Survival and Cost Considerations of Cytomegalovirus for Recipients of Allogeneic Hematopoietic Cell Transplantation

Roy Chemaly MD, MPH

Two poster presentations at this year’s BMT Tandem Meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation held in in Salt Lake City, Utah, have provided a compelling extension of the recent phase 3 clinical trial (NCT02137772; Marty FM et al., The New Engl J Med 2017 377:2433-2444) that demonstrated the efficacy of prophylactic therapy with letermovir for the prevention of cytomegalovirus (CMV) infection in patients receiving allogeneic hematopoietic stem cell transplantation (HCT).

HCT involves immunosuppression. This is necessary for the success of the transplant. But, it carries the danger of lessened resistance to potentially lethal infections like CMV. CMV is one of the most common infections that occur following transplantation. The normal post-HCT strategy for over a decade has involved blood checks for the presence of CMV nucleic acid in patients who display no symptoms of infection. If the genetic material is detected, treatment swings to a reactive response involving intravenous (IV) ganciclovir or its oral prolog, valganciclovir, or the IV application of either foscarnet or cidofovir.

The reactive approach works. But, adverse effects including myelosuppression and renal toxicity mean that therapy is short-term. Enter letermovir, and the idea of its preemptive use “from the get-go” in patients scheduled for allo-HCT, explained Roy Chemaly MD, MPH, from The University of Texas MD Anderson Cancer Center, Houston, Texas, during an interview with Contagion^®. Dr. Chemaly was involved in the phase 3 letermovir prophylaxis study published in NEJM and the poster described below.

In the poster, clinicians headed by Dr. Chemaly retrospectively examined data from an 18-hospital database of HCT patients to assess the clinical outcome and the economic burden of CMV reactivation. Between 2012 and 2015, 100 consecutive patients hospitalized at MD Anderson for allo-HCT who experienced reactivation of CMV were enrolled. The scenario for these patients was the current status quo of care, which treats CMV preemptively.

Just over half the patients were male and the majority (73%) had underlying leukemia. Fifty-nine patients underwent matched unrelated donor transplant. At the time of their hospitalization, 62 patients had acute graft versus host disease. Steroid therapy was initiated with a month of CMV reactivation in 58 patients. CMV reactivation varied widely from 2 to 174 days following allo-HCT, with a median of 32 days.

Within the first year following HCT, PET was done 192 times and involved ganciclovir, foscarnet, and valganciclovir, with IV immunoglobulin used as an adjuvant therapy 20 times. Progression to CMV disease occurred in 4 of the 100 patients. The mean hospitalization time was similar for patients treated with ganciclovir and foscarnet.

To get a better handle on inpatient costs, the researchers analyzed the data from MD Anderson and 17 other hospitals using the Vizient database. The composite data revealed that the retroactive response added to the cost of treatment, particularly when there were serious side effects to the foscarnet therapy (total direct cost per encounter US$284,006 versus US$112,195 for patients without serious side effects).

The findings “underscore the significant impact of CMV reactivation and preemptive therapy in terms of economic and clinical burden in alloHCT patients,” said Dr. Chemaly.

Whether the prophylactic letermovir strategy actually decreases the burden of CMV in the real-world beyond the recent clinical trial remains to be determined, and is the subject of ongoing analyses. For now, though, the study lays clear the clinical and economic toll of CMV in the allo-HCT setting.

The other poster honed in on the use of letermovir, using a decision-analytic model to evaluate the cost-effectiveness of the letermovir prophylaxis compared to the status-quo preemptive treatment. The total cost of patient treatment and the longer-term burden of CMV on the quality and length of life, as measured by the parameters of life years gained and quality-adjusted life years. The model was deliberately designed to be simple and relied on data obtained from the NEJM phase 3 trial, boosting confidence in the real-life ramifications of the model predictions.

Jonathan Schelfhout, PhD

“The model is able to use clinical inputs and measures of health care resource utilization from a randomized, placebo-controlled clinical trial. These data are generally considered the gold standard for model inputs,” explained Jonathan Schelfhout, PhD, Merck & Co. Inc, Kenilworth, New Jersey, in an interview with Contagion^®. Dr. Schelfhout was involved in both posters, and in the phase 3 trial of letermovir prophylaxis.

The analysis involved 1000 patients who were followed until death. The actual patient data showed that the prophylactic use of letermovir reduced the number of CMV infections that required subsequent preemptive treatment (189 vs. 443) 24 weeks after allo-HCT. “Prophylaxis with letermovir resulted in fewer cases of mortality and an increase in life years and quality-adjusted life years,” said Dr. Schelfhout.

The prophylaxis strategy did increase the costs of treatment. However, the longer-term benefits more than outweighed this expense. “The results of this model suggest that letermovir is an excellent value, with a cost per quality-adjusted-life-year of $25,222. The number is well beneath thresholds of $100,000 or $150,000 that are typically cited for evaluating whether an intervention is cost-effective in the United States. These results were robust to changes in the inputs of the model as a probabilistic sensitivity analysis indicated that letermovir was cost-effective in 93.5% of iterations at $100,000 of quality-adjusted life year gained and 95.2% of iterations at $150,000 per quality-adjusted-life-year gained,” said Dr. Schelfhout.

The relative lack of published cost data for CMV and the model’s lack of inclusion of costs other than direct treatment costs are acknowledged limitations of the approach. Further research will flesh out these aspects and, it is anticipated, continue to strengthen the case for letermovir prophylaxis.

DISCLOSURES

Roy Chemaly, MD, MPH: Chimerix Inc., grants, and personal fees; Merck & Co. Inc., grants, and personal fees; Novartis, grant; Astellas, personal fees; Oxford Immunotec, personal fees.

Jonathan Schelfhout, PhD, Merck & Co. Inc., employee.

PRESENTATIONS

Poster Session: Infectious Diseases

Roy F. Chemaly, MD

MD Anderson Cancer Center

Poster 542. Clinical & Economic Burden of Pre-Emptive Therapy (PET) of Cytomegalovirus (CMV) Infection in Hospitalized Allogeneic Hematopoietic Cell Transplant (allo-HCT) Recipients: The MD Anderson Cancer Center Experience

Jonathan Schelfhout, PhD, Merck & Co. Inc.

Poster 557. Cost Effectiveness of Letermovir as Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.