Assessment of Transitioning from High-Potency to Low-Potency Inhibitors in Chronic Myeloid Leukemia (CML) Patients: The Downgrading-Impact Project, a CML Campus Study
Authors: Abruzzese Elisabetta , Bernardi Simona , Markovic Uros , Trawinska Malgorzata Monika , Barulli Sara , Maggi Alessandro , Galimberti Sara , Bucelli Cristina , Sannipoli Daniele , D'Adda Mariella , Chiara Elena , Bonifacio Massimiliano , Russo Rossi Antonella , Beltrami Germana , Russo Sabina , Crisa' Elena , Sanpaolo Grazia , Cavazzini Francesco , Loglisci Giuseppina , Fava Carmen , Catania Federica Maria , Scortechini Anna Rita , Scappini Barbara , Rege Cambrin Giovanna , Binotto Gianni , Bocchia Monica , Facchinelli Davide , Di Veroli Ambra , Pascale Sara Pasquina , Leporace Annapaola , Bernardi Matia , Crugnola Monica 
Published: December 2024

Since the introduction of imatinib, 2nd and 3rd-generation Tyrosine Kinase Inhibitors (TKIs) with greater potency have expanded CML treatment options. Recently, the allosteric inhibitor Asciminib (ASC) has been introduced. While the goal is to achieve treatment-free remission (TFR) for all patients, only 30% currently succeed, leaving many on chronic therapy. Therapy changes or dose modulation may manage adverse events, often dose-dependent. Typically, TKIs are used in increasing order of potency, especially in resistant patients. However, for those not eligible or failing TFR, “downgrading” to drugs of lower potency with better safety profiles may be feasible.

This study assesses the Downgrading Impact (D-IMPACT) in CML patients, the reasons behind this strategy, and clinical outcomes. Data were collected via a Google Forms survey distributed in July 2024 to CML Campus Centers. Inclusion criteria were: i) CML patients on 2nd-generation or higher TKI therapy; ii) Patients who switched from a higher to a lower potency inhibitor; iii) Patients with documented side effects from high-potency TKIs.

The survey collected demographic data, treatment start and dosage, TKI before and after downgrading, therapy line, reasons for downgrading, and outcomes. It also investigated dosage de-escalation before downgrading and TFR attempts afterward. Response was assessed by qRT-PCR-IS for BCR::ABL1 at downgrading, and at 3, 6, 12 months, and the last follow-up.

We identified 137 eligible CML patients diagnosed between 1996 and 2022 in 31 centers. Median age at diagnosis was 52 years [IR 17-81], with 91 males (66.4%) and 46 females (33.6%). Sokal score: Low 48 (35%), Intermediate 55 (40.1%), High 24 (17.5%), not available 10 (7.3%). EUTOS score: Low 71 (51.8%), Intermediate 17 (12.4%), High 11 (8%), not available 38 (27.7%). TKIs before downgrading: Imatinib (IMA) 800 mg (n=8; 5.8%), Bosutinib (BOS)(n=4; 2.9%), Nilotinib (NIL) (n=58; 42.3%), Dasatinib (DAS) (n=52; 38%), Ponatinib (PON) (n=14; 10.2%), ASC (n=1; 0.7%), in first 77 (56.2%), second 40 (29.9%), third 13 (9.5%), 4th-6th 7 (5.1%) line. Treatment duration with last TKI before downgrading: 3-162 months (median 44 months). Dosage de-escalation before downgrading in 71 (51.8%) patients due to extra-hematological (n=65; 91.5%) or hematological (n=6; 8.5%) toxicity.

The TKIs used for downgrading were IMA 84 (62.2%), BOS 34 (25%), NIL 4 (2.9%), DAS 6 (4.4%), ASC 4 (2.9%), PON 3 (2.2%), Interferon 1 (0.7%). At downgrading molecular response was: MR1 in 22 (16.7%), MR2 in 37 (28%), MR3 in 29 (22%), MR4 in 26 (19.7%), MR4.5-5 in 18 (13.7%). Downgrading reasons: adverse events in 113 (89.6%), elective choice to avoid/reduce adverse events in 13 (10.4%), pregnancy in 1.

Adverse events included gastrointestinal side effects, bone-joint pain, headache, cutaneous reactions, cardiovascular events, pleural and pericardial effusions, and pulmonary hypertension. Post-downgrading molecular response at 3, 6, 12 months, and last follow-up showed BCR::ABL1 trending down in 68 (58.6%), stable in 34 (29.3%), worsened in 14 (12%). The impact of adverse events also improved. Imatinib and Bosutinib were the most chosen drugs for downgrading, with . There was no consensus on ASC and PON potency as 4 patients downgraded from PON to Asciminib and 3 from ASC. Most common switch was NIL -IMA (33%), DAS- IMA (29%), NIL-BOS (13%).

The survey also examined TFR attempts post-downgrading. Twenty-six patients (18.9%) entered TFR, with 20 (76.9%) remaining free of treatment at a median follow-up of 37 months (IR 3-320).

In conclusion, this exploratory survey shows that a downgrading approach can be safely considered in CML patients, especially for long-term treatment. In 58.6% of cases, molecular response improved without higher-generation treatment, reducing toxicity. Patients who lessen therapy can attempt a TFR: although the number of patients is limited, the relapse rate is only 23.1%.

These interesting results stimulate the expansion of the case series and warrant the introduction of future prospective studies.

Envisaging a broader context to the years to come, the introduction of generic drugs and new therapies, emphasizes the need for sustainable pharmaceutical spending. Documenting the transition from potent inhibitors to lower-impact, lower-cost options could improve resource management, ensuring access to necessary treatments without compromising care.