Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Waldenstrom's Macroglobulinemia Patients

Abstract Background Waldenstrom's Macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with immunoglobulin M (IgM) monoclonal gammopathy. Bruton's tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone, particular in patients harboring MYD88 L265P mutations. However, due to target selectivity issue, Clinical uses of early BTK inhibitors are still compromised with off-target activities to many other kinases besides BTK. Orelabrutinib is a novel, highly potent small molecule inhibitor of BTK with superior selectivity for B-cell malignancies and autoimmune diseases. Preliminary efficacy and safety data of ICP-CL-00105 in relapsed/refractory WM patients are presented here. Methods ICP-CL-00105 is a single arm, multiple centers, open label, phase 2 study in clinical and histopathological confirmed patients with R/R WM requiring treatment per IWWM-7. MYD88 and CXCR4 mutations were assessed in bone marrow samples at baseline. Orelabrutinib at a daily dose of 150mg was administered orally until disease progression or unacceptable toxicity. Blood samples for IgM were assessed at baseline and every cycle for 6 cycles and every 3 cycles thereafter by central lab. Responses were assessed in accordance with IWWM-6 and NCCN guidelines. The primary endpoint was major response rate (MRR) as assessed by IRC. Key secondary endpoints were MRR as assessed by investigator, overall response rate (ORR), duration of major response (DOMR), progression-free survival (PFS), OS, changes in IgM levels from baseline, improvement on hemoglobin levels and safety. Treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs) were assessed according to NCI CTCAE v4.03. Results As of June 1, 2021, for the 47 patients the median follow-up duration was 10.5 months. The median age was 63 years (range, 56-68 years), 40 patients (85.1%) were male. 87.2% of patients were at intermediate or high risk according to the Prognostic Scores (IPSS). The proportion of patients with MYD88 L265PCXCR4 wildtype was 83% at baseline. With a median duration of treatment of 9.2 months, MRR was 74.5% as assessed by investigator. ORR was 87.2% with 97.9% patients achieved disease control. The estimated 12-month DOMR were 89.5%. The estimated 12-month PFS and OS were 88.0% and 92.3%, respectively. The median PFS and median OS have not been reached. The MRR was higher in patients with MYD88 L265PCXCR4 wildtype (79.5%). The median IgM level was 30.3g/L at baseline. The decline in the serum IgM levels from baseline were observed with a median reduction by 79.0% (IQR: -89.4, -57.2). The median hemoglobin level at baseline was 102g/L. Durable improvement in hemoglobin levels was found in 83% of patients with a median maximal improvement of 40g/L (IQR: 24.0, 62.0). Safety data were summarized by the cutoff date of June 1, 2021. The most commonly reported AEs were thrombocytopenia (27.7%)，neutropenia (14.9%), leukopenia (10.6%), upper respiratory infection (14.9%)，weight increased (14.9%), influenza-like disease (12.8%) and rash (10.6%). Most reported AEs (89.5%) were grade 1-2. 16 patients (34.0%) reported grade ≥ 3 TEAE while 9 patients (19.1%) reported grade ≥ 3 TRAE. There was no reported grade ≥3 atrial fibrillation and/or atrial flutter, or grade ≥3 diarrhea. Only One TRAE (2.1%) resulted in drug discontinuation. Conclusion Orelabrutinib has demonstrated substantial efficacy in treating r/r WM patients under short-term follow-up. It has shown favorable safety and tolerability profile with limited off-target adverse effects. It has the potential to be a promising treatment option for r/r WM patients. Disclosures Hu: Astellas Pharma, Inc.: Research Funding. Tian: Innocare pharma: Current Employment. Zhu: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment. Zhao: Innocare pharma: Current Employment. Zhang: Innocare pharma: Current Employment.

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R2W: Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) Versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for Initial Therapy of WaldenstrőM's Macroglobulinemia: A Randomised Phase II Study

Blood ◽

10.1182/blood.v128.22.618.618 ◽

2016 ◽

Vol 128 (22) ◽

pp. 618-618 ◽

Cited By ~ 8

Author(s):

Rebecca L Auer ◽

Roger G Owen ◽

Shirley D'Sa ◽

Guy Pratt ◽

Bilyana Popova ◽

...

Keyword(s):

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Waldenström’S Macroglobulinemia ◽

Major Response ◽

Trial Treatment ◽

Duration Of Response ◽

Grade 3 ◽

Waldenström's Macroglobulinemia

Abstract Introduction Earlier studies have indicated that the combination of bortezomib and rituximab is highly active in Waldenstrőm's macroglobulinemia (WM). However, there is scope to improve the complete response rate, duration of response and toxicity profile. We evaluated the efficacy and tolerability of the addition of cyclophosphamide to bortezomib and rituximab in previously untreated patients with WM. Methods Symptomatic treatment-naïve patients were enrolled into this prospective randomised (2:1), multicentre, non-comparative Phase II study (NCT01592981). Patients were stratified according to the International Prognostic Scoring System for WM. Patients were treated with BCR (Bortezomib 1.6 mg/m2 s.c. days 1, 8, 15; Cyclophosphamide 250 mg/m2 oral days 1, 8, 15; Rituximab 375mg/m2 i.v. days 1, 8, 15, 22 cycles 2 and 5 only) or FCR (Fludarabine 40mg/m2 oral days 1-3; Cyclophosphamide 250 mg/m2 oral days 1-3; Rituximab 375mg/m2i.v. days 1, 8, 15, 22 cycles 2 and 5 only) for 6 cycles repeated every 28 days. Rituximab and bortezomib were provided free of charge by Roche and Janssen, respectively. The primary endpoint was investigator assessed overall response rate (ORR) using consensus criteria. Results Sixty patients were enrolled into this study and 59 received trial treatment (BCR=42, FCR=17). Of all registered patients, 73% were male, median (range) age was 67 years (43-87), Haemoglobin 9.8 g/dL (6.5-14.0), serum IgM paraprotein 34 g/L (3.2-80.2), plasma viscosity 3.6 mPa.s (2.0-9.3) and 25/30/45% were low/intermediate/high risk respectively. Six cycles were completed by 92.9% of BCR and 76.5% of FCR patients, one patient withdrew from the study prior to starting trial treatment. Dose reductions were needed in 38.1% of BCR and 52.9% of FCR patients and treatment delays occurred in 64.3% of BCR and 64.7% of FCR patients. ORR was 97.6% in BCR patients with 78.6% achieving a major response (CR=1, VGPR=8, PR=24, MR=7, SD=1), one patient was not assessed as no evidence of WM was found upon central review; 82.4% in FCR patients with a major response rate of 76.5% (CR=0, VGPR=3, PR=10, MR=1, SD=2), one patient stopped treatment after cycle 1 due to continuing cytopenia (grade 4). Responses were also evaluated in both marrow and peripheral blood using a disease specific multiparamater flow cytometric assay. After a median follow-up of 18 months, 54 patients were progression-free; 3 patients progressed (all BCR) and 3 patients died, 2 from myelodysplastic syndrome (MDS) (both FCR) and 1 from pneumonia (BCR). Grade 3 or higher toxicities included anemia (5 [11.9%] BCR; 3 [17.6%] FCR), neutropenia (11 [26.2%] BCR; 12 [70.6%] FCR), thrombocytopenia (7 [16.7%] BCR; 6 [35.3%] FCR) and infection (2 [4.8%] BCR; 5 [29.4%] FCR). No grade 3 or higher neuropathy was reported. Conclusions BCR and FCR are both highly effective treatments for primary therapy of WM but FCR is associated with increased toxicity and concerning incidence of secondary MDS. BCR warrants further investigation in a randomised Phase III trial. Continued follow-up of R2W patients is also important to provide reliable estimates for duration of response, progression-free survival and overall survival. Disclosures Auer: Janssen: Consultancy, Other: Drug provided for clinical trial; Bristol Myers Squibb: Consultancy. Owen:Janssen: Consultancy; Roche: Honoraria; Pharmacyclics: Consultancy.

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

Blood ◽

10.1182/blood.v108.11.2770.2770 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2770-2770

Author(s):

Luis Fayad ◽

Michael Overman ◽

Barbara Pro ◽

Peter McLaughlin ◽

Felipe Samaniego ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Bulky Disease ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

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

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Bortezomib (Velcade ™) Observational Study in China: Efficacy and Safety of Bortezomib-Based Regimen in 395 Relapsed or Refractory Multiple Myeloma Patients

Blood ◽

10.1182/blood.v112.11.5179.5179 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5179-5179

Author(s):

Zhi-Xiang Shen ◽

Hua Yan ◽

Linna Wang

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Observational Study ◽

Response Rate ◽

Complete Response ◽

Chinese Patients ◽

Efficacy And Safety ◽

Female Ratio ◽

Bortezomib Treatment ◽

Grade 3

Abstract Introduction: Multiple myeloma (MM) is a plasma-cell malignancy and overall survival for patients who have relapsed after initial therapy is approximately 2 years. Bortezomib (VELCADE TM) is a first-in-class proteasome inhibitor that has demonstrated significant anti-tumor activity in MM patients. Here we report the results of an observational study of the efficacy and safety of bortezomib-based regimens in Chinese relapsed/refractory MM patients. Methods: This was a multi-center, open-label, phase IV observational study designed to enroll 550 patients with relapsed or refractory MM. From Mar 2006 to May 2008, 500 patients with relapsed or refractory MM were enrolled from 43 medical centers in China and 395 of them were evaluated. Bortezomib (0.7 to 1.6 mg/m2 i.v.) was given on days 1, 4, 8, and 11 in in a 21-day cycle, up to a maximum of 8 cycles, combined with other agents, mainly with the addition of dexamethasone (60.1%). Major endpoint included response rate, safety and time to response. Responses of 62% patients were determined by European Group for Blood and Marrow Transplantation criteria (EBMT). Bortezomib withheld if patients developed neutropenia fever, grade 4 haematologic adverse events (AEs), or grade 3 non-haematologic AEs, and re-administered at 75% of the initial dosage after recovery. Results: In 395 evaluable cases, the median age was 59 years (range 35–82) and the male/female ratio was 1.5:1. 90% of patients were in late stage(stage II/III) and 50% of them were IgG subtype. Patients had received various prior therapies before bortezomib treatment, including VAD (31.3%), VBMCP (M2, 15.1%) and thalidomide-based regimens(14.9%), with best response rate of 10.4% complete response (CR) and 42.3% partial response (PR) from prior therapies. 311 (82%) cases of patients received 1.0–1.4mg/m2 bortezomib-based regimens treatment and 38.5% of them received at least 4 cycles of treatment. 364 patients were evaluable for response, the overall response rate was 287/364 (78.8%), 89 patients (24.5%) achieved a CR, 30(8.24%) had a nearly complete response (nCR), 168 (46.2%) had a PR, 39 (10.7%) had minimal response (MR), 24 (6.6%) had stable disease (SD), and the other 14 (3.9%) had progressive disease (PD). Median time to response was 1 cycle of treatment (range 1–6). Patients who received 4 or more cycles of bortezomib treatment achieved a higher response rate (CR+PR: 81.5%) compared to those who received fewer cycles (partly due to adverse events). And prognosis-related analysis showed that the dosage of bortezomib at 1.0 mg/m2 or more had a significant influence on the time to response and response rate, but no obvious effect on response duration, time to progress or the survival time. Drug related adverse events (AEs) were reported in 50.4% of patients during treatment, including hematologic AEs (mainly thrombocytopenia, 22.5%), gastrointestinal AEs (24.8%), and peripheral neuropathy (22.5%). The rates of grade 3–4 AEs of them were 46.1%, 11.2% and 15.7%, respectively. Serious AEs occurred in 33 (8.4%) cases and 23 (70%) patients recovered finally. Most AEs were predictable and manageable. Conclusion: Bortezomib-based regimen is effective treatment with higher response rate and is well tolerated in most Chinese patients with relapsed and refractory MM patients. Long-term follow-up is continuing.

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Single-agent bortezomib in previously untreated multiple myeloma (MM): Results of a phase II multicenter study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7504 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7504-7504 ◽

Cited By ~ 15

Author(s):

K. Anderson ◽

P. Richardson ◽

A. Chanan-Khan ◽

R. Schlossman ◽

N. Munshi ◽

...

Keyword(s):

Response Rate ◽

Axonal Neuropathy ◽

Single Agent ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Time To Progression ◽

Large Fiber ◽

Grade 3 ◽

Dose Modifications

7504 Background: Bortezomib is effective in relapsed and/or refractory MM. This trial evaluated its efficacy and safety as monotherapy in previously untreated MM. Methods: Pts with untreated, symptomatic MM were eligible, with pts receiving concomitant steroids, platelet count < 30 × 109/L, or grade > 2 peripheral neuropathy [PN] excluded. Endpoints included response rate (RR) [Bladé criteria], time to progression, safety, incidence/severity of PN, and effect of dose modifications on PN. Pts received bortezomib 1.3 mg/m2 (d1, 4, 8, 11 every 21d) for 8 cycles. Comprehensive neurologic evaluation including electrophysiologic testing [NCS] and skin biopsy was performed in a subset of pts (n = 34). Results: Sixty-six pts (47% with stage III MM) were treated and 60 pts are evaluable for response, with an overall RR of 38% (CR 10%, PR 28%). PN was reported in 55% (36/65) pts (23 grade 1, 12 grade 2). One pt with grade 3 PN was discontinued. Other common treatment-associated adverse events reported to date include grade 1–2 fatigue in 21% (6/29), and rash in 17% (5/29) pts. Preliminary analysis shows PN improved or resolved in 75% (6/8 pts, with available follow-up data) with dose reduction. At baseline, small-fiber neuropathy (SFN) was seen in 52% (17/33) and large fiber axonal neuropathy (LFN) occurred in 9% (3/34) pts by NCS. SFN worsened in 41% (7/17) pts with baseline SFN. After completion of treatment, new SFN was seen in 33% (8/24) pts and LFN in 17% (4/24) pts by NCS. Conclusion: Single agent bortezomib is active in newly diagnosed MM pts (CR 10%), has manageable toxicity and offers a steroid-sparing approach. Underlying SFN appears more common in MM than previously appreciated and can also develop during bortezomib therapy, with symptomatic PN improving with dose modification. [Table: see text]

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Efficacy and Safety of the TCM Qi-Supplementing Therapy in Patients with Myasthenia Gravis: A Systematic Review and Meta-Analysis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/6512572 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Xi-qian Yang ◽

Ling Liu ◽

Wen-yu Yang ◽

Huan-huan Dong ◽

Yi-ran Yang ◽

...

Keyword(s):

Adverse Events ◽

Myasthenia Gravis ◽

Relapse Rate ◽

Response Rate ◽

Meta Analysis ◽

Effective Rate ◽

Efficacy And Safety ◽

Total Response ◽

Total Response Rate

Background. The Traditional Chinese Medicine (TCM) Qi-supplementing therapy has been used widely for treating myasthenia gravis (MG) in China. The purpose of this meta-analysis was to evaluate the efficacy and safety of Qi-supplementing therapy as an adjunctive therapy in MG patients. Methods. Seven electronic databases were searched through June 2016. Randomized controlled trials (RCTs) evaluating the add-on effect of Qi-supplementing therapy in MG patients were included. The outcome measures were the total effective rate, relapse rate, and adverse events. Results. Twenty-three RCTs involving 1,691 MG patients were included. The included studies were of low-to-moderate quality. Meta-analysis showed that Qi-supplementing therapy combined with Western medicine (WM) significantly improved the total response rate and reduced the relapse risk during 6–24 months of follow-up. Subgroup analysis showed that Qi-supplementing therapy only affected the total response rate within the first 6 months of treatment. Moreover, the rate of adverse events was lower with the addition of Qi-supplementing therapy to WM than with WM only. Conclusions. Short-term Qi-supplementing therapy combined with WM appears to be superior to WM for improving the total response rate and reducing the relapse rate. However, more high-quality RCTs are warranted owing to methodological flaws of previous trials.

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Final safety results of BO17704 (AVAiL): A phase III randomized study of first-line bevacizumab (Bv) and cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8039 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8039-8039

Author(s):

V. Hirsh ◽

R. Ramlau ◽

J. von Pawel ◽

P. Zatloukal ◽

G. Vera ◽

...

Keyword(s):

Adverse Events ◽

Advanced Nsclc ◽

Response Rate ◽

Randomized Study ◽

Locally Advanced ◽

Safety Data ◽

Final Analysis ◽

Phase Iii ◽

Platinum Based Chemotherapy ◽

Grade 3

8039 Background: AVAiL, an international placebo-controlled phase III trial, showed that Bv-based therapy significantly improved PFS and response rate in patients with advanced/recurrent NSCLC. This report summarizes overall safety findings from AVAiL. Methods: AVAiL randomized 1,043 patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC to C 80mg/m2 (d1) and G 1,250mg/m2 (d1 and d8) q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (n=331 with safety data), Bv 15mg/kg q3w (n=329) or placebo (n=326). Bv/placebo was administered until disease progression. Primary endpoint was PFS; secondary endpoints included OS, response rate, and safety. Safety was measured using NCI-CTC version 3.0 criteria for adverse events (AEs). Results: At final analysis, the median/maximum duration of Bv therapy was 4.9/28.5 mo (Bv 7.5) and 4.3/23.4 mo (Bv 15). The most common AEs overall were hematological and gastrointestinal (GI), and occurred in similar proportions of pts in the Bv and placebo arms. Grade ≥3 AEs occurred in 80%, 83%, and 77% of pts in the Bv 7.5, Bv 15 and placebo arms, respectively. The most common grade ≥3 adverse events were hematological, mainly neutropenia and thrombocytopenia. Neutropenia was reported in 43% (Bv 7.5), 40% (Bv 15) and 34% (placebo) of pts. Grade ≥3 AEs of special interest included hypertension (7%, 9% and 2%), proteinuria (2%, 3% and 0%), bleeding (4%, 5% and 2%) and hemoptysis (0.5%, 1.2% and 1.3%). The incidence of grade 5 hemoptysis was low (0.9%, 0.9% and 0% of pts, respectively). The incidence of GI perforations (<1%), thromboembolic events (≤8%), CHF (≤1%) and wound healing complications (<1%) was low and similar between treatment arms. The incidence of serious AEs was 39%, 45% and 36% in the Bv 7.5, Bv 15 and placebo arms, respectively. No new safety signals were reported. Conclusions: After E4599, AVAiL further demonstrated the efficacy of Bv in combination with platinum-based chemotherapy in the treatment of advanced NSCLC. Final safety data confirm the well established and manageable safety profile of Bv-based therapy in pts with advanced NSCLC. [Table: see text]

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Daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (CASTOR).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.8036 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 8036-8036 ◽

Cited By ~ 4

Author(s):

Suzanne Lentzsch ◽

Katja C. Weisel ◽

Maria-Victoria Mateos ◽

Vania Hungria ◽

Markus Munder ◽

...

Keyword(s):

Residual Disease ◽

Randomized Study ◽

Safety Data ◽

Efficacy And Safety ◽

Depth Of Response ◽

Common Grade ◽

Previously Treated ◽

Grade 3 ◽

Line Of Therapy

8036 Background: Daratumumab (D), a human, CD38-targeting mAb, is well tolerated and induces deep and durable responses in patients (pts) with RRMM. We provide an update of CASTOR (NCT02136134), a multicenter, phase 3, randomized study of DVd vs Vd in RRMM. Methods: All pts received ≥1 prior line of therapy (LOT) and were administered 8 cycles (Q3W) of Vd (1.3 mg/m2 SC bortezomib on days 1, 4, 8, and 11; 20 mg PO/IV dexamethasone on days 1-2, 4-5, 8-9, and 11-12) ± D (16 mg/kg IV once weekly in Cycles 1-3, every 3 weeks for Cycles 4-8, then every 4 weeks until progression). Bortezomib-refractory pts were ineligible. Minimal residual disease (MRD) was assessed upon suspected CR and at 6 and 12 months following the first dose at sensitivities of 10–4, 10–5, and 10–6using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 2 (1-10) prior LOTs. 66% were previously treated with bortezomib and 21% were refractory to lenalidomide in their last prior LOT. After a median follow-up of 13.0 months, PFS was significantly prolonged with DVd vs Vd (median: not reached vs 7.1 months; HR, 0.33; 95% CI, 0.26-0.43; P< 0.0001). This PFS benefit was seen regardless of number of prior LOTs received, with greatest benefit observed in 1 prior line pts (median: not reached vs 7.9 months; HR, 0.22; 95% CI, 0.14-0.34; P< 0.0001). ORR was also significantly higher for DVd vs Vd (84% vs 63%), along with ≥VGPR (62% vs 29%) and ≥CR (26% vs 10%; P< 0.0001 for all). MRD-negative rates were ≥4-fold higher at all three sensitivity thresholds with DVd vs Vd (10% vs 2% at 10–5 threshold). Pts who achieved MRD negativity demonstrated prolonged PFS compared with MRD-positive pts. 37 (15%) and 58 (24%) deaths were observed in DVd vs Vd, respectively, and follow up is ongoing. The most common grade 3/4 TEAE was thrombocytopenia (45% vs 33%). Updated efficacy and safety data will be presented. Conclusions: DVd provided significant benefits with respect to PFS, ORR, depth of response, and MRD-negative rate vs Vd. No new safety signals were reported. These data continue to support the use of DVd in RRMM pts and indicate that pts with 1 prior LOT will derive the most benefit. Clinical trial information: NCT02136134.

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Efficacy and Safety of FCR (Fludarabine, Cyclophosphamide, Rituximab) Followed by Yttrium-90 Ibritumomab Tiuxetan in Relapsed Follicular Lymphoma (FL) Patients

Blood ◽

10.1182/blood.v112.11.5003.5003 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5003-5003

Author(s):

Francesco Pisani ◽

Carlo Ludovico Maini ◽

Rosa Sciuto ◽

Laura Dessanti ◽

Antonio Spadea ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Efficacy And Safety ◽

Ibritumomab Tiuxetan ◽

Prior Therapy ◽

Number Of Patients ◽

Grade 3 ◽

The Impact ◽

Yttrium 90

Abstract Background: FCR regimen has provided encouraging results in FL and Yttrium-90 Ibritumomab Tiuxetan (90Y-RIT) has been reported to be effective in patients with relapsed or refractory FL. Our study investigates the efficacy and safety of 90Y-RIT consolidation in relapsed FL patients, responding to second-line with FCR. Methods: At date reporting for this abstract we have recruited 10 patients median age 63 yrs (range 46–77). All enrolled patients were relapsed patients with histologically confirmed CD20-positive (grade 1 or 2) FL according to WHO classification. Major inclusion criteria were: age ≥ 18 years, WHO performance status of 0, 1 or 2, no prior therapy with Rituximab for 3 months and at the completion of FCR, patients achieving at least PR, with < 25% bone marrow involvement, with neutrophil count ≥ 1500/microlitre and platelet count ≥ 100000/microlitre. All patients at relapse received every 28 days FCR: F (25mg/m2×3 days), C (1gr/m2day1) and R (375mg/m2day4) for 4 cycles. Patients were restaged 4 to 8 weeks after the last course of FCR; who achieved at least a partial remission was eligible for Yttrium-90 Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg (0.3–0.4 mCi/Kg) up to a maximum dose 1184 MBq at 3 months after the completion of FCR. The patients were restaged with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy at 4 to 8 weeks after the last cycle of FCR. A complete blood cell count was obtained once a week for 12 weeks after 90Y-RIT treatment. A history and physical examination were performed together with renal and liver function once a months for 3 months after 90Y-RIT. All patients received prophylaxis with trimethoprim-sulfamethoxazolo and valacyclovir from initiation of therapy until 3 ≥ months following therapy with 90Y-RIT. Results: Between August 2005 and March 2008 nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 0.4 mCi/Kg, 3 patients at 0.3 mCi/Kg) and one patient is under treatment. All 10 patients were relapsed patients: 6 patients received 1 or 2 prior therapy regimens and 4 patients had received 3 to 5 regimens. Eight of them were previously treated with Rituximab plus chemotherapy, 2 patients had no previous Rituximab treatment history, one also had ABMT. After FCR 6 patients obtained CR and 3 PR; after 90Y-RIT treatment the ORR was 100% and CCR was 100% with median follow up of 13 months (range 5–26) and all patients are alive in CR; 3 patients in PR after FCR regimen converted to CR by 90Y-RIT. The most common grade 3 or 4 adverse events were hematologic: grade 3 or 4 neutropenia occurred in 10/10 patients treated with FCR and grade 3 or 4 neutropenia and thrombocytopenia in 9/9 patients assessable after 90Y-RIT. Following treatment with 90Y-RIT the median neutrophil nadir was 0.5 × 109/L (range 0.3 – 1.09 ×109/L) at week 5; the median platelet count nadir was 40 × 109/L ( range 12–81 × 109/L ) at week 6. One patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungus infection. No other severe infection have been recorded, no nonhematologic adverse event have been registered so far. Conclusion: Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with FL. Hematologic toxicity occurring with FCR or with radio-immunotherapy are clinically controllable and acceptable in the population composed mainly of patients with a history of prior treatment using rituximab plus chemotherapy. A longer follow up and a larger number of patients with relapsed FL are required to determine the impact of this regimen on long-term duration of response and EFS.

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Bendamustine, Bortezomib and Dexamethasone (BVD) in Patients with Relapsed-Refractory Multiple Myeloma (MM): Updated Results of a Multicenter Phase II Study

Blood ◽

10.1182/blood.v124.21.4734.4734 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4734-4734

Author(s):

Massimo Offidani ◽

Laura Maracci ◽

Laura Corvatta ◽

Liberati Anna Marina ◽

Stelvio Ballanti ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Prior Treatment ◽

New Drugs ◽

Induction Phase ◽

Grade 3 ◽

Therapy Reduction

Abstract Introduction: Bendamustine, a bifunctional alkylating agent, exerts a mechanism of action different from that of other conventional alkylators despite it remains mostly unknown. In patients with newly diagnosed or relapsed-refractory MM bendamustine has proven to be active either as monotherapy or in combination with new drugs, particularly bortezomib and immunomodulatory agents. Methods: The preliminary results of this prospective, phase II study conducted in 22 Italian centres are recently published (Blood Cancer J. 2013, 3: e162). Here we present the conclusive results of the combination Bendamustine (70 mg/m2 days 1, 8), Bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and Dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD) administered every 4 weeks in patients with relapsed-refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy. The primary endpoint of this study was achievement of a response at least PR, as to IMWG criteria, after four cycles of BVD. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Results: 75 patients were included in the study. Median age was 68 years (range 41-85 years), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. Eight of 36 evaluable patients (22%) had high-risk cytogenetics. Patients had received a median of one prior line of therapy (range 1-4). All patients had received prior treatment with new drugs, such as thalidomide (57%), lenalidomide (54.5%), bortezomib (46.5%) or both (20%). Twenty-four patients (32%) were refractory to IMIDs. Best response rate was 75%, including 14 CRs (20%), 22 VGPRs (24%) and 27 PRs (31%). Five patients (6.5%) died early. Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (48.5% vs 80%; P = 0.004). At a median follow-up of 27 months (range 18-38), 45 patients had progressed and 43 had died. Median TTP and PFS were 17 and 12.5 months, respectively while median OS was 24 months (40% at 3 years). After longer follow-up, prior therapy with bortezomib plus lenalidomide was confirmed as the only factor that significantly reduced TTP (9 vs 19 months; HR = 2.7; 95% CI = 1.3-5.8; P = 0.009), PFS (9 vs 15 months; HR = 2.1; 95% CI = 1.2-3.8; P = 0.020) and OS (17 vs 32 months; HR = 2.1; 95% CI = 1.2-3.9; P = 0.043). Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 24% and to protocol discontinuation in 11% of patients. The most frequent severe adverse events were thrombocytopenia (28%), neutropenia (20%), infections (12%), peripheral neuropathy (9%), gastrointestinal (5%) and cardiovascular events (4%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 side effects particularly thrombocytopenia and infections with, consequently, a higher rate of therapy reduction and discontinuation. Moreover, 4/5 early deaths occurred in patients aged more than 70 years. Conclusions: BVD combination is an effective and well tolerated regimen in relapsed-refractory MM. Data suggest that the optimal target of BVD maybe patients younger than 70 years who has not previously received both bortezomib and lenalidomide. Disclosures Offidani: Mundipharma, Janssen: Honoraria. Off Label Use: Bendamustine. Corvatta:Janssen: Honoraria. Ballanti:Janssen: Honoraria. Brunori:Janssen: Honoraria.

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KEYNOTE-365 cohort B: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)–pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—New data after an additional 1 year of follow-up.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.10 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 10-10

Author(s):

Leonard Joseph Appleman ◽

Michael Paul Kolinsky ◽

William R. Berry ◽

Margitta Retz ◽

Loic Mourey ◽

...

Keyword(s):

Oral Prednisone ◽

Safety Data ◽

Efficacy And Safety ◽

Castration Resistant Prostate Cancer ◽

Psa Response ◽

Positive Score ◽

Previously Treated ◽

Combined Positive Score ◽

Grade 3

10 Background: For men with mCRPC, systemic therapies such as docetaxel and cabazitaxel improve survival, but more effective treatments are needed. KEYNOTE-365 (NCT02861573) is a phase 1b/2 study to examine the safety and efficacy of pembro in combination with 4 different study medications (cohorts A, B, C, D) in mCRPC. Previous data from cohort B with a median of 20 months of follow-up showed that pembro + docetaxel and prednisone was well tolerated and had antitumor activity in patients (pts) with mCRPC previously treated with abi or enza. New efficacy and safety data after an additional year of follow-up are presented. Methods: Cohort B enrolled pts who did not respond to or were intolerant to ≥4 weeks of abi or enza in the prechemotherapy mCRPC state and whose disease progressed within 6 months of screening (determined by PSA progression or radiologic bone/soft tissue progression). Pts received pembro 200 mg IV every 3 weeks (Q3W), docetaxel 75 mg/m2 IV Q3W, and oral prednisone 5 mg twice daily. Primary end points were safety, PSA response rate (PSA decrease >50% from baseline), and ORR per RECIST v1.1 by blinded independent central review. Efficacy and safety were assessed in all pts as treated. Results: Of the 104 treated pts, median age was 68.0 years (range, 50-86), 23.1% had PD-L1–positive tumors (combined positive score ≥1), 25.0% had visceral disease, and 50.0% had measurable disease. Median time from enrollment to data cutoff was 32.4 months (range 13.9-40.3); 101 pts discontinued, primarily because of disease progression (77.9%). Efficacy outcomes are reported in the table below. Treatment-related adverse events (TRAEs) occurred in 100 pts (96.2%); the most frequent (≥30%) were diarrhea (41.3%), fatigue (41.3%), and alopecia (40.4%). Grade 3-5 TRAEs occurred in 46 pts (44.2%). Five pts (4.8%) died of AEs; 2 were treatment-related pneumonitis. Conclusions: After another year of follow-up, pembro + docetaxel and prednisone showed improved ORR and PSA response rates compared to the prior dataset in pts with mCRPC previously treated with abi or enza. Safety was consistent with known profiles of each agent and will be further evaluated in a phase 3 study (KEYNOTE-921). Clinical trial information: NCT02861573. [Table: see text]

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