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Background
Hodgkin's disease (HD) is an enigmatic lymphoid malignancy whose cell of origin has remained a mystery since the disease was first described in 1825. The hallmark of the disease is effacement of the normal lymph node architecture by a heterogeneous infiltration of normal appearing lymphocytes, plasma cells, eosinophils and fibroblasts. The one characteristic component, and presumably the malignant component, is the Reed Sternberg cell (or one of its variants), a large binucleate cell with prominent nucleoli. Hodgkin's disease is subdivided into 4 subtypes: (i) lymphocytic predominant (15 % of cases), (ii) nodular sclerosing (70 %), (iii) mixed cellularity (10 %), and (iv) lymphocyte depleted (5 %). Both the lymphocyte predominant and nodular sclerosing variants are more common in adolescents and young adults. Mixed cellularity and lymphocyte depleted are more common in older patients and frequently present with advanced disease.
The following staging system for HD recognizes the fact that HD is thought to typically arise in a single lymph node and spread to contiguous lymph nodes with eventual involvement of extranodal sites. The staging system attempts to distinguish patients with localized HD who can be treated with extended field radiation from those who require systemic chemotherapy.
Staging for Hodgkin's Disease:
Stage I:
Involvement of a single lymph node region or a lymphoid structure such as the spleen, thymus, Waldeyer's ring (I) or involvement of a single extra-lymphatic organ or site (IE)
Stage II:
Involvement of 2 or more lymph node regions on the same side of the diaphragm (hilar nodes, when involved on both sides, constitute Stage II); localized contiguous involvement of only 1 extra-nodal organ or site and lymph node region on the same side of the diaphragm (IIE). The number of lymph node regions involved should be indicated by a subscript (e.g., II3)
Stage III:
Involvement of lymph node regions or structures on both sides of the diaphragm (III), which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only 1 extra-nodal organ site (IIIE) or both (IIIE+S). These patients are further subdivided as follows:
III1: with or without involvement of splenic, hilar, celiac, or portal lymph nodes
III2: with involvement of paraaortic, iliac, and/or mesenteric lymph nodes
Stage IV:
Diffuse or disseminated Involvement of 1 or more extra-nodal organs or tissues, with or without associated lymph node involvement, or isolated extra-lymphatic organ involvement with distant (non-regional) nodal involvement
Additional Designations Applicable to any Disease Stage:
A: No symptoms
B: Unexplained fever (temperature greater than 38° C), drenching night sweats, unexplained weight loss of greater than 10 % body weight within the preceding 6 months. Pruritus alone does not qualify for B classification, nor does a short febrile illness associated with an infection
X: Bulky disease (a widening of the mediastinum by greater than 1/3 or the presence of a nodal mass with a maximal dimension greater than 10 cm)
E: Involvement of a single extra-nodal site that is contiguous or proximal to a known nodal site
CS: Clinical stage
PS: Pathological stage (as determined by laparotomy)
Staging of HD includes not only the sites of involvement, but also other factors described by the letters A, B, X, E above, i.e., a patient could have Stage IIB HD, indicating involvement of 2 or more lymph node groups on the same side of the diaphragm with the presence of systemic symptoms. Those patients initially considered candidates for radiation therapy alone may undergo a staging laparotomy to determine if the disease is truly localized or not.
Treatment of HD involves the use of radiation therapy alone (for Stage I and II disease), the use of chemotherapy (for Stage IIIB and IV), or combined radiation and chemotherapy (for patients with bulky disease and for some patients with Stage IIIA disease). Radiation therapy typically consists of treatment not only of the involved sites, but also lymphoid regions adjacent to the involved areas and prophylactic treatment to uninvolved areas. This frequently takes the form of mantle irradiation to the mediastinum and an "inverted Y" irradiation of the periaortic lymph nodes, extending down to encompass the pelvic lymph nodes. Prolonged relapse free survival in patients with Stage IA or IIA treated with total nodal irradiation is estimated at 82 %.
Despite the generally favorable results of irradiation and chemotherapy, relapses can occur in up to 40 % of those patients with advanced (Stage III or IV) disease treated with chemotherapy. In many instances, relapsed HD remains sensitive to the original chemotherapy used, indicating that relapses may not be related to the development of chemoresistance, but instead point to the importance of adequate dosing of chemotherapy. This observation also forms the rationale for high dose chemotherapy (HDC).
High dose chemotherapy bone marrow or peripheral stem cell transplant (autologous or allogeneic) is a treatment option for selected patients with HD. The basic concept behind HDC is a combination regimen of marrow ablative drugs which have different mechanism of action to maximally eradicate the malignant cells, and non-overlapping toxicity such that the doses can be maximized as much as possible. Total body irradiation (TBI) is an additional variable. Patients with the disease who are responsive to standard doses of chemotherapy, and are either asymptomatic or have a good performance status and who do not have any serious co-morbidities are considered optimal candidates for HDC.
Autologous bone marrow transplant (ABMT) or peripheral stem cell transplant (ASCT) permits the use of chemotherapeutic agents at doses that exceed the myelotoxicity threshold; consequently, a greater tumor cell kill might be anticipated. It has been suggested that the resultant effect is greater response rate and possibly an increased cure rate. Autologous bone marrow transplant entails the patient acting as his/her own bone marrow donor. The patient's marrow is harvested via aspiration from the iliac crests under general or regional anesthesia. The marrow is then preserved and re-infused following completion of a potent chemotherapy regimen. This process provides pluripotent marrow stem cells to reconstitute (i.e., rescue) the patient's marrow from the myeloablative effects of high dose cytotoxic chemotherapeutic agents.
Allogeneic bone marrow transplant refers to the use of functional hematopoietic stem cells from a healthy donor to restore bone marrow function following HDC. For patients with marrow-based malignancies, the use of allogeneic stem cells offers the advantage of lack of tumor cell contamination. Furthermore, allogeneic stem cells may be associated with a beneficial graft versus tumor effect.
Tandem (sequential) transplant protocols utilize a cycle of HDC with ASCT followed in approximately 6 months by a second cycle of HDC and/or TBI with another ASCT. This is done in an attempt to obtain greater and extended response rates. To date, there have been no definitive studies showing that tandem transplants improve response rates, event-free survival (EFS) or overall survival (OS) more than single transplants for patients with HD. Therefore, tandem transplant protocols are considered experimental and investigational.
In a clinical trial, Papadoupoulos and coleagues (2005) assessed the effectiveness of a novel regimen of tandem HDC (THDC) with autologous stem cell transplantation in the treatment of patients with poor risk lymphoma. A total of 41 patients (median age of 40 years, range of 15 to 68 years) with poor risk non-Hodgkin's lymphoma and HD were enrolled. Tandem HDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30 to 50 mg/m2) (MMt) for the 1st conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400 to 850 mg/m2), (ETCb) as the 2nd regimen. In all, 31 patients (76 %) completed both transplants, with a median time between transplants of 55 days (range of 26 to 120 days). The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate. The overall toxic death rate was 12 %. Following HDC, 10 of 24 evaluable patients (42 %) were in complete remission. The 2-year OS and EFS is 67 % (95 % confidence interval (CI): 52 % to 81 %) and 45 %, (95 % CI: 29 % to 61 %) for the 41 patients enrolled; and 69 % (95 % CI: 525 % to 586 %) and 48 % (95 % CI: 30 % to 67 %) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pre-treated patients; its role in the current treatment of high-risk lymphoma remains to be determined.
Prior to HDC-ABMT, patients generally undergo induction therapy with vincristine, doxorubicin and dexamethasone, melphalan and prednisone or other combination salvage regimens. Conventional dosages of these drugs can typically be given on an outpatient basis. Hospitalization may be required due to neutropenic fever, nausea and vomiting, mucositis, diarrhea, or inadequate oral intake. Standard severity of illness/intensity of service criteria should be applied to these admissions.
Prior to peripheral stem cell collection, an apheresis catheter may be inserted during an ambulatory surgical procedure. The apheresis catheter can be placed during the same anesthesia procedure if a bone marrow harvest is also planned. Apheresis is usually performed daily on an outpatient basis until adequate stem cells are collected. Typically, from 5 to 10 procedures are necessary.
Stem cell mobilization, in which cyclophosphamide and/or GM-CSF are used to flush the critical stem cells from the bone marrow into the peripheral circulation, may also be part of the stem cell collection. Protocols vary -- some institutions administer intermediate doses of cyclophosphamide (4 g/m2) as an outpatient procedure, followed by apheresis in 5 to 14 days when the blood counts have recovered. When high dose cyclophosphamide (6 g/m2) is used, a hospitalization of about 4 days is required for pre- and post-chemotherapy hydration. After completion of the cyclophosphamide regimen, the patient can usually be discharged; apheresis can be administered on an outpatient basis once the acute period of bone marrow hypoplasia has resolved.
Hospitalization for the HDC component of the procedure depends on the regimen. High-dose melphalan (140 to 200 mg/m2) can usually be given as an outpatient with home hydration therapy. This outpatient HDC is the exception. Other high-dose combination therapies, such as EDAP (etoposide, dexamethasone, ara-C and cisplatin) usually require hospitalization due to nausea and vomiting, mucositis, diarrhea and inadequate oral intake. Any regimen that includes TBI is likely to require a prolonged hospital stay, usually averaging about 30 days. Patients receiving HDC with or without TBI are usually initially treated in a private room for about 1 week until the blood counts start to drop. Then, patients are typically transferred to a specialized laminar flow room for the duration of their hospital stay.
Usual length of stay for patients undergoing peripheral stem cell collection with high- dose cyclophosphamide mobilization is 4 days. Other stem cell mobilization protocols normally do not require a hospital stay.
Usual length of stay for patients hospitalized for complications related to HDC depend on resolution of fever (i.e., fever-free for 48 hours while off all antibiotics), maintenance of adequate blood counts (i.e., WBC greater than 500), and resolution of other morbidities such as mucositis and diarrhea. The patient must also be able to maintain adequate oral intake. Hospital stays usually range from 2 to 4 weeks. Patients may be discharged even if an adequate platelet count is transfusion dependent; platelet transfusions can be given on an outpatient basis.
Usual length of stay for patients undergoing HDC in conjunction with TBI is 30 days. Discharge parameters are similar to above: fever-free for 48 hours, adequate blood counts (WBC greater than 1,000). Patients may be discharged even if an adequate platelet count if transfusion dependent; platelet transfusions can be given on an outpatient basis.
Studies on Autologous Transplant:
Gribben and colleagues (1989) reported the findings of a non-randomized study in which a high-dose combination chemotherapy regimen was followed by autologous bone marrow rescue (ABMR). The study was comprised of 44 patients with active HD who were resistant to standard regimen therapy. Previous treatments of the patients involved in the study were reported as follows: 2 patients had received front-line, alternating chemotherapy and failed to respond; they progressed to ABMR. The remainder of the patients had received at least 2 regimens of chemotherapy. In addition, 28 patients had also received radiotherapy. Of these 44 patients, 22 had never achieved a complete remission (CR), while the other 22 had achieved a CR in response to first-line therapy but relapsed. After the use of HDC and ABMR the following results were described -- 23 patients achieved a partial response (PR); 2 patients (initially classified as having a PR) who presented with a residual mediastinal mass at 3 months had slow resolution of the mass, and were classified as having a CR 6 months after ABMR; 4 patients had demonstrated a progressive decrease in the size of a residual mediastinal mass over 10 to 33 months without receiving further treatment; 7 patients (initially classified as having a PR) underwent post-ABMR radiotherapy to sites of residual disease, and 5 of these patients subsequently achieved a CR; 4 patients did not respond to HDC and ABMR, 3 of whom died within 6 months of the procedure; and 2 patients died of complications related to sepsis. In summary, 22 patients (50 %) achieved a CR 6 months after ABMR, and 4 other patients were free of disease progression. Two patients relapsed from CR at 7 and 9 months following ABMR; they subsequently died from progressive disease. According to the authors, the remaining 20 patients who achieved a CR remain in remission. They concluded that the use of HDC followed by ABMR appears to be an efficacious salvage regimen for patients with refractory HD.
Chopra and associates (1993) reported the results of 155 patients with relapsed or resistant HD who were treated with HDC followed by ABMR. At the time of transplant, 46 patients were primarily refractory to induction therapy, 7 were good partial responders, and 52 were in first relapse, 37 in second relapse, and 13 in third relapse. At 3 months 43 (28 %) patients were assessed as complete responders. Seventy-two (46 %) patients were assessed to have partial responses (PR). Twenty-four patients (16 %) showed no response or progression. At 6 months, 53 patients were assessed as complete responders. Thirteen patients in PR at 3 months had achieved a CR by 6 months, this occurring in 8 patients after radiotherapy to residual masses, and 5 patients without any further treatment indicative of slow resolution of their tumor masses. Fifty-one patients still had non-progressive disease with persistent CT abnormalities, 26 patients had relapsed with progressive disease, and 8 patients had died of progressive HD. Overall, 104 of 155 (67 %) had a good response to ABMR. By 6 months, there were 17 procedure-related deaths. The actuarial OS at 5 years was 55 %, with a PFS of 50 %. The authors found that patients undergoing ABMR in second and third relapse were faring significantly better than patients in first relapse and primary refractory disease.
Bierman and co-workers (1993) examined the influence of pre-transplant prognostic factors and evaluated long-term follow-up in a group of 128 patients with HD. All patients in the study were refractory to primary therapy, or had relapsed after attaining a remission, and underwent HDC followed by ABMR. Following transplantation, 57 (45 %) patients achieved CR; 9 (7 %) patients who were transplanted without evidence of disease continued in remission following the transplant. Seven (5 %) patients received localized radiation following transplantation to areas of apparent residual disease, and they converted to CR. In total, 73 (57 %) patients were in CR following transplantation, 23 (18 %) patients achieved a PR, and 21 (16 %) had no response. There were 11 (9 %) early deaths. Among the 73 patients in CR following transplantation, 34 have subsequently died; including 6 who died without evidence of disease between 6 and 59 months following transplantation. At the time of the report, 43 patients were alive, including 28 who remain free from progression. The median survival time for the entire patient group is 31.5 months, and the median failure-free survival time is 7.3 months. The estimated 4-year OS is 45 % and the 4-year failure-free survival is estimated as 25 %. The authors concluded that superior results were seen in patients without extensive prior chemotherapy and in those with a good performance status.
In a review, Mink and Armitage (2001) stated that ASCT has proven to be beneficial in selected patients with HD. Transplantation appeared to increase EFS in patients who failed to enter complete remission with initial therapy. When a patient relapses after a complete remission, transplantation is probably the best option and particularly so if the remission lasted less than 1 year. Transplantation as part of primary therapy for very high-risk patients may be beneficial, but is not standard therapy at this time. Lazarus et al (2001) reviewed data from the Autologous Blood and Marrow Transplant Registry (n = 414) to determine relapse, disease-free survival, OS, and prognostic factors in patients with relapsed HD. They concluded that autologous hematopoietic stem cell transplantation (autotransplantation) should be considered for patients with HD in first relapse or second remission.
Studies on Allogeneic Transplant:
Lundberg and associates (1991) performed a non-randomized, prospective study to ascertain whether HDC followed by allogeneic bone marrow transplantation is an effective treatment in relapsed or refractory lymphoma. The study group consisted of 22 patients with relapsed or refractory lymphoma. Seven patients had HD; the remaining 15 patients had non-Hodgkin's lymphoma (NHL). The median age was 30 years. The treatment regimen consisted of the following: cytarabine, cytoxan, TBI, and methylprednisolone. Seven patients with significant bulky disease received localized radiotherapy prior to the preparative regimen. Total body irradiation was begun 48 hours after the last dose of chemotherapy. Patients who had undergone radiotherapy treatments were precluded from the use of standard TBI-based regimens; thus, only myeloablative chemotherapy was used in those patients. Patients who were treated with TBI received graft-versus-host-disease prophylaxis with T-cell depletion and cyclosporine. The authors recounted the following results in the 7 patients with HD: 4 patients were alive; 3 in CR (19 to 43 months post-transplant) and 1 with recurrent lymphoma. The remaining 3 patients died due to the following complications; (i) aspergillus, (ii) hepatic veno-occlusive-disease, and (iii) recurrent lymphoma. The authors concluded that, allogeneic bone marrow transplantation appeared superior to salvage chemotherapy for the achievement of long-term, lymphoma-free survival and may be preferable to autologous bone marrow transplantation for selected patients.
Anderson and colleagues (1993) carried out a non-randomized, prospective study on 127 patients undergoing myeloablative therapy for relapsed or refractory HD. The purpose of the study was to determine efficacy of transplant (autologous or allogeneic) post-failure of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) - and ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine)-like regimens. The study group consisted of the following: (i) 23 patients with primary refractory disease, (ii) 34 in early first relapse or second CR, and (iii) 70 with refractory first relapse or disease beyond second CR. The median age was 29. Disease stage at diagnosis was I to IV. A total of 68 patients received autologous marrow, 6 syngeneic marrow, and 53 allogeneic marrow. The preparative regimen in 94 of the 127 patients consisted of cytoxan and TBI, or cytoxan, carmustine (BCNU) and etoposide. The remaining patients received busulfan and cytoxan or other regimens. Twelve of the 53 patients who received an allogeneic transplant have survived for a median of 1,661 days, all free of relapse (20 % actuarial survival and 22 % actuarial EFS at 5 years). Twenty-four of 68 patients who underwent an autologous transplant were alive (median survival time of 758 days; 5-year actuarial survival, 13 %), 14 of whom survived without evidence of relapse (median survival time of 740 days; 5-year actuarial EFS, 14 %). The authors determined that the EFS rate did not differ statistically when comparing allogeneic to autologous transplants. However, there was a trend toward decreased relapse rates in the allogeneic recipients. The authors state that, although autologous bone marrow transplantation is often preferred over allogeneic transplantation in HD because of perceived lower mortality, few studies have had sufficient numbers of patients to study the effect of marrow source on outcome. Moreover, their results demonstrated a lower relapse rate for HLA-identical compared with autologous marrow recipients, despite more frequent poor prognostic features among the allogeneic group. The authors concluded that, the use of HLA-identical marrow should be considered in patients who have features that suggest a higher risk for relapse, such as the presence of bulky disease and history of a short first CR, and who also have features that suggest a lower risk of non-relapse mortality.
Mendoza and co-workers (1995) studied 23 patients with relapsed or resistant aggressive lymphoma. The purpose of this study was to determine if HDC followed by allogeneic bone marrow transplant is an effective means of treatment for relapsed or aggressive Hodgkin's or NHL. The study group consisted of 23 patients -- 9 patients with stage III or IV HD and 14 patients with NHL. In the HD group, patients were accepted for transplant if they met the following criteria: (i) failure to attain a CR despite prior chemotherapy (with MOPP or ABVD), (ii) tumor progression despite chemotherapy, or (iii) relapse within 1 year of achieving remission with the MOPP and/or ABVD regimen. Patients were under age 50. The following treatment protocols were used: TBI combined with cytoxan; TBI, cytoxan and vinblastine; TBI, cytoxan and etoposide; and busulfan and cytoxan. The authors recounted the following results: 4 of the 9 patients with HD were alive and disease-free at 1.3 to 94.8 months post-transplant. There was significant toxicity associated with the treatment such as infection, hepatotoxicity, interstitial pneumonitis, hemorrhage, and graft-versus-host disease (GVHD). However, the authors stated that allogeneic bone marrow transplantation is an effective salvage treatment for relapsed or refractory lymphoma.
Laurence and Goldstone (1999) stated that there is an increasing tendency to consider allogeneic transplantation in HD. There may be some limited graft-versus-Hodgkin's lymphoma effect, but this is outweighed by the greatly increased treatment toxicity associated with the allogeneic procedure. It is possible, however, that modern low-intensity conditioning regimens, the so-called mini-allograft approach, may increase the use of allogeneic transplantation for poor-prognosis Hodgkin's lymphoma patients in the future.
In a recent review, Hale and Phillips (2000) stated that some poor-prognosis patients with HD and NHL, usually with recurrent and/or refractory disease, are rarely curable with standard chemoradiotherapy. Autologous hematopoietic stem cell transplantation has been reported to improve long-term disease-free survival in some of these patients. Unfortunately, a number of patients are unsuitable for autologous transplantation as a consequence of damaged stem cell pool involvement or other disease processes of the marrow. These individuals may benefit from allogeneic stem cell transplantation. In addition to the therapeutic effect of HDC with or without TBI, an immunologic [namely, graft-versus-lymphoma (GVLym)] effect may be present in some patients undergoing allogeneic transplantation, resulting in a lower relapse rate than autotransplants. However, allografts are often associated with a higher non-relapse mortality due primarily to GVHD; unfortunately, GVHD and GVLym are difficult to differentiate. As a result, full exploitation of this GVLym effect may necessitate the modification of commonly employed conditioning regimens. If successful, these modifications may lead to an additional reduction relapse rate without additional morbidity. Furthermore, when combined with low-intensity conditioning, such modifications may allow patients who otherwise would not be candidates for standard transplant regimens to be allografted.
Guidelines from Cancer Care Ontario (2009) recommend autologous stem cell transplantation as a treatment option for eligible chemosensitive patients with Hodgkin's lymphoma who are refractory to or who have relapsed after primary chemotherapy. These guidelines state that allogeneic stem cell transplantation is an option for chemosensitive patients with refractory or relapsed Hodgkin's lymphoma who are not candidates for autologous stem cell transplantation or who have a syngeneic (identical twin) donor. The guidelines do not recommend stem cell transplantation as part of primary therapy for Hodgkin's lymphoma.
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