Case Study of a Newly Diagnosed HL Patient: The Role of CD30 from Diagnosis to Treatment

Case Discussion published on May 17, 2016
Andreas Engert, MD
Professor of Internal Medicine, Hematology, and Oncology
University Clinic of Cologne
Cologne, Germany
Case Study of a Newly Diagnosed HL Patient: The Role of CD30 from Diagnosis to Treatment
Case Discussion in HL

Introduction

Hodgkin lymphoma is a lymphoid malignancy that typically affects young adults; the median age at diagnosis is 34 years in our database (GHSG 2016). The most often observed clinical symptoms are painless, enlarged cervical lymph nodes. However, all lymph nodes and other lymphatic tissue can be involved with this disease. Solid organs such as lung, liver, spleen, and bone marrow can also be involved and might cause specific symptoms such as cough, dyspnea, abdominal discomfort or cytopenia. The diagnosis of Hodgkin lymphoma is typically based on a lymph node biopsy showing large Hodgkin and Reed-Sternberg (H-RS) tumor cells embedded in a plethora of reactive cells. Based on histology and immunophenotype, Hodgkin lymphoma is divided into classical Hodgkin lymphoma (cHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Typically, H-RS cells express the lymphoid activation marker CD30 very strongly and are CD20 negative, whereas the malignant cells in NLPHL are typically CD30 and CD15 negative, but strongly express the B-cell marker CD20. Here we describe the diagnostic work-up and treatment of a 32-year-old female patient diagnosed with classical Hodgkin lymphoma.

This 32-year-old female patient noticed a left cervical lymph node in January 2009. The lymph node was non-tender and painless. After a period of 2 months of waxing and waning, the patient observed a more constant growth and enlargement, so she consequently consulted a medical doctor. The basic laboratory check-up at that time revealed a slightly elevated ESR of 25 mm/h. Since he was uncertain, the doctor sent the patient to a more specialized hematologist. In early May 2009, her cervical lymph node was measuring about 3 cm in diameter, and a more thorough diagnostic approach was planned by the hematologist, including a comprehensive laboratory check-up with virology and immune function tests, as well as CT scans of the cervical area, thorax, and abdomen. A large mediastinal tumor measuring more than 1/3 of the thorax as well as left-cervical and left-supraclavicular lymph nodes were diagnosed, measuring up to 3.5 cm in diameter. Subsequently, a biopsy of the left cervical lymph node was performed. The histology work-up identified 2% of large mono- or bi-nucleated blastoid giant cells and a plethora of reactive cells divided by sclerotic bands. The immunostaining showed strong positivity of CD30 in these cells with additional positive staining of CD15 and a negative staining for CD20. Thus, a diagnosis of classical Hodgkin lymphoma was made. Since she had supraclavicular and mediastinal lymph nodes involved, with no symptoms such as fever, weight loss or night sweats, the patient was diagnosed as classical Hodgkin lymphoma of nodular sclerosing subtype. The stage was Ann Arbor IIA with a large mediastinal tumor. According to the GHSG risk allocation, the patient was classified as early unfavorable classical Hodgkin lymphoma.

Risk allocation for Hodgkin lymphoma patients

The recommended work-up and studies for the initial evaluation of Hodgkin lymphoma are shown in Table 1. The modified Ann Arbor staging system allocates lymphoma patients to stages I, II, III, and IV, respectively, with stage A defined as those patients without B-symptoms, and stage B defined as unexpected fever, drenching sweats or weight loss. More recently, the FDG-PET has shown to identify metabolically active areas that can reflect the biological activity of this disease. However, FDG is not a specific biomarker and also accumulates in non-malignant tissue such as brain, heart, and kidneys. In addition, areas of inflammation can also be strongly PET-positive. In the initial work-up of our 32-year-old female patient, unfortunately, a PET-scan was not performed.

Table 1 Hodgkin lymphoma: Recommended studies for initial evaluation

Recommended for disease assessment

FDG-PET-CT (if this is done, a dedicated CT would generally not be necessary)

Recommended for toxicity assessment

Pulmonary: lung function tests
Heart: ECG, MUGA, or echocardiogram
Thyroid and gonadal functions: FSH, LH, and TSH (semen analysis and sperm storage)
Psychosocial adaptation

Mandatory for the Cotswolds classification

Individual and familial history, clinical examination as per Cotswolds recommendations
Blood counts and routine workup: ESR, LDH, alkaline phosphatase, albumin, liver function, β2-microglobulin, virology
Histology and immunophenotyping
Chest radiograms: CT of chest, abdomen, and pelvis; bone marrow biopsy if indicated (generally not necessary if PET/CT is done) (34-A) 

Initial treatment

The initial treatment of Hodgkin lymphoma patients diagnosed with early unfavorable disease is typically a combination of chemotherapy followed by some local radiotherapy.1, 2 The GHSG HD11 study3 showed that 4 cycles of ABVD followed by 30 Gy IFRT should be regarded as standard of care in this setting. Although the GHSG follow-up study, HD14, showed a significantly improved PFS in patients receiving 2x BEACOPP escalated followed by 2x ABVD and 30 Gy IFRT as compared to 4x ABVD plus 30 Gy IFRT, there was no difference in overall survival in this trial.4 Since there was also no difference in overall survival with longer follow up, 4 cycles of ABVD followed by 30 Gy IFRT remain the standard of care for early unfavorable Hodgkin lymphoma patients outside clinical trials, and the patient was treated subsequently. This treatment was rather well tolerated without major acute side effects.

Treatment for first relapse

Unfortunately, in early 2013, the patient began to suffer from shortness of breath and increasing night sweats. She also had lost more than 10% of her body weight within the last two months. A PET-CT confirmed a mediastinal mass of 8 cm in diameter that was PET-positive. A mediastinal core biopsy confirmed the diagnosis of CD30-positive/CD15-positive and CD20-negative classical Hodgkin lymphoma of nodular sclerosis subtype. In addition, there were also enlarged abdominal lymph nodes in the left inguinal and iliaca region measuring up to 3 cm in diameter. Thus, with this histologically confirmed relapsed CD30-positive classical Hodgkin lymphoma, the decision was made to treat her with two cycles of DHAP (dexamethasone, cytarabine, cisplatin) followed by high-dose chemotherapy (BEAM; carmustine, etoposide, cytarabine, melphalan) and autologous stem cell transplant. Based on two randomized clinical trials,5,6 high-dose chemotherapy has become the standard of care for relapsed Hodgkin lymphoma. The choice of chemotherapy has not been evaluated in a prospectively randomized trial, and combinations such as DHAP, ICE (ifosfamide, carboplatin, etoposide), IGEV (ifosfamide, gemcitabine, vinorelbine) or GVD (gemcitabine, vinorelbine, pegylated liposomal doxorubicin) have been used successfully (Table 2). Since there were no signs of bone marrow involvement, the patient was mobilized successfully after the first DHAP cycle and received the second cycle in a timely manner, followed by BEAM and subsequent autologous stem cell transplant. She engrafted within two weeks but developed atypical pneumonia by day 12. She fully recovered by day 25 and was subsequently discharged.

Table 2 Relapsed Hodgkin lymphoma: Selected conventional salvage regimen

Regimen

n

RR

TRM

Author

DHAP

102

88

0

Josting A. Oncol. 2002

IGEV

91

81

0

Santoro A. Oncol. 2007

ICE

65

88

2

Moskowitz C. Blood. 2001

ASHAP

57

70

0

Rodriguez J, Blood. 1999

GVD

91

70

0

Bartlett A. Oncol. 2007

The patient did well until April 2014 when she again developed progressive dyspnea, massive night sweats, and weight loss. This time, the PET-CT again identified PET-avid lesions in the lung, abdomen, and bone marrow. A bone marrow biopsy showed atypical large cells that stained positively for CD30. In addition, the biopsy of a pulmonary lesion also showed typical CD30-positive H-RS cells, so the diagnosis of a second relapsed Hodgkin lymphoma was made.

Although the prognosis of patients relapsing after high-dose chemotherapy and autologous stem cell transplant is about 4.6 years when the last remission was at least 12 months, the overall survival is only about 2.4 years for patients relapsing within 12 months.7 Unfortunately, more than 90% of Hodgkin lymphoma patients relapsing after autologous transplant ultimately die, with very few long-term responders.

Since her tumor was still strongly CD30-positive, it was decided to treat her with an antibody drug conjugate, brentuximab vedotin, that consists of a CD30-directed monoclonal antibody linked to a potent anti-tubulin agent, monomethyl auristatin E. Brentuximab vedotin had shown impressive activity in the initial phase I study.8 In the subsequent phase II pivotal clinical trial, a total of 102 patients with CD30-positive classical Hodgkin lymphoma were included. These patients received a median of 4 lines of prior treatment and all were pre-treated with high-dose chemotherapy followed by an autologous stem cell transplant. In this phase II trial, a total of 73% achieved either PR or CR, with 33% of patients achieving complete remission.9 Brentuximab vedotin was well tolerated with 20% grade III/IV neutropenia and 9% grade III peripheral sensory neuropathy. There were also grade III/IV events in 8% of patients for thrombocytopenia and 6% of patients for anemia. Thus, this rather well-tolerated drug was registered for the treatment of patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplant or at least 2 prior lines of treatment in patients not suitable for high-dose chemotherapy.

Our patient was thus treated with brentuximab vedotin at the standard dose of 1.8 mg/kg every 3 weeks intravenously. She tolerated this treatment well with some neutropenia not requiring GCSF. After 4 cycles of brentuximab vedotin, she achieved a complete remission and continued treatment with brentuximab vedotin. After 8 cycles, she noticed a peripheral sensory neuropathy grade II, so the dose of brentuximab vedotin was reduced to 1.2 mg/kg every 3 weeks, which resulted in improved neuropathy to grade I. Importantly, she could continue treatment and received a total of 16 cycles. Apart from another respiratory tract infection, which was treated with oral antibiotics, she was doing well and resumed her work as a teacher in August 2015. The patient is being regularly monitored and has remained in complete remission since.


References

  1. Fermé C, Eghbali H, Meerwaldt JH, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007;357(19):1916-1927.
  2. Engert A, Schiller P, Josting A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol. 2003;21(19):3601-3608.
  3. Eich HT, Diehl V, Görgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199-4206.
  4. von Tresckow B, Plutschow A, Fuchs M, et al. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin study group HD14 trial. J Clin Oncol. 2012;30:907-913.
  5. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. 1993;341:1051-1054.
  6. Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002;359:2065-2071.
  7. Arai S, Fanale M, Devos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma. 2013;54:2531-2533.
  8. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363(19):1812-1821.
  9. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30:2183-2189.
Last modified: May 11, 2016

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