Expert Point of View: Therapy for Hodgkin Lymphoma in the Elderly Remains Undefined


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Elderly Hodgkin lymphoma, typically defined as affecting individuals ≥ 60 years of age, remains a disease for which no standard treatment recommendation exists. This population is underrepresented in clinical studies, and survival rates in older patients with Hodgkin lymphoma are significantly and disproportionately inferior compared with younger patients.

Surveillance, Epidemiology and End Results (SEER) data reported by Brenner et al showed that Hodgkin lymphoma outcomes in elderly patients improved from 1980 to 2004.1 However, that study and others reported 5‑year progression-free survival and freedom from treatment failure rates of 30% to 45%, with 5-year overall survival rates of 40% to 55% for elderly patients.2,3 This compares with 5-year overall survival rates of > 80% to 90% for Hodgkin lymphoma populations under age 45 years.

Prior Studies

A number of analyses conducted in the 1970s to 1990s examined a variety of chemotherapy regimens, documenting modest outcomes for elderly patients with Hodgkin lymphoma.4-14 These treatments included less intensive regimens as well as therapy tailored to individual patients based on comorbidities. More intense regimens, such as BEACOPP-baseline (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], and prednisone), have been studied in elderly patients with Hodgkin lymphoma and shown to be too toxic.10,15,16 Inadequate treatment delivery for older patients may compromise the rate of cure, while comorbidities may preclude the delivery of standard chemotherapy.13,17,18

3.2.54_quote.jpgTreatment delivery and comorbidity, however, do not appear to completely explain the observed differences in the outcome of elderly patients with Hodgkin lymphoma, implicating in part a different disease biology.19 Indeed, elderly subjects with Hodgkin lymphoma frequently present with mixed-cellularity subtype, EBV positivity, advanced-stage disease, and low incidence of bulky disease. Additionally, a paucity of prognostic data exists for elderly Hodgkin lymphoma, while the potential impact of functional status on survival is largely unexplored.20 The most commonly used prognostic tool in Hodgkin lymphoma is the International Prognostic Score (IPS), which utilizes seven adverse clinical prognostic factors (including age ≥ 45 years) to predict outcome. However, only 9% of patients in that pivotal analysis were over age 55, and none were over 65 years.21

Recent Analyses

We recently conducted a multicenter retrospective analysis of elderly patients consecutively diagnosed and treated with Hodgkin lymphoma between 1999 and 2009 at five medical centers.22 We documented that that the majority of patients had a severe (ie, grade 3 or 4) comorbidity in at least one category (as scored by the Cumulative Illness Rating Scale–Geriatric system),23,24 while a significant minority of subjects had a geriatric syndrome and/or loss of activities of daily living at diagnosis.

The presence of comorbidity as a prognostic factor is particularly relevant for older patients. In a population-based study, van Spronsen et al reported that among elderly patients with Hodgkin lymphoma, 56% had a serious comorbid condition vs 13% in younger patients (< .0001).18 Additionally, Levis et al reported results of elderly patients with Hodgkin lymphoma who received lower-intensity chemotherapy6; the presence of comorbidity independently correlated with lower disease-specific and overall survival.

The most common treatment in our series was ABVD-based therapy. The overall and complete remission rates were good, with a complete remission rate of 73%; however, the incidence of bleomycin lung toxicity was 32%, which had an associated mortality rate of 25%. Moreover, the incidence of bleomycin lung toxicity was 38% vs 0% among patients who received G‑CSF (filgrastim, Neupogen) vs not, respectively (= .0001). G-CSF may induce bleomycin lung toxicity in part through recruitment of pulmonary neutrophils with associated free radical–induced pulmonary damage.25 Other series have reported an increased incidence of bleomycin lung toxicity when G-CSF was used during bleomycin-containing chemotherapy, with an associated mortality rate of 40% in patients ≥ age 40 years.26

With a median follow-up of 66 months, the 5-year overall survival for advanced-stage Hodgkin lymphoma in our series of elderly patients with Hodgkin lymphoma was < 50%. Further, most IPS factors (eg, anemia, WBC, sex, lymphopenia) were not significant on univariate analysis. On multivariate Cox regression analysis, only two factors were associated with inferior survival: (1) age ≥ 70 years and (2) loss of activities of daily living. Furthermore, we created a new survival model based on the number of these risk factors present at initial diagnosis (0, 1, or 2), showing a differential 2-year overall survival of 83%, 70%, 13%, respectively (P < .0001), and 5-year overall survival of 73%, 51%, 0%, respectively (P < .0001).

We also recently presented data among the subset of elderly patients with Hodgkin lymphoma (n = 43) who were treated on the E2496 Intergroup trial that randomly assigned patients with advanced-stage disease to six to eight cycles ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) vs Stanford V (doxorubicin, vinblastine, mechlorethamine [Mustargen], etoposide, bleomycin, vincristine, and prednisone).27 Not surprisingly, the failure-free and overall survival rates were significantly inferior for elderly patients compared with those under 60 years old, with survival rates > 30% to 35% lower for the former. Further, treatment-related mortality was comparatively higher for the elderly Hodgkin lymphoma population. The incidence rate of bleomycin lung toxicity in this prospective trial (26%) was remarkably consistent with the aforementioned retrospective series, while the bleomycin lung toxicity–related mortality rate in E2496 was 18%.

Treatment Toxicities and Alternatives

Hodgkin lymphoma is a malignancy that does not have an expected appreciable rate of treatment-related mortality. However, due in part to bleomycin and other chemotherapy-related toxicities, treatment-associated mortality is likely more common than suggested, despite the contemporary era of supportive care measures. In fact, use of granulocyte growth factors concurrently with bleomycin may exacerbate pulmonary toxicity, as noted before.

Outside of a clinical trial, I typically advocate treatment with AVD chemotherapy (doxorubicin, vinblastine, dacarbazine) for elderly Hodgkin lymphoma, withholding bleomycin a priori in most subjects over ages 60 to 65 years old. Retrospective data from Cancer and Leukemia Group B (CALGB) research suggests that bleomycin may not be needed as a component of ABVD therapy.28 If bleomycin is not administered, G‑CSF may then be used with impunity.

Another systemic therapeutic option for elderly Hodgkin lymphoma includes CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone). In a small study, Kolstad et al reported encouraging results with CHOP in this setting.29

Additionally, with respect to number of cycles of chemotherapy and use of radiotherapy (ie, for early-stage disease), I follow stage-based guidelines similar to those applied for younger patients.30

Ongoing Research

New therapeutic options, including biologically based strategies, are actively being investigated in Hodgkin lymphoma. This includes brentuximab vedotin (Adcetris), the antibody-drug conjugate, which has shown significant single-agent activity in relapsed/refractory disease.31 This and other novel agents should be explored in front-line therapy of elderly Hodgkin lymphoma through prospective clinical trials.

In addition, continued examination of the biology of the disease in elderly patients, especially the impact of Epstein-Barr virus, is warranted. Finally, results from the recently completed SHIELD study conducted by Proctor and colleagues, which included analysis of a large cohort of elderly Hodgkin patients (with functional assessments) in addition to completion of a prospective clinical trial, are eagerly awaited.32

Disclosure: Dr. Evens has received research funding from Seattle Genetics.

References

1. Brenner H, Gondos A, Pulte D: Ongoing improvement in long-term survival of patients with Hodgkin disease at all ages and recent catch-up of older patients. Blood 111:2977-2983, 2008.

2. Proctor SJ, Rueffer JU, Angus B, et al: Hodgkin’s disease in the elderly: Current status and future directions. Ann Oncol 13(suppl 1):133-137, 2002.

3. Evens AM, Sweetenham JW, Horning SJ: Hodgkin lymphoma in older patients: An uncommon disease in need of study. Oncology (Williston Park) 22:1369-1379, 2008.

4. Enblad G, Glimelius B, Sundstrom C: Treatment outcome in Hodgkin’s disease in patients above the age of 60: A population-based study. Ann Oncol 2:297-302, 1991.

5. Enblad G, Gustavsson A, Sundstrom C, et al: Patients above sixty years of age with Hodgkin’s lymphoma treated with a new strategy. Acta Oncol 41:659-667, 2002.

6. Levis A, Anselmo AP, Ambrosetti A, et al: VEPEMB in elderly Hodgkin’s lymphoma patients. Results from an Intergruppo Italiano Linfomi (IIL) study. Ann Oncol 15:123-128, 2004.

7. Levis A, Depaoli L, Bertini M, et al: Results of a low aggressivity chemotherapy regimen (CVP/CEB) in elderly Hodgkin’s disease patients. Haematologica 81:450-456, 1996.

8. Weekes CD, Vose JM, Lynch JC, et al: Hodgkin’s disease in the elderly: Improved treatment outcome with a doxorubicin-containing regimen. J Clin Oncol 20:1087-1093, 2002.

9. Zinzani PL, Magagnoli M, Bendandi M, et al: Efficacy of the VBM regimen in the treatment of elderly patients with Hodgkin’s disease. Haematologica 85:729-732, 2000.

10. Mir R, Anderson J, Strauchen J, et al: Hodgkin disease in patients 60 years of age or older. Histologic and clinical features of advanced-stage disease. The Cancer and Leukemia Group B. Cancer 71:1857-1866, 1993.

11. Stark GL, Wood KM, Jack F, et al: Hodgkin’s disease in the elderly: A population-based study. Br J Haematol 119:432-440, 2002.

12. Engert A, Ballova V, Haverkamp H, et al: Hodgkin’s lymphoma in elderly patients: A comprehensive retrospective analysis from the German Hodgkin’s Study Group. J Clin Oncol 23:5052-5060, 2005.

13. Erdkamp FL, Breed WP, Bosch LJ, et al: Hodgkin disease in the elderly. A registry-based analysis. Cancer 70:830-834, 1992.

14. Roy P, Vaughan Hudson G, Vaughan Hudson B, et al: Long-term survival in Hodgkin’s disease patients. A comparison of relative survival in patients in trials and those recorded in population-based cancer registries. Eur J Cancer 36:384-389, 2000.

15. 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 16:124-131, 2005.

16. Levis A, Depaoli L, Urgesi A, et al: Probability of cure in elderly Hodgkin’s disease patients. Haematologica 79:46-54, 1994.

17. Janssen-Heijnen ML, van Spronsen DJ, Lemmens VE, et al: A population-based study of severity of comorbidity among patients with non-Hodgkin’s lymphoma: Prognostic impact independent of International Prognostic Index. Br J Haematol 129:597-606, 2005.

18. van Spronsen DJ, Janssen-Heijnen ML, Lemmens VE, et al: Independent prognostic effect of co-morbidity in lymphoma patients: Results of the population-based Eindhoven Cancer Registry. Eur J Cancer 41:1051-1057, 2005.

19. Klimm B, Diehl V, Engert A: Hodgkin’s lymphoma in the elderly: A different disease in patients over 60. Oncology (Williston Park) 21:982-990, 2007.

20. Boll B, Bredenfeld H, Gorgen H, et al: Phase II study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma. Blood September 13, 2011 (early release online).

21. 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 339:1506-1514, 1998.

22. Evens AM, Helenowski I, Ramsdale E, et al: A retrospective multicenter analysis of elderly Hodgkin lymphoma: Outcomes and prognostic factors in the modern era. Blood November 23, 2011 (early release online).

23. Mistry R, Gokhman I, Bastani R, et al: Measuring medical burden using CIRS in older veterans enrolled in UPBEAT, a psychogeriatric treatment program: A pilot study. J Gerontol A Biol Sci Med Sci 59:1068-1075, 2004.

24. Parmelee PA, Thuras PD, Katz IR, et al: Validation of the Cumulative Illness Rating Scale in a geriatric residential population. J Am Geriatr Soc 43:130-137, 1995.

25. Azoulay E, Herigault S, Levame M, et al: Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis. Crit Care Med 31:1442-1448, 2003.

26. Martin WG, Ristow KM, Habermann TM, et al: Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma. J Clin Oncol 23:7614-7620, 2005.

27. Evens AM, Hong F, Gordon LI, et al: Efficacy and tolerability of ABVD and Stanford V for elderly advanced-stage Hodgkin lymphoma (HL): Analysis from the phase III randomized U.S. Intergroup Trial E2496. J Clin Oncol 29(suppl):Abstract 8035, 2011.

28. Canellos GP, Duggan D, Johnson J, et al: How important is bleomycin in the adriamycin + bleomycin + vinblastine + dacarbazine regimen? J Clin Oncol 22:1532-1533, 2004.

29. Kolstad A, Nome O, Delabie J, et al: Standard CHOP-21 as first line therapy for elderly patients with Hodgkin’s lymphoma. Leuk Lymphoma 48:570-576, 2007.

30. Hoppe RT, Advani RH, Ai WZ, et al: Hodgkin lymphoma. J Natl Compr Canc Netw 9:1020-1058, 2011.

31. Younes A, Bartlett NL, Leonard JP, et al: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812-1821, 2010.

32. Proctor SJ, White J, Jones GL: An international approach to the treatment of Hodgkin’s disease in the elderly: Launch of the SHIELD study programme. Eur J Haematol 75(suppl 66):63-67, 2005.


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