Blinatumomab combined with dasatinib and steroids in older patients with Philadelphia-positive ALL: Results from a phase II study

The adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have shown improved outcomes with tyrosine kinase inhibitor (TKI) based therapy. However, many older patients who are not good candidates for intensive chemotherapy are treated with a combination of TKIs and corticosteroids. Although the remission rate with TKI/steroid-based therapy is high, the short median disease-free survival (DFS) remains a limitation.¹

Blinatumomab, an anti-CD19 bispecific T-cell-engaging antibody, has emerged as a novel therapy in the treatment of relapsed/refractory (R/R) B-cell ALL and measurable residual disease (MRD)-positive B-cell ALL, as previously published on the ALL Hub. Its use in combination with TKIs, such as ponatinib, has also been studied in adult patients with newly diagnosed and R/R Ph+ ALL Ph+ ALL, as previously published on the ALL Hub; however, the feasibility of this combination in older patients with Ph+ ALL is not well known.

To address this knowledge gap, Advani et al.¹ recently published an article in Blood Advances evaluating the feasibility and outcomes of combining blinatumomab with the TKI dasatinib and prednisone in older patients with newly diagnosed Ph+ and Ph-like ALL. The key findings are summarized below.

Methods¹

This is an ongoing open-label phase II trial (NCT02143414) to assess safety and feasibility of dasatinib/prednisone induction followed with blinatumomab/dasatinib in older patients with ALL.

Eligible patients were

• ≥65 years old with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations);

• newly diagnosed or R/R with no evidence of central nervous system (CNS) disease;
• no active pericardial or pleural effusion;
• no history or presence of clinically relevant CNS pathology;
• cardiac ejection fraction of ≥45%; and
• adequate organ function.

The induction therapy consisted of dasatinib/prednisone followed with post-remission therapy (PRT) with blinatumomab/dasatinib and maintenance with dasatinib/prednisone. The detailed treatment schema is illustrated in Figure 1. The response was assessed at Days 28, 56, and 84; additional time points were dependent on response. MRD was assessed centrally by 8-color flow cytometry at Day 28 and MRD negativity was defined as <0.01%.

CR, complete remission; CRi, CR with incomplete count recovery; D, day; q.d., once daily.
*Adapted from Advani, et al.¹ 

The primary objective was to assess the feasibility (safety) of dasatinib/blinatumomab combination treatment in older patients with Ph+ ALL. Secondary objectives included estimated overall survival (OS), DFS, and the rate of MRD negativity.

Results¹

Of 12 patients receiving PRT and evaluable for dose-limiting toxicities (DLTs), four patients experienced DLTs including Grade 3 hypertension (n = 1), Grade 3 dyspnea and gastrointestinal pain (n = 1), Grade 3 dyspnea (n = 1), and Grade 3 hyperglycemia (n = 1). The DLTs were deemed acceptable following National Cancer Institute (NCI) and the Food and Drug Administration (FDA) review and the study reopened for further accrual.

Overall, 24 patients with newly diagnosed Ph+ ALL and a median age of 73 years (range, 65–87 years) were accrued. The key baseline characteristics are listed in Table 1.

Table 1. Patient baseline characteristics*

*Adapted from Advani, et al.1
Characteristic, % (unless otherwise stated)	N = 24
Patients with additional cytogenic abnormalities	79
Male	33
Race
Asian	8
Black	4
White	75
Unknown	13
Hispanic ethnicity
Hispanic	13
Not Hispanic	75
Unknown	13
Median baseline white blood cell count (range), ×1,000	7.5 (1.3–123.3)
Median bone marrow blast (range), %	89 (30–100)

Toxicities¹

During induction, treatment-related nonhematologic Grade 4 toxicities occurred in two patients. During PRT or maintenance, no Grade 4 or higher treatment related nonhematologic toxicities were observed. The hematologic and nonhematologic toxicities during PRT are shown in Figure 2.

ALT, alanine transaminase; AST, aspartate aminotransferase; AE, adverse event; GI, gastrointestinal; PRT, post-remission therapy.
*Data from Advani, et al.¹

Response/Outcomes¹

The Consolidated Standards of Reporting Trials diagram of patients is shown in Figure 3. MRD data was available for 16 of 22 patients achieving a complete response CR, of which six patients were MRD negative by flow cytometry at Day 28. Of 19 patients analyzed, 17 were in major molecular or CR at some point after treatment, with at least 12 patients achieving CR. Of seven patients with detectable transcript at the end of induction, five patients achieved CR after blinatumomab-based PRT.

With a median follow-up of 2.7 years, 3-year OS was 87% (95% confidence interval [CI], 64–96) and DFS was 77% (95% CI, 54–90).

AE, adverse event; CR, complete remission; MRD, measurable residual disease; PRT, post-remission therapy.
*Adapted from Advani et al.¹ 

Conclusion¹

The authors concluded that the combination of dasatinib and blinatumomab was well tolerated and had impressive OS and DFS in older patients with Ph+ ALL. However, a longer follow-up is warranted to determine the duration of these responses. In addition, as the current approach did not include transplantation, further studies are needed to assess response in younger patients, who are often offered transplant in first CR.