The diagnosis and management of Hodgkin Lymphoma at initial presentation is covered in some detail on the BC Cancer Agency website. The scope of this management guideline will focus on the role of stem cell transplantation in the management of relapsed and refractory Hodgkin lymphoma.
Relapsed Hodgkin lymphoma is defined as relapse of previously treated Hodgkin lymphoma more than three months following completion of all planned chemotherapy and/or radiation therapy.
Primary refractory Hodgkin lymphoma is defined as disease which has failed to respond to initial standard therapy OR disease which has been shown to progress within three months of completion of a standard course of treatment.
High dose chemotherapy and autologous stem cell transplant improves progression free survival in patients with relapsed and primary refractory Hodgkin Lymphoma as demonstrated in two randomized controlled trials (Schmitz N et al, Lancet 2002; Linch DC et al Lancet 1993). Multiple subsequent trials have demonstrated long term disease free survival in the order of 50% for patients with HL in first relapse/progression treated with HDC/ASCT (Yuen et al Blood 1997; Lavoie et al Blood 2005). For patients treated in first relapse, progression free survival is in the order of 62%. For primary progressive disease, progression free survival of 31%-39% has been reported, even in patients who did not respond to salvage chemotherapy pre HDT/ASCT (31% PFS at 5 years - Josting et al Blood 2000, 39% PFS at 15 years Lavoie et al Blood 2005). These results are clearly superior to survival historically reported with chemotherapy salvage alone 17% at 20 years for relapsed Hodgkin Lymphoma (Longo et al JCO 1992; Yuen AR et al Blood 1997 89; 814-22 Stanford non randomized experience).
Updated results of 256 autologous transplants in BC for Hodgkin Lymphoma were reported in 2014. For all patients transplanted the 10 year overall survival was 62% and failure free survival was 57%. All patients are taken to transplant in BC irrespective of their response to salvage chemotherapy, as even patients with disease which is refractory to salvage chemotherapy were shown to have a 10 year failure free survival of 31% and overall survival of 29%. (Gerrie AS et al Ann Oncol, 2014: 25(11); 2218-23).
Diagnosis of Relapse or Progression
Disease relapse is, when possible, confirmed by biopsy. Biopsy confirmation of relapse is especially important for late cases of relapse (greater than 5 years), where secondary malignancy is in the differential diagnosis. Restaging CT scans of neck, thorax, abdomen and pelvis should also be part of the relapse/ progression workup.
Referral of the patient to the Leukemia and BMT Program of BC for assessment is made at the diagnosis of relapse.
PET scanning has been shown to be predictive of outcome post HDT/SCT when performed after salvage chemotherapy and before autologous transplant. Timing of the PET scan is important - these should not be performed less than 3 weeks from the most recent cycle of chemotherapy (Juweid ME et al, JCO 2007 Consensus statement). GCSF used for stem cell collection can alter the bone marrow signal on PET scan and similarly, PET scans should be interpreted with caution if performed within <3 weeks of high dose GCSF. (Kazama et al Eur J Med Mol Imaging 2005).
Salvage chemotherapy is generally recommended to achieve some disease control and to prevent progression while arrangements for stem cell collection and pre-transplant organ function workup are underway. This process takes about 6 weeks in total, for non-urgent cases. Standard salvage chemotherapy – usually GDP (gemcitabine, cisplatin and dexamethasone) is given at the local BC Cancer Agency unit. (See protocol)
For the purposes of follow up post HDT/SCT, either a CT scan or CT PET should be performed post salvage chemotherapy and pre transplant. Ideally CT scans should be performed in the referring centre where comparative scans are easily available for interpretation of response criteria. PET scanning has been shown to be predictive of outcome post HDT/SCT when performed after salvage chemotherapy and before autologous transplant. Timing of the PET scan is important - these should not be performed less than 3 weeks from the most recent cycle of chemotherapy (Juweid ME et al JCO 2007 Consensus statement). GCSF used for stem cell collection can alter the bone marrow signal on PET scan and similarly, PET scans should be interpreted with caution if performed within <3 weeks of high dose GCSF. (Kazama et al Eur J Nucl Med Mol Imaging 2005).
Where possible, PET CT scan will be arranged in Vancouver prior to transplantation.
The assessing Bone Marrow Transplant physician will arrange workup investigations prior to high dose chemotherapy and autologous stem cell transplant. These investigations are performed to ensure that HDT can be administered without excessive toxicity. These investigations include: creatinine clearance, pulmonary function tests, ECG and echocardiogram or MUGA scan and routine viral serology. The bone marrow transplant physician assessing the patient may require further investigations based upon clinical history and examination.
Presentation of cases at BCCA Lymphoma Conference is recommended particularly to guide local oncologists with respect to post transplant assessment and the early consideration of post-transplant radiation therapy assessment in certain cases. The modality of repeated imaging can also be discussed.
Stem Cell Collection
Stem cell collection is performed in the Centennial Pavillion at Vancouver General Hospital. The patient is provided with a prescription for high dose GCSF (10mcg/kg) for a total of 5 days. This medication is administered by subcutaneous injection and the first dose is given by Hematology/ BMT nursing staff. Subsequent doses may be self-administered by the patient or by a local practitioner. Side effects of GCSF include low back/pelvic pain which can at times be quite severe.
Stem cell collection is carried out on day 4 and 5 of GCSF therapy. This procedure takes place in the Apheresis Unit at VGH. Apheresis nurses assess every patient prior to this procedure to assess the suitability of the patients peripheral veins for the apheresis procedure. In certain cases, insertion of a central line (vascath) is required for this procedure.
The Bone marrow transplant physician will review all organ function workup criteria and ensure that an adequate number of stem cells (CD34+ cells target >2 x 106/kg body weight) is collected. Arrangements are made for the patient to have a Hickman line inserted prior to hospital admission for the delivery of this therapy.
The patient is then admitted to the VGH Leukemia and BMT Unit to undergo the procedure of HDT/ASCT.
High Dose Chemotherapy with BEAM or High dose Etoposide and Melphalan (EM)
High dose chemotherapy with BEAM or EM (see protocols) is given as an inpatient at Vancouver General Hospital. 24 hours following the last dose of chemotherapy, the patients’ autologous stem cells are reinfused. Side effects of high dose chemotherapy include GI upset, mucositis, a period of pancytopenia lasting about 2 weeks with associated need for blood transfusion support and risk of serious or life threatening infection.
Mortality associated with this procedure is less than 5%. Following recovery from the initial toxicity of the transplant course, the patient is discharged for follow up at the Bone Marrow Transplant Day Ward. When the patient has had satisfactory recovery of hematological parameters and is free of fever, the patient is discharged home. All patients are given a follow up appointment with their primary BMT physician at this point. The patients’ BMT physician will arrange a follow up PET scan at 6 weeks post-transplant. At the post-transplant follow up clinic appointment, the BMT physician will arrange for subsequent lymphoma follow up to be transferred back to the referring oncologist. The Leukemia BMT physician will ensure that the patient receives the post-transplant vaccination recommendations as per the BC CDC, which should commence at 6 months post-transplant.
Carmustine/ BCNU given as part of BEAM and CBV protocols can cause pneumonitis, which may occur following initial recovery from stem cell transplant. Any patient who presents with respiratory symptoms at this point should undergo CT of chest and pulmonary function testing and should be treated empirically with high dose prednisolone.
Long term side effects of high dose chemotherapy include infertility, an increased risk of cardiac and thyroid disease and an increased risk of secondary malignancy (Lavoie et al Blood 2005; Forrest D et al JCO 2002).
Maintenance therapy post transplant: Based on the results of the AETHERA trial, post transplant therapy with brentuximab vedotin has been shown to significantly improve progression free survival for high risk Hodgkin lymphoma patients, which may translate into a higher cure rate with longer follow-up. (Moskowitz CH et al, Lancet 2015, 385; 1853-1862) All patients with relapsed/refractory Hodgkin lymphoma who undergo autologous stem cell transplantation should be considered for brentuximab maintenance therapy. This therapy is not yet funded through BCCA however a compassionate access request can be submitted for these patients.
Role of Allogeneic Transplant
In the event of relapse post autologous transplant, patients may be referred back to the BMT program for assessment with respect to suitability for reduced intensity allogeneic transplantation. Factors which predict for responsiveness to allogeneic transplantation include chemosensitivity and duration of initial response to autologous transplant. (Alvarez et al,Biol Blood Marrow Trans, 2006, 12(2); 172-83). Registry data show progression free survival rates of around 30% at three years following reduced intensity allogeneic transplant. (Robinson SP et al, Hematologica 2008, 94(2), Marcais A et al, Hematologica 2013, 98(9), Kako S et al, American Journal of Hematology, 2014, 90(2)). In the era of novel agents targeting CD30 positive cells such as brentuximab and agents targeting PD1 such as pembrolizimab and nivolumab, the role and timing of allogeneic transplant is less clear.
Long-term Follow Up
All patients who receive HDT/ASCT should undergo repeated vaccination programs six months following the date of transplantation. The guidelines for the vaccines required are available on the BC Centres for Disease Control website.
Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol. Biol Blood Marrow Transplant, 2006 Feb;12(2):172-83.
Forrest, D.L., Hogge, D.E., Nevill, T.J., Nantel, S.H., Barnett, M.J., Shepherd, J.D., Sutherland, H.J., Toze, C.L., Smith, C.A., Lavoie, J.C., Song, K.W., Voss, N.J., Gascoyne, R.D. & Connors, J.M. (2005) High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin's lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation. J Clin Oncol, 23, 7994-8002.
Gerrie, A.S., Power, M.M., Shepherd, J.D., Savage, K.J., Sehn, L.H., & Connors, J.M. Chemoresistance can be overcome with high-dose chemotherapy and autologous stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. Ann Oncol, 2014: 25(11); 2281-23.
Josting, A., Rueffer, U., Franklin, J., Sieber, M., Diehl, V. & Engert, A. (2000) Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood, 96, 1280-1286.
Juweid, M.E., Stroobants, S., Hoekstra, O.S., Mottaghy, F.M., Dietlein, M., Guermazi, A., Wiseman, G.A., Kostakoglu, L., Scheidhauer, K., Buck, A., Naumann, R., Spaepen, K., Hicks, R.J., Weber, W.A., Reske, S.N., Schwaiger, M., Schwartz, L.H., Zijlstra, J.M., Siegel, B.A. & Cheson, B.D. (2007) Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol, 25, 571-578.
Kazama, T., Swanston, N., Podoloff, D.A. & Macapinlac, H.A. (2005) Effect of colony-stimulating factor and conventional- or high-dose chemotherapy on FDG uptake in bone marrow. Eur J Nucl Med Mol Imaging, 32, 1406-1411.
Kako S, Izutsu K, Kato K, Kim SW, Mori T, Fukuda T, Kobayashi N, Taji H, Hashimoto H, Kondo T, Sakamaki H, Morishima Y, Kato K, Suzuki R, Suzumiya J; Adult Lymphoma Working Group of the Japanese Society for Hematopoietic Cell Transplantation. The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Am J Hematol, 2015 Feb;90(2):132-8.
Lavoie, J.C., Connors, J.M., Phillips, G.L., Reece, D.E., Barnett, M.J., Forrest, D.L., Gascoyne, R.D., Hogge, D.E., Nantel, S.H., Shepherd, J.D., Smith, C.A., Song, K.W., Sutherland, H.J., Toze, C.L., Voss, N.J. & Nevill, T.J. (2005) High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood, 106, 1473-1478.
Linch, D.C., Winfield, D., Goldstone, A.H., Moir, D., Hancock, B., McMillan, A., Chopra, R., Milligan, D. & Hudson, G.V. (1993) Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet, 341, 1051-1054.
Longo, D.L., Duffey, P.L., Young, R.C., Hubbard, S.M., Ihde, D.C., Glatstein, E., Phares, J.C., Jaffe, E.S., Urba, W.J. & DeVita, V.T., Jr. (1992) Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure. J Clin Oncol, 10, 210-218.
Marcais A., Porcher R., Robin M., Mohty M., Michalet M., Blaise D., Tabrizi R., Clement L., Ceballos P., Daguindau E., Bilger K., Dhedin N., Lapusan S., Bay J.O., Pautas C., Garban F., Ifrah N., Guillerm G., Contentin N., Bourhis J.H., Yakoub Agha I., Bernard M., Cornillon J., & Milpied N. Impact of disease status and stem cell source on the results of reduced intensity conditioning transplant for Hodgkin's lymphoma: a retrospective study from the French Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Haematologica, 2013 Sep;98(9):1467-75.
Moskowitz C.H., Nademanee A., Masszi T., Agura E., Holowiecki J., Abidi M.H., Chen A.I., Stiff P., Gianni A.M., Carella A., Osmanov D., Bachanova V., Sweetenham J., Sureda A., Huebner D., Sievers E.L., Chi A., Larsen E.K., Hunder N.N., Walewski J., & AETHERA Study Group. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2015 May 9;385(9980):1853-62.
Robinson, S.P., Sureda, A., Canals, C., Russell, N., Caballero, D., Bacigalupo, A., Iriondo, A., Cook, G., Pettitt, A., Socie, G., Bonifazi, F., Bosi, A., Michallet, M., Liakopoulou, E., Maertens, J., Passweg, J., Clarke, F., Martino, R., & Schmitz, N. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome. Haematologica, Feb 2009, 94 (2) 230-238
Schmitz, N., Pfistner, B., Sextro, M., Sieber, M., Carella, A.M., Haenel, M., Boissevain, F., Zschaber, R., Muller, P., Kirchner, H., Lohri, A., Decker, S., Koch, B., Hasenclever, D., Goldstone, A.H. & Diehl, V. (2002) Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet, 359, 2065-2071.
Yuen, A.R., Rosenberg, S.A., Hoppe, R.T., Halpern, J.D. & Horning, S.J. (1997) Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood, 89, 814-822.