An FDA-approved blood cancer drug has demonstrated encouraging findings, including an overall response rate (ORR) of 67%, in treatment of patients with chronic graft-versus-host-disease (cGVHD) that was not resolved by corticosteroids. 

In a multicenter study presented at the 2016 American Society of Hematology Annual Meeting, ibrutinib (Imbruvica) showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD. In addition, the majority of responders were able to reduce steroid doses to an acceptable minimal level.

Of the 42 participants who experienced GVHD, 67% responded to ibrutinib, and 71% had sustained improvements over a 5-month period. According to the researchers, the results are encouraging for a subset of patients with limited treatment options beyond corticosteroids.

Lead author of the study, David Miklos, MD, PhD, called the findings “remarkable” and said that ibrutinib appears to exceed the therapeutic benefits of other agents. “This is a very high response rate,” said Miklos, associate professor of Blood and Marrow Transplantation at the Stanford University Medical Center. “Clinicians will find these data support the use of ibrutinib in patients with steroid-refractory chronic GVHD, who currently suffer a range of symptoms that can be chronic and debilitating.”

Chronic GVHD is a serious complication of allogeneic stem cell transplantation (ASCT), in which the transplanted stem cells attack the patient’s body, causing symptoms such as rashes, mouth ulcers, dry eyes, gastrointestinal problems, shortness of breath, and decreased mobility in the joints and limbs. Although immune-suppressing corticosteroid medications are the standard treatment for cGVHD, they do not benefit all patients, Miklos explained.

For the multicenter, open-label, phase II study, researchers enrolled 42 patients with steroid dependent/refractory cGVHD following ASCT. Patients had failed 3 or fewer prior therapies for cGVHD and had either more than 25% body surface area involving an erythematous rash or a National Institutes of Health (NIH) mouth score greater than 4.

Ibrutinib was administered daily at 420 mg until cGVHD progression or unacceptable toxicities. The primary endpoint was cGVHD response based on the 2005 NIH consensus response criteria.

Results showed that 21% of responders had a complete response and 19% had a partial response. Seventy-one percent of the 28 responders had a sustained cGVHD response of at least 5 months.

Furthermore, cGVHD response was observed across multiple organs: 56% (20/25) of patients with 2 or more involved organs at base-line responded in at least 2 organs, and 42% of patients with 3 or more involved organs at baseline responded in at least 3 organs.

Patients also had meaningful improvement in their cGVHD symptoms as assessed by Lee Symptom Score improvements of greater than 7 points. Consistent with this improvement, clinician-assessed and patient-reported reductions in overall cGVHD severities were reported throughout the study, as well.

In addition, patients on ibrutinib experienced reductions in corticosteroid doses. Overall, 26 patients achieved corticosteroid doses less than .15 mg/kg daily while on ibrutinib and 5 responders were able to discontinue all corticosteroid treatment.

Regarding safety, 45% of participants experienced serious adverse events (AEs) such as pneumonia, septic shock, or severe fever. Additional AEs include fatigue, diarrhea, muscle spasms, nausea, and bruising.

As Miklos reported, however, these side effects are consistent with those previously reported for ibrutinib and those observed in patients with cGVHD on concomitant corticosteroids.

Overall, he added, ibrutinib represents a promising potential new therapy for GVHD.

“By targeting allogeneic B cells and TH2 lymphocytes, ibrutinib is targeting a pathogenic mechanism that we believe causes GVHD, while leaving protective and antitumor cytotoxic T cells intact,” said Miklos.

“This is a targeted therapy that does not just bluntly suppress the immune system; it leaves patients better able to fight their cancer as well as viral infections.”

Miklos and colleagues are recruiting participants for additional trials that will further investigate the use of ibrutinib in preventing or treating GVHD and compare it with other agents.

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Ibrutinib has showed clinically meaningful and durable responses in patients with chronic graph-versus-host-disease (cGVHD).

Ibrutinib Shows Promise in Treating GVHD After Stem Cell Transplant

More treatment does not necessarily offer more benefit for patients—at least when it comes to multiple myeloma.

According to the results of the phase III StaMINA trial evaluating posttransplant therapy in multiple myeloma, a second round of chemotherapy or stem cell transplant does not improve progression-free survival (PFS) or overall survival (OS) compared with the current standard course of treatment alone.

The addition of lenalidomide/bortezomib/dexamethasone (RVD) consolidation or a second autologous hematopoietic cell transplant (AHCT) was not superior to a single AHCT, followed by lenalidomide maintenance, in the upfront treatment of multiple myeloma.

“When compared with the current standard course of treatment alone, these data suggest that additions to standard multiple myeloma therapy do not improve benefit for patients,” said Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at the Abramson Cancer Center, University of Pennsylvania. “Based on these results, I believe that it would be reasonable to compare any new treatments to the standard therapy of melphalan followed by a single AHCT followed by lenalidomide maintenance.”

As Stadtmauer reported at the 2016 ASH Annual Meeting, despite remarkable advances in multiple myeloma therapy over the past decade, many patients will ultimately see their disease progress. Although lenalidomide maintenance after AHCT has improved PFS and OS, the role of additional interventions after AHCT, such as tandem AHCT or triple therapy consolidation, remains to be determined.

“There’s always room for improvement,” said Stadtmauer. “New therapies and interventions need to be actively investigated to see how much they further benefit the early treatment of patients with myeloma.”

From June 2010 to November 2013, researchers from 54 centers enrolled 758 transplant-eligible patients with symptomatic multiple myeloma. The patients, who were all within 2 to 12 months of initial therapy and without prior progression, were randomly assigned to receive either standard care (melphalan 200mg/m2 AHCT), standard care plus additional chemotherapy (4 cycles of RVD consolidation), or standard care plus a second round of AHCT. All arms included lenalidomide maintenance (at maximum tolerated dose up to 15 mg orally daily until progression) with dose modifications for toxicities.

Randomization was stratified by disease risk factors and center, and all patients were reviewed centrally for eligibility, response and progression. Of those enrolled, 24% were classified as high risk.

The primary objective was to compare 38-month PFS of the 3 treatment arms. PFS events included progression, nonprotocol anti-myeloma therapy, or death.

With almost all patients nearing the end of follow-up, the study’s Data and Safety Monitoring Board released the results Staudtmauer reported at ASH which showed no difference among the 3 groups in terms of the study’s primary endpoint.

At a median follow-up of 38 months, PFS was not significantly improved by these interventions: PFS rates were 52% in the single-transplant arm, 57% in the consolidation arm and 56% in the tandem transplant arm (

Outcomes were also similar with respect to OS, said Stadtmauer. At 38 months, the corresponding probabilities of OS were 82.0%, 85.7%, and 83.4%, respectively.

In high-risk patients, PFS was between 40% and 48% at 38 months, with no difference in OS. Regarding the survival rate, Stadtmauer said it was “impressive that about 77% to 79% of high-risk patients are alive at 38 months.”

Finally, second malignancies emerged in 39 of the 758 patients (5.1%), including 15 in the consolidation arm, 14 in the tandem transplant arm, and 10 in the single-transplant arm. The most frequently reported secondary malignancies were leukemia in the tandem transplant and consolidation arms and solid tumors in the single AHCT arm.

“In the era of thalidomide analogs and proteasome inhibitors used in the initial therapy for myeloma and the use of prolonged maintenance therapy with lenalidomide, posttransplant consolidation with cycles of RVD or a second transplant do not produce incremental PFS benefit,” Stadtmauer concluded.

The researchers will continue to track long-term trends and outcomes of patients in a follow-up study.

Stadtmauer EA, Pasquini MC, Blackwell B et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide and dexamethasone (RVD) consolidation with lenalidomide maintenance (ACM), tandem autoHCT with lenalidomide maintenance (TAM), and autoHCT with lenalidomide maintenance (AM) for upfront treatment of patients with multiple myeloma (MM): Primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 — StaMINA Trial). Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract LBA-1.

A second round of chemotherapy or stem cell transplant for patients with multiple myeloma does not improve PFS or OS compared to the current standard couse of treatment.

Chase Doyle

Articles

Ibrutinib Shows Promise in Treating GVHD After Stem Cell Transplant

More Treatment Does Not Necessarily Mean More Benefit in Multiple Myeloma