Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part III. Prevention and Treatment of Relapse after Allogeneic Transplantation

Abstract

In the 2nd NCI Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Prevention and Treatment of Relapse after Allogeneic Transplantation highlighted progress in developing new therapeutic approaches since the 1st Relapse Workshop. Recent insights that might provide a basis for the development of novel, practical clinical trials were emphasized, including utilization of newer agents, optimization of donor lymphocyte infusion (DLI), and investigation of novel cellular therapies. Dr. de Lima discussed preemptive and maintenance strategies to prevent relapse after transplantation, e.g., recent promising results suggestive of enhanced graft-versus-tumor activity with hypomethylating agents. Dr. Schmid provided an overview of adjunctive strategies to improve cell therapy for relapse, including cytoreduction prior to DLI, combination of targeted agents with DLI, and considerations in use of second transplants. Dr. Porter addressed strategies to enhance T-cell function, including ex-vivo activated T cells and T-cell engineering, and immunomodulatory approaches to enhance T-cell function in vivo, including exogenous cytokines and modulation of costimulatory pathways.

Post-relapse survival after haploidentical transplantation vs matched-related or matched-unrelated hematopoietic cell transplantation

“…These strategies would include improving the preparative regimen, graft engineering, pre-emptive therapy based on minimal residual disease detection, early withdrawal of immunosuppression and maintenance post transplant. 29 We have implemented a few strategies to prevent relapse after HIDT and these include manipulation of the preparative regimen by increasing the conditioning intensity. We currently have a clinical trial with fludarabine-and melphalan-based conditioning to assess if higher intensity (compared with non-ablative fludarabine/cyclophosphamide/TBI) in the HIDT setting can yield lower relapses as has been shown with MRDT and MUDT in the BMTCTN 0901 trial.…”

“…16,30 Other local strategies we are using include post-transplant maintenance therapy such as hypomethylating agents for high-risk MDS and AML patients, 20 clinical trials with FLT-3 inhibitors for AML patients who harbor the FLT-3 ITD mutation and MRD monitoring, especially for patients with Philadelphia-positive ALL. 29 Clinical trials using one or combination of different strategies aiming at preventing relapse and/or using molecular and cellular targets for post-relapse treatment are currently being investigated in many centers with the hope of better disease control after allogeneic HCT. Post-relapse survival after haploidentical HCT M Solh et al…”

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…In the first one, we analysed the outcome of 154 patients with hematologic (88%) or molecular (12%) relapse of AML or MDS after allo-HSCT. All were treated with Aza (median 4 courses; range [4][5][6][7][8][9][10][11][12][13][14] and DLI (administered to 105 patients, 68%) either as first (93%) or later (7%) salvage approach at 12 transplant centres participating in the german cooperative transplant study group [22]. The size of this patient group and the quality of data provided by the participating centres enabled us to identify patients who may benefit most from the combination of Aza and DLI.…”

“…Traditionally, treatment options were limited and have generally consisted of palliative care, low-dose or intensive chemotherapy as well as cellular therapies such as donor lymphocyte infusions [3] and second transplantation in selected cases. Still, the fact that many patients can either not tolerate intensive therapies or are refractory to these conventional interventions indicates the relevant need for novel treatment approaches [4]. Ideally, such a therapy mediates direct antileukemic effects and strengthens the graft-versus-leukemia (GvL) reaction, while on the other hand is not associated with an extensive risk for severe graft-versus-host disease (GvHD) and offers an acceptable toxicity profile.…”

Relapse post hematopoietic SCT remains the Achilles heel for the field

“…The committee acknowledged that there are several confounding factors and a lack of clinical studies. 20,21 Although the most of the focus was on preventing relapse, the committee reported on potential advances in using novel cellular therapies to address relapse. The committee acknowledged the need for prospective well-designed international studies to address the best way to manage posttransplant relapse.…”