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823 5-Azacytidine (AZA) in Combination with Ruxolitinib (RUX) As Therapy for Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)

Myeloproliferative Syndromes: Clinical
Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: Combination Therapy in MPN
Monday, December 7, 2015: 4:30 PM
W315, Level 3 (Orange County Convention Center)

Naval Daver, MD1, Guillermo Garcia-Manero, MD2, Jorge E. Cortes, MD3, Lingsha Zhou4*, Sherry Pierce, BSN, BA3*, Naveen Pemmaraju, MD3, Elias Jabbour3, Courtney DiNardo, MD3, Tapan Kadia, MD3, Gautam Borthakur, MD3, Farhad Ravandi, MD3, Marina Konopleva, MD, PhD5, Franklin Wynn6*, Stephanie Van Derbur6*, Zeev Estrov, MD3, Hagop M. Kantarjian, MD3 and Srdan Verstovsek, MD3

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, Houston, TX
2Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX
5Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
6The University of Texas M. D. Anderson Cancer Center, Houston, TX

Background:Clinical trials exclusively focusing on pts with MDS/MPN are lacking. AZA is a DNA methyltransferase (DNMT) inhibitor approved for the therapy of MDS while RUX is a JAK inhibitor approved as therapy for primary myelofibrosis and polycythemia vera. RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs.

Aim: To determine the efficacy and safety of RUX + AZA in pts with MDS/MPN requiring therapy including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia BCR-ABL1 negative (aCML), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) (ClinicalTrials.gov Identifier: NCT01787487).

Methods: A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets >200) continuously (pts with platelets below 50 were not eligible) in 28-day cycles for the first 3 cycles followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. The AZA could be started earlier than cycle 4 and/or at a higher dose in pts with proliferative disease or elevated blasts.

Results:24 pts were enrolled between March 1, 2013 and April 1, 2015. Baseline characteristics are summarized in table 1. 17 pts remain alive after a median (med) follow-up of 6.0 (3.7 – 21.3+) months. Responses were evaluated by the MDS/MPN IWG response criteria (Savona et al., Blood 2015, 125(12):1857-65). Responses were noted in 12 (50%) pts. Details of responses are shown in table 2. Med time to responses was 1.8 mos (0.7 – 5.5+) and the med duration of response is 7.0 mos (1.8 – 17.6+). Additionally, 9 pts had >5% pretreatment BM blasts: 6 of these pts had follow-up BM evaluations and 3 achieved a reduction in blasts to <5% with a med time to blast reduction of 5.5 mos (5.5 – 11.2+). Serial evaluation of bone marrow biopsies documented reduction in EUMNET fibrosis score in 3 of 11 (27%) evaluable pts after a med of 5.5 mos (2.1 – 5.6+) on therapy. The reduction was by one grade in all 3 pts (MF-2 to MF-1 in 2 pts, MF-1 to MF-0 in 1 pt) and was confirmed on a subsequent BM biopsy in 2 pts.

No pts experienced grade 3/4 non-hematological toxicity. New onset grade 3/4 anemia and thrombocytopenia were seen in 12 (50%; of which 5 had a 2+ grade change) and 8 (31%) pts, respectively. The med overall survival is 15.1+ mos. 7 pts have died: pneumonia (n=3), sepsis (n=2), progression to AML (n=1), and transition to hospice (n=1).

The AZA was started in cycle 4 in 12 pts (50%). The AZA was started earlier due to leukocytosis or increased blasts in 11 pts (46%), in cycle 1 (n=6), cycle 2 (n=4), and cycle 3 (n=1). 13 pts have discontinued protocol therapy due to leukocytosis (n=6), progression to AML (n=1), lack of response (n=3), pneumothorax (n=1), stem cell transplant (n=1), and loss of insurance (n=1), respectively.

Conclusion:Concomitant administration of RUX with AZA was feasible and effective in pts with MDS/MPNs, with expected myelosuppression as the only significant toxicity. This combination warrants further evaluation.


Table 1: Baseline characteristics (N = 24)

Characteristic

N (%) / [range]

Med age, years

71 [55 - 79]

Prior treatment

9 (38)

Diagnosis

     MDS/MPN-U

     CMML

     aCML

11 (46)

10 (42)

3 (12)

MF – DIPSS

      Int-1/ Int-2/ High

4(17)/ 11(46) / 9(37)

MDS – IPSS

       Low/ Int-1/ Int-2/ High                                 

9(38) /12(50) / 2(8) / 1(4)

Splenomegaly

12 (50)

Med WBC x 109/L

26.3 [3 - 123.2]

Peripheral blood blasts >/= 1%

17 (71%)

LDH

1040 [409 – 3567]

EUMNET fibrosis grade

      MF-1/ MF-2/ MF-3

10(42)/ 6(26)/ 1(4)

JAK2 +

6 (25)

Med JAK2 allele burden

42.2 [3 – 90]

Karyotype

Diploid

Abnormal

18 (75)

6 (25)

28-gene molecular panel in 23 pts*, (1 pt not done)

         ASXL1

         DNMT3A

         TET2

         KRAS/NRAS

         PTPN11

         IDH 2

4 (17)

4 (17)

3 (13)

2(8) / 2(8)

2(8)

2 (8)

*Mutations identified in only 1 pt included EZH2, GATA2, RUNX1, MPL, KIT.

Table 2: Response evaluation by the MDS/MPN IWG 2015 criteria

Response category

Evaluable pts

Responders/Evaluable (%)

*All responses, some pts have > 1 response

All

12/24 (50)

Clinical improvement (CI) spleen

Pts with palpable spleen > 5 cm

8/11 (73)

CI total symptom score

Pts with baseline TSS > 20

3/12 (25)

CI Hemoglobin (HGB)

Baseline HGB < 10 g/dL

1/7 (15)

CI Transfusion independence

History of transfusion dependence

1/5 (20)

Partial marrow response

Baseline and follow-up BMs

5/11 (45)

Optimal marrow response

Baseline and follow-up BMs

1/11 (9)

*No CR or PR documented

Disclosures: Daver: ImmunoGen: Other: clinical trial , Research Funding . Cortes: Pfizer: Consultancy , Research Funding ; BerGenBio AS: Research Funding ; Teva: Research Funding ; BMS: Consultancy , Research Funding ; Novartis: Consultancy , Research Funding ; Ariad: Consultancy , Research Funding ; Astellas: Consultancy , Research Funding ; Ambit: Consultancy , Research Funding ; Arog: Research Funding ; Celator: Research Funding ; Jenssen: Consultancy . Pemmaraju: Stemline: Research Funding ; Incyte: Consultancy , Honoraria ; Novartis: Consultancy , Honoraria , Research Funding ; LFB: Consultancy , Honoraria . DiNardo: Novartis: Research Funding . Konopleva: Novartis: Research Funding ; AbbVie: Research Funding ; Stemline: Research Funding ; Calithera: Research Funding ; Threshold: Research Funding .

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*signifies non-member of ASH