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Extracorporeal photopheresis shows promise for bronchiolitis obliterans syndrome
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SALT LAKE CITY — Extracorporeal photopheresis stabilized forced expiratory volume in the first breath, or FEV1, values and prolonged survival among patients with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation, according to results of a multisite retrospective cohort study presented at the BMT Tandem Meetings.
Bronchiolitis obliterans syndrome (BOS) affects approximately 10% of patients after allogeneic HSCT, usually within the first 2 years.
“Immunosuppressive therapies — mainly steroids and calcineurin inhibitors — are used to slow BOS progression; however, the prognosis remains dismal with OS of 10% to 20% at 5 years,” Mehrdad Hefazi, MD, fellow of hematology-oncology at Mayo Clinic in Rochester, Minnesota, told HemOnc Today. “Beyond steroids, there are currently no standard treatment options, with different institutions using different treatments based on their experience and the response in each patient.”
Due to suboptimal responses to conventional immunosuppressive therapies, extracorporeal photopheresis (ECP) has been explored as an immunomodulatory alternative treatment. However, data on the efficacy of ECP in this setting have been limited to a few case series that lack control groups. Further, ECP — an immunomodulatory therapy that requires collecting leukocytes from peripheral blood, exposing them to a photosensitizing agent and UV radiation, and reinfusing them — is very costly and logistically challenging, requiring regular treatments at highly specialized centers for at least several months, Hefazi said.
“One of the intriguing aspects of ECP is its ability to induce two opposing effects: activation of the immune system — as in the treatment of cutaneous T-cell lymphoma — and down-regulation of the activity of T lymphocytes, as in the treatment of allograft rejection and graft-versus-host disease,” he added. “The immunomodulatory effects of ECP may be additionally advantageous in HSCT patients, because ECP does not cause generalized immunosuppression and, thus, does not increase the risk for infectious complications and disease relapse.”
Hefazi and colleagues evaluated medical records from 1,261 consecutive patients who underwent allogeneic HSCT at Mayo Clinic in Minnesota, Arizona or Florida. Of these, 75 were diagnosed with BOS according to the NIH 2014 criteria.
After propensity-score matching for BOS severity, 26 patients who underwent 3 or more months of ECP were matched to 26 non-ECP-treated patients, who were assigned an index date corresponding to the ECP start date for their matched pairs.
Baseline transplant characteristics — including age, year of transplant, donor type, conditioning, and comorbidity index — appeared similar between the two groups. Severity grades of acute GVHD before BOS diagnosis and nonpulmonary chronic GVHD at the time of BOS diagnosis also were comparable between the two groups.
Before propensity matching, the ECP group had higher rate of treatment with calcineurin inhibitors (75% vs. 54%; P = .08); FAM, or fluticasone, azithromycin and montelukast (92% vs. 72%; P = .03); and other immunosuppressive therapies (61% vs. 33%; P = .02); however, these differences were not statistically significant after matching.
In the ECP group, patients underwent a median of 31 cycles of ECP (range, 6-60) over a median of 15 months (range, 3-58 months).
Median follow-up was 52 months for the ECP group and 47 months for the non-ECP group.
The percent predicted rate of FEV1 decline appeared faster before, rather than after, the ECP/index date in both the ECP (4.5 vs 0.2; P < .0001) and non-ECP groups (3.6 vs 0.5; P < .001). However, comparison between the two groups did not reveal a significant difference (P = .33).
On a multivariable analysis that included baseline transplant and pulmonary function test variables, matched-related donor HSCT (HR = 0.1; P = .002), ECP (HR = 0.1; P = .001) and slower rate of FEV1 decline before ECP/index date (HR = 0.7; P = .001) were associated with better OS.
“We found that patients with BOS treated with ECP for at least 3 months had a significantly better survival compared with a propensity-matched non-ECP-treated cohort,” Hefazi said. “Surprisingly, the survival benefit was independent of the ECP effects on measured pulmonary functions.”
To explore the reasons for survival difference between the ECP and non-ECP groups, researchers compared patients’ Karnofsky performance score, immunosuppressive therapies and nonpulmonary chronic GVHD status at BOS diagnosis and at last outpatient follow-up. ECP and non-ECP groups had comparable rates of moderate/severe nonpulmonary chronic GVHD at BOS diagnosis (65% for both groups) and at last follow-up (54% for both groups). Thus, the ECP effect on nonpulmonary chronic GVHD was unlikely to be responsible for the survival difference, Hefazi said.
Although the use of calcineurin inhibitors at last follow-up was comparable between the two groups, non-ECP-treated patients were more likely to be on more than a 5-mg daily prednisone dose (54% vs. 23%; P = .04) and had a greater decline in Karnofsky performance score over the course of treatment (mean difference, 9.5 vs. 1.6; P = .06).
“These results are consistent with the clinical impression that ECP may have a steroid-sparing effect in patients with BOS and improves outcomes without significantly impacting pulmonary functions,” Hefazi said.
The main study limitation was its retrospective, nonrandomized design, Hefazi said.
“The decision to start and subsequently taper ECP was at the clinician’s discretion — a process that can potentially bias the outcomes in spite of propensity matching and multivariable analysis,” he said. “Prospective randomized trials are, thus, needed to confirm the efficacy of ECP, determine its optimal schedule and standardize the response evaluation. Immunological investigations should also be incorporated into future clinical studies to elucidate the mechanism of action of ECP and to explore potential biomarkers for use before or during treatment to identify patients who will benefit from this highly innovative, yet logistically challenging, treatment strategy.” – by Alexandra Todak
Reference:
Hefazi M, et al. Abstract 48. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Gerhard C. Hildebrandt, MD, FACP
Despite advances in the prevention and management of both acute and chronic GVHD, BOS continues to present a manifestation of chronic GVHD defined by its progressive clinical course, difficulty to treat and overall high mortality. Treatment options usually include high-dose steroids and additionally utilize immunosuppressive therapies used for steroid-refractory chronic GVHD, both of which put patients at risk for severe, and potentially lethal, infections. This may even be more important for BOS, considering that pulmonary infections drive lung inflammation, which then in a vicious cycle may propagate BOS progression, requiring more immunosuppression.
Hefazi and colleagues presented a retrospective analysis of ECP among 74 patients with BOS, comparing those who underwent ECP with those who did not. Patients who received ECP for BOS had more severe disease as reflected at ECP/index time by their predicted FEV1 (42% vs. 68%) and proportion of patients classified as having moderate or severe BOS (76% vs. 36%). They also received more immunosuppression.
After correction for BOS severity and immunosuppression, better OS appeared associated with not only higher FEV1 values at ECP/index time and slower rates of FEV1 decline before ECP/index time — which may not be that surprising — but also the use of ECP in a matched analysis. For 26 patients who received ECP compared with a matched 26 patients who did not receive ECP, 5-year OS significantly improved in the former group by close to 20% (P = .01). Interestingly, this improvement in survival did not appear associated with difference in nonpulmonary chronic GVHD and was not affected by an increased rate of catheter infections, but ECP resulted in a trend toward reduced prednisone (> 5 mg) daily usage (P = .06).
This study, therefore, adds to the growing observational data on the potential benefits of ECP for BOS and underscores its ability to possibly spare steroids in these patients. The need for a prospective ECP trial for this patient population despite its logistical obstacles and challenges becomes more and more evident to eventually find answers to a growing pool of questions.
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