Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma (NHL) in the United States. Of the nearly 70,000 new cases of NHL anticipated in 2013,1 approximately 7,000 to 13,000 (10%–19%) will be follicular lymphoma, by recent estimates.2-5 For many years, the median overall survival of patients with follicular lymphoma was 10 years. However, since the introduction of rituximab (Rituxan) and radioimmunotherapy, the survival of patients with follicular lymphoma has significantly improved.6,7
More recently, the addition of rituximab as a maintenance therapy has improved progression-free survival after first-line therapy.8 With ongoing efforts to develop more effective front-line therapies, incorporating agents such as bendamustine (Treanda) and bortezomib (Velcade), there is hope for even further improvement.9
For patients with relapsed/refractory follicular lymphoma, outcomes are not nearly as favorable. Using various regimens such as rituximab, bortezomib/rituximab, bendamustine, bendamustine/bortezomib/rituximab, or radioimmunotherapy, the median progression-free survival in several important studies of relapsed/refractory follicular lymphoma has generally been in the vicinity of 1 year.10-15 In some older studies of rituximab-naive patients, results were more favorable, but today nearly all relapsed/refractory follicular lymphoma patients have had some prior exposure to rituximab. Many will even have rituximab-resistant disease at the time of relapse or progression.
Autologous Transplantation
Autologous hematopoietic cell transplantation has been utilized in follicular lymphoma for decades. While autologous hematopoietic cell transplantation is not currently recommended as consolidation of first remission for follicular lymphoma, the situation is quite different for those with relapsed/refractory follicular lymphoma.
One prospective randomized trial in relapsed/refractory disease showed a clear benefit in progression-free survival and a nearly significant improvement in overall survival in favor of autologous hematopoietic cell transplantation vs standard chemotherapy alone.16 In that study, the standard therapy arm had a median progression-free survival of about 1 year, and the autologous hematopoietic cell transplantation arms had a median progression-free survival in excess of 4 years.
Several single-center and multicenter retrospective studies have evaluated autologous hematopoietic cell transplantation for follicular lymphoma. Eight studies of more than 100 patients have been published since 2003; they collectively include over 2,500 patients.17,31 In most of these studies, the progression-free survival curve shows a plateau at around 5 years, with 30% to 50% of patients achieving long-term (5- to 15-year) remissions.
In the three most recent studies, progression-free survival was in the 48% to 56% range at 3 to 5 years.18,19,31 Importantly, in the National Comprehensive Cancer Network (NCCN) study by Evens et al, results were similar in an analysis restricted to patients who had prior rituximab exposure.18 The range of treatment-related mortality in the eight studies since 2003 was 2% to 14%, but only 2% to 3% in the three most recent studies.
While treatment-related myelodysplastic syndromes and acute myeloid leukemia can occur after autologous hematopoietic cell transplantation for follicular lymphoma, the risk is relatively low: 3% to 8% at 5 to 15 years post-transplant using conditioning regimens that do not employ total-body irradiation.20 Importantly, three separate studies suggest improved survival for follicular lymphoma patients who undergo autologous hematopoietic cell transplantation in second or third remission, vs later in the disease course, indicating that early referral for transplantation consideration is prudent.18,21,22
Allogeneic Transplantation
With allogeneic hematopoietic cell transplantation, recent results are also quite encouraging. A shift has occurred such that the majority of allogeneic hematopoietic cell transplantation procedures now performed utilize nonablative or reduced-intensity conditioning regimens. Results from five recent studies, including one multicenter study, show that treatment-related mortality with reduced-intensity conditioning is now in the 8% to 17% range at 1 year. In addition, progression-free survival in these studies was in the 57% to 85% range with median follow-up between 3 and 11 years.23-26,31
Underused Strategy
Given the low treatment-related mortality, favorable rates of long-term remission, and better results than expected with conventional therapy, one might expect that hematopoietic cell transplantation would be commonly utilized for follicular lymphoma. However, this is not the case.
According to a recent analysis of the National LymphoCare Study, fewer than 3% of patients undergoing second-line therapy for follicular lymphoma were treated with a strategy that included hematopoietic cell transplantation.27 Even if one assumes that only 30% to 50% of patients considered for second-line therapy would be hematopoietic cell transplantation candidates, this would still indicate that 10% or fewer of potential hematopoietic cell transplantation candidates are referred to a transplant center during second-line therapy.
Similarly, data from the Center for International Blood and Marrow Transplant Research (CIBMTR) shows that over the past 10 years, approximately 370 hematopoietic cell transplantations occur in the United States for follicular lymphoma each year (240 autologous and 130 allogeneic hematopoietic cell transplantations).28,29 Assuming that only 80% of U.S. hematopoietic cell transplantations are captured by the CIBMTR (a conservative estimate), as many as 460 to 470 patients may actually undergo hematopoietic cell transplantation yearly.
Now, let’s assume there are about 10,000 new cases of follicular lymphoma in the United States each year.1-5
Since the median age at diagnosis is 63, let’s further assume that about 40% of follicular lymphoma patients will, by the time they need second- or third-line therapy, remain candidates for hematopoietic cell transplantation by age alone.
Let’s further assume that 40% of these age-eligible patients will be found to be poor transplant candidates (due to comorbid conditions, or problems with stem cell collection and/or donor availability). This leaves approximately 2,400 follicular lymphoma patients each year who should be hematopoietic cell transplantation candidates. Yet, the number who actually undergo transplantation is less than 20% of that figure.
Potential Explanations
So, how can we explain the relatively low use of hematopoietic cell transplantation in follicular lymphoma? There are several potential explanations. In a general sense, (a) patients may be referred but then be found to be poor transplantation candidates, (b) patients may decline transplantation, or (c) patients may not be referred for transplantation evaluation at all.
In scenarios (a) and (b), the dropout occurs predominantly at the transplant center after an initial evaluation. We certainly have patients like this at our center. In my experience, however, this occurs very infrequently. It seems likely that the major factor is that patients are not being referred in the first place.
Why might this be? As a physician working at a transplant center, I cannot be sure. My suspicion is that many community oncologists are reluctant to refer patients for hematopoietic cell transplantation evaluation. In rare cases, this may stem from a concern about potentially losing a patient to the tertiary care center. However, among the community oncologists that I know and collaborate with, I sense a deep commitment to doing what is best for the patient.
So why are patients not referred? I believe that, for many community oncologists, their primary exposure to hematopoietic cell transplantation was during fellowship training. These experiences tended to be heavily weighted toward inpatient work, which involved dealing with patients suffering from complications of transplantation.
In some cases, this exposure occurred in an era when our ability to prevent and treat complications was more limited. They saw many fewer patients doing well after hematopoietic cell transplantation, since those patients spend much less time as inpatients. This experience, consciously or subconsciously, may lead to a perception that hematopoietic cell transplantation should be a treatment of “last resort,” and, in turn, to a reluctance to refer until late in the disease course.
Additionally, depending on where or when they trained, a practicing community oncologist may not have witnessed the important strides made in hematopoietic cell transplantation in the past 10 to 15 years, including less toxic conditioning regimens, more effective stem cell mobilization techniques, high-resolution HLA typing, and breakthroughs in supportive care. These developments, collectively, have led to a decrease in treatment-related mortality after both autologous and allogeneic hematopoietic cell transplantation, and an ability to offer transplantation to a much wider range of patients.
Nontransplant Options
At the same time, the past 15 years have seen an ever-expanding arsenal of non-transplant therapies for lymphoma such as rituximab, bendamustine, radioimmunotherapy, bortezomib, lenalidomide (Revlimid), and emerging agents such as the Bruton’s tyrosine kinase inhibitors, PI3-kinase inhibitors, mTOR inhibitors, new monoclonal antibodies, and antibody-drug conjugates. The availability of multiple nontransplant therapies makes it easier to put off the transplant referral. Many of these nontransplant therapies are marketed aggressively. Hematopoietic cell transplantation does not get marketed in the same way and so may not come to mind as readily when considering treatment options.
‘Selection Bias’
Another possible reason for patients not being referred for hematopoietic cell transplantation is that transplant studies are often criticized for being subject to patient selection bias. It is certainly true that retrospective studies and single-arm phase II trials are subject to bias, especially when comparing across trials or using historical controls. I fully agree that we need more high-quality prospective randomized phase III trials evaluating hematopoietic cell transplantation in various settings.
So one may pessimistically look at the transplantation studies I have cited above and think, “patient selection bias.” My response would be, “Send us the patients, and let us select!”
Transplant physicians spend their days trying to identify those patients most likely to benefit from, and least likely to be harmed by, a transplant procedure. Whatever thought process went into selecting patients for the studies cited above, a very similar thought process will be applied to the patients you send to a transplant center. After a discussion of the risks and benefits, I believe that many follicular lymphoma patients would be pleased to be “selected” to have a treatment that gives them the best chance for long-term remission and survival.
Educational Efforts
Those of us who work in transplant centers should strive to ensure that graduating hematology/oncology fellows have a balanced exposure to hematopoietic cell transplantation. We should also make a stronger effort to keep our community oncology colleagues informed of the advances and current state of our field, so that patients can be offered all options available, including hematopoietic cell transplantation.
Currently, based on available evidence, I recommend that follicular lymphoma patients under age 70, in first or second relapse, be referred for a transplant evaluation. Comorbidity can now be quantified using the well-validated Hematopoietic Cell Transplant Comorbidity Index (HCT-CI). Patients with an HCT-CI score of 3 or higher have increased risk of treatment-related mortality30 and may be found to be poor transplant candidates.
As new, more “targeted” therapies become available, the role of hematopoietic cell transplantation may evolve. However, despite the great enthusiasm for new and emerging agents in follicular lymphoma, their ability to produce long-term remission remains uncertain. For now, there is no therapy besides hematopoietic cell transplantation with as impressive a track record for relapsed/refractory follicular lymphoma, and we should not ignore that when recommending treatments to our patients. ■
Dr. Fenske is Associate Professor of Medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, Milwaukee.
Disclosure: Dr. Fenske reported no potential conflicts of interest.
References
1. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 63:11-30, 2013.
2. Clark C, O’Malley CO: Non-Hodgkin lymphoma, in Ries LAG, Young JL, Keel GE, et al (eds): SEER Survival Monograph: Cancer Survival among Adults: U.S. SEER Program, 1988-2001, Patient and Tumor Characteristics. Bethesda, Maryland, National Cancer Institute, SEER Program, NIH Pub. No. 07-6215, 2007.
3. Siegel R, DeSantis C, Virgo K, et al: Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 62:220-241, 2012.
4. Morton LM, Wang SS, Devesa SS, et al: Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 107:265-276, 2006.
5. Groves FD, Linet MS, Travis LB, et al: Cancer surveillance series: Non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Inst 92:1240-1251, 2000.
6. Fisher RI, LeBlanc M, Press OW, et al: New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447-8452, 2005.
7. Nooka AK, Nabhan C, Zhou X, et al: Examination of the Follicular Lymphoma International Prognostic Index (FLIPI) in the National LymphoCare Study (NLCS): A prospective US patient cohort treated predominantly in community practices. Ann Oncol 24:441-448, 2013.
8. Salles G, Seymour JF, Offner F, et al: Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. Lancet 377:42-51, 2011.
9. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: An open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203-1210, 2013.
10. Coiffier B, Osmanov EA, Hong X, et al: Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: A randomised phase 3 trial. Lancet Oncol 12:773-784, 2011.
11. Kahl BS, Bartlett NL, Leonard JP, et al: Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: Results from a multicenter study. Cancer 116:106-114, 2010.
12. Fowler N, Kahl BS, Lee P, et al: Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: The phase II VERTICAL study. J Clin Oncol 29:3389-3395, 2011.
13. Fisher RI, Kaminski MS, Wahl RL, et al: Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol 23:7565-7573, 2005.
14. Leahy MF, Turner JH: Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients. Blood 117:45-52, 2011.
15. Wiseman GA, Witzig TE: Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Cancer Biother Radiopharm 20:185-188, 2005.
16. Schouten HC, Qian W, Kvaloy S, et al: High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918-3927, 2003.
18. Evens AM, Vanderplas A, LaCasce AS, et al: Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: A comprehensive analysis from the NCCN Lymphoma Outcomes Project. Cancer, 2013 (in press).
19. Peters AC, Duan Q, Russell JA, et al: Durable event-free survival following autologous stem cell transplant for relapsed or refractory follicular lymphoma: Positive impact of recent rituximab exposure and low-risk Follicular Lymphoma International Prognostic Index score. Leuk Lymphoma 52:2124-2129, 2011.
20. Hake CR, Graubert TA, Fenske TS: Does autologous transplantation directly increase the risk of secondary leukemia in lymphoma patients? Bone Marrow Transplant 39:59-70, 2007.
21. Rohatiner AZ, Nadler L, Davies AJ, et al: Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: Long-term follow-up. J Clin Oncol 25:2554-2559, 2007.
22. Vose JM, Bierman PJ, Loberiza FR, et al: Long-term outcomes of autologous stem cell transplantation for follicular non-Hodgkin lymphoma: Effect of histological grade and Follicular International Prognostic Index. Biol Blood Marrow Transplant 14:36-42, 2008.
23. Shea T, Johnson J, Westervelt P, et al: Reduced-intensity allogeneic transplantation provides high event-free and overall survival in patients with advanced indolent B cell malignancies: CALGB 109901. Biol Blood Marrow Transplant 17:1395-1403, 2011.
24. Thomson KJ, Morris EC, Milligan D, et al: T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma. J Clin Oncol 28:3695-3700, 2010.
25. Khouri IF, McLaughlin P, Saliba RM, et al: Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111:5530-5536, 2008.
26. Khouri IF, Saliba RM, Erwin WD, et al: Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood 119:6373-6378, 2012.
27. Link BK, Miller TP, Byrtek M, et al: Second-line therapy in follicular lymphoma in the United States: Report of NLCS observational study. 2011 ASCO Annual Meeting. Abstract 8049. Presented June 6, 2011.
28. Pasquini MC, Wang Z: Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides. Available at http://www.cibmtr.org. Accessed July 2, 2013.
29. Pasquini MC: personal communication, June 2013.
30. Sorror ML, Sandmaier BM, Storer BE, et al: Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies. JAMA 306:1874-1883, 2011.
31. Robinson SP, Canals C, Luang JJ, et al: The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: An analysis from the Lymphoma Working Party of the EBMT. Bone Marrow Transplantation. June 17, 2013 (early release online).
