Impact of Patient Factors on Developing AML After MDS or CML; Ponatinib in Highly Resistant CP-CML

Certain patient and demographic characteristics that may be related to socioeconomic disparities impact the risk of developing acute myeloid leukemia (AML) after myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML), according to research presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. The meeting was held December 10-13, 2022, in New Orleans, Louisiana.

While most cases of AML appear de novo in a patient who was previously healthy, it can progress from other conditions, such as MDS or myeloproliferative disorders. Researchers from the John H. Stroger, Jr Hospital of Cook County in Chicago, Illinois, and the University of Illinois College of Medicine at Chicago analyzed the Healthcare Cost and Utilization Project National Inpatient Sample and International Classification of Disease, Tenth Revision codes to identify adult patients admitted to a hospital between 2016 and 2019 who also had a secondary diagnosis of MDS or CML.¹

Of the 79,579 patients hospitalized with AML, 4650 (5.8%) had a secondary diagnosis of MDS and 255 (0.3%) had a secondary diagnosis of CML. Both patients with MDS and CML were older than patients without those diagnoses: 69.9 years with MDS vs 61.4 years without and 62.8 years with CML vs 61.9 years without.

Among patients with AML who previously had MDS, a significantly higher proportion were male, White, had Medicare insurance, and were being treated at rural and urban non-teaching hospitals. In addition, a higher proportion were treated at small and medium-sized hospitals.

In the AML cohort, there was no difference between those who previously had MDS and those who did not in comorbidity burden, hospitalization region, and median household income.

Patients with a previous MDS diagnosis had higher odds of mortality compared with patients who did not previously have MDS, although the difference was not significant (13.0% vs 11.8%; adjusted odds ratio [AOR] 0.91, P = .41). Female patients had lower odds of mortality, although this was also not significantly different. Patients with MDS previously had a lower mean length of stay (15.3 days vs 18.5 days) and lower total hospital charges ($214,329 vs $254,635).

Among the patients who previously had CML, a higher proportion were female, Black and Hispanic, on Medicaid insurance, had lower household income, were treated in hospitals in the South region, and were treated at medium-sized hospitals compared with patients who had no previous CML diagnosis. However, these differences were not significant. There was also no difference between the 2 groups in comorbidity burden.

While patients who had a previous CML diagnosis had higher odds of mortality (17.5% vs 11.8%; AOR 1.6, P = .24), the difference was not statistically significant. Patients who were Black had significantly higher odds of mortality while female patients had non-significantly higher odds of mortality.

Similar to the group who previously had MDS, patients who had a previous diagnosis of CML had a lower mean length of stay (15.9 days vs 18.0 days) and lower total hospital charges ($231,116 vs $254,711).

Impact of Diabetes on CML Treatment

Another condition that can affect CML is diabetes. Results of a real-world study presented at ASH found that diabetes can affect both the clinical presentation of CML and the frontline treatment choice of patients with a new diagnosis.²

Most trials of tyrosine kinase inhibitors (TKIs) did not provide many opportunities for patients with multiple comorbidities to participate, requiring data from large cohorts in real-world practice to understand the management of newly diagnosed CML, researchers from across Italy explained.

They studied 1732 patients with chronic phase CML (CP-CML) diagnosed between 2012 and 2019 at 33 sites in Italy to understand the choice of TKI and incidence of early events during the first year of treatment. Patients were treated with frontline imatinib, dasatinib, or nilotinib. Imatinib is a first-generation TKI, while dasatinib and nilotinib are both second-generation TKIs.

Overall, 197 (11.4%) patients had concomitant diabetes. At baseline, patients with diabetes had a lower number of white blood cells compared with patients without diabetes. Compared with patients without diabetes, those with diabetes were older; had higher Sokal and EUTOS long-term survival scores, both of which predict survival; and were more likely to have other comorbidities, such as chronic obstructive pulmonary disease, arterial hypertension, previous neoplasm, ischemic heart disease, and cerebrovascular events.

A larger proportion of patients with diabetes were prescribed imatinib (72% vs 54%) or dasatinib (23.4% vs 15.3%), while a much higher proportion of patients without diabetes were prescribed nilotinib (30.7% vs 4.6%) (all P < .001). In the first year of treatment, 25.9% of patients with diabetes vs 18.7% of patients without had an early event that led to them permanently discontinuing frontline TKI treatment.

3-Year OPTIC Update

A 3-year update of the outcomes of the OPTIC trial (NCT02467270) highlighted the long-term efficacy and manageable safety profile of ponatinib in patients with highly resistant CP-CML, according to an abstract presented at ASH.³ The phase 2 OPTIC trial is evaluating the safety and efficacy of ponatinib, a third-generation TKI, in patients whose disease is either resistant to 2 or more prior TKIs or who have the T315I mutation. The study uses a response-based dose-adjustment strategy to optimize efficacy and improve the safety of the treatment.

The study randomized 238 patients to receive 45 mg (n = 94), 30 mg (n = 95), or 15 mg (n = 94) of ponatinib once daily. Nearly all (98%) of patients had received 2 or more prior TKIs, while half (55%) had received 3 or more, and 99% had discontinued at least 1 prior therapy because of resistance. Less than half (40%) had at least 1 baseline mutation and 23% specifically had the T315I mutation.

In the line of therapy prior to starting ponatinib, 61% of patients had achieved a complete hematologic response or worse as their best response to therapy. By 36 months in OPTIC:

1. 60% of patients on 45 mg, 40% on 30 mg, and 30% on 15 mg had reached ≤ 1% BCR-ABL1IS.
2. 64% of patients with T315I mutations on 45 mg, 25% on 30 mg, and 16% on 15 mg had achieved ≤ 1% BCR-ABL1IS.
3. Among patients without T315I mutations, 59% on 45 mg, 44% on 30 mg, and 46% on 15 mg achieved ≤ 1% BCR-ABL1IS.
4. Among patients who lost response at any time in the 45-mg and 30-mg groups, 60% and 33%, respectively, were patients who had T315I mutations.

For patients who had achieved ≤ 1% BCR-ABL1ISand then lost response when their doses were reduced to 15 mg, 27% in the 45-mg cohort and 11% in the 30-mg cohort had doses re-escalated. After re-escalation, 75% in the 45-mg group and 67% in the 30-mg group regained ≤ 1% BCR-ABL1IS.

The most common grade 3 treatment-emergent adverse events were thrombocytopenia (27%), neutropenia (18%), hypertension (9%), and anemia (8%).

Based on the findings, the authors concluded that starting ponatinib at 45 mg and reducing to 15 mg after attaining ≤ 1% BCR-ABL1IS offered the optimal benefit-risk ratio.

Optimal Third-line Treatment in CP-CML

Another abstract presented at ASH highlighted the finding that third-line ponatinib is the optimal treatment selection for patients with CP-CML who fail 2 prior TKI therapies.⁴ Researchers led by Elias Jabbour, MD, of The University of Texas MD Anderson Cancer Center, retrospectively analyzed the combined patient-level data of third-line TKI therapy from the PACE (NCT01207440) and OPTIC studies as well as patients who were being treated at MD Anderson. They compared outcomes of patients on second-generation TKIs as third-line TKI therapy with ponatinib as third-line TKI therapy.

A total of 354 patents who received third-line TKI therapy (63 patients from PACE, 87 patients from OPTIC, and 204 patients from MD Anderson) were included with a median follow-up of 46 months. This study excluded patients who had T315I mutations.

Slightly more than half (51%) received ponatinib as third-line TKI therapy while the remaining patients received second-generation TKI (19% on dasatinib, 18% on nilotinib, and 11% on bosutinib). Prior to third-line therapy, the majority (88%) received imatinib, followed by 44% who received dasatinib, 45% nilotinib, and 10% bosutinib.

Compared with patients on second-generation TKIs, patients receiving ponatinib as the third-line therapy had:

• higher rates of nonischemic cardiovascular comorbidity;
• shorter total duration of prior TKI therapies; and
• higher levels of BCR-ABL1 on the international scale.

Multivariate Cox regression using pre-matched data identified older age at the onset of third-line therapy and higher BCR-ABL1 levels as adverse prognostic factors for survival, while ponatinib in the third line was associated with a favorable survival (P = .003; HR 0.435; 95% CI 0.253-0.748).

The 4-year progression-free survival for patients on second-generation TKI was 58% compared with 75% for patients on ponatinib (P < .001). The gap between the rates narrowed after propensity score matching (78% on second-generation TKI vs 89% on ponatinib; P = .0099). Prior to matching, the 4-year overall survival (OS) rates were 57% for second-generation TKIs vs 80% for ponatinib. After matching, OS rates were 78% for second-generation TKIs and 87% for ponatinib.

“Third-line ponatinib therapy is (the) optimal selection for patients with CML-CP who failed prior 2 TKI therapies in the absence of T315I mutation,” the authors concluded.

References

1. Obeidat K, Turk E, Deenadayalan V, Litvin R, Zia M, Rifkin SD. Demographic characteristics and outcomes in patients with AML and previous diagnosis of CML or MDS. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 4032. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper170618.html
2. Capodanno I, Tiribelli M, Miggiano MC, et al. Choice of tyrosine kinase inhibitor and early events during the first year of therapy in newly diagnosed chronic phase chronic myeloid leukemia (CML) patients with concomitant diabetes: a “Campus CML” study. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 1706. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper164790.html
3. Cortes JE, Deininger MW, Lomaia E, et al. Three-year update from the OPTIC trial: a dose-optimization study of 3 starting doses of ponatinib. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 620. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper157822.html
4. Jabbour E, Sasaki K, Issa GC, et al. Outcome of third-line tyrosine kinase inhibitors in patients with chronic myeloid leukemia in chronic phase: a propensity score analysis. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 333. Accessed December 19, 2022. https://ash.confex.com/ash/2022/webprogram/Paper169772.html