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Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL)

Barbara Wassmann, Heike Pfeifer, Michael Stadler, Martin Bornhaüser, Gesine Bug, Urban J. Scheuring, Patrick Brück, Matthias Stelljes, Rainer Schwerdtfeger, Nadezda Basara, Jolanta Perz, Donald Bunjes, Georg Ledderose, Rolf Mahlberg, Anja Binckebanck, Harald Gschaidmeier, Dieter Hoelzer and Oliver G. Ottmann

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Results of longitudinal MRD analysis in bone marrow performed at the time of (or within 6 weeks before) SCT, between SCT and study entry, and during imatinib therapy and follow-up. □ represents a negative result of quantitative RT-PCR; ▪, a positive PCR reaction; and ▦, a possible nonspecific result (ie, only 1 positive PCR reaction in duplicate samples or positivity exclusively in the nested PCR). R indicates relapse with the time from start of imatinib to relapse given in parentheses; * autologous SCT; #, patients with active GvHD; and §, SCT after dose-reduced conditioning; N.D., not done; A & W, alive and well.

  • Figure 2.

    Time to progression (TTP) calculated from the start of imatinib treatment for all 27 patients. Estimated median TTP for all patients was 6.6 months (range, 0.9-31 months). The estimated progression-free survival rate for all patients was 48% ±10% at 6.6 months without censoring at the time of imatinib discontinuation.

  • Figure 3.

    Time to progression by molecular response to imatinib, which was determined by longitudinal analysis of MRD levels throughout study treatment. All patients had detectable bcr-abl transcripts at study entry. Median TTP in patients who were found to convert to PCR negativity soon after initiation of imatinib was significantly longer than in patients who remained PCR positive (28.6 months versus 3.6 months; P < .001). Estimated progression-free survival rate for MRD responders was 91% ± 9% at 12 months and 68% ± 21% at 24 months compared with 8% ± 7% at 13 months for nonresponders.

  • Figure 4.

    DFS and OS by MRD response to imatinib treatment, determined by longitudinal analysis of bcr-abl transcript levels after study entry, at which all patients were PCR positive. Median DFS and OS in patients achieving early PCR negativity was significantly superior to that in patients who remained MRD+ after initiation of imatinib (28.6 months versus 3.6 months, P < .001; and median not yet reached versus 7.1 months, P < .001, respectively). The estimated DFS and OS rates in the MRD group were 54.5% ± 21% and 80% ± 18% at 24 months compared with 8% ± 7% and 23% ± 13% in the MRD+ group, respectively. The event at month 21 is due to a death in CR.

  • Figure 5.

    TTP by remission status at SCT. Median TTP in patients beyond CR1 at SCT was significantly inferior to that in patients who received transplants in CR1 (3 months versus 21.6 months; P = .01).

Tables

  • Table 1.

    Patient characteristics at study entry

    CharacteristicsData
    No. patients 27
    Age, y, median (range) 48 (16-63)
    Sex, no. (%)
        Male 14 (52)
        Female 13 (48)
    Breakpoint, no. (%)
        M-Bcr-Abl (b2a2, b3a2) 7 (26)
        m-Bcr-Abl (e1a2) 20 (74)
    Prior imatinib therapy, no. (%)
        In CR1 during first-line therapy 9 (33)
        Salvage therapy 9 (33)
    Type of transplantation, no. (%)
        Autologous 3 (11)
        Allogeneic 24 (89)
        Matched related 14 (58)
        Matched unrelated 9 (38)
        1 antigen-mismatch unrelated 1 (4)
    Disease status at SCT, no. (%)
        CR1 21 (78)
    First or second relapse 3 (11)
        Refractory 2 (7)
        PR 1 (4)
    Conditioning, no. (%)
        Nonmyeloablative 7 (26)
        Myeloablative 20 (74)
        TBI-based 17 (85)
        Non-TBI-based 3 (15)
    Time from SCT to MRD+, mo, median (range) 3.6 (0.5-18.2)
    Time from SCT to imatinib start, mo, median (range) 4.4 (1.1-19.2)
    GvHD, no. (%)
        Active GvHD 11 (46)
        Acute GvHD grades I-II 2
        Chronic GvHD 9
            Limited 8
            Extensive 1
    Immunosuppressive therapy, no. (%)
        Steroids 2
        CSA 4
        Steroids and CSA 5
    WBCs × 109/L, median (range) 5.8 (3.1-13.2)
    ANC × 109/L, median (range) 3.9 (1.3-7.1)
    Platelets × 109/L, median (range) 157 (41-370)
    • M indicates major; m, minor; CSA, cyclosporin A.