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Hyper-CVAD with sequential blinatumomab for the treatment of adult patients with newly diagnosed Philadelphia chromosome-negative B-cell ALL

Feb 23, 2021
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Despite high rates of complete remissions, long-term survival in patients with B-cell acute lymphoblastic leukemia (ALL) is still low at ~40–50%. Blinatumomab, a bispecific T cell-engaging CD3-CD19 antibody, has shown superiority against chemotherapy in patients with relapsed/refractory B-cell ALL, inducing high rates of minimal residual disease (MRD) negativity, which is considered to be a key prognostic factor.1

Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternated with methotrexate and cytarabine (hyper-CVAD), is frequently used as a frontline chemotherapy in adult patients with B-cell ALL. At the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Nicholas Short presented initial efficacy and safety results from a phase II study of hyper-CVAD and sequential blinatumomab in patients with newly diagnosed (ND) Philadelphia chromosome-negative (Ph−) B-cell ALL (NCT02877303).2

Study design

The primary objective was relapse-free survival in patients with ND Ph− B-cell ALL. Secondary objectives included overall survival (OS), overall response rate, MRD negativity rate, and safety of the combination of hyper-CVAD with blinatumomab.

Patients ≥14 years of age with ND Ph− B-cell ALL, Eastern Cooperative Oncology Group (ECOG) performance status ≤3, adequate organ function assessed by total bilirubin ≤2 mg/dL and creatinine ≤2 mg/dL, and no significant central nervous system pathology were eligible for inclusion in the study. Prior therapy with one cycle of chemotherapy was permitted.

Treatment phases

Patients received hyper-CVAD for up to four cycles, and eight administrations of either ofatumumab or rituximab plus central nervous system prophylaxis with intrathecal methotrexate and cytarabine as the induction phase. Then, four cycles of blinatumomab were given, each consisting of 4-week continuous infusions followed by two treatment-free weeks. Following the early relapse of two patients prior to blinatumomab administration, patients with high-risk features received only two cycles of hyper-CVAD before starting blinatumomab.

The maintenance phase consisted of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) followed by one cycle of blinatumomab for a total of 15 cycles. Notably, the maintenance phase was shortened to 18 months, which is half its normal length

Results

Patient characteristics

As shown in Table 1, most of the 38 evaluable patients had a good performance status and ALL blasts with high CD19 expression. Around one third of patients had high-risk features such as persistent MRD‑positivity, low hypodiploidy or near triploidy, complex karyotype, Ph‑like phenotype (CRLF2 expression), TP53 mutations, or KMT2A rearrangement.

Table 1. Patient characteristics2

CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; WBC, white blood cell.

Characteristic

N=38

Median age, years (range)

37 (17–59)

ECOG performance status, n (%)

 

              0–1

30 (79)

              2

8 (21)

Median WBC, ×109/L (range)

3.1 (0.5–360.9)

CNS involvement at diagnosis, n (%)

4 (11)

CD20 ≥20%, n (%)

17 (52)

CD19 ≥50%, n (%)

31 (97)

Karyotype, n (%)

 

              Diploid

11 (29)

              Low hypodiploidy/near triploidy

6 (16)

              Complex

3 (8)

              High hyperdiploidy

3 (8)

              KMT2A rearrangement

3 (8)

              Others

12 (32)

CRLF2+ by flow cytometry

6 (19)

TP53 mutation

10 (27)

Efficacy

Median follow-up was 24 months (range, 2–45 months). All 38 patients achieved a complete response, with 21 ongoing without hematopoietic stem cell transplant (HSCT). Five patients relapsed on study treatment, while two out of twelve patients relapsed after HSCT, with all but one displaying high-risk features at baseline.

Responses to treatment in the study are shown in Table 2. There were high rates of relapse-free survival and OS after 2 years, with seven relapses and two deaths, one due to pulmonary embolism and one from post-HSCT complications. No patients died or relapsed beyond 2 years after therapy initiation.

These results compared favorably with historical data using hyper-CVAD and ofatumumab where the 2-year OS was similar at ~80%, however the apparent plateau with hyper-CVAD and blinatumomab appears higher.

Table 2. Response rates for patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia treated with hyper-CVAD and blinatumomab2

CR, complete response; MRD, minimal residual disease; OS, overall survival; RFS, relapse-free survival.
*Six patients were in CR and four were MRD-negative at the start of the study.

Response*

Patients (N = 38)

CR rates, n/N (%)

 

              CR after induction

26/32 (81)

              CR at anytime

32/32 (100)

MRD negativity rates, n/N (%)

 

              MRD-negative after induction

24/34 (71)

              MRD-negative at any time

33/34 (97)

30-day mortality, n/N (%)

0

RFS, %

 

              1-year

80

              2-year

71

OS, %

 

              1-year

85

               2-year

80

Safety

Four patients (13%) developed cytokine release syndrome, of which one case was Grade 3–4. Treatment-related neurological events were reported in 14 patients (45%; 15% of these were Grade 3 and 4), and there was one discontinuation due to Grade 2 encephalopathy and dysphasia.

The most common non-hematologic adverse events were

  • Infusion reactions (47%)
  • Aspartate transaminase/alanine transaminase elevation (58%)
  • Nausea/vomiting (45%)
  • Hyperglycemia (32%)
  • Hyperbilirubinemia (32%)

The most frequently reported Grade 3–4 adverse events were aspartate transaminase/alanine transaminase elevation (24%) and hyperglycemia (21%).

Conclusion

The data presented here suggest that incorporation of frontline blinatumomab into the treatment regimen of young adult patients with ND Ph− B-cell ALL is promising, with a high MRD negativity rate and encouraging 2-year overall survival at 80%. Notably, there were no relapses in patients without high-risk disease features at baseline and no relapses occurred after 2 years of treatment initiation.

Furthermore, hyper-CVAD with sequential blinatumomab demonstrated an adequate safety profile, with a low rate of Grade 3–4 treatment-related toxicities. Recruitment into the study is ongoing, with a protocol amendment to include inotuzumab ozogamicin with the aim of further improving response to treatment.

  1. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. DOI: 1056/NEJMoa1609783
  2. Short NJ, Kantarjian HM, Ravandi F, et al. Hyper-CVAD and sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia: Results from a phase II study. Oral abstract #464. 62nd ASH Annual Meeting and Exposition; Dec 6, 2020; Virtual.

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