Page 183 - 2018_11-Haematologica-web

Sirolimus-calcineurin inhibitor for chronic GvHD
in fewer relapses than in the potentially higher-risk patients who received three drugs. However, our sample size provided insufficient power to be able to detect a dif- ference in relapse. The proportion of subjects who received secondary immunosuppressive therapy in either arm of the trial was not significantly different and it made no difference whether the patient had been enrolled with “newly diagnosed” versus “inadequately responding” chronic GvHD (data not shown).
Two large studies assessed failure-free survival among patients who received non-uniform initial chronic GvHD therapy and showed that the rates of failure-free survival were either similar31 or lower32 to those in our study in the context of overall generally higher rates of moderate and severe chronic GvHD. The Consortium recently evaluated 202 subjects in a landmark analyses to deter- mine whether failure-free survival plus complete/partial responses at either 6 months or 1 year predicted down- stream clinical benefit. At 1 year, the <20% of study sub- jects who satisfied the failure-free survival plus com- plete/partial response end-point versus all other states (failure-free survival with stable/progressive GvHD, or received secondary immunosuppressive therapy) were associated over the subsequent 5 years with significantly fewer GvHD disease manifestations, lower mortality, and earlier discontinuation of immunosuppressive thera- py.33 Because a similar 6-month failure-free survival plus complete/partial response landmark analysis revealed less striking associations with downstream clinical bene- fit, the authors proposed 1-year failure-free survival plus complete/partial responses as the primary endpoint for future pivotal clinical trials of initial therapy. Although 1- year endpoint data were not available, at 6 months our two groups without complete/partial response (i.e. fail- ure-free survival with stable/progressive GvHD, or received secondary immunosuppressive therapy) behaved similarly when analyzed separately. They were, therefore, collapsed into one “stable disease/progressive disease/secondary immunosuppressive therapy” group of 47 patients for comparison to 68 patients with com- plete/partial response who satisfied the failure-free sur- vival endpoint, resulting in just over half the size of the cohort used for the Consortium landmark analysis. Our 6-month failure-free survival plus complete/partial response endpoint predicted earlier time to discontinue immunosuppressive therapy compared to that in the combined group with stable or progressive disease or secondary immunosuppressive therapy (hazard ratio,
2.05; 95% CI: 1.15-3.68; P=0.02) (Figure 5), but similar to the findings of Martin et al.,33 there was no striking sur- vival benefit at 6 months, perhaps because of the shorter follow up and/or the small sample size. Larger prospec- tive studies are needed to verify the utility of this end- point in predicting better survival and shorter duration of immunosuppressive therapy.
In summary, this randomized trial showed no difference in response rates between the two treatment arms. Analyses of nephrotoxicity and quality of life demonstrate that initial therapy of chronic GvHD with prednisone/sirolimus is an acceptable alternative and bet- ter tolerated than three-drug therapy including a CNI. Our study could not address the relative merits of prednisone/sirolimus versus prednisone ± CNI. We were not able to include a prednisone ± CNI treatment arm (cur- rent standard for initial therapy), because the study includ- ed patients with high-risk chronic GvHD or early treat- ment failure. Success rates for prednisone/sirolimus as ini- tial therapy in treatment-naïve or early inadequate respon- ders are insufficient to warrant a randomized controlled trial versus prednisone with or without CNI. For early chronic GvHD therapy, novel approaches that improve rates of complete/parital responses and failure-free sur- vival are required. Given the inherent complexity of chronic GvHD trials, we advise real-time diagnostic checklists to ensure patients’ eligibility, and real-time data auditing to protect data integrity.
Acknowledgments
The authors would like to thank the National Heart, Lung, and Blood Institute and the National Cancer Institute for sup- porting this study (grant #U10HL069294). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the laboratory of Jerome Ritz for performing all of the immunophenotyping and measuring serum BAFF levels. We thank Saurabh Chhabra, Gregory Yanik, Richard Maziarz, Suhag Parikh, Mark Litzow, Hillard Lazarus, Marcelo Pasquini, Andrew Artz, Krishna Gundabolu, Mark Juckett, Peter Westervelt, Pablo Parker, George Selby, George Chen, John Wingard, Scott Rowley, Scott Solomon, David Porter, Carlos Bachier, Paul Shaughnessy, James Essell, Marcie Riches, Thomas Shea, Michael Pulsipher, Edward Ball, John McCarty, Samantha Jaglowski, Guenther Koehne, and John Lister for enrolling patients on this trial. We thank the members of the Blood and Marrow Transplant Clinical Trials Network, the research nurses, and the patients who participated in this trial.
References
1. Socie G, Stone JV, Wingard JR, et al. Long- term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med. 1999;341(1):14-21.
2. Pidala J, Kurland B, Chai X, et al. Patient- reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on base- line data from the Chronic GVHD Consortium. Blood. 2011;117(17):4651-4657.
3. Sullivan KM, Witherspoon RP, Storb R, et al.
Prednisone and azathioprine compared with
Blood Marrow Transplant. 2001;7(5):265- prednisone and placebo for treatment of 273.
chronic graft-versus-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988;72(2):546-554.
4. Koc S, Leisenring W, Flowers ME, et al. Therapy for chronic graft-versus-host dis- ease: a randomized trial comparing cyclosporine plus prednisone versus pred- nisone alone. Blood. 2002;100(1):48-51.
5. Arora M, Wagner JE, Davies SM, et al. Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus cyclosporine and prednisone as initial thera- py for chronic graft-versus-host disease. Biol
6. Koc S, Leisenring W, Flowers ME, et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood. 2000;96(12):3995-3996.
7. Martin PJ, Storer BE, Rowley SD, et al. Evaluation of mycophenolate mofetil for ini- tial treatment of chronic graft-versus-host disease. Blood 2009;113(21):5074-5082.
8. Gilman AL, Schultz KR, Goldman FD, et al. Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children’s Oncology Group study. Biol Blood Marrow Transplant. 2012;18(1):84-91.
haematologica | 2018; 103(11)
1923