Efficacy and safety of tisagenlecleucel (Tisa-cel) in adult patients (Pts) with relapsed/refractory follicular lymphoma (r/r FL): Primary analysis of the phase 2 Elara trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7508-7508
Author(s):  
Stephen J. Schuster ◽  
Michael J. Dickinson ◽  
Martin H. Dreyling ◽  
Joaquín Martínez ◽  
Arne Kolstad ◽  
...  
Keyword(s):  
High Risk ◽  
Progressive Disease ◽  
Response Rate ◽  
B Cell Lymphoma ◽  
Disease Assessment ◽  
Cell Transplant ◽  
Phase 2 ◽  
Primary Analysis ◽  
Bulky Disease

7508 Background: Most pts with r/r FL experience multiple relapses and progressively worse clinical outcomes with each line of therapy, underlining a need for novel therapies. Tisa-cel has demonstrated durable responses and manageable safety in adult pts with r/r diffuse large B-cell lymphoma. Here we report the primary analysis of ELARA, an international, single-arm phase 2 trial of tisa-cel in adult pts with r/r FL. Methods: Eligible pts (≥18 y) had r/r FL (grades [Gr] 1-3A) after ≥2 lines of therapy or had failed autologous stem cell transplant. Bridging therapy was permitted followed by disease assessment prior to tisa-cel infusion. Pts received tisa-cel (0.6-6×108 CAR+ viable T cells) after lymphodepleting chemotherapy. The primary endpoint was complete response rate (CRR) by central review per Lugano 2014 criteria. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics. Predefined primary analysis occurred when ≥90 treated pts had ≥6 mo of follow-up. Results: As of September 28, 2020, 98 pts were enrolled and 97 received tisa-cel (median follow-up, 10.6 mo). At study entry, median age among treated pts was 57 y (range, 29-73), 85% had stage III-IV disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42% had LDH > upper limit of normal. The median number of prior therapies was 4 (range, 2-13); 78% of pts were refractory to their last treatment (76% to any ≥2 prior regimens) and 60% progressed within 2 y of initial anti-CD20–containing treatment. Of 94 pts evaluable for efficacy, the CRR was 66% (95% CI, 56-75) and the ORR was 86% (95% CI, 78-92). CRRs/ORRs were comparable among key high-risk subgroups. Estimated DOR (CR) and PFS rates at 6 mo were 94% (95% CI, 82-98) and 76% (95% CI, 65-84), respectively. Of 97 pts evaluable for safety, 65% experienced Gr ≥3 adverse events within 8 weeks post-infusion, most commonly neutropenia (28%) and anemia (13%). Any-grade cytokine release syndrome (per Lee scale) occurred in 49% of pts (Gr ≥3, 0%). Any-grade neurological events (per CTCAE v4.03) occurred in 9% of pts (Gr 3, 0%; Gr 4, 1 pt and recovered). Three pts died from progressive disease. Cellular kinetic parameters for tisa-cel were estimated using transgene levels (by qPCR) in peripheral blood. Cmax and AUC0-28d were similar between responders (CR or partial response) and non-responders (stable or progressive disease). Maximum transgene levels were reached by a median of 10 days in responders and 12.9 days in non-responders; transgene persistence was detected up to 370 days and 187 days, respectively. Conclusions: These data demonstrate the efficacy and acceptable safety of tisa-cel in pts with r/r FL, including high-risk pts after multiple lines of prior therapy, and suggest that tisa-cel may be a promising therapy for pts with r/r FL. Clinical trial information: NCT03568461.

Checkpoint Inhibition before Axicabtagene Ciloleucel Cell Therapy in Primary Mediastinal B-Cell Lymphoma (PMBCL) Treated in Real Life Setting

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Annalisa Chiappella ◽  
Anna Dodero ◽  
Anna Guidetti ◽  
Filippo Bagnoli ◽  
Vanessa Aragona ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Real Life ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Bridging Therapy ◽  
Bulky Disease ◽  
Car T

Background: Eighty-five percent of PMBCL are cured by standard therapy, but the outcome of refractory/relapsed (R/R) PMBCL is very poor. Checkpoint inhibitors (CPIs) have shown promising activity in relapsed PMBCL. Axibactagene ciloleucel (axi-cel) CAR-T cell therapy, can induce durable responses and is currently approved for the treatment of adult patients with R/R PMBCL. Aims of this analysis were: to register all Italian PMBCL patients candidate to CAR-T in the 6 active centers;to evaluate the intention to treat overall response rate (ORR, complete [CR] and partial response [PR]) in patients treated with axi-cel and CPIs for salvage or bridging before CAR-T and for relapse after CAR-T;to evaluate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Methods: In August 2019 the Italian Drug Agency (AIFA) approved axi-cel; before the reimbursement by AIFA, an expanded access program supported by Kite/Gilead started. One patient slot per month per qualified center was available. Patients were included in a large national CAR-T prospective observational study approved by ethics committees. Results: Since April 2019 to March 2020, 20 R/R PMBCL were evaluated and 18 were apheresized in order to receive axi-cel; 2 were excluded because active CNS disease in one, and eligibility to transplant, while in CR, in the second one. Their clinical characteristics were: median age 38 years (range 22-50), male 8 (44%), stage II 6 (33%), advanced stage III/IV 12 (66%), bulky disease 6 (33%); LDH upper than normal 3 (2%). Median number of prior lines was 3 (2-6); 5 patients (28%) had a previous autologous stem cell transplant and 12 (66%) received a prior radiotherapy. The majority of patients, 16 (89%) were refractory to the last treatment when they were evaluated for CAR-T eligibility; 9 of 18 patients had CPI exposure before leukoapheresis: 6 pembrolizumab and 3 nivolumab in combination with brentuximab-vedotin. No manufacturing failures were reported. Bridging therapy was performed in 16 of 18 patients (88%). Seventeen patients (94%) received lymphodepleting Flu-Cy chemotherapy and only 16 pts received CAR-T for central nervous system (CNS) progression during bridging therapy (n=1) and respiratory failure due to pneumonia (n=1); the 2 patient not infused were exposed to CPIs. Median vein to vein time was 40 days (30-79). Median follow-up time for infused patients was 209 days (9-444). CRS was observed in 12 of 16 infused patients: 5 grade 2 and 7 grade 1. ICANS (2 grade 1, 2 grade 2, 1 grade 3) was recorded in 5 patients. No differences regarding CRS and ICANS occurrence were observed in patients exposed or not to CPIs. At 30-days after the infusion, all the 16 infused patients were evaluable for response: 7 (44%) CR, 5 (31%) PR, with ORR 75%, 3 (19%) stable disease (SD) and 1 (6%) progressive disease (PD). Two patients in PR at 30 days converted to CR at 90 days, with continuous CR at 180 days; all the 3 patients in SD and 1 out of 5 in PR at 30 days progressed at 90 days. Considering the 9 patients exposed to CPIs before CAR-T, 7 out of 9 were infused and all the 7 infused were evaluable for response: 2 (29%) CR, 4 (57%) PR, with ORR 86%, and 1 (14%) died because of a rapid CNS progression after infusion. Two patients in PR at 30-days converted to CR at 90-days, one with continuous CR at 180 days after CAR-T. Conclusions: In our series of 16 infused patients, axi-cel was effective with an ORR of 75% (CR 44%) at 30-days after CAR-T infusion and ORR of 54% (CR 46%) in the 13 patients evaluable at the median follow-up time (180-days after CAR-T infusion). It is important to note the 4 patients from the original real life cohort never received axi-cel. It is noteworthy that ORR was 86% in patients receiving CPIs before CAR-T and 75% in those not exposed to CPIs. With the limitation of small number, the exposure of immune-checkpoint inhibitors seems not to affect negatively response rate and adverse events. Disclosures Chiappella: Janssen: Honoraria; Iqone: Honoraria; Servier: Honoraria; Roche: Honoraria; Celgene: Honoraria; Gilead-Kite: Honoraria; Takeda: Honoraria. Zinzani:Bayer: Consultancy. Corradini:BMS: Other; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria.

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

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2770-2770
Author(s):  
Luis Fayad ◽  
Michael Overman ◽  
Barbara Pro ◽  
Peter McLaughlin ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Bulky Disease ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

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

PET-CT Adapted Therapy After 3 Cycles of ABVD for All Stages of Hodgkin Lymphoma. Interim Analysis in 173 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1772-1772
Author(s):  
Santiago Pavlovsky ◽  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Miguel Pavlovsky ◽  
Virginia Prates ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Progressive Disease ◽  
Cell Transplant ◽  
Advanced Stage ◽  
Event Free Survival ◽  
Bulky Disease ◽  
Free Survival ◽  
Pet Ct

Abstract Abstract 1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an overall survival at 5 years of 80%. ABVD can be considered as gold standard for first line treatment for all stages of HL. Dividing patients (pts.) in different prognostic groups has aimed to reduce chemo and radio toxicity in those patients with good prognosis. A negative PET-CT, either early during treatment of ABVD or after completion of it, has shown to be a powerful prognostic tool (Hutchings: Blood 2006; Gallamini: Haematologica 2006). Our cooperative group has an experience with 584 patients with HL in early or advanced stage treated with 3 or 6 cycles of ABVD plus involved field radiotherapy with a complete remission (CR) of 91% and an event free survival (EFS) and overall survival (OS) at 60 months of 79% and 95%.(S Pavlovsky, Clin Lymp My & Leuk, 2010). Aims: Test the efficacy of treatment to all stages of HL adjusted to PET-CT results after 3 cycles of ABVD. Evaluate the outcome of pts. who have a negative PET-CT after 3 cycles of ABVD and receive no further treatment. Intensify therapy only in pts. who have persistent hyper metabolic lesions in PET-CT after 3 cycles of ABVD. Method: Since October 2005, 198 newly diagnosed pts. with HL have been included in a prospective multicenter trial. Initially all patients received 3 cycles of ABVD. After the third cycle, pts. were evaluated with a PET-CT. Those pts. who achieved CR with a negative PET-CT, received no further treatment. Those with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions by PET-TC after 3 ABVD were considered in partial remission (PR) and completed 6 cycles of ABVD and radiotherapy (RT) on PET-CT positive areas. Those patients with less than PR after 3 cycles of ABVD received ESHAP and if CR, high doses of chemotherapy and an autologous stem cell transplant (ASCT). All patients were re-evaluated at the end of treatment. The median follow up is of 30 months (3-62). Results: One hundred and seventy three patients completed three cycles of ABVD followed by a PET-CT. The median age at diagnosis was 29 years. One hundred and thirty-six (79%) had localized stage (I-II) at diagnosis and 37 (21%) presented with advanced stage (III-IV). Of 155 pts. 77 (50%) pts had IPS 0–1, 66 (43%) had IPS 2–3 and 12 (8%) had IPS 4–5. Twenty six (17%) pts. had bulky disease at diagnosis. One hundred and thirty-seven (79%) pts. achieved CR with negative PET-CT after 3 cycles of ABVD. Thirty-six (21%) were PET-CT positive, of them 32 pts achieved PR and completed a total of 6 cycles of ABVD plus RT in hyper metabolic lesions. Twenty five achieved CR (72%), 5 persisted with PR and 2 died of progressive disease. Four pts showed progressive disease (PD) after 3 ABVD and received ESHAP and ASCT, 2 achieved and remained in CR, 1 is in PR and 1 died of progressive disease. Of 173 pts who completed treatment with ABVD × 3 cycles, ABVD × 6 cycles plus RT on PET-TC positive areas or ESHAP plus ASCT, 164 pts (95%) achieved CR. Of these 164 pts., 14 pts (8%) relapsed. The EFS and OS at 36 months is 83% and 97% respectively. Patients with early negative PET-TC have an event-free survival of 87% compared to 62% (P=0,001) for pts with early positive PET CT. The OS at 36 months was 100% versus 86% respectively (<0.001). Conclusion: Treating patients with ABVD, evaluating response after 3 cycles with PET-CT, and adapting further therapy, leads to a high rate of CR avoiding more aggressive chemotherapy and radiotherapy. Three courses of ABVD without RT are adequate in patients with early CR defined by negative PET-CT. In early positive PET-CT it is possible to intensify therapy improving the otherwise bad prognosis; more aggressive treatment might also be suitable. These results need to be confirmed by a larger group of patients and a longer follow-up. Disclosures: No relevant conflicts of interest to declare.

R-HCVAD/R-MTX-Arac (R-HCVAD) Overcomes Risk Features Associated with Inferior Outcomes In the Treatment of Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1782-1782
Author(s):  
Anthony R Mato ◽  
Tatyana Feldman ◽  
Tania Zielonka ◽  
Pritish K. Bhattacharyya ◽  
Alexandria Campaiola ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cox Regression ◽  
B Cell Lymphoma ◽  
Primary Study ◽  
Newly Diagnosed ◽  
Ki 67 ◽  
Bulky Disease ◽  
Poor Risk

Abstract Abstract 1782 Background: Chemo immunotherapy (R-CHOP) has improved outcomes of both GC (germinal center) and ABC (activated B-cell) subtypes of DLBCL. However outcomes in DLBCL patients treated with R-CHOP with ABC subtype (vs. GC) and/or with poor-risk features (High IPI, high Ki-67) remain inferior. These patients might benefit from more dose-intensive or high-dose therapy approaches. In our practice at The John Theurer Cancer Center, we have employed a risk-adaptive strategy with R-HCVAD to treat patients with DLBCL with aggressive features. Methods: Utilizing Kaplan Meier (KM) survival and Cox regression analyses, we conducted a retrospective cohort study to describe the outcome of patients treated with R-HCVAD in the 1st-line setting with the following high-risk features: high Ki-67 (MIB-1), high IPI, multiple extra-nodal (EN) sites, bulky disease or immunohistochemistry (IHC) staining patterns (GC vs. non GC by Hans’ model). The primary study endpoints were PFS and OS. The proportional hazards assumption was met for this analysis. Results: 45 patients (median age 57, range 34–71 yrs) with newly diagnosed DLBCL treated with R-HCVAD (median 6 cycles, range 1–8) were available for this analysis, representing 1010 total months of follow up at-risk. Baseline characteristics included: stage III-IV (90%), IPI ≥ 3 (52%), median Ki-67 (80%, range 10–100%), median EN sites (2), non-GC subtype (34%), bone marrow (BM) involvement (38%), EBER positive (14%), HIV negative (100%). With 17 months (range 9–64 months) median follow up, median OS and PFS (graph) are not yet reached. 2-yr PFS and OS were 80% (95% CI 61–91%) and 78% (95% CI 61–88%) respectively. In Cox regression analysis, survival outcomes were not adversely affected by: patient age > 60 (HR .8, p=.18), LDH > ULN (HR 2.3, p=.3), non-GC IHC pattern (HR .5, p=.5), BM involvement (HR 1.9, p=.4), Ki-67 ≥ 80% (HR 1.7, p=.6) or EN sites ≥ 2 (HR 4.7, p=.15). Conclusions: This analysis represents the largest reported cohort of DLBCL patients treated with R-HCVAD. These data suggest that R-HCVAD can overcome traditional poor-risk features such as high IPI, high Ki-67 and non-GC IHC pattern. Future work will focus on identifying molecular markers for failure in DLBCL patients treated with dose-intensive regimens. A randomized trial comparing R-HCVAD to R-CHOP in selected high-risk patients is warranted. Disclosures: No relevant conflicts of interest to declare.

Fludarabine Plus Cyclophosphamide and Rituximab In Waldenström's Macroglobulinemia: Results In 55 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1757-1757
Author(s):  
Véronique Leblond ◽  
Laetitia Compain ◽  
Vincent Levy ◽  
Jérôme Tamburini ◽  
Alain Delmer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Progressive Disease ◽  
Response Rate ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Best Response ◽  
Previously Treated ◽  
Delayed Responses

Abstract Abstract 1757 Treatment of Waldenström's Macroglobulinemia relies on alkylator agents, nucleoside analogs and/or monoclonal antibody based therapies. We showed previously that combination of fludarabine and cyclophosphamide yields a 78% response rate (RR). We performed a retrospective study in 55 WM patients (pts) treated with RFC regimen in 10 French centers. The median age was 65 years (range: 34–79), the median IgM level measured by electrophoresis was 27.3 g/L (range: 6.5–64), the median haemoglobin level was 9.7g/dl (range: 3.7–14), the median platelet count was 174 × 109/L (range: 22–500), the median beta 2 microglobulin level was 3.4 mg/l (range: 1.7–9). In all, 40/55 pts had previously been treated with a median of 2 lines of therapy (range: 1–4), including 24 patients with relapsed disease and 16 patients with refractory disease. RFC regimen was given every 4 weeks and consisted in: Rituximab 375 mg/m2 IV Day 1, Fludarabine 40 mg/m2 per os Day 1 to Day 3, Cyclophosphamide 250 mg/m2 per os Day 1 to Day 3. 55 pts received the first cycle of RFC, and 52 received two or more cycles (median of 4 cycles, range 2–6). Main toxicity was hematological. No toxic death was observed.Response was assessed 3 months after the last RFC cycle according to response criteria agreed by the 3rd International Workshop on WM (Kimby, 2006), but delayed responses with improvement of the response occurring more than 3 months after treatment discontinuation were observed in 15 patients. The best response was evaluated in 51 pts (3 early discontinuation treatments, one progressive disease), including 26 partial responses (PR), 5 minor responses (MR), and 2 stable diseases (SD). Of note 18 very good PR/ near RC (VGPR) were observed (> 90% decrease in M-protein) . The overall response rate was 89%. Long lasting cytopenia was observed in 10 patients. In the untreated group one pt in failure had a Burkitt-like lymphoma, the other 14 pts are alive in response. In the previously treated group, 6 pts relapsed, one developed a large B-cell lymphoma. Three ASCT and 4 allogeneic SCT were performed in six patients. With a median follow-up time of 28 months, median time to treatment failure (TTF) was not reached, even in previously treated patients. There was not significant difference in the TTF duration in patients in VGPR compared with those in PR + MR.The median progression free survival time was not reached. Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was observed in two heavily treated patients and 3 pts had a secondary solid cancer. In all, 48 pts are alive, 7 patients died (4 from progressive disease, 2 from secondary cancer, and 1 from Burkitt-like transformation). Conclusion: RFC combination even in heavily treated patients with poor prognostic factors gives a very high response rate (89%) with 33% of patients achieving at least a very good partial response with acceptable toxicity. The toxicity on the hematopoietic stem cell reservoir is a major concern. This combination could be offered to relapsed/refractory patients. In first line, the choice of this combination must be discuss, increased incidence of MDS/ AML after purine analogs, and impairment of stem cell mobilization having previously been reported by us and others. Because frequent delayed responses, a long follow-up with periodic electrophoresis is needed to assess the best response after RFC. Disclosures: Leblond: ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GENZYME: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees. Tournilhac:MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; GENZYME: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees. Choquet:ROCHE : Consultancy.

PET -CT Adapted Therapy After 3 Cycles of ABVD for All Stages of Hodgkin Lymphoma. Preliminary Results in 193 Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1619-1619 ◽  
Author(s):  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Virginia Prates ◽  
Miguel A Pavlovsky ◽  
Lucia Zoppegno ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Cell Transplant ◽  
Bulky Disease ◽  
Radio Therapy ◽  
Anatomic Reduction ◽  
Pet Ct

Abstract Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PET-CT) is an important tool for treatment response assessment in Hodgkin Lymphoma (HL) treated with ABVD. It can predict response and overall outcome. The negative predictive value for PET-CT in patients (pts.) with HL is 90–94%. New recommendations define complete remission (CR) for HL as the lack of signs and symptoms of lymphoma with a negative PET-CT. OBJECTIVES: Reduce therapy in pts. who achieve early CR with negative PET-CT. Intensify treatment, only in pts. with positive PET-CT after 3 cycles of ABVD. Achieve CR, event free survival (EFS) and overall survival (OS), as good as in our historical control, when we used 3 or 6 cycles of ABVD plus involved field radio therapy (IFRT) in all pts.(LH-96) PATIENTS AND METHOD: Since October 2005, 200 newly diagnosed pts. with HL have been included in a prospective multicenter clinical trial (LH-05) All pts. received 3 cycles of ABVD and were then evaluated with a PET-CT (PET-CT +3) Pts. with a negative PET-CT+3 and absence of other signs or symptoms of lymphoma were considered in CR and received no further therapy. Pts with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions were considered in partial response (PR) and completed 6 cycles of ABVD and IFRT on PET-CT positive areas. Pts with less than PR received high doses of chemotherapy and an autologous stem cell transplant (ASCT). All pts were re-evaluated at the end of treatment with a new PET CT. One hundred and ninety three pts. have been evaluated. The median age at diagnosis was 29 years. One hundred and twenty five (65%) had localized stage (I-II) non bulky and 68 (35%) presented with advanced stage (III-IV), or bulky disease, 33 (17%) had bulky disease. RESULTS: One hundred and forty-eight (77%) achieved CR with negative PET-CT + 3. Forty-five (21%) were PET-CT+3 positive, 5 showed progressive disease. The other 40 pts. were in PR and completed a total of 6 ABVD + IFRT in PET-CT positive areas. Twenty eight achieved CR and 12 persisted with hypermetabolic lesions. Three died of progressive disease. After finishing planned treatment 178 pts. (92%) were in CR. With a median follow up of 39 months the EFS and OS at 36 months is 80% and 97% respectively. Patients with negative PET-CT +3 have an EFS of 86% compared to 61% for pts. with positive PET-CT+3 (P=0,001). We perform a multivariate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET –CT+ 3. This last parameter together with age were the only ones with statistical significance (p=0.001 and 0.046 respectively). When comparing the results LH-05 with LH-96 there is no difference in EFS and OS at 36 months (83% vs. 85% and 97 vs. 96%) but in LH-05 only 23% received 6 cycles of ABVD and IFRT compared to 61% and 100% in LH-96. This reduces the exposure to chemo and radiotherapy. CONCLUSION: With PET-CT adapted therapy after 3 cycles of ABVD, 148 pts.(77%) received only 3 cycles of ABVD as initial therapy with an EFS and OS of 80% and 97% at 36 months. In the Cox regression model, PET-CT at completion of treatment was the most significant factor associated to EFS. In this interim analysis of PET-CT adapted therapy to all stages of HL, treatment with 3 cycles of ABVD can be adequate for pts. with negative PET-CT+3. Continuing with ABVD after a positive PET-CT +3 can be considered insufficient. A longer follow-up and a larger number of pts. are necessary to confirm these results. Disclosures: No relevant conflicts of interest to declare.

Phase I/II study of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) with lenalidomide (R2-ICE) in patients with first-relapse/primary refractory diffuse large B-cell lymphoma (DLBCL) in academic and community cancer research united (ACCRU) network.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8073-TPS8073 ◽  
Author(s):  
Francis Guerra-Bauman ◽  
Betsy LaPlant ◽  
William R. Macon ◽  
Thomas E. Witzig ◽  
Umar Farooq ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Phase 2 ◽  
Overall Response ◽  
Lymphoma Therapy

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .

scholarly journals Planned Interim Analysis of a Phase 2 Study Evaluating the Combination of Pracinostat, a Histone Deacetylase Inhibitor (HDACi), and Azacitidine in Patients with High/Very High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4362-4362 ◽  
Author(s):  
Michael K Keng ◽  
Samer K. Khaled ◽  
Brenda Cooper ◽  
Erica D. Warlick ◽  
David Ramies ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Interim Analysis ◽  
Response Rate ◽  
Standard Dose ◽  
Discontinuation Rate ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Very High

Abstract Introduction: Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes. Methods: The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation (<6 months) due to lack of response. Response evaluation is performed after 2 and 6 cycles of therapy, and then every 6 months or as clinically indicated; analyses are descriptive. At a planned interim analysis, a pre-defined discontinuation rate due to adverse events (AEs) of ≤10% in the first 3 cycles ("early discontinuations"), a rate comparable to that observed with azacitidine alone in the prior study, and an overall response rate (ORR) of ≥20% were deemed desirable and would support expansion into Stage 2, wherein approximately 20 additional patients will be treated for a total of 60 evaluable patients. The study Independent Data Monitoring Committee (IDMC) in conjunction with the study Sponsor was to determine whether the study would expand based on the discontinuation rate. Results: At the time of the interim analysis (25 May 2018), 39 patients had received ≥1 dose of study treatment and 20 were evaluable for assessment of early discontinuations. Median age was 67 years, 69% were male, and 59% had high-risk MDS. Of the 20 evaluable patients, 2 patients (10%) discontinued prior to the end of Cycle 3 due to AEs (1 febrile neutropenia, Day 45 and 1 fungal infection, Day 90). In 18 subjects evaluated for response at the end of Cycle ≥2, the ORR was 28% (1 complete response, 4 partial responses). Most common Grade ≥3 AEs in the 33 patients with >1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study. Conclusions: The interim analysis of this study evaluating the efficacy and safety of pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented. Disclosures Khaled: Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

Radioimmunotherapy with 131-I tositumomab enhanced survival in good prognosis relapsed and high-risk diffuse large B-cell lymphoma (DLBCL) patients receiving high-dose chemotherapy and autologous stem cell transplantation

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8013-8013 ◽  
Author(s):  
J. Vose ◽  
P. Bierman ◽  
G. Bociek ◽  
F. Loberiza ◽  
C. Enke ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplant ◽  
B Cell Lymphoma ◽  
Autologous Stem Cell Transplant ◽  
Good Prognosis ◽  
Phase Iii ◽  
Cell Transplant ◽  
Outpatient Basis

8013 Background: The 5-year overall survival (OS) for pts with relapsed chemosensitive DLBCL with standard transplantation is approximately 40–50%. We previously piloted the addition of standard outpatient radioimmunotherapy (RIT) with 131-I tositumomab to the transplant regimen for patients with relapsed chemoresistant NHL. This phase I study demonstrated a 3 yr OS of 55% in these poor prognosis patients (JCO 23: 461–467, 2005). The current study is a follow-up phase II study in good prognosis relapsed and high risk DLBCL patients using 131-I tositumomab with BEAM (BCNU, etoposide, cytarabine, and melphalan) followed by an autologous stem cell transplant. Methods: Forty patients were accrued to the study between 2000–2005. The patients had a median age of 54 yrs (26–75) and all had a diagnosis of DLBCL. The patients had a median of two prior chemotherapies before transplant and 88% had received prior Rituximab. All patients had chemotherapy sensitive disease at the time of stem cell transplant. Following stem cell collection, all patients received a stem cell preparative regimen of 75 cGy total body dose of 131-I tositumomab (dosimetric dose day -19 and therapeutic day -12) followed by a standard BEAM transplant regimen. Autologous unpurged stem cells were infused on day 0. The median time of follow-up of the survivors is 28 months (3–68). Results: Seventy eight percent of the patients had a complete remission following the transplant. The 3 year progression free survival (PFS) is 70% (95% CI - 48 - 84%) and the 3 year OS is 81% (95% CI - 61 - 91%). The entire transplant can be delivered on an outpatient basis. No increased toxicity compared to a similar cohort receiving BEAM alone could be detected. Conclusions: The addition of 131-I tositumomab to BEAM and autologous stem cell transplant for relapsed or high-risk chemosensitive DLBCL produces a 3-yr OS of 81% without excess toxicity. This compares favorably to historical controls. This regimen is currently being tested in a phase III trial in the BMT/CTN of Rituximab/BEAM vs. 131-I tositumomab/BEAM in patients with relapsed chemosensitive DLBCL. No significant financial relationships to disclose.

Interim analysis of a phase 2 minimal residual disease (MRD)-adaptive trial of elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) for newly diagnosed multiple myeloma (MM).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8011-8011
Author(s):  
Benjamin Avi Derman ◽  
Jeffrey A. Zonder ◽  
Ankit J. Kansagra ◽  
David L. Grinblatt ◽  
Sunil Narula ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Primary Endpoint ◽  
Adaptive Design ◽  
Cell Transplant ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Study Results ◽  
The Impact

8011 Background: The addition of a monoclonal antibody to triplet induction regimens in patients (pts) with MM with intent for autologous stem cell transplant (ASCT) has resulted in higher overall and deep response rates. In this study we are investigating the impact of the addition of Elo to KRd on complete response (CR) and/or MRD-negative rates in newly diagnosed MM regardless of transplant eligibility. Methods: Pts were enrolled from four MM Research Consortium sites into this phase 2 study. All patients receive 12 cycles of Elo-KRd in 28-day cycles: Elo per standard dosing, K 20/56/70 mg/m2 days 1, 8 and 15, R 25 mg days 1-21, and dexamethasone 40 mg days 1, 8, 15, 22. ASCT eligible candidates can undergo stem cell collection after cycle 4 and then resume treatment; pts who elect to proceed to ASCT are censored for response at that time. Pts MRD(-) (<10-5) by NGS after cycles 8 (C8) and 12 (C12) proceed to Elo-Rd until progression. Patients who convert from MRD(+) to MRD(-) between C8 and C12 receive an additional 6 cycles of Elo-KRd (total 18 cycles) followed by Elo-Rd, and pts MRD(+) after C12 receive an additional 12 cycles of Elo-KRd (total 24) followed by Elo-Rd. The primary endpoint of the study is sCR and/or MRD(-) rate after C8 E-KRd. MRD status was determined by ClonoSEQ next generation sequencing (NGS, <10-5) [Adaptive Biotechnologies]. An improvement in the sCR and/or MRD(-) rate by NGS from a historical 30% to 50% at the end of C8 will be considered promising. Results: 44 pts are enrolled, 39 of whom are evaluable for response (cutoff Jan 10 2021). Median age is 62 years (range 43-81, 23% age >70) and 23 (52%) have high-risk cytogenetic abnormalities (HRCA) including 13 (30%) with >2 high-risk abnormalities (6 pts unknown cytogenetics). 34/39 (87%) have MRD trackable by clonoSEQ. The rate of sCR and/or MRD(-) by NGS at the end of C8 is 19/33 (58%), meeting the statistical threshold for establishing efficacy (2 pts censored for elective ASCT before C8 and 4 pts receiving therapy but have not reached C8). With a median follow-up of 24 months, estimated 2-year progression free survival is 87% (100% for standard risk, 79% for HRCA) and estimated 2-year overall survival is 89% (82% for HRCA). No pt who was MRD(-) by NGS after C8 has progressed, including 6 pts with HRCA. Serious adverse events occurred in 30 pts (68%). 89% experienced treatment emergent AEs, the most common (>10%) of which was pneumonia (14%). One pt had grade 5 myocardial infarction. Conclusions: Elo-KRd demonstrates tolerability consistent with known toxicities of these agents and met the primary endpoint of sCR and/or MRD(-) of >50% after 8 cycles. With longer follow-up, the study results may validate that an MRD-adaptive design for de-escalation of therapy in MM can generate deep responses while reducing treatment exposure. Clinical trial information: NCT02969837.

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