Pembrolizumab and Chemotherapy As First-Line Treatment of Patients with Newly Diagnosed Early Unfavorable or Advanced-Stage Classical Hodgkin Lymphoma: The Phase 2 Keynote-C11 Study

Abstract Background: Immunotherapeutic strategies targeting the PD-1/PD-L1 pathway have become part of standard of care for patients with classical Hodgkin lymphoma (cHL). Recent studies have investigated combinations of anti-PD-1 antibodies with conventional chemotherapy and demonstrated significant clinical benefits in the first-line setting. A phase 2 trial demonstrated that induction with pembrolizumab monotherapy followed by chemotherapy was highly effective and safe in patients with newly diagnosed, early unfavorable, or advanced-stage cHL (Allen PB et al. Blood. 2020;137[10]:1318-1326). The KEYNOTE-C11 open-label phase 2 study will build on this concept by evaluating the safety and efficacy of sequential pembrolizumab monotherapy and chemotherapy followed by pembrolizumab consolidation in adult patients with newly diagnosed, early unfavorable, or advanced-stage cHL. Study Design and Methods: Patients must have newly diagnosed, histologically confirmed, untreated (no prior chemotherapy, immunotherapy, or other systemic therapy for cHL), early unfavorable cHL (Ann Arbor stage I/II plus ≥1 National Comprehensive Cancer Network unfavorable risk factor) or advanced-stage cHL (Ann Arbor stage III/IV) and measurable disease per Lugano 2014 classification. Approximately 140 patients will be enrolled. All patients will receive pembrolizumab 200 mg IV every 3 weeks (Q3W) for 3 cycles followed by PET to determine response to pembrolizumab monotherapy. After pembrolizumab induction, all patients will receive 2 cycles of AVD (day 1 and day 15 Q4W) and undergo another assessment by PET (PET 3) to determine the next treatment course. Patients with negative findings on PET 3 (≤3 on the Deauville 5-point scale) will receive 2-4 additional cycles of AVD, depending on stage and bulk of disease; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will proceed to 4 cycles of AVD chemotherapy. Patients who are PET 3+ (≥4 on the FDG-PEG 5-point scale) and aged <60 years will transition to 2-4 cycles of escBEACOPP; those with nonbulky early unfavorable disease will receive 2 cycles, and all others will receive 4 cycles. Patients aged ≥60 years who are PET 3+ will not transition to escBEACOPP and will continue to receive AVD. Finally, all patients will receive 4 cycles of pembrolizumab 400 mg Q6W after the completion of chemotherapy. They will remain on study treatment until disease progression, unacceptable toxicity, illness preventing continuation, investigator's decision, or maximum duration of treatment, which will include 4 cycles of pembrolizumab consolidation. Adverse events will be graded per CTCAE version v5.0. The primary end point is complete response assessed by blinded independent central review (BICR) per Lugano 2014 response criteria. Secondary end points include complete response by investigator per Lugano 2014 response criteria, BICR-assessed PET negativity (score of 1, 2, or 3 per FDG-PET 5-point scale), BICR-assessed duration of complete response per Lugano 2014 response criteria, and safety and tolerability. Exploratory end points include modified progression-free survival and overall survival. The efficacy and safety analysis population will consist of all patients who received ≥1 dose of pembrolizumab. The complete response rate with 95% CI will be reported per the Clopper-Pearson exact binomial method. Duration of complete response, progression-free survival, and overall survival will be evaluated using Kaplan-Meier method. Counts and percentages of patients with adverse events will be provided. Disclosures Winter: Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy; Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria. Nahar: Merck: Current Employment. Kim: Merck: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder.

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Weekly Carfilzomib, Cyclophosphamide and Dexamethasone (wCCyd) in Elderly Newly Diagnosed Multiple Myeloma Patients: Results of a Phase 2 Study

Blood ◽

10.1182/blood.v126.23.1828.1828 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1828-1828 ◽

Cited By ~ 2

Author(s):

Sara Bringhen ◽

Davide Rossi ◽

Alessandra Larocca ◽

Paolo Corradini ◽

Piero Galieni ◽

...

Keyword(s):

Partial Response ◽

Adverse Events ◽

Board Of Directors ◽

Phase 1 ◽

Progression Free Survival ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Background Carfilzomib is a novel second generation proteasome-inhibitor with significant anti-MM activity and favorable toxicity profile. In a recent phase 1/2 study in relapsed/refractory patients (pts) a weekly schedule of carfilzomib in combination with dexamethasone showed to be effective (overall response rate of 77%) and safe (ASCO 2015). The ongoing phase 3 ARROW study is comparing once- with twice-weekly carfilzomib. In the newly diagnosed setting, no data are available on weekly carfilzomib. We designed a phase 1/2 study of weekly carfilzomib in combination with cyclophosphamide and dexamethasone (wCCyd) for newly diagnosed MM pts. Results of the dose-escalation phase 1 portion of study were previously reported (Palumbo A et al, Blood 2014), the maximum tolerated dose of weekly carfilzomib was established as 70 mg/m2. Here we report efficacy and safety results of the phase 2 portion of the study. Methods Newly diagnosed pts ineligible for autologous stem-cell transplantation due to age or co-morbidities were enrolled in the phase 2 portion of the study. Pts received IV carfilzomib at the maximum tolerated dose 70 mg/m2 on days 1, 8, 15 combined with oral cyclophosphamide at 300 mg/m2 on days 1, 8, 15 and oral dexamethasone at 40 mg on days 1, 8, 15, 22, in 28-daycycles. After the completionof 9 cycles, pts received 28-day maintenance cycles with carfilzomib at 70 mg/m2 on days 1, 8, 15 until disease progression or intolerance. The primary objectives were to determine the efficacy and safety of wCCyd. The secondary objectives included the evaluation of time to progression, progression-free survival, time to next therapy and overall survival. Response was assessed according to the modified International Uniform Response Criteria. Adverse events (AEs) were graded following NCI-CTCAE v4. Results As of July 15, 2015, 47 newly diagnosed MM pts were enrolled in the phase 2 portion of the study. Median age was 72 years, 23% of pts were older than 75 years, 30% had ISS stage III, 34% had unfavorable FISH profile [t(4;14) or t (14;16) or del17p or amp1]. Toxicityand response data were available in 40 pts, who completed atleast the first cycle; 7 pts were still receiving their first cycle of treatment. Pts received a median of 6 cycles (range 1-9). Overall, 80% of pts achieved at least a partial response, 60% at least a very good partial response, and 28% a near complete response. Responses improved over time (Table 1). During the study, 9 pts progressed or died, the progression-free survival at 1 year was 75%. Grade (G) 3-4 drug-related adverse events included neutropenia (22%, 9 pts), thrombocytopenia (7%, 3 pts), infection (10%, 4 pts), acute pulmonary edema (5%, 2 pts), creatinine increase (5%, 2 pts), fever (2.5%, 1 pt), fatigue (2.5%, 1 pt) and headache (2.5%, 1 pt). G1-2 hypertension was reported in 6 pts (15%). No peripheral neuropathy was reported. Overall, the wCCyd regimen was well tolerated, 4 pts (10%) required carfilzomib dose-reduction (G3 hematologic toxicities [2 pts], G3 headache [1 pt] and G2 fatigue [1 pt]) and 9 pts (22%) required treatment discontinuation due to adverse events (2 infections, 1 acute pulmonary edema, 1 creatinine increase, 1 fever, 1 pt condition, 1 second tumor, 1 pericardial effusion, 1 sudden death). Conclusions This is the first prospective study evaluating once-weekly carfilzomib in treatment-naïve MM. wCCyd therapy appears safe and effective in newly diagnosed MM pts. Responses became deeper with subsequent cycles and toxicities were manageable. The response rate observed with weekly carfilzomib compares favorably with similar studies with standard twice-weekly carfilzomib infusion. Updated results will be presented at the meeting. Table 1. 2nd cycle 6th cycle 9th cycle Complete Response 17% 26% 33% At least near Complete Response 29% 39% 40% At least Very Good Partial Response 66% 82% 87% At least Partial Response 86% 87% 87% Disclosures Bringhen: Janssen-Cilag, Celgene, Novartis: Honoraria; Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Larocca:Janssen-Cilag, Celgene: Honoraria. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Gaidano:Celgene, Onyx: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

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High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials

Scientific Reports ◽

10.1038/s41598-020-80724-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Junyao Yu ◽

Huaping Du ◽

Xueshi Ye ◽

Lifei Zhang ◽

Haowen Xiao

Keyword(s):

Meta Analysis ◽

Primary Cns Lymphoma ◽

Central Nervous System Lymphoma ◽

Progression Free Survival ◽

Complete Response ◽

Cns Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Newly Diagnosed ◽

Dose Methotrexate

AbstractWith the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.

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Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.21.01045 ◽

2021 ◽

pp. JCO.21.01045

Author(s):

Pieter Sonneveld ◽

Meletios A. Dimopoulos ◽

Meral Beksac ◽

Bronno van der Holt ◽

Sara Aquino ◽

...

Keyword(s):

Multiple Myeloma ◽

Minimal Residual Disease ◽

Residual Disease ◽

Progression Free Survival ◽

Complete Response ◽

Primary Study ◽

Controlled Clinical Trial ◽

Newly Diagnosed ◽

Consolidation Treatment ◽

Minimal Residual

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

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CTNI-21. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

Neuro-Oncology ◽

10.1093/neuonc/noab196.246 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi63-vi64

Author(s):

Zhong-ping Chen ◽

Cheng-Cheng Guo ◽

Yang Qun-ying ◽

Jia-Wei Li ◽

Shao-xiong Wu ◽

...

Keyword(s):

Dna Methyltransferase ◽

Radiation Treatment ◽

Gene Promoter ◽

Progression Free Survival ◽

Common Adverse Event ◽

Phase 2 ◽

Newly Diagnosed ◽

Phase 2 Study

Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) gene promoter, which confers a limited clinical response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with a methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been conducted to evaluate efficacy and safety of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. The study was conducted in 2 stages: Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). At the end of this stage, 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. All patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. All 29 patients have completed treatment and patients are in the follow-up phase of the study. Consistent with our prior experience, myelosuppression was the most common adverse event. As of March 2021, 22/29 (75.9%) subjects had disease progression. The median progression free survival for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Sixteen (16/29; 55.2%) patients had died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

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Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease

Blood ◽

10.1182/blood-2018-11-884577 ◽

2019 ◽

Vol 133 (16) ◽

pp. 1720-1728 ◽

Cited By ~ 9

Author(s):

Lu Zhang ◽

Ai-lin Zhao ◽

Ming-hui Duan ◽

Zhi-yuan Li ◽

Xin-xin Cao ◽

...

Keyword(s):

Treatment Failure ◽

Progression Free Survival ◽

Castleman Disease ◽

Phase 2 ◽

Newly Diagnosed ◽

Free Survival ◽

Multicentric Castleman Disease ◽

End Point ◽

Phase 2 Study ◽

Grade 3

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti–interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice a week for 1 year) was administered for 2 years or until treatment failure. The primary end point was durable tumor and symptomatic response for at least 24 weeks. Twelve patients (48%) achieved the primary end point with no relapse, 3 patients (12%) demonstrated stable disease, and 10 patients (40%) were evaluated as treatment failure. Even when considering all patients, there were significant (P < .05) improvements in median symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobulin G. Among responders, the median levels of all evaluated parameters significantly improved, to the normal range, after treatment. The regimen was well tolerated. One patient died of pulmonary infection and 1 patient had a grade 3 adverse event (rash); 2 patients died following disease progression. Estimated 1-year progression-free survival and overall survival were 60% and 88%, respectively. The TCP regimen is an effective and safe treatment of newly diagnosed iMCD patients, particularly when siltuximab is unavailable. This trial was registered at www.clinicaltrials.gov as #NCT03043105.

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Phase II Activity of Belinostat (PXD-101), Carboplatin, and Paclitaxel in Women With Previously Treated Ovarian Cancer

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e31825736fd ◽

2012 ◽

Vol 22 (6) ◽

pp. 979-986 ◽

Cited By ~ 50

Author(s):

Don S. Dizon ◽

Lars Damstrup ◽

Neil J. Finkler ◽

Ulrik Lassen ◽

Paul Celano ◽

...

Keyword(s):

Ovarian Cancer ◽

Confidence Interval ◽

Progression Free Survival ◽

Complete Response ◽

Median Number ◽

Clinical Activity ◽

Phase 2 ◽

Resistant Disease ◽

Novel Approach

BackgroundPreclinical data show that belinostat (Bel) is synergistic with carboplatin and paclitaxel in ovarian cancer. To further evaluate the clinical activity of belinostat, carboplatin, and paclitaxel (BelCaP), a phase 1b/2 study was performed, with an exploratory phase 2 expansion planned specifically for women with recurrent epithelial ovarian cancer (EOC).MethodsThirty-five women were treated on the phase 2 expansion cohort. BelCap was given as follows: belinostat, 1000 mg/m2 daily for 5 days with carboplatin, AUC 5; and paclitaxel, 175 mg/m2 given on day 3 of a 21-day cycle. The primary end point was overall response rate (ORR), using a Simon 2 stage design.ResultsThe median age was 60 years (range, 39–80 years), and patients had received a median of 3 prior regimens (range, 1–4). Fifty-four percent had received more than two prior platinum-based combinations, sixteen patients (46%) had primary platinum-resistant disease, whereas 19 patients (54%) recurred within 6 months of their most recent platinum treatment. The median number of cycles of BelCaP administered was 6 (range, 1–23). Three patients had a complete response, and 12 had a partial response, for an ORR of 43% (95% confidence interval, 26%–61%). When stratified by primary platinum status, the ORR was 44% among resistant patients and 63% among sensitive patients. The most common drug-related adverse events related to BelCaP were nausea (83%), fatigue (74%), vomiting (63%), alopecia (57%), and diarrhea (37%). With a median follow-up of 4 months (range, 0–23.3 months), 6-month progression-free survival is 48% (95% confidence interval, 31%–66%). Median overall survival was not reached during study follow-up.ConclusionsBelinostat, carboplatin, and paclitaxel combined was reasonably well tolerated and demonstrated clinical benefit in heavily-pretreated patients with EOC. The addition of belinostat to this platinum-based regimen represents a novel approach to EOC therapy and warrants further exploration.

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Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma

Blood ◽

10.1182/blood-2009-08-233155 ◽

2010 ◽

Vol 115 (3) ◽

pp. 475-480 ◽

Cited By ~ 61

Author(s):

Nicholas Di Bella ◽

Raymond Taetle ◽

Kathryn Kolibaba ◽

Thomas Boyd ◽

Robert Raju ◽

...

Keyword(s):

Median Time ◽

Single Agent ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Complete Response ◽

Low Grade ◽

Free Survival ◽

Ann Arbor ◽

Duration Of Response ◽

Unconfirmed Complete Response

Abstract This study evaluated the efficacy and safety of single-agent bortezomib in indolent B-cell lymphoma that had relapsed from or was refractory to rituximab. Sixty patients enrolled: 59 were treated with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles; responders could receive 4 additional cycles; maintenance was optional. Fifty-three evaluable patients completed more than 2 cycles. The median age was 70 years, 53% female, Ann Arbor stage III-IIIE (28%) and IV (65%); 43 patients (72%) had more than 2 prior regimens; and 6 patients went on to maintenance. Overall responses are as follows: 1 complete response (1.9%), 3 unconfirmed complete response (5.7%), 3 partial response (5.7%), 34 stable disease (64.2%), and 12 progressive disease (22.6%). Median time to response = 2.2 months (range, 1.2-5.3 months); duration of response = 7.9 months (2.8-21.3 months); 1-year survival was 73% and 2-year survival was 58%; median survival = 27.7 months (range, 1.4-30.9 months); median progression-free survival = 5.1 months (range, 0.2-27.7 months), median time to progression = 5.1 months (range, 0.2-27.7 months), and median event-free survival = 1.8 months (range, 0.2-27.7 months). Treatment-related grade 3 or 4 adverse events included: thrombocytopenia (20%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8% each). This study demonstrates that bortezomib has modest activity against marginal zone and follicular lymphoma; it has the potential for combination with other agents in low-grade lymphomas. Maintenance therapy should be explored further.

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Identification Of Diffuse Large b-Cell Lymphoma (DLBCL) Subtypes Defined By The Expression Of Stromal Proteins and Their Association With Proangiomirs and Antiangiomirs

Blood ◽

10.1182/blood.v122.21.3020.3020 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3020-3020

Author(s):

Natalia Morais Borges ◽

Marina Lourenço de Conti ◽

Tathiana Azevedo de Andrade ◽

Maria Dirlei Begnami ◽

Antonio Correa Alves ◽

...

Keyword(s):

Conflicts Of Interest ◽

Antiangiogenic Therapy ◽

B Cell Lymphoma ◽

Tumor Stroma ◽

Complete Response ◽

High Expression ◽

Advanced Stage ◽

Nucleic Acid Isolation ◽

Ann Arbor ◽

Low Expression

Abstract The identification of subtypes of DLBCL defined by expression of genes related to tumor stroma (Lenz et al, 2008) may determine new paths in the treatment of these diseases using anti-angiogenic drugs. The relationship of these genes with the pro- and antiangiomiRs is still unknown. Aims 1) to classify DLBCL cases according to the signature stromal-1 and stromal-2 using tissue microarray (TMA) and immunohistochemistry; 2) to evaluate the expression of pro- and antiangiomiRs in paraffin embedded tissues affected by DLBCL and correlate them with the signatures of the tumor stroma. Methods 111 DLBCL (NOS and variants, all HIV negative) admitted to the Hospital São Paulo between 2000 and 2010 were included in this study. Expression of CD68 (stromal-1 marker) was classified into four (0-3) levels. To analyze the expression of CD34 (MVD, stromal-2), we conducted a manual count of microvessels in the entire field of TMA. We performed miRNA extraction from paraffin samples using RecoverAll ™ Total Nucleic Acid Isolation Kit for FFPE Tissues (Applied Biosystems). Real-time quantitative PCR was performed using TaqMan® Small RNA kit Assays and normalized with U18 and RNU44. Pro-angiomirs Let-7f, miR-92a, miR-130a, miR-210, miR-296 and miR-378 and anti-angiomiRs miR-16, miR-20b, miR-221 and miR-328 were selected for analyses and were considered differentially expressed when tumor samples levels were 1.2 times higher or lower than normal samples. Results Stromal-1 cases had high expression of CD68 (scores 2-3) and low expression of CD34 (quartiles I-II) (32.6% of cases), and as stromal-2 cases had low expression of CD68 (scores 0-1) and high expression of CD34 (quartiles III-IV) (11.6% of cases). The 40 cases that had high expression of both CD68 and CD34 (42.1%) were additionally considered as stromal-2, due to high MVD scores. Cases of low expression of CD68 and CD34 (13.7% of cases) were not scored. We observed a statistically significant relationship between the median expression of CD34 and Ann Arbor stage (I-II versus III-IV), with a predominance of high MVD expression in patients with advanced stage disease (III-IV). The median of vessels in stages I-II was 82.5 (range 9 to 240) and in stages III-IV was 111 (range 12-297) (p = 0.0276, Mann-Whitney). For the marker CD68 (stromal-1) and for the other variables, there were no statistically significant associations between groups. 101 of 111 initial cases were considered suitable for analysis of microRNAs. We observed overexpression of angiomiRs miR-92a, miR-296, miR-210, miR-378, Let-7f and miR-130a in 100%, 56.5%, 55,5%, 48.5%, 14.9% and 13.9% of cases, respectively. Among antiangiomiRs we found underexpression of miR-20b, miR-221, miR-16 and miR-328 in respectively 65.7%, 45.5%, 27.7% and 12.9%. We also observed a correlation between overexpression of miR-20b and low MVD (p = 0.0225, Mann-Whitney) and overexpression of miR-221 and low MVD (p = 0.0339, Mann-Whitney), suggesting a correlation between increased antiangiomiRs expression and low angiogenesis profile. For other variables, there were no statistically significant differences between groups. Conclusion Stromal-2 signature was found in 53.7% of cases. The higher MVD in cases of DLBCL with advanced stage (Ann Arbor III-IV) shows a possible association between angiogenesis and more aggressive/disseminated disease, being a possible target for antiangiogenic therapy in cases that do not achieve a complete response with R-CHOP. Two angiomiRs emerge as potential new targets: proangiomiR miR-92a, overexpressed in 100% of DLBCL, and antiangiomiR miR-20b, underexpressed in 65.7% of cases. Our study provides new information about the importance of the role of microRNAs in the development of DLBCL, which can be exploited as a therapeutic target for patients with this malignant disease of high prevalence. (Supported by FAPESP 2010/17668-6). Disclosures: No relevant conflicts of interest to declare.

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Phase 2 Trial of Concurrent Monosialotetrahexosylganglioside in the Prophylactic Treatment of Bortezomib-Induced Peripheral Neuropathy in Patients of Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.5399.5399 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5399-5399

Author(s):

Liang Wang ◽

Zhongjun Xia ◽

Xiaoqin Chen

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Partial Response ◽

Subcutaneous Injection ◽

Complete Response ◽

Phase 2 ◽

Newly Diagnosed ◽

Female Ratio ◽

Phase 2 Trial

Abstract Backgrounds Bortezomib is an important drug in the treatment of multiple myeloma (MM), and peripheral neuropathy (PN) is a significant dose-limiting toxicity of bortezomib. No effective prophylaxis has been defined for PN. Monosialotetrahexosylganglioside (GM), a nerve-protecting drug, is often used to promote growth of nerve and function restoration of damaged nerve. The role of GM in the prophylaxis of bortezomib-induced PN in MM patients has never been investigated. Methods A phase 2 clinical trial was conducted in newly diagnosed MM patients to evaluate the value of GM in the prophylaxis of bortezomib-induced PN. All eligible patients were treated with VD (bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,15,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) or CyBorD (cyclophosphamide 300mg/㎡,po,d1 ,8,15, bortezomib 1.3mg/㎡,subcutaneous injection, d1 ,8,1 5,22, and dexamethasone 40mg, po,d1 ,8,15,22, 4 weeks a cycle) for at least 4 cycles. GM was used at a dosage of 100mg/day intravenously at d1 -2, 8-9, 15-16, 22-23. No other nerve-protective drugs or thalidomide-containing regimens were allowed. The primary endpoint was overall incidence rate of PN (the grade of PN was recorded according to CTCAE v3.0). The secondary endpoints included duration of PN, complete response rate after 4 cycles of treatment, 1-year PFS and OS rate. (This trial was registered in ClinicalTrial.gov, NCT02093910). Results From February 2014 to February 2015, 25 patients of newly diagnosed MM were enrolled. The median age was 55 years old (37-75), and male to female ratio was 19:6. 5 patients had ISS stage I disease, 6 patients with stage II, and the remaining 14 patients with stage III. All patients received a median of 4 cycles (range 2-9) of Bortezomibcontaining regimens. At the time of data analysis, 84% of patients had at least partial response, 48% had at least very good partial response, and 24% had complete response. 7 patients experienced PN after a median of 2 cycles (range 1-4) of treatment, resulting in the overall PN rate of 28%. Among these 7 patients, only 1 patient (4%) had grade 2 PN, leading to dose reduction of bortezomib, and all other patients had grade 1 PN. During treatment, 1 patient (4%) had grade 2 diarrhea, and another 1 patient (4%) had herpes zoster infection. The concurrent use of GM did not introduce new side effects and seemed not compromise the efficacy of bortezomib. At a median follow up time of 8 months, 1-year PFS rate and OS rate were speculated to be 69.8% and 100%, respectively. Conclusions The early-term analysis of this phase 2 trial found it feasible to concurrently use GM and bortezomib-containing regimens, and GM had the potential role of reducing bortezomib-induced PN rate and severity without compromising efficacy. This needs to be validated in future phase 3 randomized clinical trials. Disclosures No relevant conflicts of interest to declare.

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Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)

Blood ◽

10.1182/blood.v128.22.3463.3463 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3463-3463

Author(s):

Hideki Nakasone ◽

Kiriko Terasako-Saito ◽

Teiichi Hirano ◽

Atsushi Wake ◽

Seiichi Shimizu ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

Induction Treatment ◽

High Dose ◽

Induction Phase ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Free Survival

Abstract [Background] Multiple myeloma (MM) is generally considered incurable. Recently, novel drugs, including bortezomib, have demonstrated a survival benefit for newly diagnosed MM patients compared with classical treatments. Complete response (CR) after treatment is known to be associated with superior progression-free survival. Thus, we prospectively evaluated the efficacy and safety of boretezomib + dexamethasone (BD) for patients with newly diagnosed MM, followed by autologous hematopoietic stem cell transplantation (ASCT). We added BD consolidation therapy to aim CR if CR was not achieved after ASCT. [Patients and methods] This clinical study prospectively recruited newly diagnosed MM patients eligible for ASCT between 2010 and 2012. Due to health insurance issues in Japan, two courses of high-dose dexamethasone (HD-DX) had been administrated prior to BD induction treatment until Nov. 2011, while BD was administrated as an initial induction treatment since Dec. 2011. BD induction treatment included 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with 20mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. This BD induction cycle was repeated every 3 weeks for 4 courses. Thereafter, filgrastim-based mobilization and ASCT following high-dose melphalan administration was performed. If patients did not achieve CR after ASCT, BD consolidation therapy (bortezomib: 1.3 mg/m2 on days 1, 8, and 15; dexamethasone 20 mg/day on days 1-2, 8-9, and 15-16) every 4 weeks was added to target CR (Figure 1) (UMIN-CTR: UMIN000002442). [Results] The median observational duration among survivors was 1536 days (range: 464-2023) at this analysis. Of the 47 enrolled MM patients, 46 (male 27; female 19) were eligible for BD induction treatment, while the remaining one achieved CR before BD induction. The median age of the patients was 59 (range: 35-67) years. Of the 44 patients whose karyotype analyses were available, normal karyotype was observed in 35. Abnormal karyotype included complex type in 4, diploid in 1, and other abnormalities in 4. FISH revealed deletion of p53 in 5 of 39 patients whose information was available; deletion of 13-chromosome in 16 of 42, IgH-MAF fusion in 1 of 40; IgH-FGFR3 fusion in 5 of 41; IgH-BCL1 fusion in 9 of 39. Of the 46 MM patients, 19 received HD-DX prior to BD induction, and 34 received ASCT after BD induction treatment (Figure 1). During the BD induction phase, 3 patients experienced disease progression, and BD treatment was discontinued in 9 patients because of their consent withdrawal (n=2) and adverse events (n=7) including interstitial pneumonia in 2, persistent neuropathy in 1, CMV enterocolitis in 1, heart failure in 1, diabetes mellitus in 1, and liver dysfunction in 1. After BD induction phase (n=46), their response was >= CR in 4 (8%), very good partial response (VGPR) in 10 (22%), partial response (PR) in 18 (39%), stable disease (SD) in 2 (4%), and progression or withdrawal in 12 (26%). After ASCT, their response was >=CR in 9 (20%), VGPR in 11 (24%), PR in 12 (26%), SD in 1 (2%), and additional progression or withdrawal in 1 (2%). Of the 24 patients who received ASCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses (range: 1- 8). BD consolidation was discontinued in 4 patients due to persistent neuropathy or cytopenia. Finally, maximum response after ASCT with or without BD consolidation was >= CR in 19 (41%), VGPR in 7 (15%), PR in 6 (13%), < SD in 2 (2%, Figure 2). Through BD consolidation, CR was achieved in 8 of 11 patients with post-ASCT VGPR and 2 of 12 patients with post-ASCT PR. In total, 4-year progression-free survival (PFS) and overall survival (OS) was 43% (95%CI: 28-57%) and 80 % (95%CI: 64-90%), respectively. Focusing on CR patients after ASCT and those who actually received BD consolidation, PFS adjusted for karyotype and age were not different between CR patients after ASCT and after BD consolidation, while patients with VGPR or less after consolidation had significantly lower PFS (Figure 3). [Conclusion] BD induction and ASCT provided CR rate of 27% among ASCT patients, although BD induction may expectedly cause adverse events including persistent neuropathy and viral infections. Patients who achieved CR after ASCT showed good PFS, and targeting CR through BD consolidation might improve CR rate. It is worthwhile to prospectively compare the efficacy of BD consolidation only for patients who failed to achieve CR or universal consolidation strategy. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

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