Azra Raza, M.D. - aamds.org in Therapy.pdf · Advances in therapy of non-del5q lower risk MDS Azra...

Advances in therapy of non-del5q lower risk MDS

Azra Raza, M.D.Professor of MedicineDirector, MDS CenterColumbia University

New York, NY

Predicting Survival : A Prognostic Nightmare

YEARS

IPSS-R and Overall Survival

Risk categoryNo. (%) of patients

SurvivalMed Years

Very low 1313 8.8

Low 2646 5.3

Intermediate 1433 3

High 898 1.6

Very high 722 0.8

Blood 2012;120(12): 2454-2465

Mortality of MDS patients with or without AML evolution

Blood 2012;120(12): 2454-2465)

Risk categoryNo. (%) of patients

Patients who

SurvivalMed Years

Died with AML, no. (%)

Died without AML, no. (%)

Very low 1313 8.8 46 (13) 304 (87)

Low 2646 5.3 174 (17) 861 (83)

Intermediate 1433 3 205 (26) 568 (74)

High 898 1.6 207 (33) 421 (67)

Very high 722 0.8 193 (31) 422 (69)

Advances in therapy of non-del5q LR-MDS

• Lenalidomide• HMA• Experimental trials

Lenalidomide

• MDS 002• MDS 005• Combination of lenalidomide and ESA• French Compassionate Program for the treatment of

ESA resistant lower risk non del5q MDS patients

MDS 002A Phase II study of lenalidomide in transfusion dependent patients with non-del5q low and

intermediate-1 risk MDSAzra Raza et al

Blood. 2008;111:86-93

Blood. 2008;111:86-93

Lenalidomide in low/Int-1 transfusion Dependent non-del(5q) patients (MDS 002)

Of 214 patients, overall HI seen in 43% and TI in 26%

50% patients responded within 5 weeks

90% patients responded within 12 weeks

Raza et al, Blood, 1(111): 83, January 2008

MDS 005Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in

RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS)

without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3

Study

Valeria Santini et alBLOOD: 124(21) December 6, 2014

MDS 005

• RBC-TD pts • IPSS Low/Int-1-risk MDS without del(5q)• Unresponsive or refractory to ESAs or serum

erythropoietin > 500 mU/mL• 2:1 randomization to oral LEN 10 mg daily or placebo• Pts with TI ≥ 56 days or erythroid response by Day

168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal

BLOOD: 124(21) December 6, 2014

• The primary endpoint was RBC-TI ≥ 56 days

• Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety

• Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response.


• The intent-to-treat population comprised 239 pts– LEN 160– PBO 79

• Baseline characteristics were comparable across treatment groups– Median age 71 years– 68% male– Median time from diagnosis 2.6 years

• Pts received– Median of 3.0 pRBC units/28 days– 84% received prior therapy, including ESAs (79%)


Results

• 26.9% LEN pts achieved RBC-TI ≥ 56 days versus 2.5% PBO (P < 0.001)

• 90% of pts with RBC-TI responded within 16 weeks of treatment

• Median duration of RBC-TI was 8.2 months

• Myelosuppression was the main adverse event (AE) in the LEN versus PBO groups

• In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed.


Conclusions

These data were consistent with response rates seen in the MDS-002 trial


Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk

MDS without 5q deletion

A Toma et al

LeukemiaAdvance online publication 15 January 2016; doi: 10.1038/leu.2015.296

Leukemia advance online publication 15 January 2016; doi: 10.1038/leu.2015.296

• A randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS

• Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm)


RESULTS

• ITT analysis showed HI-E after four treatment cycles in 23% in the L arm and 39% in the LE arm (P=0.044)

• RBC-TI was seen in 14% and 24% of the patients in the L and LE arms respectively (P=0.13)

• Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47)

• Side effects were moderate and similar in the two arms

• Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E


Conclusion

Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-

del5q MDS patients with anemia resistant to ESA


HMA

• Well established role in higher risk MDS• RBC-TI rates of 10–60% and hematologic

improvement in 25–55% of patients• One prospective trial showed ~20% TI to HMA in ESA-

refractory patients

Low-Dose Hypomethylating Agents Are Effective in Patients with Low- or Intermediate-1-Risk Myelodysplastic Syndrome: A Report on Behalf of the MDS Clinical Research Consortium

Short N1, Garcia-Manero G1, Montalban Bravo G1, Sasaki K1, Sekeres M2, Komrokji R3, Steensma D4, DeZern A5, Roboz G6, Kadia T1, Borthakur G1, DiNardo C1, Miller D1, Estrov Z1, Pemmaraju N1, Daver N1, Verstovsek S1,

Kantarjian H1, Jabbour E1

Blood 2015 126:94; December 4, 2015

Presenter

Presentation Notes

Thank you for the opportunity to present here this morning. Today I will be presenting a report on behalf of the MDS Clinical Research Consortium on the use of low-dose hypomethylating agents in patients with low or intermediate-1-risk myelodysplastic syndromes

Low-Dose HMAs in LR-MDS: Study Design

• Open-label phase II trial

• Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN

• Pts were treated with AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2

IV daily for 3 consecutive days on a 28-day cycle

• Endpoints: ORR, response duration, transfusion independence, cytogenetic response, event-free survival, OS, safety

Blood 2015 126:94; December 4, 2015

Presenter

Presentation Notes

CMML, chronic myelomonocytic leukemia; ECOG, Eastern Cooperative Oncology Group; HMAs, hypomethylating agents; IPSS, International Prognostic Scoring System; IWG, International Working Group; LR, lower risk; MDS, myelodysplastic syndrome; PS, performance status. Rami S. Komrokji, MD: Short and colleagues[1] conducted a phase II trial of a shorter duration of low‑dose HMAs in patients with IPSS lower‑risk MDS or CMML (N = 91). The optimal schedule of those medications in lower‑risk patients is not known, and some believe that lower‑dose hypomethylation could be as efficacious, if not more so than standard doses. In this study, between November 2012 and October 2015, 91 patients with lower-risk MDS received just 3 days of either azacitidine 75 mg/m2 or decitabine 20 mg/m2 every 4 weeks for at least 2 cycles. The endpoints included ORR, duration of response, transfusion independence, cytogenetic response, event-free survival, OS, and safety. Reference Short N, Garcia-Manero G, Bravo GM, et al. Low-dose hypomethylating agents (HMAs) are effective in patients (pts) with low- or intermediate-1-risk myelodysplastic syndrome (MDS): a report on behalf of the MDS Clinical Research Consortium. Program and abstracts of the 57th American Society of Hematology Annual Meeting and Exposition; December 5-8, 2015; Orlando, Florida. Abstract 94.

Low-Dose HMAs in LR-MDS: Study Design

• 88 pts with lower-risk MDS were treated– 83 of them evaluable for response assessment

• 37 pts received AZA (36%) and 53 pts (64%) received DAC

• The median follow-up was 13 months (range 2-30 months) and median number of cycles received was 9 (range 2-29 cycles

Blood 2015 126:94; December 4, 2015

RESULTS

• The overall HI was 61%– CR 32 (39%) – Cri 11 (13%)– HI 8 (10%)

• 9/38 (24%) achieved TI

• Median time to best response was 2.2 months (range 0.8 to 19.6 months)

Blood 2015 126:94; December 4, 2015

C O N C LU S I O N S

• Low-dose HMA therapy appears safe and effective in LR-MDS

• Randomized phase II trial evaluating low-dose azacitidine vs decitabine vs best supportive care in progress

Blood 2015 126:94; December 4, 2015

HMA: The Immunity Dimension

• Two groups now show that azacytidine and decitabineactivate endogenous retroviral sequences which in turn induce an antiviral response in ovarian and colorectal carcinoma cells

Cell 162, August 27, 2015; Cell 162, 974, 2015; Cell 162, 961, 2015.

ImetelstatTelomerase inhibitor targets malignant cells with a high

level of telomerase activity

Imetelstat produced CRs and PRs in pts with ET and MF, as well as molecular responsiveness in a substantial

subset of pts with spliceosome mutations

Imetelstat RARS and RARS-T: Conclusions

– Of 8 pts who were transfusion dependent at baseline, 3 achieved transfusion independence on study

– Treatment has a generally acceptable safety profile

Tefferi A, et al. ASH 2015. Abstract 55

Presenter

Presentation Notes

MF, myelofibrosis; RARS, refractory anemia with ring sideroblasts; RARS-T, RARS with thrombocytosis.

Other Agents

• Luspatercept• Eltrombopag• Rigosertib• Immunetherapies

Unmet needs of non del5q LR-MDS patients

• The majority of patients remain transfusion dependent either continuously or episodically

• The last disease modifying agent to be approved was more than a decade ago

THE END

Azra Raza, M.D. - aamds.org in Therapy.pdf · Advances in therapy of non-del5q lower risk MDS Azra...

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