: 1 complete response (4%) and 2 partial responses (8%). Five patients had stable disease (19%). Eight patients (31%) experienced some decrease in tumor burden (Figure 1). At data cut-off, 2 patients demonstrated durable responses, as they were still on study treatment after 9.2 and 7.4 months, respectively. Figure 1 Figure 1. Conclusions: Early results from this Phase II study of the pan-PI3K inhibitor, buparlisib, demonstrate encouraging clinical activity, and a favorable safety profile in heavily pretreated patients with relapsed or refractory DLBCL. These data suggest that targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL. Future combination studies with buparlisib will take a mechanism-based approach. Disclosures Younes: Novartis, Curis, J&J: Research Funding; Bayer, BMS, Celgene, Incyte, Janssen R&D: Honoraria; Sanofi, Seattle Genetics, Takeda Millenium: Honoraria. Mukherjee:Novartis Healthcare Pvt. Ltd. India: Employment. Williams:Novartis: Employment. Herbst:Novartis: Employment. Tavorath:Novartis: Employment. Kim:Novartis, Celgene, Takeda: Research Funding.

Rituximab and CODOX-M / IVAC Without Stem Cell Transplantation For Poor Risk Diffuse Large B Cell Lymphoma (IPI3-5) and Burkitts Lymphoma Is Feasible and Gives a High Response Rate: Preliminary Results Of a Phase 2 UK National Cancer Research Institute Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4348-4348 ◽  
Author(s):  
Andrew McMillan ◽  
Kirit M Ardeshna ◽  
Jo Gambell ◽  
Andrew Jack ◽  
Amy Kirkwood ◽  
...  
Keyword(s):  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Poor Risk ◽  
Large B Cell Lymphoma ◽  
Pet Scanning ◽  
Burkitts Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Introduction R-CHOP is the standard of care for patients with diffuse large B cell lymphoma (DLBCL) however poor risk patients (IPI 3-5) still have an inadequate outcome. Neither first remission high dose chemotherapy and peripheral blood stem cell transplantation (HDC+PBSCT) nor selection of cases for intensification by interim PET scanning have demonstrated a proven benefit. In the case of Burkitts lymphoma (BL) there is a paucity of data on the addition of Rituximab to the CODOX-M and IVAC regimen. Patients and Methods 113 patients with DLBCL and 37 with BL were recruited from 53 UK sites between May 2008 and April 2013. Median age was 49 years (18-65). For DLBCL patients IPI scores were 3 – 72 ( 64%), 4 -40 (35%) and 5 – 1 (1%). All patients received the modified CODOX-M and IVAC regimen including all CNS directed therapy( Mead et al Ann Oncol. 2002 Aug;13(8):1264-74) and 8 doses of rituximab. The primary end point of the study was Progression Free survival (PFS) and secondary endpoints included toxicity and CR rate. Results The main toxicities reported were neutropenia ( 89% grade 3 or 4), thrombocytopenia (84.2% grade 3 or 4), infection 61.6% grade 3 or 4 and mucositis (30.1% grade 3 or 4). 4 patients were excluded from toxicity assessment as they did not start therapy after registration. There were 8 treatment related deaths observed (infection with neutropenia (5), GI haemorrhage (1), acute cerebral haemorrhage (1) and bowel perforation (1) ). 78 patients with DLBCL and 31 with BL have completed all therapy ( 78.5 % of patients with available data) with an overall response rate of 92 % for DLBCl and 94% for BL. In patients who completed all therapy CR was achieved in 34 (44%), CR (u) in 8 (10%) and PR in 30 (38%) for DLBCL patients and CR was achieved in 21 (68%), CR (u) in 6 (19%) and PR in 2 (6%) in BL patients. 3 patients ( 2 DLBCL and 1 BL) who progressed during therapy have been included in the response analysis. End of treatment PET scanning was not obligatory. 80 patients with DLBCL and 30 patients with BL remain alive and without progression at a median follow up of 18.6 and 19.3 months respectively. Conclusion The R-CODOX-M -R-IVAC regimen can be delivered to patients with poor risk DLBCL in a multicentre setting. High rates of haematological toxicity and consequent infection are inevitable with treatment of this intensity but appear acceptable when compared with other treatments such as HDC+PBSCT. Response rates are encouraging in view of the very poor risk IPI profile of the patients included in this study. Burkitts lymphoma patients also achieved an excellent response rate with no apparent additional toxicity attributable to the addition of rituximab to the regimen. We currently plan the first analysis for the primary endpoint of PFS in 2015. The Trial was supported by Leukaemia and Lymphoma Research (LLR). Disclosures: McMillan: Roche: Consultancy, Honoraria; Amgen: Research Funding. Off Label Use: Rituximab usage in Burkitts Lymphoma. Ardeshna:Roche: Honoraria, Research Funding. Jack:Roche/Genentech: Research Funding. Patmore:Roche: Consultancy, Honoraria. Pettengell:Roche: Honoraria; Amgen: Honoraria. Linch:Roche: Honoraria, Research Funding.

scholarly journals Rituximab-CHOP and Central Nervous System Prophylaxis Using Intrathecal Methotrexate in Primary Breast Diffuse Large B-Cell Lymphoma: A Prospective, Multicenter, Single-Arm Phase II Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4076-4076
Author(s):  
Ho-Young Yhim ◽  
Cheolwon Suh ◽  
Seok Jin Kim ◽  
Deok-Hwan Yang ◽  
Hyeon-Seok Eom ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intrathecal Methotrexate ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma

Background: Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). To prevent CNS recurrence, we designed this phase II trial that addressed feasibility and activity of conventional immunochemotherapy and CNS prophylaxis. Methods: This prospective, multicenter, single-arm phase II study was conducted to evaluate efficacy and safety of 6 cycles of conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP) with the addition of 4 doses of intrathecal methotrexate (IT MTX; 12mg) during the first 4 cycles of R-CHOP in patients with primary breast DLBCL. Primary breast lymphoma was defined as lymphoma involving one or both breasts as a sole extranodal site regardless of specific nodal involvement status. The primary end-point was 2-year progression-free survival (PFS). Secondary end-points included cumulative incidence of CNS recurrence, overall survival (OS), and safety. All patients provided written informed consents and the study was registered at www.clinicaltrials.gov as #NCT01448096. Results: Thirty-three patients with primary breast DLBCL were enrolled between Jan 2012 and Jul 2017 in the Consortium for Improving Survival of Lymphoma (CISL) member institutions. The median age was 50 years at diagnosis (range, 29-75) and all were female. Right breast involvement was more common than left (18 [55%] vs 14 [42%]) and bilateral breast involvement was found in one patient (3%). Nodal involvement was present in 16 patients (49%), primarily in regional nodes (14 patients). Thus, the Ann Arbor stage was IE in 17 (52%), IIE in 13 (39%), IIIE in 2 (6.1%), and IV in 1 (3.0%). ECOG performance status was ≥2 in 1 patient (3%) and serum LDH level was elevated in 9 (27%). Therefore, the IPI and the CNS-IPI risk were mainly low (28 patients, 85%; respectively). No patients had CNS involvement at diagnosis. 32 (97%) of the 33 patients completed R-CHOP as planned, and the remaining patient withdraw a consent after four cycles of R-CHOP because of poor tolerance. CNS prophylaxis using IT MTX was completed as planned in 31 patients (94%), but it was discontinued in 2 patients because of patient's refusal. These 2 patients received two and three IT MTX doses, respectively. 32 patients (97%) were evaluable for treatment response and all these patients achieved a complete response. At the cutoff date of this analysis (10 Jul 2019), all patients who entered a follow-up phase had at least 24.0 months of follow-up. With a median follow-up duration of 46.1 months (IQR 31.1-66.8), 6 patients had experienced treatment failure and 3 of these died. The 2-year PFS and OS were 81.3% (95% CI, 67.7-94.8) and 93.5% (95% CI, 84.9-100.0), respectively (fig 1A and B). Of the 6 patients with treatment failure, diseases involved CNS with or without lymph nodes in 4 patients and breasts in 2 patients (1 ipsilateral and 1 contralateral breast recurrence). 3 of the four patients with CNS recurrence had isolated CNS recurrences (2 brain parenchymal and 1 meningeal disease) and one had a concurrent meningeal and lymph nodal recurrence. All 4 patients with CNS recurrence had received prophylactic IT MTX as planned by protocol. The 2-year cumulative incidence of CNS recurrence, taking into account the competing risk of death, was 12.5% (95% CI, 0.3-23.2, fig 1C). Although the number of patients with intermediate CNS-IPI risk was small (5 patients, 15%), the cumulative incidence of CNS recurrence did not differ significantly according to the CNS-IPI risk group. All CNS recurrences occurred within the first 2 years after enrolment. Toxicities were generally manageable during the R-CHOP and IT MTX treatment. No deaths as a result of toxicity occurred during treatment. Conclusion: Our study shows that conventional R-CHOP with prophylactic IT MTX is feasible in patients with primary breast DLBCL. However, given a substantially high rate of CNS recurrence, further studies to properly define the best strategy for CNS prophylaxis should be needed in patients with primary breast DLBCL. Figure 1 Disclosures Yoon: F. Hoffmann-La Roche Ltd: Research Funding. Kim:Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Phase II Study of Enzastaurin, a Protein Kinase C Beta Inhibitor, in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

2007 ◽  
Vol 25 (13) ◽  
pp. 1741-1746 ◽  
Author(s):  
Michael J. Robertson ◽  
Brad S. Kahl ◽  
Julie M. Vose ◽  
Sven de Vos ◽  
Mary Laughlin ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
B Cell ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Kinase C ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

PurposeProtein kinase C beta (PKCβ) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCβ, enzastaurin, in patients with relapsed or refractory DLBCL.Patients and MethodsEnzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for ≥ two cycles (one cycle = 28 days), objective response, and toxicity.ResultsFifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for ≥ two cycles, and eight patients remained free from progression for ≥ four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry.ConclusionTreatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

scholarly journals 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 ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4162-4162 ◽  
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.

scholarly journals Phase I Study of Oral Azacitidine (CC-486) Plus Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3567-3567
Author(s):  
Brian T. Hess ◽  
Leandro Cerchietti ◽  
Lindsey Hendrickson ◽  
Elizabeth Hill ◽  
Anshu Giri ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Global Methylation ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Methylation Patterns ◽  
Large B Cell

Abstract Background A significant portion of diffuse large B-cell lymphoma (DLBCL) patients (35-40%) relapse or are refractory to frontline chemotherapy. The standard of care for relapsed/refractory (R/R) DLBCL patients has been salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) in eligible patients. Epigenetic alterations, such as aberrant DNA methylation patterns, have been linked to chemotherapy resistance in DLBCL. CC-486 is an oral hypomethylating inhibitor that inhibits DNA methyltransferase, and has provided evidence for chemotherapy sensitization in DLBCL (Clozel T, et al. Cancer Discovery, 2013). This provides rationale for addition of CC-486 to standard cytotoxic chemotherapy rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in R/R DLBCL patients who are candidates for ASCT. Here we report the results of the phase 1 trial investigating this combination. Methods Eligibility included age ≥ 18, a diagnosis of R/R DLBCL, follicular lymphoma grade 3B, or DLBCL transformed from indolent lymphoma who were candidates for salvage chemotherapy and ASCT consolidation. The study was conducted via standard 3+3 dose escalation of CC-486 at 200 mg (dose level (DL) 1), 300 mg (DL 2), and 150 mg (DL -1). A Dose limiting toxicity (DLT) was defined as grade ≥ 3 adverse event (AE) as defined by CTCAE v5 leading to ≥ 7 day delay in cycle (C) 1 or 2 of R-ICE chemotherapy as well as grade ≥ 2 vomiting/diarrhea, persisting 48 hours despite best supportive care. Patients received up to three 21-day cycles. CC-486 was given as a 7 day lead in prior to C1 and then on days 8-21 of C1 and C2 with doses held based on cytopenias/AE's per protocol. G-CSF was mandated with each cycle. The primary objective was to determine the recommended phase 2 dose (RP2D) of CC-486 in combination with R-ICE chemotherapy. Secondary objectives included overall response rate (ORR)/complete remission (CR) per 2014 IWG criteria, peripheral blood stem cell (PBSC) collection feasibility, and proportion of patients receiving ASCT consolidation. Biomarker objectives included assessment of locus specific and global methylation patterns in ctDNA at set time points. Results The study has completed accrual with enrollment of nine patients from two institutions, all of which completed planned therapy. Eight (89%) of the patients had relapsed < 1 year from completion of frontline chemotherapy. Six patients were treated at the DL1 (200 mg), three patients were treated at DL2 (300 mg), and zero patients were treated at DL-1 (150 mg) with baseline characteristics described in table 1. The most common AE's (figure 1) included nausea (78%), thrombocytopenia (78%), anemia (56%), neutropenia (55.6%), fatigue (44%), and constipation (44%). Compared with DL1, DL2 was associated with greater incidence of grade ≥ 3 hematologic AE's/cycle including neutropenia (42% v 6%), anemia (29% v 11%), and thrombocytopenia (42% v 6%); higher incidence of neutropenic fever/cycle (28.5% vs 0%); more frequent delays in day 1 of C2 or C3 of R-ICE chemotherapy (80% vs 0%); and higher rate of CC-486 doses missed in C2 and C3 due to cytopenias (40% and 4%) respectively. One DLT occurred at DL2 in a patient with grade 5 neutropenic sepsis. A planned safety review of the three patients at DL2 established that no further patients would be enrolled at this dose. No DLTs were noted in the six patients enrolled at DL1. The ORR(CR) of the 8 evaluable patients was 50%(50%) and 4/9 patients proceeded to ASCT. With a median follow up of 9.5 months (range 1.2-25.1) the median PFS and OS were 4.0 months (95% CI 2.1-NR) and 10.7 months (95% CI 9.5-NR) respectively. All 4 patients successfully collected PBSCs (defined as ≥ 3.0 x 10^6 CD34 cells/kg) with median of 4.08 x 10^6 cells/kg. Biomarker studies are pending. Discussion Patients enrolled at DL1 (200 mg) tolerated this combination well with expected hematologic AE's, no episodes of neutropenic fever, few missed doses of CC-486, no delays in R-ICE chemotherapy, and no DLTs. The CR rate was 50% and a high proportion of patients (89%) enrolled after relapsing < 1 year from completion of frontline therapy. Biomarker studies may provide information regarding DLBCL populations likely to benefit from combinations of chemotherapy and epigenetic priming. Biomarker studies related to locus specific and global methylation patterns in ctDNA will be presented at the ASH conference. Figure 1 Figure 1. Disclosures Hess: BMS: Speakers Bureau; ADC Therapeutics: Consultancy. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Hill: Eli Lilly and Company: Ended employment in the past 24 months.

Interim Report of Phase II Study of Bortezomib Plus CHOP Every 2 Weeks in Patients with Disseminated Stage Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2688-2688
Author(s):  
Jeong Eun Kim ◽  
Dae Ho Lee ◽  
Soon Il Lee ◽  
Jae Hoon Lee ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Large B Cell Lymphoma ◽  
Number Of Patients ◽  
Grade 3 ◽  
Dose Dense ◽  
Large B Cell

Abstract Abstract 2688 Poster Board II-664 Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and dose-dense CHOP therapy has improved the treatment results of diffuse Large B-cell lymphoma (DLBCL) patients. Nevertheless, a substantial number of patients progress or relapse. Bortezomib is a proteasome inhibitor that is widely used in myeloma treatment and was recently approved for use in mantle cell lymphoma treatment. Its antitumor activity in DLBCL patients was reported in several studies, both as a single agent and in combination with chemotherapy. In this study, we tried to add bortezomib to dose-dense CHOP every 2 weeks to evaluate the complete response (CR) rate and safety of the treatment. Patients with previously untreated disseminated stage DLBCL and age 70 years or less were eligible. All patients received CHOP (Cyclophosphamide 750 mg/m2 IV, doxorubicin 50mg/m2 IV, vincristine 1.4mg/m2 IV on day 1, and prednisolone 100mg PO on days 1 to 5) and granulocyte colony-stimulating factor at a dose of 5μg/kg from days 4 to 13 every 2 weeks. Bortezomib, as recommended by the previous phase I trial, was administered at a dose of 1.6mg/m2 on days 1 and 4 of each cycle. Thirty-five patients were enrolled from March, 2007 to March 2009. Total 188 cycles of treatment were done. Twenty-six patients finished planned 6 cycles of treatment, while 9 patients could not continue all planned treatment due to treatment related toxicities and one patient experienced disease progression after 5 cycles of treatment. Twenty-four patients had a CR (92.4%), one patient had a partial response (3.8%), and one patient had a progressive disease (3.8%). Grade 3 hematologic toxicity episodes occurred including 20 anemia (10.7%), 4 neutropenia (2.1%), and 6 thrombocytopenia (3.2%). Grade 4 hematologic toxicity episodes comprised 2 anemia (1.6%), 11 neutropenia (5.9%), and 6 thrombocytopenia (3.2%). One patient died of severe infection with neutropenia. Among 35 patients, grade 3 non-hematologic toxicity occurred with fatigue (11.4%), nausea (2.9%), vomiting (5.7%), diarrhea (8.6%), abdominal pain (8.6%), and sensory neuropathy (20.0%). One patient experienced grade 4 constipation. This interim analysis shows that bortezomib plus dose-dense CHOP every two weeks showed promising activity in disseminated DLBCL patients as the first-line treatment with acceptable toxicity. Further accrual will be continued till the planned patient enrollment goal for phase II results. Disclosures: No relevant conflicts of interest to declare.

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