New Insights into Transformed Follicular Lymphoma from the National LymphoCare Study

Patients with follicular lymphoma (FL) whose cancer has transformed into diffuse large B-cell lymphoma (DLBCL) often have a poor prognosis, with overall survival of just one to two years. However, the prognosis of patients whose FL eventually transforms, or who present with transformed FL, from the time of their FL diagnosis, is largely unknown because this patient population is largely excluded from clinical studies.

With the large, prospective, multicenter, observational National LymphoCare Study (NLCS), researchers have been able to detail the disease presentation, treatment patterns, and clinical outcomes of nearly 2,700 patients with newly diagnosed FL. Results of the analysis were recently published in Blood by Nina D. Wagner-Johnston, MD, from the Siteman Cancer Center at Washington University in St. Louis, Missouri, and colleagues.

“Our study features the largest series of patients with transformed FL at the time of diagnosis and provides a unique opportunity to learn more about the clinical behavior of this population,” Dr. Wagner-Johnston and colleagues wrote. The study included a database of 2,652 patients who were diagnosed with FL within six months of informed consent and no prior lymphoma history. Patients were enrolled between March 2004 and March 2007 and were subsequently followed from enrollment through June 2014 or until death, withdrawal of consent, or loss to follow-up.

Patients were categorized as transformed – either suspected or confirmed – by site investigators, and patient status was collected quarterly on electronic case report forms. The study also included the subset of patients with transformation at the time of initial FL diagnosis – a population that is mostly undocumented in the literature.

The researchers calculated the median time to transformation, progression-free survival (PFS), and overall survival.

At a median follow-up of 6.8 years, 14.3 percent of patients (n=379) had pathologically confirmed (5.5%; n=147) or clinically suspected (8.7%; n=232) transformation. Twenty-five of the suspected patients were ultimately confirmed to have transformed.

“The NLCS database is 4.5- to 10-times larger than all previously described transformed FL studies,” Dr. Wagner-Johnston and co-authors wrote, “and the number of patients with transformations is nearly twice that of the largest series.”

The following factors determined at diagnosis were associated with an increased transformation risk:

  • ECOG performance status >1 (hazard ratio [HR] = 2.12; 95% CI 1.27-3.55)
  • Extranodal sites >1 (HR=1.39; 95% CI 1.07-1.81)
  • Elevated lactate dehydrogenase (HR=1.57; 95% CI 1.17-2.10)
  • B symptoms (HR=1.35; 95% CI 1.06-1.72)

As seen in the TABLE, rituximab plus chemotherapy was the most commonly prescribed treatment for patients initially diagnosed with FL. Of the patients treated with combination chemotherapy, half received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), 23 percent received R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone), and 17 percent received fludarabine-containing regimens. “There was a surprising low use of ASCT [autologous stem cell transplantation] and yet outcomes were quite good,” Dr. Wagner-Johnston added.

The risk of transformation was similar in patients treated with R-CHOP compared with R-CVP (adjusted HR=0.94; 95% CI 0.62-1.42). In addition, maintenance rituximab was associated with a reduced transformation risk (HR=0.67; 95% CI 0.46-0.97).

“With the exception of the subset of patients with transformed FL at diagnosis, patients with transformation had significantly worse overall survival compared with patients without transformation,” Dr. Wagner-Johnston and her co-authors observed. The same was true for five-year survival (75% [95% CI 70-79%] in the non-transformed FL group vs. 85% [95% CI 83-86]; p<0.0001 in the transformed group). After transformation, the median PFS was 1 year, while the median overall survival was 4.9 years.

Another key finding of the study: Post-transformation survival was similar between patients diagnosed with transformation based on clinical characteristics or by biopsy, “the gold standard for diagnosing a transformation of FL,” the authors wrote.

Compared with the “dismal” prognosis described in historical reports, they concluded, these new results “raise the question as to whether this change [in outcome] reflects advancements in current treatments. The disparity seen in the relatively short median post-transformation PFS of approximately one year compared with the longer overall survival additionally suggests improvements in treatment.”

“We did not see a change in the overall incidence of transformation compared with historical reports, suggesting that perhaps modern chemoimmunotherapy has not altered the risk of transformation,” Dr. Wagner-Johnston said. While the findings demonstrated a lower risk of transformation in treated patients compared with observed patients, she added, “I do not believe that this observational data should impact a clinician’s decision to initiate treatment versus adopting a watchful-waiting approach.”


Reference

Wagner-Johnston ND, Link BK, Byrtek M, et al. Outcomes of transformed follicular lymphoma in the modern era: A report from the National LymphoCare Study (NLCS). Blood. 2015 June 23. [Epub ahead of print].

TABLE. Initial Treatment Approaches and Risk of Transformation
Factor

Patients, number (%)

Overall confirmed transformation rate Confirmed transformation adjusted HR, (95% CI) Overall confirmed or suspected transformation rate

Confirmed or suspected transformation adjusted HR (95% CI)

Observed patients

555

(21%)

7.6% 1 17.8% 1

Treated patients

2,097

(79%)

6.2% 0.57

(0.39-0.83)

13.4%

0.58

(0.46-0.75)

R-CVP

300

(11%)

6.3% 1 13.3% 1

R-CHOP

641

(24%)

6.2% 0.83

(0.46-1.5)

13.3%

0.94

(0.62-1.42)

Chemotherapy without rituximab

71

(3%)

8.5% 1 18.3% 1
Chemotherapy with rituximab

1,284

(48%)

6.5% 0.82

(0.33-2.07)

13.4%

0.61

(0.34-1.11)

Observation

609

(23%)

4.9% 1 13% 1

Rituximab maintenance

529

(20%)

4.5% 0.87

(0.5-1.52)

9.2%

0.67

(0.46-0.97)

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