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Efficacy of Hyper-CVAD-R in preventing CNS relapse in aggressive B-cell lymphomas

Oct 11, 2021
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Central nervous system (CNS) involvement in aggressive B-cell lymphomas is associated with very poor prognosis and remains a major diagnostic and prognostic challenge. Numerous therapeutic routes exist, like the dose adjusted EPOCH plus rituximab (DA-EPOCH-R) regimen, which was established to enhance effectiveness in proliferative lymphoid neoplasms while reducing the toxicity associated with chemoimmunotherapy. However, not all treatments are suitable for patients that have a higher risk of CNS relapse, such as those with baseline bone marrow (BM) or CNS involvement. The Hyper-CVAD plus rituximab (HCVAD-R) regimen includes high-dose methotrexate (MTX), cytarabine (Ara-C), and intrathecal (IT) chemotherapy, aiming to specifically target and prevent CNS disease.

Samra, et al. sought to evaluate the long‐term safety and efficacy of the HCVAD-R regimen in adults with Burkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL), focusing on its effectiveness in limiting CNS relapse.

Study design

Baseline characteristics

Overall, 102 patients with newly diagnosed BL or HGBL treated with the HCVAD-R regimen between January 2000 and January 2018 were retrospectively reviewed. Of the 79 adult patients who were selected, 54 (69%) had confirmed BL and 25 (31%) HGBL. Table 1 lists the baseline characteristics for the cohort. There were no significant differences between the two study arms.

Table 1. Baseline characteristics*

Characteristic, n (%) (unless otherwise stated)

Total (N = 79)

BL (n = 54)

HGBL (n = 25)

p-value

Age at diagnosis [range], years

44 [18–77]

42 [18–77]

47 [20–75]

0.24

              Age ≥60 years

20 (25)

12 (22)

8 (32)

0.51

Male

51 (65)

36 (67)

15 (60)

0.75

ECOG Performance Status 0–1

52/75 (69)

35/52 (67)

17/23 (74)

0.76

Stage 4

70 (89)

49 (91)

21 (84)

0.67

BM disease

58 (73)

42 (78)

16 (64)

0.31

Extramedullary disease

36 (46)

24 (44)

12 (48)

0.96

CNS disease at diagnosis

22 (28)

15 (28)

7 (28)

1.00

              Positive CSF

16 (20)

11 (20)

5 (20)

 

              Parenchymal disease

1 (2)

0

1 (4)

 

              Clinical manifestations

5 (6)

4 (8)

1 (4)

 

LDH ≥3 ULN

50 (63)

38 (70)

12 (48)

0.10

HIV-related

11 (14)

9 (17)

2 (8)

0.49

DHL

NA

NA

7 (28)

 

IPI, n [range]

NA

NA

3.5 [2–5]

 

CNS-IPI, n [range]

NA

NA

3 [1–4]

 

BL, Burkitt leukemia/lymphoma; BM, bone marrow; CNS, central nervous system; CSF, cerebrospinal fluid; DHL, double-hit lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; HGBL, high-grade B-cell lymphoma; HIV, human immunodeficiency virus; IPI; international prognostic index; LDH, lactate dehydrogenase; NA, not applicable; ULN; upper limit of normal.
*Adapted from Samra, et al.1

Eligibility criteria included age ≥15 years and Eastern Cooperative Oncology Group (ECOG) performance status ≤3 with no restrictions for older age, organ dysfunction, or presence of human immunodeficiency virus (HIV).

CNS prophylaxis comprised 16 IT doses of alternating MTX/Ara-C. For patients with baseline CNS involvement, IT therapy was administered twice weekly until clearance, then weekly for 4 doses after which prophylaxis was resumed.

Results

Table 2. Outcomes of patients with BL and HGBL treated with HCVAD-R*

Treatment outcome

Total (N = 79)

BL (n = 54)

HGBL (n = 25)

p-value

CR rate, n (%)

68/75 (91)

49/51 (96)

19/24 (79)

0.16

Early death <30 days, n (%)

2 (3)

2 (4)

0

0.84

Early death <60 days, n (%)

5 (6)

4 (7)

1 (4)

0.93

Relapse, n (%)

15/68 (22)

8/49 (16)

7/19 (37)

0.13

CNS relapse, n (%) 

4 (5)

2 (4)

2 (8)

0.43

              Isolated CNS relapse, n (%) 

2 (50)

1 (50)

1 (50)

 

Death, n (%) 

46 (58)

31 (57)

15 (60)

1.00

              Death in CR, n (%)

21 (27)

18 (33)

3 (12)

 

Overall survival

 

 

 

0.86

              Median, months [95% CI]

71 [18–NR]

125 [13–NR]

25 [17–NR]

 

              5-year, (%) [95% CI]

52 [42–64]

55 [44–70]

44 [28–68]

 

Relapse-free survival

 

 

 

0.62

              Median [95% CI], months

127 [54–NR]

126 [50–NR]

NR [10–NR]

 

              5-year [95% CI], %

58 [48–72]

59 [47–75]

57 [39–85]

 

Cumulative incidence of relapse

 

 

 

 

              5-year [95% CI], %

21 [11–30]

14 [4–24]

37 [14–59]

0.06

Cumulative incidence of CNS relapse

 

 

 

 

              5-year [95% CI], %

6 [0–12]

4 [0–10]

11 [0–25]

0.31

BL, Burkitt leukemia/lymphoma; CI, confidence interval; CNS, central nervous system; CR, complete remission; HGBL, high-grade B-cell lymphoma; NR, not reached.
*Adapted from Samra, et al.1

The cumulative incidence of relapse (CIR) was associated with baseline BM (27% vs 0%; p = 0.02) and CNS (42% vs 12%; p < 0.01) involvement. Nearly all deaths in complete remission (CR) (76%) were treatment-related, predominantly due to infections (48%) and secondary myeloid malignancies (19%). With a median follow up of 50 months, 33 patients (42%) were alive in CR (23 BL, 10 HGBL) and only one patient with relapsed disease (CR1 duration 6 years) remained alive in CR2 for more than 5 years after salvage with DA-EPOCH-R regimen.

The 5-year overall survival (OS) and relapse-free survival (RFS) rates were inferior in patients ≥60 years of age (OS, 30% vs 59%; p < 0.01; RFS, 38% vs 65%; p < 0.01) and in those with baseline CNS involvement (OS, 23% vs 63%; p < 0.01; RFS, 26% vs 71%; p < 0.01).

In patients aged <60 years with no CNS or BM involvement (n = 19; 10 BL and 9 HGBL), the 5-year OS and RFS rates were 68% and 86%, respectively. Patients with higher Burkitt Lymphoma International Prognostic Index had worse outcomes (5-year OS: 83% vs 67% vs 42%; 5-year RFS, 91% vs 80% vs 45% in patients with Burkitt Lymphoma International Prognostic Index low vs intermediate vs high, respectively).

Multivariate analyses

In multivariate analysis adjusted for age, ECOG performance status, LDH, CNS disease, and HIV status:

  • Age and CNS involvement were independent predictors for worse OS (p < 0.01 for both) and RFS (p = 0.02 and p < 0.01, respectively).
  • ECOG performance status was predictive of OS when the multivariate analysis was restricted to patients with CNS disease.
  • The CIR was 21% (BL 14%; HGBCL 37%; p = 0.06); higher in patients with baseline BM (27% vs 0%; p = 0.02) or CNS (42% vs 12%; p < 0.01) involvement.
  • The median time to relapse was 75 months (range, 0.5–228.1 months).
  • Patients <60 years without CNS or BM disease had the most favorable outcomes (5-year OS, RFS, and CIR rates of 68%, 86%, and 0%, respectively).

Four patients had CNS relapse at a median of 5.6 months from diagnosis (range, 7.1–11.3 months), two of which had isolated parenchymal relapse and two who had leptomeningeal with systemic relapse. Three of the four had baseline CNS disease and all four died from their disease at a median of 2.5 months after CNS relapse. The 5-year CNS CIR was 6% (BL 4%; HGBL 11%, p=0.31); 16% with baseline CNS involvement (p = 0.03).

Of the 22 patients with CNS involvement at baseline:

  • Three had CNS relapse (one isolated parenchymal and two leptomeningeal with systemic relapse).
  • Overall, 18 patients died due to disease (n = 10), infection (n = 5, all but 1 were in CR), toxicity (n = 1), or unknown (n = 2).
  • Multivariate analysis showed that ECOG performance status was predictive of OS.

Conclusion

Overall, the data from this long-term follow-up support the use of HCVAD-R as an effective regimen for BL and HGBCL, one that can prevent CNS relapse, especially among patients with high-risk features such as baseline BM or CNS involvement. However, a crucial limitation is the high risk of treatment-related toxicity and deaths in CR, particularly in patients 60 years of age and older. Therefore, regimens containing high-dose MTX and Ara-C should be reserved for patients with a higher risk of CNS relapse, while DA-EPOCH-R is preferable for patients with low-risk BL/HGBCL and for those who may not tolerate intensive treatment.

  1. Samra B, Khoury JD, Morita K, et al. Long term outcome of Hyper-CVAD-R for Burkitt leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS relapse. Blood Adv. 2021. Online ahead of print. DOI: 1182/bloodadvances.2021004427

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