The Overall Response Rate Of Azacitidine In Patients With Intermidiate-2 And High Risk Myelodysplastic Syndromes: A Retrospective Chart Review Study From Greece

Abstract Background: DNA hypomethylating agent, decitabine, has become the current standard therapy for patients with higher-risk myelodysplastic syndromes (MDS). Decitabine was launched in China in August 2009 without clinical trials. According to some retrospective studies, the efficacy and safety are similar to those reported in other countries, but there is still a lack of large-scale prospective clinical trials. So we start a prospective clinical trial in China to compare the effect and safety of decitabine in MDS, which was registered at clinicaltrials.gov (NCT02013102). Design: Adults with intermediate or high risk MDS by the International Prognostic Scoring System (IPSS≥0.5) were randomized to receive either decitabine 20 mg/m2 IV daily for 5 days (arm Ⅰ) or decitabine 12 mg/m2 IV daily for 8 days (arm Ⅱ) every four weeks. Patients continued to receive study drug for 4 cycles until death, disease progression, intercurrent illness preventing further administration of treatment, unacceptable adverse event or decision by the patient to withdraw from the study. And supportive care were permitted. The primary end point was overall response rate (ORR, CR+mCR+PR) by International Working Group (IWG 2006) criteria, secondary end points included CR, mCR, PR, HI, safety, et al. Results: We enrolled a total of 198 patients between 8/2013 and 12/2017, among which 7 patients didn't take decitabine, and 191 were included in the analysis. 94 in arm Ⅰ recieved decitabine and 97 in arm Ⅱ. 32.8% of patients withdrew from the study for a variety of reasons, including progression and death (5.1%), personal decision (13.6%), adverse events (6.6%), and other causes (7.6%). The median age of patients in arm Ⅰ was 54.88 years old and 54.82 years old in arm II. The median follow-up was 106 days for patients in both arms. The patients received a mean 2.5 cycles of decitabine therapy for arm Ⅰ and 2.0 cycles for arm Ⅱ. The overall response rate was 39.3% in total, and 41.5% and 38.1% (p=0.6598) for patients in arm Ⅰ and arm Ⅱ, respectively. And CR was 18.1% and 14.4% (p= 0.5584) , PR was 6.4% and 3.1% (p=0.3257) , mCR was 17.0% and 20.6% (p=0.5814) , HI was 3.2% and 1.0% (p=0.3633) , for patients in armⅠand armⅡ, respectively (Table 1). Among all patients, 38.7% were intermediate-1 risk, 40.3% were intermediate-2 risk, 20.4% were high risk. Analysis of response by MDS patient subtypes is shown in Table 2. Those who were higher risk experienced higher ORR and CR, while the difference is not significant between two arms (p>0.05). As expected, cytopenias were the most frequent complications (76.4%). Grade 3-4 neutropenia, thrombocytopenia and anemia considered to be at least possibly related to the study drug occurred at rates of 23.0%, 34.6%, and 34.6% of patients, respectively. Nonhematologic adverse events were also common including abnormal metabolism and nutrition (23.40% vs 18.56%), abnormal gastrointestinal function (29.79% vs 41.24%), cardiac disorders (11.70% vs 14.43%), infection and infectious diseases (32.98% vs 36.08%), abnormal skin and subcutaneous tissue and so on, which were no significant differences between two ams. During the study there were 17 SAE, only 7 cases were possibly related to drug therapy, such as pulmonary infection, Sepsis, myelosuppression, intracranial hemorrhage, hepatic failure, and arrhythmia. Conclusions: The use of 5-day and 8-day schedule decitabine is safe and effective in patients with intermediate and high risk MDS, among which there was no significant differences. Disclosures No relevant conflicts of interest to declare.

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Safety And Tolerability Of Azacitidine In Patients With Intermidiate-2 And High Risk Myelodysplastic Syndromes In GreeceA Retrospective Chart Review Study For The Daily Practise

Value in Health ◽

10.1016/j.jval.2014.03.1317 ◽

2014 ◽

Vol 17 (3) ◽

pp. A225

Author(s):

V Pappa ◽

V Fragoulakis ◽

N Maniadakis ◽

C Tsatalas ◽

P Zikos ◽

...

Keyword(s):

High Risk ◽

Myelodysplastic Syndromes ◽

Chart Review ◽

Retrospective Chart Review ◽

Review Study

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Ixazomib and dexamethasone in high risk smoldering multiple myeloma: A clinical and correlative pilot study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8051 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8051-8051

Author(s):

Sham Mailankody ◽

Meghan Salcedo ◽

Elizabet Tavitian ◽

Neha Korde ◽

Nikoletta Lendvai ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Overall Response Rate ◽

Response Rate ◽

Objective Response ◽

Pilot Trial ◽

Progression Free Survival ◽

Overall Response ◽

Smoldering Multiple Myeloma ◽

Increased Risk

8051 Background: Patients with high risk smoldering multiple myeloma (HR-SMM) have an increased risk of progression to multiple myeloma (MM)- median time < 2 years. The standard management of these patients currently is close clinical monitoring; however, randomized trials show longer progression-free and overall survival in in HR-SMM patients treated with the oral immunomodulatory drug lenalidomide. We report the use ixazomib, the first oral proteasome inhibitor, in combination with dexamethasone in the setting of HR-SMM. Because proteasome inhibitors can provide deep clinical responses in patients with MM, we set the pre-specified threshold for efficacy high (overall response rate of ≥75%). Methods: In this single arm pilot trial of ixazomib/dexamethasone, patients received 12 4-week cycles of ixazomib/dexamethasone followed by ixazomib maintenance for 24 cycles. The primary endpoint is best overall response after 12 cycles and second objectives include duration of response, safety, and progression free survival. Results: 14 patients with HR-SMM were enrolled between 06/2016 and 03/2018. The median age is 65 years and 10 (71%) of patients were male. 11 (79%) patients were high-risk by the PETHEMA criteria, 2 (14%) by the Mayo Clinic criteria and 1 (7%) by both. At data cut-off (02/07/2019), patients completed a median of 17 cycles and 10 (71%) are continuing treatment. 4 patients have stopped treatment (2 patients for raise in serum markers without progression to MM, and 1 each for toxicities, and co-morbidities unrelated to treatment). 9 (64%) achieved an objective response (8 PR, and 1 VGPR) and no patient has progressed to MM. Non-heme adverse events included 3 grade 1 GI events, 2 grade 3 lung infection, 1 grade 2 acute kidney injury, and 1 had grade 1 fatigue that was possibly related to treatment. Conclusions: Ixazomib/dexamethasone appears well tolerated with high overall response (9/14; 64%) in patients with HR-SMM. Although the trial does not meet our pre-specified threshold for efficacy (i.e. best overall response rate of 75%), with a median follow-up of 17 months, no patient progressed to MM and only 2 patients had serologic progression. These results support further evaluation of ixazomib/dexamethasone alone and in combination with other agents as treatment for patients with HR-SMM. Clinical trial information: NCT02697383.

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Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG)

Blood ◽

10.1182/blood.v112.11.330.330 ◽

2008 ◽

Vol 112 (11) ◽

pp. 330-330 ◽

Cited By ~ 25

Author(s):

Kirsten Fischer ◽

Stephan Stilgenbauer ◽

Carmen D Schweighofer ◽

Raymonde Busch ◽

Jasmin Renschler ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Trial ◽

Lymphocytic Leukemia ◽

Study Group ◽

Overall Response ◽

Grade 3

Abstract Introduction: Bendamustine, an alkylating agent with additional properties of a purine analogue, has shown considerable activity in monotherapy for solid and lymphoid malignancies including chronic lymphocytic leukemia (CLL). In vitro studies have demonstrated synergistic pro-apoptotic effects of bendamustine and the CD20 antibody rituximab (BR) in primary CLL cells. Encouraging clinical results have been obtained using BR combination treatment in relapsed/refractory and previously untreated Non-Hodgkin’s lymphoma. This phase II trial represents the first study evaluating the efficacy and toxicity of bendamustine in combination with rituximab in patients (pts) with relapsed or refractory CLL. Patients and Methods: 81 pts with a median number of 2 (1–3) pretreatments were enrolled between March 2006 and June 2007. Patients received 70 mg/m² bendamustine on day 1 and 2 combined with 375mg/m² rituximab for the first cycle and 500 mg/m² for the second and subsequent cycles. BR treatment was administered every 28 days for up to 6 courses. Blood samples were taken for molecular cytogenetics by fluorescence in situ hybridization (FISH) and analysis of the immunoglobulin heavy chain (IgVH) mutational status prior to the first treatment course. Assessment for minimal residual disease (MRD) was performed by four-colour flow cytometry of peripheral blood and bone marrow. Primary endpoint of the trial was the overall response rate (ORR). Secondary endpoints included toxicity, duration of response, event-free survival, MRD response rate and overall response rate in biological defined risk groups. Results: 81 pts (mean age 66.7 years) received a total of 328 treatment cycles. A mean number of 4.5 courses was administered. In total 123 CTC grade 3/4/5 adverse events were reported, most frequently on myelosuppression and infections: grade 3/4 anemia occurred in 6.1%, grade 3/4 leukopenia/neutropenia and thrombocytopenia in 11.9% and 9.1% of all given courses, respectively. 16 episodes (4.9%) of CTC grade ≥3 infections were documented, most of them could be successfully managed. However, treatment related mortality occurred in 3.7% of pts: three pts died due to severe infections associated with treatment related neutropenia including 1 fatal pneumonia, one sepsis after diagnosis of Richter’s syndrome and 1 urosepsis. In 62 pts data for response assessment were available: 19 pts were not evaluable for response due to withdrawal or missing of consent, violation of enrolment criteria or early discontinuation of therapy. The overall response was 77.4% with complete remissions (CR) in 14.5% (9 pts) and a partial response (PR) in 62.9% of pts (39 pts). An MRD level below 10E-4 was measured after completion of therapy in 2 of 30 evaluable pts in peripheral blood, while none of the pts achieved MRD negativity in bone marrow. Stable disease (SD) was achieved in 17.7% (11 pts) whereas 3 pts (4.8%) had progressive CLL (PD). Differences in response were observed among genetic subgroups: 12 of 13 pts with 11q- achieved a remission with 11 PR and 1 CR (ORR: 92.3%). Accordingly, 8 of 8 patients with +12 responded (7 PR, 1 CR). In the high-risk group with 17p-, four of nine pts showed a partial remission (ORR: 44,4%). 29 of 39 pts (ORR: 74.4%) with unmutated IgVH status were responsive to BR. Conclusion: Bendamustine plus rituximab is an effective treatment regimen for pts with relapsed and/or refractory CLL and has notable activity in high-risk CLL disease. Major but tolerable treatment toxicities were myelosuppression and infections. Ongoing trial follow-up analysis will define response duration and long-term safety. In a forthcoming trial the German CLL Study group will investigate the efficacy of BR in comparison to fludarabine-based immunochemotherapy (FCR) for first-line treatment of CLL.

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Azacitidine (AZA) Combined with Idarubicin in Untreated Patients with High Risk MDS – Results of a Phase I/II Study of the Groupe Francophone Des Myelodysplasies

Blood ◽

10.1182/blood.v120.21.1720.1720 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1720-1720 ◽

Cited By ~ 1

Author(s):

Lionel Ades ◽

Benoit de Renzis ◽

Ramzi Jeddi ◽

Jacques Delaunay ◽

Thorsten Braun ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Disease Progression ◽

Stable Disease ◽

Overall Response Rate ◽

Response Rate ◽

Conflicts Of Interest ◽

Performance Status ◽

Single Agent ◽

Overall Response

Abstract Abstract 1720 Background: hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, if it is able to increase overall survival in MDS, AZA yields only about 30% of marrow response (including CR+PR+ mCR), Idarubicin given at conventional dose (12 mg/m2/d during 3 days) is the anthracycline of choice in the intensive chemotherapy given with cytarabine in patients with high risk MDS and, given as a single agent, induces up to 30% of complete remission (CR) in elderly AML patients. Thus, we designed a phase I/II study evaluating the safety and efficacy of 2 doses of Idarubicin combined with Azacitidine in high risk MDS patients (clinical trial NCT01305135). Methods: For this trial Azacitidine was combined with increasing doses of Idarubicin. Main Inclusion criteria were: (1) IPSS int 2 or high MDS, or CMML with WBC < 13,000/mm3 and marrow blasts > 10% or AML with 20–30% marrow blasts (corresponding to EU label for AZA) (2) Age 3 18 years (3) Performance Status (PS) <=2 (4) no prior treatment except ESAs. Patients received Azacytidine 75 mg/m2/d SC during 7 days every 4 weeks combined on day 8 of each cycle to Idarubicin 5 mg/m2 (administered by 1 hour IV infusion) in the first cohort of 10 patients, escalated to Idarubicin 10 mg/m2 IV in the second cohort of 10 patients after review of toxicity (especially hematological) of the 1st cohort by the independent DSMB r. The primary endpoint of the study was response after 6 cycles according to IWG criteria. Data were analyzed at the reference date of June, 1St 2012. Results: The 20 study patients (from 8 centers) were enrolled between Dec 2010 and Feb 2012, including 7 women and 13 men with a median age of 75 years. At inclusion, WHO classification was RCMD in 1 pt, CMML in 1 pt, RAEB-1 in 6 pts, RAEB-2 in 7 pts, AML in 3 pts and unclassified in 2 pt. Median marrow blasts were 6.5% (0–26) Karyotype (IPSS) was favorable in 7 pts, int in 3 pts and unfav in 8 pts (2 pts had cytogenetic failure). IPSS was high in all patients. PS was 0 in 28% pts, 1 in 50% and 2 in 22%. A total of 92 cycles of treatment had been administrated with a median number of 5 cycles/patient and 10 pts had received 6 or more cycles. 14 patients had terminated the study due to side effects (severe febrile pancytopenia, n=2), disease progression (n=5, after 2–10 cycles), death (disease progression, severe septic shock after Cycle 2, and unrelated coma), stable disease after 6 cycles (n=3), and patient decision (n=1). Overall 7 pt had died. 18 SAEs were reported observed in 9 patients, including 10 episodes of febrile neutropenia, 3 episodes of bleeding and 5 unrelated SAE. Of the 20 patients enrolled in the study, 19 were evaluable for response after 3 cycles, including 10/10 in the First cohort and 9/10 in the second cohort. One patient achieved CR, 2 PR, 1 mCR and 2 additional patients achieved stable disease with HI, leading to an Overall response rate of 6/19 (32%). Two patients were still on study but did not reached cycle 6. Thus, after 6 cycles, 17 patients, only could be evaluated. Among them 9/17 (53%) patients were still on study, 2 pts had died, 3 progressed, 2 had experienced sides effects and had terminated the study and 1 pt had withdrawn consent. Two patients achieved CR (including 1 already in CR at cycle 3), 2 PR and 2 additional patients achieved stable disease with HI leading to an Overall response rate of 6/17 (35%). At the time of the present analysis, none of the responder had relapsed. Conclusion: The phase I/II results presented here show that Idarubicin can be combined to Azacitidine with acceptable toxicity. Whether the azacitidine- Idarubicin combination can improve the outcome of higher risk MDS patients will be evaluated in a phase II randomized trial comparing this combination (and other combinations of azacitidine with other drugs) to azacitdine alone alone. Data of the present phase I/II trial will be updated at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Hochrisiko-CLL: Zielgerichtete Kombinationstherapie verbessert das Überleben

Karger Kompass Onkologie ◽

10.1159/000517059 ◽

2021 ◽

pp. 1-3

Author(s):

Katja Zirlik

Keyword(s):

Cardiac Arrest ◽

High Risk ◽

Adverse Events ◽

Chronic Lymphocytic Leukaemia ◽

Overall Response Rate ◽

Lymphocytic Leukaemia ◽

Response Rate ◽

Complete Response ◽

Overall Response ◽

To Receive

Background: Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. Methods: We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2–6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. Findings: 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n = 64) or ibrutinib alone (n = 62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7–47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p = 0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. Interpretation: The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. Funding: TG Therapeutics.

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Results from a Phase IIa Study of the Anti-CXCL12 Spiegelmer Olaptesed Pegol (NOX-A12) in Combination with Bendamustine/Rituximab in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.1996.1996 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1996-1996 ◽

Cited By ~ 8

Author(s):

Michael Steurer ◽

Marco Montillo ◽

Lydia Scarfò ◽

Francesca Romana Mauro ◽

Johannes Andel ◽

...

Keyword(s):

Single Dose ◽

High Risk ◽

Partial Response ◽

Peripheral Blood ◽

Overall Response Rate ◽

Response Rate ◽

Tp53 Gene ◽

Overall Response ◽

High Risk Patients ◽

Risk Patients

Abstract Background Olaptesed pegol (NOX-A12) is a novel, potent, L-stereoisomer RNA aptamer that binds and neutralizes CXCL12/SDF-1, a chemokine which attracts and activates immune- and non-immune cells via interaction with the receptors CXCR4 and CXCR7. Signaling of CXCL12 is pivotal to the interactions of leukemic cells with bone marrow microenvironment. The therapeutic concept of olaptesed is to inhibit such tumor-supporting pathways and thereby mobilizing and sensitizing CLL cells to therapy. Here we aim to assess the activity and safety of olaptesed in combination with bendamustine and rituximab (BR) in patients with relapsed / refractory CLL. Methods Twenty-eight relapsed or refractory CLL patients were enrolled and treated in this open-label, single-arm Phase IIa study. To investigate PK/PD, a pilot dose of 1 to 4 mg/kg olaptesed alone was administered to 3 patients per dose group (plus one additional replacement pt) before start of the regular treatment regimen (pilot group). Patients were treated using a dose titration design with intravenous (IV) olaptesed at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg at cycles 1, 2 and 3, respectively, at 1 hour before rituximab treatment. During cycles 4 to 6, olaptesed was dosed at the highest individually titrated dose. Rituximab was administered IV at doses of 375 mg/m² on day 1 of the 1st28-day cycle and 500 mg/m² on day 1 of subsequent cycles. Bendamustine (70 - 100 mg/m²) was given IV on days 2-3 (cycle 1) or days 1-2 (cycles 2-6) of each 28-day cycle following administration of rituximab. Clinical response was assessed according to NCI-WG Guidelines (Hallek M et al. Blood 111; 2008: 5446-56). Results To date, 24 patients completed treatment (12 women, 12 men) with a median age of 68.5 years (range 52 to 79). At screening 5, 9 and 10 patients presented with Binet stage A, B and C, respectively. The median number of prior treatment lines was 1 (range 1-2). Seven high-risk patients presented an unfavorable disease state being relapsed within 24 months after fludarabine/bendamustine treatment (5 pts) and/or presenting a deletion/mutation of the TP53 gene (3 pts). Most patients (19 of 24) were previously treated with fludarabine or bendamustine. A flow cytometric analysis of CD19+/CD5+CLL cells showed a rapid mobilization into the peripheral blood by a single dose of olaptesed which lasted throughout the observational time of 72h. Interestingly, CXCR4 expression levels increased on CLL cell surface in the periphery after olaptesed treatment. This increase, which peaked at 24h, likely reflects the extended circulation of CLL cells in the periphery due to the sustained blockade of CXCL12 by olaptesed. Reduction of lymphadenopathy by ≥ 50% was achieved in 14 out of 21 evaluable patients with reported enlarged lymph nodes by the end of treatment. Concomitantly, rapid reduction of lymphocytosis in peripheral blood with normalization by treatment cycle 2 – 3 was observed and the CLL to leukocyte ratio significantly improved. Efficacy was assessed at the end of cycles 3 and 6. In the full-analysis-set, which excludes two non-evaluable patients (drop-out after the 1st cycle due to adverse events), the overall response rate was 96%: Three patients (14%) achieved a complete response at end of cycle 6 (2 confirmed, 1 investigator reported) and eighteen patients (82%) achieved a partial response (fifteen at end of cycle 6 and three at end of cycle 3). Notably, all seven high-risk patients (defined as relapsed within 24 months after fludarabine/bendamustine treatment and/or presenting a deletion/mutation of the TP53 gene) responded to treatment with olaptesed + BR with a partial response. One patient had a progressive disease. Olaptesed at 1, 2 and 4 mg/kg at a single dose and in combination with BR was safe and well tolerated. The observed adverse reactions were qualitatively and quantitatively as expected for patients treated with BR. Conclusion Olaptesed in combination with BR was safe and well tolerated. Compared with historical data, olaptesed showed superiority over baseline therapy with regards to overall response rate and increasing rates of complete remission, warranting further development of this Spiegelmer in CLL. Disclosures Montillo: Janssen: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment.

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Bortezomib in Combination with Dexamethasone, Cyclophosphamide, Etoposide, and Cisplatin (V-DCEP) for the Treatment of Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2139.2139 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2139-2139 ◽

Cited By ~ 11

Author(s):

Kelly Valla ◽

Jonathan L. Kaufman ◽

Charise Gleason ◽

Lawrence H. Boise ◽

Leonard T Heffner ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Median Time ◽

Salvage Therapy ◽

Research Funding ◽

Overall Response Rate ◽

Response Rate ◽

University Hospital ◽

High Dose ◽

Overall Response

Abstract Introduction Despite therapeutic advances in multiple myeloma, disease relapse is common. Combination therapy with dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) has been utilized as an effective salvage regimen for over a decade, and a recent study reported that DCEP provided an overall response rate of 45.1% when used as salvage therapy in patients who had previously received novel agents (Park S, et al. 2014). Aside from hematologic toxicities, DCEP is generally well-tolerated. In fact, the toxicity profile of DCEP has been compared to high dose cyclophosphamide in the setting of stem cell mobilization and is considered less toxic than the latter. Based upon the synergy noted when proteasome inhibitors are combined with genotoxic therapy, we have combined bortezomib with DCEP in a series of relapsed myeloma patients. Herein we report our experience with the addition of bortezomib to DCEP in relapsed/refractory disease. Patients and Methods We performed a retrospective evaluation of patients with relapsed/refractory multiple myeloma treated at Emory University Hospital from October 2011 until March 2014. Patients received dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) at standard doses in combination with bortezomib at either a dose of 1 mg/m2 or 1.3 mg/m2 administered on Days 1 and 4 of each cycle given every 28 days. Indications for receiving V-DCEP are either cytoreduction prior to SCT (cohort 1) or as salvage therapy (cohort 2). Results Among the 51 patients (49% male and 51% female) included in analysis, the median age at the time of diagnosis is 58 years (range 30-78) and the time of treatment with V-DCEP is 62 years (range 33-79). Among patients that received V-DCEP as cytoreduction prior to SCT, median prior lines of therapy were 1 (0-8). Among the patients that received V-DCEP as salvage therapy, median number of prior lines of therapy was 3 (1-6). ISS 3 disease was seen in 70% of patients and high risk disease in 72.5% of pts (del 17p: 31%; PCL: 19%; extramedullary disease: 33%; complex CTG: 11%) and t(4;14): 6%). Median time from diagnosis to initiation of V-DCEP therapy among cohort 1 is 18 months (0-86) and among cohort 2 is 31 months (12-105) months. Median serum creatinine before C1D1 is 1.17 (0.61-6) and serum bilirubin is 0.6 (0.1-2.8). 31% of patients needed dose reductions from our standard protocol due to organ dysfunction. 47% of patients received ≥2 cycles. The median time to next cycle is 28 days (20-46) and time to next treatment after V-DCEP is 35 days (25-451) suggesting good hematologic recovery. The overall response rate (≥PR) amongst both cohorts with V-DCEP is 47.8% (40% and 51.6% overall response for cohorts 1 and 2, respectively). Figure 1 illustrates response rates. 10 patients that presented with renal insufficiency had renal response including 2 of the 5 patients on hemodialysis. While the median PFS for cohort 1, as expected has not reached, for cohort 2, it is 8 months (95% CI 5.7-10.3). At a median follow-up of 17 months, from the time of V-DCEP initiation, median OS for cohort 2 is 10 months (95% CI 5-14.9). Median overall survival for this predominantly high risk group of patients from diagnosis in cohort 1 is 78 months (95% CI 47-108) and 49 (95% CI 17-80.7) months in cohort 2, respectively. While only 1 patient with grade 2 peripheral neuropathy (PN) received V-DCEP, change from baseline existing PN was seen in 19% of patients (no grade 3/4 events). Conclusions During this era where minimizing alkylator therapy is a consideration, certain indications exist for using V-DCEP such as cytoreduction prior to SCT or as salvage therapy serving as bridge to next line of therapy. Addition of bortezomib to DCEP is deemed safe and is an effective cytoreductive regimen in the treatment of multiple myeloma. Figure 1 Figure 1. Disclosures Gleason: Celgene: Consultancy; Novartis: Consultancy. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

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A Phase 2 Study to Assess the Feasibility and Tolerance of the Combination of Elotuzumab, Lenalidomide, and Dexamethasone (ERd) in the Induction, Consolidation, and Maintenance Treatment of Transplant-Eligible Patients Newly Diagnosed with Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2019-130277 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 603-603 ◽

Cited By ~ 4

Author(s):

Jesus G. Berdeja ◽

Tara K. Gregory ◽

Suman Kambhampati ◽

Bertrand M. Anz ◽

Stefano R. Tarantolo ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Maintenance Treatment ◽

Overall Response Rate ◽

Response Rate ◽

Survival Rates ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Overall Response

Background: The introduction of novel agents such as proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) with and without corticosteroids has revolutionized treatment (tx) and improved survival rates for MM. IMID/PI triplets such as VRD (bortezomib, lenalidomide, dexamethasone), VTD (bortezomib, thalidomide, dexamethasone), or KRD (carfilzomib, lenalidomide, dexamethasone) are preferred inductions for transplant-eligible patients (pts). Unfortunately, the PI often has unique safety events such as peripheral neuropathy (PN) or cardiac issues that can impact the quality of life. Elotuzumab is a mAb with a dual mechanism of action (tagging MM cells and activating NK cells by binding SLAMF7). The combination of elotuzumab, lenalidomide, and dexamethasone (ERd), is active, well-tolerated, and approved by the FDA for pts with relapsed MM. In this study, we will determine the feasibility of incorporating ERd into a transplant-eligible pt population. Methods: Pts with newly diagnosed MM requiring chemotherapy planning to undergo autologous stem cell transplantation (ASCT) were enrolled. Induction of elotuzumab at 10 mg/kg was administered IV on days (D) 1, 8, 15, 22 of the 1st 2 28-day cycles and days 1, 15 of the third and fourth 28-day cycles. Lenalidomide was dosed at 25 mg orally on D 1-21 of each 28 day induction cycle. Dexamethasone was administered IV concurrent with elotuzumab (28mg orally 3-24 hours prior to infusion and 8 mg IV with elotuzumab), with 40 mg orally administered on D 8 and 22 of cycles 3 and 4. After completion of the 4 induction cycles, pts proceeded to mobilization and ASCT though pts who refused transplantation were allowed to proceed directly to consolidation and maintenance if the investigator believed the pt was deriving benefit. 70-120 days after ASCT, 4 cycles of consolidation were administered (dosing similar to cycles 3-4 of induction but with lenalidomide at 15mg). Pts then went on to maintenance with elotuzumab 20 mg/kg IV on D 1, oral lenalidomide 10mg +/- 5 mg D 1-21 and dexamethasone 28mg oral/8 mg IV prior to elotuzumab infusion were dosed in 28-day cycles for up to 24 months. The primary endpoint was the induction feasibility rate (IFR) defined as the percentage of pts successfully completing 4 cycles of induction tx with ERd and able to start ASCT. Secondary end points were complete response rate (≥nCR), overall response rate (≥PR), progression-free survival (PFS) and overall survival (OS). AEs were assessed according to CTCAE V4 and responses were assessed using the revised IMWG criteria. Results: 52 pts were enrolled: 56% male, median age 61 ys, 12% RISS III, 21% high-risk cytogenetics [17p del, t(4;14), and/or t(14;16)]. To date, 26 (50%) pts remain on active tx. 4 pts refused transplantation despite being eligible and were excluded from the IFR calculation. The IFR was 69% and the best overall response rate (ORR) was 92% (69% ≥ VGPR). With a median follow up of 20 mos, median PFS and OS for all pts were not reached. The 18 mo PFS and OS were 83% and 89% respectively. The most common AEs were fatigue (59.6%), diarrhea (42.3%) and nausea (42.3%). PN was seen in 29%, and all events were ≤ G2. There were 28 SAEs in 20 pts, including 12 tx-related SAEs. There was 1 tx-related death due to heart failure in a pt with no history of prior cardiac issues who had subsequent therapy. 29% of pts met the high-risk (HR) criteria (defined as RISS III or high risk cytogenetics) and 29% of pts were considered standard-risk (RISS I and no high-risk cytogenetics). The best ORR was 87% (67% ≥ VGPR) for HR pts and 93% (53% ≥ VGPR) for SR pts and the IFR was 57% for HR pts and 64% for SR pts. The median PFS and OS were 20.5 mos and 22.0 mos respectively for HR pts and have not been reached for SR pts. Conclusions: ERd induction, consolidation and maintenance was feasible and well tolerated in conjunction with ASCT in transplant-eligible pts. Despite high ORR for all pts, HR patients had inferior PFS and OS. This study supports the continued evaluation of this regimen in SR pts. Disclosures Berdeja: Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; Poseida: Research Funding; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding. Gregory:Takeda: Speakers Bureau; Celgene: Speakers Bureau; Poseida: Research Funding; Amgen: Speakers Bureau. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination of elotuzumab, lenalidomide, and dexamethasone in the induction, consolidation, and maintenance treatment of transplant-eligible patients newly diagnosed with multiple myeloma.

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Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes

Journal of Clinical Oncology ◽

10.1200/jco.20.02341 ◽

2021 ◽

pp. JCO.20.02341 ◽

Cited By ~ 2

Author(s):

David A. Sallman ◽

Amy E. DeZern ◽

Guillermo Garcia-Manero ◽

David P. Steensma ◽

Gail J. Roboz ◽

...

Keyword(s):

Overall Survival ◽

Adverse Events ◽

Allele Frequency ◽

Myelodysplastic Syndromes ◽

Median Overall Survival ◽

Overall Response Rate ◽

Response Rate ◽

Variant Allele ◽

Variant Allele Frequency ◽

Overall Response

PURPOSE Approximately 20% of patients with TP53-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. METHODS This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043 ). RESULTS Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%). CONCLUSION Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.

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