Pretransplant Conditioning Regimens Reduce Treatment Failure After HSCT

Sergio A. Giralt, MD

Sergio A. Giralt, MD

Relapse remains the most important cause of treatment failure after hematopoietic stem cell transplant (HSCT) in patients with hematologic malignancies. Emerging strategies to improve HSCT outcomes by reducing the risk of relapse include novel drugs and targeted radiotherapy as part of the conditioning regimen followed by allogeneic HSCT. Some of the novel conditioning regimens were reviewed by Sergio A. Giralt, MD, at a satellite symposium to the 2017 BMT Tandem Meetings.¹

The spectrum of conditioning regimens in use ranges from low intensity to high intensity, with the former relying on a later graft-versus-host disease (GVHD) effect with decreased regimen-related toxicity while the latter increases the immediate antitumor effect at the cost of higher toxicity.

“We can reduce nonrelapse mortality by reducing the intensity of the regimen and relying on a GVHD effect but we pay a price by increasing the risk of relapse,” said Giralt, chief of the Adult Bone Marrow Transplant Service and the Melvin Berlin Family Chair in Multiple Myeloma at Memorial Sloan Kettering Cancer Center, New York City. Strategies that allow for exploiting dose intensity without increasing nonrelapse mortality are needed.

The best way to improve outcomes is early referral, but even that may not impact results in individuals with primary induction failure, who still represent about 30% to 40% of patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS), Giralt said. New graft sources can potentially lower relapse rates, and the use of KIR genotype—advantaged donors and cord blood (as opposed to haploidentical transplant), is currently being explored for this purpose.

New preparative regimens may allow for elimination of cells that could be potentially resistant to current conditioning strategies, Giralt said. Adding targeted agents to the pretransplant conditioning regimen has the potential to increase the antitumor effect. Options include gemtuzumab ozogamicin, an anti-CD33 monocloncal antibody; Iomab-B, a radiolabeled antibody—drug conjugate targeted against CD45; and rituximab, an antibody directed against CD20.

Optimizing delivery of currently used agents is another possibility, such as pharmacokinetic (PK)-directed therapy with intravenous busulfan. A 50% reduction in the dose of busulfan in the conditioning regimen in patients with advanced MDS/AML is associated with a significant decline in 18-month relapse-free survival compared with a high-intensity regimen. By adjusting the dose of busulfan to target an average daily area under the curve of 6000 µmol/min, a significant benefit in event-free survival is realized in patients with AML/MDS, and more so in patients with active disease.

Increasing radiation exposure to the tumor can reduce the risk of relapse, particularly the risk of early relapse; that is especially important in patients with active disease, “which represents for us today our major challenge,” said Giralt. Total body irradiation (TBI), however, cannot be safely dose-escalated. A novel method to deliver high-dose radiation directly to the tumor bed is targeted skeletal radiotherapy using ¹⁶⁶Holmium-DOTMP, a beta-emitting radiophosphonate. A phase I/II study found very high rates of complete remission among 41 patients treated with this technique but high rates of hypertension and grade 3/4 elevated creatinine at 9 months.²

Use of the radioimmunoconjugate iodine-131 tositumomab combined with B-BEAM (carmustine, etoposide, cytarabine, and melphalan) was not successful at improving progression-free survival or overall survival (OS) compared with rituximab plus BEAM in patients with relapsed diffuse large B-cell lymphoma.³

Targeting the CD45 antigen as a way to deliver high-dose radiation to the bone marrow is currently being explored. Some 85% to 90% of acute leukemias express CD45 and, importantly, it is absent from nonhematopoietic tissues. Iomab-B, an iodine-131 anti-CD45-based conditioning regimen, followed by allogeneic HSCT in patients with advanced AML/MDS was developed at Fred Hutchinson Cancer Research Center in Seattle, and has been tested in patients aged 50 and older with relapsed/refractory disease who were not candidates for a standard transplant.

Fifty-eight patients with active disease were treated (mean age, 63 years). In the first stage, single patients were treated at doses escalating in 2-Gy increments until the first dose-limiting toxicity (DLT). In the second stage, cohorts of 4 patients were started at the next lower dose, and doses were escalated in increments of 2 Gy if no DLT occurred. An additional cohort of 4 patients were treated at the same level if one patient experienced a DLT.

It was possible to deliver a total of 12 to 26 Gy to the bone marrow; the estimated maximal tolerated dose (MTD) was 24 Gy. Ten days following the treatment, patients received reduced intensity fludarabine (30 mg/m²/day) and low-dose TBI. At the MTD of 24 Gy to the liver, the mean dose delivered to the marrow was 36.1 Gy and the mean dose delivered to the spleen was 101.5 Gy. At 1 year, the rate of nonrelapse mortality was 22%, the relapse rate was 40%, and OS was 41%.⁴ “These are patients with active disease, where the relapse rate is expected to be almost 78%,” said Giralt.

A multicenter pivotal randomized 2-arm crossover phase III trial (SIERRA) of Iomab-B CD45 versus investigator’s choice prior to HSCT in patients aged 55 years and older with active, relapsed, or refractory AML has been designed, with a primary endpoint of durable complete remission at 6 months (NCT02665065).

The BMT Tandem Meeting Symposium was sponsored by an unrestricted educational grant from Actinium Pharmaceuticals, Inc, which is developing Iomab-B.

References

• Giralt SA. Clinical outcomes of new and emerging targeted conditioning regimens. Presented at: 2017 BMT Tandem Meetings; February 23-26, 2017; Orlando, FL.
• Christoforidou AV, Saliba RM, Williams P, et al. Results of a retrospective single institution analysis of targeted skeletal radiotherapy with (166)Holmium-DOTMP as conditioning regimen for autologous stem cell transplant for patients with multiple myeloma. Impact on transplant outcomes. Biol Blood Marrow Transplant. 2007;13(5):543-549. doi: 10.1016/j.bbmt.2006.12.448.
• Vose JM, Carter S, Burns LJ, et al. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013;31(13):1662-1668. doi: 10.1200/JCO.2012.45.9453.
• Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114(27):5444-5453. doi: 10.1182/blood-2009-03-213298.