New Indication for Ibrutinib in Chronic Graft Versus Host Disease

The FDA approved ibrutinib in August 2017 to treat adults with chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy.

This is the first FDA-approved therapy to treat cGVHD.

Hematopoietic stem cell transplants (HSCT) are a treatment option for patients who need bone marrow replacement. The need for this replacement can arise from cancers such as lymphoma, conditions such as aplastic anemia, and toxicity of the bone marrow during high-dose chemotherapy.

Possible sources of stem cells include umbilical cord blood, peripheral blood, and bone marrow. Each source has its advantages and disadvantages, varying by accessibility, collection technique, and outcomes in infectious and disease progression.

Because HSCT involves transplanted cells from a donor, it is imperative to have a match as close as possible to the recipient. A human leukocyte antigen mismatch is the most prominent risk factor for both acute graft versus host disease (aGVHD) and cGVHD. Additional risk factors include the age of recipient and the donor, a female donor to male recipient, parity of female donor, and the source of the stem cells.¹

What do aGVHD and cGVHD look like?

As diagnostic criteria for aGVHD and cGVHD are complicated, can overlap, and depend on not only timing of presentation but also signs and symptoms upon presentation. It is best to consult guidelines and experts regarding this matter.²

As a generalization, however, both acute and chronic GVHD can happen any time after the day of transplant, otherwise known as day 0. We do, however, tend to see aGVHD within 3 months of day 0, with skin, gut, and liver manifestations, and cGVHD, usually presenting after 3 months and involving multiple sites, in addition to those mentioned for aGVHD.³

How is GVHD treated?

HSCT patients are presumed to already be on prophylactic immunosuppressive therapy, caught up on possible vaccinations, and adherent to cancer screenings, skin/eye checks, and psychiatric and physical rehabilitation. For aGVHD, mainstay therapy is steroids. For grade I, topical steroid therapy alone should suffice.³ Grade II-IV are treated with systemic steroids, with rapid, 86-day taper showing as much effectiveness as a slow, 147-day taper.⁴ If systemic steroid therapy fails, salvage therapy with various monoclonal antibodies (MABS) is the next step. Treatment of cGVHD follows a similar pathway, with slight modifications in preferred steroids and length of treatment.⁵

The most recently approved therapy for cGVHD is a TKI called ibrutinib (IMBRUVICA).

Ibrutinib (IMBRUVICA) Prescribing Information⁶

Ibrutinib is an antineoplastic agent of the tyrosine kinase inhibitor (TKI) class. It selectively and irreversibly binds to Bruton’s tyrosine kinase (Btk), an enzyme with a pivotal role in B cell proliferation, maturation, and malignancies (Parmar).

Its FDA indications include:

· Mantle cell lymphoma (MCL) patients who have received at least one prior therapy;

· Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with or without 17p deletion;

· Waldenstrom’s macroglobulinemia; and

· Marginal zone lymphoma requiring systemic therapy after having received at least one prior anti-CD20-based therapy.

Ibrutinib was most recently indicated for cGVHD after failure of 1 line of systemic therapy.

The medication is supplied as 140-mg capsules that should not be open or chewed. They should, however, be taken with a full glass of water. The dose depends on the indication: 560 mg by mouth, once daily for MCL and MZL, and 420 mg by mouth, once daily for the remaining indications. The drug should be continued until disease progression or toxicity and the patient can no longer tolerate the medication.

Just as certain drug levels can be “falsely” elevated, ibrutinib and other BCR-related kinase inhibitors can induce a lymphocytosis that are easy to mistake for disease progression, absent other clinical findings.^7,8 This is an asymptomatic, ibrutinib-induced migration of cells from tissue into peripheral blood and defined as absolute lymphocyte count >5000/uL or an increase of at least 50% from the patient’s baseline.⁸ The purpose of this adverse effect is to result in a reduction of lymph node size.

The oral bioavailability of ibrutinib is low, at 2.9% in a fasted state. Food increases both Cmax and AUC and depending on the type, can do so by different amounts but no more than by fourfold. The drug is 97% protein-bound and has a high Vd of 10,000 L.

Ibrutinib is extensively metabolized by the liver and is a CYP3A4 substrate, requiring dose adjustments with moderate CYP3A inhibitors and avoidance of administration with CYP3A inducers. The drug is 80% fecally eliminated and 20% renally eliminated, with an elimination half-life of 4 to 6 hours.⁹

Three MCL and CLL trials cited in a study showed the most common adverse reactions, defined as an incidence of >/= 20% “bruising, constipation, diarrhea, musculoskeletal pain, nausea, neutropenia, pyrexia, and upper respiratory tract infection.” Additionally, the most common grade 3 or 4 adverse reactions, defined as an incidence of >/= 5%, “were anemia, neutropenia, pneumonia, and thrombocytopenia.”⁸

FDA approval for cGVHD was based on an open-label, multicenter, single-arm trial of 42 patients with cGVHD after failure of first-line therapy. Eighty-eight percent of patients had at least 2 organs of involvement, and responses were seen in all organs involved. The overall response rate was 67%, with a median time-to-response of 12.3 weeks.¹⁰

References:

1. Cleveland Clinic. Graft vs Host Disease: an overview in bone marrow transplant.

my.clevelandclinic.org/health/articles/graft-vs-host-disease-an-overview-in-bone-marrow-transplant. Accessed September 29, 2017.

2. Socie G, Ritz J. Current issues in chronic graft-versus-host disease. Blood. 2014;124(3):374—84.

doi: 10.1182/blood-2014-01-514752.

3. Garnett C, Apperley JF, Pavlu J. Treatment and management of graft-versus-host disease:

improving response and survival. Ther Adv Hematol.

2013;4(6):366-78. doi: 10.1177/2040620713489842.

4. Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J Rare Dis.

2007;4;2:35.

5. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;

125(4):606—15.

doi: 10.1182/blood-2014-08-551994.

6. Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics LLC; 2017. imbruvica.com/docs/librariesprovider7/default-document-library/prescribing_information.pdf. Accessed August 29, 2017.

7. Burger JA. Bruton’s tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig

Rep. 2014

;

9(1):44-9. doi: 10.1007/s11899-013-0188-8.

8. Kim ES, Dhillon S. Ibrutinib: a review of its use in patients with mantle cell lymphoma or

chronic lymphocytic leukaemia. Drugs. 2015;

75(7):769-76. doi: 10.1007/s40265-015-0380-3.

9. Ibrutinib. In: Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood

Village, Colorado, USA. micromedexsolutions.com.ezproxy.lib.uconn.edu/. Accessed August 29, 2017.

10. FDA expands ibrutinib indications to chronic GVHD [news release]. August 2, 2017. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm569711.htm. Accessed September 29, 2017.