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You Make the Call: What would you advise when biopsy results show nodular lymphocyte-predominant Hodgkin lymphoma but lab and bone marrow tests are negative?

August 30, 2022

September 2022

Elizabeth Brém, MDElizabeth Brém, MD
HS Clinical Associate Professor
Division of Hematology/Oncology
UC Irvine Health





A 59-year-old patient was referred to me after a circulating tumor DNA (ctDNA) screening test indicated he likely had a lymphoproliferative cancer. Extensive work-up revealed enlarged lymph nodes (2-3 cm in size) in the retroperitoneum and iliac region. A PET scan confirmed uptake of radiotracer by these nodes, as well as a focal splenic lesion. All other work-up (labs and bone marrow biopsy) have come back negative, but the lymph node biopsy showed nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). What would you advise?


While ctDNA assays are used commonly in clinical practice by our solid tumor colleagues, they have not been routinely adopted into care outside of clinical trials in lymphoma. Additionally, to my knowledge, there is not an FDA-approved ctDNA assay for lymphomas. Another assay known as Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) has shown to have prognostic value and is being used as an integrated biomarker in several ongoing and upcoming intergroup trials. It has been shown that a 2.5 log reduction in ctDNA levels after two cycles of initial therapy (major molecular response [MMR]) for diffuse large B-cell Lymphoma (DLBCL) is associated with improved 24-month event-free survival of 82% vs. 46%.1 In patients undergoing CAR T-cell therapy for relapsed or refractory DLBCL, undetectable ctDNA via CAPP-Seq is associated with improved outcomes. Patients with detectable ctDNA had a median progression-free survival of three months compared to not reached in those for whom ctDNA could not be detected.2 For patients with central nervous system lymphoma, it was found that ctDNA could be readily found in both cerebrospinal fluid (100%) and plasma (78%).3 In this setting, ctDNA has high potential to be used diagnostically (given the invasiveness of brain biopsy) and prognostically, as patients with detectable ctDNA during treatment had inferior outcomes: 6.2 times higher risk of progressive disease and 7.9 times higher risk of mortality. Though ctDNA has high prognostic potential for lymphoma, to date, the data available have focused on aggressive lymphomas. Additionally, it has not yet been shown that treatment at the time of ctDNA positivity will improve outcomes, particularly in the context of an indolent disease like NLPHL. The role of ctDNA in screening for lymphoma has not yet been defined.

I teach my trainees to think of NLPHL as a low-grade non-Hodgkin lymphoma (HL). Histopathologically, Reed-Sternberg cells are absent and the lymphoma cells are CD20 positive. Clinically, it has an indolent course and when it transforms, it tends to transform to DLBCL, not classical HL.4 NLPHL is a rare disease that accounts for about 5% of HL, and HL accounts for only about 10% of lymphomas.5 A number of therapies can be used for NLPHL, including radiation therapy (RT) for limited-stage disease, rituximab alone, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with or without rituximab.4 In general, patients with this disease have an excellent prognosis. An analysis of patients in the German Hodgkin Study Group who experienced relapse after initial therapy (RT ± chemotherapy, chemotherapy, or rituximab) showed that five-year overall survival (OS) was 89.5% for the entire cohort and was 97.2% for those who had only received anti-CD20 therapy or RT.6 A similar study from British Columbia found an OS of 91% for their cohort.7

The patient in this case has stage II disease. I am going to make two assumptions: 1) this patient is asymptomatic, given that the ctDNA test was done for screening, and 2) the radiotracer uptake on the PET/CT was low, meaning there is not concern for histologic transformation. I would advocate for watch-and-wait. I would use rituximab alone if the patient becomes symptomatic, as this can be effective in many cases and avoids the short- and long-term toxicity of chemotherapy like CHOP or ABVD; however, these chemotherapies can be used at first relapse. I personally don’t find surveillance imaging helpful in indolent disease and would only repeat PET/CT if symptoms are developing or there is concern for transformation. This patient likely has splenic involvement based on PET/CT. Data suggest that patients with NLPHL with splenic involvement are at higher risk of transformation (46% vs. 14%),7 but transformation is still not 100%. Because of this, I would strongly emphasize the signs and symptoms of transformation during patient education and would clinically monitor this patient more closely with follow-up every three months instead of every six months, for example.


  1. Kurtz DM, Scherer F, Jin MC, et al. Circulating tumor DNA measurements as early outcome predictors in diffuse large B-cell lymphoma. J Clin Oncol. 2018;36(28):2845-2853.
  2. Frank MJ, Hossain NM, Bukhari A, et al. Monitoring of circulating tumor DNA improves early relapse detection after axicabtagene ciloleucel infusion in large B-cell lymphoma: results of a prospective multi-institutional trial. J Clin Oncol. 2021;39(27):3034-3043.
  3. Mutter JA, Alig S, Lauer EM, et al. Profiling of circulating tumor DNA for noninvasive disease detection, risk stratification, and MRD monitoring in patients with CNS lymphoma. Blood. 2021;138(Supplement 1):6.
  4. Eichenauer DA and Engert A. How I treat nodular lymphocyte-predominant Hodgkin lymphoma. Blood. 2020;136(26):2987-2993.
  5. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA: Cancer Journal for Clinicians. 2022;72(1):7-33.
  6. Eichenauer DA, Plütschow A, Schröder L, et al. Relapsed and refractory nodular lymphocyte-predominant Hodgkin lymphoma: an analysis from the German Hodgkin Study Group. Blood. 2018;132(14):1519-1525.
  7. Al-Mansour M, Connors JM, Gascoyne RD, et al. Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin’s lymphoma. J Clin Oncol. 2010;28(5):793-799.


I have a 22-year-old patient that presented with extreme thrombocytosis (3,000 × 109/L). No mutation was found on testing of the peripheral blood for JAK2, CALR, and MPL mutations, as well as BCR-ABL1 translocations. A myeloid mutation panel showed no other mutations associated with myeloproliferative neoplasm (MPN). A bone marrow biopsy showed MPN, best classified as essential thrombocythemia (ET). The patient has no prior history of thrombosis and no bleeding or acquired von Willebrand syndrome (aVWS) at diagnosis. She is currently being treated with pegylated interferon (PEG-IFN). My question is: should the target platelet count be less than 400 × 109/L or another threshold? Her platelet count is around 500 × 109/L now, and she is tolerating the PEG-IFN well. Should we also give her low-dose aspirin? I found some data that recommended against it in asymptomatic patients who are at a low risk for thrombosis.

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.


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