The presence of additional cytogenetic abnormalities (<scp>ACAs</scp>) or Philadelphia chromosome variants do not adversely affect the achievement of treatment‐free remission in chronic myeloid leukemia

The long-term survival of patients with chronic myeloid leukemia in the chronic phase (CML-CP) has markedly improved since the introduction of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). Treatment with imatinib or second-generation TKIs is associated with 10-year CML-specific overall survival (OS) of 90 + %.1 Treatment-free remission (TFR) has emerged as an important therapeutic goal for selected patients with CML-CP achieving a durable deep molecular response (DMR; BCR::ABL1 transcripts ≤0.01% on the international scale [IS]) and wishing to discontinue treatment. This approach helps mitigate the risks associated with long-term TKI therapy, including side effects and financial toxicity.2, 3 Various studies have shown that longer durations of TKI therapy and durable DMR were associated with improved TFR rates. Patients with a durable DMR for at least 5 years had a 5-year TFR rate >80%, compared with 40%–50% for those with a DMR duration of 2 years.4-6 In a recent report, Claudiani and colleagues investigated the impact of additional chromosomal abnormalities (ACAs) and variant Philadelphia chromosome translocations (Var-Ph) on TFR rates.7 High-risk ACAs comprised trisomy 8, 17, 19, or 21, extra copies of the Philadelphia chromosome (Ph), isochromosome 17q, deletion of chromosome 7 or 7q, rearrangements involving 3q26.2 (MECOM) or 11q23 (KMT2A), and complex karyotype. Low-risk ACAs were other chromosomal abnormalities not included in the high-risk category. Var-Ph included three-way translocations involving chromosomes 9 and 22 with a third partner. The analysis included 19 patients: 10 with Var-Ph, seven with high-risk ACAs, and two with low-risk ACAs.7 The median duration of therapy before TKI discontinuation was 120 months (range, 48–186 months) in patients with high-risk ACAs and 71 months (range, 29–184 months) in those with Var-Ph. The median duration of DMR before TKI discontinuation was 67 months (range, 29 to 113 months) and 56 months (range, 20 to 140 months) in the high-risk ACAs group and the Var-Ph group, respectively (p = 0.42). The 2-year TFR rate was 53% overall: 86% in the high-risk ACAs group and 30% in the Var-Ph group (p = 0.05). The authors concluded that high-risk ACAs correlated with a better outcome compared with Var-Ph, possibly due to the shorter duration of TKI therapy and DMR in the Var-Ph group.7 We previously reported our experience with TKI discontinuation and TFR in a cohort of 284 patients with CML-CP in DMR.4 Of the 267 patients with available cytogenetic results at baseline, 231 (87%) had a classical Ph, 20 (7%) had high-risk ACAs, eight (3%) had Var-Ph, and eight (3%) had low-risk ACAs.8 High-risk ACAs consisted of extra copies of the Ph in 11 patients, trisomy 8 in three patients, a complex karyotype in three patients, trisomy 21 in one patient, isochromosome 17q in one patient, and monosomy 7 in one patient. Low-risk ACAs consisted of deletion Y in two patients, trisomy 4, t(16;17)(q22;q25), t(3;15)(q21;q15), inv(5)(q22q31), t(15;20)(p10;p10), and addition 17p in one patient each. At the time of TKI discontinuation, 13 of the 36 patients (36%) were receiving imatinib, nine (25%) were on dasatinib, nine (25%) on nilotinib, three (8%) on ponatinib, and two (6%) on bosutinib. The duration of TKI therapy and duration of DMR in the subsets of classical Ph, high- and low-risk ACAs, and Var-Ph are shown in Table S1. Five of the 36 patients (14%) lost major molecular response (BCR::ABL1 transcripts >0.1% IS) after a median of 3 months (range, 1 to 15 months) from TKI discontinuation. Of those five patients, four resumed TKI therapy and one did not resume treatment due to the presence of multiple comorbidities. All four patients who restarted TKI therapy achieved a complete molecular response (undetectable BCR::ABL1 transcripts) after a median duration of 6 months (range, 3 to 17 months). The 5-year TFR rate was 80% overall: 79% in patients with a classical Ph, 89% with high-risk ACAs, 70% with Var-Ph, and 88% with low-risk ACAs (p = 0.65) (Figure 1). Our analysis suggests that the presence of ACAs and of Var-Ph was not associated with a worse TFR outcome. Both low- and high-risk ACAs were associated with a 5-year TFR rate of over 80%, while Var-Ph (though in a limited number of patients) was associated with a TFR rate of 70%. The small sample size in Var-Ph precludes a definitive conclusion. Patients with Var-Ph also had the shorter duration of TKI therapy and of durable DMR before attempting TFR, potentially explaining the slightly lower TFR rate. Based on these findings, the presence of ACAs or Var-Ph should not be considered indicators of worse TFR and should not influence decisions regarding TKI discontinuation. For patients with CML-CP, we recommend attempting TFR after a durable DMR, ideally of 5 years or more. No funding was provided for this work. K.S. received research funding and consultancy fees from Novartis; and is on the advisory board for Daiichi-Sankyo and Pfizer. G.C.I. received research funding from Celgene, Kura Oncology, Syndax, and Novartis; and consultancy fees from Novartis and Kura Oncology. E.J. received research grants from Abbvie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from Abbvie, Adaptive Biotechnologies, Amgen, BMS, Genentech, Incyte, Novartis, Pfizer, and Takeda. H.K. received research grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer; and honoraria from AbbVie, Amgen, Aptitude Health, Ascentage, Astellas Health, Astra Zeneca, Ipsen, Pharmaceuticals, KAHR Medical Ltd, NOVA Research, Novartis, Pfizer, Precision Biosciences, and Taiho Pharmaceutical Canada. F.G.H. has no conflicts of interest to disclose. Data may be shared to qualified researchers upon reasonable request to the corresponding author. No identifying data will be provided. Supplemental Table S1. Duration of TKI therapy, duration of DMR, and TFR rates by cytogenetics. 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