scholarly journals High Grade B Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements Treated with DA-EPOCH-R Induction and Nivolumab Consolidation Treatment: Interim Results of the HOVON-152 Phase II Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1414-1414
Author(s):  
A. Vera de Jonge ◽  
Erik D. van Werkhoven ◽  
Marcel Nijland ◽  
Koen de Heer ◽  
Marjolein W.M. Van Der Poel ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
Immune Surveillance ◽  
B Cell Lymphoma ◽  
Induction Treatment ◽  
Grade 3 ◽  
Minimal Residual

Abstract Introduction Patients with high grade B cell lymphoma that harbor a MYC rearrangement with concomitant BCL2 and/or BCL6 rearrangements (double hit and triple hit (HGBL-DH/TH)) face a poor prognosis upon standard treatment with R-CHOP [Rosenwald, JCO 2019]. DA-EPOCH-R might yield higher complete metabolic remission (CMR) rates and longer disease free survival (DFS) as compared to R-CHOP, but improvement of overall survival (OS) has not been demonstrated [Dunleavy, Lancet Haematol 2018]. Tumors with MYC overexpression may be susceptible for immune checkpoint inhibition (CI) [Casey, Science 2016], providing a rationale for CI after reaching CMR to improve tumor immune surveillance for minimal residual disease (MRD) positive disease. Here, we present data of the planned interim analysis of 33/97 patients included in the HOVON-152 trial (NCT03620578). Methods HOVON-152 is a prospective, multi-center, single arm phase II trial. Inclusion criteria are newly diagnosed HGBL-DH/TH; age ≥ 18 year; WHO performance status 0-3; Ann Arbor stage II-IV. During the screening period for rearrangements patients receive 1 cycle of R-CHOP followed by 5 cycles of DA-EPOCH-R induction treatment. All patients receive intrathecal prophylaxis. All diagnostic lymphoma samples are centrally reviewed. PET-CT scans are performed at diagnosis, midterm and end-of-induction. Patients in CMR after induction treatment (Deauville 1-3 or a negative lymphoma biopsy in case of Deauville 4) proceed with Nivolumab consolidation (480 mg iv every 4 weeks) for one year. The primary objective is to improve 12 months DFS with Nivolumab consolidation from 70% to 85% in patients in CMR after induction treatment. Secondary objectives include evaluation of CMR rates, OS and safety. Exploratory side studies investigate blood-based biomarkers for response prediction by immune profiling using multicolor flow cytometry after 1 cycle of R-CHOP and molecular circulating tumor DNA (ctDNA) analyses using ClonoSEQ (Adaptive Biotechnologies, Seattle) after 1 cycle of R-CHOP and at midterm. Results From August 2018 to June 2021, 69 of planned 97 patients have been enrolled. Baseline characteristics of the first 33 patients included in the interim analysis are shown in Table 1. Dose adjustments of EPOCH (according to protocol) resulted in 48% of patients receiving dose level ≤1 and 52% dose level ≥ 2 at the last cycle. After induction, 20/33 patients (61%; 95% CI 42%-77%) reached CMR. 11/33 patients (33%) did not reach CMR and 2/33 (6%) patients went off protocol (due to progression). During DA-EPOCH-R, one patient (3%) experienced grade 5 AE (sepsis), 9 patients (27%) experienced a grade 4 AE, and 9 (27%) patients grade 3. Neurotoxicity led to dose adjustments or discontinuation of vincristine in 52% of the patients. In an amendment the vincristine dose was capped at 2 mg/cycle. Twenty patients received 6 cycles of Nivolumab consolidation. One patient had a grade 4 AE (neutropenia); 2 patients had a grade 3 AE (one lung infection and one colitis (reason for going off protocol)). The Data Safety Monitoring Board recommended to continue the trial. Exploratory biomarker analyses show that patients achieving CMR after DA-EPOCH-R (data available for 19/20 patients) have higher percentages of T cells (p=0.04) after 1 cycle of R-CHOP than patients that do not achieve CMR (data available for 12/13 patients). ctDNA analysis was possible in 16/28 patients (in 12/28 patients no clone could be detected for monitoring). 10/16 patients achieved CMR, of which 9/10 were negative for minimal residual disease (MRD) at midterm. The patient that was MRD positive at midterm relapsed shortly after CMR. 4/5 patients that did not achieve CMR were MRD positive at midterm. Conclusions Interim analysis of the HOVON-152 trial demonstrates that 61% (95% CI 42%-77%) of the patients with HGBL-DH/TH achieve CMR after induction with DA-EPOCH-R. Toxicity of DA-EPOCH-R consists mainly of neurotoxicity leading to a protocol amendment (dose cap of vincristine). Nivolumab consolidation is safe with only one patient going off protocol due to colitis. Biomarkers for CMR after induction with DA-EPOCH-R point out to ctDNA-based MRD negativity at midterm and to higher T percentages after 1 cycle of R-CHOP, supporting the hypothesis of contributive immune surveillance for response in patients with HGBL-DH/TH. The trial is ongoing. Figure 1 Figure 1. Disclosures Nijland: Roche: Research Funding; Nordic Nanovector: Research Funding; Takeda: Research Funding. Van Der Poel: Roche, Janssen, Abbvie: Honoraria. Klerk: Van Lanschot Kempen: Other: I have an investment porfolio which is managed by Van Lanschot Kempen as a portfolio manager (vermogensbeheerder). Van Lanschot Kempen invests on my behalf, and takes investment decisions on a discretionary basis. I am not involved in the investment decis. Pegtel: Exbiome BV: Current holder of individual stocks in a privately-held company; Takeda: Other: Travel compensation. Mutis: Novartis: Research Funding; ONK Therapeutics: Research Funding; Janssen: Honoraria; Takeda: Research Funding; Genmab: Research Funding. Zijlstra: Takeda: Research Funding. Kersten: BMS/Celgene: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding; Milteny Biotech: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy. Chamuleau: Gilead: Research Funding; Genmab: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Nivolumab as immune checkpoint inhibitor (inhibiting PD-1) in consolidation phase for the treatment of DH/TH-HGBL patients.

scholarly journals Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Final Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Mats Jerkeman ◽  
Martin Hutchings ◽  
Riikka Räty ◽  
Karin Fahl Wader ◽  
Anna Laurell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Molecular Remission ◽  
Mantle Cell ◽  
Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 >30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 >30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

Detection of p57KIP2 Gene Methylation Is Useful Marker for Minimal Residual Disease in Diffuse Large B Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4415-4415
Author(s):  
Kazumi Hagiwara ◽  
Hirokazu Nagai ◽  
Toshiya Yokozawa ◽  
CHiaki Kato ◽  
Motohiro Hamaguchi ◽  
...  
Keyword(s):  
B Cell ◽  
Promoter Region ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Methylation ◽  
Methylated Dna ◽  
Large B Cell Lymphoma ◽  
Tumor Dna ◽  
Minimal Residual

Abstract Background: The t(14;18)(q32;q21) translocation, which causes a BCL2/IgH gene rearrangement, is a characteristic chromosomal abnormality found mainly in B cell lymphomas, and its detection and quantification is useful for monitoring of minimal residual disease (MRD) in follicular lymphoma (FL). However, in diffuse large B cell lymphoma (DLBCL), the frequency of this rearrangement is relatively low. We revealed that the promoter region of p57KIP2 gene is frequently methylated in B cell lymphomas. Aberrant DNA methylation in the promoter regions of genes is known as the major mechanism for inactivation of tumor suppressor genes, so the detection of the methylation is expected to be used as a promising tumor specific marker. Therefore, we investigated the possibility of p57KIP2 gene promoter methylation as a biomarker for MRD detection in B cell lymphoma, especially in DLBCL. Methods: We analyzed lymphoid cell line DNA, tumor DNA from 64 patients with DLBCL, and 4 patients with FL. The bisulfite-modified DNA was used as a template for conventional methylation-specific PCR (MSP) and real-time quantitative MSP (Q-MSP). Results: In clinical samples (tumor DNA), p57KIP2 gene methylation was detected by Q-MSP in 73% (47/64) DLBCL, and 50% (2/4) FL. Using cell line DNA, which was fully methylated in promoter region of p57KIP2 gene, we determined the detection limit of Q-MSP assay. The methylated DNA could be detected in the presence of a 1000-fold excess of unmethylated DNA by Q-MSP. We could validate the level of methylated DNA in each sample by Q-MSP evaluating the p57KIP2/b-actin ratio. The sensitivity to detect MRD in bone marrow by this method was found to be equivalent to real time quantitative PCR for BCL2/IgH major breakpoint region. Conclusion: The methylation of p57KIP2 gene is detected at high frequency in DLBCL. This biomarker is thought to be conventional and widely applicable to the detection of MRD in DLBCL.

A Phase II Trial of Rituximab-CHOP Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (90Y-IT) for Previously Untreated Elderly Diffuse Large B-Cell Lymphoma (DLBCL) Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2720-2720
Author(s):  
Pier Luigi Zinzani ◽  
Mariapaola Fina ◽  
Monica Tani ◽  
Vittorio Stefoni ◽  
Letizia Gandolfi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chop Chemotherapy ◽  
Ibritumomab Tiuxetan ◽  
Off Label ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Abstract 2720 Poster Board II-696 Introduction: In 2008 we published a phase II trial abuot the combination of 6 cycles of CHOP plus 90Y-IT for previously untreated elderly patients with DLBCL. The CCR was 95% with OS at 2 years of 95% and PFS at 2 years of 75%. The results of this study support a further evaluation of 90Y-IT in combination of chemotherapy. We conducted a prospective, single-arm, non-randomized, phase II trial with CHOP plus Rituximab followed by 90Y-IT reducing the number of CHOP cycles from 6 to 4 but introducing Rituximab. The rational is to utilize all the therapeutic approaches (chemotherapy, immunotherapy and radioimunotherapy) reducing conventional chemotherapy and probably related toxicity. Patients and Methods: Patient elegibility was represented by: patients older than 60 years with biopsy proven, untreated, bidimensionally mesurable stage II, III or IV DLBCL. Expression the CD-20 antigen; WHO performance status of 0 to 2. patients were treated with standard CHOP chemotherapy plus Rituximab every 21 days for 4 cycles. Patients were restaged 4 to 6 weeks after completion of 4 cycles of R-CHOP chemotherapy. Patients achieving CR, PR or SD after chemotherapy were eligible for consolidation with 90Y-IT provided the granulocyte count was greater than 1500/microl, the platelet count exceded 100.000/microl and the bone marrow examination at the completion of chemotherapy demostrated no more than 25% involvement with lymphoma. All patients were to receive a single dose of 90Y-IT 14.8 MBq/kg (0.4 mCi/kg). Fifty-five patients have been enrolled: 26 were male and 29 female; the median age was 70 years (range 60–83); 17 were stage II, 38 were stage III-IV. Results: Fifty-one patients had completed the R-CHOP treatment and the overall response rate was 94.1% including 30 (58.8%) of patients in CR and 17 (35.3%) in PR. Treatment was well tolerated; grade 3–4 AEs are comparable with previous experience and the most common grade 3–4 AEs was neutropenia. At this time 47 patients had just received 90Y-IT and 45 are evaluable. In particular, 9/17 (52.9%) patients converted from PR to CR after treatment with 90Y-IT. Conclusions: These preliminary data indicate that radioimmunotherapy appears highly effective and feasible as “consolidation” after 4 cycles of immunochemotherapy in elderly DLBCL patients, improving quality of response without any cumulative toxicity. Disclosures: Off Label Use: The drug Yttrium 90 (90Y) Ibritumomab Tiuxetan (90Y-IT) (Zevalin) is off-label for Diffuse Large B-Cell Lymphoma (DLBCL).

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.

A Phase II Trial of Ofatumumab In Subjects with Waldenstrom's Macroglobulinemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1795-1795 ◽  
Author(s):  
Richard R. Furman ◽  
Herbert Eradat ◽  
Julie C. Switzky ◽  
Suzanne R. Hayman ◽  
Craig C. Hofmeister ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Rapid Rise ◽  
Grade 3

Abstract Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM <4 g/dL and 1 of 5 pts with IgM >4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had >5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.

Integration of Rituximab and Liposomal Doxorubicin (DOXIL®) Into CODOX-M/IVAC for HIV-Negative and HIV+ Adults with Untreated Burkitt's Lymphoma (BL): Results of a Prospective Multicenter Phase II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2669-2669
Author(s):  
Andrew M. Evens ◽  
Kenneth R. Carson ◽  
Chadi Nabhan ◽  
Borko Jovanovic ◽  
Paul Barr ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Liposomal Doxorubicin ◽  
Cell Lymphoma ◽  
Survival Rates ◽  
B Cell Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Grade 3 ◽  
Hiv Negative

Abstract Abstract 2669 Background: The survival of adult BL has improved with intensification of multi-agent chemotherapy, although 2-year survival rates remain <65–70%. Efforts to improve survival, as well as decrease treatment-related toxicities are needed. Further, there are no prospective clinical studies to date that have examined the addition of rituximab into the CODOX-M/IVAC regimen. Methods: Eligible patients for this investigator-initiated, 5-site phase II clinical trial included: newly diagnosed BL and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and BL (according to WHO 2008 definition) regardless of HIV status. Eligibility for HIV+ patients included: no evidence of multi-drug resistant HIV infection or concurrent AIDS defining illness and CD4 count >350/mcL. Patients were classified as low risk (LR) if they had all of the following factors present: 1) normal LDH, 2) stage I/II disease, 3) ECOG performance status (PS) <2, and 4) no mass >10 cm. All other patients were “high risk” (HR). LR patients received 3 consecutive cycles of CODOX-M, while HR patients received 4 alternating cycles of CODOX-M and IVAC. For CODOX-M, methotrexate 3.0 gram/m2 i.v. was used. Further, liposomal doxorubicin (40 mg/m2) was utilized in lieu of doxorubicin (day 1 of all CODOX-M cycles), while intravenous rituximab (500 mg/m2) was added to days 0 and day 8 of each CODOX-M cycle and days 0 and 6 of IVAC cycles. In addition, as a corollary analysis, frequent assessment of ejection fraction (EF) was performed in all patients (baseline, s/p 2 cycles, and 4 weeks after completion of therapy). Results: Twenty-five patients (22 male and 3 female) enrolled from March 2007 through April 2011. The median age was 44 years (range, 23–70 years). Furthermore, 5 (20%) patients were >60 years. All patients had classical BL, while 1 patient had concomitant BCL-2 expression. There were 20 HR and 5 LR patients; 3 of the HR and 1 LR patient were HIV+, while the remaining patients were HIV-negative. Median PS at study entry was 1, while PS=2 in 6 (24%) patients. Further, 3 (15%) HR patients had + central nervous system disease (2 parenchymal, 1 leptomeningeal). Additionally, 7 (35%) HR patients had bulky disease >10 cm (2 (10%) with dominant mass >20cm), 8 (40%) of all patients had bone marrow involvement, and 15 (75%) had an elevated LDH. 24 of 25 patients were evaluable for toxicity and response/survival. Therapy was completed at a median of 13.5 weeks (range, 11–20) for HR patients and a median of 10 weeks for LR (range, 9–12). With respect to toxicity, myelosuppression was overall comparable (58% of patients experienced grade 4 thrombocytopenia with only 4% grade 4 anemia) to prior CODOX-M/IVAC data, while the incidence of mucositis also appeared similar to prior reports (38% grade 3, 13% grade 4). Other clinically relevant grade 3 toxicities included neutropenic fever (33%), transaminitis (33%), diarrhea (8%), elevated creatinine (8%), and seizure (4%). Notably, there was no grade 3 or 4 neuropathy. After 2 cycles of therapy, two grade 2 and two grade 3 cardiac events were noted (all depressed EF, no clinical evidence of congestive heart failure). The two grade 3 events occurred in a 70-year-old and 69-year-old man, both with HR disease, and the latter with history of myocardial infarction. Among all patients, the median change in EF at baseline vs study end was: −2% (range, −22% to +11%). In terms of outcomes, the response rate after 2 cycles of therapy was 100% with a 67% complete remission (CR) rate. At a median follow-up of 24 months, the 2-year PFS and OS rates for all patients were 86% and 86%, respectively (LR 2-year PFS and OS both 100%; and HR 2-year PFS and OS both 82%). Furthermore, the 2-year PFS and OS rates for HR, HIV-negative patients were 91% and 91%, respectively (see Figure 1), while the disease-specific survival (DSS) for this subgroup of patients was 100%. Of the 3 deaths on trial, 2 were due to progressive disease in HIV+ HR patients, while the 3rd was a 71 year-old HIV-negative HR subject who died in CR at 14 months from unknown causes. Conclusions: Altogether, the integration of rituximab and liposomal doxorubicin into CODOX-M/IVAC for adult BL was feasible and associated with similar tolerability compared with prior reports. Additionally, this regimen was associated with excellent survival rates, especially for HIV-negative BL. Disclosures: Evens: Ortho-Biotec: Research Funding. Off Label Use: Doxil in the treatment of Burkitt's lymphoma. Carson:Genentech: Speakers Bureau. Nabhan:Genentech: Research Funding, Speakers Bureau. Gregory:Genentech: Advisory Board. Gordon:Genentech: Consultancy, Speakers Bureau.

A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 59-59 ◽  
Author(s):  
Ranjana Advani ◽  
Daniel Lebovic ◽  
Mark Brunvand ◽  
Andy I. Chen ◽  
Andre Goy ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Antibody Drug Conjugate ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
Dose Levels ◽  
Anti Tumor Activity

Abstract Abstract 59 Introduction: CD22 is a lineage marker expressed in most B-cell lymphomas. DCDT2980S is an ADC consisting of an anti-CD22 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a potent microtubule disrupting agent linked to the antibody via a protease-cleavable peptide linker. DCDT2980S exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma and is being evaluated in a Phase I study to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity in patients (pts) with relapsed/refractory B-cell NHL. Methods: Pts receive DCDT2980S intravenously every 21 days at dose levels 0.1 to 3.2 mg/kg until disease progression or unacceptable toxicity. Intrapatient dose escalation based on tolerability at higher doses is permitted. Following determination of the recommended Phase II dose (RP2D) based on protocol-defined dose-limiting toxicities (DLTs) occurring within 21 days of dosing, additional pts with indolent and aggressive B-cell NHL are being enrolled to further evaluate safety and efficacy based on Cheson response criteria. Here we report the RP2D and preliminary safety and efficacy results. Results: To date, 35 pts (57% male), median age 66 years (range 30–85) have been enrolled: diffuse large B-cell lymphoma (DLBCL, n=18), follicular lymphoma (FL, n=11), transformed FL (n=4), and small lymphocytic lymphoma (n=2). Enrolled patients were heavily pre-treated: 26 pts had received ≥ 3 prior regimens, all pts had received prior rituximab, and 7 pts received prior high-dose therapy followed autologous or allogenic stem cell transplantation. Overall, pts received a median of 4 doses (range 1–25) of DCDT2980S in 7 dose-escalation cohorts, and 2 expansion cohorts at the RP2D. All 3 pts treated with DCDT2980S at 3.2 mg/kg developed Grade 4 neutropenia following the first dose, one of which constituted a DLT. No DLTs were reported in the 6 pts treated at 2.4 mg/kg, which is the RP2D. Across all dose levels, the most common treatment-emergent adverse events (AE) in ≥ 20% of pts were diarrhea (34%), fatigue (34%), nausea (31%), neutropenia (26%), decreased appetite (23%), vomiting (23%), and peripheral edema (20%). Treatment-emergent Grade ≥ 3 AEs were reported in 9 (27%) pts including 5 out of 9 pts who were treated at the RP2D of 2.4 mg/kg. Overall, neutropenia (24%) was the only Grade ≥ 3 AE in ≥ 10% of pts (24%) and was the only Grade ≥ 3 AE reported in > 1 pt (n=2) treated at the RP2D. Eight (26%) pts across all dose levels experienced a serious AE (SAE) of which one Grade 3 dehydration in a pt treated at 3.2 mg/kg was attributed to DCDT2980S. Treatment discontinuation due to AEs occurred in 3 pts: Grade 3 neutropenia (n=1) and Grade 3 peripheral sensory neuropathy (n=2). No deaths were reported within 30 days of the last dose of DCDT2980S. Assessment of Cycle 1 PK after the first dose of DCDT2980S indicated that the exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE increased with dose. The clearance estimates of both acMMAE and total antibody were similar across doses from 1.0–3.2 mg/kg. The volume of distribution estimates for acMMAE and total antibody approximated plasma volume and did not change with dose and suggest dose-proportional increase of acMMAE and total antibody exposures for doses of 1.0–3.2 mg/kg. Early evidence of anti-tumor activity was observed. At the RP2D of 2.4 mg/kg, 2 of 3 pts with DLBCL had > 75% reduction in tumor sum of perpendicular dimensions (SPD) and negative PET scans; 1 partial response was noted in a pt with FL treated at 1.8 mg/kg. These 3 pts continue on study, each having received at least 8 cycles of study treatment. Two additional pts with DLBCL receiving 0.5 mg/kg and 3.2–2.4 mg/kg had > 50% reduction in tumor SPD and discontinued study treatment after 8 and 6 cycles, respectively, to undergo stem cell transplant. Conclusions: In this early experience, DCDT2980S is well tolerated, has a favorable safety profile and has evidence of anti-tumor activity in in a heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDT2980S in B-cell malignancies. Disclosures: Advani: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Lebovic:Genentech: Speakers Bureau. Brunvand:Genentech: Speakers Bureau. Chen:Genentech: Research Funding. Chang:Genentech: Research Funding. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.

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.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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