Final Results From a Phase I Combination Study of Lenalidomide and Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS) Sekeres MA.

Slides:

Advertisements

Similar presentations

Evaluation of Oral Azacitidine Using Extended Treatment Schedules: A Phase I Study Garcia-Manero G et al. Proc ASH 2010;Abstract 603.

Advertisements

Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma

Dr Kavita Raj Consultant Haematologist Guys and St Thomas’ Hospital.

台北榮總血液腫瘤科楊元豪 / 高志平大夫. 2 Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative treatment in patients.

Brown JR et al. Proc ASH 2013;Abstract 523.

Jennifer Vaughn, MD Bart Scott, MD.  Myelodysplastic syndromes ◦ Clonal hematopoetic disorder in which ineffective or dysplastic cell production leads.

Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously.

1Coiffier B et al. Proc ASH 2010;Abstract 114.

Palumbo A et al. Proc ASH 2012;Abstract 446.

LaCasce A et al. Proc ASH 2014;Abstract 293.

Roberts AW et al. Proc ASH 2014;Abstract 325.

Results of a Phase 2 Randomised, Open- Label, Study of Lower Doses of Quizartinib (AC220; ASP2689) in Subjects with FLT3-ITD Positive Relapsed or Refractory.

1 Baz R et al. Proc ASH 2014;Abstract Lacy MQ et al.

Single-Agent Lenalidomide in Patients with Relapsed/Refractory Mantle Cell Lymphoma Following Bortezomib: Efficacy, Safety and Pharmacokinetics from the.

Michael Dickinson, Haematologist

Therapeutic Response to Azacitidine (AZA) in Patients with Secondary Myelodysplastic Syndromes (sMDS) Enrolled in the AVIDA Registry 1 Prospective Trial.

Treatment with Bendamustine- Bortezomib-Dexamethasone in Relapsed/Refractory Multiple Myeloma Shows Significant Activity and Is Well Tolerated Ludwig H.

Arsenic Trioxide (ATO) in the Consolidation Treatment of Newly Diagnosed APL — First Interim Analysis of a Randomized Trial (APL 2006) by the French Belgian.

Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Relapsed/Refractory Multiple Myeloma: Results from a Phase I Study After Full Enrollment.

A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Updated.

A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat vs Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes.

Rituximab efficacy in other haematological malignancies Christian Buske.

Ibrutinib in Combination with Bendamustine and Rituximab Is Active and Tolerable in Patients with Relapsed/Refractory CLL/SLL: Final Results of a Phase.

CB-1 MDS Classification and Prognosis John M. Bennett, MD University of Rochester Medical Center Hematomorphologist Chair, MDS Foundation.

Ruan J et al. Proc ASH 2013;Abstract 247.

Lenalidomide Is Safe and Active in Waldenstrom Macroglobulinemia (WM) 1 Updated Results from a Multicenter, Open-Label, Dose-Escalation Phase 1b/2 Study.

Updated Results of a Phase I First-in-Human Study of the BCL-2 Inhibitor ABT-199 (GDC-0199) in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic.

Maintenance Therapy with Bortezomib plus Thalidomide (VT) or Bortezomib plus Prednisone (VP) in Elderly Myeloma Patients Included in the GEM2005MAS65 Spanish.

A Phase 3 Prospective, Randomized, International Study (MMY-3021) Comparing Subcutaneous and Intravenous Administration of Bortezomib in Patients with.

Inotuzumab Ozogamicin (IO; CMC544), a CD22 Monoclonal Antibody Attached to Calicheamycin, Produces Complete Response (CR) plus Complete Marrow Response.

Safety and Efficacy of Abbreviated Induction with Oral Fludarabine (F) and Cyclophosphamide (C) Combined with Dose-Dense IV Rituximab (R) in Previously.

A Phase 2 Study of Single-Agent Brentuximab Vedotin for Front- Line Therapy of Hodgkin Lymphoma in Patients Age 60 Years and Above: Interim Results Yasenchak.

A Phase II Study of Lenalidomide for Previously Untreated Deletion (del) 5q Acute Myeloid Leukemia (AML) Patients Age 60 or Older Who Are Not Candidates.

Best of ASH 2007 Myelodysplastic Syndromes Lloyd E. Damon, MD.

Low Dose Decitabine Versus Best Supportive Care in Elderly Patients with Intermediate or High Risk MDS Not Eligible for Intensive Chemotherapy: Final Results.

A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma Shah.

Ibrutinib in Combination with Rituximab (iR) Is Well Tolerated and Induces a High Rate of Durable Remissions in Patients with High- Risk Chronic Lymphocytic.

Phase II Trial of R-CHOP plus Bortezomib Induction Therapy Followed by Bortezomib Maintenance for Previously Untreated Mantle Cell Lymphoma: SWOG 0601.

VANTAGE 095: An International, Multicenter, Open-Label Study of Vorinostat (MK-0683) in Combination with Bortezomib in Patients with Relapsed or Refractory.

Brentuximab Vedotin in Combination with RCHOP as Front-Line Therapy in Patients with DLBCL: Interim Results from a Phase 2 Study Yasenchak CA et al. Proc.

MM-005: A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose for the Combination of Pomalidomide, Bortezomib,

ANCO 2006 ASH UPDATE MDS Joseph M. Tuscano, M.D. UC Davis Cancer Center.

Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphoma: Final Results of the Phase Ib/II Ro-CHOP Study Dupuis J et al. Proc ASH.

Preliminary Results of a Multicenter Phase II Trial of 5-Day Decitabine as Front-Line Therapy for Elderly Patients with Acute Myeloid Leukemia (AML) Cashen.

Campos M et al. Proc EHA 2013;Abstract B2009.

Campos M et al. Proc EHA 2013;Abstract B2009.

Final Results from a Phase 2 Study of Pracinostat in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML)1 CC-486 (Oral.

Myelodysplastic syndrome(MDS)

Azacitidine 75 mg/m2 per day x 7 days q28

Reeder CB et al. ASCO 2009; Abstract (Poster)

DiNardo C et al. Proc ASH 2015;Abstract 327.

Randomized, Open-Label Phase 1/2 Study of Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple.

Oki Y et al. Proc ASH 2013;Abstract 252.

Mateos MV et al. Proc ASH 2013;Abstract 403.

5-Azacytidine (AZA) in Combination with Ruxolitinib (RUX) as Therapy for Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)1

Rigosertib + Azacitidine in Patients With Higher-Risk MDS

Ruxolitinib + Azacitidine in Newly Diagnosed or R/R, Intermediate- or High-Risk Myelofibrosis New Findings in Hematology: Independent Conference Coverage.

Dimopoulos MA et al. Proc ASH 2012;Abstract LBA-6.

Erba HP et al. Blood 2008;112: Abstract 558

Fowler NH et al. Proc ASCO 2010;Abstract 8036.

Kantarjian H et al. Cancer 2009;[Epub ahead of print].

Fenaux P et al. Lancet Oncol 2009;10(3):

Ferrajoli A et al. Proc ASH 2010;Abstract 1395.

Jakubowiak AJ et al. Proc ASH 2010;Abstract 862.

Biological Characterization

Grövdal M et al. Blood 2008;112:Abstract 223.

Pollyea DA et al. Proc ASCO 2011;Abstract 6505.

Lyons RM et al. J Clin Oncol 2009;27(11):

ASH Review 2018: Update on Myelodysplastic Syndrome

Kantarjian HM et al. Blood 2008;112:Abstract 635.

Presentation transcript:

Final Results From a Phase I Combination Study of Lenalidomide and Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS) Sekeres MA et al. Blood 2008;112:Abstract 221.

Introduction Current standard therapy for IPSS intermediate-1-, intermediate- 2-, and high-risk MDS is single agent hypomethylating agent such as azacitidine. Lenalidomide is the standard of care for del (5q) MDS. Lenalidomide also has activity in non-del (5q) MDS (Blood 2008;111:86) Combining azacitidine and lenalidomide has potential to improve outcomes in higher risk MDS when compared to either agent alone. Study objectives: –Safety of combination therapy with lenalidomide and azacitidine in patients with higher risk MDS –Efficacy of combination therapy with lenalidomide and azacitidine in patients with higher risk MDS Source: Sekeres MA et al. Blood 2008;112:Abstract 221.

Mechanism of Action of Lenalidomide in MDS Lenalidomide targets malignant cells in the bone marrow microenvironment T cells Erythroid progenitors VEGF Bone marrow vessels Lenalidomide NKT cells TNF-  Erythrocytes Lenalidomide Haemoglobin Growth arrest Cytolysis? del 5q myelodysplastic clone Blocks Stimulates Lenalidomide IL-2 IFN- Source: With permission from Sekeres MA et al. Blood 2008;112:Abstract 221.

Methyltransferase Inhibitor (MTI) Induced DNA Hypomethylation and Gene Activation Azacitidine (AZA) and decitabine (DAC) are incorporated into DNA in lieu of cytosine residue Inactivates DNA methyltransferase (DMT) Leads to formation of newly synthesized DNA with unmethylated cytosine residues Results in hypomethylation and transcription of previously quiescent genes DMT AZA A:T C:G G:C C:G G:C m m DMT DAC A z D M T A:T C:G G:C C:G G:C

Trial Design Standard 3+3 Phase I design Patients with higher risk MDS as defined below were eligible: –IPSS score ≥ 1.5 (Int-2 risk or high risk) –FAB subtype RAEB-1 or RAEB-2 Six cohorts predefined in the trial Source: Sekeres MA et al. Blood 2008;112:Abstract 221.

Dose LevelAzacitidine ScheduleLenalidomide Schedule 175 mg/m 2 SC days 1-55 mg PO days mg/m 2 SC days 1-55 mg PO days mg/m 2 SC days mg PO days mg/m 2 SC days 1-5, mg PO days mg/m 2 SC days 1-5, mg PO days mg/m 2 SC days 1-5, mg PO days 1-21 Lenalidomide + Azacitidine: Dosing Table Source: Sekeres MA et al. Blood 2008;112:Abstract 221.

CharacteristicMedian (range), n=18 Age68 years (52-78) Female/Male (n)6/12 Time from Diagnosis5 weeks (2-106) Baseline: Hemoglobin (g/dL) Platelets (/mm 3 ) Absolute neutrophil count (/mm 3 ) Erythropoietin (IU/L) Bone marrow blast count (%) , IPSS (n): Intermediate-1 risk Intermediate-2 risk High risk Source: Sekeres MA et al. Blood 2008;112:Abstract 221. Lenalidomide + Azacitidine: Baseline Characteristics

No dose-limiting toxicities were reached in all the dosing cohorts. Median absolute neutrophil count decreased 26% within the first 8 weeks. Median platelet count decrease was 0% (mean=24%) within the first 8 weeks. Cycle 2 was delayed for five patients (≤9 days) for recovery of counts or “other” reasons. Lenalidomide + Azacitidine: Toxicity Results Source: Sekeres MA et al. Blood 2008;112:Abstract 221.

Clinical Response (n=18)% (n) Overall response rate72% (13) Complete response (CR) Partial response (PR) Hematologic improvement (HI) Bone marrow complete response 39% (7) 6% (1) 17% (3) 11% (2) Source: Sekeres MA et al. Blood 2008;112:Abstract 221. Lenalidomide + Azacitidine: Efficacy Results

Dosing CohortAza DoseLen Dose IPSS Risk Group Grade 3/4 Non-Heme Toxicities Maximum Response 1 75 mg/m 2 SC days mg PO days Int-1 2 Int CR 1 progression 2 75 mg/m 2 SC days mg PO days Int-2 1 High 2 1 CR 1 PR, 1 HI 3 75 mg/m 2 SC days mg PO days Int-2 2 High 0 2 CR 1 SD 4 50 mg/m 2 SC days 1-5, mg PO days Int-1 2 Int CR 1 SD 5 50 mg/m 2 SC days 1-5, mg PO days Int-2 1 High 2 1 HI, 1 SD 1 progression 6 50 mg/m 2 SC days 1-5, mg PO days Int-1 1 Int-2 1 High 2 1 HI 2 bone marrow CR Source: Sekeres MA et al. Blood 2008;112:Abstract 221. Lenalidomide + Azacitidine: Go Forward Dose for Phase II Study

Summary and Conclusions The combination of azacitidine and lenalidomide has acceptable toxicity with good response rates. The go forward dose was established for Phase II studies. Source: Sekeres MA et al. Blood 2008;112:Abstract 221.

Epigenetic Therapy With 5-Azacytidine, Valproic Acid, and ATRA in Patients With High- Risk AML or MDS: Results of the French VIVEDEP Phase II Study Raffoux E et al. Blood 2008;112:Abstract 763.

Introduction Azacytidine (AZA) is a validated therapy in patients with high-risk MDS, including patients with 20-30% marrow blasts. There is no clear standard therapy for elderly patients with AML, who are unfit to receive standard induction chemotherapy. Histone deacetylase (HDAC) inhibitors, including valproic acid, have shown activity in AML/MDS. Synergy of hypomethylating agents and HDAC inhibitors is supported by in vitro data. ATRA is a differentiating agent, and sensitivity to ATRA may be restored in non-APL cells through epigenetic mechanisms. Study objectives: –To assess the efficacy and safety of AZA and valproic acid (VPA) followed by ATRA treatment in patients with high-risk AML or MDS. Source: Raffoux E et al. Blood 2008;112:Abstract 763.

Phase II Multicenter Study of Combined AZA, VPA and ATRA Treatment in Patients with Higher-Risk AML or MDS Eligibility (n=65) Untreated elderly (≥70 years) AML AML in 1 st relapse (either if secondary AML or if 1 st CR duration < 18 months) High-risk MDS (refractory anemia with excessive blasts [RAEB] or RAEBt with IPSS Int-2- or high- risk score) AZA 75 mg/m 2 /day SC days 1-7 VPA mg/kg/day PO days 1-7 ATRA 45 mg/m 2 /day PO days 8-28 q4wks x 6 cycles Source: Raffoux E et al. Blood 2008;112:Abstract 763.

Characteristic Age, median (range)72 years (50-87) Female/Male (n)27/38 Diagnosis Group (n): Untreated AML Relapsed AML High-Risk MDS Median white blood cell (10 9 /L) 2.3 Median platelet count (10 9 /L) 43 Median marrow blasts (%) 31 Karyotype (n): Standard-risk High-risk Failure/not done Patient Population (n=65) Source: Raffoux E et al. Blood 2008;112:Abstract 763.

Clinical Response (n=62) Overall response after 6 cycles Complete response Partial response 24% 21% 3% Best response during study Complete response Partial response 29% 23% 6% Source: Raffoux E et al. Blood 2008;112:Abstract 763. Efficacy Results

CR + PR (31% at 6 mos)Death (31% at 6 mos) 6 mos estimation P-value 6 mos estimation P-value Age ≥ 70 years24%0.5053%0.025 Female25%0.2147%0.03 PS (WHO) ≥ 20%0.1057%0.008 WBC ≥ 1.5x10 9 /L26%0.4731%0.96 Platelets < 50x10 9 /L19%0.0239%0.10 Marrow blasts > 30%29%0.4442%0.05 High-risk karyotype24%0.5248%0.003 Relapsed AML31%0.7262%0.01 Source: Raffoux E et al. Blood 2008;112:Abstract 763. Prognostic Factors for CR/PR And Death

Adverse EventN eventsMean cycle ± SD Infections Pneumonia Septicemia Aspergillosis ± 3.3 Confusion331.7 ± 1.4 Asthenia202.0 ± 1.5 Constipation131.0 ± 1.1 Hemorrhage132.0 ± 1.4 Somnolence121.3 ± 1.4 Nausea/vomiting102.5 ± 1.7 Subcutaneous puncture reaction91.7 ± 1.9 Source: Raffoux E et al. Blood 2008;112:Abstract 763. Non-Hematological Adverse Events Grades 3-4

Summary and Conclusions Combination therapy with AZA, VPA and ATRA has a promising 25% to 30% response rate in patients with high risk AML/MDS. Response rates do not appear to differ by baseline cytogenetic risk, relapse status or percentage of marrow blasts. Future and larger studies are needed to better define the respective roles of these agents. Source: Raffoux E et al. Blood 2008;112:Abstract 763.