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How I Treat How I treat advanced classical Hodgkin lymphoma Peter Johnson and Hayley McKenzie Cancer Research UK Center, University of Southampton, Southampton, United Kingdom
The development of curative systemic treatment of Hodgkin lymphoma was recently voted one of the top 5 achievements of oncology in the last 50 years (http://cancerprogress.net/top-5-advances-modern-oncology). The high expectation of cure (above 80%) with initial therapy, even for advanced disease, is tempered by the recognition of some important limitations: not all patients are cured, especially those in older age
groups, and patients have suffered debilitating or, in some cases, fatal long-term side effects. The challenge for modern treatment approaches is to improve the cure rate and, at the same time, minimize the long-term damage resulting from treatment. After several decades during which we have tested a variety of different ways to combine conventional cytotoxic treatments with or without radiotherapy but have identified no effective new
approaches, the field is once again moving forward. The developments that hold the greatest promise in this respect are the application of functional imaging with 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) to make an early judgment of the success of treatment and the introduction of some highly active new agents such as antibody-drug conjugates. (Blood. 2015;125(11):1717-1723)
Introduction A 45-year-old man presented with progressively increasing breathlessness, a dry cough, drenching night sweats, and significant weight loss. Physical examination identified enlarged lymph nodes in both sides of the neck and both supraclavicular fossae. A chest radiograph showed widening of the mediastinum, which a computed tomographic (CT) scan confirmed as being the result of lymph nodes of maximum diameter 12 cm, accompanied by small pleural effusions, enlarged aortocaval nodes, and a focal defect in the spleen. Hemoglobin was 114 g/L, total white cell count was 9.2 3 109/L, lymphocyte count was 1.0 3 109/L, erythrocyte sedimentation rate was 48 mm/h, albumin was 31 g/L, and b2-microglobulin was 3.1 mg/L. A biopsy from one of the cervical nodes demonstrated grade 2 nodular sclerosing Hodgkin lymphoma. An FDG-PET scan (Figure 1A) demonstrated increased uptake in bilateral cervical, supraclavicular, mediastinal, subcarinal, paraesophageal, paraaortic and aortocaval nodes, as well as a focus of uptake in the left iliac bone, which had not been noted on the CT scan.
What baseline investigations are required? After diagnosis by excisional or core needle biopsy, initial evaluation should include a thorough history and clinical examination, in addition to routine blood counts, erythrocyte sedimentation rate, lactate dehydrogenase, and a virology screen. A baseline chest x-ray should be performed. PET-CT imaging at baseline is advised, because it can lead to a change in stage in 10% to 30% of patients.1 This also enables greater accuracy when this modality is used in subsequent response assessment. Although no large-scale prospective studies have been carried out, the sensitivity (87.5% to 100%) and specificity (86.7% to 100%) of PET-CT for detecting bone marrow involvement2-4 means that bone marrow biopsy need no longer be part of routine staging. Cardiac function should be evaluated with an echocardiogram in those older than age 65 years or those with risk factors for cardiovascular disease such as diabetes mellitus or hypertension. Pulmonary function
Submitted September 26, 2014; accepted December 26, 2014. Prepublished online as Blood First Edition paper, January 6, 2015; DOI 10.1182/blood-201409-551556.
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tests should be performed in those with a history of respiratory disease or with risk factors such as a history of heavy smoking. We would not routinely repeat cardiac or pulmonary function testing during the course of treatment. All postpubertal men should be offered sperm storage at diagnosis. In women, oocyte or embryo cryopreservation should be discussed prior to regimens containing significant doses of alkylating agents. After treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), one third of males have transient azoospermia, but almost no females experience early ovarian failure; the risk is much greater with alkylating chemotherapy.5
What is the best initial therapy for advanced disease? The original observation that advanced Hodgkin lymphoma could be eradicated with 4-drug mechlorethamine, vincristine, procarbazine, and prednisolone (MOPP) combination chemotherapy6 was followed by 3 decades of experimentation with different cytotoxic regimens. The ABVD combination devised by Bonnadonna in the 1970s was shown to be a significant improvement with better disease control and less long-term toxicity,7 but further refinements using multiagent alternating, hybrid,8-10 dose-intense,11,12 and even myeloablative regimens13,14 failed to improve the results further, despite their theoretical appeal based on various mathematical models of tumor responsiveness. The one apparent exception to this was the escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (eBEACOPP) regimen devised by the German Hodgkin study group (GHSG), which showed superior disease control and overall survival (OS) compared with an alternating regimen of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) and ABVD.15,16 Subsequent randomized studies have shown that eBEACOPP results in better initial tumor control than ABVD,17-19 but it has been harder to © 2015 by The American Society of Hematology
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Figure 1. Coronal FDG-PET images of the thorax. (A) Prior to initiation of therapy and (B) following 2 cycles of ABVD.
show an OS benefit, mainly because second-line therapy for the minority of patients whose disease recurs after ABVD therapy is very often successful, whereas salvage after failure of eBEACOPP is less reliable, and in at least one study, the treatment-related mortality was higher.18 A recent meta-analysis suggested some survival benefit (about 7% at 5 years) from initial treatment with eBEACOPP.20 The main deterrent for the use of eBEACOPP for all patients is its toxicity. Many will be rendered infertile and suffer from prolonged severe fatigue.21 All patients experience severe myelosuppression, and a small number develop secondary myelodysplasia or acute leukemia.22 The regimen is too toxic for use in those older than age 60 years.23 Although there is no excess of treatment-related mortality, two-thirds of patients experience grade 3 to 4 infections, including febrile neutropenia,24 resulting in high rates of hospitalization during treatment at significant cost. Administration of growth factor is necessary with each cycle at an additional financial burden. By contrast, ABVD is much less toxic: the majority of patients will retain their fertility,25 and there does not appear to be any excess of leukemia or other second malignancies. An important aspect of using ABVD is that the dose intensity should be maintained. Many patients will experience myelosuppression, particularly neutropenia, but it has been shown that if the patients have good performance status and no significant comorbidity, it is safe to continue with treatment at full dose and on schedule, irrespective of the neutrophil count.26 We do not routinely use growth factors, given the febrile neutropenia rate of less than 10%,27 but they can safely be given when indicated. Suggestions that they may exacerbate lung toxicity were not supported in a small pilot study of polyethylene glycolfilgrastim with ABVD, in which no excess lung toxicity was observed.28 There is no good predictive test for bleomycin-related lung toxicity in those with normal baseline pulmonary function tests. Vigilance is required during treatment, and those who develop respiratory symptoms or who have a severe cutaneous reaction should be carefully evaluated, if necessary, with high-resolution CT scans of the thorax. Bleomycin can be dose-reduced or omitted altogether if there is evidence of abnormal infiltrates.
Do baseline prognostic features help to guide therapy? An analysis of the correlates of progression-free survival (PFS) among more than 5000 patients with advanced Hodgkin lymphoma treated
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mainly during the 1980s yielded a 7-factor score that was able to discriminate groups of differing outcome, although less than 10% were identified in the worst category.29 If anything, the results of similar analyses in the more recent past have shown a progressive improvement in the outcomes, so that the worst 7% of patients now show a 62% freedom from progression at 5 years.30 This makes it hard to define a group with sufficiently poor prognosis a priori to require a different approach to treatment, and studies that have tested the intensification of therapy for those in the higher-risk groups have all shown negative results. The patient in the case described had a prognostic score of 3, giving a predicted freedom from progression of 60% in the original model or 74% in the more recent analysis from the British Columbia Cancer Agency. The difficulty of applying purely clinical prognostic factors has led to the exploration of biomarkers which may better reflect the underlying biology of Hodgkin lymphoma. These include circulating cytokines,31-33 chemokines,34 and soluble receptors such as CD30,35 as well as analyses of the tumor itself by gene expression profiling36,37 or enumeration of infiltrating macrophages.38 All of these are potentially interesting areas for research but are as yet unproven and in need of prospective validation, especially those that depend on immunostaining, which are generally subject to poor reproducibility. For this reason, most clinicians will treat all patients with advanced Hodgkin lymphoma with the same initial approach, regardless of the baseline characteristics. In the United Kingdom and the United States, this has generally meant using ABVD, whereas clinicians in Northern Europe have tended to favor eBEACOPP. The patient described in this case commenced treatment with ABVD.
Can therapy be adapted according to response? Although baseline characteristics have been of limited usefulness in selecting therapy, there is increasing evidence that using functional imaging to make an early assessment of the response can be helpful, particularly for the likelihood of treatment failure, which may be amenable to correction if detected early. Hodgkin lymphoma shows avidity for FDG in almost all cases, and FDG-PET is an effective means of determining the metabolic activity in sites of involvement.39 Retrospective studies of patients treated with ABVD suggested that FDG-PET performed after 2 cycles of treatment can be highly predictive of treatment success or failure.40 This appears to provide better prognostic information than CT scans,41 with a high negative predictive value, giving a 2-year PFS of approximately 95% and a reasonable positive predictive value, with PFS between 13% and 27%.39 Interestingly, this assessment supersedes all the clinical baseline prognostic information.42 Thus, even patients with adverse baseline characteristics had an excellent prognosis if the interim FDG-PET was negative, whereas those with low initial risk showed poor PFS if the interim scan showed persistent metabolic activity. It is not clear however, whether the same observations hold true for more intensive regimens such as eBEACOPP. In making these assessments, it is important to note that there are key issues of quality control in the performance of the scans and their interpretation, but the introduction of the 5-point scale for reporting has greatly improved the reliability and reproducibility of the results (Table 1).43,44 At interim, a score of 1 to 2 should be considered a complete metabolic response in patients receiving standard treatment; a score of 4 to 5 is considered positive and thus treatment has failed.39 A score of 3 is variably interpreted. In trials in which PET is used as
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Table 1. The 5-point scale for the assessment of interim FDG-PET scans 1
No uptake
2
Uptake less than or equal to mediastinum
3
Uptake greater than mediastinum but less than or equal to liver
4
Moderately increased uptake compared with liver
5
Markedly increased uptake compared with liver and/or new lesions
X
New areas of uptake unlikely to be related to lymphoma
a determinant of de-escalation, a score of 3 may be considered positive to prevent undertreatment. However, when interim scanning has been used to determine whether treatment should be escalated, then 3 is usually considered negative. A number of prospective studies have now been performed that use interim FDG-PET assessment to guide the modulation of therapy. The international Response Adjusted Therapy for Hodgkin Lymphoma (RATHL) study (NCT00678327) tested the use of FDG-PET after 2 initial cycles of ABVD in more than 1200 patients, after which those with an interim PET score of 1 to 3 were randomly assigned to either continue ABVD or receive doxorubicin, vinblastine, and dacarbazine (AVD) without bleomycin to determine whether pulmonary toxicity could be reduced for those with a good prognosis.45 Conversely, patients with an interim PET score of 4 or 5 proceeded to intensification with either eBEACOPP every 3 weeks or the similar BEACOPP-14, given at 2-week intervals. The smaller US Intergroup study (NCT00822120) and the Italian lymphoma group study (NCT00795613) used a similar approach, with interim FDG-PET after 2 cycles of ABVD followed by intensification to BEACOPP for those with positive scans. The rates of metabolic remission after 2 cycles of ABVD were very similar in all 3 trials at about 85%.46-48 The results of treatment in the PET-positive group were also similar and appear to be superior to the historical controls used in previous studies, with subsequent metabolic response rates of 75% or more and projected failure-free survival figures at 2 years of 65% to 75%. The importance of these findings is that they suggest that it may be possible to start with the less toxic ABVD and expose only the minority of patients for whom this is unlikely to be curative to the more intensive BEACOPP regimen. This will need to be confirmed by longer followup of the studies, but many centers, our own included, now carry out an interim FDG-PET scan after 2 cycles of ABVD and will intensify treatment on the basis of a persistently positive result. This was the case for the patient described, whose interim PET scan showed persistent (grade 4) FDG uptake in the left cervical nodes, with lower-level uptake in the mediastinal, paratracheal, and subcarinal nodes (Figure 1B). He went on to receive 4 cycles of BEACOPP-14 after which the scan became negative, and his treatment was completed with 2 further cycles. He has remained in remission since the completion of BEACOPP-14, 4 years ago.
At completion of chemotherapy In those with a negative interim PET scan, we perform a restaging CT scan at the end of treatment. In those with a positive interim scan, we perform a further PET-CT scan to determine whether or not escalation of therapy has yielded a metabolic response. Biopsy of any persistently FDG-avid area should be carried out if possible, prior to commencing salvage chemotherapy. If only localized FDG avidity at a site of previous disease is present, then consolidation radiotherapy can be considered as an alternative.
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Radiotherapy was the earliest form of effective treatment for Hodgkin lymphoma,49 but it has become an increasingly controversial component of treatment algorithms. This is mainly because of the emergent risks of long-term toxicity from second malignancies and accelerated cardiovascular disease within the irradiated field.50-56 Many of these problems arose from the use of extended fields and relatively high doses of radiation that were previously recommended; modern radiotherapy techniques appear to be much safer because both field size and dose are limited.57,58 Nonetheless, we recognize that it is preferable to avoid irradiation unless it adds significantly to the rate of cure. In advanced Hodgkin lymphoma, consolidation radiotherapy has conventionally been used for patients with a bulky site of disease at presentation or a residual mass at the completion of initial chemotherapy. Prior to the advent of functional imaging, a randomized trial showed that in patients treated with the hybrid MOPP-ABV (doxorubicin, bleomycin, vinblastine) regimen for 8 cycles, there was no advantage to using radiotherapy for those in complete radiologic remission.59 There appears to be a trade-off between the efficacy of prior chemotherapy and the advantage from irradiation: the more intensive the chemotherapy and the higher the complete remission rate, the less radiation adds to the results. In a large United Kingdom study, the elective omission of consolidation radiotherapy after ABVD was associated with inferior survival, despite the irradiated group’s having more bulky disease and fewer complete responses (CRs), indicating that conventional imaging is probably inadequate for selecting those in need of more treatment.60 Using FDG-PET to select residual masses that need consolidation appears to be a much better strategy. In the GHSG HD15 study, only patients with FDG-avid residual masses of more than 2.5 cm after BEACOPP therapy were selected for 30 Gy involved-field radiotherapy, with excellent results.61 Those with a PET-negative partial response had PFS of 92.1% at 4 years, very similar to those with a CR (92.6%), whereas even those who were PET-positive had 86.2% PFS. The use of radiotherapy in this study included only 11% of patients without any apparent reduction in survival by comparison with previous GHSG studies in which it was used in up to 70% of cases. There are less conclusive data on the omission of radiotherapy in PET-negative patients after treatment with ABVD, but longer followup from the RATHL study45 should provide more clarity on this front. In many centers, consolidation radiotherapy is now reserved for those with a localized residual FDG-avid mass at the completion of chemotherapy.
What new agents hold significant promise? After decades in which no new active agents emerged for treating Hodgkin lymphoma, the last few years have seen significant progress, in particular with the development of the antibody-drug conjugate brentuximab vedotin. This combines an antibody to the CD30 molecule, which is expressed on Reed-Sternberg cells, with an antitubulin, monomethyl auristatin E.62 The efficacy seen in early-phase studies has been impressive, with 76 objective responses (and 34% CRs) among 102 patients with recurrent disease who had already undergone high-dose therapy and autologous stem cell rescue.63 This level of efficacy as a single agent, combined with a favorable side effect profile largely confined to myelosuppression and neuropathy, has led to the investigation of brentuximab vedotin in combination with chemotherapy with a view to its incorporation into first-line treatment. Unexpected and severe pulmonary toxicity occurred when it was combined
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with ABVD,64 but the omission of bleomycin appears to have solved this problem, and a prospective trial, ECHELON-1 (NCT01712490) is now in progress testing AVD with brentuximab vedotin against ABVD in patients with stage III and IV disease. Entry to this trial would be my current preferred approach for a patient with advanced disease. Blockade of the programmed death-1 (PD-1) pathway also holds significant promise. Pembrolizumab and nivolumab are two anti-PD-1 antibodies that have undergone phase 1 trials, with reported response rates of 53%65 and 87%,66 respectively. Nivolumab is currently being assessed in a phase 2 trial in patients whose disease has progressed after autologous stem cell transplantation (NCT02181738). A number of other new treatments are emerging, such as inhibitors of histone deacetylase,67 phosphoinositol 3-kinase,68 or the mammalian target of rapamycin,69 but these are at an earlier stage of investigation, and the results to date are less compelling.
How does our approach change for older patients? Although the results of treatment of advanced Hodgkin lymphoma have improved markedly among those presenting in childhood, youth, or middle age, the outcomes in the 20% of patients older than 65 years at the time of diagnosis have changed much less.70 The prolonged use of bleomycin in ABVD in this group is attended by significant rates of severe pulmonary impairment (43% in one North American intergroup study71), and more intensive approaches such as BEACOPP result in high treatment-related mortality (21% in a GHSG trial72), a problem only partly attenuated by the omission of etoposide in the BEACOPP regimen, in which there were still 12% treatment-related deaths.73 Attempts have been made to develop regimens specifically for use in older patients, such as vinblastine, cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone, and bleomycin (VEPEM-B),74 which has been tested in a prospective United Kingdom study of 31 early-stage and 72 advanced-stage patients with a median age of 73 years.75 The 3-year PFS was 74% for early-stage patients and 58% for advanced-stage patients, with a low (1%) incidence of bleomycin toxicity. Similar results were seen with the GHSG prednisolone, vinblastine, doxorubicin, and gemcitabine (PVAG) regimen in a phase 2 study.76 Among 59 patients with a median age of 68 years, of whom 55 had advanced disease, 1 patient died of treatment-related toxicity, and the grade 3 to 4 respiratory toxicity rate was 7%. Three-year OS and PFS rates were 66% and 58%, respectively. The Nordic Lymphoma Group has investigated the cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen and reported a retrospective series of 27 patients of median age 71 years (range, 61 to 80 years) of whom more than half had significant comorbidities.77 Among 18 patients with advanced disease, the CR rate was 72% and the 3-year PFS was 72%, with 1 treatment-related death. Those who are older than age 65 years or who have abnormal pulmonary function tests should receive bleomycin for 2 cycles only or have it omitted altogether. In those with proven cardiac dysfunction or with cardiac risk factors, a nonanthracycline regimen such as chlorambucil, vinblastine, procarbazine, and prednisone (ChIVPP)78 may be considered. The dose of mediastinal radiotherapy should also be carefully considered. In practice, it remains extremely difficult to specify the standard approach to treatment in older patients who constitute a heterogeneous group. Selection of a regimen depends on the severity and pattern of
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comorbidity, and it is clear that new approaches are needed. Several trials are in progress testing the use of brentuximab vedotin in this context, either as a single agent (ISRCTN77650947) or in combination with chemotherapy (NCT01476410 and NCT01716806) or rituximab (NCT01805037), and it is hoped that these may improve the benefit to toxicity ratio.
How do we follow up patients in first remission? There is no substitute for taking a good history and performing a thorough clinical examination in the follow-up of Hodgkin lymphoma. Moreover, there is increasing evidence that patientreported symptoms are the most effective means of detecting a recurrence.79 Follow-up frequency in trials has been based on the Cotswolds recommendations and consists of visits every 3 months during the first 2 years, every 4 months during the third year, and every 6 months during the fourth and fifth years.80 Chest x-rays are performed in those with previous mediastinal disease. We aim to discharge patients from routine follow-up at 5 years, with specific advice concerning monitoring for long-term toxicity or recurrence. Retrospective analysis has indicated that routine PET or CT scanning holds little value in identifying relapses81,82 and cannot be recommended in patients achieving a negative interim or end-of-treatment PET-CT scan.
The approach for refractory and recurrent disease A range of salvage therapies have been tested in the 20% to 30%83 of patients with advanced disease whose lymphoma is refractory to, or relapses after, initial treatment. The salvage regimens appear to be largely interchangeable. The single-arm phase 2 trials performed do not offer direct comparison between regimens, but overall response rates of 60% to 80% have been found.84,85 A randomized comparison of sequential single-agent high-dose therapy versus continued conventional salvage therapy showed no difference in efficacy.86 Favored salvage regimens in our center include ifosfamide, carboplatin and etoposide (ICE), epirubicin in place of carboplatin (IVE), and cytarabine and cisplatin (DHAP). Patients who are eligible and achieve a complete metabolic response should proceed to autologous stem cell transplantation in second remission. Assuming successful mobilization of stem cells, the standard high-dose regimen used prior to stem cell transplantation is carmustine, etoposide, cytarabine, and melphalan (BEAM). This is based on the 2 randomized controlled trials that compared high-dose chemotherapy followed by autologous stem cell transplantation to conventional chemotherapy in patients in whom a second remission had been achieved. Both studies showed significantly improved freedom from progression in the group receiving high-dose therapy, although the small numbers enrolled prevented conclusive demonstration of improved OS.87,88 Allogeneic transplantation may also have a role in the treatment of relapsed and refractory disease, especially for patients who suffer a further recurrence after autologous transplantation. Long-term survival benefit has not been demonstrated because of the absence of randomized trials and the potential for selection bias in cohort studies. In 1 prospective study of 78 patients with multiply-relapsed disease,
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HOW I TREAT ADVANCED HODGKIN LYMPHOMA
4-year estimated PFS and OS were 24% and 43%, respectively.89 A clinically significant graft-versus-lymphoma effect after donor lymphocyte infusion has been shown,90 and with improvement in treatment-related mortality with reduced-intensity regimens, this strategy remains an important option for those with poor responses to salvage therapy.
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drug conjugates, which appear to be one means to deliver a locally concentrated cytotoxic agent while avoiding high systemic exposure. The emergent data on immunomodulating antibody therapy is also encouraging, and a new generation of trials incorporating this approach is imminent.
Authorship Conclusion The modern treatment of advanced Hodgkin lymphoma is highly effective in the majority of patients, and much current research is directed at improving the subsequent quality of life while retaining the efficacy of first-line treatment. The key developments in this area are the increasing use of FDG-PET interim scanning to guide further treatment, and the introduction of new agents such as the antibody-
Contribution: P.J. and H.M. co-wrote the manuscript. Conflict-of-interest disclosure: P.J. has received honoraria for participation in advisory boards and educational symposia from Millennium-Takeda and Bristol-Myers Squibb. The remaining author declares no competing financial interests. Correspondence: Peter Johnson, Somers Cancer Research Building, Southampton General Hospital, Tremona Rd, Southampton SO16 6YD, United Kingdom; e-mail: [email protected].
References 1. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and nonHodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. 2. El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/ computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol. 2012;30(36):4508-4514. 3. Moulin-Romsee G, Hindie´ E, Cuenca X, et al. (18)F-FDG PET/CT bone/bone marrow findings in Hodgkin’s lymphoma may circumvent the use of bone marrow trephine biopsy at diagnosis staging. Eur J Nucl Med Mol Imaging. 2010;37(6): 1095-1105. 4. Adams HJ, Kwee TC, de Keizer B, et al. Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol. 2014;25(5): 921-927. 5. van der Kaaij MA, van Echten-Arends J, Simons AH, Kluin-Nelemans HC. Fertility preservation after chemotherapy for Hodgkin lymphoma. Hematol Oncol. 2010;28(4):168-179. 6. Devita VT Jr, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med. 1970;73(6):881-895. 7. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252-259. 8. Canellos GP, Anderson JR, Propert KJ, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327(21):1478-1484. 9. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol. 2003;21(4):607-614. 10. Johnson PWM, Radford JA, Cullen MH, et al; United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519). Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin’s lymphoma: results of the United Kingdom Lymphoma Group
LY09 Trial (ISRCTN97144519). J Clin Oncol. 2005;23(36):9208-9218. 11. Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684-691. 12. Hoskin PJ, Lowry L, Horwich A, et al. Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2009;27(32): 5390-5396. 13. Arakelyan N, Berthou C, Desablens B, et al; Groupe Ouest-Est d’Etude des Leucemies ´ et Autres Maladies du Sang. Early versus late intensification for patients with high-risk Hodgkin lymphoma-3 cycles of intensive chemotherapy plus low-dose lymph node radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation: five-year results of a randomized trial on behalf of the GOELAMS Group. Cancer. 2008;113(12):3323-3330. 14. Federico M, Bellei M, Brice P, et al; EBMT/GISL/ ANZLG/SFGM/GELA Intergroup HD01 Trial. High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin’s lymphoma responding to front-line therapy. J Clin Oncol. 2003;21(12):2320-2325. 15. Diehl V, Franklin J, Pfreundschuh M, et al; German Hodgkin’s Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-2395. 16. Engert A, Diehl V, Franklin J, et al. Escalateddose BEACOPP in the treatment of patients with advanced-stage Hodgkin’s lymphoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009;27(27):4548-4554. 17. Viviani S, Bonadonna G, Santoro A, et al. Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin’s disease: ten-year results. J Clin Oncol. 1996;14(5): 1421-1430. 18. Carde PP, Karrasch M, Fortpied C, et al. ABVD (8 cycles) versus BEACOPP (4 escalated cycles 5. 4 baseline) in stage III-IV high-risk Hodgkin
Lymphoma (HL): First results of EORTC 20012 Intergroup randomized phase III clinical trial [abstract]. J Clin Oncol. 2012;30(Suppl 15s). Abstract 8002. 19. Mounier N, Brice P, Bologna S, et al; Lymphoma Study Association (LYSA). ABVD (8 cycles) versus BEACOPP (4 escalated cycles $ 4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014;25(8): 1622-1628. 20. Skoetz N, Trelle S, Rancea M, et al. Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14(10):943-952. 21. Behringer K, Mueller H, Goergen H, et al. Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol. 2013;31(2):231-239. 22. Eichenauer DA, Thielen I, Haverkamp H, et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2014;123(11): 1658-1664. 23. Wongso D, Fuchs M, Plutschow ¨ A, et al. Treatment-related mortality in patients with advanced-stage hodgkin lymphoma: an analysis of the german hodgkin study group. J Clin Oncol. 2013;31(22):2819-2824. 24. Fossa˚ A, Fiskvik IH, Kolstad A, et al. Two escalated followed by six standard BEACOPP in advanced-stage high-risk classical Hodgkin lymphoma: high cure rates but increased risk of aseptic osteonecrosis. Ann Oncol. 2012;23(5): 1254-1259. 25. Hodgson DC, Pintilie M, Gitterman L, et al. Fertility among female hodgkin lymphoma survivors attempting pregnancy following ABVD chemotherapy. Hematol Oncol. 2007;25(1):11-15. 26. Boleti E, Mead GM. ABVD for Hodgkin’s lymphoma: full-dose chemotherapy without dose reductions or growth factors. Ann Oncol. 2007; 18(2):376-380. 27. Minuk LA, Monkman K, Chin-Yee IH, et al. Treatment of Hodgkin lymphoma with adriamycin, bleomycin, vinblastine and dacarbazine without routine granulocyte-colony stimulating factor support does not increase the risk of febrile neutropenia: a prospective cohort study. Leuk Lymphoma. 2012;53(1):57-63.
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28. Younes A, Fayad L, Romaguera J, Pro B, Goy A, Wang M. Safety and efficacy of once-per-cycle pegfilgrastim in support of ABVD chemotherapy in patients with Hodgkin lymphoma. Eur J Cancer. 2006;42(17):2976-2981. 29. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21): 1506-1514. 30. Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in advanced-stage Hodgkin’s lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383-3388. 31. Casasnovas RO, Mounier N, Brice P, et al; Groupe d’Etude des Lymphomes de l’Adulte. Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin’s lymphoma: a study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2007;25(13):1732-1740. 32. Sarris AH, Kliche KO, Pethambaram P, et al. Interleukin-10 levels are often elevated in serum of adults with Hodgkin’s disease and are associated with inferior failure-free survival. Ann Oncol. 1999;10(4):433-440. 33. Vassilakopoulos TP, Nadali G, Angelopoulou MK, et al. Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin’s lymphoma. Haematologica. 2001; 86(3):274-281. 34. Sauer M, Plutschow ¨ A, Jachimowicz RD, et al. Baseline serum TARC levels predict therapy outcome in patients with Hodgkin lymphoma. Am J Hematol. 2013;88(2):113-115. 35. Visco C, Nadali G, Vassilakopoulos TP, et al. Very high levels of soluble CD30 recognize the patients with classical Hodgkin’s lymphoma retaining a very poor prognosis. Eur J Haematol. 2006; 77(5):387-394. 36. Scott DW, Chan FC, Hong F, et al. Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013;31(6):692-700. 37. Chetaille B, Bertucci F, Finetti P, et al. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood. 2009;113(12): 2765-2775. 38. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875-885. 39. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048-3058. 40. Hutchings M, Mikhaeel NG, Fields PA, Nunan T, Timothy AR. Prognostic value of interim FDGPET after two or three cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol. 2005;16(7): 1160-1168. 41. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006;107(1):52-59. 42. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint ItalianDanish study. J Clin Oncol. 2007;25(24): 3746-3752. 43. Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the First International
Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009;50(8):1257-1260. 44. Barrington SF, Qian W, Somer EJ, et al. Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging. 2010;37(10):1824-1833. 45. Johnson P, Frederico M, Fossa A, et al. Response rates and toxicity of response-adapted therapy in advanced Hodgkin lymphoma (HL): Initial results from the international RATHL Study [abstract]. Haematologica. 2013;98(suppl 2):02. Abstract T003. 46. Gallamini A, Rossi A, Patti C, et al. Early Treatment Intensification in Advanced-Stage High-Risk Hodgkin Lymphoma (HL) Patients, with a Positive FDG-PET Scan After Two ABVD Courses – First Interim Analysis of the GITIL/FIL HD0607 Clinical Trial [abstract]. Blood. 2012; 120(21). Abstract 550. 47. Johnson P, Federico M, Fossa A, et al. Responses and chemotherapy dose adjustment determined by PET-CT imaging: first results from the international Response Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) Study [abstract]. Hematol Oncol. 2013;31(S1). Abstract 126. 48. Press OW, LeBlanc M, Rimsza LM, et al. A Phase II Trial of Response-Adapted Therapy of Stages III–Iv Hodgkin Lymphoma Using Early Interim FDG-PET Imaging: US Intergroup S0816. Hematol Oncol. 2013;31(S1). Abstract 124. 49. Peters MV. A study of survivals in Hodgkin’s disease treated radiologically. AJR Am J Roentgenol. 1950;63:299-311. 50. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA. 1993; 270(16):1949-1955. 51. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol. 2002; 20(8):2101-2108. 52. Ng AK, Bernardo MV, Weller E, et al. Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood. 2002; 100(6):1989-1996. 53. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003; 290(4):465-475. 54. Travis LB, Hill D, Dores GM, et al. Cumulative absolute breast cancer risk for young women treated for Hodgkin lymphoma. J Natl Cancer Inst. 2005;97(19):1428-1437. 55. Franklin J, Pluetschow A, Paus M, et al. Second malignancy risk associated with treatment of Hodgkin’s lymphoma: meta-analysis of the randomised trials. Ann Oncol. 2006;17(12): 1749-1760. 56. Hodgson DC, Gilbert ES, Dores GM, et al. Longterm solid cancer risk among 5-year survivors of Hodgkin’s lymphoma. J Clin Oncol. 2007;25(12): 1489-1497. 57. De Bruin ML, Sparidans J, van’t Veer MB, et al. Breast cancer risk in female survivors of Hodgkin’s lymphoma: lower risk after smaller radiation volumes. J Clin Oncol. 2009;27(26): 4239-4246. 58. Koontz MZ, Horning SJ, Balise R, et al. Risk of therapy-related secondary leukemia in Hodgkin lymphoma: the Stanford University experience over three generations of clinical trials. J Clin Oncol. 2013;31(5):592-598. 59. Aleman BM, Raemaekers JM, Tirelli U, et al; European Organization for Research and Treatment of Cancer Lymphoma Group. Involvedfield radiotherapy for advanced Hodgkin’s
lymphoma. N Engl J Med. 2003;348(24): 2396-2406. 60. Johnson PW, Sydes MR, Hancock BW, Cullen M, Radford JA, Stenning SP. Consolidation radiotherapy in patients with advanced Hodgkin’s lymphoma: survival data from the UKLG LY09 randomized controlled trial (ISRCTN97144519). J Clin Oncol. 2010;28(20):3352-3359. 61. Engert A, Haverkamp H, Kobe C, et al; German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikament¨ose Tumortherapie. Reducedintensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828):1791-1799. 62. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010; 363(19):1812-1821. 63. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189. 64. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, doseescalation study. Lancet Oncol. 2013;14(13): 1348-1356. 65. Moskowitz CH, Michot J, Martinelli G, et al. PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study [abstract]. Blood. 2014;124(21). Abstract 290. 66. Armand PA, Lesokhin AM, Halwani A, et al. Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma - Preliminary Safety, Efficacy and Biomarker Results of a Phase I Study [abstract]. Blood. 2014;124(21). Abstract 289. 67. Younes A, Sureda A, Ben-Yehuda D, et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol. 2012;30(18):2197-2203. 68. Meadows SA, Vega F, Kashishian A, et al. PI3Kd inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood. 2012;119(8):1897-1900. 69. Johnston PB, Inwards DJ, Colgan JP, et al. A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010;85(5):320-324. 70. Sjoberg ¨ J, Halthur C, Kristinsson SY, et al. Progress in Hodgkin lymphoma: a populationbased study on patients diagnosed in Sweden from 1973-2009. Blood. 2012;119(4):990-996. 71. Evens AM, Hong F, Gordon LI, et al. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol. 2013;161(1):76-86. 72. Ballova V, Ruffer ¨ JU, Haverkamp H, et al. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin’s disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol. 2005;16(1): 124-131. 73. Halbsguth TV, Nogova´ L, Mueller H, et al. Phase 2 study of BACOPP (bleomycin, adriamycin, cyclophosphamide, vincristine, procarbazine,
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and prednisone) in older patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG). Blood. 2010;116(12): 2026-2032. 74. Levis A, Anselmo AP, Ambrosetti A, et al; Intergruppo Italiano Linfomi (IIL). VEPEMB in elderly Hodgkin’s lymphoma patients. Results from an Intergruppo Italiano Linfomi (IIL) study. Ann Oncol. 2004;15(1):123-128. 75. Proctor SJ, Wilkinson J, Jones G, et al. Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study. Blood. 2012;119(25):6005-6015. 76. Boll ¨ B, Bredenfeld H, Gorgen ¨ H, et al. Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma. Blood. 2011;118(24):6292-6298. 77. Kolstad A, Nome O, Delabie J, Lauritzsen GF, Fossa A, Holte H. Standard CHOP-21 as first line therapy for elderly patients with Hodgkin’s lymphoma. Leuk Lymphoma. 2007;48(3): 570-576. 78. Selby P, Patel P, Milan S, et al. ChlVPP combination chemotherapy for Hodgkin’s disease: long-term results. Br J Cancer. 1990;62(2): 279-285. 79. Radford JA, Eardley A, Woodman C, Crowther D. Follow up policy after treatment for Hodgkin’s disease: too many clinic visits and routine tests? A review of hospital records. BMJ. 1997; 314(7077):343-346.
HOW I TREAT ADVANCED HODGKIN LYMPHOMA
80. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol. 1989; 7(11):1630-1636. 81. Dryver ET, Jernstrom ¨ H, Tompkins K, Buckstein R, Imrie KR. Follow-up of patients with Hodgkin’s disease following curative treatment: the routine CT scan is of little value. Br J Cancer. 2003;89(3): 482-486. 82. Dann EJ, Berkahn L, Mashiach T, et al. Hodgkin lymphoma patients in first remission: routine positron emission tomography/computerized tomography imaging is not superior to clinical follow-up for patients with no residual mass. Br J Haematol. 2014;164(5):694-700. 83. Townsend W, Linch D. Hodgkin’s lymphoma in adults. Lancet. 2012;380(9844):836-847. 84. Josting A, Rudolph C, Mapara M, et al. Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicenter study of the German Hodgkin Lymphoma Study Group (GHSG). Ann Oncol. 2005;16(1):116-123. 85. Baetz T, Belch A, Couban S, et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin’s disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol. 2003;14(12):1762-1767. 86. Josting A, Muller ¨ H, Borchmann P, et al. Dose intensity of chemotherapy in patients with
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relapsed Hodgkin’s lymphoma. J Clin Oncol. 2010;28(34):5074-5080. 87. Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet. 1993;341(8852):1051-1054. 88. Schmitz N, Pfistner B, Sextro M, et al; German Hodgkin’s Lymphoma Study Group; Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomised trial. Lancet. 2002;359(9323): 2065-2071. 89. Sureda A, Canals C, Arranz R, et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin’s lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Espan˜ol de Linfomas/Trasplante de Medula ´ Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012;97(2): 310-317. 90. Peggs KS, Hunter A, Chopra R, et al. Clinical evidence of a graft-versus-Hodgkin’s-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet. 2005;365(9475): 1934-1941.
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2015 125: 1717-1723 doi:10.1182/blood-2014-09-551556 originally published online January 6, 2015
How I treat advanced classical Hodgkin lymphoma Peter Johnson and Hayley McKenzie
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How I Treat How I treat advanced classical Hodgkin lymphoma Peter Johnson and Hayley McKenzie Cancer Research UK Center, University of Southampton, Southampton, United Kingdom
The development of curative systemic treatment of Hodgkin lymphoma was recently voted one of the top 5 achievements of oncology in the last 50 years (http://cancerprogress.net/top-5-advances-modern-oncology). The high expectation of cure (above 80%) with initial therapy, even for advanced disease, is tempered by the recognition of some important limitations: not all patients are cured, especially those in older age
groups, and patients have suffered debilitating or, in some cases, fatal long-term side effects. The challenge for modern treatment approaches is to improve the cure rate and, at the same time, minimize the long-term damage resulting from treatment. After several decades during which we have tested a variety of different ways to combine conventional cytotoxic treatments with or without radiotherapy but have identified no effective new
approaches, the field is once again moving forward. The developments that hold the greatest promise in this respect are the application of functional imaging with 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) to make an early judgment of the success of treatment and the introduction of some highly active new agents such as antibody-drug conjugates. (Blood. 2015;125(11):1717-1723)
Introduction A 45-year-old man presented with progressively increasing breathlessness, a dry cough, drenching night sweats, and significant weight loss. Physical examination identified enlarged lymph nodes in both sides of the neck and both supraclavicular fossae. A chest radiograph showed widening of the mediastinum, which a computed tomographic (CT) scan confirmed as being the result of lymph nodes of maximum diameter 12 cm, accompanied by small pleural effusions, enlarged aortocaval nodes, and a focal defect in the spleen. Hemoglobin was 114 g/L, total white cell count was 9.2 3 109/L, lymphocyte count was 1.0 3 109/L, erythrocyte sedimentation rate was 48 mm/h, albumin was 31 g/L, and b2-microglobulin was 3.1 mg/L. A biopsy from one of the cervical nodes demonstrated grade 2 nodular sclerosing Hodgkin lymphoma. An FDG-PET scan (Figure 1A) demonstrated increased uptake in bilateral cervical, supraclavicular, mediastinal, subcarinal, paraesophageal, paraaortic and aortocaval nodes, as well as a focus of uptake in the left iliac bone, which had not been noted on the CT scan.
What baseline investigations are required? After diagnosis by excisional or core needle biopsy, initial evaluation should include a thorough history and clinical examination, in addition to routine blood counts, erythrocyte sedimentation rate, lactate dehydrogenase, and a virology screen. A baseline chest x-ray should be performed. PET-CT imaging at baseline is advised, because it can lead to a change in stage in 10% to 30% of patients.1 This also enables greater accuracy when this modality is used in subsequent response assessment. Although no large-scale prospective studies have been carried out, the sensitivity (87.5% to 100%) and specificity (86.7% to 100%) of PET-CT for detecting bone marrow involvement2-4 means that bone marrow biopsy need no longer be part of routine staging. Cardiac function should be evaluated with an echocardiogram in those older than age 65 years or those with risk factors for cardiovascular disease such as diabetes mellitus or hypertension. Pulmonary function
Submitted September 26, 2014; accepted December 26, 2014. Prepublished online as Blood First Edition paper, January 6, 2015; DOI 10.1182/blood-201409-551556.
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tests should be performed in those with a history of respiratory disease or with risk factors such as a history of heavy smoking. We would not routinely repeat cardiac or pulmonary function testing during the course of treatment. All postpubertal men should be offered sperm storage at diagnosis. In women, oocyte or embryo cryopreservation should be discussed prior to regimens containing significant doses of alkylating agents. After treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), one third of males have transient azoospermia, but almost no females experience early ovarian failure; the risk is much greater with alkylating chemotherapy.5
What is the best initial therapy for advanced disease? The original observation that advanced Hodgkin lymphoma could be eradicated with 4-drug mechlorethamine, vincristine, procarbazine, and prednisolone (MOPP) combination chemotherapy6 was followed by 3 decades of experimentation with different cytotoxic regimens. The ABVD combination devised by Bonnadonna in the 1970s was shown to be a significant improvement with better disease control and less long-term toxicity,7 but further refinements using multiagent alternating, hybrid,8-10 dose-intense,11,12 and even myeloablative regimens13,14 failed to improve the results further, despite their theoretical appeal based on various mathematical models of tumor responsiveness. The one apparent exception to this was the escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (eBEACOPP) regimen devised by the German Hodgkin study group (GHSG), which showed superior disease control and overall survival (OS) compared with an alternating regimen of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) and ABVD.15,16 Subsequent randomized studies have shown that eBEACOPP results in better initial tumor control than ABVD,17-19 but it has been harder to © 2015 by The American Society of Hematology
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Figure 1. Coronal FDG-PET images of the thorax. (A) Prior to initiation of therapy and (B) following 2 cycles of ABVD.
show an OS benefit, mainly because second-line therapy for the minority of patients whose disease recurs after ABVD therapy is very often successful, whereas salvage after failure of eBEACOPP is less reliable, and in at least one study, the treatment-related mortality was higher.18 A recent meta-analysis suggested some survival benefit (about 7% at 5 years) from initial treatment with eBEACOPP.20 The main deterrent for the use of eBEACOPP for all patients is its toxicity. Many will be rendered infertile and suffer from prolonged severe fatigue.21 All patients experience severe myelosuppression, and a small number develop secondary myelodysplasia or acute leukemia.22 The regimen is too toxic for use in those older than age 60 years.23 Although there is no excess of treatment-related mortality, two-thirds of patients experience grade 3 to 4 infections, including febrile neutropenia,24 resulting in high rates of hospitalization during treatment at significant cost. Administration of growth factor is necessary with each cycle at an additional financial burden. By contrast, ABVD is much less toxic: the majority of patients will retain their fertility,25 and there does not appear to be any excess of leukemia or other second malignancies. An important aspect of using ABVD is that the dose intensity should be maintained. Many patients will experience myelosuppression, particularly neutropenia, but it has been shown that if the patients have good performance status and no significant comorbidity, it is safe to continue with treatment at full dose and on schedule, irrespective of the neutrophil count.26 We do not routinely use growth factors, given the febrile neutropenia rate of less than 10%,27 but they can safely be given when indicated. Suggestions that they may exacerbate lung toxicity were not supported in a small pilot study of polyethylene glycolfilgrastim with ABVD, in which no excess lung toxicity was observed.28 There is no good predictive test for bleomycin-related lung toxicity in those with normal baseline pulmonary function tests. Vigilance is required during treatment, and those who develop respiratory symptoms or who have a severe cutaneous reaction should be carefully evaluated, if necessary, with high-resolution CT scans of the thorax. Bleomycin can be dose-reduced or omitted altogether if there is evidence of abnormal infiltrates.
Do baseline prognostic features help to guide therapy? An analysis of the correlates of progression-free survival (PFS) among more than 5000 patients with advanced Hodgkin lymphoma treated
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mainly during the 1980s yielded a 7-factor score that was able to discriminate groups of differing outcome, although less than 10% were identified in the worst category.29 If anything, the results of similar analyses in the more recent past have shown a progressive improvement in the outcomes, so that the worst 7% of patients now show a 62% freedom from progression at 5 years.30 This makes it hard to define a group with sufficiently poor prognosis a priori to require a different approach to treatment, and studies that have tested the intensification of therapy for those in the higher-risk groups have all shown negative results. The patient in the case described had a prognostic score of 3, giving a predicted freedom from progression of 60% in the original model or 74% in the more recent analysis from the British Columbia Cancer Agency. The difficulty of applying purely clinical prognostic factors has led to the exploration of biomarkers which may better reflect the underlying biology of Hodgkin lymphoma. These include circulating cytokines,31-33 chemokines,34 and soluble receptors such as CD30,35 as well as analyses of the tumor itself by gene expression profiling36,37 or enumeration of infiltrating macrophages.38 All of these are potentially interesting areas for research but are as yet unproven and in need of prospective validation, especially those that depend on immunostaining, which are generally subject to poor reproducibility. For this reason, most clinicians will treat all patients with advanced Hodgkin lymphoma with the same initial approach, regardless of the baseline characteristics. In the United Kingdom and the United States, this has generally meant using ABVD, whereas clinicians in Northern Europe have tended to favor eBEACOPP. The patient described in this case commenced treatment with ABVD.
Can therapy be adapted according to response? Although baseline characteristics have been of limited usefulness in selecting therapy, there is increasing evidence that using functional imaging to make an early assessment of the response can be helpful, particularly for the likelihood of treatment failure, which may be amenable to correction if detected early. Hodgkin lymphoma shows avidity for FDG in almost all cases, and FDG-PET is an effective means of determining the metabolic activity in sites of involvement.39 Retrospective studies of patients treated with ABVD suggested that FDG-PET performed after 2 cycles of treatment can be highly predictive of treatment success or failure.40 This appears to provide better prognostic information than CT scans,41 with a high negative predictive value, giving a 2-year PFS of approximately 95% and a reasonable positive predictive value, with PFS between 13% and 27%.39 Interestingly, this assessment supersedes all the clinical baseline prognostic information.42 Thus, even patients with adverse baseline characteristics had an excellent prognosis if the interim FDG-PET was negative, whereas those with low initial risk showed poor PFS if the interim scan showed persistent metabolic activity. It is not clear however, whether the same observations hold true for more intensive regimens such as eBEACOPP. In making these assessments, it is important to note that there are key issues of quality control in the performance of the scans and their interpretation, but the introduction of the 5-point scale for reporting has greatly improved the reliability and reproducibility of the results (Table 1).43,44 At interim, a score of 1 to 2 should be considered a complete metabolic response in patients receiving standard treatment; a score of 4 to 5 is considered positive and thus treatment has failed.39 A score of 3 is variably interpreted. In trials in which PET is used as
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Table 1. The 5-point scale for the assessment of interim FDG-PET scans 1
No uptake
2
Uptake less than or equal to mediastinum
3
Uptake greater than mediastinum but less than or equal to liver
4
Moderately increased uptake compared with liver
5
Markedly increased uptake compared with liver and/or new lesions
X
New areas of uptake unlikely to be related to lymphoma
a determinant of de-escalation, a score of 3 may be considered positive to prevent undertreatment. However, when interim scanning has been used to determine whether treatment should be escalated, then 3 is usually considered negative. A number of prospective studies have now been performed that use interim FDG-PET assessment to guide the modulation of therapy. The international Response Adjusted Therapy for Hodgkin Lymphoma (RATHL) study (NCT00678327) tested the use of FDG-PET after 2 initial cycles of ABVD in more than 1200 patients, after which those with an interim PET score of 1 to 3 were randomly assigned to either continue ABVD or receive doxorubicin, vinblastine, and dacarbazine (AVD) without bleomycin to determine whether pulmonary toxicity could be reduced for those with a good prognosis.45 Conversely, patients with an interim PET score of 4 or 5 proceeded to intensification with either eBEACOPP every 3 weeks or the similar BEACOPP-14, given at 2-week intervals. The smaller US Intergroup study (NCT00822120) and the Italian lymphoma group study (NCT00795613) used a similar approach, with interim FDG-PET after 2 cycles of ABVD followed by intensification to BEACOPP for those with positive scans. The rates of metabolic remission after 2 cycles of ABVD were very similar in all 3 trials at about 85%.46-48 The results of treatment in the PET-positive group were also similar and appear to be superior to the historical controls used in previous studies, with subsequent metabolic response rates of 75% or more and projected failure-free survival figures at 2 years of 65% to 75%. The importance of these findings is that they suggest that it may be possible to start with the less toxic ABVD and expose only the minority of patients for whom this is unlikely to be curative to the more intensive BEACOPP regimen. This will need to be confirmed by longer followup of the studies, but many centers, our own included, now carry out an interim FDG-PET scan after 2 cycles of ABVD and will intensify treatment on the basis of a persistently positive result. This was the case for the patient described, whose interim PET scan showed persistent (grade 4) FDG uptake in the left cervical nodes, with lower-level uptake in the mediastinal, paratracheal, and subcarinal nodes (Figure 1B). He went on to receive 4 cycles of BEACOPP-14 after which the scan became negative, and his treatment was completed with 2 further cycles. He has remained in remission since the completion of BEACOPP-14, 4 years ago.
At completion of chemotherapy In those with a negative interim PET scan, we perform a restaging CT scan at the end of treatment. In those with a positive interim scan, we perform a further PET-CT scan to determine whether or not escalation of therapy has yielded a metabolic response. Biopsy of any persistently FDG-avid area should be carried out if possible, prior to commencing salvage chemotherapy. If only localized FDG avidity at a site of previous disease is present, then consolidation radiotherapy can be considered as an alternative.
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Radiotherapy was the earliest form of effective treatment for Hodgkin lymphoma,49 but it has become an increasingly controversial component of treatment algorithms. This is mainly because of the emergent risks of long-term toxicity from second malignancies and accelerated cardiovascular disease within the irradiated field.50-56 Many of these problems arose from the use of extended fields and relatively high doses of radiation that were previously recommended; modern radiotherapy techniques appear to be much safer because both field size and dose are limited.57,58 Nonetheless, we recognize that it is preferable to avoid irradiation unless it adds significantly to the rate of cure. In advanced Hodgkin lymphoma, consolidation radiotherapy has conventionally been used for patients with a bulky site of disease at presentation or a residual mass at the completion of initial chemotherapy. Prior to the advent of functional imaging, a randomized trial showed that in patients treated with the hybrid MOPP-ABV (doxorubicin, bleomycin, vinblastine) regimen for 8 cycles, there was no advantage to using radiotherapy for those in complete radiologic remission.59 There appears to be a trade-off between the efficacy of prior chemotherapy and the advantage from irradiation: the more intensive the chemotherapy and the higher the complete remission rate, the less radiation adds to the results. In a large United Kingdom study, the elective omission of consolidation radiotherapy after ABVD was associated with inferior survival, despite the irradiated group’s having more bulky disease and fewer complete responses (CRs), indicating that conventional imaging is probably inadequate for selecting those in need of more treatment.60 Using FDG-PET to select residual masses that need consolidation appears to be a much better strategy. In the GHSG HD15 study, only patients with FDG-avid residual masses of more than 2.5 cm after BEACOPP therapy were selected for 30 Gy involved-field radiotherapy, with excellent results.61 Those with a PET-negative partial response had PFS of 92.1% at 4 years, very similar to those with a CR (92.6%), whereas even those who were PET-positive had 86.2% PFS. The use of radiotherapy in this study included only 11% of patients without any apparent reduction in survival by comparison with previous GHSG studies in which it was used in up to 70% of cases. There are less conclusive data on the omission of radiotherapy in PET-negative patients after treatment with ABVD, but longer followup from the RATHL study45 should provide more clarity on this front. In many centers, consolidation radiotherapy is now reserved for those with a localized residual FDG-avid mass at the completion of chemotherapy.
What new agents hold significant promise? After decades in which no new active agents emerged for treating Hodgkin lymphoma, the last few years have seen significant progress, in particular with the development of the antibody-drug conjugate brentuximab vedotin. This combines an antibody to the CD30 molecule, which is expressed on Reed-Sternberg cells, with an antitubulin, monomethyl auristatin E.62 The efficacy seen in early-phase studies has been impressive, with 76 objective responses (and 34% CRs) among 102 patients with recurrent disease who had already undergone high-dose therapy and autologous stem cell rescue.63 This level of efficacy as a single agent, combined with a favorable side effect profile largely confined to myelosuppression and neuropathy, has led to the investigation of brentuximab vedotin in combination with chemotherapy with a view to its incorporation into first-line treatment. Unexpected and severe pulmonary toxicity occurred when it was combined
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with ABVD,64 but the omission of bleomycin appears to have solved this problem, and a prospective trial, ECHELON-1 (NCT01712490) is now in progress testing AVD with brentuximab vedotin against ABVD in patients with stage III and IV disease. Entry to this trial would be my current preferred approach for a patient with advanced disease. Blockade of the programmed death-1 (PD-1) pathway also holds significant promise. Pembrolizumab and nivolumab are two anti-PD-1 antibodies that have undergone phase 1 trials, with reported response rates of 53%65 and 87%,66 respectively. Nivolumab is currently being assessed in a phase 2 trial in patients whose disease has progressed after autologous stem cell transplantation (NCT02181738). A number of other new treatments are emerging, such as inhibitors of histone deacetylase,67 phosphoinositol 3-kinase,68 or the mammalian target of rapamycin,69 but these are at an earlier stage of investigation, and the results to date are less compelling.
How does our approach change for older patients? Although the results of treatment of advanced Hodgkin lymphoma have improved markedly among those presenting in childhood, youth, or middle age, the outcomes in the 20% of patients older than 65 years at the time of diagnosis have changed much less.70 The prolonged use of bleomycin in ABVD in this group is attended by significant rates of severe pulmonary impairment (43% in one North American intergroup study71), and more intensive approaches such as BEACOPP result in high treatment-related mortality (21% in a GHSG trial72), a problem only partly attenuated by the omission of etoposide in the BEACOPP regimen, in which there were still 12% treatment-related deaths.73 Attempts have been made to develop regimens specifically for use in older patients, such as vinblastine, cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone, and bleomycin (VEPEM-B),74 which has been tested in a prospective United Kingdom study of 31 early-stage and 72 advanced-stage patients with a median age of 73 years.75 The 3-year PFS was 74% for early-stage patients and 58% for advanced-stage patients, with a low (1%) incidence of bleomycin toxicity. Similar results were seen with the GHSG prednisolone, vinblastine, doxorubicin, and gemcitabine (PVAG) regimen in a phase 2 study.76 Among 59 patients with a median age of 68 years, of whom 55 had advanced disease, 1 patient died of treatment-related toxicity, and the grade 3 to 4 respiratory toxicity rate was 7%. Three-year OS and PFS rates were 66% and 58%, respectively. The Nordic Lymphoma Group has investigated the cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen and reported a retrospective series of 27 patients of median age 71 years (range, 61 to 80 years) of whom more than half had significant comorbidities.77 Among 18 patients with advanced disease, the CR rate was 72% and the 3-year PFS was 72%, with 1 treatment-related death. Those who are older than age 65 years or who have abnormal pulmonary function tests should receive bleomycin for 2 cycles only or have it omitted altogether. In those with proven cardiac dysfunction or with cardiac risk factors, a nonanthracycline regimen such as chlorambucil, vinblastine, procarbazine, and prednisone (ChIVPP)78 may be considered. The dose of mediastinal radiotherapy should also be carefully considered. In practice, it remains extremely difficult to specify the standard approach to treatment in older patients who constitute a heterogeneous group. Selection of a regimen depends on the severity and pattern of
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comorbidity, and it is clear that new approaches are needed. Several trials are in progress testing the use of brentuximab vedotin in this context, either as a single agent (ISRCTN77650947) or in combination with chemotherapy (NCT01476410 and NCT01716806) or rituximab (NCT01805037), and it is hoped that these may improve the benefit to toxicity ratio.
How do we follow up patients in first remission? There is no substitute for taking a good history and performing a thorough clinical examination in the follow-up of Hodgkin lymphoma. Moreover, there is increasing evidence that patientreported symptoms are the most effective means of detecting a recurrence.79 Follow-up frequency in trials has been based on the Cotswolds recommendations and consists of visits every 3 months during the first 2 years, every 4 months during the third year, and every 6 months during the fourth and fifth years.80 Chest x-rays are performed in those with previous mediastinal disease. We aim to discharge patients from routine follow-up at 5 years, with specific advice concerning monitoring for long-term toxicity or recurrence. Retrospective analysis has indicated that routine PET or CT scanning holds little value in identifying relapses81,82 and cannot be recommended in patients achieving a negative interim or end-of-treatment PET-CT scan.
The approach for refractory and recurrent disease A range of salvage therapies have been tested in the 20% to 30%83 of patients with advanced disease whose lymphoma is refractory to, or relapses after, initial treatment. The salvage regimens appear to be largely interchangeable. The single-arm phase 2 trials performed do not offer direct comparison between regimens, but overall response rates of 60% to 80% have been found.84,85 A randomized comparison of sequential single-agent high-dose therapy versus continued conventional salvage therapy showed no difference in efficacy.86 Favored salvage regimens in our center include ifosfamide, carboplatin and etoposide (ICE), epirubicin in place of carboplatin (IVE), and cytarabine and cisplatin (DHAP). Patients who are eligible and achieve a complete metabolic response should proceed to autologous stem cell transplantation in second remission. Assuming successful mobilization of stem cells, the standard high-dose regimen used prior to stem cell transplantation is carmustine, etoposide, cytarabine, and melphalan (BEAM). This is based on the 2 randomized controlled trials that compared high-dose chemotherapy followed by autologous stem cell transplantation to conventional chemotherapy in patients in whom a second remission had been achieved. Both studies showed significantly improved freedom from progression in the group receiving high-dose therapy, although the small numbers enrolled prevented conclusive demonstration of improved OS.87,88 Allogeneic transplantation may also have a role in the treatment of relapsed and refractory disease, especially for patients who suffer a further recurrence after autologous transplantation. Long-term survival benefit has not been demonstrated because of the absence of randomized trials and the potential for selection bias in cohort studies. In 1 prospective study of 78 patients with multiply-relapsed disease,
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4-year estimated PFS and OS were 24% and 43%, respectively.89 A clinically significant graft-versus-lymphoma effect after donor lymphocyte infusion has been shown,90 and with improvement in treatment-related mortality with reduced-intensity regimens, this strategy remains an important option for those with poor responses to salvage therapy.
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drug conjugates, which appear to be one means to deliver a locally concentrated cytotoxic agent while avoiding high systemic exposure. The emergent data on immunomodulating antibody therapy is also encouraging, and a new generation of trials incorporating this approach is imminent.
Authorship Conclusion The modern treatment of advanced Hodgkin lymphoma is highly effective in the majority of patients, and much current research is directed at improving the subsequent quality of life while retaining the efficacy of first-line treatment. The key developments in this area are the increasing use of FDG-PET interim scanning to guide further treatment, and the introduction of new agents such as the antibody-
Contribution: P.J. and H.M. co-wrote the manuscript. Conflict-of-interest disclosure: P.J. has received honoraria for participation in advisory boards and educational symposia from Millennium-Takeda and Bristol-Myers Squibb. The remaining author declares no competing financial interests. Correspondence: Peter Johnson, Somers Cancer Research Building, Southampton General Hospital, Tremona Rd, Southampton SO16 6YD, United Kingdom; e-mail: [email protected].
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28. Younes A, Fayad L, Romaguera J, Pro B, Goy A, Wang M. Safety and efficacy of once-per-cycle pegfilgrastim in support of ABVD chemotherapy in patients with Hodgkin lymphoma. Eur J Cancer. 2006;42(17):2976-2981. 29. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21): 1506-1514. 30. Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in advanced-stage Hodgkin’s lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383-3388. 31. Casasnovas RO, Mounier N, Brice P, et al; Groupe d’Etude des Lymphomes de l’Adulte. Plasma cytokine and soluble receptor signature predicts outcome of patients with classical Hodgkin’s lymphoma: a study from the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2007;25(13):1732-1740. 32. Sarris AH, Kliche KO, Pethambaram P, et al. Interleukin-10 levels are often elevated in serum of adults with Hodgkin’s disease and are associated with inferior failure-free survival. Ann Oncol. 1999;10(4):433-440. 33. Vassilakopoulos TP, Nadali G, Angelopoulou MK, et al. Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin’s lymphoma. Haematologica. 2001; 86(3):274-281. 34. Sauer M, Plutschow ¨ A, Jachimowicz RD, et al. Baseline serum TARC levels predict therapy outcome in patients with Hodgkin lymphoma. Am J Hematol. 2013;88(2):113-115. 35. Visco C, Nadali G, Vassilakopoulos TP, et al. Very high levels of soluble CD30 recognize the patients with classical Hodgkin’s lymphoma retaining a very poor prognosis. Eur J Haematol. 2006; 77(5):387-394. 36. Scott DW, Chan FC, Hong F, et al. Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013;31(6):692-700. 37. Chetaille B, Bertucci F, Finetti P, et al. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood. 2009;113(12): 2765-2775. 38. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875-885. 39. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 2014;32(27):3048-3058. 40. Hutchings M, Mikhaeel NG, Fields PA, Nunan T, Timothy AR. Prognostic value of interim FDGPET after two or three cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol. 2005;16(7): 1160-1168. 41. Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006;107(1):52-59. 42. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint ItalianDanish study. J Clin Oncol. 2007;25(24): 3746-3752. 43. Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the First International
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From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 1717-1723 doi:10.1182/blood-2014-09-551556 originally published online January 6, 2015
How I treat advanced classical Hodgkin lymphoma Peter Johnson and Hayley McKenzie
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