Chronische myeloische Leukämie

V636 PD-1-Expression und molekulares Rückfallrisiko bei Patienten mit chronischer myeloischer Leukämie und Nilotinib-Stopp-Versuch

Christian Michel, Marburg, D

Introduction: The mechanism underlying treatment free remission (TFR) in patients with chronic myeloid leukemia (CML) supposedly involves restored anti-CML immunity. As murine data previously suggested that Programmed Cell Death Protein-1 (PD1)-induced immune escape in CML could be overcome by PD-1 inhibition, we wished to prospectively assess a hypothetical link between PD1 expression on cytotoxic CD8-positive T cells (CTL) and TFR probability in patients treated within the German CML-V study (TIGER). TIGER randomized into a treatment with nilotinib monotherapy and a combination treatment with nilotinib plus pegylated interferon a2b (pegIFN).

Methods: Within a substudy of the TIGER trial (EUDRACT 2010-024262-22), frequencies of PD-1-positive CTL were quantitated by fluorescence-activated cytometry at months 12, 36 and 48 after study treatment initiation in both therapy arms. TFR was defined as a BCR-ABL level according to the international scale (IS) of 0.1% or less without therapy. Patients in the nilotinib monotherapy arm were divided into patients with a high versus a low proportion of PD-1+CTL using a median split of the PD-1+CTL proportion at month 12 after study start. To estimate TFR probabilities in PD-1-high and PD-1-low patients, Kaplan-Meier method and the log-rank test were used.

Results: Between 08/2012 (CML-V study start) and 06/2020 PD-1-positive CTL were quantitated from 286 patients. Of these, 241 achieved a deep molecular remission of MR4 or better, of whom 146 patients started a TFR attempt and were thus eligible for analysis. While the PD-1+CTL proportion was significantly higher in CML patients than in healthy donors, the decline of PD-1+CTL at months 12, 36 and 48 did not correlate with TFR-probability. The estimated hazards for relapse in PD-1+ CTL high versus PD-1+ CTL low cohorts were also not significantly different (Hazard ratio (HR) 0,95; 95%-CI: 0.37-2.39). The final updated results will be presented at the meeting.

Conclusions: In this prospective substudy of the CML-V trial, an association between molecular remission depth, PD-1-positive CTL frequencies and risk of molecular relapse after nilotinib stop could not be found. Thus, targeting the PD1-checkpoint to overcome CTL exhaustion might not be a good strategy to improve TFR rates in CML.


V157 Absetzversuche nach TKI-Therapie bei Patienten mit chronischer myeloischer Leukämie außerhalb von klinischen Studien: Zwischenergebnisse der Epidemiologischen Studie zur Versorgungslage von CML-Patienten in Deutschland (CML VI)

Katharina Kohlbrenner, Mannheim, D

Introduction: With the advent of tyrosine kinase inhibitors (TKI), the outcome of patients with chronic myeloid leukemia (CML) has improved significantly. Treatment-free remission (TFR) is a growing treatment goal. Information on discontinuation of TKI (TKI-stop) outside of clinical trials is limited. Methods: Within the CML VI trial, patients with newly diagnosed CML between 1.1.2013 and 31.12.2019 were registered and followed annually. Primary endpoint was the time to and reason for switching of any first line treatment. In this analysis, we focused on TFR-data.

Results: 540 adult patients have been registered from 91 centers, 512 were evaluable. Median age at diagnosis was 59 years (range 16-100), 271 patients (53%) were male. Information on first-line TKI- treatment was available for 470 patients: 195 (41%) patients were treated with imatinib, 136 (30%) with nilotinib and 139 (30%) with dasatinib. TKI switch was reported in 163 cases (34%) after median of 10 month (range 0-68 month).

So far, TKI-stop for more than one month has been reported in 67 patients: Reasons for TKI-stop was intolerance in 33 patients, attempt for TFR in 25 patients, patient wish (8) und unknown (1). Median age at diagnosis of the 25 patients with TFR-attempt was 67 years (range 26-86), 14 (56%) were male. Median TKI-treatment before TKI-stop was 53.5 month (range 32-76). Only 6 patients (24%) met all criteria for a TFR-attempt as defined by Hochhaus et al (Onkopedia 2018): 23 patients (92%) with typical b2a2 or b3a2-BCR-ABL1 transcripts, 22 patients (88%) were monitored on International Scale (IS), 22 (88%) had optimal response in first-line, 19 (76%) achieved deep molecular remission (DMR), 17 (68%) had a stable DMR for at least 24 month, and only 8 patients (32%) were treated for ≥ 5 years. After all, 23 patients (92%) had a TKI-treatment for at least 3 years. So far, 15 patients are still in TFR with a median TFR-duration of 15.7 months (range 1-36). However, 10 patients had to restart TKI after loss of molecular remission after median of 5.6 months (range 3-11).

Conclusion: This interim report of the CML-VI registry provides information on baseline characteristics and treatment of CML patients outside of clinical trials. In routine care data demonstrate high switching rates of first-line treatment and frequent TKI-stop without meeting the guideline criteria. The CML registry offers the chance to collect important data including TFR-data outside of clinical trials.


V381 Bosutinib (BOS) versus Imatinib (IMA) bei neu diagnostizierter chronischer myeloischer Leukämie (CML) in der chronischen Phase (CP): Finale 5-Jahres auswertung der BFORE-Studie
Tim Henrik Brümmendorf, Aachen, D

Introduction: Approval of BOS for patients (pts) with newly diagnosed Philadelphia-chromosome- positive (Ph+) CP CML was based on primary results from BFORE (phase 3 trial; NCT02130557); it showed superior efficacy vs IMA in the modified intent-to-treat (ITT) population (Ph+ with e13a2/e14a2 transcripts) after ≥12 mo follow-up. We report the final efficacy/safety results after 5 y (240 wks) of follow-up.

Methods: Pts were randomized to receive 400 mg once daily BOS (n=268) or IMA (n=268; 3 untreated). Efficacy was assessed in the ITT population (all randomized pts), and safety in all treated pts. Database lock: June 12, 2020.

Results: At study completion (BOS vs IMA), 59.7% vs 57.4% were still on treatment (Tx); 86.6% vs 86.2% completed 5 y on study. Median duration on Tx and study was 55 mo for pts receiving BOS or IMA; respective median dose intensity was 394 vs 400 mg/d. Most common reasons for permanent Tx discontinuation (BOS vs IMA) were adverse events (AE; 25.0% vs 12.5%) and lack of efficacy (4.9% vs 16.2%). Cumulative major molecular response (MMR) rate by 60 mo was higher with BOS vs IMA (73.9% vs 64.6%), as were cumulative molecular response MR4 (58.2% vs 48.1%) and MR4.5 rates (47.4% vs 36.6%; Table). Responses were achieved earlier for pts in the BOS vs IMA arm. Cumulative incidence functions for MMR, MR4 and MR4.5 were higher with BOS vs IMA (HR [95% CI]: MMR 1.34 [1.10-1.64], MR4 1.34 [1.07-1.69], MR4.5 1.41 [1.09-1.83]). Superior MRs with BOS vs IMA were consistent across Sokal risk groups (Table). On-Tx transformations to accelerated/blast phase occurred in 6 BOS- and 7 IMA-treated pts. No transformations occurred after 24 mo. 60-mo event free- and overall survival rates (BOS vs IMA) were similar (Table).
Any grade Tx-emergent AEs (TEAEs) occurred in 98.9% (grade 3/4, 73.5%) and 98.9% (grade 3/4, 57.0%) of BOS vs IMA-treated pts. Among TEAE clusters of special interest, gastrointestinal, liver and rash were more frequent (≥10% difference in any grade TEAEs) in the BOS arm, and edema and musculoskeletal in the IMA arm.

Conclusions: These final results from BFORE continue to support the use of first-line BOS as a standard of care in pts with CP CML.


V32 Bosutinib (BOS) in der Zweitlinie der chronischen myeloischen Leukämie (CML) in der CP: finale 10-Jahresdaten der Phase 1/2-Studie
Tim Henrik Brümmendorf, Aachen, D

Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and for newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or ‐intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and its extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only (n=284) were included.

Results: 19% of pts were on BOS at y 10, 13% were still receiving BOS at study completion after ≥10 y and 19% completed ≥10 y of FU. Median (range) Tx duration was 26 (< 1-170) mo and FU duration 54 (1-172) mo. Median (range) dose intensity was 436 (87-599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response/disease progression, 27%) and adverse events (AEs; 26%). Cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates are shown in the Table for pts with a valid baseline assessment. Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 >50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier overall survival 72% (Table). 55 deaths (IM-R, n=41; IM-I, n=14) occurred on study due to disease progression (n=30), AEs (n=16; none BOS-related), or other (n=5) or unknown (n=4) causes. Any grade Tx-emergent AEs (TEAEs) occurring in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%); median cumulative duration of the respective events was 32, 9 and 133 days. Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation — most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%).

Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use for CP CML after imatinib failure.

V207 Gesundheitsbezogene Lebensqualität von Patienten mit chronischer myeloischer Leukämie im Vergleich zur Restbevölkerung
Marcel Lorch, Mannheim, D

Introduction: The majority of patients with chronic myeloid leukemia (CML) require lifelong treatment with tyrosine kinase inhibitors (TKI). Therefore, appreciation of patients' Health-related quality of life (HRQoL) and symptom burden is critical. However, data on HRQoL in patients with CML are scarce.

Methods: In order to compare the HRQoL of CML patients at diagnosis to the general population EORTC QLQ-C30 data were obtained during screening visits as part of the CML V (TIGER)-study and analysed if filled in within 45 days after diagnosis and if ≥ 50% of items for each scale were completed. Linear transformation for raw scores into values between 0 and 100 was used. For comparison with the general population (Nolte S et al., 2020), patients were divided in five age groups (18-39 years (y), 40-49 y, 50-59 y, 60-69 y and ≥ 70 y) and distinguished by sex. All groups were compared to the expected mean of the corresponding general population norm data. To detect clinical meaningful differences, we applied a cut-off of ≥/≤ 10 points. Comparisons were performed with the t-test. Level of significance was 0.05.

Results: In total, questionnaires of 454 CML patients (275 men, 179 women, median age 50 y.) were analyzed. Clinically meaningful differences to the general population in Germany were mainly found in women for the subscale emotional functioning (EF) and in the age group 40-49 y for EF, role and social functioning. Looking at sex specific age groups, differences were present in all groups except for women between 60-69 y. No differences were found for the total sample and male patients across all ages. Except for patients ≥ 70 y presenting lower pain scales, no differences were found for symptom scales. Results are summarized in Table 1.

Conclusions: Differences were gender- and age-related and rather levelled out when considering the entire group. For symptom subscale items no differences were found compared to the general population emphasizing the fact that CML is diagnosed mostly in asymptomatic patients. With this analysis, we established a profound basis for QoL analysis in CML patients for prospective assessment between and within German trials.