Achieving Molecular Remission before Allogeneic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: Impact on Relapse and Long-Term Outcome

Abstract

Allogeneic stem cell transplantation (alloHSCT) in first complete remission (CR1) remains the consolidation therapy of choice in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The prognostic value of measurable levels of minimal residual disease (MRD) at time of conditioning is a matter of debate. We analyzed the predictive relevance of MRD levels before transplantation on the clinical outcome of Ph+ ALL patients treated with chemotherapy and imatinib in 2 consecutive prospective clinical trials. MRD evaluation before transplantation was available for 65 of the 73 patients who underwent an alloHSCT in CR1. A complete or major molecular response at time of conditioning was achieved in 24 patients (37%), whereas 41 (63%) remained carriers of any other positive MRD level in the bone marrow. MRD negativity at time of conditioning was associated with a significant benefit in terms of risk of relapse at 5 years, with a relapse incidence of 8% compared with 39% for patients with MRD positivity (P = .007). However, thanks to the post-transplantation use of tyrosine kinase inhibitors (TKIs), disease-free survival was 58% versus 41% (P = .17) and overall survival was 58% versus 49% (P = .55) in MRD-negative compared with MRD-positive patients, respectively. The cumulative incidence of nonrelapse mortality was similar in the 2 groups. Achieving a complete molecular remission before transplantation reduces the risk of leukemia relapse even though TKIs may still rescue some patients relapsing after transplantation.

Transplantation in adults with relapsed/refractory acute lymphoblastic leukemia who are treated with blinatumomab from a phase 3 study

“…For adults with relapsed or refractory (R/R) ALL, the long‐term prognosis has been poor, with allogeneic hematopoietic stem cell transplantation (HSCT) performed in patients in CR after salvage therapy as the only potentially curative approach . Patients with no measurable disease (ie, molecular or minimal residual disease [MRD] remission) prior to HSCT consistently fare better than those with MRD …”

“…4 Patients with no measurable disease (ie, molecular or minimal residual disease [MRD] remission) prior to HSCT consistently fare better than those with MRD. [5][6][7][8] Blinatumomab, a bispecific T-cell-engaging (BiTE Ⓡ ) immuno-oncology therapy, redirects endogenous T-cells to cell surface antigen-expressing cancer cells (ie, CD19expressing B cells). After encouraging results obtained in phase 2 studies, [9][10][11][12] a phase 3 study (TOWER study) was conducted in 405 patients with R/R Philadelphia chromosome (Ph)-negative B-cell precursor ALL.…”

Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome‐positive acute lymphoblastic leukemia

“…13,14 Development of the ability to detect minimal residual disease (MRD) far below the level of 5% blast cells has changed the landscape of risk stratification over the last decade. 11,[15][16][17] Several studies have shown that chemotherapy combined with TKI, which gives a higher complete remission (CR) rate and further MRD reduction, enables allogenic HSCT in a larger proportion of patients. 18 Despite the evident benefit of giving TKI before allogenic HSCT, available data regarding the post-transplant use of TKI are limited.…”

The Persistence of Minimal Residual Disease in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: We Know It's Bad, Now What?

“…More recently, several retrospective studies have shown that MRD positivity measured prior to allogeneic hsct is also predictive relapse in adults with Ph+ ALL [3][4][5]. However, given that these have all been retrospective studies, patient populations, treatment strategies (including those with and without [6]. In this series, all patients were treated with a TKI (imatinib) plus chemotherapy, and then patients with a suitable donor underwent allogeneic hsct in CR1.…”