NEW YORK (FRONTLINE MEDICAL NEWS) – Allogeneic hematopoietic stem cell transplantation (alloHCT) using HLA-compatible donors results in excellent long-term progression-free survival in younger high-risk chronic lymphocytic leukemia (CLL) patients, an analysis of data from a European Society for Blood and Marrow Transplantation registry cohort suggests.

AlloHCT may, in some patients, be preferable to sequential targeted therapy, according to Michel van Gelder, MD.

Patients with relapsed/refractory CLL have very high responses with the kinase inhibitors ibrutinib and idelalisib or the BCL2 inhibitor venetoclax, but the risk of becoming treatment refractory remains a concern when these drugs are used sequentially, particularly in those with high cytogenetic risk resulting from del(17p), TP53 mutation, or del(11q), Dr. van Gelder said at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.

This is especially true for those progressing with Richter’s syndrome, who comprise about one-third of patients, he noted.

“On the other hand, allogeneic stem cell transplantation can induce prolonged progression-free survival,” said Dr. van Gelder of Maastricht (the Netherlands) University Medical Center.

Further, most alloHCT patients become minimal residual disease negative, which predicts prolonged progression-free survival (PFS).

“The down-side, of course, is nonrelapse mortality,” he said, noting that NRM depends on factors such as age, performance status, and HLA match.

In a recent risk factor analysis currently pending publication, he and his colleagues found, in a large group of patients, that age, performance status, remission at time of transplant, donor relationship, HLA and sex match each had an impact on 5-year PFS after alloHCT.

The more risk factors a patient had, the worse the outcome, he said.

Based on current knowledge, the place for alloHCT in CLL treatment is in patients with high-risk cytogenetics. Patients can be treated first with a kinase inhibitor or venetoclax followed by transplant, or they can wait for progression and then do the transplant, he said.

Those without high risk cytogenetics but with short PFS after treatment with a kinase inhibitor or venetoclax may also be candidates for alloHCT, he added.

“Preferably they should be young [and] have a good matched donor and low comorbidity,” he said.

In the current study, the focus was on younger CLL patients. “We tried to identify factors that predict for a low 2-year NRM and a high 8-year PFS. We studied the impact of high risk cytogenetics, and, for this study, we chose del(17p) and del(11q), and we tried to officialize the PFS, the relapse incidence, and the nonrelapse mortality of so-called ‘good transplant risk CLL patients’ with these high cytogenetic risk factors,” he explained.

In 197 patients under age 50 years (median 46 years) with a median follow-up of 90 months in an updated EBMT registry cohort, the most important relevant prognostic factor for 2-year NRM was the donor HLA match (adjusted hazard ratio, 2.5 for a matched unrelated donor, 4.0 for a partially matched unrelated donor, both vs. a matched sibling), and predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio, 1.7), and partially HLA matched unrelated donor (HR, 2.8).

High-risk cytogenetics did not significantly impact 8-year PFS, Dr. van Gelder said, noting that this confirms findings from prior studies.

Most of the patients included in the analysis were fludarabine refractory, 70% had del(17p), 35% had del(11q), and the median number of prior treatments was 3. Additionally, 12% had previous autologous transplant, 62% had remission at time of transplant, and most had good performance status, he said.

Conditioning regimens varied by site, 42% of patients had an HLA-matched sibling donor, and 50% had a matched unrelated donor.

Based on the regression model, a reference patient with high risk cytogenetics (del[17p] and/or del[11q]) and good transplant characteristics (age 46 years, no prior autologous stem cell transplantation, remission at the time of alloHCT and HLA- and sex-matched sibling donor) was created. A reference patient with poor transplant characteristics (not in remission at the time of transplant, with an unrelated, non-sex-matched donor) was also created. The predicted 2-year NRM for the good transplant risk patient was 12.1%, and 8-year PFS was more than 50%, Dr. van Gelder said.

For the poor risk patient, 2-year NRM was 37%, and PFS was below 50%, he said.

“So, in conclusion … good transplant risk young patients with a low nonrelapse mortality and high 8-year progression-free survival can be identified,” he said.

The problem in clinical practice is determining whether – and when – to do a transplant in a young patient, he continued.

“There are a lot of possibilities. Nobody knows, of course, what is the best regimen, but a problem in these patients is that, if they have progression with Richter’s transformation, then you are lost,” he said. “So, if you would like to prevent this, and you have a patient with a low nonrelapse mortality risk, maybe it is better to do the transplant before.”

As for whether alloHCT can be done after kinase inhibitor therapy, the data are limited, but data presented at EBMT 2017 suggest the approach is feasible and effective. In 43 younger patients who underwent alloHCT after ibrutinib treatment, including 37% with TP53 mutation, the 1-year NRM and PFS rates were 9% and 63%, which is “in the same range as in the era before kinase inhibitors,” Dr. van Gelder said regarding the abstract presented by Peter Dreger, MD.

In 32 patients who underwent alloHCT after idelalisib treatment, including 44% with del(17p)/del(11q) and 85% in remission at the time of alloHCT, early follow-up showed that 6-month NRM and PFS was 7% and 83%, respectively, according to another abstract presented by Johannes Schetelig, MD.

“It’s all about balancing the risks. On the one hand you can use sequential therapies. On the other, if you have patients with high-risk cytogenetics [and] CLL in remission and you have a well-matched donor, maybe you should consider the transplant earlier, Dr. van Gelder said. “If you have a good transplant patient in remission, I would propose [that you] don’t wait too long.”

Dr. van Gelder reported having no relevant disclosures.


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