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Controversies in the Management of Relapsed and Primary Refractory Hodgkin’s Lymphoma By Craig H. Moskowitz, MD

Abstract: The majority of patients with Hodgkin’s lymphoma (HL) are cured with radiation therapy and/or combination chemotherapy. However, patients who relapse after attaining a complete remission with a full course standard chemotherapy program such as ABVD, and those with primary refractory disease have a poor outcome with standard dose second-line chemotherapy (SDSC) regimens. Two phase III random assignment trials comparing SDSC with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are reported. Each study demonstrated a statistically significant improvement in both event-free survival (EFS) and progression-free survival (PFS) for the patients treated on the

HDT arms, but neither was powered to show an overall survival advantage. Importantly, in the study by the German HL study group there was a superior PFS for the transplanted patients who had an initial remission duration of either greater than or less than 1 year (Fig 1, reprinted with permission). Based on these two clinical trials nearly all patients with relapsed or refractory disease should be considered transplant-eligible. Despite improvements in supportive care, long-term EFS has improved by at most 10% in recent reports. Therefore, disease-related, patient-specific, and treatmentrelated prognostic factors must predict outcome and will be discussed in this section.

CHEMOSENSITIVE DISEASE IS REQUIRED TO ACHIEVE BENEFIT FROM HIGH-DOSE THERAPY (HDT)/AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT)

above, of the 161 patients enrolled, 13 patients could not be randomly assigned secondary to dexa-BEAM related mortality (eight patients) or severe infection. In relapsed and refractory HL, ifosfamide-based regimens can achieve the above stated goals. Balzarotti et al7 has recently reported the results of 62 patients treated with the IGEV regimen. IGEV consists of ifosfamide 2000 mg/m2 intravenously (IV) d 1 to 4; gemcitabine 800 mg/m2 IV d 1 and 4; vinorelbine 20 mg/m2 IV d 1; prednisolone 100 mg/m2 IV d 1 to 4, and G-CSF support. The treatment program consisted of four cycles of IGEV administered at 3-week interval followed by HDT for responding patients. The response rate to IGEV was 84%. The median number of CD34⫹ cells collected was 6.6 ⫻106/kg after a median of two (range 1 to 3) apheresis procedures. Extramedullary side effects were minimal. We reported the results of a comprehensive program for the treatment of 82 patients with uniform cytoreductive chemotherapy with only two cycles of ifosfamide, carboplatin, and etoposide (ICE) with responders offered HDT and ASCT. All patients in this trial had biopsy-proven relapsed or refractory disease, and our data were analyzed by intent to treat. ICE chemotherapy was a highly effective SDSC regimen in HL. The response rate to ICE was 90% with no ICE-related extramedullary toxicity. The median number of

High dose therapy and autologous stem cell transplantation (ASCT) is the best curative option for patients with relapsed and primary refractory Hodgkin’s lymphoma (HL).1-5 Chemosensitive disease to standard dose second-line chemotherapy (SDSC) is necessary for transplant eligibility in the United States. There is limited information regarding the optimal SDSC regimen. The requirements for an effective SDSC regimen are as follows: demonstration of cytoreduction in at least 75% of patients with minimal extramedullary toxicity and without severe bone marrow suppression compromising the ability to collect an adequate number of peripheral-blood progenitor cells (PBPCs).6 Specifically, in the phase III randomized German study described

From the Lymphoma and Hematology Services, Memorial Sloan-Kettering Cancer Center, New York, NY. Author’s disclosure of potential conflicts of interest is found at the end of this article. Address reprint requests to Craig H. Moskowitz, MD, Assistant Attending Physician, Lymphoma and Hematology Services, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: [email protected]. © 2004 by American Society of Clinical Oncology. 1092-9118/04/360-367

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361 response on the basis of computed tomography (CT) criteria to SDSC have a survival advantage,9 in HL, response rate is sometimes difficult to assess because of large residual fibrotic masses. For example, despite a 90% response rate to two cycles of ICE chemotherapy in HL, most patients cannot achieve a true clinical remission (CR) as defined by Cheson criteria.10 THE ROLE OF FUNCTIONAL IMAGING IN PATIENTS WITH HL

Fig 1. Freedom from treatment failure for patients in randomized German Hodgkin’s disease study group (GHSG) study separated by initial remission duration. Reprinted with permission.4

CD34⫹ cells/kg collected was 7.6 ⫻106/kg after a median of two apheresis procedures.8 In contrast to diffuse large B cell lymphoma (DLBCL), where patients achieving a complete

Functional imaging improves the accuracy of initial HL staging. For many years gallium scanning has complemented CT for staging and response evaluation. Fluorine-18 fluorodeoxyglucose positron emission tomography (PET) has replaced gallium scanning in the United States as the functional imaging test of choice for a variety of reasons that include improved resolution, reduced nonspecific abdominal uptake, and ease of administration.11-13 A critical question facing physicians regarding PET imaging in HL is the positive predictive value (PPV) and negative predictive value (NPV) in the evaluation of a residual mass. Since 1994 all patients with HL at Memorial Sloan-Kettering Cancer Center (MSKCC) were enrolled on intent to treat trials encompassing two doses of ICE– based chemotherapy followed by ASCT for responders. The second study had more patients with poor prognostic factors (Fig 2). Functional imaging studies pre- and post-ICE are available on all 173 patients. After excluding the 22 patients who failed ICE chemotherapy, we compared the outcome of the 152 patients by response to ICE (complete or partial response) or normalization of functional imaging versus abnormal functional imaging pre-ASCT. In study one all patients had gallium imaging and in study two all patients had PET scans. In both clinical trials the most important risk factor predicting outcome in these patients was abnormal functional imaging pre-ASCT. If one combines the two programs there is a marked survival advantage for those patients who have normal functional imaging at the time of transplant. On the basis of this information more intensive cytoreduction or extending standard regimens in patients with abnormal functional imaging pre-ASCT warrants a prospective clinical trial14 (Fig 2).

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Fig 2. Event-free survival of patients treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2003 on the basis of the results of functional imaging (FI) tests pre-autologous stem cell transplantation.

PRIMARY REFRACTORY HL

Some reports have suggested that patients with primary refractory disease do less well than those patients who achieved an initial remission to front-line therapy.15,16 Therapy for patients with primary refractory HL has changed in the past decade because progression-free survival (PFS) is only 8% to 15% when SDSC is administered. Results with HDT indicate an improved PFS of 30% to 40%. A major problem with the published refractory disease series is the lack of a uniform definition of primary refractory disease. Definitions of refractory disease in the literature range from progression of disease on upfront therapy to a partial response three months posttreatment. Moreover, the inclusion of patients with unconfirmed pathology may result in the incorporation of patients with aggressive non-Hodgkin’s lymphoma (NHL), with a nonmalignant disorder (infection or sarcoid-like reactions) or patients with residual radiologic abnormalities but no active HL into a HDT program. These other non-HL entities are often strongly positive on functional imaging; thereby making histologic confirmation even more imperative.

We have recently reported our results on 91 patients with primary refractory HL of which eight (9%) patients were found to have diffuse large B cell lymphoma on the repeat biopsy. In these cases, the initial diagnosis of HL was confirmed by pathology review. This has both prognostic as well as therapeutic implications while the choice of SDSC in NHL nearly always incorporates rituximab. Our data indicates that HDT/ ASCT is standard treatment for patients with primary refractory HL, if chemosensitivity to SDSC has been established. Although data from the autologous bone marrow transplant registry (ABMTR) found no difference in overall survival in the patients transplanted with chemorefractory versus chemosensitive disease; many patients in this series had no available data concerning response to SDSC. Our patients have all received SDSC and had repeat imaging studies before HDT. There is a marked survival advantage for patients who have chemosensitive disease. In fact, survival is identical for patients with chemosensitive relapsed or primary refractory disease treated at MSKCC from 1993 to 200317 (Fig 3).

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Fig 3. Event-free survival of relapsed versus primary refractory patients treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2003. HL, Hodgkin’s lymphoma.

PROGNOSTIC FACTORS IN RELAPSED AND REFRACTORY HL

There are some reports suggesting that augmenting therapy for patients with refractory HL is beneficial; but primary refractory disease is but one of many prognostic factors affecting outcome.18 The factors that affect outcome are summarized in Table 1.19-23 Unfortunately, there is limited information using these prognostic factors to change therapy. In our first study of ICE followed by HDT and ASCT, Cox regression analysis determined that the factors associated with a poor outcome pre-ICE were: extranodal sites of disease (ENS), p ⫽ .001, initial response duration less than 1 year (p ⫽ .001), and B symptoms (p ⫽ .001). Using this three-factor model, we identified three groups of patients with widely disparate outcomes with this treatment approach. Clinically however, relapsed and refractory HL can be divided into two groups: favorable – those with

Table 1. Adverse Prognostic Factors for Treatment Outcome After ASCT for Hodgkin’s Disease Vancouver: Stanford: City of Hope: MD Anderson: Boston: SFGM: ABMTR: Nebraska:

B symptoms at relapse, extranodal disease at relapse, duration of 1st CR ⬍ 12 months B symptoms at relapse, pulmonary/bone marrow involvement, more than minimal disease at ASCT ⬎ 2 prior regimens, extranodal disease at relapse, PSC as sole stem cell source ⬎ 2 prior regimens, extranodal involvement, abnormal performance status, chemorefractory ⬎ 1 extranodal site, ECOG classification ⬎ 0, progressive disease at ASCT Extranodal relapse, duration of CR ⬍ 12 mo Chemorefractory, abnormal LDH KPS ⬍ 90% second-line IPI

Abbreviations: ASCT, autologous stem cell transplantation; CR, clinical remission; PSC, peripheral stem cells; SFGM, Societe Francaise de Greffe de Moelle; ECOG, Eastern Cooperative Oncology Group; ABMTR, autologous bone marrow transplant registry; LDH, lactate dehydrogenase; KPS, Karnofsky performance status; IPI, International Prognostic Index

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Fig 4. Event-free survival (EFS) of patients treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2003 based on pretreatment risk factors.

zero or one risk factors and unfavorable – those with two or three risk factors. Patients with favorable disease have a PFS of 76% while patients with unfavorable disease have a progression-free survival (PFS) of only 26%. (Fig 4)24 CAN RISK-ADAPTED THERAPY IMPROVE EFS IN PATIENTS WITH RELAPSED/REFRACTORY HL?

This three-factor model was the basis of our third-generation, risk-adapted comprehensive study (MSKCC protocol 98 to 71). In this study, patients with zero or one risk factor (extranodal disease (ENS), initial response duration ⫽ 1 year, or B symptoms at time of study enrollment), group A, were treated exactly the same as in the second-generation program; in that study EFS was 80%. Patients with two risk factors, group B, received one dose of standard dose ICE followed by one dose of augmented ICE second-line therapy as well as a more dose-intense transplant conditioning regimen. Finally, for patients with all three risk factors, group C, the program was

changed. Now cytoreduction was done with transplant doses of ICE followed by stem cell support; this is followed by a second autotransplant for responding patients. This three-arm study, however, uses one universal theme: Patients must have chemosensitive disease to their “ICE” therapy; group A to standard doses of ICE, group B to augmented ICE, and group C to transplant doses of ICE. Although median follow-up is still short (30 months) patients with multiple risk factors appear to have an improved outcome with a more intensive risk-adapted approach. (Fig 5)25 ALLOGENEIC TRANSPLANTATION

The use of HDT and ASCT is standard therapy for chemosensitive relapsed and primary refractory HL. The indications for and the use of allogeneic stem cell transplantation (AlloSCT) in patients with relapsed or primary refractory HL are poorly defined. The two main reasons to consider AlloSCT are (1) Infusion of a lymphoma-free stem cell product (not a concern in HL), and (2) The graft versus lymphoma effect. The major problem

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Fig 5. Event-free survival (EFS) of patients treated at Memorial Sloan-Kettering Cancer Center from 1993 to 2003 based on a risk-adapted approach. RF, regional failure.

with AlloSCT is the high treatment-related mortality compared to ASCT. The European Bone Marrow Transplantation registry recently reported the results of a matched study of ASCT versus AlloSCT for lymphoma for patients treated between 1982 and 1998. All lymphomas were included in the analysis, of which 167 patients had HL. Unfortunately, in HL the transplantrelated mortality for AlloSCT was extremely high at 51.7%. In addition, HL was the only lymphoma where relapse-free survival was inferior for AlloSCT as compared to ASCT.26 The transplant conditioning regimen in AlloSCT was originally intended to cytoreduce lymphoma while providing immunosuppression to prevent graft rejection. It has become clear in the past decade that the benefit for AlloSCT is largely related to immune-mediated graft versus lymphoma effect. This premise has led to the use of reduced-intensity (RI) or nonmyeloablative (NMT) conditioning regimens to achieve engraftment and allow for the development of a graft versus lymphoma effect as the main form of therapy for the tumor. A few general approaches are currently being used.27 The NMT approaches

include using immunosuppressive chemotherapy agents, generally fludarabine, in combination with an alkylating agent.28 Another technique is based on using low-dose, total-body irradiation with or without fludarabine.29 Lastly, Mackinnon et al30 have led the effort using a T-cell depleted approach by incorporating the humanized monoclonal antibody alemtuzumab for T-cell depletion followed by fludarabine and melphalan; donor lymphocyte infusions are added for patients with residual disease or those not evolving to 100% donor chimerism.30 The RI conditioning regimen approaches have used standard ASCT conditioning regimens, most commonly BEAM (carmustine, etoposide, cytarabine, and melphalan).31 These ASCT regimens cytoreduce lymphoma with low transplant-related toxicity and support allogeneic engraftment. Only general recommendations can be made using AlloSCT. (1) A conventional AlloSCT should not be administered in patients who have failed ASCT. (2) NMT is reasonable therapy for patients who have failed ASCT provided that the disease responds to some form of salvage chemotherapy. (3) In patients with a human leukocyte antigen-

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identical sibling donor who have poor risk disease as defined as initial remission duration of less than 1 year with concomitant B symptoms and stage IV disease, RI AlloSCT with regimens such as BEAM should be considered before ASCT. (4) The use of ASCT for cytoreduction followed by NMT in poor risk patients is a reasonable study alternative to RI AlloSCT in poor risk patients. FUTURE STUDIES

In conclusion, HDT and ASCT are standard therapy for patients with relapsed and primary refractory HL provided chemosensitivity is established. Future studies need to evaluate the role of abnormal PET scan as part of risk-adapted therapy Great strides made in the management of HL in the past decades stem from carefully done prospective clinical trials, but despite our best therapy, 15% of patients with HL will die of their disease. It is critical that new agents be studied in HL. A number of phase I/II studies are under way

evaluating anti-CD30 monoclonal antibody therapy. Similar to rituximab therapy in NHL, these antibodies may be used post-ASCT to treat minimal residual disease. More importantly, one should not forget that radiotherapy remains a treatment modality that can be exploited as opposed to eliminated in the management of HL.32,33 The accuracy of the radiation treatment volume could be improved by incorporating PET scan information to help determine the gross tumor volume. In addition, intensity-modulated radiation therapy broadens the range of radiation treatment options, while minimizing the radiation dose to normal tissues. This is particularly useful for patients with bulky and/or complex mediastinal disease or for areas that have been irradiated previously.34 AUTHOR’S DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST Research Funding—Bristol-Myers Squibb; IDEC; Genentech.

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