Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: Combination Therapy in MPN
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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