Mini-hyper-CVD plus inotuzumab ozogamicin ± blinatumomab in adult R/R Ph− B-ALL

Historically, adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) have experienced poor outcomes with intensive chemotherapy; however, the introduction of antibodies targeting CD19, CD20, and CD22 and chimeric antigen receptor T-cell therapies in pre-B-cell ALL (B-ALL) has transformed the treatment landscape for adults with ALL. This had led to the Food and Drug Administration (FDA) approval of four salvage therapies; blinatumomab, a CD19 bi-specific T-cell engager; inotuzumab ozogamicin (InO), an antibody-drug conjugate targeting CD22; and two chimeric antigen receptors, tisagenlecleucel and brexucabtagene autoleucel.

The phase II results of low-intensity chemotherapy (mini-hyperfractionated-CVD) combined with InO ± blinatumomab in adult patients with newly diagnosed Philadelphia-chromosome (Ph) negative B-ALL have been previously reported on the ALL Hub. Here, we summarize an article published by Kantarjian et al.¹ in Journal of Hematology & Oncology on the long-term impact of mini-hyper-CVD + InO ± blinatumomab in adult patients with R/R Ph- B-ALL.

Study design

This phase II study (NCT01371630) included patients with R/R Ph− ALL CD22 positive pre-B-ALL, an Eastern Cooperative Oncology Group Performance Status of ≥3, normal cardiac function (ejection fraction >50%), and adequate organ function (serum bilirubin ≤1.95 mg/dL and serum creatinine ≤2.0 mg/Dl).

Patients 1 to 67 received:

• Mini-hyper-CVD for ≤8 cycles, with InO for the first 4 cycles
• InO at a dose of 1.3–1.8 mg/m² on Day 3 of Cycle 1 and 0.8–1.3 mg/m² on Day 3 of Cycles 2–4
• Maintenance included POMP (6-mercaptopurine + vincristine + methotrexate + prednisone) chemotherapy for ≤3 years

Patients 68 and onwards were given an amended treatment regimen:

• InO was administered in fractionated lower doses for the first four cycles of mini‑hyper‑CVD (0.6 mg/m² on Day 2 and 0.3 mg/m² on Day 8 of Cycle 1; 0.3 mg/m² on Day 2 and 8 of Cycles 2–4), followed by 4 cycles of blinatumomab.
• Maintenance included 12 cycles of POMP and four cycles of blinatumomab.

The primary endpoints were the overall response rate, defined by a complete remission (CR); CR with incomplete platelet recovery; CR with incomplete hematologic recovery; and overall survival rate. Secondary endpoints included safety, relapse-free survival (RFS), the rate of subsequent stem cell transplantation (SCT), and minimal residual disease (MRD) negativity. Figure 1 outlines the study design for the protocol pre- and post-amendment.

Figure 1. Study design in A patients 1–67 and B patient 68 onwards* 

AraC, cytarabine; hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; blina, blinatumomab InO, inotuzumab ozogamicin; IT, intrathecal; MTX, methotrexate POMP, 6-mercaptopurine, vincristine, methotrexate, and prednisone.
*Data from Kantarjian, et al.¹

Results

In total, 110 patients were treated with a median age of 37 years. Baseline characteristics are summarized in Table 1.

Table 1. Baseline characteristics*

Updated efficacy¹

The overall response rate was 83%, 80% of whom responded after the Cycle 1 and 20% responding after subsequent cycles. By salvage status, the overall response rate was 92%, 59%, and 57% after salvage 1, 2 and 3+, respectively. MRD negativity rates were higher after salvage 1 than salvage 2+. Morphologic responses and MRD-negativity rates by salvage status are reported in Figure 2.

Figure 2. Overall morphologic responses and B MRD-negativity by salvage status*

CR, complete remission; CRi, CR with incomplete count recovery; CRp, CR with incomplete platelet recovery; MRD, minimal residual disease; ORR, overall response rate.
*Data from Kantarjian et al.¹

Of the 53 patients receiving SCT in CR, 29 occurred before the protocol amendment and 24 occurred after. For patients who did not undergo SCT, 10 were still alive at a median follow-up of 43 months.

At a median follow-up of 48 months, the estimated 3-year OS rate was 40% and the estimated RFS was 37%. The median OS and RFS was 17 months and 13 months, respectively. The 3-year OS rates significantly differed by salvage and MRD status and was similar in patients receiving and not receiving SCT (Figure 3). By TP53 mutational status (n = 60), the 3-year OS rate was 63% vs 9% for patients with wild-type TP53 versus mutated TP53, respectively.

Figure 3. 3-year OS by A treatment modality, B salvage line, C MRD status, and D SCT*^† 

MRD, minimal residual disease; SCT, stem cell transplantation
*Data from Kantarjian, et al.^1
†p = 0.0002 for difference in salvage line and p = 0.0005 for difference in MRD status

In a post-hoc analysis, this combination regimen yielded a higher  median OS (17 months vs 6 months) and 3-year OS (40% vs 11%) when compared with InO monotherapy (p < 0.001). In the multivariate analyses, increased peripheral blood blasts percentage (p = 0.001), high-risk cytogenetics (p < 0.001), and presence of TP53 mutation (p = 0.004) at baseline were independently associated with worse survival outcomes. On the other hand, a lower fractionated dose of InO followed by blinatumomab was independently associated with improved survival (p = 0.033).

Safety

Overall, the treatment was well-tolerated with mostly Grade 1–2 adverse events (AEs) reported.

• A total of seven deaths were reported within the first 4 weeks of treatment before the protocol amendment; these were due to infections (n = 4), intracranial hemorrhage (n = 1), sinusoidal obstruction syndrome (n = 1), and unknown causes (n = 1).
• Nine deaths were reported in CR; these were due to infections (n = 2), myocardial infarction (n = 1), broncho pulmonary hemorrhage (n = 1), liver graft-versus-host disease (n = 1), and unknown causes (n = 4).
• The median time to platelet and neutrophil recovery in Cycle 1 was 23 days and 16 days, respectively; for subsequent cycles, the median time was 22 days and 17 days, respectively.
• There were no blinatumomab discontinuations due to treatment-related AEs.

Grade 3–5 AEs occurring in two or more patients are summarized in Table 2.

Table 2. Grade 3–5 AEs*

Conclusion

In this longer-term follow-up analysis, mini-hyper-CVD plus InO ± blinatumomab was found to be effective and well-tolerated in adult patients with Ph− R/R ALL, with higher survival in those treated with vs without blinatumomab in Salvage 1, as well as those achieving MRD-negativity. This study yielded better survival outcomes when compared with historical data on single-agent InO or blinatumomab. Ongoing trials are currently investigating the value of MRD by next-generation sequencing in subsequent CR and the incorporation of dose-dense blinatumomab with mini-hyper-CVD plus InO. Future research investigating this combination treatment in multi-institutional trials is needed to establish this regimen as the new standard of care in R/R ALL.