Biol Blood Marrow Transplant 25 (2019) 20022007
`
`Biology of Blood and
`Marrow Transplantation
`
`j o u r n a l h o m e p a g e : w w w . b b m t . o r g
`
`~ ,;?nJCT
`
`Transplantati~~~~or d Cellular Therapy
`
`Ibrutinib for Chronic Graft-versus-Host Disease After Failure of Prior
`Therapy: 1-Year Update of a Phase 1b/2 Study
`
`Edmund K. Waller1,*, David Miklos2, Corey Cutler3, Mukta Arora4, Madan H. Jagasia5, Iskra Pusic6,
`Mary E.D. Flowers7, Aaron C. Logan8, Ryotaro Nakamura9, Stephen Chang10, Fong Clow11,
`Indu D. Lal12, Lori Styles12, Samantha Jaglowski13
`
`1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia
`2 Department of Medicine, Medicine/BMT Division, Stanford University School of Medicine, Stanford, California
`3 Division of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts
`4 Department of Hematology, Oncology and Transplant, University of Minnesota, Minneapolis, Minnesota
`5 Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
`6 Division of Oncology, BMT and Leukemia Section, Washington University School of Medicine, St. Louis, Missouri
`7 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
`8 Division of Hematology and Blood and Marrow Transplantation, Department of Medicine, University of California San Francisco, San Francisco, California
`9 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California
`10 Department of Biostatistics, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California
`11 Department of Biometrics and Data Management, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California
`12 Department of Clinical Science, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California
`13 Division of Hematology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio
`
`Article history:
`Received 26 March 2019
`Accepted 24 June 2019
`
`Key Words:
`Chronic graft-versus-host
`disease
`Steroid-dependent chronic graft-
`versus-host disease
`Steroid-refractory chronic graft
`versus host disease
`Ibrutinib
`Bruton’s tyrosine kinase inhibitor
`
`A B S T R A C T
`Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In
`a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with
`active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of
`Bruton’s tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a
`median follow-up of 26 months (range, .53 to 36.7 months), best overall response rate in the all treated population
`was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial
`response. Sustained responses of 20, 32, and 44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29
`responders, respectively. Of 26 patients with 2 involved organs, 19 (73%) showed responses in 2 organs. Six of 10
`patients (60%) with 3 involved organs showed responses in 3 organs. Eleven of 18 patients (61%) who had sclerosis
`at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42
`patients (64%) reached a corticosteroid dose of <.15 mg/kg/day during the study; 8 discontinued corticosteroid treat-
`ment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with
`the safety profile seen at the time of the original analysis. Common grade 3 adverse events (AEs) were pneumonia
`(n = 6), fatigue (n = 5), and diarrhea (n = 4). The onset of new grade 3 AEs decreased from 71% in the first year of treat-
`ment to 25% in the second year (n = 12). AEs leading to discontinuation occurred in 18 patients (43%). At a median fol-
`low-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed
`previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable
`safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance
`in the therapeutic management of patients with cGVHD.
`© 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access
`article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
`
`Financial disclosure: See Acknowledgments on page 2006.
`* Correspondence and reprint requests: Edmund K. Waller, Winship Cancer
`Institute of Emory University, 1365 Clifton Road, Atlanta, GA 30322.
`E-mail address: ewaller@emory.edu (E.K. Waller).
`
`INTRODUCTION
`Chronic graft-versus-host disease (cGVHD), a serious and
`often fatal complication of hematopoietic cell transplantation
`(HCT), affects as many as 70% of patients post-HCT [1,2]. A sub-
`stantial proportion of patients with cGVHD fail to receive benefit
`from frontline therapy and develop steroid-dependent or -refrac-
`tory disease [3,4]. The efficacy of treatment options for patients
`
`https://doi.org/10.1016/j.bbmt.2019.06.023
`1083-8791/© 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.
`(http://creativecommons.org/licenses/by-nc-nd/4.0/)
`
`

`

`E.K. Waller et al. / Biol Blood Marrow Transplant 25 (2019) 20022007
`
`2003
`
`with steroid-dependent or -refractory cGVHD is mixed, of limited
`duration, and associated with significant toxicity [38]. Thus, ste-
`roid-sparing therapies with sustained efficacy and more accept-
`able adverse event (AE) profiles are needed.
`Ibrutinib, a first-in-class, once-daily Bruton’s tyrosine kinase
`(BTK) inhibitor, is the only treatment approved by the US Food
`and Drug Administration for adults with cGVHD after failure of 1
`lines of systemic therapy [9]. A Phase 1b/2, open-label, single-arm
`study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) that
`involved 42 patients with active cGVHD who were steroid-
`dependent or -refractory demonstrated the activity and safety of
`ibrutinib in these patients [10]. After a median follow-up of 14
`months, the best overall cGVHD response rate was 67% (complete
`response [CR], 21%; partial response [PR], 45%) and AEs were
`acceptable [9,10]. This report describes an additional 12 months of
`follow-up for patients in this study.
`
`METHODS
`A detailed description of this study has been published previously [10]. In
`brief, eligible patients had steroid-dependent or -refractory cGVHD after HCT
`and had received 3 previous regimens for cGVHD. Steroid-dependent was
`defined as the presence of cGVHD manifestations requiring a glucocorticoid dose
`greater than or equal to prednisone .25 mg/kg/day (.5 mg/kg every other day or
`equivalent) for 12 weeks. Steroid-refractory was defined as the presence of
`cGVHD manifestations despite treatment with a glucocorticoid dose greater than
`or equal to prednisone .5 mg/kg/day (1 mg/kg every other day or equivalent) for
`4 weeks. Patients were also required to have either ˃25% body surface area in
`accordance with National Institutes of Health (NIH)-defined criteria for “ery-
`thematous rash” or a total mouth score of 4 points by NIH-defined criteria [11].
`Patients receiving ibrutinib in Phase 1b could continue treatment in
`Phase 2 if no dose-limiting toxicities were experienced. In these patients,
`ibrutinib was continued in Phase 2 at the same dose as in Phase 1. The recom-
`mended Phase 2 dose identified in Phase 1 of the study was ibrutinib
`420 mg/day.
`Safety and activity in long-term follow-up were assessed according to
`previously described criteria [10]. Safety was assessed until 30 days after the
`last dose of ibrutinib, and response assessments were completed every 12
`weeks until progressive disease. Response criteria for patients with sclerosis
`were based on summing the total percentage of body surface area affected by
`
`sclerosis (moveable and nonmoveable) at baseline and determining the pro-
`portion of patients with a 50% decrease or complete resolution in sclerotic
`manifestations. Exploratory analysis included failure-free survival (FFS),
`defined as the interval between the date of first dose and the death date, the
`date of initiating subsequent cGVHD therapy, or the start date of relapse of
`underlying malignancy, whichever occurred first. Post hoc analysis of overall
`survival was calculated as the number of months from first dose date of study
`treatment to the date of death or last known alive date. Failure-free survival
`and overall survival were determined using Kaplan-Meier methodology.
`Institutional review board/Independent ethics committee approval was
`obtained from each participating institution. This study was conducted in
`accordance with the principles of the Declaration of Helsinki, International
`Conference on Harmonization Guidelines, and all patients provided written
`informed consent. Requests for access to individual participant data from
`clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be
`submitted through Yale Open Data Access (YODA) Project site at http://yoda.
`yale.edu.
`
`RESULTS
`As of September 18, 2017, the median follow-up was 26
`months (range, .53‒36.7 months), and the duration of treatment
`ranged from .2 to 37 months (median, 4.4 months). A total of 27
`patients (64%) were steroid-dependent, 7 (17%) were steroid-
`refractory, and 8 (19%) had a history of both steroid-dependent
`and -refractory disease. Most patients (88%) had 2 organs
`involved at baseline (Supplementary Table S1).
`With this additional 1 year of follow-up, the best overall
`cGVHD response rate was 69% (29 of 42) in the all treated popula-
`tion, including 13 patients (31%) who achieved a CR and 16 (38%)
`who achieved a PR (Figure 1). Individual responses over time for
`the response-evaluable population are shown in Supplementary
`Figure S1. Among the 29 responders, sustained responses of 20,
`32, and 44 weeks were observed in 20 (69%), 18 (62%), and 16
`(55%) patients, respectively. Responses were observed across
`multiple organs (Supplementary Figure S2).
`In an exploratory analysis, the Kaplan-Meier point estimate
`for failure-free survival in all treated patients at 18 months
`was 51%. Patients were followed for up to 37 months (median,
`
`14%
`(n=6)
`
`SD
`
`5%
`(n=2)
`
`PD
`
`ORR 69%
`
`31%
`(n=13)
`
`38%
`(n=16)
`
`■
`
`CR
`
`PR
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`Percent of patients*
`
`Figure 1. Best overall cGVHD response. cGVHD, chronic graft-versus-host disease; CR, complete response; ORR, overall response rate (ie, best overall cGVHD
`response rate); PD, progressive disease; PR, partial response; SD, stable disease. *Five patients who had no response assessment during the study were considered
`nonresponders and are not represented in the figure but are included in the best overall cGVHD response rates reported.
`
`

`

`2004
`
`E.K. Waller et al. / Biol Blood Marrow Transplant 25 (2019) 20022007
`
`Table 1
`Response in Multiple Organs in Patients Who Responded to Ibrutinib
`
`Parameter
`
`Responders, n
`
`Sustained
`response
`
`20 wk
`
`32 wk
`
`44 wk
`
`Organs
`showing
`response
`
`2 organs
`
`3 organs
`
`NA
`
`29
`
`29
`
`29
`
`NA
`
`NA
`
`NA
`
`Sustained
`response
`rate, n (%)
`
`Responders
`with 2
`or 3 organs
`involved at
`baseline, n
`
`NA
`
`20 (69)
`
`18 (62)
`
`16 (55)
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`26*
`
`10y
`
`Best
`ORR,
`n (%)
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`19 (73)
`
`6 (60)
`
`ORR, overall response rate; N/A, not applicable.
`* Number of responders with 2 involved organs at baseline.
`y Number of responders with 3 involved organs at baseline.
`
`26 months), and the estimated survival rate at 24 months was
`71% (95% confidence interval, 52% to 83%) based on post hoc
`overall survival analysis.
`Among the 26 responders who had 2 organs affected by
`cGVHD at baseline, 19 (73%) had a response in 2 organs
`(Table 1). Similarly, among the 10 responders who had 3
`organs affected by cGVHD at baseline, 6 (60%) had a response
`in 3 organs. A total of 18 patients had sclerosis at baseline,
`with a median body surface area of 45% (range, 9% to 81%)
`affected by sclerosis. Most patients with sclerosis (61%) had a
`Karnofsky Performance Status score of 70 to 80. Of the 18
`patients with sclerosis at baseline, 11 (61%) showed a decrease
`in sclerosis (50% decrease or complete resolution).
`Among all treated patients (N = 42), 18 (43%) had a clinically
`meaningful improvement (7-point decrease) in the Lee cGVHD
`Symptom Scale total summary score, with substantially more
`responders reporting improvement compared with nonrespond-
`ers (17 of 29 [59%] versus 1 of 13 [8%]). Clinically meaningful
`
`improvement in the Lee cGVHD Symptom Scale total summary
`score on 2 consecutive visits was achieved by 12 patients
`(29%). By week 26, 12 responders (41%) had improvement in the
`Lee cGVHD Symptom Scale total summary score, compared with
`1 nonresponder (8%). By week 52, 16 responders (55%) had
`improvement in the Lee cGVHD Symptom Scale total summary
`score, compared with 1 nonresponder (8%).
`Among all 42 treated patients, 27 (64%) reached a corticoste-
`roid dose of <.15 mg/kg/day during the study. In the responders,
`the median corticosteroid dose decreased from .3 mg/kg/day
`(range, .1 to 1.3 mg/kg/day) at baseline (n = 29) to .1 mg/kg/day
`(range, 0 to .2 mg/kg/day) at week 52 (n=18) (Figure 2). Eight of
`29 responders (28%) discontinued corticosteroid treatment.
`None of the 8 patients had resumed corticosteroid treatment at
`the time of study closure, and 7 patients remained in response.
`The 1 patient who did not maintain response per investigator did
`not meet the 2005 NIH cGVHD Consensus Panel Response Crite-
`ria for progression and was started on subsequent therapy
`(extracorporeal photopheresis) for cGVHD at 166 days after dis-
`continuation of systemic steroids.
`Safety findings for this updated analysis were consistent with
`those in the original analysis, with treatment-emergent adverse
`events (TEAEs) being primarily grade 1 and 2 in severity (Table 2).
`The most common (˃20% of patients) all-grade TEAEs were fatigue
`(57%), diarrhea (40%), muscle spasms (33%), nausea (29%), and
`bruising (24%), and the most common (10% of patients) grade
`3 TEAEs were pneumonia (14%), fatigue (12%), and diarrhea
`(10%). Analysis of TEAEs by time period demonstrated that the
`most frequent (10%) TEAEs occurred primarily during the first 6
`months (Supplementary Table S2). Serious TEAEs occurred in 22
`patients (52%), grade 3 serious TEAEs occurred in 19 patients
`(45%), and there were no new fatal TEAEs (Supplementary
`Table S3). Similar to all-grade TEAEs, analysis of serious TEAEs by
`time period demonstrated that most occur primarily during the
`first 6 months (Supplementary Table S4). There were 6 serious
`AEs listed as pneumonia. The 1 fatal pneumonia was bacterial
`(Enterococcus). The remaining 5 nonfatal pneumonias included 1
`each of bacterial, fungal (Aspergillus), and multiagent (bacterial,
`fungal, and viral) origin and 2 of unknown etiology. At baseline,
`
`Responders
`
`Non-responders
`
`N=13
`
`N=12
`
`N=11
`
`N=4
`
`N=26
`
`N=25
`
`N=25
`
`N=25
`
`N=2
`
`N=1
`
`N=1
`
`N=22
`
`N=21
`
`N=20
`
`N=19
`
`N=19
`
`N=18
`
`N=18
`
`N=18
`
`N=29
`
`0.3
`
`N=29
`
`N=28
`
`0.2
`
`0.1
`
`0.0
`
`Dose (mg/kg/day)
`
`W e e k
`
`2 4
`
`W e e k
`W e e k 1 6
`W e e k 1 2
`W e e k 8
`W e e k
`B a s elin e
`
`4
`
`2 0
`
`5 2
`
`W e e k 5 6
`W e e k
`W e e k 4 8
`W e e k 4 4
`W e e k 4 0
`W e e k 3 6
`W e e k 3 2
`W e e k 2 8
`W e e k 2 4
`W e e k 2 0
`W e e k 1 6
`W e e k
`W e e k 8
`W e e k
`B a s elin e
`
`1 2
`
`4
`
`Figure 2. Median corticosteroid doses decreased throughout treatment. N represents the number of patients at each visit. A responder is defined as a patient who
`achieved a partial response or better. A nonresponder is defined as a patient who did not achieve a partial response or better. For each patient, steroid doses during
`or after progressive disease (per the 2005 National Institutes of Health's cGVHD Consensus Panel response criteria) are excluded.
`
`

`

`E.K. Waller et al. / Biol Blood Marrow Transplant 25 (2019) 20022007
`
`2005
`
`Table 2
`TEAEs Occurring in 10% of Patients Regardless of Cause
`
`TEAE, n (%)
`
`Fatigue
`
`Diarrhea
`
`Muscle spasms
`
`Nausea
`
`Bruising
`
`Headache
`
`Pneumonia
`
`Pyrexia
`
`Upper respiratory tract infection
`
`Dyspnea
`
`Fall
`
`All Grades, n (%)
`
`Grade 1-2, n (%)
`
`Grade 3-4, n (%)
`
`Grade 5, n (%)
`
`24 (57)
`
`17 (40)
`
`14 (33)
`
`12 (29)
`
`10 (24)
`
`8 (19)
`
`8 (19)
`
`8 (19)
`
`8 (19)
`
`7 (17)
`
`7 (17)
`
`19 (45)
`
`13 (31)
`
`13 (31)
`
`12 (29)
`
`10 (24)
`
`6 (14)
`
`2 (5)
`
`7 (17)
`
`8 (19)
`
`5 (12)
`
`7 (17)
`
`5 (12)
`
`4 (10)
`
`1 (2)
`
`0
`
`0
`
`2 (5)
`
`5 (12)
`
`1 (2)
`
`0
`
`2 (5)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (2)
`
`0
`
`0
`
`0
`
`0
`
`Cough
`
`Peripheral edema
`
`Constipation
`
`Contusion
`
`Hyperglycemia
`
`Hypokalemia
`
`Hypophosphatemia
`
`Mouth ulceration
`
`Vomiting
`
`6 (14)
`
`6 (14)
`
`5 (12)
`
`5 (12)
`
`5 (12)
`
`5 (12)
`
`5 (12)
`
`5 (12)
`
`5 (12)
`
`6 (14)
`
`6 (14)
`
`5 (12)
`
`5 (12)
`
`2 (5)
`
`2 (5)
`
`3 (7)
`
`5 (12)
`
`5 (12)
`
`0
`
`0
`
`0
`
`0
`
`3 (7)
`
`3 (7)
`
`2 (5)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`A second fatal TEAE caused by bronchopulmonary aspergillosis occurred but did not meet the threshold cutoff (10%) for common TEAE.
`
`71% of patients were taking ibrutinib concomitantly with moder-
`ate or strong cytochrome P450 3A (CYP3A) inhibitors, and 52%
`were taking immunosuppressants other than prednisone. Grade
`3 TEAEs were similar in patients taking ibrutinib concomitantly
`with CYP3A inhibitors and those without CYP3A inhibitors (73%
`versus 89%) or immunosuppressants (77% versus 75%). With addi-
`tional follow-up, there were no new cases of atrial fibrillation
`(1 case in the initial report [10]) or major hemorrhage.
`Grade 3 TEAEs decreased over time (Figure 3; Supple-
`mentary Table S2). Serious grade 3 TEAEs (year 1, 45%
`[n = 19 of 42]; year 2, 8% [n = 1 of 12]) and any-grade
`TEAE bleeding events (year 1, 48% [n = 20 of 42]; year 2, 17%
`[n = 2 of 12]) decreased in the second year of treatment.
`Furthermore no additional patients required a dose reduc-
`tion (33%; n = 14). TEAEs leading to discontinuation occurred in
`18 patients (43%).
`
`DISCUSSION
`This extended follow-up demonstrated durable and clini-
`cally meaningful outcomes in patients with cGVHD who failed
`
`100K
`
`....
`t ....
`
`'&
`~
`~
`l
`
`""'
`
`,.,.
`
`°"
`
`71"
`
`(n=30)
`
`Year1
`(n=42)
`
`""
`
`ln:31
`
`Year2
`(n=12)
`
`Figure 3. Decreasing frequency of grade 3 TEAEs over time.
`
`1 previous therapy. The CR rate increased from 21% to 31%,
`and the 32-week sustained response rate increased from 48%
`to 62% with continued follow-up [10]. Similarly, the median
`corticosteroid dose continued to decrease over time to doses
`associated with minimal toxicity, an important goal in the
`treatment of patients with cGVHD [12]. This is an important
`clinical benefit with ibrutinib given the numerous serious side
`effects of corticosteroids, including infection, avascular necro-
`sis, hypertension, poor glycemic control, mood swings, osteo-
`porosis, and weight gain [12,13].
`Sclerotic manifestations represent a challenging aspect of
`managing cGVHD. Patients with sclerotic manifestations of
`cGVHD experience functional impairment and report signifi-
`cantly more changes in skin color, skin thickness, and joint stiff-
`ness compared with patients without sclerotic cGVHD [14].
`Recognizing that improvements in sclerosis may require a longer
`duration of treatment than was captured in the original analysis,
`it is notable that more than half of patients with sclerosis in this
`study had clinically meaningful improvement in sclerosis with
`ibrutinib treatment with longer follow-up.
`Quality of life is substantially impaired in patients with cGVHD
`[1517]. The Lee cGVHD Symptom Scale assesses patient-
`perceived cGVHD symptom burden by evaluating the impact of
`disease manifestations [18]. Collection of the Lee cGVHD Symptom
`Scale total summary score continued during the follow-up period,
`with more than half of responders reporting improvement.
`Improvement in Lee cGVHD Symptom Scale scores supports the
`high rate of CR observed and demonstrates the patient-perceived
`benefit of ibrutinib’s effects on reducing symptom burden.
`Safety findings for this updated analysis were consistent with
`the original analysis. No new or unexpected findings were
`observed. Most AEs were of low-grade severity and consistent
`with the known tolerability profile of ibrutinib. Common AEs—
`fatigue, diarrhea, muscle spasms, nausea, and bruising—were
`consistent with previously reported observations in patients
`with B-cell malignancies and patients with cGVHD treated with
`corticosteroid-containing therapies [9,1922]. Rates of AEs were
`not higher in patients also receiving CYP3A inhibitors and other
`
`

`

`2006
`
`E.K. Waller et al. / Biol Blood Marrow Transplant 25 (2019) 20022007
`
`immunosuppressants, suggesting that ibrutinib can be used
`safely in patients with cGVHD concomitantly taking CYP3A inhib-
`itors or immunosuppressants. Although atrial fibrillation and
`major hemorrhage have been associated with ibrutinib treat-
`ment
`for B-cell malignancies, no major hemorrhage was
`observed in this study, and only 1 patient experienced atrial
`fibrillation,
`in association with multilobular pneumonia
`[20,23,24]. With additional follow-up, there were no new fatal
`TEAEs. In the initial report, [10] 2 fatal TEAEs occurred, 1 due to
`pneumonia (etiology, Enterococcus) and the other due to bron-
`chopulmonary aspergillosis. The patient with bronchopulmonary
`aspergillosis had a history of fungal pneumonia and was not on
`anti-fungal prophylaxis. During ibrutinib treatment, patients at
`risk for opportunistic infection should receive standard-of-care
`prophylaxis as appropriate and be monitored for infection [9,19].
`When medically necessary, anti-infective therapy should be
`administered accordingly [9,19].
`Limitations of this analysis include the open-label design
`and lack of comparator group. It is also possible that reduced
`doses of prednisone would have been observed in some
`patients over time without treatment with ibrutinib. However,
`patients enrolled in this study were steroid-dependent or
`-refractory and had been unable to maintain a reduced steroid
`dose despite previous attempts. Therefore, the reduction in
`steroid doses observed herein, together with the acceptable
`tolerability and sustained responses observed with longer-
`term follow-up, are clinically meaningful and demonstrate a
`substantial advance in the therapeutic management of
`patients with cGVHD.
`Several questions remain concerning the role of ibrutinib in
`the treatment landscape for cGVHD. The mechanism of action of
`ibrutinib in treating steroid-dependent or -refractory cGVHD
`was initially postulated to involve inhibition of BTK in B cells,
`leading to reduced production of autoreactive antibodies or inhi-
`bition of a homologous enzyme in T cells, interleukin-2-inducible
`T cell kinase (ITK),
`leading to selective suppression of Th2
`immune responses that may contribute to the pathogenesis of
`cGVHD [25,26]. Given that the half maximal inhibitory concen-
`tration (IC50) of ibrutinib for BTK is 1.5 nM, compared with
`4.9 nM for ITK, the clinical efficacy of ibrutinib in treating steroid-
`refractory cGVHD could be due to BTK inhibition, ITK inhibition,
`or targeting of enzymatic pathways in both B cells and T cells
`[27]. The duration of ibrutinib therapy for cGVHD is unknown at
`this time. It is reassuring that our patients who discontinued ibru-
`tinib did not experience worsening cGVHD or a flare in symptoms
`(data not shown), and thus there does not seem to be a need to
`taper ibrutinib. The mechanism of sustained efficacy that devel-
`oped in patients treated with ibrutinib in whom treatment could
`be discontinued while maintaining response is of great interest
`and also remains to be defined. Notably, patients with the most
`consistent and durable responses to ibrutinib in this study
`included those with sclerosis, a pathological condition postu-
`lated to be mediated in part by Th2-polarized T cells. Ibrutinib
`is currently being evaluated in the frontline cGVHD setting in
`the INTEGRATE Phase 3 study (PCYC-1140-IM; ClincalTrials.
`gov identifier NCT02959944) comparing ibrutinib in combina-
`tion with corticosteroids versus placebo with corticosteroids
`in patients with new-onset cGVHD. In this Phase 3 study,
`patients responding to treatment are able to discontinue ibru-
`tinib after a minimum of 48 weeks of therapy. Finally, in the
`present study, patients had received 3 previous therapeutic
`regimens for cGVHD, and thus the potential role of ibrutinib
`in patients with highly resistant disease (ie, failed more than
`3 previous regimens) is unknown. As additional evidence for
`current and emerging therapies expands, the outlook for
`
`patients with cGVHD is promising and will continue to evolve
`as additional evidence is collected.
`
`ACKNOWLEDGMENTS
`The authors thank all of the patients who participated in
`this trial and their families.
`Financial disclosure: Medical writing support was provided
`by Lauren D’Angelo, PhD, and funded by Pharmacyclics LLC, an
`AbbVie Company, Sunnyvale, California, USA, and Janssen
`Research and Development, Titusville, New Jersey, USA.
`Conflict of interest statement: E.K.W.: leadership role for
`and patents, royalties, or other intellectual properties from
`Cambium Medical Technologies; consultancy/advisory role
`and honoraria for Novartis, Amgen, Celldex, and CSL Behring;
`patents, royalties, or other intellectual properties from Cam-
`bium Medical Technologies; research funding from Celldex
`and Novartis; stock or other ownership in Cerus, Chimerix,
`Cambium Medical Technologies, and Cambium Oncology; and
`travel, accommodations, or expenses from Pharmacyclics LLC,
`an AbbVie Company. D.M.: consultancy/advisory role for
`Pharmacyclics LLC, an AbbVie Company, Janssen, Adaptive
`Biotechnologies, Kite-Gilead, Novartis, and Juno; speakers
`bureau for Pharmacyclics LLC, an AbbVie Company, Adaptive
`Biotechnologies, and Kite-Gilead; and patent for ibrutinib
`therapy of chronic graft-versus-host disease with Pharmacy-
`clics LLC, an AbbVie Company. C.C.: consultancy/advisory role
`for Pharmacyclics LLC, an AbbVie Company, Genentech, Pfizer,
`Kite, Jazz, Sandoz, Bristol-Myers Squibb, Incyte, Astellas, and
`Kadmon; and expert testimony for Pharmacyclics LLC, an
`AbbVie Company. M.A.: nothing to disclose. M.H.J.: honoraria
`from Mallinckrodt and Kadmon; consultancy/advisory role for
`Incyte and Kadmon; and research funding from Janssen and
`Mallinckrodt. I.P.: travel, accommodations, or expenses from
`Pharmacyclics LLC, an AbbVie Company. M.E.D.F.: honoraria,
`speakers bureau, and travel, accommodations, or expenses
`from Astellas and Mallinckrodt; consultancy/advisory role for
`Pharmacyclics LLC, an AbbVie Company, and CSL Behring; and
`research funding from Pharmacyclics, LLC, an AbbVie Com-
`pany, and Incyte/Novartis; A.C.L.: consultancy/advisory role
`for Amgen, Adaptive Biotechnologies, Agios, Jazz, Shire, and
`Pfizer; and research. Funding from Pharmacyclics LLC, an
`AbbVie Company, Astellas, Novartis, Kite, and Jazz. R.N.: con-
`sultancy/advisory role for Merck. S.C.: employed by Pharma-
`cyclics LLC, an AbbVie Company, and stock or other ownership
`in AbbVie, Johnson and Johnson, Portola, Abbott, and Ipsen. F.
`C.: employed by, leadership role for, and travel, accommoda-
`tions, or expenses from Pharmacyclics LLC, an AbbVie Com-
`pany; and stock or other ownership in AbbVie.
`I.D.L.:
`employed by Pharmacyclics LLC, an AbbVie Company and
`spouse employment with The Permanente Medical Group; and
`stock or other ownership in AbbVie, Gilead Sciences, Clovis,
`Infinity, The Permanente Medical Group, and Reviva Pharma-
`ceuticals. L.S.: employed by Pharmacyclics LLC, an AbbVie
`Company, and stock or other ownership in AbbVie. S.J.: consul-
`tancy/advisory role for Pharmacyclics LLC, an AbbVie Company,
`Kite, Novartis, and Juno; research funding from Pharmacyclics
`LLC, an AbbVie Company, Kite, Unum, Novartis, Janssen, and
`Amgen; and travel, accommodations, or expenses from Kite,
`Novartis, and Juno.
`
`SUPPLEMENTARY MATERIALS
`Supplementary material associated with this article can be
`found in the online version at doi:10.1016/j.bbmt.2019.06.023.
`
`

`

`E.K. Waller et al. / Biol Blood Marrow Transplant 25 (2019) 20022007
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