'Impressive' Results After Change of HSCT Conditioning Regimen in Myelofibrosis Patients

Liam Davenport

March 28, 2019

FRANKFURT, Germany — For patients with myelofibrosis who are about to undergo hematopoietic stem cell transplant (HSCT), switching from a conditioning regimen based on cyclosporine to one based on busulfan dramatically improved relapse and mortality rates, Italian researchers discovered after performing a before and after comparison.

The study compared outcomes in 2000–2010 and 2011–2018 for transplants in more than 160 patients with myelofibrosis.

Between those two periods, patients went from mostly receiving conditioning regimens based on cyclosporine, to almost all being given regimen containing  thiotepa, busulfan, and fludarabine (TBF).

Patrizia Chiusolo, MD, PhD, assistant professor of hematology at Università Cattolica del Sacro Cuore, Rome, Italy, showed that, between the two treatment eras, 5-year relapse rates fell from almost 40% to just over 10%.

Over the same period, mortality rates decreased from 66% at 5 years to just under 40%, with the TBF conditioning regimen calculated to have improved survival by 60%.

This was underscored by the high rate of full donor chimerism achieved by 100 days with the new regimen. Crucially, rates of graft versus host disease (GVHD) were unchanged between the two eras.

The results were presented here at the European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019.

Chiusolo told the audience that the improved results with the later conditioning regimen may be because of the reduced dose of busulfan.

"Perhaps we are able to achieve a better result in terms of overall survival but also in terms of low transplant-related mortality," she said.

She also noted that the centers performed fewer splenectomies after 2010 to reduce pretransplant mortality, and thus ended up treating patients with larger spleens.

Donal McLornan, MD, PhD, consultant haematologist at Guy's and St Thomas' NHS Foundation Trust, London, UK, who co-chaired the session, said that the results were "very impressive."

He told Medscape Medical News that the relapse rates "are very different from what we've seen before with other retrospective and prospective studies, and I think it's probably reflective of the rate of chimerism".

McLornan added that the use of the TBF conditioning regimen is "very interesting...particularly for myelofibrosis."

"It's certainly underexplored in some countries outside Italy, and something that will be need to be looked at in a prospective manner," he said.

"When you see the more recent data they're showing with regards to GVHD, their engraftment rates and their overall survival, it's certainly something that should be explored prospectively."

Study Details

In order to compare the impact of changing the condition regimen on outcomes with allogeneic transplantation for myelofibrosis, Chiusolo and colleagues looked at results at two transplant centers in Genoa and Rome.

They divided the procedures into two eras, 2000–2010 and 2011-2018, during which 67 patients and 96 patients underwent HSCT, respectively.

From 2000 to 2010, the majority (60%) of patients received conditioning with cyclophosphamide and thiotepa, while 24% had another cyclosporine-based regimen and the remaining 16% had a range of drug combinations. Only one patient received TBF during this period.

In the 2011–2018 group, the proportion of patients who received the TBF conditioning regimen increased to 86%, with just 7% given fludarabine plus thiotepa, and 6% having busulfan and fludarabine.

For the post-2010 conditioning regimen, patients were given thiotepa 5 mg/kg on days 6 and 5 prior to HSCT, were given busulfan 3.2 mg/kg on days 4 and 3, and given fludarabine 50 mg/m2 on days 4, 3, and 2.

There were other differences between the 2000–2010 and 2011–2018 cohorts, with significantly fewer alternative donors in the earlier period, at 41% vs 84% after 2010 (P = .0001), and correspondingly more sibling donors.

Chiusolo pointed out that there were also baseline patient characteristic differences between the two eras.

Patients treated after 2010 were significantly older than earlier patients, at a median aged of 58 years vs 53 years (P = .001).

Moreover, patients treated later were more likely to be high risk on both the Dynamic International Prognostic Scoring System (DIPSS) and Transplant Score, at 96% vs 78% (P = .02).

Differences Between the Two Eras

Following transplantation, the cumulative incidence of acute and chronic GVHD was comparable in the two treatment eras.

Among patients treated between 2000 and 2010, 37% developed grade II–IV acute GHVD vs 28% of patients treated between 2011 and 2018, while 28% and 19%, respectively, developed chronic GHVD.

There were also comparable rates of non-relapse mortality between the two eras, at 5-year rates of 32% for patients treated in 2000–2010 and 25% for those treated in 2011–2018 (P = .3).

However, Chiusolo showed that there was a significant difference between the two eras in terms of proportion of patients who achieve full donor chimerism within 100 days.

For those treated in 2000–2010, 61% of patients receiving sibling donor grafts achieved full donor chimerism, as did 60% of those given grafts from alternative donors.

Among the patients treated from 2011–2018, these figures reached 100% and 91%, respectively.

This was reflected in the change in conditioning regimen, as similar results were seen when the researchers compared patients who received TBF conditioning with those who had other regimens.

Furthermore, molecular analysis in a subgroup of 18 patients indicated that 17 were negative for myelofibrosis-related mutations at 30 days posttransplant.

Specifically, 16 patients were negative for the JAK2 mutation, despite 44% of the 2000–2010 cohort and 51% of those treated after 2010 being positive at baseline.

Of more clinical significance, patients with myelofibrosis treated in 2011–2018 had a markedly reduced rate of relapse at 5 years compared with those treated earlier, at 12% vs 37% (P = .0001).

Patients treated from 2011–2018 also had significantly better 5-year survival than those treated 2000–2010, at 66% vs 39%.

When the team looked at the Transplant Score across 137 patients from the cohort, they found that both spleen size and prior transfusions had a marked impact on overall survival.

The 48 patients with a spleen size ≤22 cm and who had received ≤20 transfusions had a 5-year survival of 78%.

This compared with a survival rate of 45% among the 53 patients with a spleen size >22 cm or >20 transfusions and just 22% among the 36 patients with a spleen size >22 cm and >20 transfusions.

This difference remained when the researchers performed Cox multivariate analysis of factors associated with overall survival.

They found that a high DIPSS risk score was associated with a significantly increased mortality risk following HSCT for myelofibrosis, at a relative risk of 3.3 (P = .02), as was a high Transplant Score, at a relative risk of 2.7 (P = .007).

Conversely, receiving a TBF conditioning regimen was associated with a significantly reduced mortality risk, at a relative risk vs other conditioning regimens of 0.4 (P = .01).

No sources of funding were disclosed. Chiusolo and McLornan have disclosed no relevant financial relationships.

European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting 2019: Oral Session 2-7. Presented March 25, 2019.

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