Inventory: Current status and future direction of third-line treatment for chronic myeloid leukemia

ATP-competitive tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is the main drug for the treatment of Philadelphia chromosome (Ph) + chronic myeloid leukemia (CML).

Although TKI has greatly improved the overall survival of CML patients, there are still many patients with treatment failure, and the more treatment lines, the worse the prognosis.

At present, there are clear guidelines for the treatment of first-line and second-line CML.
However, regardless of NCCN guidelines, ELN guidelines or Chinese guidelines, there are no clear standard programs and guidelines for the treatment of third-line and above CML.

The choice of third-line TKI depends on the patient's comorbidities, past adverse events (AE), mutation characteristics, drug interactions and compliance, but treatment options are relatively limited.

Therefore, there is still a large unmet need for CML patients who are resistant/intolerant to two or more TKIs.

This article counts the current and under-development drugs for CML, and looks forward to possible future treatment directions.

Current status of third-line CML treatment: Resistance: 15%-20% of second-line drugs due to resistance during first-line imatinib treatment for 5 years [1], second-line treatment has a higher resistance rate, 60%-70% of patients Major molecular remission (MMR) and complete cytogenetic remission (CCyR) cannot be achieved after two years of treatment [2].

Many CML patients have a higher risk of disease progression, and the more TKIs used sequentially, the worse the outcome.

Intolerance: Due to off-target effects, current TKIs have long-term toxicity, and patients receiving ≥2 TKI treatments have a higher risk of intolerance.

Mutations: Sequential use of TKI can lead to the emergence of drug-resistant mutations, among which the T315I mutation will lead to resistance to all existing TKIs except Pranatinib.

In second-line treatment, the overall incidence of T315I mutations is 2-14%, accounting for 9-53% of all mutations in second-line BCR-ABL1 [3].

Treatment options: In cases of intolerance and resistance to second-line treatment, there is a lack of treatment options with good benefits.

Currently commonly used international third-line therapies include Pranatinib (third-generation TKI, not listed in China) and homoharringtonine (protein translation inhibitor, which induces apoptosis of tumor-bearing cells BCR-ABL1).

According to ELN 2020 recommendations, for patients who have no significant cardiovascular risk factors and are resistant to second-generation TKIs and have no specific mutations, prnatinib is better than replacement for second-generation TKIs.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is an option for almost all patients with TKI resistance/intolerance.

If performed within the first year of diagnosis, the 5-year survival rate after allo-SCT is 70%, and 60% after one year.

Guidelines: Due to lack of sufficient data, the guidelines for third-line and above treatment recommendations are not clear.

Although the guidelines suggest the timing of second-line patients should switch to third-line therapy (for example, second-line 6 months or 12 months BCR-ABL1IS>10%), the clinical benefits of such recommendations have not been confirmed.

The guidelines do not clearly specify the milestones for third-line and above treatment, but it is generally believed that BCR-ABL1IS>1% or less than CCyR represents poor response to treatment and a greater risk of disease progression.

The second-generation TKI is used for third-line treatment: related studies are mainly reports with a small number of cases, showing poor long-term outcomes.

Third-generation TKI for third-line treatment: Posutinib and Pranatinib have been approved for third-line treatment internationally, and the efficacy and safety of their core studies are shown in Table 1.

Table 1.
Core research data of Posutinib and Pranatinib.
Third-line CML drugs under investigation are currently developing new BCR-ABL1 targeted therapies, focusing on third-line and/or patients with T315I mutations because of the treatment of these patients Limited choices and limited effects.

The overview of third-line CML drugs currently under development is shown in Table 2.

Table 2.
The third-line BCR-ABL1 targeted drug 01HQP1351 (olverembatinib) [6] HQP1351 is a third-generation TKI with T315I activity.

In the phase I trial, 94.
5%, 81%, and 60.
5% of patients achieved complete hematological remission (CHR), major cytogenetic remission (MCyR) and CCyR, respectively, and 37.
2% achieved MMR.

It is worth noting that more patients with T315I mutation have achieved CHR, MCyR, CCyR, and MMR than those without mutations.

Two phase II trials: In CC201, 96.
8%, 75.
6%, 65.
9%, and 48.
8% of patients achieved CHR, MCyR, CCyR, and MMR, respectively.

In CC202, 60.
9%, 52.
2%, and 26.
1% of patients achieved CHR, MCyR, and MMR, respectively.

In both studies, thrombocytopenia was the most common hematological adverse event (TEAE) during treatment, and the most common non-hematological TEAE was skin pigmentation.

02PF-114 [7] PF-114 is another third-generation TKI, similar in structure to Pranatinib, but modified to avoid inhibition of VEGF-R, and strive to minimize cardiovascular toxicity.

In a phase I/II dose exploration study involving 51 patients, the best safety and efficacy dose cohort (300 mg QD) had 11 patients.

6/11 patients achieved MCyR and 4/11 patients achieved MMR.

Twelve patients in the study had T315I mutations, of which 3/12 and 4/12 achieved CHR and MCyR.

Eleven patients receiving QD ≥400 mg reported Grade 3 skin toxicity.

03Vodobatinib (K0706) [8] Vodobatinib is also a BCR-ABL1 TKI, but it has no activity on T315I.

Phase I data showed that of the 35 patients, 7 patients achieved CCyR and 4 patients maintained CCyR.

Five patients achieved MMR and two patients achieved MR4.
5.

After the protocol was revised, the study excluded patients with the T315I mutation.
The protocol revision was caused by the disease progression of two patients with the T315I mutation in the first cycle of the study.

04Asciminib (ABL001) [9,10] Asciminib is a new mechanism of BCR-ABL1 inhibitor, the mechanism is named Specific Targeting the ABL Myristoyl Pocket (STAMP).

Asciminib binds to the myristoyl pocket of ABL kinase in a non-ATP-competitive manner, so it has different drug resistance characteristics from TKI.
While it is active against the T315I mutation, the off-target effect is effectively restricted due to the conservation of the myristoyl pocket.

Because of its complementarity with ATP-competitive TKI sites, Asciminib may also work synergistically with TKI to overcome mutations and reduce TKI-related toxicity.

In the phase I trial, asciminib monotherapy or combination therapy with imatinib, nilotinib, or dasatinib was evaluated in patients who were resistant or intolerant to ≥2 TKIs.

It was discovered that the recommended dose for patients without T315I mutation is 40 mg BID, and the recommended dose for patients with T315I mutation is 200 mg BID.

Among patients without T315I mutations, 92%, 60%, and 54% of patients achieved CHR, MCyR, and CCyR, respectively.

At 6 months and 12 months, 24% and 36% of patients achieved MMR.

Among patients with T315I mutation, 88%, 55%, and 41% of patients achieved CHR, MCyR, and CCyR, respectively.

At 6 months and 12 months, 21% and 26% of patients achieved MMR, respectively.

The five most common TEAEs of all grades were fatigue (29.
3%), headache (28.
0%), elevated lipase levels (26.
7%), arthralgia (24.
0%), and nausea (24.
0%).

In the ongoing phase III trial (ASCEMBL), 233 adult CML-CP patients who have previously received ≥2 TKI treatments were randomly assigned at a 2:1 ratio to receive Asciminib 40mg BID (n=157) or Bosutinib 500mg QD ( n=76) Treatment.

At week 24, the MMR rates of the Asciminib group and the Bosutinib group were 25.
5% and 13.
2%, respectively, reaching the primary study endpoint.

Other indicators at week 24 (ASC vs.
BOS): MR4: 10.
8% vs.
5.
3%, MR4.
5: 8.
9% vs.
1.
3%, CCyR: 40.
8% vs.
24.
2%.

The incidence of grade 3 AE in the Asciminib group and Bosutinib group was 50.
6% and 60.
5%, respectively.

The most common grade ≥3 AEs were thrombocytopenia (17.
3% vs.
6.
6%), neutropenia (14.
7% vs.
11.
8%), diarrhea (0% vs.
10.
5%), and elevated levels of alanine aminotransferase (0.
6% vs.
14.
5%).

The rate of discontinuation of treatment due to adverse events in the Asciminib group (5.
8%) was lower than that in the Bosutinib group (21.
1%).

05 Other non-BCR-ABL targeted therapies [11] Several ongoing trials are studying the efficacy of TKI in combination with various other drugs.
These studies are aimed at directly reducing the tumor burden of patients, which has certain significance for patients with subsequent CML, but More sufficient data verification is needed. These combination drugs include: interferon-α, PD-1/PD-L1 inhibitors, thiazolidinediones, dipeptidyl peptidase IV inhibitors, JAK/STAT inhibitors, Wnt/β-catenin inhibitors, Liposome antisense oligodeoxynucleotides, TGF-β inhibitors, RAS inhibitors, rapamycin inhibitors, histone deacetylase inhibitors, demethylation drugs, Aurora kinase pathway inhibitors, and BCL -2 inhibitor.

In summary, third-line and above CML treatments have high drug resistance/intolerance rates, lack of effective treatment options (especially in China), and lack of clear guidelines.
The third-line therapies being developed are mainly focused on the new BCR-ABL1 TKI, and Committed to solving some of the major problems of the existing third-generation TKIs (such as high cardiovascular toxicity); in addition, asciminib, a representative of a new type of treatment mechanism, acts through the STAMP inhibition mechanism, and the overall efficacy and safety are better than in the phase III study Posutinib, which brings more possibilities for the treatment of CML, may help solve the key unmet needs in the later treatment of CML. References: [1] Hochhaus A.
Leukemia.
2016;30(5):1044-54.
[2] Cortes JE.
J Clin Oncol.
2018;36.
[3] Soverini S.
Leuk Res.
2014;38:10 -20.
[4] Cortes JE.
Am J Hematol.
2016;91:1206-14.
[5] Cortes JE.
Blood.
2018;132:393-404.
[6] Qian Jiang et.
al, Abstract #651, ASH 2020.
[7] ClinicalTrials.
gov.
NCT02885766.
[8] Jorge E.
Cortes et.
al, Abstract #652, ASH 2020.
[9] Jorge E.
Cortes et.
al, Abstract #650, ASH 2020.
[10 ] Hochhaus A.
et.
al, Abstract #LBA-4, ASH 2020.
[11] Cortes and Lang J Hematol Oncol (2021) 14:44.
MCC No.
TAS2104160, valid period 2022-04-06, data expired, deemed the same Void.

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