Commentary (Van Gelder/Schouten)-Follicular Lymphoma: Expanding Therapeutic Options

Ganti et al present quite an extensive overview of follicular lymphoma, with most of their emphasis on clinical practice. Many of the issues they touch upon demonstrate that we cannot draw firm conclusions about the superiority of various treatments over others, due to a variety of study limitations. These challenges to interpretation include the indolent course of the disease in most patients (and thus the long follow-up needed to draw firm conclusions), the often small number of patients in this category, the retrospective nature of most studies, differences in risk factors, and the relative lack of randomized studies. As is also the case with efficacy, the most beneficial treatment strategy in follicular lymphoma remains to be established. To clarify these problems for the clinical practitioner, we feel that some issues related to treatment goals deserve to be elaborated upon. Progression-Free vs Overall Survival
These days, oncologists consider progression-free survival to be the most important parameter by which to judge the benefit of therapy, as it usually correlates more or less with survival. It is clearly shown in the review by Ganti et al that this is not the case in follicular lymphoma. Nevertheless, the majority of studies published limit their end point to progression- free survival. First, we need to consider the issue of immediate treatment at diagnosis vs watchful waiting. Up until the present time, there has been no evidence supporting the hypothesis that immediate treatment results in a survival benefit. However, this question has only been tackled by two publications. Despite a better diseasefree survival, no benefit in overall survival was shown by either quite intensive treatment (ProMACEMOPP- ie, prednisone, methotrexate, cyclophosphamide [Cytoxan, Neosar], etoposide, mechlorethamine [Mustargen], vincristine [Oncovin], procarbazine [Matulane], prednisone- plus total nodal irradiation) or with a low-intensity regimen of chlorambucil (Leukeran) as initial treatment, compared to watchful waiting. Second, the issue of treatment intensity must be taken into account. Although higher response rates may be obtained by more intensive chemotherapy regimens or combined modalities, it remains to be seen whether these better responses translate into improved survival. Clearly, from the studies referenced in this overview, it can be concluded that follicular lymphoma is a therapysensitive disease. However, the main argument for treatment should be benefit rather than response. To Cure or Not to Cure?
Most doctors try hard to cure their patients of diseases, but at least until now, this aim has been quite difficult to achieve in patients with follicular lymphoma. Most advanced-stage patients will eventually relapse after treatment, demonstrating that cure has not been achieved. Furthermore, because of the indolent behavior of follicular lymphoma in most cases, cure is difficult to define, as relapses may occur decades later. Therefore, more observation time is needed for proper evaluation of recent, possibly more efficacious treatments that produce long progression-free survivals, such as immunochemotherapy and highdose chemotherapy with autologous stem-cell rescue. However, this longer observation time is not compatible with the career goals of many clinical researchers. Probably the same argument holds true for the lack of randomized studies. At present, only radiotherapy in early-stage disease or allogeneic stem cell transplantation seems able to eradicate all clonogenic follicular lymphoma cells, resulting in cure. In addition, a small randomized study of the value of high-dose chemoradiotherapy followed by autologous stem cell transplantation (SCT) shows an improved survival.[1] Thus, for the early-stage patient, one may start with radiotherapy, which in most patients has good efficacy, relieves symptoms, and avoids systemic toxicity. Allogeneic stem cell transplantation, on the other hand, should only be employed when the toxicity of this treatment outweighs the risk of disease progression (ie, chemoresistance). Although many clinicians today will perform allogeneic stemcell transplantation after reduced-intensity conditioning (especially when patients have undergone prior autografting, which should be considered), it still must be shown that this transplantation strategy produces results comparable to those obtained with myeloablative conditioning in terms of relapse-free survival. Persistence of Follicular Lymphoma
One intriguing question remains: Why is it that this highly treatmentsensitive disease cannot be cured by known therapies? Clearly, we are able to destroy many malignant cells; however, because of the relapsing pattern in virtually all patients, the malignant clonogenic cell in follicular lymphoma is able to "hide" from these effects. Initially, a deregulated function of the antiapoptotic bcl-2 gene by the t(14;18) translocation contributes to the development of the lymphoma, although the t(14;18) alone may not be sufficient for neoplastic transformation.[ 2] In the first instance, the antiapoptotic effect of upregulated bcl-2 can be circumvented by chemotherapy- induced upregulation of other proapoptotic molecules. However, the fact that in many cases only partial responses are obtained (and that relapses frequently occur even after "complete responses") suggests the persistence of refractory clonogenic lymphoma cells. The nature of these cells is not yet known. One possibility is that, as seen in acute myeloid leukemic blasts, a side population exists with intrinsic drug efflux capacity,[3] from which new lymphoma cells will grow. Additional chemotherapeutic resistance mechanisms could develop, like p53 gene mutations or repression of caspase transcription,[4] and these clonogenic cells will eventually give rise to chemoresistant lymphoma. The existence of such chemoresistant mechanisms in mature B-cells is supported by observations that after myeloablative treatment and allogeneic stem cell transplantation, host-type immunoglobulin production may persist for many years.[5] Speculating that malignant cells retain characteristics of their normal counterpart, we may then ask why the intrafollicular cell responding against an antigen (before it develops to an effector cell and memory cell) is so important to the human immune system that it harbors such an activated antiapoptotic machinery, making it refractory to every treatment except radiotherapy. Symptom Relief Still the Predominant Goal
In our opinion, the treatment of patients with follicular lymphoma should only be initiated in cases of symptomatic disease, irrespective of age. If the patient suffers from the disease, one should offer a treatment that is highly effective in resolving the symptoms, accompanied by the least possible toxicity and not compromising survival. For this purpose, several suitable regimens are currently at our disposal. In the meantime, the clinical usefulness of new strategies is eagerly awaited.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. 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.
2. Yarkoni S, Lishner M, Tangi I, et al: Bcell non-Hodgkin’s lymphoma: Evidence for the t(14;18) translocation in all hematopoietic cell lineages. J Natl Cancer Inst 88:973-979, 1996.
3. Wulf GG, Wang RY, Kuehnle I, et al: A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia. Blood 98:1166-1173, 2001.
4. Wagner KW, King F, Nomoto K, et al: Activation and suppression of the TRAIL death-receptor pathway in chemotherapy sensitive and resistant follicular lymphoma cells. Cancer Biol Ther 2:534-540, 2003.
5. Schouten HC, Sizoo W, Vantveer MB, et al: Incomplete chimerism in erythroid, myeloid, and lymphocyte-B lineage after T-celldepleted allogeneic mone-marrow transplantation. Bone Marrow Transplant 3:407-412, 1988.