Hematopoietic Cell Transplantation for Hodgkin Lymphoma

Role of Autologous Hematopoietic Cell Transplantation in Hodgkin Lymphoma

High-dose chemotherapy (HDT) and auto-HCT are the standard of care for treatment of relapsed or refractory (R/R) HL with chemosensitive disease. Two randomized trials testing multiagent chemotherapy compared to intensification with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) have shown superior event-free survival (EFS) for patients receiving the intensive chemotherapy supported by auto-HCT. The lack of overall survival (OS) benefit in the randomized trials is attributed to patients in the chemotherapy-only arms receiving HCT at the time of second relapse. A prospective nonrandomized trial by the Groupe d’Etudes des Lymphomes de l’Adulte group revealed a 5-year OS rate of 71% in the transplant group versus 32% in patients who did not undergo auto-HCT and received chemotherapy alone. A Cochrane systematic review and metaanalysis in 2013 demonstrated superior progression-free survival (PFS) for patients with R/R disease who undergo auto-HCT compared to conventional chemotherapy alone with a trend for improved OS.

Factors that Predict Recurrence After Transplant

Certain prognostic factors have been recognized to forecast disease progression after transplant. The most important feature that predicts for success of transplant is the duration of remission (> or < 12 months) after initial chemotherapy.

Other prognostic factors include:

• Stage III/IV disease

• Extranodal disease

• B symptoms

• Bulky disease at diagnosis (> 5 cm)

• Anemia (hemoglobin < 10 g/dL)

• Disease status at time of transplant

The Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model is based on factors available at the time of transplant and was developed based on the outcomes of 728 patients with R/R HL who underwent an auto-HCT. (The CIBMTR includes a voluntary working group of more than 450 transplantation centers worldwide that contribute detailed data on consecutive allo- and auto-HCTs to a statistical center at the Medical College of Wisconsin in Milwaukee and the National Marrow Donor Program [NMDP] Coordinating Center in Minneapolis. Participating centers are required to report all transplants consecutively.) The multivariate model identified four major risk factors at the time of auto-HCT with the following relative weights: Karnofsky performance score < 90 and chemotherapy resistance at transplant were each assigned 1 point, whereas at least 3 chemotherapy regimens pre-HCT and extranodal disease at auto-HCT were each assigned 2 points. Based on the total score summed for the four adverse risk factors, three risk groups were identified: low (score = 0), intermediate (score = 1–3), and high (score = 4–6). The 4-year PFS for the low, intermediate, and high-risk groups was 71%, 60%, and 42%, respectively.

Refractory HL in contrast to relapsed disease has a disappointing prognosis and will be discussed later in the chapter. There are various definitions of primary refractory disease, but all include patients with disease progression during front-line therapy; additionally, many also include patients with progressive disease within 90 days of completion of frontline therapy or patients failing to achieve a partial response (PR) to initial therapy. An Italian study reported that at 8 years, the OS of patients whose initial complete remission (CR) was longer than 12 months was 54% while those in CR shorter than 12 months was 28%. However, in those patients who had primary induction failure, the 8-year OS was 8%. Among patients who undergo auto-HCT with primary refractory disease, long-term survival is as high as 48% at 10 years for those with chemosensitive disease to salvage second-line chemotherapy.

Objectives of Salvage Chemotherapy Before Transplant

The importance of a complete response to therapy before transplant cannot be overstated. Attainment of a positron emission tomography (PET) negative CR has been shown to have a positive predictive value of 93% for PFS at 2 years, and is a strong predictor for long-term survival post–auto-HCT. Nevertheless, patients who have a PR or stable disease to salvage chemotherapy can still be cured with an auto-HCT, although the risk of relapse is appreciably higher in these groups.

Minimizing disease burden before transplant is achieved with salvage chemotherapy, radiotherapy or targeted agents (such as brentuximab vedotin or checkpoint inhibitors), or a combination of these. Commonly two to three cycles of salvage chemotherapy are administered with subsequent restaging, and patients who do not attain a CR with initial salvage therapy often proceed to further salvage therapy before transplant. Frequently used salvage regimens consist of chemotherapy alone as well as combination of chemotherapy and immunotherapy agent as shown in Table 25.1 . There are no randomized trials that directly compare salvage chemotherapy for relapsed HL. Response rates for these regimens in various phase II studies ranged from 60% to 85 %.

Impact of Conditioning Regimen

The therapeutic rationale of HDT with auto-HCT relies on enhanced cytotoxicity through the delivery of myeloablative doses of chemotherapy or total body irradiation (TBI). The principles of success for HDT are a steep dose-response curve using active synergistic cytotoxic agents that have a short half-life and primarily hematopoietic toxicity.

The goal of the preparative conditioning regimen is to eradicate remaining malignant cells that are present after the salvage chemotherapy. Peripheral blood progenitor cells are infused after the completion of the conditioning regimen to facilitate bone marrow recovery and “rescue” the hematopoietic system from myeloablative chemotherapy.

Different HDT regimens are associated with their own unique toxicities based on the individual agents or modalities used. For example, alkylating agents such as BCNU (carmustine) or TBI have a higher risk of idiopathic pneumonia syndrome (IPS), which is a leading pulmonary toxicity after HDT.

A prospective study to define the impact of conditioning regimens on overall outcomes for HL has not been done, and the choice of HDT regimen has been based predominantly on institutional experience and preference as well as patient comorbidities. Several regimens are considered standard and routinely used for both HL and non-Hodgkin lymphoma (NHL), and the most commonly used regimens are as follows:

• BEAM (BCNU, etoposide, cytarabine, melphalan)

• CBV (cyclophosphamide, BCNU, etoposide [VP-16])

• BuCy (busulfan and cyclophosphamide)

• BuCyE (busulfan, cyclophosphamide and etoposide)

• TBI containing treatment

A retrospective registry study through CIBMTR including over 1000 HL patients from 1995 to 2008 evaluated the outcomes of those who received an auto-HCT, and revealed, upon multivariate analysis, that patients who received BEAM had a superior OS compared to all other regimens. In that analysis, factors associated with inferior OS for all patients included older age, male gender, body mass index < 18.5 kg/m ² , Karnofsky performance scale < 90, chemoresistant disease, higher number of previous regimens of chemotherapy received, shorter time from diagnosis to auto-HCT, and use of bone marrow graft. In the same analysis, the development of IPS was most common after CBV- or TBI-based regimens, and patients who developed IPS had much worse PFS and OS.

Poor-Risk Hodgkin Lymphoma and Autologous Transplant

Refractory HL is particularly difficult to treat with poor outcomes; nonetheless, the treatment of choice remains HDT and auto-HCT given the high relapse rate with chemotherapy alone. Longo et al. reported a median survival of only 16 months in 51 patients treated with methotrexate, oncovin, procarbazine, prednisone (MOPP) chemotherapy who never achieved a CR. There is a paucity of prospective data to guide treatment decisions in this patient population, though the lack chemosensitive disease in both the primary refractory and the relapsed setting exhibit debatable benefit from HDT and auto-HCT.

In a report of 75 consecutive patients with biopsy-confirmed primary refractory HL, patients received conventional dose cytoreductive chemotherapy followed by HDT and auto-HCT. At a median follow-up of 10 years for surviving patients, the EFS, PFS, and OS rates were 45%, 49%, and 48%, respectively. Only chemosensitivity to standard-dose second-line chemotherapy predicted for a better survival, thus responding patients had an EFS, PFS, and OS of 60%, 62%, and 66%, respectively, versus 19%, 23%, and 17% for patients who had a poor response to second-line chemotherapy. In the review of available literature, results of auto-HCT after induction therapy failure for HL demonstrate EFS in the range of 30% to 42% at 5 years and OS in the range of 34% to 60% at 5 years.

Some groups have explored intensifying the conditioning regimen to improve efficacy of auto-HCT in poor-risk HL. Nieto et al. have published using an all-alkylator construct of busulfan (Bu) and melphalan (Mel) that achieves a precise systemic exposure to Bu through prospective pharmacokinetic monitoring, and then building upon that with the addition of gemcitabine (Gem) and vorinostat (SAHA). The Gem-Bu-Mel combination exploits the synergy between Gem and alkylating agents based on deoxyribonucleic acid (DNA) damage repair inhibition, and the addition of SAHA, a histone deacetylase inhibitor, increases DNA damage response and apoptosis. In this phase II study, 80 patients were enrolled with median age of 31 years (range, 13–65 years). Forty-one percent of patients had primary refractory disease and 36% had extranodal relapses, while at the time of transplant, 30% of patients had PET-positive disease. These patients were compared to a cohort of 45 patients that were eligible for this trial but received BEAM instead. Despite these high-risk patients, results from this novel conditioning regimen were very promising. At median follow-up of 34.5 months (range 26–72 months), both 2-year PFS (65% vs. 51%, P = .008) and OS (89% vs. 73%, P = .0003) favored the Gem/Bu/Mel cohort. No treatment-related deaths were noted, and toxicities were manageable with the most common side effects being mucositis, dermatitis, and transaminase elevation. However, for both of these intensive conditioning trials, the upper age limit was capped at 65 years because of increased risk of adverse side effects.

These are promising results from phase II trials and require confirmation with prospective phase III randomized clinical trials. The increased risk of pulmonary complications mandated that radiation near the lung fields was either done 30 days before Bu infusion or held until after completion of transplant with full recovery of counts.

Given these results, the preference would be to attempt high-dose therapy followed by auto-HCT in transplant eligible patients with the qualification that chemosensitivity should be demonstrated even if a CR is not attainable. Table 25.2 summarizes the data regarding auto-HCTs in HL.