To complement The ASCO Post’s comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapeutic regimens for chronic myeloid leukemia (CML). For full details of these study abstracts, visit hematology.org/Annual-Meeting/.
ABSTRACT 188: Combining the allosteric ABL1 inhibitor asciminib (ABL001) with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 compound mutants1
Methods: In patients with CML who acquire compound mutations (at least two) in the same BCR-ABL1 molecule, therapeutic options are extremely limited. Asciminib is a recently developed allosteric inhibitor targeting the myristoyl-binding pocket of the ABL1 kinase, with activity against many imatinib-resistant BCR-ABL1 mutants, including T315I.2 Investigators successfully profiled asciminib against a panel of BCR-ABL1 single and compound mutants expressed in murine Ba/F3 cells followed by human testing.
Syed Ali Abutalib, MD
Results: Asciminib inhibited the proliferation of cells containing most imatinib-resistant BCR-ABL1 point mutations tested, with the notable exception of substitutions at position F359, which is located in the myristoyl-binding pocket. Consistent with this finding, next-generation sequencing of BCR-ABL1 in five patients with evidence of clinical resistance to asciminib revealed three patients with expansion of variants of position F359 on treatment.
Combining asciminib with ponatinib resensitized even the problematic, currently untreatable T315I-inclusive compound mutants at clinically achievable concentrations, which was not achieved combining asciminib with other approved ATP-site tyrosine kinase inhibitors. Additionally, the combination of asciminib and ponatinib resulted in suppression of T315I-inclusive compound–mutant resistant clones using in vitro mutagenesis screens and significantly prolonged survival of mice compared with either agent alone in an in vivo T315I-inclusive compound–mutant murine xenograft model.
Clinical Implications: These early findings support combining asciminib with ponatinib as a treatment strategy for improving management and mitigating the emergence of highly resistant BCR-ABL1 compound mutations in patients with CML.
ABSTRACT 26: Introducing a predictive score for successful treatment-free-remission in CML3
Methods: Data from the largest available tyrosine kinase inhibitor stopping trial, EURO-SKI,4 showed that the most important variable associated with prolonged treatment-free remission is the duration of deep molecular responses. However, to date no clinical tool exists to guide clinicians and patients in predicting the likelihood of success of treatment-free remission.
Investigators conducted a retrospective analysis of clinical data from 172 patients with chronic phase CML in whom treatment was discontinued after a minimum duration of treatment with atyrosine kinase inhibitor of 3 years and discontinuation of a tyrosine kinase inhibitor after achievement of confirmed ≥ MR4.0 (corresponding to BCR-ABL/ABL ≤ 0.01% international scale). The training set included 118 patients, and the validation set, 54 patients.
Results: In the training set, the 2-year treatment-free-remission in MR3.0 was 67.4% (95% confidence interval [CI] = 66.5%–68.3%), and the 2-year treatment-free remission in MR4.0 was 56.8% (95% CI = 55.9%–57.7%). After loss of MR4, the 1-year probability of MR3.0 loss was 77% (95% CI = 70.8%–73.2%). In a univariate analysis, the variables most significantly associated with higher treatment-free-remission in MR3.0 and treatment-free remission in MR4.0 were age at diagnosis > 40 years (P = .029 and P = .002), absence of previous tyrosine kinase inhibitor resistance (P = .003 and P = .068), longer duration of MR4 (P = .003 and P < .0001), and ≥ MR4.5 at stopping (P = .026 and P = .004). The Cox multivariable model identified the following variables for both treatment-free-remissions in MR3.0 and MR4.0: duration (number of years) of MR4.0, previous tyrosine kinase inhibitor resistance (yes vs no), age at diagnosis (≤ 40 years vs > 40 years), and transcript type (e13a2 vs others).
Using these variables, the investigators developed a predictive score that was able to identify a good-risk population (2-year treatment-free-remissions in MR3.0, 81.8%; 2-year treatment-free-remissions in MR4.0, 80%); intermediate-risk (66.6% and 61.5%), and poor-risk (42.3% and 30.8%; overall log-rank test P = .00092 and P < .0001 for treatment-free remission in MR3.0 and treatment-free-remission in MR3.0, respectively; Table 1). The score was tested on the validation cohort of 54 patients (Table 2), with similar results.
Clinical Implications: This retrospective study identifies variables strongly associated with prolonged treatment-free-remission. If validated in larger patient cohorts, the resulting predictive score presented here might help in tailoring the choice of tyrosine kinase inhibitor discontinuation to the individual patient. Also, most patients who lose MR4.0 inevitably lose MR3.0, suggesting the importance of a more intense monitoring strategy in this subgroup.
ABSTRACT 498: Pregnancy management in patients with CML: To treat or not to treat? Report of 224 outcomes of the European Leukemia Net (ELN) database5
Methods: Patients completing pregnancy were grouped as follows: 1) 47 patients diagnosed with CML while pregnant; 2) 75 patients who achieved deep molecular remission (corresponding to BCR-ABL/ABL ≤ 0.01% international scale); 3) 90 patients with ≤ MR3.0 (corresponding to BCR-ABL/ABL ≤ 0.1% international scale).
Results
• CML Diagnosed During Pregnancy: In all, 48 babies were born. CML was diagnosed in 21 patients during the first; 15, during the second; and 11, during the third trimester (range, 3–38 weeks). Sixteen patients were not treated until delivery; 15 were treated with interferon, 19 were treated with imatinib, 12 were treated during the second trimester (> 16 week), and 7 were treated during the third trimester. Three babies were preterm (35–37 weeks), and one pregnancy was ongoing. No birth defects were observed. Seven newborns had a low birth weight (< 2.5 kg), six were exposed to imatinib late in the pregnancy, and three were preterm. Follow-up was uneventful. The majority of patients achieved ≥ MR3.0 after starting a tyrosine kinase inhibitor.
• Pregnancy inPatients Who Achieved Deep Molecular Remission: In all, 81 babies were born. Six patients were in treatment-free-remission (no therapy) for more than 12 months, and eight stopped a tyrosine kinase inhibitor in order to conceive (2–8 months before conception). A total of 22 patients were treated during pregnancy: 12 with a tyrosine kinase inhibitor (8 with imatinib, 4 with nilotinib; 1 in the first trimester [never stopped imatinib]), 7 in the second trimester, and 4 in the third trimester; 10 patients received interferon. No births defects were observed, and two pregnancies were ongoing at the time of this report submission. A total of 58 pregnancies were carried without any CML treatment. A total of 26 maintained deep molecular response; 28, ≤ MR3.0 and considered in treatment-free-pregnanc; and 5 had > 10% transcript levels at delivery, considered as high tumor burden. None of the patients experienced disease progression after pregnancy, and four patients maintained treatment-free remission. Four patients did not return to MR3.0 < 12 months after restarting a tyrosine kinase inhibitor; three were switched to a more potent tyrosine kinase inhibitor, rapidly achieving ≥ MR3.0; and one patient, who did not, is in hematologic remission after 3 years.
• Pregnancy in Patients During Remission at ≤ MR3.0: In all, 95 babies were born. About 29 had stopped tyrosine kinase inhibition prior to conception (5 of them had a high tumor burden at the onset of pregnancy). A total of 58 patients (61%) were treated with interferon (n = 20), tyrosine kinase inhibitors (n = 35), or hydroxyurea (n = 3). A total of 13 patients were treated with imatinib during the first trimester (10 throughout the pregnancy). Among the untreated patients, 6 were surprisingly in deep molecular response at delivery, 20 were in treatment-free-pregnancy, and 11 had a high tumor burden. Two babies were born with polydactyly and hypospadias (interferon treatment since the first trimester), and two exhibited a nonclosed foramen ovale (imatinib during second and third trimesters), which was considered unlikely to be related to treatment. Four patients progressed to blast crisis and died after pregnancy, but all were not compliant with therapy.
Clinical Implications: This is the first, large, multicenter report focusing on treatment of CML during pregnancy. These results suggest that patients with CML can pursue a normal life including planning a family during treatment, with several caveats:
- Based on the three different situations examined, treatment with interferon is confirmed to be safe. In contrast, tyrosine kinase inhibitors should not be used during pregnancy.
- Selected tyrosine kinase inhibitors, specifically imatinib and nilotinib, which have little placental transfer, can be started after organogenesis.
- Patients at the onset of pregnancy can delay therapy without jeopardizing their future CML outcome.
- If therapy during pregnancy is deemed necessary, interferon can induce and maintain hematologic remission, or, if introduced earlier, interferon can preserve molecular remission after tyrosine kinase inhibitor interruption, and tyrosine kinase inhibitors can reduce a high tumor burden.
Caution should be taken when considering stopping tyrosine kinase inhibition prior to conception due to the possibility of losing response, yet an early stop (at first positive pregnancy test, 4–5 weeks) may be considered. ■
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca and Partner Therapeutics.
REFERENCES
1. Eide CA, Zabriskie MS, Savage SL, et al: Combining the allosteric ABL1 inhibitor asciminib (ABL001) with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 compound mutants. 2019 ASH Annual Meeting & Exposition. Abstract 188. Presented December 7, 2019.
2. Hughes TP, Mauro MJ, Cortes JE, et al: Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med 381:2315-2326, 2019.
3. Claudiani S, Metelli S, Kamvar R, et al: Introducing a predictive score for successful treatment free remission in chronic myeloid leukemia. 2019 ASH Annual Meeting & Exposition. Abstract 26. Presented December 7, 2019.
4. Saussele S, Richter J, Guilhot J, et al: Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): A prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol 19:747-757, 2018.
5. Abruzzese E, Turkina AG, Apperley JF, et al: Pregnancy management in CML patients: To treat or not to treat? Report of 224 outcomes of the European Leukemia Net database. 2019 ASH Annual Meeting & Exposition. Abstract 498. Presented December 8, 2019.
Acknowledgment: Dr. Abutalib would like to extend his gratitude to and acknowledge Jason R. Gotlib, MD, Professor of Medicine at Stanford University, for his critical review of this article.
