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Directly proceeding to HSCT after remission improves ALL outcomes
SALT LAKE CITY — Patients with relapsed or refractory acute lymphoblastic leukemia who achieved complete response to inotuzumab ozogamicin and directly proceeded to hematopoietic stem cell transplantation showed promising OS, according to study results presented at the BMT Tandem Meetings.
As HemOnc Today previously reported, trial results showed treatment with inotuzumab ozogamicin (Besponsa; Wyeth Pharmaceuticals, Pfizer) — an anti-CD22 antibody conjugated to calicheamicin — improved remission rates compared with standard chemotherapy among patients with relapsed or refractory ALL.
Partow Kebriaei, MD, professor in the department of stem cell transplant and cellular therapy at The University of Texas MD Anderson Cancer Center, and colleagues evaluated whether prior transplant and proceeding directly to HSCT after attaining remission with inotuzumab ozogamicin predicted post-HSCT survival.
“This is an important study in ALL because inotuzumab ozogamicin is an extremely effective agent in the salvage setting, allowing significant numbers of patients to achieve deep remissions, and subsequently proceed to transplant,” Kebriaei told HemOnc Today. “However, it is associated with liver toxicity and, unfortunately, this is a toxicity that overlaps with the toxicity of most conditioning regimens. So, it is important to investigate how we can optimize the use of inotuzumab ozogamicin among patients planned for subsequent transplantion.”
Kebriaei and colleagues evaluated data from two clinical trials of 236 patients treated with inotuzumab ozogamicin, 101 (43%; median age, 37 years; range, 20-71; 55% men) of whom proceeded to allogeneic HSCT. Sixty-two percent of patients received inotuzumab ozogamicin as first salvage treatment, and 85% of patients had no prior HSCT.
A majority of patients received matched related (25%) or unrelated (45%) HSCT, mostly with peripheral blood as the cell source (62%). Conditioning regimens were mostly myeloablative (60%) and total body irradiation based (62%).
Median OS following HSCT for all 101 patients was 9.2 months, and 41% (95% CI, 31-51) achieved 2-year OS.
Among 86 patients with a first HSCT, median OS was 11.8 months, and 2-year OS was 46% (95% CI, 35-56).
Twenty-eight patients lost complete response — or never achieved it — while waiting for HSCT and received additional treatments prior to HSCT.
The 73 patients who received no additional treatments and proceeded directly to HSCT had the best survival outcomes, with a median OS that was not reached (95% CI, 8.5-not reached) and a 2-year OS rate of 51% (95% CI, 39-62).
Fifty-nine of these patients (80%) achieved minimal residual disease negativity, and 49 (67%) were in first salvage therapy.
Survival 100 days after HSCT was 73.2% (95% CI, 63.4-80.7) for all patients, 75.6% (95% CI, 65.1-83.3) among patients undergoing first allogeneic HSCT, and 75.3% (95% CI, 63.8-83.7) among patients who directly proceeded to HSCT.
Nineteen patients experienced veno-occlusive disease.
“The initial early assessment following transplantation did not show a survival benefit to inotuzumab ozogamicin use pretransplant because there were early deaths from toxicity, namely veno-occlusive disease,” Kebriaei said. “Only with longer follow-up did we see benefit due to decreased relapse rates in the inotuzumab ozogamicin-treated patients.”
Multivariate analyses confirmed no prior HSCT and minimal residual disease negativity during inotuzumab ozogamicin treatment predicted lower risk for mortality following HSCT. Older age, higher baseline lactate dehydrogenase, higher last bilirubin measurement before HSCT and use of thiotepa predicted worse OS.
“Studies suggest increased risk for veno-occlusive disease with increased cycles of inotuzumab ozogamicin, so it’s critical to be ready to go to transplant quickly once remission is achieved,” Kebriaei said. “Continued studies are needed to see if further improvement in outcomes will occur if we avoid particularly hepatotoxic conditioning regimens and extensive inotuzumab ozogamicin exposure prior to transplant.” – by Alexandra Todak
Reference:
Kebriaei P, et al. Abstract 44. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Disclosures: The authors report no relevant financial disclosures.
Perspective
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The overall prognosis of relapsed and refractory ALL has been extremely grim historically with complete response rates using multiagent chemotherapy salvage regimens in the 20% to 30% range and median OS of only a few months. Minimal residual disease negativity could hardly be achieved and was reported as low as 4% in NCT01363297 for patients who received chemotherapy salvage treatment.
Two new immunotherapeutic agents, blinatumomab (Blincyto, Amgen) — a bispecific T-cell engager, or BiTE, linking CD19 positive B-ALL cells and CD3 positive T cells together — and inotuzumab, an antibody directed against CD22 and linked to a cytotoxic agent from the class of calicheamicins called ozogamicin, have provided new hope by not only inducing significant hematologic response rates, but also by strongly increasing rates of minimal residual disease negativity, a prerequisite for reduced relapse risk and successful allogeneic HSCT both in newly diagnosed and relapsed/refractory ALL.
Kebriaei and colleagues presented on the role of inotuzumab ozogamicin prior to allogeneic HSCT for relapsed/refractory ALL by conducting a subgroup analysis of two important studies — NCT01363297 and NCT01564784 — and looking at OS after allogeneic HSCT and related risk factors. The researchers highlighted a few key messages:
For patients with relapsed/refractory ALL, identify donor and donor availability early, as those patients who went straight from inotuzumab ozogamicin to first allogeneic HSCT in complete remission/complete remission with incomplete hematologic recovery (CR/CRi) had the best outcome, with a 2-year OS probability of 51.1% and median OS not reached. Twenty-eight of 101 patients did not achieve a CR with inotuzumab ozogamicin or relapsed prior to their transplant and, including these patients, 2-year survival probability was 45.7% for all patients undergoing first HSCT. For all patients undergoing their first or second allogenic HSCT, 2-year survival probability was 41%. Together, this suggests that having a donor ready for allogenic HSCT as soon as a CR/CRi can be achieved, is favorable;
In addition, multivariate analyses confirmed the benefit of achieving minimal residual disease negativity on overall outcome;
Comparing these outcomes to overall outcomes for relapsed/refractory ALL reported in the NCT01363297 trial — which showed similar minimal residual disease negativity of 78% for inotuzumab ozogamicin-treated patients vs. only 4% in salvage chemotherapy-treated patients, and an OS for the entire group of 7.7 months with inotuzumab ozogamicin and 6.7 months with salvage chemotherapy — as well as the median OS of 7.4 months reported in the NCT01564784 trial for relapsed/refractory patients treated with inotuzumab at higher doses, outcomes for those patients of these trials, who had received allogenic HSCT, was clearly superior; and
A level of caution must be raised, as 19 patients (18.8%) included in the presentation by Kebraiei and colleagues developed VOD, emphasizing the risk for VOD among patients having received inotuzumab ozogamicin and proceeding with transplant. A careful evaluation, especially in the presence of risk factors for VOD, is warranted.
Overall, inotuzumab ozogamicin seems to be a promising approach for patients with this historically infaust prognosis, and whether inotuzumab ozogamicin or blinatumomab should be the preferred agent to bring patients to transplant will most likely depend on patient- and disease-dependent factors, which will require further investigation before a decision can be made.
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