New Conditioning Regimens May Prevent Blood Cancer Relapses

Partow Kebriaei, MD

Patients with hematologic malignancies who receive a hematopoietic stem cell transplant (HSCT) still risk treatment failure through relapse. As part of a conditioning regimen prior to allogenic HSCT, strategies are emerging to improve HSCT outcomes by reducing the risk of relapse. Several of these conditioning regimens were reviewed during a satellite symposium to the 2017 BMT Tandem Meetings (the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation).¹

The spectrum of conditioning regimens ranges from low-intensity to high-intensity, with the former relying on a 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 Sergio A. Giralt, MD, chief, Adult Bone Marrow Transplant Service and the Melvin Berlin Family Chair in Multiple Myeloma, Memorial Sloan Kettering Cancer Center, New York City, during the satellite symposium.

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 affect results in individuals with primary induction failure who still represent about 30% to 40% of patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), said Giralt. New graft sources could lower relapse rates, and the use of KIR genotype-advantaged donors and cord blood (as opposed to haploidentical transplant) are currently being explored.

New preparative regimens, including novel drugs and targeted radiotherapy, may help eliminate cells that could be resistant to current conditioning strategies, Giralt said. Adding targeted agents, such as Iomab-B, a radiolabeled antibody—drug conjugate targeted against CD45, and rituximab (Rituxan), an antibody directed against CD20, to the pretransplant conditioning regimen has the potential to increase the antitumor effect.

Targeting the CD45 antigen is currently being explored as a way to deliver high-dose radiation to the bone marrow. 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 or MDS, was developed at Fred Hutchinson Cancer Research Center in Seattle and has been tested in patients ≥50 years 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, which was escalated in increments of 2 Gy if no DLT occurred. An additional cohort of 4 patients was treated at the same level if 1 patient experienced a DLT.

It was possible to deliver 12 to 26 Gy to the bone marrow; the estimated maximum tolerated dose (MTD) was 24 Gy. Ten days following the treatment, patients received reduced-intensity fludarabine (30 mg/m²/day) and low-dose total body irradiation (TBI). The mean doses delivered to the marrow and spleen were 36.1 Gy and 101.5 Gy, respectively. At 1 year, the rate of nonrelapse mortality was 22%, the relapse rate was 40%, and overall survival (OS) was 41%.²

“These are patients who have more resistant disease, but at the same time have less tolerance for traditional cytotoxic chemotherapies,” said Partow Kebriaei, MD, in an interview withTargeted Therapies in Oncology^TMafter the session.

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

“We’re very interested in the trial, which is using a radiolabeled anti-CD45 antibody and targeted radiation to help patients who are older and have active leukemia. It’s a way to allow us to use a reduced-intensity conditioning regimen, but one that’s still very targeted and focused to their disease,” said Kebriaei, associate professor, Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, who is also an investigator on the SIERRA trial.

Optimizing the delivery of currently used agents is another possibility, such as pharmacokinetic-directed therapy with intravenous busulfan (Busulfex, Myleran). A 50% reduction in the dose of busulfan in the conditioning regimen in patients with advanced AML or MDS 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 mcmol/min, a significant benefit in event-free survival is realized in patients with active disease.

Increasing radiation to the tumor can also reduce the risk of relapse, particularly the risk of early relapse in patients with active disease. TBI, however, cannot be safely dose-escalated. A novel method to deliver high-dose radiation to the tumor bed is targeted skeletal radiotherapy using Holmium-166-DOTMP, a beta-emitting radiophosphonate. A phase I/II study found very high rates of CR among 41 patients treated with this technique, but also high rates of hypertension and grade 3/4 elevated creatinine at 9 months.³

Use of the radioimmunoconjugate iodine-131 tositumomab combined with B-BEAM (carmustine, etoposide, cytarabine, and melphalan) was not successful at improving OS compared with rituximab plus BEAM in patients with relapsed diffuse large B-cell lymphoma.⁴

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

References:

1. Giralt SA. Clinical outcomes of new and emerging targeted conditioning regimens. Presented at: 2017 BMT Tandem Meetings; February 23-26, 2017; Orlando, FL.
2. Pagel JM, Gooley TA, Rajendran J, et al. Allogeneic hematopoietic cell transplantation after con- ditioning with 131I-anti-CD45 antibody plus udarabine and low-dose total body irradiation for el- derly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2009;114(27):5444-5453. doi: 10.1182/blood-2009-03-213298.
3. 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.
4. 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 di use 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.