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Sirolimus-calcineurin inhibitor for chronic GvHD
Discussion
In this phase II, multicenter, randomized trial comparing two CNI-free approaches against a CNI-containing com- parator arm, the comparison of two versus three drugs showed similar outcomes with the CNI-free chronic GvHD therapy. Subjects who received prednisone/sirolimus had better renal and physical function at 2 and 6 months, but these improvements did not result in long-term advantages for recipients of the two-drug immunosuppressive therapy. However, between 6 and 12 months, 20%-30% of subjects treated with two drugs and 11%-24% treated with three drugs had already switched to secondary immunosuppres- sive therapy, potentially attenuating longer-term associa- tions. Earlier studies suggested that narrower targeting of CNI and sirolimus blood levels might mitigate nephrotoxi- city.9,25 Data to evaluate this were not collected, but it is con- ceivable that side effects, particularly with three drugs, were partially mitigated by detailed study guidance for managing CNI and sirolimus blood levels.
Our hypothesis was that CNI-free two-drug immuno- suppressive therapy would not impede Treg expansion and would thereby abrogate chronic GvHD better than would three-drug immunosuppressive therapy. The few statistically significant associations that we observed in Treg number and BAFF serum levels were inconsistent and/or difficult to understand suggesting that chronic GvHD biomarker response associations are more complex than Treg alone. Rates of secondary therapy for lack of efficacy between day 90 and day 180 were almost double with two-drug immunosuppressive therapy compared to three-drug therapy, which might have attenuated predict- ed Treg response associations.
We learned important lessons to inform and potentially improve future study design in chronic GvHD. Had phase II been positive, the 51 additionally accrued subjects beyond the phase II target would have jump-started phase III accrual, thereby confirming “built-in” adaptive phase II/III design utility. Second, to begin endpoint review com- mittee adjudications 3 years after enrollment and then dis- cover that 10% of subjects had been ineligible was prob- lematic. For a complex clinical syndrome like chronic GvHD, our fundamental eligibility criterion that required patients to be “diagnosed according to NIH guidelines” was too open to misinterpretation. This problem was resolved after introducing a screening checklist to confirm that patients met the NIH diagnostic criteria for chronic GvHD (Online Supplementary Material). Lastly, a similar problem existed with respect to complete/partial response evaluations. While considerable efforts have been made to standardize and develop more objective chronic GvHD response instruments,26 case report forms for this trial had multiple sections with categorical check boxes and required measures in many organs. The completion of case report forms was inconsistent and has been consid- ered burdensome by others.27 Months of iterative commu- nications between the endpoint review committee, site investigators, and the Data Coordinating Center to clean
Table 3. Treatment success.
Two drugs
Treatment success at 6 months
Three drugs P-value
Treatment successa Yes
(N=72)
35 (48.6%) [95% CI: 36.7%-60.7%]
(N=66)
33 (50.0%) [95% CI: 37.4%-62.6%]
0.871
CR 3 6 PR 32 27
No
Relapse Secondary therapy Death
Not in CR/PR
Treatment successb Yes
37 (51.4%) [95% CI: 39.3%-63.4%] 1
14
4
18
33 (50.0%) [95% CI: 37.4%-62.6%] 3
7
6
17
Treatment success at 2 years
10 (14.7%) [95% CI: 7.3%-25.4%]
9 (15.5%) [95% CI: 7.4%-27.4%]
CRoffIST 3 7 CRonIST 7 2
0.899
No
VGPRc off IST VGPRc on IST PRoffIST PRonIST Progression Relapse Secondary therapy Deathd
Not evaluablee
58 (85.3%) [95% CI: 74.6%-92.7%] 6
4
1
9
1
5
28
4
4
49 (84.5%) [95% CI: 72.6%-92.7%] 1
3
3
7
2
8
18
7
8
Two drugs: prednisone/sirolimus, three drugs: prednisone/sirolimus/calcineurin-inhibitor; aTreatment success at 6 months is defined as a complete (CR) or partial response (PR) without secondary systemic immunosuppressive therapy (IST) and no recurrent malignancy or death through 6 months after randomization.bPartial response is excluded from the definition of treat- ment success at 2 years.cVery good partial response (VGPR) is defined as having trivial residual and asymptomatic graft-versus-host disease features, while on a prednisone dose that is physio- logical or less (defined as ≤5 mg daily or ≤10 mg every other day).This category splits further into truly off all IST (meaning also off sirolimus and/or calcineurin inhibitor or not. dDeath, relapse, and secondary therapy are mutually exclusive, based on which event occurred first. eParticipant withdrew study consent.
Figure 3. Cumulative incidence of discontinuation of all systemic immunosup- pressive therapy without the need to add additional therapy by 2 years.
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