Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation

Abstract

Relapse of pediatric acute lymphoblastic leukemia (ALL) remains the main cause of treatment failure after allogeneic stem cell transplantation (alloSCT). A high level of minimal residual disease (MRD) before alloSCT has been shown to predict these relapses. Patients at risk might benefit from a preemptive alloimmune intervention. In this first prospective, MRD-guided intervention study, 48 patients were stratified according to pre-SCT MRD level. Eighteen children with MRD level X1 Â 10 À4 were eligible for intervention, consisting of early cyclosporine A tapering followed by consecutive, incremental donor lymphocyte infusions (n ¼ 1-4). The intervention was associated with graft versus host disease Xgrade II in only 23% of patients. Event-free survival in the intervention group was 19%. However, in contrast with the usual early recurrence of leukemia, relapses were delayed up to 3 years after SCT. In addition, several relapses presented at unusual extramedullary sites suggesting that the immune intervention may have altered the pattern of leukemia recurrence. In 8 out of 11 evaluable patients, relapse was preceded by MRD recurrence (median 9 weeks, range 0-30). We conclude that in children with high-risk ALL, immunotherapy-based regimens after SCT are feasible and may need to be further intensified to achieve total eradication of residual leukemic cells.

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab

“…30,31,36 In the first year posttransplant there is little tolerance for chemotherapy, and hardly any chance for cure without proceeding to another transplant, which is only beneficial in a low or preferably negative MRD state. 7,8,10,12,37 We have shown that blinatumomab administration was feasible and had impressive antileukemic activity against highly chemorefractory disease in our pediatric patients, as has already been shown for adult B-ALL. 31,36 Six of 9 patients achieved complete remission after blinatumomab treatment irrespective of leukemia burden prior to the start of therapy.…”

“…[3][4][5][6] Level of pre-transplant minimal residual disease (MRD) has been shown to be an important adverse prognostic parameter for estimating the risk of relapse; MRD, therefore, influences long-term event-free survival after allogeneic stem cell transplantation. [7][8][9][10][11][12] In particular, patients who relapsed posttransplant have an extremely poor prognosis and need to achieve another hematologic remission or an even more advantageous very low or negative MRD level before proceeding to a subsequent SCT. 6 Additional chemotherapy will often be of limited benefit and may be associated with high toxicity.…”

Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells

“…The OS for adults with ALL who relapse after initial therapy is poor, with less than 10% 5-year OS and a median survival of 2-3 months (19,(24)(25)(26). To date, the most common relapse-reduction strategy after HSCT involves immune manipulation, ranging from donor lymphocyte infusion (DLI) to second HSCT (27)(28)(29). While graft-versus-host disease (GVHD) reduces relapse risk (30), conventional (not genetically modified) DLI provides minimal benefit in these patients, with remission rates below 10% and a high GVHD incidence (31,32).…”

Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia

“…86 This encouraging experience is contrasted by observations of more limited and largely temporary effects of such pre-emptive measures in acute leukemia, suggesting insufficiency to prevent overt relapse in many patients. 35,39,[87][88][89][90] Additional (pre-emptive) post-HCT therapy Useful additional post-HCT therapy could encompass conventional chemotherapies (ideally non-cross-resistant to those used for prior therapies), Ab-based therapeutics, epigenetic modifying drugs and/or molecularly targeted agents. Supporting this strategy, Platzbecker et al 91 observed that 16 out of 20 patients with CD34 þ AML or myelodysplastic syndromes who received the DNA methyltransferase I inhibitor, azacitidine, after they experienced a decrease in CD34 þ donor chimerisms to o80% responded with either increasing donor chimerism or stabilization thereof.…”