Dear Editors
Corticosteroids are still the standard initial therapy for acute graft‐versus‐host‐disease (aGVHD), but are effective in only approximately half of cases [1]. Many treatment options have been tested and used as second line, but none have been established yet as the standard of care.
Our institution has been using ruxolitinib for steroid‐refractory aGVHD (SR‐aGVHD), as well as chronic GVHD, for the past several years. We conducted a retrospective review (approved by IRB) of patients who were treated with ruxolitinib for SR‐aGVHD over a 2‐year period (2015–2016). SR‐aGVHD was defined as no response in any stage of GVHD in any organ after 5 days of steroids initiation or worsening GVHD stage in any organ after 3 days of steroids. Primary aGVHD and aGVHD/chronic GVHD (cGVHD) overlap were both included. We defined high‐risk acute GVHD by using acute GVHD risk score refined by Minnesota group [2]. Only patients who received> 14 days of ruxolitinib were considered evaluable for response assessment.
Thirty‐six patients were included in the analysis described in Table 1. Methylprednisolone 2 mg/kg/day was used as initial steroid in most patients; however, different doses were used at the physician discretion. Twenty‐four patients (67%) received at least 14 days of treatment and were evaluable for response; the overall response rate (ORR) was 58% (95% CI 38%‐78%) with 25% obtaining a complete (CR). Of those who were evaluable for response, the median overall survival (OS) was 7.4 months (95% CI UTQ‐15.9) for responders compared with 0.9 months (95% CI 0.7–1.1) for nonresponders (P < 0.001). The relapse rate of primary disease was 8%; one patient relapsed while on ruxolitinib and two within 6 months following discontinuation. Ruxolitinib was well tolerated; hematologic toxicity was generally mild, and there were no cases of treatment‐related mortality reported.
Table 1:
Patient Characteristics
| Demographics n = 36 | ||
| Median Age (range) | 55 years (27–72) | |
| Male | 20 (56%) | |
| Disease for Transplant | ||
| AML | 15 (44%) | |
| MDS/MPN | 12 (31%) | |
| Others | 9 (25%) | |
| Stem cell sources | ||
| Matched-Sibling | 7 (19%) | |
| Haploidentical Related | 5 (14%) | |
| Unrelated | 24 (67%) | |
| Conditioning regimens | ||
| Myeloblative | 35 (97%) | |
| Reduced Intensity | 1 (3%) | |
| GVHD Prophylaxis* | ||
| CNI/MTX | 23 (64%) | |
| CNI/MMF/PT CY | 7 (19%) | |
| Others | 6 (17%) | |
| GVHD Treatment | ||
| Median number of treatments | ||
| Prior to Ruxolitinib | 2 (0–5) | |
| With Ruxolitinib | 1.5 (0–5) | |
| Median time from steroid start to Rxolitiib | 16.5 (2–280) | |
| Starting dose of ruxolitinib | ||
| 5mg Daily | 1 (3%) | |
| 5mg BID | 26 (72%) | |
| 10 mg BID | 9 (25%) | |
| Ruxolitinib treatment Duration | ||
| Median Days (range) | 21.5 (1–560) | |
| ≥14 days of treatment | 67% | |
| Evaluable for Response (n = 24) | ||
| Complete Response | 6 (25%) | |
| Partial Response | 8 (33%) | |
| No Response | 10 (42%) | |
| Risk Factor | Responders | Non-responders |
|---|---|---|
| Skin-aGVHD | 7 (50%) | 2 (20%) |
| GI-aGVHD | 10 (71%) | 8 (80%) |
| Liver-aGVHD | 2 (15%) | 5 (50%) |
| > 1 organ | 5 (35%) | 6 (60%) |
| Low Albumin | 13 (93%) | 8 (80%) |
| Reason for discontinuation | ||
| Treatment failure | 15 (64%) | |
| Relapse of primary disease | 1 (3%) | |
| Cytopenias | 3 (14%) | |
| Issues obtaining ruxolitinib | 4 (17%) | |
| Complete Response | 1 (3%) | |
GVHD prophylaxis included calcineurin inhibitors (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF); post‐transplant cyclophosphamide (PT CY)
The data presented herein are similar to what was recently reported from the REACH1 trial [3]. However, in our study, SR‐aGVHD was defined as worsening disease after 3 days of steroids or no improvement in 5 days versus 3 days or 7 days, respectively, in REACH1. In addition, we included patients who received numerous prior treatments for SR‐aGVHD, while REACH1 only allowed patients to receive calcineurin inhibitors. Thus, our patients were more heavily treated which may account for differences in response rates; in our study, the ORR was 58% with 25% CR compared to 73% with 56% CR in REACH1. Our study did not have explicit eligibility criterion and may reflect more real‐world use of ruxolitinib for SR‐aGVHD. Several patients were given very short durations of ruxolitinib < 14 days before transitioning to comfort care or expiring, and these patients were excluded as response was difficult to assess and likely does not reflect the efficacy of ruxolitinib.
Additionally, in a moderate/severe cGVHD, ruxolitinib induces high response rates, and reduction to physiologic doses/discontinuation of prednisone was possible in 90% of patients at a median of 106 days (range, 31–365) from starting ruxolitinib [4, 5]. In conclusion, ruxolitinib appears to be a viable treatment option for SR‐aGVHD.
References
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