Page 80 - 2019_04-Haematologica-web

M. Kenealy et al.
Table 4. Efficacy: clinical benefit at 12 months, overall response rate (ORR) & best response achieved by assigned treatment cohort; those who received treatment.
Clinical benefit at 12 months (SD or better) MDS
AML
CMML
IPSS-R Very Low/Low
IPSS-R Intermed/High/Very High
Overallresponserate (Bestresponse)
MDS
AML
CMML
IPSS-R Very Low/Low
IPSS-R Intermed/High/Very High
Best response achieved CR
PR
Marrow CR
Marrow CR+HI
HI only
SD
PD
Death prior to C3 first response assessment
Missing data/not evaluable
AZA n=79
n (%[Exact 95% CI])
52 (65% [54-75]) 38 (63% [50-75]) 5 (62% [24-91]) 9 (75% [43-95]) P=0.7
22 (85% [65-96]) 28 (57% [42-71]) 45 (57% [45-68]) 36 (60% [47 - 72]) 3 (43% [10-82]) 6 (50% [21-79]) 15 (58% [37-77]) 28 (58% [43-72])
17 (22%)
0 2(2%)
LEN+AZA n=80 P n (%[Exact 95% CI])
43 (54% [42-65]) 0.2 34 (58% [44-70]) 0.6 4 (36% [11-69]) 0.4 5 (50% [19-81]) 0.4
P=0.4
12 (57% [34-78])
0.052 28 (52% [38-66]) 0.7 55 (69% [57-79]) 0.14 41 (69% [56 - 81]) 0.3
6 (55% [23-83])
8 (80% [44-97]) 0.2
>0.99 14 (67% [43-85]) 0.6
2 (2%) 8 (10%) 18 (23%) 22 (28%) 3 (4%) 6 (8%)
3 (4%)
5 (6%)
5 (6%) 23 (29%) 15 (19%) 4 (5%) 4 (5%)
2 (2%)
37 (69% [54-80]) 0.3
20 (25%)
CR: complete response; HI: hematologic improvement; PD: progressive disease; PR: partial response; SD: stable disease.
azacitidine. Overall, there was very good durability of responses and good survival. Unsurprisingly, those with lower-risk disease according to established prognostic scores lived longer.
Our eligibility included patients with potentially lower- risk disease subtypes in contrast to other recent clinical tri- als such as AZA0019 and SWOG S111721 which defined eligibility based on prognostic score. This inclusion was based on earlier data showing similar response rates across all IPSS groups7 and an acknowledgement that a proportion of those with apparent lower-risk disease have outcomes more in keeping with those with higher prog- nostic scores. Despite this, and though it is an indirect comparison of populations, our cohort risk compares sim- ilarly to the SWOG S1117 cohort with respect to propor- tion of patients with Very Low/Low IPSS-R; 31.3% Sekeres cohort compared to our ALLG MDS4 32% (AZA) and 38% (AZA + LEN).
It is possible that the dose and scheduling of treatment in this protocol may have impacted on responses. Phase 1 data by Sekeres26 supported the decision to reduce the number of days of azacitidine dosing to five when com- bining with lenalidomide, in order to reduce the risk of treatment limiting toxicity in the first two cycles. Given the lack of excessive toxicity in our combination arm and the high median number of azacitidine cycles (11 cycles in our cohort compared to SWOG 1117 median 23-25 weeks treatment) we did achieve the implementation of this
treatment combination on a broad multi-centre setting. However, we have not shown that full azacitidine dosing of seven days per cycle in combination with lenalidomide is feasible. In addition, the concurrent as opposed to con- secutive administration of the two agents on this protocol may have reduced overall efficacy. The dose of lenalido- mide selected for this study was based on a Phase II study in MDS,21 however, subsequent studies have utilised high- er doses of lenalidomide in combination – mostly sequen- tial - in AML30 and high-risk MDS31 which may improve efficacy. The option of using lenalidomide prior to the introduction of azacitidine could be considered as an extrapolation of the findings by Zeidan et al. who demon- strated enhanced erythroid improvement in low -risk (non-5q deletion) MDS.31 Finally, consideration could be given to commencing both agents from C1 rather than delaying the introduction of lenalidomide until C3 in an attempt to improve efficacy, although early progressions or deaths in our study were uncommon with 10 deaths or disease progression within the first 2 cycles of treatment (5 in each arm).
There was no central review of pathology in this study. Responses were provided by the site investigators and only reviewed centrally if there were discrepancies or questions. IWG criteria for response was adopted, though its application in patients experiencing both dis- ease and treatment related cytopenias is complex, and the application and consistency across many sites was
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