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`Ibrutinib Effective against Graft-Versus-Host Disease - National Cancer Institute
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`Ibrutinib Relieves Chronic Graft-Versus-Host Disease
`Symptoms
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`January 11, 2017, by NCI Staff
`
`The targeted cancer therapy ibrutinib (Imbruvica®) can
`effectively treat a common and serious complication of a
`type of stem cell transplant, findings from a small clinical trial
`show.
`
`Patients in the trial had blood cancers and were
`experiencing symptoms of chronic graft-versus-host
`disease (GVHD) after receiving a transplant of donated
`blood stem cells, known as an allogeneic transplant. The
`patients’ symptoms—including widespread skin rashes and
`painful mouth ulcers—had persisted despite standard
`treatment with corticosteroids.
`
`Widespread skin rashes are among
`the common symptoms of chronic
`graft-versus-host disease.
`Credit: S.R. Riddell, F.R. Applebaum PLOS
`Med 2007; DOI:
`10.1371/journal.pmed.0040198 (CC BY 1.0)
`
`Following treatment with ibrutinib, approximately two-thirds
`of patients in the trial experienced improvements in their
`GVHD-related symptoms. In 21% of these patients, the
`symptoms resolved entirely. And the symptom relief was
`enduring, lasting for up to 5 months or longer in many
`patients, according to results reported in December at the American Society of Hematology annual
`meeting.
`
`Having a new option for patients with chronic GVHD who do not adequately respond to corticosteroids
`would be an important advance, said the trial’s lead investigator, David Miklos, M.D., of the Stanford
`University Cancer Center.
`
`“Ibrutinib appears to exceed the therapeutic benefits of other agents” for patients experiencing sustained
`symptoms from GVHD, Dr. Miklos said in a news release.
`
`Steven Pavletic, M.D., of the Experimental Transplantation and Immunology Branch in NCI’s Center for
`Cancer Research (CCR) agreed.
`
`“This is good news and major progress against chronic GVHD,” said Dr. Pavletic, an expert on the
`condition. More effective and safer treatments for GVHD are “an area of unmet need,” he continued.
`“Currently there is no FDA-approved agent for chronic GVHD.”
`Chronic GVHD: A Serious Problem
`In the United States each year, approximately 10,000 people with blood cancer receive allogeneic stem
`cell transplants. GVHD occurs when these transplanted cells attack the patient’s healthy cells and tissues.
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`https://www.cancer.gov/news-events/cancer-currents-blog/2017/ibrutinib-stem-cell-transplant-gvhd
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`Ibrutinib Effective against Graft-Versus-Host Disease - National Cancer Institute
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`This cellular assault develops in as many as 40% of patients and can cause multiple, often debilitating
`symptoms, which can also include significant shortness of breath and limb and joint pain.
`
`In addition to these symptoms, GVHD “also has significant mortality associated with it,” explained
`Wyndham Wilson, M.D., Ph.D., of the CCR Lymphoid Malignancies Branch.
`
`In some patients, GVHD occurs in the first weeks and months after the stem cell transplant, known as acute
`GVHD. Chronic GVHD occurs when the condition arises or persists months after the transplant.
`
`Corticosteroids are the standard treatment for both acute and chronic GVHD, but for many patients they
`are not always effective or they eventually stop working, Dr. Wilson said. Long-term use of corticosteroids
`also can have its own serious side effects, including immune system suppression, he added.
`
`Ibrutinib is approved by the Food and Drug Administration (FDA) for the treatment of some patients with B
`cell-related cancers, including some types of leukemia and lymphoma. The drug targets a protein known
`as BTK, which is present in B cells and other types of immune cells. BTK is a component of an
`important signaling pathway in B cells and blocking it can stop these cells from becoming activated.
`Ibrutinib also inhibits the activity of a similar protein, ITK, on B cells and T cells. Several studies have shown
`that improper activation of both of these types of immune cells are common in chronic GVHD.
`
`A study published in 2014 showed that treatment with ibrutinib alleviated symptoms in mouse models of
`corticosteroid-resistant GVHD. These findings set the stage for human trials of ibrutinib in patients
`experiencing GVHD.
`‘Favorable’ Findings
`To be eligible for the phase II trial, patients had to have either a skin rash on more than 25% of their body or
`significant mouth ulcers despite having received up to three prior regimens for GVHD. The 42 patients in
`the trial had been experiencing GVHD-related symptoms for many months, with a median duration of 13.7
`months.
`
`Treatment with ibrutinib not only led to substantial reductions in GVHD-related symptoms, but many
`patients in the trial were able to reduce their steroid dose and a handful were able to stop using them
`altogether.
`
`Using a standardized scoring system for assessing illness-related symptoms, most patients reported having
`far less severe symptoms than before they started ibrutinib. And many patients who responded to the drug
`had reductions in the levels of blood-based markers associated with GVHD, including those linked to
`inflammation and connective tissue scarring.
`
`Nearly half of patients in the trial experienced serious side effects from ibrutinib, including high fevers and
`pneumonia. These side effects are typical for patients treated with ibrutinib, said Samantha Jaglowski,
`M.D., an investigator on the trial from the Ohio State University James Cancer Center.
`
`Overall, Dr. Jaglowski continued, most of the side effects were manageable.
`
`For many patients with chronic GVHD, Dr. Wilson said, the risk of side effects from ibrutinib may well
`outweigh the impact of the GVHD symptoms they’re experiencing. He called the trial results “remarkable,”
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`given how long patients in the trial had been experiencing GVHD-related symptoms.
`
`“These are people who have already gone through the standard therapies and clearly their symptoms
`were being poorly controlled,” he said. “Chronic GVHD can be a terrible condition, and these results are
`extremely favorable.”
`Moving Toward the Clinic
`It’s still too early to say what kind of impact these results will have on the care of patients with chronic
`GVHD, Dr. Jaglowski said.
`
`Earlier this year, the FDA granted ibrutinib a Breakthrough Therapy Designation for patients with chronic
`GVHD that is not being controlled by other therapies like corticosteroids. This designation allows the FDA to
`expedite its review of a drug for marketing approval based on early data suggesting that it has efficacy in
`a serious or life-threatening disease or condition.
`
`One important question that needs to be answered is how long patients with chronic GVHD need to take
`ibrutinib to control their symptoms, Dr. Wilson said.
`
`When it comes to drugs that are involved in suppressing an immune-related attack, he explained,
`“sometimes it’s just a matter of breaking the cycle.” Patients who respond well to ibrutinib could go on a
`“drug holiday,” he continued, to see if the symptom relief persists.
`
`“This is clearly a first study and as more experience is gained with using ibrutinib in this patient
`population, we will learn better how to use it,” Dr. Pavletic said.
`
`More information on the other drugs patients in the trial were using to help control GVHD-related symptoms
`or infections will be important moving forward, he continued, as some may interact with ibrutinib and lead
`to or worsen side effects. He noted that 14 patients in the trial had to drop out because of side effects.
`
`“I anticipate that, with more experience and attention to possible drug interactions and ibrutinib dose
`adjustments, the rate of side effects may actually go down,” he continued. “It is very encouraging that 12
`patients maintained sustained responses for up to 2 years, and my hope is that more treated patients
`could get to that point.”
`
`At least one trial may help to address some of the outstanding questions around using ibrutinib in patients
`with GVHD.
`
`AbbVie and Pharmacyclics, which jointly market ibrutinib, plan to launch a phase III clinical trial of ibrutinib
`to treat GVHD in the first half of 2017. However, the trial will test the drug as part of initial therapy for
`patients with chronic GVHD, not patients who have already developed treatment resistance.
`
`According to a spokesperson for Pharmacyclics, the companies will file for regulatory approval of ibrutinib
`for the treatment of chronic GVHD later this year.
`
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