Hodgkin’s lymphoma is a lymphoid neoplasm derived from germinal B cell, defined by the presence of Hodgkin and Reed-Sternberg cells and specific cellular background.
There are two subtypes of Hodgkin’s lymphomas: classical, accounting for 95% of cases, and nodular lymphocyte predominant Hodgkin’s lymphoma, for the rest of 5%.
The most common subtype of classical Hodgkin’s lymphoma is the nodular sclerosis variant, characterized by the presence of collagen band dividing tumor into nodules, lacunar cells, mononuclear Reed-Sternberg variants and reactive infiltrate that typically includes eosinophils and lymphocytes.
It is a curable disease that affects predominantly young patients (15-35 years old), with a generally good prognosis if a complete response to chemotherapy is obtained after the first-line treatment. The incidence varies with regions: 14.4% of lymphoid neoplasm cases in the United Kingdom and 8.76% in the United States of America(1).
In the past few years, we have noticed a significant progress regarding the management of the patient with Hodgkin’s lymphoma, reaching curability in at least 80% of the cases(1).
Relapsed refractory cases remain a challenging problem for hematologists. The current practice includes salvage chemotherapy followed by ASCT in case of chemosensitivity, but sustained remission can be achieved in only 50% of cases.
The addition of anti-CD30 antibody to the pretransplant therapy or posttransplant consolidation and maintenance has improved outcomes, but there are young patients who relapsed even after ASCT and brentuximab therapy(2).
Fewer solutions are available for them: allogeneic transplantation, clinical trials and also some novel drugs(2).
Novel therapies, with very good results and safety profile risks, are based on immunotherapies targeting programmed cell death-1 (PD-1) receptor, nivolumab and pembrolizumab.
Nivolumab is a PD-1 antibody that inhibits the PD-1 pathway, enhancing T-cell response, including antitumor responses; it acts by blocking the attachment of PD-L1 and PD-L2 ligands to the PD-1 receptor, which leads to the reduction of tumor growth. Reed-Sternberg cells are characterized by the genetic changes at the 9p24.1 locus, which lead to PD-L1 and PD-L2 overexpression, with extensive, mixed, inflammatory cell infiltration on the microenvironment(3).
Nivolumab seems to be a safe choice for patients heavily pretreated as a bridge to allogeneic transplantation after ASCT and brentuximab relapses, as well as salvage therapy in case of allogeneic transplant failure(3,4).
In May 2016, a healthy young male of 32 years old presented for dry cough and dyspnea associated with fever over the past two months.
The imagistic evaluation revealed a paramediastinal process of 65/45 mm on the right lung upper lobe, surrounded by numerous pulmonary nodules with a blurred outline and massively enlarged mediastinal lymph nodes: anterior of the aorta, subcarinal and in both pulmonary hila.
The bronchoscopy evaluation revealed tracheal mucosa with irregular, microgranular and congested appearance. The bronchoalveolar lavage described modified bronchial mucosa with macrophages, lymphocytes, neutrophils, eosinophils, and atypical cells. The bacteriological screening was negative.
The biopsy of the lung was performed; the histopathological examination revealed nodular infiltration consisting of polymorphic cells – large, mono-multinucleated cell-shaped suggesting Hodgkin/Reed-Sternberg cells, surrounded by a reactive environment formed by lymphocytes, eosinophils, histiocytes and neutrophils.
The immunophenotype of tumor cells was CD30+, CD15-, rare CD20+ cells, CD45-.
Based on a previous examination (imagistic, lung biopsy), the classical Hodgkin’s lymphoma nodular sclerosis IVB stage diagnosis was established.
Bone marrow biopsy showed no malignant infiltration. Ebstein Barr serology was negative. A PET-CT scan was not performed before treatment.
According to prognostic factors – male gender, stage IV, lymphopenia (WBC 12500/uL, lymphocytes = 600/uL) – the patient had an IPS of 3, with an overall survival rate around 78%.
Between May and September 2016, the patient received six BEACOPP chemotherapy courses, achieving a complete response at the final examination (imagistic evaluation).
Two months later, in November 2016, he presented for respiratory symptoms. The chest X-ray evaluation revealed a nodular opacity of 18/17 cm right juxtahilar of medium intensity.
The CT evaluation revealed clusters of a liquid collection on the right superior upper lobe (56/48 mm) and on the right middle lobe (under 1 mm). The patient was directed to the pneumologist for further investigation. After fibroscopy, bronchoalveolar lavage and lung biopsy, the relapsed of Hodgkin’s lymphoma was confirmed.
In January 2017, the patient was proposed for chemotherapy intensification and ASCT.
He received one course of DHAP chemotherapy, but due to the long-lasting hematological complications (severe pancytopenia with prolonged need of transfusion and opportunistic infections), he was switched to brentuximab 1.8 mg/mp, starting on February 2017.
PET-CT reevaluation in March 2017 showed no metabolic activity. He continued brentuximab vedotin applications until June 2017, when ASCT was performed. It was very well tolerated, without complications.
PET-CT reevaluation after ASCT in September 2017 revealed relapsed and progressive disease, with new active lesions localized in the right middle lobe and increased metabolic activity in splenic parenchyma.
We continued the administration of brentuximab chemotherapy after ASCT, but with dose reduction due to neuropathy. The relapse of Hodgkin’s lymphoma was confirmed again on lung biopsy in December 2017.
Due to disease progression after ASCT and brentuximab therapy, the chemotherapy options were discussed and we decided in favor of salvage chemotherapy. So, the patient received six courses of GVD (gemcitabine, vinorelbin, liposomal doxorubicin) between January and April 2018, but with no response at the PET-CT reevaluation – disease progression with increasing size of existing lesions located in the superior upper lobe and right middle lobe.
Allogeneic stem cell transplantation (allo-SCT) was planned, but it was not performed due to the lack of a matching donor and also the lack of chemosensitivity at that time.
Despite the medical history with multiple regimes of chemotherapy, relapsed in less than three months after ASCT, progressive disease under brentuximab and accumulated toxicity, our patient was young, with no other comorbidities or diseases, with very good performance status and an enormous wish to reach curability.
That was the moment when we opted for a novel therapy with an anti-PD-1 antibody, nivolumab.
In June 2018, nivolumab 3 mg/kg was started, the treatment being purchased by patient’s personal resources – as the drug was not yet reimbursed by the National Insurance Company and no clinical trials were available in our country.
Three months later, PET-CT revealed regression of lung lesions (dimensions and FDG intake). Until now, he received 14 courses of nivolumab, very well tolerated and with no hematological or other toxicities.
The PET-CT reevaluation is programmed to be performed in April 2019. After this evaluation, we should decide what is next for our patient.
The option for allogeneic stem cell transplantation is still a viable choice at this time, but there is still no suitable donor. Another option could be the haploidentical transplant from his father, because we consider that in this particular case the advantage of transplantation is superior to any other possible treatment, with a superior overall survival and progressive free survival.
Although therapy of advanced-staged Hodgkin’s lymphoma has improved over the last few years, there are still up to 10% of patients who do not achieve complete remission and another 20-30% of responding patients who relapse after treatment(2).
It is a well-known fact that patients who relapsed after the first course of chemotherapy have a low chance to cure after the second-line therapy, especially when the relapse occurred in less than six months after the first treatment.
In these cases, the international guidelines recommend salvage chemotherapy followed by autologous stem cell transplantation(2).
In most cases, second-line therapy includes regimens such as ICE (ifosfamide, carboplatin, etoposide), GVD (gemcitabine, vinorelbine, liposomal doxorubicin), DHAP (dexamethasone, cytarabine, cisplatin) or brentuximab vedotin(2). The superiority of any of these options has not been definitively established(5,6,7), and sustained remissions can be achieved in approximately 50% of cases(8).
The relapsed cases after ASCT remain very challenging, with longevity directly related to the time of relapse after transplantation.
In these cases, the first option is brentuximab vedotin, an anti-CD30 antibody. In some patients, the single agent brentuximab vedotin represents an option before HDCT and ASCT, and consolidating treatment is recommended after HDCT and ASCT in patients with poor prognostic factors(9,10).
It also appears to improve the outcome and is being investigated in chemotherapy combination in frontline settings(9,11).
However, there still remains a minority of patients who relapse after ASCT, with very poor outcomes and a median survival rate (OS) of 1-2 years(1,2).
The third and fourth regimen can be used including single or combined chemotherapy, immunomodulatory agents, histone deacetylase inhibitors and radiation therapy, but with very few response rates and short duration of remissions(1,2).
Allogeneic SCT represents a potentially curative option for young patients, chemosensitive, with good performance status and a good risk-benefit ratio, but is limited by significant transplant-related morbidity and mortality, with an OS ranging from 45% to 66%(1,2,10).
If not previously used, brentuximab has shown major efficacy as a bridge to allogeneic transplantation(12) or after allogeneic transplantation relapses(13).
The novel therapy is centered on the use of nivolumab or pembrolizumab in patients with disease recurrence after HDCT followed by ASCT and brentuximab terapy(14).
Nivolumab and pembrolizumab are PD-1 blocking antibodies that have remarkable efficacy in heavily pretreated patients with progressive disease, with remissions rate up to 87% observed in clinical trials(15,16).
Nivolumab seems to be a safe choice for patients heavily pretreated as a bridge to allogeneic transplantation after ASCT and brentuximab relapses, as well as salvage therapy in case of allogeneic transplant failure(17,18,19).
The durability of response to nivolumab is still unknown, and clearly more information is required to quantify the risk of immune toxicity(1,2,4).
In patients with multiple relapses, who have no other treatment option, palliative treatment based on gemcitabine or/and regional radiotherapy is recommended(10).
Clinical studies have shown that treatment with nivolumab is an effective choice in patients with relapsed/progressive disease who were treated with multiple lines of chemotherapy, including brentuximab vedotin and ASCT.
The initiation of nivolumab in our patient treatment enhances his clinical and imagistic response and allows us to check an suitable donor for allogeneic transplantation.
This clinical case confirms the efficacy of nivolumab therapy, leading to new horizons in Hodgkin’s lymphoma curability.
Conflict of interests: The authors declare no conflict of interests.