Carlson, Robert H.
NEW ORLEANS—New findings showing that hematopoietic stem cell transplants are more accessible for patients previously not considered good candidates were highlighted in a news conference here at the American Society of Hematology Annual Meeting.
“We are overcoming historic barriers to transplantation such as matched donor and age, and improving long-term survival outcomes for those undergoing this procedure,” said the moderator, Jeffrey Miller, MD, Deputy Director of the Masonic Cancer Center and the Clinical and Translational Sciences Institute at the University of Minnesota.
Miller said the “practice-changer” in transplant has been reduced intensity of the preparative regimen. “Reduced intensity transplant has rapidly increased the number of transplants done because it makes it acceptable to do in the elderly, whether it's a haploidentical graft, or after any of the other grafts. I think greater than 90 percent of the people who need transplants are getting them.
“Between the cord blood and haploidentical transplant, unrelated donor transplant, and matched sibling donor, there is nobody who needs a transplant who should not get it in this day and age as long as they are healthy enough to undergo the transplant.”
Non-myeloablative related haplo-identical bone marrow transplant was the focus of a study by researchers at Johns Hopkins Kimmel Cancer Center, who reported that reduced-intensity transplant with post-transplant cyclophosphamide was not associated with prohibitive toxicities in patients over age 70.
And, from University College London Cancer Institute, research showed that access to transplants has improved considerably for ethnic minority patients, who have historically had more difficulty securing a suitably matched donor. Researchers say this is due in part to aggressive recruitment, global registries, and the use of new options such as the haploidentical-equivalent blood transplants.
Encouraging outcomes in older patients are being achieved following non-myeloablative haplo-identical blood or marrow transplantation (haploBMT) with high-dose post-transplantation cyclophosphamide (Abstract 158).
“Almost every patient has at least one haploidentical relative—parents and biological children are haploidentical by definition, and siblings are potentially—but until recently haploBMT carried excessive risk, particularly in older patients who are at higher risk of GvHD [graft vs. host disease] and end-organ toxicity,” Yvette Kasamon, MD, Associate Professor of Oncology and Medicine at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said in reporting the results.
In their retrospective study of patients undergoing transplant, the Johns Hopkins team found no apparent decrement in overall outcome in patients 70 or older when compared with those in their 50s. “Advanced age is no longer a barrier to successful outcomes with partially HLA-mismatched BMT,” she said.
YVETTE KASAMON, MD
The researchers evaluated the safety and efficacy of non-myeloablative haploBMT in 273 consecutive patients with poor-risk or advanced hematologic malignancies who were age 50 to 75 and received post-transplantation cyclophosphamide.
She explained that alloreactive T-cells are maximally stimulated on days 3 and 4 post-transplant, and thus have heightened sensitivity of being killed by high-dose cyclophosphamide. In contrast, non-alloreactive T-cells are quiescent and therefore relatively resistant to being killed by the cyclophosphamide.
The patients' median age was 61, and 10 percent were over 70. All had first-degree or half-sibling haploidentical donors.
Patients received cyclophosphamide (14.5 mg/kg IV days -6 and -5), fludarabine (30 mg/m2 IV days -6 to -2), total body irradiation (200 cGy day -1), and T-cell replete bone marrow (272 patients) or peripheral stem cells (one patient).
GvHD prophylaxis consisted of high-dose post-transplantation cyclophosphamide (50 mg/kg IV) either once (on day 3 for 10 patients) or twice (days 3 and 4 for 263 patients), along with mycophenolate mofetil and tacrolimus.
Maintenance therapy was permitted and included rituximab in 55 of 126 patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukemia.
Post-transplantation treatment was done in the outpatient setting.
With a median follow-up of 2.1 years, the two-year probability of progression-free survival (PFS) was 39 percent, and the two-year probability of overall survival was 53 percent. When the results were categorized by the patients' age, the two-year PFS probabilities at 2.1 years for patients in their 50s, 60s, and 70s were 39, 36, and 39 percent, respectively. The corresponding two-year probabilities for overall survival were 51, 56, and 44 percent.
“Notably, we found no statistically significant association between advanced-age patients and those 50 to 59, either in non-relapse mortality or PFS,” Kasamon said. “Although older age was associated with a tendency toward more grade 2 to 4 acute GvHD, relative to patients age 50 to 59, there was no evident increase in severe acute GvHD.”
“Since many elderly patients may lack a suitable matched sibling donor, the haplo option becomes more attractive,” Kasamon concluded, adding that considering data from this and similar studies, Johns Hopkins now has no upper age limit for reduced-intensity haploBMT transplants, and relies instead on functional and physical status to identify suitable candidates.
Non-European BMT Patients
Allogeneic transplant may be the only chance for cure for many patients with leukemia or lymphoma, but approximately two-thirds must find an unrelated donor. This is difficult for minority patients because the majority of donors in registries are of white northern European descent.
But, registries are expanding with the development of cord blood and haploidentical transplant, and researchers at University College London Cancer Institute's Anthony Nolan Research Unit, which manages the UK's stem cell donor registry, found that about 61 percent of non-white northern European patients were able to find a 9/10 or 10/10 matched donor (Abstract 2138).
ROBERT N. LOWN, MD
“This is a significant improvement on historical estimates,” said Robert N. Lown, MD, Medical Officer. “The use of cord blood or haploidentical transplants has leveled the playing field for non-white northern European patients seeking transplants other than with a HLA-identical sibling.”
The study followed 332 consecutive transplant patients, three-quarters of whom were white Northern European and the remaining 25 percent were non-white Northern European with similar underlying disease.
No significant differences were found between the groups in the total number of patients receiving transplants when considering all sources—63 percent for white Northern European and 56 percent for non-white Northern Europeans.
JEFFREY MILLER, MD
Non-white northern European patients did have more cord blood (21% vs. 3%), and haplo-identical transplants (10% vs. 1%), while white northern European patients had more fully matched donor transplants (69% vs. 20%).
Lown reported a slight difference in wait time from the search request to transplant between the two groups—a median of 110 days for white northern Europeans versus 132 days for non-white northern Europeans. But the data did not indicate whether the delay would impact outcomes, he said.
It is not known whether cure rates and survival with cord blood or haploidentical donor sources are as good as with unrelated donors, he added. “While we are bridging the gap in access, our next step is to identify potential minority transplant candidates earlier to determine their eligibility and help them seek the right transplant option. The battle is by no means won.”
Watch on the iPad edition of this issue as Yvette Kasamon elaborates, in an interview with OT reporter Dan Keller, on the encouraging outcomes in older patients using haplo-identical bone marrow transplantation followed by high-dose cyclophosphamide.
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