Plenary Paper
`
`(i)blood
`
`CLINICAL TRIALS AND OBSERVATIONS
`
`Ibrutinib for chronic graft-versus-host disease after failure of
`prior therapy
`David Miklos,1 Corey S. Cutler,2 Mukta Arora,3 Edmund K. Waller,4 Madan Jagasia,5 Iskra Pusic,6 Mary E. Flowers,7
`Aaron C. Logan,8 Ryotaro Nakamura,9 Bruce R. Blazar,3 Yunfeng Li,10 Stephen Chang,10 Indu Lal,10 Jason Dubovsky,10
`Danelle F. James,10 Lori Styles,10 and Samantha Jaglowski11
`
`1Stanford University School of Medicine, Stanford, CA; 2Dana-Farber Cancer Institute, Boston, MA; 3Department of Medicine, University of Minnesota,
`Minneapolis, MN; 4Winship Cancer Institute of Emory University, Atlanta, GA; 5Vanderbilt-Ingram Cancer Center, Nashville, TN; 6Division of Oncology,
`Washington University School of Medicine, St. Louis, MO; 7Fred Hutchinson Cancer Research Center, Seattle, WA; 8University of California San Francisco
`Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 9City of Hope, Duarte, CA; 10Pharmacyclics LLC, an AbbVie Company, Sunnyvale,
`CA; and 11Division of Hematology, The Ohio State University Cancer Center, Columbus, OH
`
`Key Points
`
`•
`
`Ibrutinib induced a high rate of
`sustained responses for
`patients with cGVHD and
`inadequate response to
`corticosteroid-containing
`therapy.
`• This trial supported the
`approval of ibrutinib for
`treatment of adult patients
`with cGVHD after failure of
`$1 lines of systemic therapy.
`
`Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem
`cell transplantation with few effective options available after failure of corticosteroids.
`B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine
`kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models,
`ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the
`safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response
`to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior
`treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy
`end point was cGVHD response based on 2005 National Institutes of Health criteria. At
`a median follow-up of 13.9 months, best overall response was 67%; 71% of responders
`showed a sustained response for ‡20 weeks. Responses were observed across involved
`organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan
`response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day
`at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids.
`The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and
`bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with
`ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ‡1 prior treatments for cGVHD.
`Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more
`lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869. (Blood. 2017;130(21):2243-2250)
`
`Introduction
`
`Chronic graft-versus-host disease (cGVHD) is a serious and life-
`threatening complication of allogeneic hematopoietic stem cell trans-
`plantation affecting 30% to 70% of patients.1 It is a leading cause of
`late nonrelapse mortality for transplant patients, also contributing to
`morbidity and a decrease in quality of life.2-5 Corticosteroids, the
`standard frontline treatment, are typically administered for a median of
`2 to 3 years,6 leading to substantial morbidity. An effort to decrease
`corticosteroid doses has led to their use in combination with other
`immunosuppressants, such as cyclosporine, tacrolimus, and sirolimus,
`in frontline or second-line settings, despite a lack of clinical evidence
`supporting additional efficacy after combining these agents with
`corticosteroids.7-12 Patients who have persistent cGVHD after frontline
`therapy and require a change in treatment have a 2.5 times increased risk
`of nonrelapse mortality13; however, there is no standard of care or
`
`approved second-line treatment.14 An effective treatment option for
`patients with cGVHD that fails to respond to initial therapy remains an
`unmet medical need.15
`Both B and T cells play critical roles in the pathogenesis of
`cGVHD.16-19 A lower incidence of cGVHD after in vivo T-cell
`depletion confirms T-cell involvement, although higher rates of
`infections and relapse of underlying malignancy complicate this
`approach.20,21 Host-reactive B cells are also associated with the
`development of cGVHD,18 and rituximab provides clinical benefit;
`however, alloreactive B cells recur after treatment discontinuation.22
`Ibrutinib is a first-in-class, once-daily inhibitor of Bruton tyrosine
`kinase (BTK). Activation of the B-cell receptor triggers the BTK
`signaling pathway, which regulates B-cell survival.23 Ibrutinib also
`inhibits interleukin-2–inducible T-cell kinase (ITK); stimulation of
`
`Submitted 6 July 2017; accepted 6 September 2017. Prepublished online as
`Blood First Edition paper, 18 September 2017; DOI 10.1182/blood-2017-07-
`793786.
`
`The online version of this article contains a data supplement.
`
`There is an Inside Blood Commentary on this article in this issue.
`
`The publication costs of this article were defrayed in part by page charge
`payment. Therefore, and solely to indicate this fact, this article is hereby
`marked “advertisement” in accordance with 18 USC section 1734.
`© 2017 by The American Society of Hematology
`
`BLOOD, 23 NOVEMBER 2017 x VOLUME 130, NUMBER 21
`
`2243
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`2244 MIKLOS et al
`
`BLOOD, 23 NOVEMBER 2017 x VOLUME 130, NUMBER 21
`
`ITK, mediated by phospholipase C g (PLCg), is involved in the
`selective activation of T-cell subsets that drive immune reactivity
`toward healthy tissues.24 In preclinical models, mice that received
`BTK- or ITK-deficient bone marrow transplants did not develop
`cGVHD, indicating that both kinases play critical roles in cGVHD
`pathogenesis.25 By inhibiting both BTK and ITK, ibrutinib has the
`potential to provide a clinical benefit for cGVHD. In preclinical models,
`ibrutinib delayed progression and improved clinical manifestations
`of cGVHD.25 In a recent analysis of patients with relapsed chronic
`lymphocytic leukemia after allogeneic hematopoietic stem cell trans-
`plantation, ibrutinib was tolerable and effective.26
`Based on the biological rationale and compelling preclinical data, a
`phase 1b/2 study was designed to evaluate the safety and efficacy of
`ibrutinib in patients with cGVHD that has failed to respond to at least
`1 systemic corticosteroid-based therapy and who needed additional
`treatment. Supported by the results of this trial, ibrutinib was recently
`approved in the United States for the treatment of adult patients with
`cGVHD after failure of 1 or more lines of systemic therapy.
`
`Patients and methods
`
`Patients
`
`Starting on July 14, 2014, eligible patients were enrolled if they were aged
`$18 years, had steroid-dependent or -refractory cGVHD after hematopoietic
`stem cell transplant, and had received #3 prior regimens for cGVHD. Steroid-
`dependent disease was defined as cGVHD requiring prednisone $0.25 mg/kg per
`day for $12 weeks; refractory disease was defined as progressive cGVHD,
`despite treatment with prednisone $0.5 mg/kg per day for $4 weeks. Active
`cGVHD was required, and patients were to have either .25% body surface area
`erythematous rash or a National Institutes of Health (NIH) mouth score .4.
`These manifestations were selected because they were expected to respond
`rapidly to an effective therapy, and thus the patient could potentially avoid long-
`term exposure to an ineffective therapy.
`Pretransplant use of ibrutinib for reasons other than cGVHD, such as for
`the treatment of leukemia or lymphoma, was permitted. All patients received
`systemic corticosteroid therapy for cGVHD prior to and during the study;
`concomitant use of other immunosuppressive therapies including extracorporeal
`photopheresis was also permitted; however, preexisting corticosteroid and
`immunosuppressant doses must have been stable for 14 days before initiating
`ibrutinib. Doses of concomitant corticosteroids and immunosuppressants could
`be tapered during the study as clinically indicated.
`
`Study design and treatment
`
`This phase 1b/2, open-label, multicenter study was designed to determine the
`safety and efficacy of ibrutinib in patients who failed $1 therapy for cGVHD.
`Phase 1b was conducted using a modified 31313 design to evaluate the safety of
`daily oral ibrutinib and determine the recommended phase 2 dose (RP2D).
`Treatment was initiated at an ibrutinib dose of 420 mg with 6 to 27 patients being
`evaluated in phase 1b depending on the frequency of dose limiting toxicities
`(DLTs) and need for dose reductions. If unacceptably high DLTs were seen, the
`ibrutinib dose could be sequentially reduced to 280 mg and then 140 mg. Patients
`in phase 1b who did not experience a DLT were permitted to continue treatment
`and follow-up in phase 2 at their phase 1 dose. In phase 2, patients were treated
`with ibrutinib at the RP2D along with preexisting immunosuppressants for
`cGVHD and followed for signs of progression or improvement of cGVHD.
`Approximately 34 patients were to be enrolled in phase 2 with a total target
`enrollment of ;40 patients in phase 1b and phase 2 who were treated at the RP2D.
`For this analysis, patients were followed until September 1, 2016.
`The study (registered at www.clinicaltrials.gov as #NCT02195869) was
`approved by the institutional review board or independent ethics committee at
`each institution and was conducted in accordance with the principles of the
`Declaration of Helsinki and the International Conference on Harmonization
`Guidelines. All patients provided written informed consent.
`
`Study end points and evaluations
`
`The primary end point for phase 1b was safety and tolerability, which included
`the number of DLTs occurring within the first 28 days on ibrutinib. The primary
`efficacy endpoint for phase 2 was the best overall cGVHD response rate, which
`was defined as the proportion of all patients who achieved a complete response
`(CR) or partial response (PR). All patients who had at least 1 response
`assessment were considered response-evaluable. Nonresponders were defined
`as those patients who had stable disease, had progressive disease, or were not
`evaluable. The response criteria were based on those provided by the 2005 NIH
`cGVHD Consensus Panel27 and subsequently modified to include the following
`2 changes based on publication of the 2014 NIH response criteria28: a change in
`organ score from 0 to 1 was not considered progression, and an organ was
`deemed nonevaluable for response when the organ response was confounded by
`a non-cGVHD–related factor. Under the original protocol, response assess-
`ments were conducted every 12 weeks. A protocol amendment added an
`additional response assessment at week 5.
`Secondary efficacy end points included sustained response of $20 weeks,
`changes in corticosteroid requirement over time, and patient-reported change in
`the Lee cGVHD Symptom Scale. A decrease by $7 points was considered
`clinically meaningful and related to improved quality of life.29 Physicians and
`patients also reported overall cGVHD severity scores. Patients were evaluated
`for safety; adverse events (AEs) were graded using the National Cancer Institute
`Common Terminology Criteria for Adverse Events, version 4.03.
`Exploratory analyses included pharmacodynamic studies in which the
`effect of ibrutinib on immune cell signaling pathways, cytokines, chemokines,
`and factors that promote tissue fibrosis was evaluated. BTK and ITK occupancy
`was determined using a biotinylated covalent-binding probe to capture all
`unoccupied kinase. Pelleted flash-frozen peripheral blood mononuclear cells
`were resuspended in lysis buffer and split into 2 aliquots: 1 aliquot was
`incubated with the probe and the other aliquot was incubated with biotinylated
`primary ITK or BTK antibody to determine the total quantity of ITK or BTK
`protein in the sample. MSD streptavidin plates (Meso Scale Diagnotics, LLC)
`were used to separate biotin-conjugated proteins. The level of unoccupied or
`total ITK or BTK protein was quantified with a secondary antibody and Sulfo-
`tag detection antibody using an MSD S600 Instrument.
`Immunoglobulin E (IgE)–induced basophil activation was assayed via flow
`cytometry using markers for CD63, CD123, and HLA-DR according to the
`validated procedures indicated in the BD FastImmune protocol (BD Biosci-
`ences). Briefly, 20 mL of stimulation buffer plus anti-human IgE was added to
`100 mL of heparin blood and incubated at 37°C for 15 minutes. Degranulation
`was halted by transferring the reaction to ice and adding 10 mL of 20 mM EDTA.
`After staining with the appropriate antibody cocktail, red blood cells were lysed,
`and the samples were fixed in 0.5% paraformaldehyde. Samples were analyzed
`using a BD FACSCalibur flow cytometer (BD Biosciences).
`Activation of PLCg1-Y783 in CD4 T cells was measured using a phospho-
`flow analysis. Viable, cryopreserved T cells were assayed via flow cytometry using
`antibodies for CD4, CD3, and pPLCg1 Tyr783 (Cell Signaling) with an anti-rabbit
`Alexa Fluor A488 (Molecular Probes) secondary antibody. Briefly, peripheral
`blood mononuclear cells were thawed, washed, and centrifugally plated onto
`precoated anti-CD3 (stimulated) or uncoated (unstimulated) wells of a sterile 6-well
`polystyrene cell culture dish for 5 minutes before cold quenching at 4°C. After
`staining for extracellular markers, cells were fixed with BD Cytofix and
`permeabilized with BD Perm Buffer III. The cells were then stained for intracellular
`markers, washed, and analyzed using a BD FACS Aria sorting flow cytometer.
`
`Statistical analysis
`
`With a sample size of at least 40 patients and assuming a best overall cGVHD
`response rate of ;50%, the study was expected to have 90% power to show an
`efficacious treatment effect. The cGVHD response rate and its 95% exact binomial
`confidence interval were calculated using the exact test for binomial distribution.
`All secondary end points and safety analyses were summarized using
`descriptive statistics, including means, standard deviations, and medians for
`continuous variables and proportions for discrete variables.
`For biomarker analyses, levels of factors were determined at baseline and
`various time points after ibrutinib treatment. The values at each time point were
`expressed as a proportion of baseline value and depicted as a heat map.
`
`

`

`BLOOD, 23 NOVEMBER 2017 x VOLUME 130, NUMBER 21
`
`IBRUTINIB FOR cGVHD
`
`2245
`
`Results
`
`Patients
`
`Six patients were enrolled in phase 1b at a dose of 420 mg. No DLTs
`were reported, and as a result, no dose reductions were necessary, and
`the RP2D of ibrutinib was determined to be 420 mg daily. An additional
`36 patients were treated at 420 mg in phase 2 (total of 42 patients). The
`baseline characteristics of the patients are listed in Table 1. Patients had
`undergone both myeloablative and nonmyeloablative stem cell trans-
`plant for a variety of underlying malignancies (supplemental Table 1,
`available on the Blood Web site). As expected, mouth and skin were the
`most frequently involved organs, and 85% of patients showed evidence
`of cGVHD in $2 organs. The median Karnofsky Performance Status
`score was 80, with 60% of patients having a score between 60 and
`80. Of the 42 patients, 28 had steroid-dependent cGVHD, 6 had steroid-
`refractory cGVHD, and 8 had a history of both steroid-dependent
`and -refractory disease. The concomitant
`immunosuppressive
`agents, which were continued during treatment with ibrutinib, are
`summarized in supplemental Table 2.
`At a median follow-up of 13.9 months (range, 0.5-24.9 months),
`12 patients (29%) were still receiving ibrutinib and 30 (71%) had
`discontinued treatment. Treatment duration ranged from 5.6 to
`24.9 months for the 12 patients who continued treatment. The most com-
`mon reasons for treatment discontinuation were AEs (n 5 14), cGVHD
`progression (n 5 5), or patient decision (n 5 6); 2 patients discontinued
`after resolution of cGVHD symptoms (supplemental Table 3).
`
`Table 1. Baseline demographic and clinical characteristics of the
`patients
`
`Characteristic
`
`Median age (range), y
`
`Male sex
`
`Number of transplants
`
`1
`
`2
`
`Type of transplant
`
`Myeloablative
`
`Nonmyeloablative
`
`Type of donor
`
`Related
`
`Unrelated
`
`HLA matching of cell graft between donor and
`
`recipient
`
`Matched
`
`Partially matched
`
`Stem cell source
`
`Peripheral blood stem cell
`
`Bone marrow
`
`Cord blood
`
`Total (N 5 42)*
`
`56 (19-74)
`
`22 (52)
`
`29 (93)
`
`3 (7)
`
`18 (43)
`
`24 (57)
`
`17 (40)
`
`25 (60)
`
`37 (88)
`
`5 (12)
`
`37 (88)
`
`4 (10)
`
`1 (2)
`
`Median time from transplant (range), mo
`
`Median time from transplant to diagnosis of cGVHD
`
`25.7 (2.7-79.5)
`
`7.6 (1.5-76)
`
`(range), mo
`
`Median time from initial cGVHD diagnosis (range), mo
`
`13.7 (1.1-63.2)
`
`Steroid dependence of cGVHD
`
`Steroid-dependent cGVHD
`
`Steroid-refractory cGVHD
`
`28 (67)
`
`6 (14)
`
`8 (19)
`
`Safety
`
`Most AEs were grade 1 or 2 (Table 2), with the most common being
`fatigue, diarrhea, muscle spasms, nausea, and bruising. The most com-
`mon grade $3 AEs were pneumonia, fatigue, and diarrhea. Infectious
`complications of any grade were reported for 29 (69%) patients includ-
`ing 15 (36%) grade$ 3 events. Serious AEs are listed in supplemental
`Table 4. Two patients had a relapse of their underlying malig-
`nancy (acute lymphocytic leukemia [after 43 days on ibrutinib therapy]
`and prolymphocytic leukemia [after 308 days of ibrutinib therapy]).
`There were 7 deaths during the study with 2 occurring due to AEs
`(multilobular pneumonia and bronchopulmonary aspergillosis) while
`the patients were on ibrutinib; the other 5 deaths occurred in the follow-
`up period after the patients had discontinued ibrutinib, with 3 deaths
`attributed to cGVHD and 2 to unknown causes. No major hemorrhage
`events were observed. Atrial fibrillation (grade 3) was reported in
`1 patient.
`Dose reductions resulting from AEs were reported for 13 patients
`(31%); the most common AE leading to dose reductions was fatigue
`(n 5 6). AEs led to treatment discontinuation in 14 patients (33%), with
`the most common reasons being fatigue (n 5 3) and pneumonia (n 5 2).
`The median duration of treatment was 1.8 months (range, 0.2-8.7 months)
`for patients who discontinued treatment due to unacceptable toxicity.
`For the 7 patients with progression of cGVHD, the median time to
`progression was 5.6 months (range, 1.7-15.7).
`
`Efficacy
`
`In the all treated population, the overall response rate (ORR), based on
`the 2005 NIH cGVHD Consensus Panel response criteria, was 67%,
`with a CR rate of 21% and a PR rate of 45% (Figure 1). Five patients
`discontinued treatment and left the study before a response assessment.
`Excluding these 5 patients, the ORR in the response-evaluable
`population was 76%. Of the 28 responders, 20 (71%) showed a
`
`Both
`
`Number of involved organs
`
`1
`
`2
`
`3
`$4
`Involved organ
`
`Mouth
`
`Skin
`
`Gastrointestinal system
`
`Liver
`
`Lungs
`
`Median Karnofsky Performance Status Score (range)
`.80
`70-80
`
`60
`
`Median prior lines of treatment of cGVHD (range)
`
`6 (14)
`
`24 (57)
`
`9 (21)
`
`3 (7)
`
`36 (86)
`
`34 (81)
`
`15 (36)
`
`3 (7)
`
`2 (5)
`
`80 (60-100)
`
`17 (40)
`
`22 (52)
`
`3 (7)
`
`2 (1-3)
`
`Mean prednisone dose at enrollment (range), mg/kg per
`
`0.31 (0.1-1.3)
`
`day
`
`Prior therapies for cGVHD
`
`Corticosteroids
`
`Tacrolimus
`
`Extracorporeal photopheresis/PUVA
`
`photochemotherapy
`
`Rituximab
`
`Mycophenolate mofetil
`
`Cyclosporine
`
`Sirolimus
`
`Other immunosuppressants
`
`42 (100)
`
`21 (50)
`
`11 (26)
`
`11 (26)
`
`10 (24)
`
`8 (19)
`
`7 (17)
`
`2 (5)
`
`Data are presented as n (%) unless indicated otherwise.
`PUVA, psoralen and ultraviolet A.
`*Of the 43 patients who received ibrutinib, 1 patient was excluded from the
`analysis because of the presence of relapse of the underlying malignancy evident
`from laboratory assessments of blood drawn before the first dose, but not resulted
`until after treatment initiation.
`
`

`

`2246 MIKLOS et al
`
`BLOOD, 23 NOVEMBER 2017 x VOLUME 130, NUMBER 21
`
`Table 2. Treatment-emergent adverse events reported in ‡10% of
`patients regardless of the cause
`
`Pharmacodynamic and biomarker studies
`
`Adverse event
`(N 5 42)
`
`Fatigue
`
`Diarrhea
`
`Muscle spasms
`
`Nausea
`
`Bruising
`
`Upper respiratory
`
`tract infection
`
`Pneumonia
`
`Pyrexia
`
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Grade 5
`
`5 (12)
`
`7 (17)
`
`8 (19)
`
`8 (19)
`
`6 (14)
`
`3 (7)
`
`1 (2)
`
`4 (10)
`
`3 (7)
`
`14 (33)
`
`4 (10)
`
`3 (7)
`
`3 (7)
`
`4 (10)
`
`5 (12)
`
`0
`
`1 (2)
`
`2 (5)
`
`5 (12)
`
`4 (10)
`
`1 (2)
`
`0
`
`0
`
`0
`
`4 (10)
`
`2 (5)
`
`2 (5)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1 (2)
`
`1 (2)
`
`0
`
`0
`
`0
`
`0
`
`Pharmacodynamic studies showed that mean steady-state occupancy
`levels of BTK and ITK were 93% (range, 46% to 99%; n 5 36) and
`37% (range, 0% to 71%; n 5 38), respectively, on day 8 of treatment.
`These steady-state occupancy levels were observed as early as 4 hours
`after treatment initiation and persisted for the analysis period. BTK
`occupancy was sufficient to effectively block 91% of BTK-driven
`basophil activation in an ex vivo IgE stimulation assay. Furthermore,
`measurement of ITK-mediated activation of PLCg1-Y783 in CD4
`T cells conducted for 4 patients revealed that ITK kinase function was
`inhibited by a mean of 73% (range, 52% to 86%) on day 8 (Figure 4).
`A biomarker analysis based on samples from all 42 patients showed
`a significant reduction in soluble plasma factors that are markers of
`inflammation and lymphocyte activation, including tumor necrosis
`factor-a and soluble CD25. Reductions in several chemotactic factors,
`including C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif
`chemokine ligand 10 (CXCL10), were observed. An analysis of factors
`associated with tissue fibrosis revealed reductions in epidermal growth
`factor and granulocyte-macrophage colony-stimulating factor. These
`changes occurred after ibrutinib was administered, and an overall
`downward trend was maintained for measured time points (Figure 5).
`
`Discussion
`
`Treatment with ibrutinib in patients with cGVHD that had failed 1 or
`more lines of systemic therapy resulted in a high frequency of sustained
`responses. The study population was heterogeneous, representative of
`many cGVHD patients requiring additional systemic therapy. Using
`the NIH cGVHD Consensus panel response criteria, ibrutinib treatment
`
`7
`
`SD
`
`2
`
`PD
`
`ORR
`67%
`
`9
`
`100%
`
`80%
`
`60%
`
`40%
`
`Responders, %
`
`20%
`
`19
`
`0%
`
`CR
`■
`PR
`■
`
`Figure 1. Best cGVHD response. The best cGVHD response was measured based
`on the 2005 NIH response criteria in patients with cGVHD (N 5 42). The 5 patients
`who had no response assessment during the study are included in the denominator
`in this intent-to-treat analysis. Reasons for discontinuing the study before a response
`assessment included toxicity (n 5 4) and noncompliance with study drug (n 5 1).PD,
`progressive disease; SD, stable disease.
`
`Headache
`
`Fall
`
`Cough
`
`Constipation
`
`Dyspnea
`
`Hyperglycemia
`
`Hypokalemia
`
`6 (14)
`
`4 (10)
`
`3 (7)
`
`4 (10)
`
`1 (2)
`
`0
`
`1 (2)
`
`2 (5)
`
`2 (5)
`
`0
`
`1 (2)
`
`2 (5)
`
`Peripheral edema
`
`1 (2)
`
`4 (10)
`
`Data are presented as n (%).
`
`0
`
`0
`
`0
`
`1 (2)
`
`3 (7)
`
`3 (7)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`sustained response for $20 weeks and 22 (79%) showed evidence of
`response at their first response assessment. For the 24 responders whose
`first efficacy assessment was conducted at week 13, the median time
`to initial response was 87 days; however, for the 4 responders who
`were enrolled after the protocol amendment and whose first response
`assessment occurred at week 5, the median time to initial response was
`30 days.
`Analysis by organ domain showed similar rates of response in the
`skin (88%), mouth (88%), and gastrointestinal organs (91%). Of
`25 responders with $2 involved organs, 20 (80%) showed a response
`in $2 organs (Table 3). Ten of 11 patients who were previously treated
`with rituximab had response assessments; 7 (64%) of these patients
`responded to ibrutinib. Patients with steroid-dependent cGVHD
`appeared to have somewhat better responses to ibrutinib than patients
`with steroid-refractory or both steroid-dependent and -refractory
`cGVHD with best ORRs of 75% vs 50% vs 50% and CR rates of
`25% vs 17% vs 13%, respectively. There did not appear to be a sub-
`stantial difference in best response between patients using additional
`immunosuppressants at baseline (n 5 22) when compared with those
`who did not (n 5 20) with ORRs of 64% vs 70% and CR rates of 18%
`vs 25%.
`The median corticosteroid dose among responders decreased from
`0.29 mg/kg per day (range, 0.06-1.30 mg/kg per day) at baseline (n 5 42)
`to 0.12 mg/kg per day (range, 0.00-0.18 mg/kg per day) at week 49
`(n 5 12) (Figure 2). Five responders completely discontinued cortico-
`steroids during response to ibrutinib treatment. Overall, 26 patients (62%)
`reached a corticosteroid dose of ,0.15 mg/kg per day during the study.
`The ORR results were supported by exploratory analyses of patient-
`reported symptoms, which showed clinically meaningful improve-
`ments (at least a 7-point decrease in Lee cGVHD Symptom Scale
`overall summary score) in 10 of the 42 (24%) treated patients on at least
`2 consecutive visits. Clinically meaningful improvement in summary
`scores was reported for 17 of 28 (61%) responders and 1 of 14 (7%)
`nonresponders. The median Total Summary Score for responders
`decreased from 32.8 (n 5 28) to 25.7 at week 49 (n5 15). Median
`overall clinician-assessed cGVHD severity score improved from 7
`(n 5 41) to 3 at week 49 (n5 15). A corresponding improvement in
`median patient-reported overall cGVHD score from 7 (n 5 42) to 4 at
`week 49 (n 5 14) was reported in the all-treated population (Figure 3).
`
`

`

`BLOOD, 23 NOVEMBER 2017 x VOLUME 130, NUMBER 21
`
`IBRUTINIB FOR cGVHD
`
`2247
`
`Table 3. Sustained response rate, organ response, and response in
`multiple organs among patients who responded to ibrutinib
`
`Sustained response
`of $20 wk
`
`Organ
`Skin
`
`Mouth
`
`Gastrointestinal
`
`Organs showing
`
`response
`$2 organs
`
`No. of responders
`
`Sustained response
`rate n (%)
`
`28
`
`20 (71)
`
`No. of responders with organ
`
`involvement at baseline
`
`24
`
`24
`
`11
`No. of patients with ‡2 involved
`organs at baseline among
`
`Best ORR, n (%)
`21 (88)
`
`21 (88)
`
`10 (91)
`
`responders
`
`25
`
`Best ORR, n (%)
`20 (80)
`
`yielded an ORR for cGVHD of 67% in these pretreated patients, with
`nearly one-third achieving a CR. The ORR in the response-evaluable
`patient population was 76%, allowing for comparison with histor-
`ical reports of efficacy of other second-line therapies. Sustained
`response was observed with 71% of
`responders maintaining
`response for $20 weeks. Similar response rates were seen across
`affected organs, and 80% of patients with multiple organ involve-
`ment showed response in $2 organs. Observed responses were
`associated with decreased corticosteroid use and an improvement in
`cGVHD symptoms.
`Although response rates ranging from 20% to 70% have been
`reported in studies of second-line agents for cGVHD,15 these results
`were often based on small, uncontrolled trials with suboptimal study
`designs. Subsequent randomized studies to confirm the initial results
`were all unsuccessful. To explain the discrepancy between the results
`of early trials and subsequent randomized studies, Martin et al analyzed
`60 early cGHVD trials using 10 clinical trial quality indicators.30
`The analysis of these trials, most of which were conducted before
`publication of the NIH standardized response criteria for cGVHD,27
`showed that the studies satisfied an average of only 2.5 of the 10 clinical
`trial quality measures.30 The investigators concluded that poor study
`design, including lack of rigorous entry, organ response, and overall
`response criteria, may have biased the reported efficacy in the early
`phase studies, leading to later unsuccessful controlled studies with the
`same agents. In 2005, the NIH cGVHD Consensus panel developed
`response criteria to improve evaluation of cGVHD response27;
`
`implementation of these criteria has been shown to reduce bias in the
`reported efficacy of second-line treatment of cGVHD.31 Although
`the NIH criteria were created to provide the most objective assessments
`of response, they still represent a subjective determination of cGVHD
`activity by the clinician. Because the present study used the NIH-
`defined response criteria, the ORR in this study is more robust than
`those reported in historical studies.
`This cGVHD study is the first to report sustained response as an
`efficacy endpoint. This end point is clinically relevant because cGVHD
`patients generally require therapy for an extended period, and short-
`term responses do not allow for resolution of disabling symptoms or
`tapering of corticosteroids. Without a sustained response, the most
`common approach to improve response is the addition of new agents
`to ongoing therapy with corticosteroids.32 Nearly three-quarters of
`responders in this study maintained their response for $20 weeks, and
`this was accompanied by meaningful reductions or discontinuation in
`corticosteroid use. Although the reduction of steroid doses in this open-
`label study could have been influenced by the investigators’ assessment
`of response, our results suggest that ibrutinib may have a steroid-
`sparing effect, which could reduce the morbidity associated with long-
`term corticosteroid use.33
`The clinical efficacy of ibrutinib in cGVHD is further supported
`by an overall improvement in Lee cGVHD Symptom Scale score in
`61% of responders. The Lee Symptom Scale directly measures the
`effect of ibrutinib on patient quality of life and symptom burden based
`on the multiorgan manifestations of the disease.4 The positive effect on
`symptom burden among responders was reinforced by a decrease in
`cGVHD severity scores reported by both clinicians and patients.
`Ibrutinib showed an acceptable safety profile in this pretreated
`cGVHD patient population, with AEs similar to those observed in
`ibrutinib-treated patients with B-cell malignancies and for patients
`with cGVHD treated with concomitant corticosteroids. One-third of
`patients discontinued treatment because of AEs. The relatively higher
`discontinuation rate for AEs compared with those observed in patients
`with B-cell malignancies may reflect that most patients had a low
`Karnofsky Performance Status score, comorbidities, and reduced
`fitness level, consistent with the relapsed cGVHD population on
`ongoing immunosuppressants. As expected for cGVHD patients on
`long-term corticosteroid treatment, AEs, including hyperglycemia
`and infections, were observed. AEs associated with ibrutinib, such
`as major bleeding and atrial fibrillation, occurred infrequently in this
`population.
`
`Responders
`■
`
`Nonresponders
`■
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`Median weekly average of daily
`
` corticosteroid doses
`
`Figure 2. Change in corticosteroid doses over time.
`Median change in weekly average of daily corticosteroid
`doses for responders over time. Responders include patients
`with a best overall response of CR and PR (n 5 28). Nonre-
`sponders include patients with stable disease, patients with
`progressive disease, and patients who were not evaluable for
`response (n 5 14).
`
`No. of patients
`Responders
`Nonresponders
`
`0
`
`4
`
`8
`
`12 16 20 24 28 32 36 40 44 48 52 56
`Time, weeks
`
`27
`14
`
`27
`13
`
`27
`12
`
`25
`5
`
`23
`3
`
`23
`2
`
`21
`2
`
`18
`
`18
`
`17
`
`17
`
`15
`
`12
`
`10
`
`8
`
`

`

`2248 MIKLOS et al
`
`BLOOD, 23 NOVEMBER 2017 x VOLUME 130, NUMBER 21
`
`•
`
`Clinician assessment
`
`Patient assessment
`■
`
`Figure 3. Improvement in cGVHD symptoms and severity.
`Change in clinician-assessed and patient-reported severity of
`cGVHD over time.
`
`5
`
`5
`
`13
`34
`31
`
`5
`
`4
`
`30
`20
`Time, weeks
`25
`20
`18
`
`5
`
`4
`
`37
`17
`16
`
`4
`
`3
`
`40
`
`50
`
`49
`15
`14
`
`7
`
`6
`
`5
`
`10
`
`0123456789
`
`Median overall severity scores
`
`0
`
`10
`
`0
`Week
`Clinician assessment 41
`Patient assessment 42
`
`5
`11
`10
`
`BTK occupancy of .90% was observed, and target occupancy
`results showed higher average engagement of BTK than ITK. Func-
`tionally relevant blockade of both kinases was observed, indicating that
`both BTK and ITK were sufficiently inhibited to induce biologic im-
`pact. These data are consistent with those of prior in vivo CLL patient
`experiences.24
`Ibrutinib is unique in its ability to exert effects on B cells and T cells,
`both of which have been implicated in the pathogenesis of cGVHD.25
`Biomarker analyses conducted on this population support the notion
`that ibrutinib targets the cellular and molecular pathways responsible
`for cGVHD. A striking number of cGVHD-related inflammatory,
`chemotactic, and fibrotic factors were significantly decreased across all
`patients following ibrutinib therapy, suggesti