Very early/early relapses of acute lymphoblastic leukemia show unexpected changes of clonal markers and high heterogeneity in response to initial and relapse treatment

Abstract

Minimal residual disease (MRD) quantified after induction treatment of childhood acute lymphoblastic leukemia (ALL) predicts risk of relapse. It has been assumed that early relapses derive from a residual population of leukemic cells, which is still present after induction and that relapsed disease will consequently be more resistant to treatment. To test these hypotheses, we performed a prospective study on patients treated according to the frontline-trial ALL-BFM 2000, which used MRD response for risk-group stratification. Patients (n ¼ 45) showed a median time to relapse of 1.5 years. In 89% of patients at least one T-cell-receptor/immunoglobulin gene rearrangement chosen for initial MRD quantification remained stable; however, at least one of the preferred markers for MRD stratification at relapse was different to diagnosis in 50% of patients. A similar proportion of very early, early and late relapses appeared to gain a marker at relapse although backtracking-analysis revealed that in 77% of cases, the gained markers were present as small sub-clones at initial diagnosis. Comparing initial and relapse MRD response to induction, 38% of patients showed a similar, 38% a better and 25% a poorer response after relapse. These data demonstrate an unexpectedly high clonal heterogeneity among very early/early relapses and challenge some current assumptions about relapsed ALL.

Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome

“…4,29 Nearly 90% of patients with very early relapses were stratified as high-risk or greater at initial diagnosis indicating that clinical and genetic features present at diagnosis affect survival after relapse. 30,31 In this study, two-thirds of the T-cell relapses occurred within 18 months, but contrary to previous findings, immunophenotype was not an individual prognostic factor for OS since it was over-ruled by other co-variates in the adjusted regression analysis. Interestingly, the interaction between WBC at diagnosis and T-cell immunophenotype created a strong prognostic variable.…”

High sensitivity and clonal stability of the genomic fusion as single marker for response monitoring in ETV6‐RUNX1‐positive acute lymphoblastic leukemia

“…Additionally, some Ig/TCR markers might only be present in subclones of different sizes with potentially different response kinetics to treatment, which may result in an over-or underestimation of those subclones. [3][4][5][6][7][8][9][10][11] Furthermore, the subgroup of ETV6-RUNX1-positive ALL frequently harbors a variety of different Ig/TCR markers at diagnosis, often showing evidence of oligoclonality. 12,13 This might result in false negative results or over-and underestimation of MRD values at different timepoints during therapy.…”

Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment

“…This is reminiscent of a large clinical study that reported the loss of both diagnostic MRD markers at relapse in 11% of patients. 38 We then screened 10 cases (5 VHR-ALL and 5 SR-ALL) systematically for the presence of 23 clonal specific Ig/TCR rearrangements in the diagnostic and corresponding xenografts, looking at replica from the same passage number and at serially passaged xenografts ( Figure 6). We sequenced all detected bands of the expected size to verify accuracy of the PCR on xenograft material at least once.…”