Is “Watching and Waiting” Enough for Patients With Nodular Lymphocyte-Predominant Hodgkin Lymphoma?

For patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), active surveillance appeared to be a feasible initial management strategy, according to an analysis published in Blood by researchers at Memorial Sloan Kettering Cancer Center (MSKCC). Furthermore, NLPHL, which comprises just 5% of Hodgkin lymphoma cases, has an excellent prognosis regardless of treatment strategy, corresponding author David J. Straus, MD, told ASH Clinical News.

“Opinions differ about initial management of patients diagnosed with NLPHL [because] many patients present with local disease and are treated with radiation therapy or with combined modality treatment with chemotherapy and radiotherapy,” he explained. “Patients with more advanced disease are treated with systemic treatments including chemotherapy, rituximab alone, or rituximab in combination with chemotherapy.”

In this report, the researchers retrospectively analyzed treatment outcomes for 163 patients (median age = 40 years; range = 16-75 years) who were newly diagnosed with NLPHL between 1974 and 2016.

“Because of the frequent indolent course of NLPHL and the question of whether interventions affect ultimate outcome, we have adopted a conservative approach at MSKCC, like that for low-grade non-Hodgkin lymphoma (NHL), with active surveillance of patients presenting with low tumor bulk and without symptoms,” he added. “For such patients, the important question may be ‘when and if,’ rather than ‘what.’ In our retrospective experience, 23% of patients were successfully managed with this approach and had excellent outcomes.”

Management strategies, determined by the treating physicians, in the entire cohort were:

  • radiotherapy alone (46%)
  • active surveillance (23%)
  • chemotherapy (16%)
  • combined modality (12%)
  • rituximab monotherapy (4%)

Primary outcomes included progression-free survival (PFS; defined as time from diagnosis to biopsy-proven disease progression, initiation of additional treatment, or death from any cause) and second PFS (PFS2; defined as time from disease progression to relapse to second biopsy-proven disease progression, second initiation of further treatment, or death from any cause). Rates of transformation, secondary malignancies, and death (associated with or not associated with lymphoma) were also evaluated throughout the study period.

Most patients (74%) had stage I/II disease, including 23 of the 37 patients (62%) who received active surveillance. Baseline characteristics were similar for patients across the treatment groups, but patients managed with active surveillance were more likely to have advanced-stage (Ann Arbor stage III/IV) disease (38% vs. 22%; p=0.09) and to be older (median age = 47 vs. 39 years; p=0.03).

Of the nearly one-quarter of patients who received active surveillance, 28 (76%) never required treatment, and those who did were mostly managed with local radiotherapy or rituximab monotherapy, with a median time to first treatment of longer than five years.

During a median follow-up of 69 months (range = 4-512 months), the authors observed 40 PFS events, 13 PFS2 events, and seven overall survival (OS) events. This included 10 PFS events, one PFS2 event, and no OS events in the active surveillance group. Thirty-seven of the 40 PFS events were considered disease relapses or progressions; the other three patients died without experiencing disease progression or relapse.

Overall, the five-year estimates for PFS, PFS2, and OS were 85%, 97%, and 99%, respectively.

Survival outcomes were excellent in all treatment groups, and median PFS was not reached in any group. Specifically, in patients who received active surveillance, 27% progressed during follow-up, eight of whom had NLPHL and two of whom had transformed disease. Only one patient experienced a second relapse event.

“As could be expected, active surveillance was associated with a shorter PFS when compared with any other treatment,” the authors wrote, with five-year PFS rates of 77% and 87%, respectively (p=0.017). PFS2 was similar between the groups, with five-year PFS2 rates of 95% with active surveillance and 97% with any other treatment (p=0.71). No patient in the active surveillance group died, while five-year OS for any other treatment group was 98% (p=0.38).

Looking at risk factors for PFS, the authors found that bulky disease ≥5 cm (hazard ratio [HR] = 3.0; 95% CI 1.3-7.0; p=0.01) and extranodal disease (HR=7.5; 95% CI 2.1-27.4; p=0.002) were associated with shorter PFS. If patients who initially received active surveillance required additional treatment, the addition of radiotherapy improved PFS (HR=0.34; 95% CI 0.17-0.66; p<0.001), particularly in those with early-stage disease (HR=0.43; 95% CI 0.19-0.97; p=0.035).

This was an exploratory analysis, though, and “in keeping with the excellent prognosis and indolent course of NLPHL, event numbers were insufficient to conclusively compare specific treatments,” the authors cautioned.

During the follow-up, the authors observed 24 disease transformations and secondary cancers in the entire cohort, which occurred at a median of 7 years (range = 0.4-15.6 years) and 7.8 years (range = 1.1-24.8 years) following diagnosis. This included two transformations (5.4%) and two secondary cancers (5.4%) in the active surveillance group, compared with 10 (7.9%) and 10 (7.9%) across other treatment groups (p value not reported). Overall, the rates of transformation and secondary cancers were less than 1% per year, per patient. However, the authors noted that follow-up was possibly too short to truly capture the incidence of secondary cancers.

Other limitations of the study include its retrospective design, its inclusion of patients from only MSKCC, the lack of a random treatment allocation, and the shorter follow-up in patients with active surveillance versus any other treatment.

This rare form of Hodgkin lymphoma has an excellent prognosis, regardless of treatment strategy.

Further collaborative efforts may provide definitive answers about which subgroups of patients with NLPHL can be safely managed with active surveillance, but the authors concluded, “In the absence of randomized trials, it might be advisable to approach NLPHL in selected patients (e.g., those without risk factors for progression such as bulky or extranodal disease) in a similar fashion to indolent NHL.”

The authors report no conflicts of interest.

References

Borchmann S, Joffe E, Moskowitz CH, et al. Active surveillance for nodular lymphocyte-predominant Hodgkin lymphoma. Blood. 2019 February 15. [Epub ahead of print]

In this single-institution retrospective analysis, interestingly, patients who received active surveillance as their primary management strategy had a remarkably favorable outcome. Only 27% of these patients required treatment, and despite a lower PFS, there was no difference in OS compared with patients receiving initial treatment. Notably, only two patients managed with active surveillance experienced transformation and no patients died because of lymphoma. These results support a “watch-and-wait” strategy in select patients with NLPHL, similar to standard practice in patients with indolent NHL.

Given the retrospective nature of this study and the modest cohort size, criteria for optimal patient selection for active surveillance cannot be determined. In addition, treatment allocation was individualized based on physician discretion and was likely influenced by clinical characteristics that may be difficult to control for within the context of multivariable analyses. Nonetheless, given the rarity of this entity, observational data such as this must be relied on to guide clinical practice, and the extremely favorable outcome seen in patients undergoing active surveillance provides reassurance for the safety of this approach.

Laurie Sehn, MD, MPH
Medical Oncologist, BC Cancer Agency
Clinical Associate Professor, University of British Columbia
Vancouver, BC

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