How to follow Hodgkin’s after a documented remission has always been controversial. Historically,  follow-up protocols were based on a report generated in 1999 by pathologists, radiologists and oncologists from the Cotswolds meeting in 1999. This report recommended that patients be assessed every 3 months during the first 2 years post-therapy, every 4 months during the third year, every 6 months during the fourth and fifth years, and annually thereafter. However, subsequent literature has continued to question the need for such frequent imaging. The uncertainty about the value of routine radiological investigations in the detection of relapse has increased after two studies showed that most relapses are detected as a result of patient-reported symptoms, not radiological investigations. Farther uncertainty was introduced by availability of PET scans. American College of Radiology recommends CT scans every 6 months for two years, then annually for 3 years but lists PET as “no consensus”. BC guidelines dont recommend any CT scanning. That is also ESMO recommendation of 2010. NCCN does not recommend PET. It has surveillance recommendations for imaging for chest x-ray or CT every 6-12 months for 2-5 years and abdominal/pelvic CT(category 2B) every 6-12 months for first 203 years. Surveillance PET should nto be done routinely due to risk of false positives. Management decisions should not be made on PET alone…” After 5 years it recommends annual chest imaging for patients at increased risk of lung cancer and annual breast screening 8-10 years after therapy or at age 40.

Ng AK, Constine LS, Deming RL, Wolkov HB, Hoppe RT, Abrams RA, Mendenhall NP, Morris DE, Yahalom J, Chauvenet A, Hudson MM, Winter JN, Mauch PM, Expert Panel on Radiation Oncology-Hodgkin’s Disease Work Group. Follow-up of Hodgkin’s Disease. [online publication]. Reston (VA): American College of Radiology (ACR); 2005. 6 p. [43 references]

E T Dryver et al, Follow-up of patients with Hodgkin’s disease following curative treatment: the routine CT scan is of little value British Journal of Cancer (2003) 89, 482–486.

ESMO – http://annonc.oxfordjournals.org/content/21/suppl_5/v168.full

http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Lymphoma/HodgkinsDisease.htm

Maeda LS, Horning SJ, Iagaru AH, et al. Role of FDG-PET/CT surveillance for patients with classical Hodgkin’s disease in first complete response: the Stanford University experience [abstract]. Blood 2009;114:Abstract 1563.

Zinzani PL, Stefoni V, Tani M, et al. Role of [18F]fluorodeoxyglucose positron emission tomography scan in the follow-up of lymphoma. J Clin Oncol 2009;27:1781–1787.

nccn.org, Hodgkin, 2015

Rituxan is a promising drug for Hodgkin’s but more studies need to be done. Oxaliplatin is currrently in a clinical trial: Oxaliplatin in Treating Patients With Relapsed or Refractory Non-Hodgkin’s Lymphoma., NCT00006473, completed but not published yet. It is a Phase II trial to study the effectiveness of oxaliplatin in treating patients who have relapsed or refractory non-Hodgkin’s lymphoma.

According to results recently published in the journal Blood, Rituxan® (rituximab) appears to be a promising agent in the treatment of some patients with recurrent Hodgkin’s. Rituxan® is a monoclonal antibody approved for treatment of non-Hodgkin’s lymphoma (NHL) and binds to an antigen called CD 20. A small subset of patients with Hodgkin’s lymphoma (3% to 8%) has a type of cancer called CD 20 lymphocyte predominant Hodgkin’s lymphoma, characterized by a large proportion of their cancer cells expressing CD 20. Patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma tend to have a higher rate of recurrence following standard therapy than other patients with Hodgkin’s lymphoma.

Researchers from Germany recently conducted a clinical trial to evaluate the effectiveness of Rituxan® in the treatment of recurrent Hodgkin’s lymphoma. The trial involved 14 patients with CD 20 lymphocyte predominant Hodgkin’s lymphoma, or Hodgkin’s lymphoma with over 30% of their cancer cells expressing CD 20. Patients were on average 9 years from diagnosis and had stopped responding to at least one prior therapy. Overall, 12 patients had an anti-cancer response to Rituxan®, with 8 patients achieving a complete disappearance of detectable cancer and 4 patients achieving a partial anti-cancer response. Two patients had progressive disease. One year following therapy, 9 of the 12 responding patients demonstrated no signs of cancer progression. Furthermore, at over 20 months following therapy, the average duration of responses has not yet been reached. Side effects were generally mild and moderate, allowing for the majority of patients to receive treatment on an outpatient basis.

The researchers concluded that Rituxan® is a viable treatment option for patients with relapsed Hodgkin’s lymphoma that expresses the CD 20 antigen clinical trials.

Combination of the two was recenlty tried in 8 elderly relapsed/ reefractory patients. One complete response, 3 partial response and 3 minimal response were obtained at 11 months of median time follow-up.

The combination of these two drugs with gemcitabine has recently been reported as well in a single phase II study. Rituximab, gemcitabine and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo.

In summary, there are two Phase II trials that demonstrate some effectiveness of Rituxan in a specific subset of Hodgkin’s Lymphoma. First, it needs to be determined if the patient has lymphocyte predominant disease. Most plans will consider this therapy to be investigational but where coverage is availble it is certainly an interesting and promising option.

Rehwald U, Schultz H, Reiser M, et al. Treatment of relapsed CD20+ Hodgkin lymphoma with monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101:420-424.

Rehwald U, Schulz H, Reiser M, et al. German Hodgkin Lymphoma Study Group (GHSG): treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood. 2003;101: 420-424.

D. Re, R. K. Thomas, K. Behringer, and V. Diehl
From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential
Blood, June 15, 2005; 105(12): 4553 – 4560.

Addeo R, Caraglia M, Costanzo R, Faiola V, Montella L, Abbruzzese A, Del Prete S. Oxaliplatin/rituximab combination in the treatment of intermediate-low grade non-Hodgkin’s lymphoma of elderly patients. Oncol Rep. 2004 Jul;12(1):135-40

T El Gnaoui , J Dupuis , K Belhadj , J-P Jais , A Rahmouni , C Copie-Bergman , I Gaillard , M Diviné , I Tabah-Fisch , F Reyes , and C Haioun Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy
Annals of Oncology Advance Access published on August 1, 2007, DOI 10.1093/annonc/mdm133.
Ann Oncol 18: 1363-1368.

Gemcitabine and vinorelbine are somewhat effective but toxic when few options remain, but more investigation is needed.

The optimum therapy for patients with relapsed or refractory aggressive HOdgkin’s not qualifying for high-dose chemotherapy is not known. Hodgkin’s lymphoma patients who relapse or do not respond to primary treatment require an adequate salvage therapy. HDCT followed by ASCT is the treatment of choice for this group of patients. Only a few relapsed patients can be cured by conventional chemotherapy and/or RT.

Combinations of gemcitabine and vinorelbine ahve been studied; recently Doxorubicin has been added and studied for salvage. GVD is a well-tolerated, active regimen for relapsed HL with results similar to those reported for more toxic regimens. High RRs in patients in whom prior transplant failed confirms this regimen’s activity even in heavily pretreated patients.

A. Spencer, K. Reed and C. Arthur. (2007) Pilot study of an outpatient-based approach for advanced lymphoma using vinorelbine, gemcitabine and filgrastim. Internal Medicine Journal 37:11, 760–766

NL Bartlett , D Niedzwiecki , JL Johnson , JW Friedberg , KB Johnson , K van Besien , AD Zelenetz , BD Cheson , GP Canellos , and For the Cancer Leukemia Group B
Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804 Ann Oncol 18: 1071-1079, 2007

Some 20-30 % of patients with Hodgkin’s lymphoma achieve a remission and then relapse and some do not respond to standard therapy, such as ABVD and are called refractory.  In general, the longer the initial complete remission, the better the outlook with any form of salvage therapy.
A variety of treatment regimens have been used for patients in these groups of Hodgkin’s disease. In addition to MOPP or ABVD in patients who received the opposite regimen initially, a number of other treatments have been used, including ICE chemotherapy. Unfortunately, the number of patients achieving extended survival free of Hodgkin’s disease is quite poor, although patients with no adverse risk characteristics (see above) have been reported to have 5-year failure-free survivals as high as 50%. For this reason a variety of high dose approaches have been studies. Autologous bone marrow transplantation can cure patients with multiply relapsed Hodgkin’s disease. Because of the superior results in patients treated early in the course of the disease, most advocates of bone marrow transplantation would prefer to use it as part of the treatment of the initial relapse following any effective initial chemotherapy regimen. In this setting, patients who receive an alternate standard chemotherapy regimen and achieve at least a partial remission then undergo autologous transplantation. Rerfractory patients also benefit from ASCT. The results in this setting have yielded durable remissions in 47% to 85% of patients. In a randomized trial conducted in Europe, patients with relapsed, chemosensitive Hodgkin’s disease had a significantly better failure-free survival with transplantation rather than continuing standard dose chemotherapy. This patient fits into this group.

In some patients in whom HDC fails, allogeneic HSC transplantation may be a viable option. In this method, myeloablative therapy (chemotherapy and sometimes RT) is followed by the infusion of HSCs from a genetically matched donor. This offers the potential for an immunological antitumor effect from T-cells provided by the HSC donor, which may improve the chances for cure of the disease. Historically, allogeneic transplantation for Hodgkin disease has been considered too high risk for most patients due a high transplant-related mortality. However, evolution of transplant protocols to include less toxic conditioning regimens, such as min-ablative approaches, will likely expand the utility of this option for patients with refractory Hodgkin disease. Allogeneic transplantation for Hodgkin is considered standard of care already at this time. For example, NCCN (HODG-12) lists it as a category 3 recommendation.

Mink SA, Armitage JO. High-dose therapy in lymphomas: A review of the current status of allogeneic and autologous stem cell transplantation in Hodgkin’s disease and non-Hodgkin’s lymphoma. Oncologist. 2001;6(3):247-256.

nccn.org, Hodgkin’s 2012

Lazarus HM, Loberiza FR Jr, Zhang MJ, et al. Autotransplants for Hodgkin’s disease in first relapse or second remission: A report from the autologous blood and marrow transplant registry (ABMTR). Bone Marrow Transplant. 2001;27(4):387-396.

Evgeny Klyuchnikov The Role of Allogeneic Stem Cell Transplantation in Relapsed/Refractory Hodgkin’s Lymphoma PatientsAdvances in Hematology
Volume 2011 (2011), Article

Canellos GP, Mauch PM. Hematopoietic cell transplantation in classical Hodgkin lymphoma. In: UpToDate, Basow, DS (Ed), UpToDate,Waltham,MA, 2013. Literature review current through March 2013.

Moskowitz AJ, Perales MA, Kewalramani T, et al. Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br J Haematol 2009; 146:158.

Sarina B, Castagna L, Farina L, et al. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood 2010; 115:3671.

Thomson KJ, Peggs KS, Smith P, et al. Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin’s lymphoma following autologous stem cell transplantation. Bone Marrow Transplant 2008; 41:765

Corradini P, Sarina B, Farina L. Allogeneic transplantation for Hodgkin’s lymphoma. Br J Haematol 2011; 152:261

Hodgkin Lymphoma: A Comprehensive Update on Diagnostics and Clinics By Andreas Engert, Springer 2010.