A Placebo-Controlled Phase III Trial of Patient-Specific Immunotherapy with Mitumprotimut-T (ID-KLH) and GM-CSF Following Rituximab in Patients with CD20+ Follicular Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 236-236 ◽  
Author(s):  
Arnold S. Freedman ◽  
Sattva Neelapu ◽  
Craig R Nichols ◽  
Michael Robertson ◽  
Benjamin Djulbegovic ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Study Drug ◽  
Low Risk ◽  
Phase Iii ◽  
Patient Specific ◽  
Gm Csf ◽  
Blinded Study ◽  
Combined Data

Abstract Background: Early studies demonstrated that patients with indolent B-cell lymphomas have the capacity to mount anti-idiotype (Id) B-cell immune responses following active immunization with patient-specific Id proteins. Durable clinical remissions were observed in patients undergoing vaccination in chemotherapy-induced first remissions. This study evaluated the efficacy and safety of active immunotherapy with mitumprotimut-T (Id- KLH, SPECIFID™, Favrille, San Diego, CA) and GM-CSF (sargramostim, LEUKINE®) in patients with CD20+ follicular lymphoma. Mitumprotimut-T is a patient-specific therapeutic vaccine composed of the Id protein produced by proprietary recombinant technology from the malignant lymphoma biopsy specimen and conjugated to KLH, a potent immunogenic protein. Patients and Methods: Patients with treatment-naïve (T-N) or relapsed/refractory (R/R) WHO Grade 1–3 CD20+ follicular lymphoma received rituximab infusions at 375 mg/m2 weekly for 4 weeks, and those achieving a complete response (CR), partial response (PR), or stable disease (SD) at Week 11 were randomized to mitumprotimut-T (1 mg subcutaneously on Day 1) and GM-CSF (250 mcg subcutaneously daily on Days 1–4) or placebo and GM-CSF. Randomization was stratified by prior therapy (T-N vs. R/R) and response to rituximab (CR/PR vs. SD). Patients were immunized monthly × 6, every other month × 6, and then every 3 months until disease progression (PD). The primary efficacy endpoint was time-to-progression (TTP), which was assessed by an independent central radiology review. Results: 349 patients were randomized; their median age was 54 years (range, 21–86 years), 79% were T-N, 85% had an ECOG performance status of 0, and 86% had Stage III-IV disease. Thirty-four randomized patients (10%) did not receive blinded study drug: 28 because mitumprotimut-T could not be produced, 5 due to PD prior to start of blinded study drug, and 1 who withdrew for personal reasons. The mean number of courses was 10.6 (range, 1–21), and was comparable in the 2 groups. After a median follow-up of 40 months, 215 patients (62%) had progressed, 113 who were randomized to mitumprotimut-T and 102 who had received placebo. Median TTP from randomization was 9.0 months for patients randomized to mitumprotimut-T/GM-CSF and 12.6 months for placebo/GM-CSF (hazard ratio = 1.384, p = 0.019). Significantly more patients with high-risk FLIPI and fewer patients with low-risk FLIPI were unexpectedly randomized to mitumprotimut-T (p = 0.0042). After adjusting for FLIPI risk group in a Cox regression model, there was no significant difference in TTP between the two arms in the intent-to-treat population (p = 0.128), in patients with high risk FLIPI (p = 0.891), in patients with intermediate/low risk FLIPI (p = 0.143), in the 315 patients treated with blinded study drug, or in any of the patient subsets based on stratification factors. Comparisons of TTP between the two treatment arms using the investigators assessment of response were consistent with those obtained from central radiology review. There were no significant differences between the two treatment arms in objective responses (CR+PR) to rituximab at Week 11 (57.6%, combined data from both arms) or in objective responses any time on study (64.7%, combined data). Treatment was usually well tolerated, with 76% of adverse events graded as mild or moderate. The most common side effect was local injection site reaction, reported in 94% of patients. Conclusion: This Phase 3 trial showed no improvement in TTP with mitumprotimut-T and GM-CSF following rituximab in CD20+ follicular lymphoma.

Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: results of a randomized phase III trial.

1998 ◽  
Vol 16 (9) ◽  
pp. 2930-2936 ◽  
Author(s):  
A Ravaud ◽  
C Chevreau ◽  
L Cany ◽  
P Houyau ◽  
N Dohollou ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Low Risk ◽  
Phase Iii ◽  
Colony Stimulating Factor ◽  
Phase Iii Trial ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE A randomized unblinded phase III trial was designed to determine the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to accelerate recovery from febrile neutropenia induced by chemotherapy. PATIENTS AND METHODS A total of 68 patients with febrile neutropenia following chemotherapy defined as axillary temperature greater than 38 degrees C and absolute neutrophil count (ANC) less than 1 x 10(9)/L were included. After stratification for high- and low-risk chemotherapy to induce febrile neutropenia, treatment was randomized between GM-CSF at 5 microg/kg/d or control, both being associated with antibiotics. RESULTS GM-CSF significantly reduced the median duration of neutropenia from 6 to 3 days for ANC less than 1 x 10(9)/L(P < .001) and from 4 to 3 days for ANC less than 0.5 x 10(9)/L (P=.024), days of hospitalization required for febrile neutropenia, and duration of antibiotics during hospitalization. The greatest benefit with GM-CSF appeared for patients who had received low-risk chemotherapy, for which the median duration of ANC less than 1 x 10(9)/L was reduced from 7 to 2.5 days (P < .001) and from 4 to 2 days for ANC less than 0.5 x 10(9)/L (P=.0011), the duration of hospitalization during the study from 7 to 4 days (P=.003), and the duration on antibiotics during hospitalization from 7 to 3.5 days (P < .001). A multivariate analysis, using Cox regression, showed that variables predictive for recovery from neutropenia were GM-CSF (P=.0010) and time interval between the first day of chemotherapy and randomization (P=.030). There was no benefit for GM-CSF when high-risk chemotherapy was considered. CONCLUSION GM-CSF significantly shortened duration of neutropenia, duration of neutropenic fever-related hospitalization, and duration on antibiotics during hospitalization when febrile neutropenia occurred after low-risk chemotherapy, but not high-risk chemotherapy.

Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results

2009 ◽  
Vol 27 (18_suppl) ◽  
pp. 2-2 ◽  
Author(s):  
S. J. Schuster ◽  
S. S. Neelapu ◽  
B. L. Gause ◽  
F. M. Muggia ◽  
J. P. Gockerman ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Disease Free Survival ◽  
Vaccine Dose ◽  
Complete Response ◽  
Phase Iii ◽  
Patient Specific ◽  
Autologous Tumor ◽  
Gm Csf

2 Background: In previous trials, tumor-specific purified idiotype (Id) protein conjugated to keyhole limpet hemocyanin (KLH) administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induced follicular lymphoma (FL)-specific immune responses and molecular remissions (Nat Med. 1999;5:1171–7). Methods: We conducted a prospective randomized double-blind placebo-controlled multicenter phase III study of patient-specific autologous tumor-derived Id vaccine in advanced stage previously untreated FL patients (pts) with a lymph node adequate for vaccine production (≥ 2cm). Pts achieving complete response (CR) or complete response unconfirmed (CRu) after chemotherapy (PACE: prednisone, doxorubicin, cyclophosphamide, etoposide) were stratified by International Prognostic Index risk group and randomized 2:1 to receive either vaccination with Id-KLH/GM-CSF or control (KLH/GM-CSF). The primary endpoint was disease free survival. Results: 234 pts were enrolled; 177 (76%) achieved CR/CRu and were randomized. Of 177 randomized pts, 117 maintained CR/CRu ≥ 6 mo per protocol requirement and then received at least one dose of vaccine, 55 relapsed before vaccination, 4 were vaccine manufacturing failures, and 1 violated protocol. Pts who received ≥ one vaccine dose constituted the modified intent-to-treat population for determination of efficacy. 76 pts received Id-KLH/GM-CSF and 41 pts received the control (KHL/GM-CSF). No serious adverse events were attributed to Id vaccination. At a median follow-up of 56.6 mo (range 12.6 –89.3 mo), median time to relapse after randomization for the Id-KLH/GM-CSF arm was 44.2 mo, versus 30.6 mo for the control arm (p = 0.045; HR = 1.6). Conclusions: Id vaccination after a chemotherapy-induced remission of ≥ 6 mo prolongs remission duration in pts with FL. Compared to other phase III Id vaccine trials, the positive outcome of this study may reflect application of Id vaccine in pts in CR/CRu or use of hybridomas to produce Id. Genomic and immune response analyses are planned on residual autologous tumor and blood samples. Additional studies of this patient-specific vaccine in FL pts pretreated with anti-CD20 antibody-containing chemotherapy are indicated. [Table: see text]

Long-Term Follow-Up of Patients Treated in a Phase 2 Trial with MyVax® Personalized Immunotherapy (Recombinant Id-KLH with GM-CSF) after Chemotherapy as Initial Treatment for Follicular Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2438-2438 ◽  
Author(s):  
John M. Timmerman ◽  
Julie Vose ◽  
Ronald Levy ◽  
Martha Mayo ◽  
Dan Denney
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Patient Specific ◽  
Treatment Schedule ◽  
Phase 2 ◽  
Variable Regions ◽  
Gm Csf ◽  
Immunization Series

Abstract Background: The tumor-specific variable regions of the clonal immunoglobulin (idiotype or Id) expressed by malignant B cell NHL can be used as a target for active immunotherapy. MyVax® Personalized Immunotherapy is a patient-specific, recombinant Id protein conjugated to Keyhole Limpet Hemocyanin (Id-KLH) and administered with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). Several Phase 2 clinical trials have been conducted to determine the immunogenicity of MyVax® Personalized Immunotherapy. Patients and Methods: The patients all had previously untreated follicular lymphoma and achieved at least a partial response to either CVP chemotherapy (16 patients) or CVP + CHOP chemotherapy (5 patients) to be eligible to receive 5 series of immunizations with MyVax® Personalized Immunotherapy. Each immunization series consisted of MyVax® Personalized Immunotherapy administered SQ on Day 1 and GM-CSF alone on Days 2–4. The immunizations were administered over 24 weeks. The first 4 immunization series were administered every 4 weeks. The 5th immunization series was administered 12 weeks after the 4th immunization. Results: There were a total of 21 evaluable patients in the study. Both cellular and humoral immune anti-idiotype responses (IRs) were elicited using this treatment schedule. Thirteen of the 21 patients (62%) mounted an anti-idiotype immune response. Ten of the 21 patients mounted a humoral anti-idiotype response while 7 of 16 patients evaluated mounted a cellular anti-idiotype response. Immunizations with MyVax® Personalized Immunotherapy appear to be safe and well tolerated. Adverse events reported in this trial were mostly mild to moderate and transient in nature. Follicular Lymphoma International Prognostic Index (FLIPI) scores for these patients indicate that most of the patients were in the intermediate or high-risk categories. The median follow-up is over 5.5 years in this trial. The median time to disease progression was 37.7 months measured from the end of chemotherapy. Ten of the 21 patients in this trial remain progression free between 47 months and 71 months post chemotherapy as of their last follow-up. Four of the patients that remain in remission are in the high risk category by FLIPI score. Conclusions and Discussion: These results suggest that patients with a poorer prognosis according to their FLIPI score can achieve significant remissions following treatment with MyVax® Personalized Immunotherapy. MyVax® Personalized Immunotherapy is currently in a late-stage Phase 3 trial.

scholarly journals Vaccination With Patient-Specific Tumor-Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma

2011 ◽  
Vol 29 (20) ◽  
pp. 2787-2794 ◽  
Author(s):  
Stephen J. Schuster ◽  
Sattva S. Neelapu ◽  
Barry L. Gause ◽  
John E. Janik ◽  
Franco M. Muggia ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Disease Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Patient Specific ◽  
Autologous Tumor ◽  
Double Blind ◽  
Free Survival ◽  
Gm Csf ◽  
Disease Free

Purpose Vaccination with hybridoma-derived autologous tumor immunoglobulin (Ig) idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) and administered with granulocyte-monocyte colony-stimulating factor (GM-CSF) induces follicular lymphoma (FL) –specific immune responses. To determine the clinical benefit of this vaccine, we conducted a double-blind multicenter controlled phase III trial. Patients and Methods Treatment-naive patients with advanced stage FL achieving complete response (CR) or CR unconfirmed (CRu) after chemotherapy were randomly assigned two to one to receive either Id vaccine (Id-KLH + GM-CSF) or control (KLH + GM-CSF). Primary efficacy end points were disease-free survival (DFS) for all randomly assigned patients and DFS for randomly assigned patients receiving at least one dose of Id vaccine or control. Results Of 234 patients enrolled, 177 (81%) achieved CR/CRu after chemotherapy and were randomly assigned. For 177 randomly assigned patients, including 60 patients not vaccinated because of relapse (n = 55) or other reasons (n = 5), median DFS between Id-vaccine and control arms was 23.0 versus 20.6 months, respectively (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.16; P = .256). For 117 patients who received Id vaccine (n = 76) or control (n = 41), median DFS after randomization was 44.2 months for Id-vaccine arm versus 30.6 months for control arm (HR, 0.62; 95% CI, 0.39 to 0.99; P = .047) at median follow-up of 56.6 months (range, 12.6 to 89.3 months). In an unplanned subgroup analysis, median DFS was significantly prolonged for patients receiving IgM-Id (52.9 v 28.7 months; P = .001) but not IgG-Id vaccine (35.1 v 32.4 months; P = .807) compared with isotype-matched control-treated patients. Conclusion Vaccination with patient-specific hybridoma-derived Id vaccine after chemotherapy-induced CR/CRu may prolong DFS in patients with FL. Vaccine isotype may affect clinical outcome and explain differing results between this and other controlled Id-vaccine trials.

scholarly journals A Prognostic Model Incorporating Tumor Lesion Morphology and Texture Features Identifies High-Risk Patient Subpopulations in De Novo DLBCL and FL

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Xiao Li ◽  
Skander Jemaa ◽  
Richard AD Carano ◽  
Thomas Bengtsson ◽  
Joseph N Paulson ◽  
...  
Keyword(s):  
High Risk ◽  
Fdg Pet ◽  
De Novo ◽  
Risk Group ◽  
Low Risk ◽  
Phase Iii ◽  
Publicly Traded ◽  
Prognostic Performance ◽  
Pet Scans ◽  
Worse Prognosis

Background: Despite effective first-line (1L) treatment options for patients with NHL almost 40% of patients with diffuse large B cell lymphoma (DLBCL) will have a poor response or disease progression after 1L treatment. In follicular lymphoma (FL) 15-20% of patients experience early relapse, and almost 8% may develop transformation to more aggressive forms of the disease (such as DLBCL) after 1L treatment. More accurate identification of patients at high-risk for a poor prognosis with the standard of care could lead to improved outcomes. Although the International Prognostic Index (IPI) and its FL extension (FLIPI) are often used to stratify patients by prognosis, they have relatively modest sensitivity and specificity for predicting individualized risk. Radiomics is a promising approach to improve upon existing prognostic models because it provides a comprehensive quantification of tumor lesion morphology and texture derived from FDG-PET scans and may provide new and important information about disease biology and progression risk on an individual level. Methods: A collection of 107 radiomics features [pyradiomics v2.20] that describe shape, size or volume and texture of tumor lesions, including complex features that are believed to reflect the underlying biological tumor phenotype and microenvironment, were derived for n=1093 de novo DLBCL patients with available baseline FDG-PET scans from the Phase III GOYA study (NCT01287741) evaluating obinutuzumab plus CHOP chemotherapy (G-CHOP) versus rituximab plus CHOP chemotherapy (R-CHOP) (Vitolo, et al. J Clin Oncol 2017). The same set of features were also extracted from n=451 de novo FL patients with available baseline FDG-PET scans from the Phase III GALLIUM study (NCT01332968) comparing obinutuzumab plus chemotherapy with rituximab plus chemotherapy [Marcus, et al. N Engl J Med 2017]. To investigate the association between the derived radiomics features along with baseline clinical variables and progression-free survival (PFS), a Cox proportional hazard model with L1 regularization was trained and internally validated using the GOYA study. We used a nested Monte Carlo Cross Validation (nMCCV) strategy to train our model and provide high- and low-risk group predictions on held-out samples of data. This modeling strategy allows us to make a group prediction on all GOYA patients while reducing overfitting. To evaluate prognostic performance, we ported the final model trained using the GOYA study (called the Li prognostic model) to the fully independent GALLIUM study. Results: Using our nMCCV approach we identified 11 factors, with an inclusion probability of &gt;50%, that are associated with PFS of DLBCL patients (Figure A). Included within the top features are several image-derived morphometric (i.e. metabolic tumor volume, surface area) and radiomics features (i.e. tumor elongation, NGTDM contrast, GLCM inverse variance). When stratifying patients on the predicted (via majority vote) low-risk vs high-risk groupings we found that our high-risk group had significantly worse prognosis vs the low-risk group (Figure B). In comparison, the high-risk group from the IPI model (defined as IPI &gt; 2) had significantly worse prognosis vs the low-risk group, but the performance was slightly worse than our model (Figure C). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 72.7% [70.0-76.6] and 59.8% [54.8-65.2] (vs 74% [70.0-78.2] and 60.4% [55.1-66.2] for the IPI model). After training and testing in the DLBCL population, we evaluated the prognostic performance of our model in an independent set of FL patients. We found that high-risk FL patients had a significantly worse prognosis than the low-risk group (Figure D). PFS probability estimates at 2 and 5 years for predicted high-risk patients was 77.4% [69.8-85.8] and 48.9% [39.5-60.5] (vs. 80% [0.748-0.856] and 58.3% [51.6-65.9] in the full group). Conclusions: Radiomics features are prognostic in DLBCL and provide a modest improvement in prognostic performance when combined with traditional IPI scores, clinical features, and lab values (vs IPI alone). Our prognostic signature, developed in DLBCL, has significant prognostic performance in an independent dataset of patients with FL. While these results are promising, our FL validation dataset was relatively small and further evidence is required to confirm our findings. Disclosures Li: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jemaa:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Carano:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Bengtsson:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Paulson:F. Hoffmann-La Roche: Current equity holder in private company, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Jansen:F. Hoffmann-La Roche: Current Employment; Molecular Health GmbH: Ended employment in the past 24 months; F. Hoffmann-La Roche, Abbvie, Alphabet, other (non-healthcare), indexed funds and ETFs: Current equity holder in publicly-traded company. Nielsen:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Hibar:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company.

Aggressive Chemotherapy (CHOEP-14) and Rituximab or High-Dose Therapy (MegaCHOEP) and Rituximab for Young, High-Risk Patients with Aggressive B-Cell Lymphoma: Results of the MegaCHOEP Trial of the German High — Grade Non-Hodgkin Lymphoma Study Group (DSHNHL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 404-404 ◽  
Author(s):  
Norbert Schmitz ◽  
Maike Nickelsen ◽  
Marita Ziepert ◽  
Matthias Haenel ◽  
Peter Borchmann ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Conventional Chemotherapy ◽  
High Risk Patients ◽  
Risk Patients ◽  
Aggressive B Cell Lymphoma

Abstract Abstract 404 Comparison of conventional chemotherapy with high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT) administered to young, high-risk patients with aggressive B-cell lymphoma as part of first-line therapy gave conflicting results; none of the randomized studies used rituximab (R) in combination with conventional or HDT. In March 2003 we started a randomized phase III study for young (18-60 years), high-risk (age-adjusted IPI 2 or 3) patients with aggressive lymphoma. For patients with B-cell lymphomas this study compared 8 cycles of CHOEP-14 (CHOP + etoposide 300 mg/m2 given every 2 weeks) with MegaCHOEP. The MegaCHOEP program used cyclophoshamide (1500 mg/m2 in cycle 1; 4500 mg/m2 in cycles 2 and 3; 6000 mg/m2 in cycle 4), doxorubicin (70 mg/m2 in all cycles), vincristine (2 mg, all cycles), etoposide (600 mg/m2 , cycle 1; 960 mg/m2 , cycles 2 and 3; 1480 mg/m2, cycle 4), and prednisone (500 mg, all cycles) to be administered every 21 days. Hematopoietic stem cells were harvested after cycles 1 and 2 and reinfused after HDT cycles 2, 3, and 4. Feasibility, safety, and efficacy of MegaCHOEP + / - R have been described (Glass et al. Blood 2006 and BMT 2006). The phase III study originally had four arms (8 × CHOEP – 14, 8 × CHOEP – 14 and 6 × R, MegaCHOEP, and MegaCHOEP and 6 × R). Treatment arms without R were closed in June 2004 because other studies (e.g the MInT study) had shown major improvement in outcome parameters when R was added to chemotherapy. The study continued comparing 8 × CHOEP – 14 and 6 × R (375 mg/m2) with MegaCHOEP and 6 × R (375 mg/m2). At the time of this analysis 346 patients (pts) had been recruited; 216 pts. (median age 48 years, LDH > N 97 %, stage III or IV 96%, ECOG > 1 35%) had been randomized until 07 / 07 and were availabel for this planned interim analysis ( 8 × CHOEP – 14 + 6 × R, n = 91; MegaCHOEP + 6 × R, n = 94; 8 × CHOEP – 14, n = 15; MegaCHOEP, n = 16). Major toxicities included mucositis, diarrhea, and infections all of which were significantly more frequent in the MegaCHOEP arm of the study. Treatment – related deaths occurred in 5 / 94 pts. ( 5.3%) in the MegaCHOEP arm and in 1 / 91 pts. (1.1 %) in the R – CHOEP arm (p = 0.211). Surprisingly, the 3 – year event – free survival ( EFS : time from randomization to either disease progression, no CR / CRu at the end of treatment, initiation of salvage therapy, relapse or death from any cause) was better after conventional than after HDT / ASCT: 71.0% after 8 × CHOEP-14 + 6 × R vs. 56.7 % after MegaCHOEP + 6 × R (p = 0.050). After a median observation time of 29 months the estimated 3-year overall survival was 83.8 % after 8 × CHOEP – 14 + 6 × R and 75.3 % after MegaCHOEP + 6 × R (p = 0.142). Progression – free survival was 76.0 % after 8 × CHOEP – 14 + 6 × R and 64.6 % after MegaCHOEP + 6 × R (p = 0.119). A comparison of the rituximab-containing treatment arms (8 × CHOEP 14 + 6 × R and Mega CHOEP + 6 × R) with the chemotherapy – only arms (8 × CHOEP -14 and MegaCHOEP) revealed a 27.1 % difference in the 3-year EFS-rate ( p = 0.003 ) pointing to the unexpectedly high efficacy of R particularly in untreated, young, high-risk patients with aggressive B-NHL. These data were presented to the members of the study group and the data safety and monitoring committee who decided to stop the MegaCHOEP arm of the study. In conclusion, 8 × CHOEP -14 + 6 × R gave excellent results in young, high-risk patients with untreated aggressive B cell lymphoma. The 3-year EFS and OS are the best ever reported for this group of patients. MegaCHOEP + 6 × R was no better than aggressive conventional chemotherapy regarding any of the study endpoints; EFS (primary endpoint of the study) was significantly worse. Because of higher toxicity and inferior survival the MegaCHOEP arm was discontinued. HDT / ASCT has no role to play as part of first-line therapy for patients with high-risk aggressive B cell lymphoma if rituximab is combined with aggressive conventional chemotherapy. Disclosures: Schmitz: Roche: Honoraria, Research Funding. Nickelsen:Roche: Honoraria. Trümper:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Research Funding. Glass:Roche: Honoraria, Research Funding.

Comparing Toxicities and Survival Outcomes with Total Therapy 4 (TT4) for 70-Gene (R70)-Defined Low-Risk Multiple Myeloma (MM) to Results Obtained with Total Therapy 3 Protocols TT3A and TT3B

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 368-368 ◽  
Author(s):  
Elias J. Anaissie ◽  
Frits van Rhee ◽  
Antje Hoering ◽  
Sarah Waheed ◽  
Yazan Alsayed ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
Phase Iii ◽  
Survival Outcomes ◽  
Phase Iii Trial ◽  
Baseline Characteristics ◽  
Total Therapy ◽  
Timing Of Onset

Abstract Abstract 368 Background: TT3, incorporating bortezomib and thalidomide with induction prior to and consolidation after melphalan 200mg/m2-based transplants and 3 year maintenance with VTD (year 1) and TD (years 2+3) in TT3A and with VRD for 3 years in TT3B resulted in a high CR rate of ∼60% and, in the 85% of patients with GEP-defined low-risk MM, 5-yr OS/EFS of 80%/78%; 5-year CR duration estimate was 88%. Patients and Methods: Phase III trial TT4 for low-risk MM randomized patients between standard (S) and light (L) arms. TT4-L applied 1 instead of 2 cycles of induction therapy with M-VTD-PACE prior to and 1 instead of 2 cycles of consolidation with dose-reduced VTD-PACE after tandem transplantation. M-VTD-PACE comprised melphalan, bortezomib, thalidomide, dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide. TT4-S applied standard single dose melphalan 200mg/m2, while TT4-L used a 4-day fractionated schedule of melphalan 50mg/2 on days 1–4. VRD maintenance for 3 years was identical in both arms. Here we report, for both TT4 arms combined, on grade >2 mucosal toxicities, applying CTCAE version 3.0, and on efficacy (CR, EFS, OS) in relationship to TT3 in low-risk MM. At the time of analysis, median follow-up on TT4 is 10.7 months and on TT3A/B 62.3/33.4 months. To facilitate comparisons between trials with different follow-up times, TT3 data were backdated to follow-up time comparable to TT4 as of this reporting time. Results: Baseline characteristics were similar in TT3 (n=364) and TT4 (n=165) in terms of B2M both >=3.5mg/L and >5.5mg/L, and elevated levels of CRP, creatinine, and LDH. Presence of cytogenetic abnormalities (CA) overall and in terms of CA13/hypodiploidy was similar in both. Fewer TT4 patients had ISS-1 (31% v 43%, P=0.010) and more had hemoglobin <10g/dL (35% v 26%, P=0.029). While neither trial had GEP-defined high-risk in the 70-gene model (R70), the more recently validated R80 distribution showed 7% high-risk in TT4 v 3% in TT3 (P=0.031). DelTP53 was more prevalent in TT4 than TT3 (39% v 10%, P<0.001), and MY favorable subgroup designation pertained to 3% in TT4 v 12% in TT3 (P=0.002). Toxicities are reported per protocol phase. During induction (TT4, n=160; TT3, n=364), grade >2 mucosal toxicities included colitis in 0%/1% (P=0.32), esophagitis/dysphagia in 0%/1% (P=0.33), GI mucositis, NOS in 1%/1% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.99). With transplant-1, (TT4, n=139; TT3, n=344), grade >2 mucosal toxicities included colitis in 3%/1% (P=0.24), esophagitis/dysphagia in 1%/5% (P=0.03), gastritis in 1%/0% (P=0.29), GI mucositis, NOS in 1%/2% (P=0.73) and stomatitis/pharyngitis in 0%/5% (P=0.008); with transplant-2 (TT4, n=105; TT3, n=294), grade >2 mucosal toxicities included colitis in 4%/3% (P=0.77), esophagitis/dysphagia in 0%/2% (P=0.20), GI mucositis, NOS in 2%/3% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.58). With consolidation (TT4, n=85; TT3, n=280), grade >2 mucosal toxicities included colitis in 0%/3% (P=0.36) and GI mucositis, NOS in 0%/1% (P=0.99). Timing of onset and final levels of CR differed substantially between TT4 and TT3 in favor of TT4 (P=0.006); no differences were observed in OS (P=0.36), EFS (P=0.66), and CR duration (P=0.12). Conclusion: TT4 (both arms combined) provided, despite higher proportions of patients with unfavorable characteristics than in TT3, superior CR rate and comparable survival outcomes to TT3's low-risk population. GI toxicities were reduced in TT4 v TT3. Results of TT4 arms will be presented. Disclosures: No relevant conflicts of interest to declare.

The Bruton's Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 156-156 ◽  
Author(s):  
Nathan H Fowler ◽  
Ranjana H Advani ◽  
Jeff Sharman ◽  
Sonali M. Smith ◽  
Jesse McGreivy ◽  
...  
Keyword(s):  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Median Time ◽  
Phase I Study ◽  
Study Drug ◽  
Employment Equity ◽  
Phase Ii Studies ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 156 Background Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling and is essential for normal B-cell development. Subtypes of non-Hodgkins lymphoma (NHL) may be dependent on chronic activation of the BCR pathway and primary follicular lymphoma (FL) cells have been found to maintain enhanced signaling when compared to normal B-cells (Irish JM, et al. Blood 2006; 108: 3135). Ibrutinib is an orally administered, covalently-bound inhibitor of BTK which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. Based on promising preclinical data in B-cell malignancies, a phase I study was conducted to test the safety, tolerability, pharmacokinetics, and pharmacodynamics of ibrutinib in relapsed NHL. We report the long-term tolerability and sustained activity of ibrutinib in FL patients in this study with extended follow-up. Methods Adult patients with relapsed or refractory B-cell lymphoma were eligible for trial entry and 16 patients with FL were enrolled in this Phase I study. Ibrutinib was administered orally with dose escalation according to protocol-defined dose-limiting toxicities (DLT) to define a maximum tolerated dose (MTD) or until 3 dose levels above attainment of full BTK occupancy. A 28-day on/7-day off (intermittent) schedule was evaluated in 5 cohorts (1.25–12.5 mg/kg PO qd) and a once daily oral dose (without a drug holiday) in 2 cohorts (8.3 mg/kg and 560-mg fixed dose). Patients were evaluable for safety if they received study drug. Efficacy was evaluated in all patients who received 2.5 mg/kg or higher (which achieves full BTK occupancy) and had one on-study imaging assessment. Efficacy was also analyzed at higher doses to determine if there was improved efficacy. Responses were assessed every 2 months using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Median age 60 (41–71), equal numbers of males and females, median time from diagnosis 54 months (19–186), median number of prior therapies 3 (1–5) including: stem cell transplantation (6%), alkylators (88%), anthracyclines (56%), nucleoside analogs (19%), and rituximab (100%). FLIPI scores at baseline: low risk = 19%, intermediate risk = 37%, high risk = 44%. Treatment-emergent AEs occurring in ≥ 25% included: diarrhea (50%), fatigue (44%), nausea (38%), cough (31%) and myalgia (25%). Observed grade 3 AEs included: anemia, anxiety, hypersensitivity, hypokalemia, hypophosphatemia, decreased neutrophil count, non-cardiac chest pain, pancytopenia, pneumonia and vomiting (one event each). A Grade 4 hypokalemia occurred and was considered to be related to study drug by the investigator. One case of myelodysplastic syndrome occurred 29 days after the last dose of ibrutinib in a patient with pre-existing anemia and multiple lines of prior treatment and was considered to be unrelated by the investigator. One patient in the 2.5 mg/kg/day intermittent cohort experienced DLTs of grade 2 neutropenia resulting in the ibrutinib dose being held > 7 days and a grade 4 hypokalemia. One patient in the 8.3 mg/kg/day intermittent cohort experienced a Grade 3 hypersensitivity reaction. No DLTs were observed in the 12.5 mg/kg/day cohort and the MTD was not reached. In the 16 patients with FL, 11 patients received ibrutinib at 2.5 mg/kg or higher and were evaluable for efficacy (2 patients at 2.5 mg/kg, 1 at 5 mg/kg, 3 at 8.3 mg/kg intermittent, 3 at 12.5 mg/kg, 2 at 8.3 mg/kg continuous dosing). Median time on ibrutinib was 7 months (0–29). Overall response rate (ORR) 54.5% (3 CRs, 3 PRs), duration of response (DOR) 12.3 months, median PFS 13.4 months. In the 9 patients who received ibrutinib at 5 mg/kg or higher, the median time on ibrutinib, ORR and DOR were similar to the efficacy in the 11 patients. However, there was a slight trend toward improved PFS of 19.6 months; 2 patients are still responding to ibrutinib at 25 and 29 months. Conclusions The BTK inhibitor ibrutinib (PCI-32765) is well tolerated and active in patients with relapsed FL. Based upon drug occupancy and clinical responses, a dose of 5 mg/kg/day or above is recommended for phase II studies. Extended dosing did not appear to increase toxicity and response rates improved with continued treatment in some patients. Phase II studies with ibrutinib in FL are planned. Disclosures: Advani: Pharmacyclics, Inc: Research Funding. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. McGreivy:pharmacyclics: Employment. Kunkel:Pharmacyclics: Employment, Equity Ownership. Troung:Pharmacyclics, Inc: Employment, Equity Ownership. Zhou:Pharmacyclics, Inc.: Employment, Equity Ownership.

Frontline Therapy with Low Risk Chemotherapy (R-CVP/R-CHOP) in Follicular B-Cell Lymphoma Recently Diagnosed. Clinical Experience in Two Centers of Bogotá, Colombia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4893-4893
Author(s):  
Carlos Daniel Bermudez ◽  
Martha Leticia Suarez ◽  
Sergio Andres Cancelado ◽  
Carlos Alberto Ramirez
Keyword(s):  
High Risk ◽  
Partial Response ◽  
Follicular Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Low Risk ◽  
Long Term Results ◽  
Severe Toxicity ◽  
Primary Therapy ◽  
Overall Response

Abstract Abstract 4893 Background: The follicular lymphoma (FL) it is a subset of non-Hodgkin lymphomas, accounting for between 15% and 30% of new diagnoses of lymphoma. It has raised many combinations of treatments, but the long-term results remain unchanged. At present there is no consensus on the first line therapy for the management of follicular lymphoma. Since the advent of rituximab use, this change, achieving better response rates and survival, the paradigm is the use of R-CHEMO, but there are many active combinations, including the use CVP, CHOP, FCM, and others, which have shown benefit, but with consequences given for severe toxicity, and treatment-related deaths. In Colombia, the situation it is not different, the use of chemotherapy is left for consideration by the treating physician. This study aimed to assess treatment preferences for patients with new diagnosis of follicular lymphoma in Colombia, evaluate the responses of the combination R-CHEMOTHERAPY in our population, considering the specific ethnic characteristics and limitations of a developing country. Patients and Methods: The study included patients diagnosed with follicular lymphoma confirmed by hematopathologist with experience by performing at least 10 immunohistochemical tumor markers. This study is a descriptive study. During the study took into account the principles of autonomy, beneficence and justice written in the Belmont report. Informed consent was obtained from patients for participation in this study. It also welcomes the resolution expressed law Colombian Ministry of Health No. 008 430 1993 (4 October 1993) Article 11 investigation classified as safe. We analyzed cases diagnosed from January 2007 to July 2011 in two private institutions in the city of Bogotá, Colombia, we obtained 20 cases meeting the inclusion criteria. All the patients were scheduled to undergo primary therapy with 6 cycles of full-dose R-CVP or R-CHOP. Results: in this group, there were 5 men and 15 women (75% of all patients), and the median age at diagnosis was 56 years, the initial stage was 10% for stage II, 40% for stage III and the remaining 50% for stage IV, the bone marrow compromise reached by 45% (9 cases). The initial functional status classified by the ECOG scale was 0: 45%, 1: 50% and 3: 5%. the B symptoms were present in 95% of the patients analyzed. In accordance with the International Prognostic Index (FLIPI), we find the following: low risk: 25% (5 cases), intermediate risk: 35% (7 cases) and high risk: 40% (8 patients). the pathological grading was grade 1: 55% (11 patients), grade 2 for 35% (4 patients) and 3 for 10% (2 patients). When we reviewed found that the preferred treatment, for 80% of the population uses the R-CVP and the remaining 20% use of R-CHOP scheme, one patient in the R-CHOP group was complicated with high-risk febrile neutropenia requiring hospitalization. There were no treatment-related deaths. We found that 80% of patients achieved a complete hematologic remission and 20% partial response for an overall response of 100%. If we analyze separately patients treated with R-CVP scheme was 75% complete response and 25% partial response, with an overall response of 100%. Conclusion: This study shows the preference of treatment in 2 institutions in Bogotá, Colombia, which are in accordance with international guidelines, the results show a population with similar general characteristics with the others studies, in which a 100% overall hematologic response was achieved, 75% complete response for the R-CVP and 100% for the R-CHOP, however the latter with 25% of severe infectious complications. We consider a good treatment strategy for the implementation in our population is the R-CVP scheme, which is well tolerated, showing benefit in our patients and remission rates even higher than the studies previously published. Disclosures: No relevant conflicts of interest to declare.

Risk Adjusted Management of Newly Diagnosed High and Intermediate FLIPI Follicular Lymphoma Using (90)Y Ibritumomab Tiuxetan

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1794-1794
Author(s):  
Neil L Berinstein ◽  
Nancy M Pennell ◽  
Rashmi Weerasinghe ◽  
Matthew C. Cheung ◽  
Eugenia Piliotis ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Newly Diagnosed ◽  
Ibritumomab Tiuxetan ◽  
Cell Counts ◽  
Post Therapy

Abstract Background: Although the natural history of follicular lymphoma is indolent with a median overall survival of about 12-15 years, the disease is heterogeneous. The 5 and 10 year overall survival (OS) of low, intermediate and high risk FLIPI is 91%, 78% and 53% and 71%, 51% and 36% using standard rituximab-based treatment. 5-year progression-free survival (PFS) is 80%, 70% and 48% respectively. Methods: Based upon this we conducted an investigator-initiated single-centre Phase II trial of intensified therapy with CHOP-R followed by (90)Y ibritumomab tiuxetan consolidation and 24 months of rituximab maintenance as treatment for patients with intermediate and high-risk newly diagnosed symptomatic follicular lymphoma. 33 patients were enrolled. Results: The addition of (90)Y ibritumomab tiuxetan was well tolerated but resulted in asymptomatic grade 3 or 4 thrombocytopenia and neutropenia in11-36% and 10-24% of patients between weeks 2-8 post (90) Y. After 9 years of follow-up (median follow-up 61 months) the 0S for intermediate and high risk FLIPI was 95% and 78%. The 5 year PFS was 79% and 64% for intermediate and high risk FLIPI, respectively. Responses at three months post consolidation were as follows: 3/33 (9%) achieved CR, 25/33(76%), achieved CRU, 1/33(3%) had PR, and 1/33(3%) had PD. Three patients did not receive (90)Y ibritumomab tiuxetan due to disease progression 2/33(6%), or death 1/33(3%). Of 19 patients who had a molecular marker for their lymphoma, 18 (95%) achieved molecular remissions in peripheral blood with CHOP-R therapy. Nine (47%) of these patients have been recently assessed for MRD and remain in molecular remission. The therapy resulted in decreased levels of IgG, IgM and IgA below the lower normal level in 33%, 40% and 23% of patients respectively post therapy. These levels did not recover in most of these patients. B cells were depleted to undetectable levels during therapy including rituximab maintenance. In 18 evaluable patients only 11 recovered normal B cell counts post maintenance rituximab. There was no correlation between normal B-cell recovery and Ig levels. Many patients with low or no B cell counts had normal IgG levels, whereas some patients who regained normal B cell counts were still unable to reach normal Ig levels. No patient developed human anti-mouse antibody. Immunity to measles, mumps, or rubella was retained post therapy. Patients did not have significant infections or opportunistic infections (although 2 developed Grade 1 shingles post (90)Y ibritumomab tiuxetan) and none required IVIG. Conclusions: We conclude that this intensified regimen is highly active in cyto-reducing lymphoma in high and intermediate risk FLIPI follicular lymphoma patients. The toxicity is tolerable although a significant percentage of patients will end up with persistent asymptomatic reductions in B cells and serum Ig. Only randomized trials will determine whether this regimen enhances outcome over standard of care in this higher risk follicular lymphoma population. References: 1.Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices. Nooka AK, Nabhan C, Zhou X, Taylor MD, Byrtek M, Miller TP, Friedberg JW, Zelenetz AD, Link BK, Cerhan JR, Dillon H, Sinha R, Shenoy PJ, Levy D, Dawson K, Hirata JH, Flowers CR. Ann Oncol. 2013 Feb;24(2):441-8. doi: 10.1093/annonc/mds429. Epub 2012 Oct 5 2.Validation, revision and extension of the Follicular Lymphoma International Prognostic Index (FLIPI) in a population-based setting. van de Schans SA, Steyerberg EW, Nijziel MR, Creemers GJ, Janssen-Heijnen ML, van Spronsen DJ. Ann Oncol. 2009 Oct;20(10):1697-702. doi: 10.1093/annonc/mdp053. Epub 2009 Jun 23. PMID: 19549712 Disclosures Buckstein: Novartis: Honoraria; Celgene: Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document