Pharmacy SIG Literature Update: A Focus on Graft-Versus-Host Disease

In this month’s Pharmacy SIG Literature Update: a focus on graft-versus-host disease.

Literature summaries are provided as information only. Please refer to the original published articles for complete details on study methodology, results and discussion.

*** Must read. Landmark publication that affects practice

** Recommend reading. Secondary paper that adds to literature

* Consider reading. Cursory importance to the practice

**Bolanos-Meade J, Reshef R, Fraser R, eta l. Prevention of graft versus host disease with Hematopoietic Cell Transplantation with Reduced Intensity Conditioning—a comparison of three prophylaxis regimens (tacrolimus/mycophenolate mofetil/cyclophosphamide, tacrolimus/methotrexate/bortezomib or tacrolimus/methotrexate/maraviroc) versus tacrolimus/methotrexate: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol 2019 March; 6(3):e132–e143. PMID: 30824040

  • The PROGRESS 1 study is a phase II trial of adult patients receiving RIC HSCT and randomized to one of 3 treatment arms: TAC/MMF/PTCy (post-transplant cyclophosphamide), TAC/MTX/BOR (bortezomib), and TAC/MTX/MVC (maraviroc).
  • The primary end point of GVHD-free, relapse-free survival (GRFS) of each arm was compared to a contemporary control arm of TAC/MTX at centers not participating in the trial.
  • Compared to the control group, hazard ratios for 1-year GRFS was 0.72 (0.54-0.94) TAC/MMF/PTCy, 0.98 (0.76-1.27) TAC/MTX/BOR, 1.11 (0.86-1.41) TAC/MTX/MVC. There were no statistically significant differences in neutrophil recovery, full donor chimeras, or graft failure.
  • Patients receiving TAC/MMF/PTCy had significantly less grade III-IV acute GVHD (2% vs 13%), chronic GVHD requiring immunosuppression (22% vs 37%), and GVHD-free survival at 1 year (53% vs 37%) when compared to the control group.
  • The authors conclude that TAC/MMF/PTCy was the most promising intervention among the three options and should be studied prospectively to TAC/MTX in a phase III randomized trial.

*** Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versushost disease. N Engl J Med 2020;382:1800-10. PMID: 32320566

  • REACH2 was a multicenter, randomized, open-label phase III trial evaluating ruxolitinib for treatment of with glucocorticoid-refractory acute GVHD in patients age 12 and older (n = 309)
  • Patients were randomized 1:1 to ruxolitinib 10 mg twice daily vs. investigator’s choice of best available therapy, and stratified according to baseline grade of aGVHD (II vs. III vs. IV)
  • For the primary endpoint, overall response at day 28 was higher in the ruxolitinib group than the control group (62% vs. 39%), OR 2.64 (95% CI, 1.65-4.22; P<0.001); rates of CR for those receiving ruxolitinib vs. control were 34% vs. 19%, respectively.
  • Durable overall response at day 56 was higher in the ruxolitinib vs. control group (40% vs. 22%), OR 2.38 (95% CI, 1.43-3.94; P<0.001).
  • The cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group vs. 39% in the control group.
  • The median FFS was significantly longer in the ruxolitinib group (5.0 months vs. 1.0 month; HR for relapse or progression of hematologic disease, non–relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60)
  • By day 56, 21% of patients in the ruxolitinib group had discontinued glucocorticoids vs 14% in the control group.
  • Of 155 patients receiving investigator’s choice, 49 (32%) crossed over to receive ruxolitinib.
  • Treatment discontinuation occurred in 111/154 (72%) in the ruxolitinib group and 132/155 (85%) in the control group, most often related to lack of efficacy. The median duration of therapy was 63 days in the ruxolitinib group vs. 29 days in the control group.
  • The most common grade ≥ 3 ADEs in the ruxolitinib and control groups, respectively, were thrombocytopenia (27% vs. 15%), anemia (22% vs. 19%), and neutropenia (13% vs. 9%).
  • Authors conclude that among patients with grade II to IV glucocorticoid-refractory acute GVHD, ruxolitinib therapy led a significantly higher overall response than control therapy at day 28 and a higher durable overall response at day 56, with higher incidence of cytopenias and cytomegalovirus infection compared to control.

***Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. NEJM. 2021;385:228-38. PMID: 34260836

  • Phase 3, open-label, randomized trial of ruxolitinib 10 mg PO BID vs investigator’s choice x 6 months for the treatment of SR or SD, cGVHD in patients ≥12 years or older previously treated with at least 2 systemic therapies in addition to steroids
  • 359 patients were randomized, with 42.9% having moderate cGVHD and 56.5% having severe cGVHD. 71.4% of patients were classified as SR, and 21.8% as SD
  • ORR at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs 25.6%, p<0.001). Best ORR up to week 24 was 76.4% in the ruxolitinib group vs 60.4% in the control group (p=0.001). Of those with a response at any time, probability of maintaining that response at 12 months was 68.5% with ruxolitinib vs 40.3% with control. 3
  • Median FFS was also longer in the ruxolitinib group (18.6 months vs 5.7 months, p=0.001) in addition to higher symptom response (24.2% vs 11.0%, p=0.001). 61 patients crossed over from the control group to the ruxolitinib group, with an ORR of 78.7%.
  • Median DOT was 25.6 weeks in the ruxolitinib group vs 24 weeks in the control group. Thrombocytopenia (15.2% vs. 10.1%) and anemia (12.7% vs. 7.6%) were the most commonly reported ADEs in the ruxolitinib and control groups, respectively. Infectious complications were similar in both groups.
  • Authors conclude that in patients with SR or SD cGVHD, ruxolitinib provides a significantly better ORR, FFS, and symptom response than investigator’s choice

**Jagasia M, Lazaryan A, Bachier CR, et al. ROCK2 inhibition with belumosudil (KDO25) for the treatment of chornic graft-versus-host disease. JCO. 2021;39:1888-98. PMID: 33877856

  • Phase IIa, open-label, dose-finding study of belumosudil (ROCK2 inhibitor) 200 mg PO QD, 200 mg PO BID, or 400 mg PO BID for the treatment of SR cGVHD in patients ≥18 years who had received 1-3 systemic therapies in addition to a CNI or ECP
  • 54 patients were enrolled, with 78% having severe cGVHD. 50% of patients had at least 4 organs involved, and 50% had received at least 3 prior therapies.
  • ORR at a median follow-up of 29 months was 65%, 69%, and 62% in the 200 mg QD, 200 mg BID, and 400 mg BID cohorts, respectively. >75% of responses were achieved by week 8. Late responses (>24 weeks) were observed in lung, joint/fascia, and eye GVHD.
  • FFS was 76% and 47% at 6 and 12 months, respectively and OS at 12 months was 82%. Median DOR was 35 weeks and steroid treatment was discontinued in 19% of patients and reduced in 67% of patients.
  • Median dose intensity was 98%, with relative dose intensity >95% in 77%, 63%, and 71% across the dosing cohorts. ADEs reported in at least 20% of patients were URI (46%), diarrhea (33%), fatigue (33%), nausea (33%), increased LFTs (33%), dyspnea (30%), headache (24%), peripheral edema (24%), cough (22%), and hypertension (20%). Only 2 patients (4%) experience grade >3 cytopenias.
  • Authors conclude that belumosudil demonstrated high ORR and OS rates with steroid dose reductions and limited toxicity

*** Cutler C, Lee S, Arai, S, and et al. Belumosudil for Chronic Graft-versus-Host Disease (GVHD) After 2 or More Prior Lines of Therapy: ROCKstar Study. Blood 2021: July 15 online. PMID: 34265047

  • This phase 2, randomized, multicenter study evaluated belumosudil 200mg QD (n=66) and 200mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy (LOT). Primary endpoint was best overall response (ORR=CR + PR) according to 2014 NIH Consensus Criteria. Median treatment duration of 10 months with a median follow-up of 14 months.
  • Belumosudil is an oral selective inhibitor of rho-associated coiled-coil-containing protein kinase2 (ROCK2). 4
  • Baseline characteristics were similar between treatment arms. Median age, 56 years; 31% had moderate cGVHD and 67% had severe cGVHD per NIH; 52% had ≥4 organs involved; median of 3 prior LOTs; 72% were refractory to last therapy; 34% had previous ibrutinib; and 29% had previous ruxolitinib.
  • Primary endpoint: best ORR (95% CI) of belumosudil 200mg QD and 200mg BID was 74% (62%- 84%) and 77% (65%-87%), respectively with high response rates in all subgroups. All affected organs demonstrated CR.
  • Secondary endpoints: Median DOR was 54 weeks; 44% have remained on therapy for ≥1 year. Overall failure-free survival (FFS) rate (95%CI) was 75% (66%-81%) and 56% (47%-64%) at 6 and 12 months, respectively. 2-year OS rate (95% CI) was 89% (82%-93%). Low rates of NRM (7%) and relapse (3%). Mean corticosteroid (CS) dose was reduced by 54% in those who responded with 21% discontinuing CS. 22% were able to discontinue CNI therapy.
  • Symptom reduction with 200mg QD and 200mg BID were 59% and 62%, respectively.
  • AEs: median relative dose intensity (RDI) was 99.7%; 81% received RDI >95%. Most common grade 3/4 AEs were pneumonia (8%), hypertension (6%), and hyperglycemia (5%). Of the 83 patients who discontinued treatment, 12% were due to possible drug-related AEs. Only 1 report of CMV reactivation that was unrelated to belumosudil.
  • The authors concluded that this study demonstrated promising efficacy and a favorable safety profile for belumosudil therapy in patients with SR cGVHD. Responses were sustained and clinically meaningful. Responses were observed in all organs, which was clinically significant because CR and PR were achieved in difficult-to-treat organs such as the lungs and liver, and in organs with fibrotic manifestations such as skin. Based on similar efficacy and safety, 200mg QD is the preferred dosage.

*Doris M. Ponce, Ioannis Politikos, et al, Guidelines for the Prevention and Management of Graftversus-Host Disease after Cord Blood Transplantation. Transplantation and Cellular Therapy. 2021 July; 27(7):540-544. PMID: 34210500

  • This review outlines the guidelines for the prevention and management of acute and chronic GVHD (aGVHD, cGVHD) following cord blood transplant (CBT) in a question-and-answer format. Questions addressed: how GVHD prophylaxis and management after CBT differs from adult donor graft sources, what is most commonly used, and less common GVHD prophylactic regimens in CBT.
  • Double unit CBT (dCBT), myeloablative conditioning, and absence of anti-thymocyte globulin (ATG) are risk factors associated with aGVHD whereas prior aGVHD and dCBT are risk factors associated with cGVHD. The degree of HLA mismatch was not associated with either aGVHD or cGVHD.
  • The skin, skin/GI tract, and GI tract alone are the most frequently affected organs by aGVHD. Skin followed by mild ocular and oral involvement are most frequently affected by cGVHD after CBT.
  • Since graft cell dose must be considered, there is no specific recommendation towards the optimization of HLA-match grade to potentially mitigate severe GVHD.
  • The management of aGVHD after CBT with prednisone is no different from other graft sources and should be initiated promptly at the time of clinical diagnosis. Lower GI aGVHD after CBT is potentially life-threatening, and any CBT recipient with diarrhea must be promptly evaluated and treated. Patients with diarrhea and a negative infectious workup require systemic 5 corticosteroids. In addition, the presence of Clostridium difficile and/or viral infection does not exclude concurrent aGVHD.
  • Management of cGVHD after CBT is similar to the management of cGVHD when transplanted by other cell sources. Prednisone 0.5 to 1 mg/kg/day (or IV equivalent) is considered front-line therapy for moderate to severe cGVHD. Topical steroids may be used for mild skin cGVHD or as ancillary therapy for moderate/severe cGVHD. At time of publication, ibrutinib was the only approved agent for patients with cGVHD after failure of one or more previous therapies; however, since that time belumosudil has been granted an FDA indication for cGVHD for those who have failed at least two prior lines of systemic therapy.
  • Grade II aGVHD has been associated with a reduced risk of relapse and either a favorable or no adverse effect on overall mortality; while grade III-IV aGVHD was associated with reduced relapse risk offset by increased transplantation-related mortality and inferior survival. Survival to be either improved or unaffected by cGVHD.
  • Consistent with the lower severity of GVHD post-CBT and higher OR to treatment, CBT recipients achieve a high rate of successful immunosuppression discontinuation, have a low burden of disabilities related to cGVHD, and improved quality of life

**Kitko C., Pidala J., et al, NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report. Transplantation and Cellular Therapy. 2021 July; 27(7):540-544. PMID: 33839317

  • The objective of this project was to improve recognition of cGVHD using the current NIH guidelines. Another goal was to review approaches allowing earlier diagnosis of cGVHD before meeting NIH criteria when irreversible changes in organ function have occurred.
  • Many patients do not meet NIH diagnostic criteria until irreversible manifestations of the disease have already developed. Therefore, tools are needed to recognize or predict the imminent onset of cGVHD at an earlier stage before NIH diagnostic criteria are formally met. This will allow investigation of pre-emptive interventions that prevent progression to irreversible organ damage and avoid the need for systemic therapy.
  • For transplant providers, knowledge and confidence can be improved by targeted training sessions. Ehealth tools can be used to educate and facilitate the implementation of the NIH criteria in clinical practice. Recently, the eGVHD app (www.uzleuven.be/egvhd) was shown to improve the accuracy of GVHD assessment among health care professionals. 6
  • Members recommend it is crucial to properly document the pretransplant baseline status of multiple organ systems in patients in order to correctly identify new abnormalities developing after hematopoietic cell transplant (HCT).
  • The guidelines propose the use of a checklist (table 1) to be completed before HCT to document the presence of signs and symptoms. It also provides follow-up evaluation criteria starting from D100 post-HCT and a threshold for referral to specialized transplant team (table 2).
  • The guidelines recommend empowering patients to actively participate in monitoring and reporting symptoms to facilitate early diagnosis and help monitor treatment response with the potential for improved outcomes. Telemedicine represents an attractive option for patients who have difficulty accessing chronic GVHD monitoring by their providers due to distance from the transplant center
  • Another strategy to facilitate earlier diagnosis of chronic GVHD focuses on specific organs associated with high morbidity or mortality.


ADE: adverse drug event

aGVHD: acute graft-versus-host disease

BID: twice daily

BOR: bortezomib

cGVHD: chronic graft-versus-host disease

CNI: calcineurin inhibitor

CR: complete response

dCBT: double unit cord blood transplant

DOR: duration of response

DOT: duration of therapy

ECP: extracorporeal photopheresis

FFS: failure-free survival

IV: intravenous

LFTs: liver function tests

MMF: mycophenolate mofetil

MTX: methotrexate

MVC: maraviroc

OR: odds ratio

ORR: overall response rate

OS: overall survival

PR: partial response

PTCy: post-transplant cyclophosphamide

SD: steroid-dependent

SR: steroid-refractory

TAC: tacrolimus

URI: upper respiratory infection

ASTCT Pharmacy SIG Research Working Committee: Jennifer Collins, Kelly Gaffney, Katie Gatwood, Arpita Gandhi, Jitesh Kawedia, Binni Kunvarjee, Andrew Lin, Dennis Marjoncu, Jonathan Ptachcinski, Julianna Roddy, Lily Yan

Tags: SIG, Literature, GVHD, Pharmacy

Theme picker