Highlights in Graft-vs-Host Disease From the 2021 Transplantation & Cellular Therapy (TCT) Meetings of the ASTCT and the CIBMTR
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April 2021 Volume 19, Issue 4, Supplement 14
A SPECIAL MEETING REVIEW EDITION
Highlights in Graft-vs-Host Disease From the 2021
Transplantation & Cellular Therapy (TCT) Meetings of
the ASTCT and the CIBMTR
A Review of Selected Presentations From the 2021 TCT Meetings Digital Experience •
February 8-12, 2021
Special Reporting on:
• R
uxolitinib Versus Best Available Therapy in Patients With Glucocorticoid-Refractory Chronic Graft-Vs-Host
Disease: Primary Findings From the Phase 3, Randomized REACH3 Study
• C
alcineurin Inhibitor–Free Graft-Versus-Host Disease Prophylaxis in Hematopoietic Cell Transplantation With
Myeloablative Conditioning Regimens and HLA-Matched Donors: Results of the BMT CTN 1301 PROGRESS II Trial
• Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults
• P
hase I Study De-Intensifying Exposure of Post-Transplantation Cyclophosphamide After HLA-Haploidentical
Hematopoietic Cell Transplantation for Hematologic Malignancies
• P
reliminary Safety and Efficacy of Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Newly Diagnosed Severe
Acute Graft-Versus-Host Disease: Interim Results From the EQUATE Study
• Durable Discontinuation of Immunosuppressive Therapy: Clinical Results From the Chronic GvHD Consortium
• B
elumosudil for Chronic Graft-Versus-Host Disease After 2 or More Prior Lines of Therapy: The ROCKstar Study
(KD025-213)
• H
ealth Care Resource Utilization and Costs of Steroid-Related Complications in Patients With Graft-Versus-Host
Disease
• S
econdary Graft-Versus-Host Disease Prophylaxis With Oral Proteasome Inhibitor Ixazomib Is Associated With
Low Incidence of Recurrent, Late Acute, and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper Within the
First Year Post-Allogeneic Stem Cell Transplantation
PLUS Meeting Abstract Summaries
With Expert Commentary by:
Yi-Bin Chen, MD
Director, Hematopoietic Cell Transplant & Cellular Therapy Program
Cara J. Rogers Endowed Scholar
Division of Hematology/Oncology
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
ON THE WEB:
hematologyandoncology.net
Indexed through the National Library of Medicine
(PubMed/MEDLINE), PubMed Central (PMC), and EMBASEWhen steroids are
not enough for your
patient’s acute GVHD
Indications and Usage
Jakafi is indicated for treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adult and pediatric
patients 12 years and older.
Approval Was Based on REACH11
REACH1 was an open-label, single-arm, multicenter study of Jakafi in combination with steroids in patients who had
Grade II-IV steroid-refractory acute GVHD occurring after allogeneic hematopoietic stem cell transplant.1 A total of
71 patients were enrolled, of whom 49 were refractory to steroids alone and evaluable for efficacy.1
The primary endpoint was overall response rate (complete response, very good partial response, or partial response)
at Day 28 based on the Center for International Blood and Marrow Transplant Research (CIBMTR) criteria.
Patients in REACH1 Began Jakafi as Early as 3 Days After Steroid Initiation
Inclusion criteria included2:
• Progression after 3 days of ≥2 mg/kg/day methylprednisolone or equivalent
• Failure to improve after 7 days of ≥2 mg/kg/day methylprednisolone or equivalent
• Treatment with ≥1 mg/kg/day methylprednisolone for skin GVHD (or skin plus upper GI GVHD)
and development of GVHD disease in an additional organ
• Inability to achieve a 50% taper of steroid dose without a return of GVHD
CR, complete response; GI, gastrointestinal; GVHD, graft-versus-host disease; ORR, overall response rate; PR, partial response;
REACH, Ruxolitinib in PatiEnts with RefrACtory Graft-Versus-Host Disease After Allogeneic Stem Cell Transplantation; VGPR, very good partial response.
Important Safety Information
• Treatment with Jakafi can cause thrombocytopenia, • Tuberculosis (TB) infection has been reported.
anemia and neutropenia, which are each dose‐related Observe patients taking Jakafi for signs and
effects. Perform a pre‐treatment complete blood symptoms of active TB and manage promptly. Prior
count (CBC) and monitor CBCs every 2 to 4 weeks to initiating Jakafi, evaluate patients for TB risk
until doses are stabilized, and then as clinically indicated factors and test those at higher risk for latent
infection. Consult a physician with expertise in the
• Manage thrombocytopenia by reducing the dose treatment of TB before starting Jakafi in patients with
or temporarily interrupting Jakafi. Platelet evidence of active or latent TB. Continuation of Jakafi
transfusions may be necessary during treatment of active TB should be based on the
overall risk‐benefit determination
• Patients developing anemia may require blood
transfusions and/or dose modifications of Jakafi • Progressive multifocal leukoencephalopathy (PML)
has occurred with Jakafi treatment. If PML is
• Severe neutropenia (ANCVisit
hcp.Jakafi.com/gvhd Majority of Patients Achieved a Response at Day 281
to see
Full Prescribing Primary Endpoint: Over Half of Responses Were
Information Complete Responses
and to learn more
ORR at Day 28
about Jakafi
57% Responders
28/49
Subgroup Analysis: ORR at Day 28 by Baseline aGVHD Grade1
Grade II Grade III Grade IV
100% 41% 44%
13/13 11/27 4/9
• When discontinuing Jakafi, myeloproliferative • In myelofibrosis and polycythemia vera, the most
neoplasm-related symptoms may return within one common nonhematologic adverse reactions
week. After discontinuation, some patients with (incidence ≥15%) were bruising, dizziness, headache,
myelofibrosis have experienced fever, respiratory and diarrhea. In acute graft-versus-host disease, the
distress, hypotension, DIC, or multi‐organ failure. most common nonhematologic adverse reactions
If any of these occur after discontinuation or while (incidence >50%) were infections and edema
tapering Jakafi, evaluate and treat any intercurrent
illness and consider restarting or increasing the • Dose modifications may be required when
dose of Jakafi. Instruct patients not to interrupt or administering Jakafi with strong CYP3A4 inhibitors
discontinue Jakafi without consulting their physician. or fluconazole or in patients with renal or hepatic
When discontinuing or interrupting Jakafi for reasons impairment. Patients should be closely monitored
other than thrombocytopenia or neutropenia, consider and the dose titrated based on safety and efficacy
gradual tapering rather than abrupt discontinuation
• Use of Jakafi during pregnancy is not recommended
• Non‐melanoma skin cancers including basal cell, and should only be used if the potential benefit justifies
squamous cell, and Merkel cell carcinoma have the potential risk to the fetus. Women taking Jakafi
occurred. Perform periodic skin examinations should not breastfeed during treatment and for
2 weeks after the final dose
• Treatment with Jakafi has been associated with
increases in total cholesterol, low-density lipoprotein Please see Brief Summary of Full Prescribing
cholesterol, and triglycerides. Assess lipid Information for Jakafi on the following pages.
parameters 8-12 weeks after initiating Jakafi.
Monitor and treat according to clinical guidelines
for the management of hyperlipidemia
References: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.
2. Data on file. Incyte Corporation. Wilmington, DE.hyperlipidemia.
hyperlipidemia. ADVERSE
ADVERSEREACTIONS REACTIONSTheThe following
following clinically
clinically transfused
transfused perpermonth
month waswas1.21.2in in
patients
patientstreated
treated with
withJakafi andand
Jakafi 1.71.7
significant
significant adverse
adverse reactions
reactions arearediscussed
discussed in in
greater
greater detail
detail in in
other
other in in
placebo
placebo treated
treated patients.Thrombocytopenia
patients.ThrombocytopeniaIn In thethe
twotwo
Phase
Phase 33
sections
sections of of
thethelabeling:
labeling: • Thrombocytopenia,
• Thrombocytopenia, Anemia
Anemia andand clinical studies,
clinical studies, in in
patients
patients whowho developed
developed Grade
Grade 3 or 44
3 or
Neutropenia
Neutropenia [see[seeWarnings
Warnings andandPrecautions
Precautions(5.1) (5.1)in in FullFull
Prescribing
Prescribing thrombocytopenia,
thrombocytopenia, thethemedian
median time
timeto to
onset
onsetwaswas approximately
approximately
Information]
Information] • Risk
• Risk of ofInfection
Infection [see[seeWarnings
Warnings andand Precautions
Precautions (5.2)
(5.2) 8 weeks.
8 weeks. Thrombocytopenia
Thrombocytopenia waswasgenerally
generally reversible
reversible with dose
with dose
BRIEF
BRIEFSUMMARY: SUMMARY:ForForFullFullPrescribing PrescribingInformation, Information, in in
FullFull
Prescribing
Prescribing Information]
Information] • Symptom
• Symptom Exacerbation
Exacerbation Following
Following reduction
reduction or or
dosedoseinterruption.
interruption. TheThemedian
median timetimeto to
recovery
recovery of of
platelet
platelet
seeseepackage
packageinsert. insert. Interruption
Interruption or or
Discontinuation
Discontinuation of ofTreatment
Treatment with
with Jakafi
Jakafi [see[see counts
counts above
above 5050× 10× 10 /L /L
9 9
waswas 1414days.
days.Platelet
Platelettransfusions
transfusions were
were
CONTRAINDICATIONS
CONTRAINDICATIONS None.None. Warnings
Warnings andand Precautions
Precautions (5.3)(5.3)in in
FullFull
Prescribing
Prescribing Information]
Information] administered
administered to to
5%5% of of
patients
patients receiving
receiving Jakafi
Jakafi andandto to
4%4% of of
patients
patients
WARNINGS
WARNINGSAND ANDPRECAUTIONS
PRECAUTIONSThrombocytopenia, Thrombocytopenia, • Non-Melanoma
• Non-Melanoma SkinSkin Cancer
Cancer [see[seeWarnings
Warnings andand Precautions
Precautions (5.4)
(5.4) receiving
receiving control
controlregimens.
regimens. Discontinuation
Discontinuation of of
treatment
treatment because
because of of
Anemia
Anemiaand andNeutropenia
Neutropenia Treatment
Treatment withwith Jakafi
Jakafi cancan cause
cause in in
FullFull
Prescribing
Prescribing Information].Clinical
Information]. ClinicalTrials TrialsExperience
Experienceinin thrombocytopenia
thrombocytopenia occurred
occurred in inClinically
Clinicallyrelevant
relevantlaboratory
laboratoryabnormalities
abnormalitiesareareshown shownin in Table4. 4. DRUG
Table DRUGINTERACTIONS
INTERACTIONSFluconazole FluconazoleConcomitant Concomitant (range,
(range, 2 to2 to 2121 years)
years) andand included
included 1818 children
children (age (age2 to2 toSPECIAL MEETING REVIEW EDITION
Ruxolitinib Versus Best Available Therapy in Patients With
Glucocorticoid-Refractory Chronic Graft-Vs-Host Disease: Primary
Findings From the Phase 3, Randomized REACH3 Study
C
hronic graft-vs-host disease compared with best available therapy.4 or best available therapy. They received
(GVHD) occurs in approxi- Dr Stephanie J. Lee presented six 28-day treatment cycles. Patients
mately 30% to 70% of all the primary analysis of REACH3, a could continue previous treatment
patients who undergo allogeneic stem randomized, open-label, phase 3 study with glucocorticoids and/or calci-
cell transplant (alloSCT), and this con- comparing ruxolitinib vs best available neurin inhibitors. The best available
dition is a leading cause of nonrelapse therapy in patients with corticosteroid- therapy was chosen by the investiga-
mortality and morbidity.1,2 The stan- refractory or corticosteroid-dependent tor and could include extracorporeal
dard first-line treatment is systemic cor- chronic GVHD.5 The trial enrolled photopheresis, low-dose methotrexate,
ticosteroids. However, approximately 329 patients (median age, 49 years; mycophenolate mofetil, everolimus,
50% of patients become corticosteroid- range, 12-76 years) who had under- sirolimus, infliximab, rituximab, pen-
refractory or corticosteroid-dependent.3 gone alloSCT and had developed tostatin, imatinib, or ibrutinib. Infec-
No standard second-line treatment has moderate or severe corticosteroid- tion prophylaxis was permitted per
been defined. Ruxolitinib is a selective refractory or corticosteroid-dependent institutional practice.
Janus kinase (JAK) 1 and 2 inhibitor. chronic GVHD. Approximately 61% The primary endpoint was overall
In the open-label, phase 3 REACH2 of patients were male. Chronic GVHD response rate (ORR) per National
trial, ruxolitinib improved the median was moderate in 48% and severe in Institutes of Health (NIH) consensus
failure-free survival in patients with 52%. Patients were randomly assigned criteria at week 24.5 The key second-
glucocorticoid-refractory acute GVHD 1:1 to ruxolitinib at 10 mg twice daily ary endpoints were failure-free survival
Kaplan-Meier median (Ruxolitinib vs BAT)
100
Failure-Free Survival Probability (%)
Not reached vs 5.7 months
HR, 0.370 (95% Cl, 0.268-0.510); PH I G H L I G H T S I N G R A F T- V S - H O S T D I S E A S E F R O M T H E 2 0 2 1 T C T M E E T I N G S
100 Kaplan-Meier median (Ruxolitinib vs BAT)
Probability of Patients Maintaining Not reached vs 6.24 months
80
a Response (%)
60
Ruxolitinib
40 BAT
20
Events
Ruxolitinib: 40/126
0 BAT: 60/99 Censored Data
0 2 4 6 8 10 12 14 16 19 20 22 24 26 28
Months
Number of Patients at Risk
Ruxolitinib 126 117 101 85 71 63 53 46 34 24 27 18 9 1 0
BAT 99 78 62 47 36 33 28 19 16 10 8 4 3 2 0
Figure 2. The duration of response in the phase 3 REACH3 trial, which compared ruxolitinib vs best available therapy in patients with
refractory chronic graft-vs-host disease. BAT, best available therapy. Adapted from Zeiser R et al. TCT abstract 82. Transplant Cell Ther.
2021;27(3 suppl).5
and improvement in the modified Lee therapy (odds ratio [OR], 2.99; 95% superior efficacy compared with the
symptom score (mLSS) of at least 7 CI, 1.86-4.80; PSPECIAL MEETING REVIEW EDITION
Calcineurin Inhibitor–Free Graft-Versus-Host Disease Prophylaxis in
Hematopoietic Cell Transplantation With Myeloablative Conditioning
Regimens and HLA-Matched Donors: Results of the BMT CTN 1301
PROGRESS II Trial
R
egimens that include a calci assigned to receive a CD34-positive control, P=.27), 60.3% for the cyclo-
neurin inhibitor are standard selected peripheral blood stem cell phosphamide arm (vs control; P=.41),
for the prevention of GVHD graft without posttransplant immuno- and 52.6% for the control (Figure 3).
in patients undergoing hematopoietic suppression (n=114), cyclophospha- There was no significant difference in
stem cell transplant (HCT). Treat- mide after a bone marrow graft with- the CRFS rate between the CD34-
ment with calcineurin inhibitor–free out additional immunosuppression positive selection and cyclophospha-
strategies using T-cell depletion, either (n=114), or tacrolimus/methotrexate mide arms (P=.72). The 1-year rate
through CD34-positive–selected T-cell after a bone marrow graft as the con- of overall survival was 75.7% for the
depletion or post-transplant cyclo- trol (n=118). The primary endpoint CD34-positive selection arm (HR,
phosphamide, has also been associated was chronic GVHD (moderate/severe) 1.74; 95% CI, 1.09-2.80; P=.02),
with low rates of chronic GVHD.1,2 Dr relapse-free survival (CRFS) at 12 84.6% for the cyclophosphamide
Marcelo C. Pasquini presented results months after enrollment. Secondary arm (HR, 1.02; 95% CI, 0.60-1.72;
from BMT CTN 1301, a phase 3 trial endpoints included overall survival P=.95), and 84.2% for the control.
that compared 2 calcineurin inhibitor– and transplant-related mortality. The HR for the comparison between
free approaches vs a standard regimen Among the 346 patients enrolled, the CD34-positive selection and cyclo-
among patients with acute leukemia or 327 received HCT (300 per protocol).3 phosphamide arms for overall survival
myelodysplasia and a human leukocyte The arm receiving CD34-positive was 1.78 (95% CI, 1.09-2.89; P=.02).
antigen (HLA)-matched related or selection had the highest rate of non- Transplant-related mortality rates at 1
unrelated donor.3 compliance, with only 86% patients year were 16.5% for the CD34-posi-
The patients’ median age was 51 receiving per-protocol therapy. At 1 tive arm, 12% for the cyclophospha-
years (range, 13-66 years), and 43.1% year, the rate of CRFS was 60.2% for mide arm, and 7% for the control arm
were female. Patients were randomly the CD34-positive selection arm (vs (CD34-positive vs control, P=.020;
Figure 3. Chronic graft-
vs-host disease relapse-free 1.0
survival in BMT CTN 1301,
a phase 3 trial that compared
prophylaxis with 2 calcineurin 0.8
CRFS Survival Probability
inhibitor–free approaches vs
a standard regimen among
patients with acute leukemia 0.6
or myelodysplasia and an
HLA-matched related or
0.4
unrelated donor. CRFS, chronic CD34-selected graft 1-year: 60.2% (95% CI, 50.3%-68.7%)
graft-vs-host disease relapse-free PTCy 1-year: 60.3% (95% CI, 50.5%-68.7%)
survival; HLA, human leukocyte Tacrolimus/methotrexate 1-year: 52.6% (95% CI, 43.1%-61.3%)
0.2
antigen; PTCy, post-transplant CD34-selected graft 2-year: 50.6% (95% CI, 40.8%-59.6%)
cyclophosphamide. Adapted PTCy: 2-year: 48.1% (95% CI, 38.5%-57.1%)
Tacrolimus/methotrexate 2-year: 41.0% (95% CI, 32.0%-49.9%)
from Pasquini MC et al. TCT 0.0
abstract LBA1. Transplant Cell
Ther. 2021;27(3 suppl).3 0 3 6 9 12 15 18 21 24
Number at Risk Months Post-Randomization
CD34-selected
graft 114 101 81 72 64 56 54 51 49
PTCy 114 104 83 70 66 63 59 57 47
Tacrolimus/
methotrexate 118 110 92 73 60 52 49 48 42
8 Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021H I G H L I G H T S I N G R A F T- V S - H O S T D I S E A S E F R O M T H E 2 0 2 1 T C T M E E T I N G S
of infection were significantly higher
ABSTRACT SUMMARY Nonrelapse Mortality Among Patients Diag- with either calcineurin inhibitor–free
nosed With Chronic Graft-Versus-Host Disease: An Updated Analysis strategy vs tacrolimus/methotrexate.
From the Chronic GVHD Consortium Rates of overall survival were similar
for cyclophosphamide without addi-
To better understand and identify patients at highest risk for nonrelapse mortality, tional immunosuppression and tacro-
researchers analyzed the incidence, risk factors, and causes of nonrelapse deaths among limus/methotrexate, but those patients
patients enrolled in 2 prospective, longitudinal observational trials conducted through treated with CD34-positive–selected
the Chronic GVHD Consortium (Abstract 83). Among 937 patients with chronic GVHD peripheral blood stem cell grafts
requiring new systemic treatment, 54% were incident chronic GVHD cases (occurring had lower overall survival owing to
3 months after increased transplant-related mortality.
diagnosis). The patients’ median age was 52 years (range, 18-78 years), and 50% of
patients had previously developed grade 2 to 4 acute GVHD. At a median follow-up of 4 References
years, there were 333 deaths. Causes of death included chronic GVHD in 37.8%, relapse 1. Solomon SR, Sanacore M, Zhang X, et al. Calcineu-
in 25.0%, infection in 16.9%, and respiratory failure in 9.6%. In a multivariate analysis, rin inhibitor–free graft-versus-host disease prophylaxis
with post-transplantation cyclophosphamide and brief-
nonrelapse mortality was significantly associated with the use of reduced-intensity con- course sirolimus following reduced-intensity peripheral
ditioning, bilirubin levels higher than 2 mg/dL at study enrollment, moderate-to-severe blood stem cell transplantation. Biol Blood Marrow
involvement of the skin or lungs at enrollment, worse physical functioning score, and Transplant. 2014;20(11):1828-1834.
2. Barba P, Hilden P, Devlin SM, et al. Ex vivo CD34+-
decreased walk test distance. selected T cell-depleted peripheral blood stem cell grafts
for allogeneic hematopoietic stem cell transplantation
in acute leukemia and myelodysplastic syndrome is
associated with low incidence of acute and chronic
cyclophosphamide vs control, P=.09). vs the control). graft-versus-host disease and high treatment response.
The 2-year rates of grade 2/3 infection The study investigators concluded Biol Blood Marrow Transplant. 2017;23(3):452-458.
3. Pasquini MC, Luznik L, Logan B, et al. Calcineurin
were 69.2% for the CD34-positive that neither of the calcineurin inhibi- inhibitor-free graft-versus-host disease (GVHD) pro-
arm, 60.6% for the cyclophosphamide tor–free strategies were superior to phylaxis in hematopoietic cell transplantation (HCT)
arm, and 43.9% for the control arm tacrolimus/methotrexate in terms of with myeloablative conditioning regimens (MAC) and
HLA-matched donors: results of the BMT CTN 1301
(P=.0006 for either experimental arm the primary endpoint, CRFS.3 Rates Progress II trial [TCT abstract LBA1]. Transplant Cell
Ther. 2021;27(3 suppl).
Ruxolitinib for the Treatment of Chronic GVHD and Overlap
Syndrome in Children and Young Adults
I
n chronic GVHD, the JAK 1/2 concurrent triazole antifungal therapy. (n=6). Four patients had involvement
inhibitor ruxolitinib is approved Doses increased to a maximum of 10 of a single organ. Four patients had
by the US Food and Drug Admin- mg twice daily as tolerated. Responses overlap syndrome. Sixteen patients
istration for the treatment of adults.1 were evaluated using the 2014 NIH were receiving daily prednisone at a
Experience in children younger than consensus panel response criteria. Two median dose of 0.5 mg/kg/day (range,
12 years is limited. Dr YunZu Michele hours after administration of ruxoli- 0.08-1.5 mg/kg/day) at the time of
Wang described a pediatric dosing tinib, phosphorylation of STAT5 on ruxolitinib initiation. The median time
strategy for the use of ruxolitinib in lymphocytes was evaluated in a subset from diagnosis of chronic GVHD to
children with chronic GVHD.2 This of patients using flow cytometry as a initiation of ruxolitinib was 181 days
retrospective chart review examined surrogate of JAK/STAT5 inhibition. A (range, 17-1792 days). The median
data from 20 patients (median age, lower percentage of phosphorylation dose of ruxolitinib at initiation was
14.6 years; range, 5-26 years) who indicated greater inhibition. 5 mg daily (range, 2.5-10 mg daily).
received ruxolitinib orally, either at Among the 20 patients enrolled, Eleven patients were receiving concur-
5 mg twice daily for children who chronic GVHD was severe in 10, rent triazoles at the time of ruxolitinib
weighed 25 kg or more or 2.5 mg moderate in 9, and mild in 1.2 The initiation and began treatment at
twice daily for those who weighed less most common organs involved were a 50% dose reduction. Six patients
than 25 kg. The dose was halved at the skin (n=17), eyes (n=8), mouth received the maximal daily dose of 20
the study start in patients treated with (n=6), and gastrointestinal (GI) system mg (Figure 4).
Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021 9SPECIAL MEETING REVIEW EDITION
Phosphorylation of STAT5 on
lymphocytes was absent or decreased
15
2 hours after ruxolitinib in 5 of 6
Number of Patients
evaluated patients, which suggests
adequate JAK inhibition in the pedi- 10
atric population.2 The ORR was 70%.
Two patients with moderate cases of
chronic GVHD manifesting in the
skin achieved a complete response at 86 5
and 311 days after starting ruxolitinib,
respectively. Twelve patients achieved
a partial response, at a median of 48
days (range, 18-120 days) from the 0
first ruxolitinib dose, including 2 of 0 5 10 15 20 25
the patients with overlap syndrome at
baseline. Among the patients without
Ruxolitinib (mg)
a response to treatment, 1 had stable Figure 4. Maximum daily dose of ruxolitinib among children and young adults treated
disease and 5 had progressive disease. for chronic graft-vs-host disease and overlap syndrome. Adapted from Wang Y et al. TCT
Organs that showed responses to rux- abstract 298. Transplant Cell Ther. 2021;27(3 suppl).2
olitinib included the skin, joints, GI
tract, liver, and muscle. All 7 patients
with sclerotic-type chronic GVHD of were maintained at a median of 411 ing strategy for ruxolitinib in this study
the skin had responses to ruxolitinib. days (range, 84-1127 days) from the was safely tolerated and demonstrated
Among the 3 patients with lung initiation of ruxolitinib. promise for treating chronic GVHD
involvement, pulmonary function tests All patients developed AEs. Rux- in children.
stabilized in 2. Sixteen of the patients olitinib was discontinued in 3 patients,
were receiving corticosteroids at the owing to 1 case each of neutropenia, References
time of enrollment. During the study thrombocytopenia, and elevated ala- 1. Jagasia M, Zeiser R, Arbushites M, Delaite P,
Gadbaw B, Bubnoff NV. Ruxolitinib for the treat-
period, 13 of these patients were able nine aminotransferase. No patients ment of patients with steroid-refractory GVHD: an
to discontinue corticosteroid treatment developed fungal infections or pneu- introduction to the REACH trials. Immunotherapy.
or were in the process of doing so. Nine mocystis pneumonia. Two patients 2018;10(5):391-402.
2. Wang Y, Teusink-Cross A, Myers K, et al. Ruxoli-
of the 12 patients with a response were died from complications of progressive tinib for the treatment of chronic GVHD and overlap
continuing treatment with ruxolitinib severe chronic GVHD. The investiga- syndrome in children and young adults [TCT abstract
at the time of the report. The responses tors concluded that the pediatric dos- 298]. Transplant Cell Ther. 2021;27(3 suppl).
Phase I Study De-Intensifying Exposure of Post-Transplantation
Cyclophosphamide After HLA-Haploidentical Hematopoietic Cell
Transplantation for Hematologic Malignancies
T
he standard dosage (50 mg/ given on day +4 was equivalent to 25 fludarabine, HLA-haploidentical bone
kg/day) and timing (days mg/kg/day on days +3/+4.2,3 marrow, and GVHD prophylaxis with
+3/+4) of cyclophosphamide Dr Meredith Jo McAdams pre- cyclophosphamide. The first 5 patients
after HLA-haploidentical HCT were sented data from a phase 1 dose de- received cyclophosphamide at 50 mg/
largely extrapolated from murine skin escalation study of cyclophosphamide.4 kg/day on days +3/+4 for comparative
allografting models.1 In murine HCT, The study enrolled 19 patients ages 21 data (dose level 1), followed by a 3+3
studies have demonstrated that 25 mg/ to 47 years; 50% had a disease risk dose de-escalation to 25 mg/kg/day
kg/day was superior to 50 mg/kg/day index of high or very high. The patients on days +3/+4 (dose level 2; n=7) and
on days +3/+4 at preventing GVHD, underwent myeloablative condition- then 25 mg/kg on day +4 only (dose
and that a single dose of 25 mg/kg ing with daily intravenous busulfan/ level 3; n=7). Then all patients received
10 Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021H I G H L I G H T S I N G R A F T- V S - H O S T D I S E A S E F R O M T H E 2 0 2 1 T C T M E E T I N G S
4
Maximal Grade
3
PTCy 50 mg/kg/day on days +3/+4
2 PTCy 25 mg/kg/day on days +3/+4
PTCy 25 mg/kg on day +4
1
0
ly
+4
+4
on
/
/
+3
+3
4
y+
ys
ys
da
da
da
n
n
on
o
o
ay
ay
kg
/d
/d
g/
kg
kg
m
g/
g/
25
m
m
50
25
Figure 5. The maximum grade of severe acute graft-vs-host disease among patients in a phase 1 study that evaluated de-intensifying exposure
of post-transplant cyclophosphamide after HLA-haploidentical hematopoietic cell transplant. HLA, human leukocyte antigen; PTCy, post-
transplant cyclophosphamide. Adapted from McAdams MJ et al. TCT abstract 11. Transplant Cell Ther. 2021;27(3 suppl).4
mycophenolate mofetil (days +5 to was 294 days (range, 40-473 days).4 2 patients developed maximal grade 1
+35) and sirolimus (days +5 to +80). No patients at dose levels 2 or 3 devel- acute GVHD and 1 developed maxi-
The primary endpoint was to evaluate oped grade 3 or 4 acute GVHD (Fig- mal grade 2 acute GVHD. Neutrophil
whether lower doses of post-transplant ure 5), whereas 1 patient at dose level and platelet engraftment occurred
cyclophosphamide could prevent cases 1 developed grade 4 disease. At dose more quickly at dose levels 2 and 3
of severe, acute GVHD. level 2, 1 patient developed maximal compared with dose level 1.
The median duration of follow-up grade 1 acute GVHD. At dose level 3, Poor graft function was seen in 1
patient at dose level 1. Primary graft
failure occurred in 1 patient at dose
ABSTRACT SUMMARY Comparable Outcomes for Matched and level 2. Relapse before engraftment
Mismatched Unrelated Donor Transplantation With the Addition of occurred in 1 patient at dose level 3.
Abatacept to Standard Graft-Versus-Host Disease Prophylaxis Two patients at dose level 3 devel-
oped engraftment syndrome, which
The multicenter ABA2 trial demonstrated that triple therapy with abatacept plus a resolved rapidly without therapy in
calcineurin inhibitor and methotrexate is more effective for acute GVHD prophylaxis both cases. Split chimerism (100%
than a calcineurin inhibitor plus methotrexate alone, while maintaining an acceptable donor myeloid; 0%-6% donor T-cell)
safety profile. The original trial enrolled 112 patients ages 6 years and older who had was reported in 1 patient treated at
hematologic malignancies and received an unrelated donor HCT (Watkins B et al. J Clin dose level 2 and 1 patient treated at
Oncol. doi:10.1200/JCO.20.01086). Abatacept at 10 mg/kg was administered on days dose level 3; the latter patient required
–1, 5, 14, and 28. A secondary analysis of the ABA2 trial compared outcomes from 43 a second HCT. Mucositis appeared to
patients who received triple therapy and had a 7/8 HLA donor with those from a control be less severe and shorter in duration
group of 69 patients who received a calcineurin inhibitor plus methotrexate only (plus with lower cyclophosphamide dosing.
placebo) and had an 8/8 HLA donor (Abstract 33). The cumulative incidence of grade 3 Fevers within the first month post-
to 4 acute GVHD at day 180 was significantly lower in the triple therapy (7/8 HLA) group HCT were not substantially different
than in the control (8/8 HLA) group (2.3% vs 14.8%, P=.03). With a median follow-up of at dose level 2 compared with dose
25 months in survivors, the 2-year event-free survival rate was 74.0% with triple therapy level 1, but they were higher and more
(7/8 HLA) vs 60.3% with control therapy (8/8 HLA) (P=.08). A multicenter, randomized protracted at dose level 3.
controlled trial (ABA3) is opening to determine whether outcomes with 7/8 HLA can be The study investigators concluded
further improved by lengthening abatacept coverage. that de-escalation of cyclophospha-
mide dosing after HLA-haploidentical
Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021 11SPECIAL MEETING REVIEW EDITION
HCT appears feasible and effective in are needed to confirm whether this cyclophosphamide prevents graft-versus-host disease by
inducing alloreactive T cell dysfunction and suppres-
maintaining protection against severe strategy is superior to the current dos- sion. J Clin Invest. 2019;129(6):2357-2373.
acute GVHD, while promoting more ing schedule. 3. Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon
rapid engraftment and less early post- DJ, Kanakry CG. Optimized timing of post-trans-
plantation cyclophosphamide in MHC-haploidentical
transplant toxicity.4 Further studies References murine hematopoietic cell transplantation. Biol Blood
across larger cohorts of patients, as 1. Mayumi H, Good RA. Long-lasting skin allograft Marrow Transplant. 2020;26(2):230-241.
tolerance in adult mice induced across fully allogeneic 4. McAdams MJ, Dimitrova D, Sadler J, et al. Phase I
well as longer follow-up studies of (multimajor H-2 plus multiminor histocompatibility) study de-intensifying exposure of post-transplantation
the impact of de-escalated cyclophos- antigen barriers by a tolerance-inducing method using cyclophosphamide (PTCy) after HLA-haploidentical
phamide on immune reconstitution, cyclophosphamide. J Exp Med. 1989;169(1):213-238. hematopoietic cell transplantation (HCT) for hemato-
2. Wachsmuth LP, Patterson MT, Eckhaus MA, Ven- logic malignancies [TCT abstract 11]. Transplant Cell
chronic GVHD, relapse, and survival, zon DJ, Gress RE, Kanakry CG. Post-transplantation Ther. 2021;27(3 suppl).
Preliminary Safety and Efficacy of Itolizumab, a Novel Targeted Anti-
CD6 Therapy, in Newly Diagnosed Severe Acute Graft-Versus-Host
Disease: Interim Results From the EQUATE Study
C
D6 is a co-stimulatory recep- studies in patients receiving alloHCT Dr John Koreth presented interim
tor predominantly expressed showed that ex vivo depletion of donor study results from EQUATE, an ongo-
on T cells that acts as a cru- CD6-positive T cells lowered the inci- ing phase 1b/2 study of itolizumab in
cial regulator of T-cell activation and dence of acute GVHD, providing a combination with corticosteroids for
is implicated in the pathogenesis of rationale for therapeutically targeting newly diagnosed severe acute GVHD
multiple autoimmune diseases. Acti- CD6 in acute GVHD.3 Itolizumab, (grade 3-4) after first alloHCT.5 The
vated leukocyte cell adhesion molecule a humanized immunoglobulin G1 phase 1b portion is an open-label,
(ALCAM), a CD6 ligand, is expressed monoclonal antibody undergoing eval- 3+3 dose-escalation study evaluating
on antigen-presenting cells, as well uation as treatment for acute GVHD, doses of 0.4, 0.8, 1.6, and 2.4 mg/kg
as epithelial and endothelial cells of binds CD6 and blocks interaction administered intravenously every 2
acute GVHD target organs, including with ALCAM to inhibit T-cell activity weeks through day 57. As of Novem-
the skin and the GI tract.1,2 Previous and trafficking.4 ber 13, 2020, 10 patients completed
Figure 6. Changes from
baseline in the use of systemic 0
% Change From Baseline
corticosteroids among patients
with newly diagnosed severe
acute graft-vs-host disease who –20
received itolizumab in the phase
in Total Dose
1b/2 EQUATE study. Adapted
from Koreth J et al. TCT abstract –40
LBA4. Transplant Cell Ther.
2021;27(3 suppl).5
–60
–80
–100
1 15 29 43 57 85
Day
12 Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021H I G H L I G H T S I N G R A F T- V S - H O S T D I S E A S E F R O M T H E 2 0 2 1 T C T M E E T I N G S
treatment: 4 with 0.4 mg/kg, 3 with respectively (Figure 6). Itolizumab References
0.8 mg/kg, and 3 with 1.6 mg/kg. All decreased the CD6 levels on T cells in 1. Consuegra-Fernández M, Julià M, Martínez-
Florensa M, et al. Genetic and experimental evidence
patients received corticosteroids at an a dose-dependent manner within 24 for the involvement of the CD6 lymphocyte receptor
initial dose of 1 to 2 mg/kg/day. Their hours of the first dose, a reduction that in psoriasis. Cell Mol Immunol. 2018;15(10):898-906.
mean age was 48 years (standard devia- was maintained throughout the treat- 2. Ma C, Wu W, Lin R, et al. Critical role of
CD6highCD4+ T cells in driving Th1/Th17 cell
tion, 15.7 years), 90% were male, and ment period. immune responses and mucosal inflammation in IBD.
90% were white. The graft source was Across the dosing cohorts, all J Crohns Colitis. 2019;13(4):510-524.
peripheral blood for 80% and bone patients developed at least 1 AE. Most 3. Soiffer RJ, Weller E, Alyea EP, et al. CD6+ donor
marrow T-cell depletion as the sole form of graft-versus-
marrow for 20%, and 80% had an AEs were mild to moderate in severity.5 host disease prophylaxis in patients undergoing alloge-
HLA-matched donor. The mean time The most common AEs were hypomag- neic bone marrow transplant from unrelated donors. J
to onset of GVHD was 43 days, and nesemia (n=3) and peripheral edema Clin Oncol. 2001;19(4):1152-1159.
4. Bughani U, Saha A, Kuriakose A, et al. T cell
100% of patients had GI involvement. (n=3). One mild infusion reaction was activation and differentiation is modulated by a
At day 57, the ORR was 50% with noted. Six patients had serious AEs, CD6 domain 1 antibody itolizumab. PLoS One.
0.4 mg/kg, 100% with 0.8 mg/kg, and including recurrent GVHD (n=1), 2017;12(7):e0180088.
5. Koreth J, Loren AW, Nakamura R, et al. Preliminary
100% with 1.6 mg/kg.5 The median sepsis (n=2; 1 event was considered a safety and efficacy of itolizumab, a novel targeted anti-
percent corticosteroid dose reduction dose-limiting toxicity), fever (n=1), CD6 therapy, in newly diagnosed severe acute graft-
at day 85 was 93%, 87%, and 91% COVID-19 (n=1), and disseminated versus-host disease: interim results from the EQUATE
study [TCT abstract LBA4]. Transplant Cell Ther.
for the 0.4, 0.8, and 1.6 mg/kg groups, nocardia (n=1). 2021;27(3 suppl).
Durable Discontinuation of Immunosuppressive Therapy: Clinical
Results From the Chronic GvHD Consortium
S
uccessful treatment of chronic tion of immunosuppressive therapy During the median follow-up
GVHD often requires long-term was defined as cessation of all immu- of 95.3 months (range, 11.3-181.5
use of systemic immunosuppres- nosuppressive therapy for at least 12 months), 33% (95% CI, 28%-37%)
sive agents, which can impair immune months. Data for patients who discon- of patients were able to discontinue
function, increase the risk of oppor- tinued immunosuppressive therapy for immunosuppressive therapy for 12 or
tunistic infections, and confer a high less than 12 months were censored. more months (Figure 7).3 In the multi-
toxicity burden. Among patients stop- Immunosuppressive therapy that was variate analysis controlling for clinical
ping immunosuppressive therapy for stopped and then restarted before 12 and patient-reported variables, durable
the first time, approximately 50% will months had elapsed was considered immunosuppressive therapy discontin-
need to resume therapy, after a median continuous therapy. uation was less likely in patients who
of 3 months.1 Therefore, durable dis- The patients’ median age was 51.9 received myeloablative conditioning,
continuation of immunosuppressive years (range, 18.0-78.0 years). The had a platelet count of 100,000/μL
therapy may represent a true cure. Prior donor type was HLA-matched related or higher, had moderate/severe lower
studies of immunosuppressive therapy for 37.6%, HLA-matched unrelated GI involvement, and had a higher
discontinuation reported long-term for 44.7%, and other in 18%. The (worse) Lee symptom overall score. In
rates between 27% and 68%.1,2 This transplant source was peripheral blood contrast, mild lower GI involvement
variation might be explained by dif- for 89%, bone marrow for 6.6%, and and cord blood (vs peripheral blood)
ferences in the population, treatment, cord blood for 4.4%. The severity of as a graft source were associated with
and graft sources, among other factors. chronic GVHD was mild for 15.2%, a greater likelihood of immunosup-
Dr George L. Chen reported moderate for 51.2%, and severe for pressive therapy discontinuation. In a
the results of a retrospective analysis 32.2%. The median time from allo- second analysis including NIH overall
of factors associated with durable HCT to chronic GVHD diagnosis chronic GVHD severity, patients with
discontinuation of immunosuppres- was 7.7 months (range, 1.0-141.3 severe disease were less likely to attain
sive therapy.3 The data were drawn months), and the median time from durable discontinuation (HR, 0.53;
from 2 prospectively followed cohorts chronic GVHD onset to enrollment 95% CI, 0.31-0.90; P=.02).
from the Chronic GVHD Consor- was 0.9 months (range, 0.0-12.0 The investigators noted that most
tium (n=684). Durable discontinua- months). patients in this study with chronic
Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021 13SPECIAL MEETING REVIEW EDITION
Figure 7. Results in a
retrospective analysis evaluating 1.0 0.0
durable discontinuation of
immunosuppressive therapy 0.9 0.1
in cohorts from the Chronic
GVHD Consortium. Adapted 0.8 0.2
Cumulative Incidence Estimate
from Chen GL et al. TCT
abstract 8. Transplant Cell Ther. 0.7 Death or relapse 0.3
2021;27(3 suppl).3
0.6 0.4
0.5 On therapy or off forH I G H L I G H T S I N G R A F T- V S - H O S T D I S E A S E F R O M T H E 2 0 2 1 T C T M E E T I N G S
Figure 8. Duration
of response in the 1.0
ROCKstar trial of
belumosudil at different
doses in patients with
Duration of Response (probability)
0.8
previously treated
chronic graft-vs-host
disease. BID, twice 0.6
daily; QD, once daily.
Adapted from Cutler
C et al. TCT abstract 0.4
9. Transplant Cell Ther.
Belumosudil 200 mg QD
2021;27(3 suppl).4 Belumosudil 200 mg BID
0.2 Overall
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88
Weeks
Number at Risk
Belumosudil 200 mg QD 48 43 37 31 31 29 26 24 21 20 17 15 11 10 6 5 5 3 1 1 1 1 0
Belumosudil 200 mg BID 51 48 44 41 35 30 28 21 19 16 15 15 14 11 9 7 5 4 3 2 2 1 0
Overall 99 91 81 72 66 59 54 45 40 36 32 30 25 21 15 12 10 7 4 3 3 2 0
response criteria, as assessed by the complete response was reported in 7 reported in 21% and 64% of patients,
investigators. Additional endpoints patients.4 The responses were consis- respectively.
included duration of response, failure- tent across key subgroups. The median The most common grade 3/4
free survival, improvement in the duration of response for both groups AEs were pneumonia (9% in the
mLSS of at least 7 points from baseline, pooled was 50 weeks. At 12 months, daily group vs 6% in the twice daily
and corticosteroid dose reductions or the median failure-free survival for group), hypertension (6% in both
discontinuations. both groups pooled was 58% (Figure groups), and hyperglycemia (5% in
The ORR was 73% (95% CI, 8). Improvement in the mLSS of at both groups).4 Eight patients died dur-
60%-83%; PSPECIAL MEETING REVIEW EDITION
Health Care Resource Utilization and Costs of Steroid-Related
Complications in Patients With Graft-Versus-Host Disease
C
orticosteroids are often pre- resource utilization and costs associ- tion (80%) and events involving the
scribed to treat GVHD. How- ated with corticosteroid complications metabolic/endocrine system (32%),
ever, the prevalence, health during the 24 months after corticoste- the GI tract (29%), or bone/muscle
care resource utilization, and costs of roid initiation were calculated, accord- (20%). Among patients with at least 1
corticosteroid-associated complications ing to International Classification of corticosteroid complication, the mean
are not well quantified. Dr Elizabeth Diseases codes for any corticosteroid and median costs associated with cor-
J. Bell described the results of a ret- complication in position 1 or 2 on the ticosteroid complications throughout
rospective cohort study that analyzed claims. Corticosteroid complications the 24 months from corticosteroid
the health care resource utilization and related to the bone/muscle, GI tract, initiation were $164,787 and $50,834,
costs of complications from cortico- infections, and metabolic/endocrine respectively (Figure 9). The mean
steroid use in patients with GVHD.1 system were also described, based on and median costs in the 408 patients
The investigators reviewed the Optum their clinical relevance. treated with corticosteroids for 3
Research Database to identify patients This study included 689 patients.1 months or more were $171,434 and
in the United States with a diagnosis Their median age was 55 years (stan- $56,542, respectively. In those who
of GVHD who received systemic dard deviation, 18 years), and 60% had only acute GVHD (n=146), the
corticosteroids between July 1, 2010 were male. The median length of cor- mean and median costs were $183,944
and August 31, 2019 and who were ticosteroid use during the 24 months and $46,093, whereas in those with
insured with commercial insurance after corticosteroid initiation was 126 chronic GVHD (n=142), these costs
plans or Medicare Advantage plans. days (range, 52 to 273 days). Overall, were $113,199 and $34,285, respec-
Patients with a baseline diagnosis of 97% of patients developed at least 1 tively. Costs were driven primarily by
GVHD were included. Health care type of complication, including infec- hospitalizations (Figure 10).
$164,787 $167,473
180,000 Ambulatory
($50,834) ($57,680)
Emergency
160,000 $6355 $6985
Hospitalizations
$13,430 $15,075
Pharmacy
140,000
Other medical costs
Cost, Mean (median), $
120,000
$75,289
100,000 $67,861 ($2057)
($3360)
$2,319
80,000 $47,101 $344 $603
$140,637 $143,299 ($1164) $609
60,000 $36
$1501
40,000 $69.880
$64,077
$136 $35
20,000 $45,077 $23 $29
$152
$2802
$1978 $464 $2452
0 $4213
Any Complications Infection Metabolic or Gastrointestinal Bone or Muscle
(N=665) (n=548) Endocrine Condition Condition Condition
(n=223) (n=201) (n=136)
Figure 9. Health care costs related to corticosteroid complications among patients with graft-vs-host disease. Costs are shown during the 2
years after corticosteroid initiation for patients with at least 1 complication. Adapted from Bell EJ et al. TCT abstract 12. Transplant Cell Ther.
2021;27(3 suppl).1
16 Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021H I G H L I G H T S I N G R A F T- V S - H O S T D I S E A S E F R O M T H E 2 0 2 1 T C T M E E T I N G S
Figure 10. Reasons for
hospitalizations related
to corticosteroids during Infection (n=548) 72 (395/548)
the 2 years after treatment
initiation among patients
with graft-vs-host disease.
Adapted from Bell EJ Gastrointestinal (n=201) 33 (67/201)
et al. TCT abstract 12.
Transplant Cell Ther.
2021;27(3 suppl).1 Bone or muscle (n=136) 29 (40/136)
Metabolic or endocrine (n=223) 26 (57/223)
Any complications (N=665) 66 (437/665)
0 25 50 75 100
Patients With ≥1 Hospitalization (%) (n/N)
The study investigators concluded and costs than chronic GVHD. A aspects of the complications, including
that there are substantial health care limitation to this study is that some severity and suspected causality.
resource utilization and costs associ- conditions were present at baseline,
ated with corticosteroid-related com- and worsening of these conditions Reference
plications in patients with GVHD.1 after corticosteroid initiation could not 1. Bell EJ, Yu J, Bhatt V, et al. Healthcare resource
utilization and costs of steroid-related complications
Acute GVHD was associated with be accurately identified. Future studies in patients with graft versus host disease [TCT abstract
higher health care resource utilization will be needed to elucidate the clinical 12]. Transplant Cell Ther. 2021;27(3 suppl).
Secondary Graft-Versus-Host Disease Prophylaxis With Oral
Proteasome Inhibitor Ixazomib Is Associated With Low Incidence of
Recurrent, Late Acute, and Chronic GVHD and Facilitated Calcineurin
Inhibitor Taper Within the First Year Post-Allogeneic Stem Cell
Transplantation
R
ecipients of reduced-intensity data from an open-label, prospective, HCT between 100 and 150 days prior
and nonmyeloablative con- single-center pilot study of ixazomib to enrollment, and did not have active
ditioning with calcineurin for secondary GVHD prophylaxis and acute or chronic GVHD.2 Patients
inhibitor–based prophylaxis often facilitation of calcineurin inhibitor received ixazomib at 4 mg orally once
develop GVHD during tapering of taper.2 weekly administered in a 3 weeks on,
immunosuppression drugs. Ixazomib Eligible patients had a hemato- 1 week off schedule. The treatment
is an oral proteasome inhibitor with logic malignancy treated with reduced was continued for 1 year or until the
immunomodulatory properties that intensity or non-myeloablative allo- prophylactic calcineurin inhibitor was
has a tolerable safety profile.1 Natasia HCT and calcineurin inhibitor–based completely tapered, whichever came
T. Rodriguez, BSN, RN, presented GVHD prophylaxis, had undergone first. The primary endpoint was the
Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021 17SPECIAL MEETING REVIEW EDITION
1.00
Grade 2-4 aGVHD/cGVHD
Cumulative Incidence of
0.75
0.50
0.25
33.31% (95% CI, 10.94-57.9)
0.00
0 (4.5) 2 (6.5) 4 (8.5) 6 (10.5) 8 (12.5)
Months Post-Enrollment (months post-HSC)
Figure 11. The cumulative incidence of grade 2 to 4 acute and chronic GVHD at 1 year after HCT in patients treated with ixazomib
prophylaxis. aGVHD, acute graft-vs-host disease; cGVHD, chronic graft-vs-host disease; HCT, hematopoietic stem cell transplant. Adapted
from Rodriguez NT et al. TCT abstract 84. Transplant Cell Ther. 2021;27(3 suppl).2
efficacy of ixazomib for the preven- post-HCT, the cumulative incidence of (n=5), decreased lymphocyte count
tion of recurrent or late grade 2 to 4 grade 2 to 4 acute and chronic GVHD (n=2), anemia (n=1), and rash (n=1).
acute GVHD or chronic GVHD at 1 was 33.3% (95% CI, 10.95%-57.9%; Seven patients required a dose reduc-
year post-HCT. Additional endpoints Figure 11). No patients died during tion of ixazomib owing to side effects,
included treatment-related mortality, the study. The incidence of relapse was and 5 patients left the study owing to
relapse rate, survival analysis, safety, low; 1 patient who discontinued ixazo- toxicity.
and immune reconstitution. mib early relapsed with low-grade fol-
The trial enrolled 18 patients.2 licular lymphoma that did not require References
Their median age was 58 years (range, therapy. 1. Chhabra S, Visotcky A, Pasquini MC, et al. Ixazomib
for chronic graft-versus-host disease prophylaxis follow-
45-69 years). Most patients (89%) Progression-free survival at 1 year ing allogeneic hematopoietic cell transplantation. Biol
were male. All patients had received a was 88% (95% CI, 67%-100%), and Blood Marrow Transplant. 2020;26(10):1876-1885.
peripheral blood stem cell graft, and GVHD-free/relapse-free survival at 1 2. Rodriguez NT, Lee J, Flynn L, et al. Secondary graft-
versus-host disease (GVHD) prophylaxis with oral
16 of the patients (89%) were 10/10 year was 77% (95% CI, 56%-100%).2 proteasome inhibitor ixazomib is associated with low
HLA-matched. Four patients devel- There was a rapid and sustained incidence of recurrent, late acute and chronic GVHD
oped GVHD, and had either severe recovery in T-cell subpopulations and and facilitated calcineurin inhibitor taper within the
first year post allogeneic stem cell transplantation [TCT
overlap syndrome (n=2), mild de novo B-cell reconstitution at 3, 6, and 12 abstract 84]. Transplant Cell Ther. 2021;27(3 suppl).
chronic GVHD (n=1), or recurrent months post-HCT. Grade 3/4 AEs
grade 2 acute GVHD (n=1). At 1 year included decreased neutrophil count
18 Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021H I G H L I G H T S I N G R A F T- V S - H O S T D I S E A S E F R O M T H E 2 0 2 1 T C T M E E T I N G S
Highlights in Graft-vs-Host Disease From the 2021 Transplantation
& Cellular Therapy (TCT) Meetings of the ASTCT and the CIBMTR:
Commentary
Yi-Bin Chen, MD
Director, Hematopoietic Cell Transplant & Cellular Therapy Program
Cara J. Rogers Endowed Scholar
Division of Hematology/Oncology
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
S
everal interesting abstracts on tion of GVHD, possibly as a platform Based on these results, it appears
graft-vs-host disease (GVHD) to deliver maintenance therapy or that tacrolimus/MTX remains the
were presented at the 2021 cellular therapy to decrease the risk standard of care in this setting,
Transplantation & Cellular Therapy of disease relapse. The trial randomly although post-transplant cyclophos-
(TCT) meetings, which were the assigned patients (≤65 years) under- phamide alone appears to be a reason-
combined, all-virtual annual meetings going myeloablative transplant to 3 able alternative. Notably, in routine
of the American Society for Trans- different platforms to prevent graft- practice, post-transplant cyclophos-
plantation and Cellular Therapy and vs-host-disease. The control arm con- phamide is usually given with tacro-
the Center for International Blood & sisted of tacrolimus and methotrexate limus and mycophenolate, and one
Marrow Transplant Research. There (MTX) with a bone marrow graft wonders if the inclusion of these
were studies with implications for cur- source. The second arm evaluated other agents would have significantly
rent clinical practice, as well as future a bone marrow graft source with changed the observed results.
research, in both acute and chronic post-transplant high-dose cyclophos- Dr Muna Qayed presented data
GVHD. phamide given on days 3 and 4 after from a subanalysis of the ABA2 trial.2
transplant. Treatment in the third arm The ABA clinical trials are studying
Prevention of GVHD consisted of ex vivo T-cell depletion the role of abatacept, which is a co-
Historically, prevention of GVHD using CD34-selected peripheral blood stimulatory inhibitor, for the preven-
has focused on acute GVHD, given stem cells. tion of GVHD. The ABA2 trial had
the timing of presentation and early The study used an interesting 2 arms and enrolled patients with
effects on long-term outcomes. How- primary endpoint of chronic GVHD- fully matched donors (8/8 human
ever, clinical research has recently free and relapse-free survival, which leukocyte antigen [HLA]-matched),
emphasized the prevention of chronic was referred to as CRFS.1 The analysis as well as patients with single-antigen
GVHD as an increasingly important showed that there was no statistically mismatched, unrelated donors (7/8
outcome. This shift is emphasized in significant difference in the primary HLA-matched). The trial compared
the composite primary endpoints of endpoint among the 3 treatment standard treatment with a calcineurin
several recent major clinical trials. arms. A key secondary endpoint was inhibitor (CNI) plus MTX vs CNI/
The phase 3 Blood and Marrow overall survival, and participants who MTX with the addition of abatacept.
Transplant Clinical Trials Network received T-cell depletion had a lower Previously published results from the
(BMT CTN) 1301 PROGRESS II overall survival of 75.7% at 1 year, ABA2 trial suggested that the addi-
trial enrolled patients who had compared with approximately 84% tion of abatacept improved outcomes,
received myeloablative, fully matched in the other 2 arms, which was mostly especially in patients receiving grafts
transplants from a related or unrelated driven by an increase in transplant- from 7/8 matched, unrelated donors.3
donor.1 The motivation behind this related mortality. It should be noted This secondary analysis of the ABA2
trial was to develop a calcineurin that chronic GVHD was significantly data compared the outcomes of these
inhibitor–free regimen for the preven- reduced in the T-cell depleted arm. 7/8 patients, who received a CNI
Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021 19SPECIAL MEETING REVIEW EDITION
with MTX plus abatacept, to the fully based regimens for these patients. It based regimens.
matched 8/8 patients treated with would be an important advance to The study by Dr McAdams exam-
CNI/MTX on the ABA2 trial. The have data from large clinical trials in ined whether the dose of cyclophos-
primary endpoint was the incidence this group of patients to determine the phamide could be safely reduced.5
of severe acute (overall, grades 3-4) standard of care. These investigators showed in murine
GVHD at 6 months. The incidence Dr Meredith McAdams presented models that 50 mg/kg was not abso-
was strikingly lower in the patients data from a phase 1 study that evalu- lutely necessary; instead, 25 mg/kg
who received abatacept, at 2.3%, vs ated de-intensified exposure to post- given only on day 4 seemed to confer
14.8% in the 8/8 CNI/MTX arm. transplant cyclophosphamide given equivalent efficacy.6,7 This phase 1
There were no significant differences after HLA haploidentical hematopoi- study followed a dose de-escalation
in other outcomes, such as chronic etic cell transplant.5 Post-transplant design to test this hypothesis. All of
GVHD or overall transplant-related high-dose cyclophosphamide-based the patients received a myeloablative
mortality. However, the decrease in regimens have emerged as the stan- conditioning regimen, followed by a
severe acute GVHD was quite com- dard of care for patients undergoing haploidentical bone marrow graft, and
pelling, with trends toward better haploidentical and mismatched, unre- then GVHD prophylaxis consisting
progression-free survival and overall lated donor transplants. As mentioned of post-transplant cyclophosphamide,
survival in the patients who received above, this platform is also being stud- sirolimus, and mycophenolate. The
abatacept. ied in the setting of transplants from dose of cyclophosphamide was then
These results lay the groundwork fully matched and mismatched unre- successively lowered in the different
for the ongoing ABA3 trial, which lated donor transplants. Historically, cohorts. The first 5 patients received
is focusing on patients receiving 7/8 post-transplant cyclophosphamide is the standard 50 mg/kg/day on both
matched grafts to confirm whether administered at a dose of 50 mg/kg/ days 3 and 4. The next cohort received
the addition of abatacept can improve day given on days 3 and 4 after trans- 25 mg/kg/day on both days, followed
outcomes.4 Currently, there is no plant. Although this schedule appears by a third cohort that received 25 mg/
standard of care for these patients. to successfully prevent GVHD, it is kg only on day +4.
Historically, treatment had included associated with toxicities, such as acute Impressively, none of the 11
the addition of polyclonal antithymo- fluid shifts, electrolyte abnormalities, patients in the dose de-escalated
cyte globulins. More recently, many and cardiac events, and it also appears cohorts developed grade 3 to 4 acute
clinicians have shifted toward the use to significantly delay engraftment GVHD. Although the number of
of post-transplant cyclophosphamide- compared with conventional CNI- patients in this phase 1 trial was small,
the results are compelling. In addi-
tion, engraftment of neutrophils and
platelets appeared to be faster among
ABSTRACT SUMMARY Orca-T, a Precision Treg-Engineered Donor patients receiving lower doses of cyclo-
Product, in Myeloablative HLA-Matched Transplantation Prevents phosphamide. However, some patients
Acute GVHD With Less Immunosuppression in an Early Multicenter in the dose de-escalated cohorts had
Experience significant delays in assuming full
donor chimerism. Moving forward,
Infusion of donor-derived high-purity regulatory T cells preceding adoptive transfer of
as post-transplant cyclophosphamide–
conventional T cells may prevent GVHD while maintaining anticancer immunity. Orca-T
based regimens become increasingly
is an engineered graft product. Purified regulatory T cells are sorted and administered
popular, these early findings do merit
on day 0 of HCT, along with hematopoietic stem cells. Conventional T cells are then
further study, as it should be essential
administered on day 2. In this phase 1/2 trial, 50 patients with hematologic malignan-
to define the minimum dose of cyclo-
cies undergoing myeloablative conditioning received Orca-T plus GVHD prophylaxis
phosphamide needed for utility.
with tacrolimus or sirolimus during HCT with either matched related (n=62) or unre-
Dr Andrea Henden presented the
lated (n=38) donors (Abstract 88). The control group (n=144) received standard-of-care
results of a basic science investigation
treatment with peripheral blood stem cell and prophylaxis with methotrexate plus
that evaluated how interferon lambda
tacrolimus; 56% of these patients had matched related donors. The incidence of grade
protects gastrointestinal stem cells
2 to 4 acute GVHD was 10% in the Orca-T group vs 30% in the control group (P=.0018).
from acute GVHD in murine trans-
The rates of moderate-to-severe chronic GVHD were 3% vs 46%, respectively (P=.016).
plant models.8 Acute GVHD of the
Preliminary results for 1-year GVHD-free/relapse-free survival rates were 75% with Orca-
lower intestine is responsible for the
T vs 31% with control (P=.006). No differences in infectious complications were seen.
majority of the morbidity and mor-
tality observed with acute GVHD.
20 Clinical Advances in Hematology & Oncology Volume 19, Issue 4, Supplement 14 April 2021You can also read
