Impact of treatment regimen on risk of secondary malignancies in patients with follicular lymphoma

Follicular lymphoma (FL) is the most prevalent indolent lymphoma type. Although it is characterized by slow growth and chemosensitivity, the high rate of relapse remains a concern. The introduction of targeted therapy with the CD20 antibody rituximab in 1997 was welcomed, and over the last 20 years this drug has improved the prospects of many patients with indolent non-Hodgkin lymphoma (iNHL). Prusilla and colleagues, recently published in the British Journal of Haematology results of a retrospective study looking at the impact of this and other treatments on the risk of secondary malignancy.¹

Secondary hematological malignancies (SHM), with an incidence of 2.9% in 10 years, are the third most common cause of death amongst patients with FL.² In particular, the incidences of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are rising.³ One of the reasons for this increase might be improved overall survival or the use of particular therapeutic regimens. However, the risk of developing SHM amongst different lymphoma subtypes, such as FL, has not been previously studied. To find out the incidence of SHM, and therapy-associated risks, researchers evaluated hospital records of 1028 patients with FL. All patients underwent treatment after rituximab approval.

Patient demographics

• The median follow-up was 67 months (0–226)
• Median age at the time of initial diagnosis was 60 years (17–100)
• 5% of patients were female
• Progression-free survival (PFS) was 89.5% and 52.7% at 1 and 5 years, respectively
• Disease-specific survival (DSS) was 97.2% at 1-year and 90.4% at 5-year
• Overall survival (OS) was 96.7% and 84.2% for 1-year and 5-year, respectively

Table 1. Patient characteristics CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; FLIPI, follicular lymphoma International Prognostic Index; LDH, lactate dehydrogenase; RDT, radiation therapy; SCT, stem cell transplantation

Characteristics

n

%

B-symptoms at diagnosis

166

16.6

Elevated LDH at diagnosis

226

29.0

FLIPI

  0–1

  2

  3–5

 

335

257

317

 

36.8

28.3

34.9

Number of treatment lines

  1

  2

  ≥3

 

621

220

127

 

64.2

22.7

13.1

Treated patients

  CHOP-like first-line therapy

  Bendamustine-containing first-line therapy

  Fludarabine-containing first-line therapy     

  RDT only in first-line

  Rituximab in any of the treatment lines

  Rituximab in first-line treatment

  SCT in any of the treatment lines

968

576

63

27

109

823

725

66

94.2

56.0

6.1

2.6

10.6

85.0

70.5

6.4

Key findings

Table 2. Incidence of secondary hematological malignancies

Secondary hematological malignancy

Number of patients (14/1028)

MDS

5

AML

4

acute lymphoblastic leukemia

1

acute promyelocytic leukemia

1

large granular lymphocytic leukemia

1

chronic myeloid leukemia

1

multiple myeloma

1

• Seven patients were diagnosed at a median time of 62.5 months (25–143)
• The median time to the diagnosis of MDS and AML after first line treatment was 55 months (41–93) and 51 months (25–137), respectively.
• The 5-year risk of SHM was 1.1% while the estimated 10-year risk was 2.7%.
• Overall SHM standardized incidence ratio (SIR) was 6.2 (95% Cl: 3.4–10.5),
  • 22 (95% Cl: 7.1–51.3) for MDS
  • 9 (95% Cl: 3.2–30.3) for AML
• B-symptoms (fever, night sweats, and weight loss) at the time of diagnosis, high FLIPI score and the number of treatment lines received was associated with significantly higher risk of SHM (p= 0.008, p= 0.044 and p= 0.016, accordingly)
• ≥ 3 lines of treatment was an independent risk factor for the SHM with an odds ratio of 5(95% CI, 1.2–20.7, p= 0.026)
• The 5-year risk of SHM after the first-line treatment was 0.5% but tripled after the second-line treatment to 1.6%
• SIR for SHM was 2.45 (95% CI, 0.8–7.6) in patients treated with one line of treatment, 6.9 (95% CI, 2.6–18.3) with two lines, and 15.9 (95% CI, 7.6–33.4) with ≥ 3 lines of treatment
• Chemotherapy showed a trend (p= 0.329) towards a higher risk of SHM at 5-years (1.2% of risk compared to 0.1% without) and 10 years (3.3% and 0.1%, respectively)
• Anthracycline-containing therapy carried the 5-year risk of 1.3% and an estimated 10-year risk of 3.7%.
• Using any chemotherapy as a first-line treatment increased the risk of MSD (p< 0.001) and AML (anthracycline-containing therapy p = 0.003 and other chemotherapy (p= 0.009)
• There was no correlation between the risk of SHM and gender, lactate dehydrogenase level (LDH) (p= 0.221) or hemoglobin level (p= 0.283) at the time of diagnosis
• Treatment with or without rituximab, or with/without SCT did not have a significant impact on risk of SHM risk (p= 0.302 and p= 0.269, respectively)
• In patients treated with SCT, the risk of SHM increased from 3.7% at 5-years to an estimated 9% after 10 years

Conclusions

The study found that risk of SHM is low after first-line treatment but increases with subsequent lines of treatment. Using a chemo-free immunotherapy approach only would be beneficial in low-risk patients as chemotherapy was associated with higher risk of SHM. However, real SHM numbers might be underestimated due to exclusion of secondary lymphomas caused by the inability to distinguish primary from secondary tumors.