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Defibrotide represents ‘major advance’ for severe veno-occlusive disease after HSCT
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Defibrotide was associated with improved 100-day survival among patients who developed severe hepatic veno-occlusive disease after hematopoietic stem cell transplantation, according to phase 3 study results presented at the BMT Tandem Meetings.
The intervention also was associated with improved complete response at day 100, measured by an improvement in total bilirubin and resolution of multi-organ failure, results showed.
“Previously, there was no approved therapy for severe veno-occlusive disease, which is typically characterized by multi-organ failure, and the treatment standard was at best supportive care, with an unacceptable mortality in excess of 80%,” Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, the R.J. Corman professor of medicine at Harvard Medical School and HemOnc Today’s myeloma section editor, said in an interview. “The development of defibrotide has been long but arguably well worth the wait, as it’s very encouraging to now have something for our patients for whom we had nothing before.”
Improved survival, reduced toxicity
Paul G. Richardson
In a multicenter, international study, Richardson and colleagues prospectively evaluated data from 102 patients (median age, 21 years; 63% male) with severe hepatic veno-occlusive disease (VOD) diagnosed by Baltimore criteria, which includes the development of VOD within 21 days after undergoing HSCT. Patients also had to have severe renal and/or pulmonary failure by day 28 post–HSCT.
Patients received 25 mg/kg defibrotide (Defitelio, Jazz Pharmaceuticals) daily for at least 21 days.
The analysis also included a rigorously selected group of 32 historical control patients (median age, 18 years; 56% male) who had severe VOD with multi-organ failure. These patients were derived from the sequential, masked review of nearly 7,000 patients who underwent HSCT 6 months or more prior to the first use of defibrotide at each participating institution.
“Because we had phase 2 data from several studies showing defibrotide could reduce mortality by almost half — including one study that included more than 150 patients — there was felt to be no equipoise to a randomized prospective trial in such a sick population for whom no other effective therapy existed,” Richardson said. “The decision was therefore made to utilize a novel historical control methodology. The outcomes of the historical control group proved very similar to registry data that has since become available in two independent settings — the Center for International Blood and Marrow Transplant Research and the registry of the Japan Marrow Donor Program — as well as from literature reviews and meta-analysis, so the historical control we used does appear to be robust.”
Median duration of defibrotide therapy in the treatment group was 22 days (range, 1-60).
By day 100, 23.5% of patients in the defibrotide arm achieved a complete response to therapy — defined as an improvement in total bilirubin to less than 2 mg/dL and resolution in renal and/or pulmonary dysfunction — compared with 9.4% of historical controls (P = .013).
Significantly more patients were alive at 100 days in the defibrotide arm compared with historical controls (38.2% vs. 25%; P = .034).
A separate analysis of these data explored the number needed to treat in the setting of intensive care and critically ill patients. The number of patients needed to treat to achieve a complete response by day 100 was seven, and the number needed to treat to prevent one death by day 100 was eight. Researchers said this compared favorably with the number needed to treat to prevent short-term mortality in acute, life-threatening conditions with other standards of critical care, which ranged from 1 to 59.
Adverse events occurred more frequently in the historical control arm. The most common adverse events in the defibrotide arm that were attributable to therapy included hypotension (39% for defibrotide vs. 50% for historical control), diarrhea (25% vs. 41%) and vomiting (21% vs. 25%).
“There was also a low rate of significant hemorrhage seen with defibrotide, which proved generally manageable with holding treatment, using appropriate factor support and platelet transfusion and resuming therapy once the patient stabilized,” Richardson said.
These data formed the basis for the approval of defibrotide in the European Union last year. In December, Jazz Pharmaceuticals announced the initiation of a rolling submission of a new drug application to the FDA.
“There is no other drug approved for the treatment of VOD, and we hope that the availability of defibrotide is therefore going to be a major advance in the field, with the European approval reflecting this,” Richardson said. “Defibrotide is now being embraced by the transplant community not only for the treatment of VOD, but also for its prevention, which is a key area for additional studies.”
Beyond VOD
Researchers also conducted another analysis — presented by Selim Corbacioglu, MD, of the University of Regensburg in Germany — on the use of defibrotide in a compassionate use program in the EU comprised of 710 patients with VOD.
In this population, the 100-day survival rate with defibrotide was 54% (95% CI, 0.5-0.58). The 25-mg/kg dose of defibrotide was associated with the highest 100-day survival rate (58%; 95% CI, 0.51-0.63).
“What is so compelling about the compassionate use program in the EU, and the U.S. expanded access program, are that the results are actually as good — if not better — than the phase 3 trial,” Richardson said. “That is really important because it suggests that even in centers that don’t necessarily have a lot of experience with defibrotide, the results and safety appear to be very consistent.”
Defibrotide may have treatment implications beyond VOD.
These studies — as well as a randomized, prospective trial in high-risk children by Corbacioglu and colleagues, published in 2012 in The Lancet — showed “a meaningful reduction” in the rate of graft-versus-host disease, Richardson said.
“That’s a very important area for further evaluation in my opinion,” Richardson said. “Moreover, defibrotide does not appear to compromise the ability of patients to remain disease free from their underlying malignancies. In fact, there is evidence that defibrotide — through its effects on endothelial stabilization — may enhance the antitumor activity of other drugs, which will also be an important area of future research.” – by Alexandra Todakn
References:
Corbacioglu S, et al. Lancet. 2012;doi:10.1016/S0140-6736(11)61937-7.
The following were presented at: BMT Tandem Meetings; Feb. 11-15, 2015; San Diego:
Corbacioglu S, et al. Defibrotide for treatment of severe hepatic veno-occlusive disease: An update from the international compassionate use program in 710 patients.
Richardson PG, et al. Defibrotide for treatment of severe hepatic veno-occlusive disease: An analysis of clinical benefit as determined by number needed to treat to achieve response and to improve survival.
Richardson PG, et al. Updated results from the ongoing U.S. treatment IND study using defibrotide for patients with hepatic veno-occlusive disease.
For more information:
Paul G. Richardson, MD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: paul_richardson@dfci.harvard.edu.
Disclosure: Richardson and Corbacioglu report research funding from and advisory/consultant roles with EUSA Pharma, Gentium SpA and Jazz Pharmaceuticals. Other researchers report employment with and equity ownership in Jazz Pharmaceuticals.
Perspective
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Gerhard Hildebrandt, MD, FACP
More than 15 years ago, Richardson and colleagues reported on 19 patients with severe VOD who were treated with defibrotide, leading to resolution of findings in 42% and six patients surviving beyond day +100. Results were interpreted as “compelling and warranting further evaluation,” considering historical mortality rates exceeded 80%. Since then, the transplant community has literally craved to reach where we are now: having access to a drug that can combat plus possibly prevent VOD as a deleterious complication after transplant, for which our armamentarium is otherwise sparse.Three presentations at the most recent BMT Tandem Meetings in San Diego underscored the rationale of using defibrotide in the treatment of VOD. The first, an update from the International Compassionate Use Program — which included 710 patients from 312 centers worldwide who had received defibrotide for VOD following transplant or post-chemotherapy and radiotherapy — reported an OS at day +100 of 58% in the 25-mg/kg a day group. Richardson presented data from a previous multicenter study, which demonstrated a number needed to treat of seven to achieve one complete response and of eight to prevent one death.
Lastly, in an update on the current Treatment IND study (NCT00628498) — which included 641 patients with VOD, presenting the largest and still ongoing prospective evaluation to date — day +100 survival in allograft patients was 50%, and day +100 survival in autograft patients was 66%. Treatment seemed well tolerated, safe and without excessive bleeding rates.
Therefore, defibrotide presents light after darkness in the treatment of VOD. Its preventive role and its use in combination therapies is currently being investigated. Whether similar protective effects on the endothelium from being damaged by graft-versus-host disease (GVHD) reactions are responsible for the recently reported reduction in GVHD and whether its use is beneficial in posttransplant microangiopathy needs to be explored further. Last but not least, preliminary data suggest defibrotide mediated antitumor effects, underscoring the multifaceted potential of this novel drug.
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