Chronic GVHD (cGVHD) remains the most important cause of late non-relapse mortality post allogeneic hematopoietic SCT (HSCT). Although first-line treatment of cGVHD with steroids is well established, evidence for second-line treatment remains limited. Here, we report a dual center retrospective analysis of the off-label salvage treatment of steroid-refractory cGVHD with everolimus. Out of 80 patients with a median age of 50 (17–70) years, 14 (17%) suffered from mild, 39 (49%) from moderate and 27 (34%) from severe cGVHD. At the final analysis, median follow-up after introduction of everolimus was 724 (14–2205) days. Thirty-four patients (43%) required the addition of further immunosuppression during everolimus-based therapy. Global NIH Severity Score improved in 34 patients (43%), remained stable in 37 patients (46%) and worsened in 9 patients (11%). The total sum of Global NIH Severity Scores in all patients assessable was significantly reduced after treatment with everolimus (P<0.0001). Most frequent grade 3/4 toxicities included infections (n=30) and thrombocytopenia (n=15). There was a single case of relapse. Everolimus-based salvage treatment of refractory cGVHD results in significant improvement of the NIH Severity Score without impairing control of the malignant disease. Finally, these preliminary results demand further verification in prospective trials.
Allogeneic hematopoietic SCT (HSCT) has become a standard of care curative approach for the vast majority of hematological diseases.1,2 With more and more transplants being done and significantly reduced rates of TRM observed over the decades, the number of patients surviving has increased steadily.3, 4, 5 In long-term survivors of allogeneic HSCT the appearance of chronic GVHD (cGVHD) compromises patients’ quality of life requiring long-term immunosuppression associated with significant toxicity.6, 7, 8, 9 In contrast, accumulating evidence suggests a strong and beneficial effect of cGVHD on the control of the underlying malignant disease as a consequence of persisting graft-versus-malignancy effects. This explains reduced relapse rates and improved OS in patients with milder forms of cGVHD.10, 11, 12, 13, 14 On the other hand, severe forms of cGVHD may require high-level immunosuppression thereby compromising sufficient disease control and favoring relapse as well as infections.15,16 Therefore, optimal treatment of cGVHD is difficult to achieve in these cases and refractory courses are common.17,18
Established and evidence-based treatment options for cGVHD are rare and limited to a steroid-based first-line therapy. Evidence for second-line treatment remains limited with no single agent having been approved for salvage treatment yet.19,20 The initial attempt to introduce inhibitors of the mechanistic target of rapamycin (mTOR) such as sirolimus (rapamycin) to cGVHD treatment was hampered by the toxicity profile including severe microangiopathy particularly when being used in combination with calcineurin inhibitors (CNI).21, 22, 23 Everolimus, a derivate of sirolimus, first binds to cyclophilin FK-BP12 before inhibiting mTOR and consequently blocks Ag-driven proliferation and differentiation of T and B lymphocytes (Figure 1).24,25 Whether everolimus’s slightly different mechanism of action is associated with an improved toxicity profile is unclear to date.26,27 Everolimus is an approved drug for immunosuppressive treatment in solid organ transplantation as well as an approved anti-neoplastic agent in kidney, breast and neuroendocrine pancreatic cancer.28, 29, 30, 31 However, data on the use of everolimus in allo-SCT are very limited. Attempts to introduce everolimus for prophylaxis of acute GVHD (aGVHD) failed because of significant side effects such as sinusoidal obstruction syndrome and transplant-associated microangiopathy, again most likely as a result of combination with CNI.32 Nevertheless, a single preliminary report from Jedlickova et al.33 in 21 patients suggests everolimus as a promising candidate for the treatment of sclerodermatous cGVHD.
Here, we report a dual center retrospective cross-sectional analysis on the salvage treatment of refractory cGVHD with everolimus in 80 patients. We demonstrate that everolimus represents an effective treatment option for the majority of patients with steroid-refractory cGVHD. Everolimus exerts a manageable toxicity profile and a very low relapse rate of the underlying malignant disease.
Subjects and methods
Study design and patients
The aim of this cross-sectional retrospective analysis was to evaluate the response rates and the toxicity profile of everolimus in two German transplant centers (center A, Regensburg University Medical Center, Department of Internal Medicine III; center B, Würzburg University Medical Center, Department of Internal Medicine II, Allogeneic Stem Cell Transplantation Center). All patients with active cGVHD who failed at least one line of steroid-based therapy and received an off-label salvage treatment with everolimus between October 2005 and December 2011 were included in this analysis. The date of final analysis was 27 July 2012.
cGVHD and response to treatment
Severity of cGVHD was assessed applying the cGVHD global severity score and organ grading according to the NIH Consensus Criteria.34 Response to treatment was assessed using two different approaches.
On a metric basis, response to treatment was calculated as the difference between the global NIH Severity Score before and after treatment separating the following categories of cGVHD: none (zero points), mild (one point), moderate (two points) and severe (three points): Δ Score=(NIH Severity Score after treatment) minus (NIH Severity Score before treatment). Response to treatment was to be assessed at three time points. This always included an overall response assessment at the end of treatment or at last follow-up and was to be completed by two interim assessments at 3 and 6 months after initiation of treatment with everolimus where possible.
On a categorical basis, response to treatment was subdivided into five categories: CR, total remission of all reversible signs and symptoms of cGVHD at end of treatment; PR, improvement in at least one organ by at least one score; progressive disease, worsening in at least one organ; mixed response, improvement in one organ and worsening in another organ at the same time; and stable disease, no change in cGVHD severity in any organ.
The type of cGVHD was defined as follows: Classic cGVHD, cGVHD signs and symptoms without features of aGVHD; overlap syndrome, features of both cGVHD and aGVHD.34 The mode of presentation of cGVHD was defined as progressive if cGVHD developed directly from active aGVHD, as quiescent if aGVHD had remitted before cGVHD development and as de novo if there was no history of aGVHD.
Assessment of potential toxicities
Clinical data were obtained from the patients’ records in a retrospective manner. Everolimus plasma levels were measured as trough levels by two laboratories (Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, Regensburg, Germany; Labor Limbach, Heidelberg, Germany) using a liquid chromatography–mass spectrometry. Potential treatment-related toxicities were classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (National Cancer Institute, Bethesda, MD, USA).
Continuous variables are expressed as median values with ranges. Categorical variables are expressed as absolute numbers and respective percentages. Medians in two groups were compared using the Mann–Whitney U-test where indicated. Differences between start and end of treatment with everolimus were compared using the Wilcoxon signed-rank test. A P-value of less than 0.05 was considered significant. Statistical analyses and graphs were conducted using Prism 5.04 software (GraphPad Software Inc., CA, USA).
A total of 80 patients with steroid-refractory cGVHD (center A, 49 patients; center B, 31 patients) treated with everolimus between October 2005 and December 2011 were analyzed retrospectively. Detailed patients’ characteristics are presented in Table 1. Median age was 50 years ranging from 17 to 70 years. Median follow-up after allogeneic HSCT was 3.5 years ranging from 0.5 to 12 years and median follow-up after introduction of everolimus was 724 days ranging from 14 to 2205 days. At baseline, 14 patients (17%) suffered from mild, 39 (49%) from moderate and 27 (34%) from severe therapy-refractory cGVHD. Of note, 9 out of 14 patients with mild cGVHD regressed from prior moderate (n=7) or severe (n=2) cGVHD. Details are presented in Table 2. Primary treatment of cGVHD before everolimus included mainly steroids, CNI, inosine monophosphate dehydrogenase inhibitors, MTX or sirolimus.
Delivery of treatment and toxicities
Median treatment duration was 477 days (Figure 2a). Patients received daily oral everolimus doses ranging from 0.125 to 6 mg resulting in median plasma levels of 4.0 ng/mL ranging from 1.1 to 7.4 ng/mL (Figure 2b). Thirty-nine patients (49%) had individual median plasma levels within the targeted range between 3 and 5 ng/mL. Treatment with everolimus was discontinued in 51 patients (64%) while 29 patients (36%) were continued on everolimus. Most frequent reasons for discontinuation of treatment included toxicities (n=14, 27%), achievement of a CR (n=12, 24%) and incomplete response of cGVHD (n=12, 24%; Table 3). In four patients (5%), everolimus-based treatment was temporarily paused for a median duration of 266 days ranging from 45 to 721 days. Most frequent grade 3/4 toxicities according to CTCAE included infections in 30 cases (38%) and thrombocytopenia in 15 cases (19%). In four patients treated at Center A, thrombocytopenia was most likely attributable to transplant-associated microangiopathy resulting in termination of treatment with everolimus and subsequent resolution of thrombocytopenia. Two of these patients with transplant-associated microangiopathy received a combination with a CNI while the other two patients had a history of transplant-associated microangiopathy on CNI. Eighteen patients (23%) died, six of whom (33%) were still on everolimus with a median treatment duration of 197 (12–429) days. Five out of the 18 patients who died had achieved a PR (n=3) or a CR (n=2) of cGVHD. Infectious complications were the main cause of death. There was a single case of relapse in the entire treatment series: this patient with Hodgkin’s lymphoma was still alive with a follow-up of 846 days at the time of analysis. Of note, median everolimus plasma levels were significantly higher in patients with grade 3/4 infections as compared with those without (4.5 vs 3.8 ng/mL; P<0.05). Nine of 30 patients with grade 3/4 infections (30%) showed median everolimus plasma levels above the targeted upper cutoff of 5 ng/mL.
Initiation of concomitant immunosuppression
In 34 patients (43%), everolimus-based therapy was supplemented by the addition of at least one further immunosuppressant during the course of treatment. Concomitant immunosuppression included mainly steroids, CNI, inosine monophosphate dehydrogenase inhibitors, MTX, rituximab and photopheresis.
Response to treatment
On the basis of the metric assessment comparing the NIH Severity Score before introduction of everolimus and at last follow-up or end of treatment, 34 patients (43%) improved, 37 patients (46%) remained stable and 9 patients (11%) progressed. The total sum of NIH Severity Scores in all patients assessable was significantly reduced at last follow-up or end of treatment with everolimus (173 vs 131; P<0.0001). Interim assessments at 3 (164 vs 139; P<0.001) and 6 months (147 vs 114; P<0.001) provided similar results. These results are depicted in Figure 3. Of note, 5 of the 34 patients improving had to stop therapy with everolimus because of toxicity while in 15 of the 46 patients not improving, treatment with everolimus was stopped because of toxicity (n=9) or death (n=6).
On a categorical basis, 16 patients (20%) achieved CRs and 24 patients (30%) achieved PRs of cGVHD. The remaining 40 patients (50%) showed mixed responses, remained stable or progressed. Twenty-two of 40 patients (55%) achieving CRs or PRs on a categorical basis received everolimus as the only new agent, whereas in 18 patients (45%), the addition of concomitant immunosuppressants was required. All responses including interim responses at 3 and 6 months are presented in Table 4 illustrating that the rate of CRs can increase over time.
There was no obvious pattern of response to treatment with everolimus in particular organs. There was no difference in response to treatment in patients with classic cGVHD compared with patients with overlap syndrome (data not shown). There was no correlation between individual median everolimus plasma levels and response rates of cGVHD as measured by the change in NIH Severity Scores in the course of treatment. Sixty-nine patients (86%) were continued on a co-medication with steroids. Overall co-medication with steroids declined significantly in the course of everolimus-based therapy from a median of 0.38 (0.03–1.52) mg/kg to 0.08 (0–1.1) mg/kg prednisolone per day (P<0.0001). In 23 of these cases (33%), steroids could be terminated while in 21 further cases (30%) steroids could be reduced by at least 50%.
Steroid-refractory cGVHD represents a common and persisting challenge in allogeneic HSCT as standardized and approved treatment options are still awaited.19,20 Unfortunately, results with second-line immunosuppressants are regularly derived from smaller retrospective analyses providing a wide range of overall response rates of 25–80%.8,35,36 With patients experiencing a significant reduction of their quality of life and severe forms of cGVHD being associated with increased mortality rates, the treating physician is regularly forced to choose from a variety of different treatment options, putting the patient at risk of relapse or infectious complications.15,16 Therefore, there is a strong need for immunosuppressive drugs offering a manageable toxicity profile while not compromising disease control.20
With this goal, we retrospectively investigated all patients having received treatment of their steroid-refractory cGVHD based on the mTOR inhibitor everolimus, a sirolimus-like substance that first showed activity in a limited group of patients with cGVHD.33 On a categorical basis, 50% of our patients responded with a CR or PR to everolimus-based therapy. Accordingly, the total sum of NIH Severity Scores significantly dropped during therapy with everolimus, documenting a 43% response rate. This includes a very promising rate of 30% of CRs solely limited by the fact that everolimus-based salvage therapy was supplemented by the initiation of at least one additional immunosuppressant in one-third of these cases. Beyond all formal remissions achieved, co-medication with steroids could be significantly reduced or even terminated in the course of therapy. This effect deserves particular attention as long-term use of steroids is frequently associated with severe complications. On the other hand, severe hematological toxicities and infections dominated the toxicity profile of everolimus-based therapy as described before in patients following kidney or allogeneic HSCT.37 These findings are in line with retrospective observations made with sirolimus, which is not surprising as both drugs act through inhibition of mTOR.21,22 Dosing of everolimus was set individually, always targeting a trough plasma level between 3 and 5 ng/mL, which was achieved in 49% of the cases. Interestingly, we did not observe a correlation between everolimus plasma levels and response to treatment. On the other hand, the appearance of severe infectious complications was significantly associated with higher and off-range everolimus plasma levels. Taken together, an increase above the targeted range does not appear to be of further benefit and careful dosing should be recommended.
We documented a single case of relapse of the malignant disease in the entire series of patients, which could be a result of graft-versus-malignancy effects associated with cGVHD. However, prior observations with sirolimus applied for primary prophylaxis of GVHD already suggested a beneficial anti-malignancy effect that may have contributed to disease control in the current series as well.38 This promising effect is very likely based on anti-angiogenetic and anti-proliferative features of mTOR inhibitors in general.39 Given the challenge of treating cGVHD without impairing disease control, this feature of mTOR inhibitors may reflect a selective advantage as compared with other immunosuppressants that are more likely to abrogate the beneficial graft-versus-malignancy effect without offering an alternative antineoplastic mode.23,40
In our series, everolimus-based salvage treatment of refractory cGVHD resulted in significant improvement of the NIH Severity Score including CRs allowing the reduction of steroids. So far, data on everolimus in cGVHD are very limited and to our knowledge the current analysis represents the largest assessment in steroid-refractory cases to date. The observed toxicity profile highlighted myelotoxicity and dose-dependent severe infections as major complications while control of the malignant disease was not impaired. This effective disease control could have either been caused by enhanced graft-versus-malignancy effects in association with cGVHD and/or the beneficial anti-malignancy effects of everolimus itself. Finally, we wish to emphasize the retrospective nature of our analysis demanding further verification of these preliminary data in prospective clinical trials.
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We wish to thank our patients participating in this study. Parts of this work have been presented at the annual meeting of the American Society for Hematology (ASH) in Atlanta 2012.41 This work contains parts of the doctoral theses of JS and ML. We also thank Judy Peng, PhD, for critical reading of the manuscript.
SM and DW designed the study, provided patient care, analyzed data and wrote the paper; ML: collected and analyzed data, created figures and wrote the paper; JS: collected and analyzed data and contributed to the manuscript; DD and JA provided patient care and contributed to the manuscript; EH designed the study, provided patient care and contributed to the manuscript; MK, GUG and HE provided patient care and contributed to the manuscript.
SM received honoraria and travel grants from Novartis, Germany. DW and EH received research funding from Novartis, Germany. ML, JS, MK, DD, JA, HE and GUG declare no conflict of interest.
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Mielke, S., Lutz, M., Schmidhuber, J. et al. Salvage therapy with everolimus reduces the severity of treatment-refractory chronic GVHD without impairing disease control: A dual center retrospective analysis. Bone Marrow Transplant 49, 1412–1418 (2014) doi:10.1038/bmt.2014.170
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