Front-Line Treatment of Indolent Non-Hodgkin Lymphomas




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Front-Line Treatment of Indolent Non-Hodgkin Lymphomas

Igor Aurer


Division of Hematology, Department of Internal Medicine, University Hospital Center and Medical School, Zagreb, Croatia.
Indolent non-Hodgkin lymphomas (NHLs) are slowly growing neoplasms derived from peripheral lymphoid cells and characterized by a prolonged clinical course [1]. Many patients have active disease for months or even years with a good quality of life (QoL) and no or only minimal symptoms. In Caucasians and areas of moderate climate, almost all cases are of B cell origin. This article reviews available front-line treatment options for patients with newly diagnosed indolent B cell NHL (B-NHL).

The adoption of Classification-Revised European-American Lymphoma (REAL) and World Health Organization (WHO) classifications has significantly improved the ability of hematopathologists to distinguish different types of lymphomas [2]. The most frequent types of indolent B-NHL are follicular lymphoma (FL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL). The average age at diagnosis is approximately 65 years. Many patients are elderly and have significant comorbidities that affect their QoL and ability to tolerate treatment. Indolent NHLs respond well to radiotherapy and to a variety of chemotherapeutic regimens but are incurable with standard treatment due to a propensity for relapse, except for a small percentage of patients presenting with localized, ie stage I disease. Generally, the course of the disease is characterized by multiple relapses and remissions that tend to become ever shorter until the patient finally dies of infection, NHL, or an unrelated disorder. Randomized studies have shown that deferring treatment in patients with asymptomatic, slow-growing disease until progression does not jeopardize their survival [3–5]. If this “watchful waiting” approach is used, approximately 15% of patients die from unrelated causes without ever needing lymphoma treatment. However, this method is not universally accepted, as will be discussed later in more detail.

A variety of chemotherapy regimens has been advocated for treatment of indolent B-NHLs. While more aggressive regimens usually result in higher complete remission rates and sometimes in improved event-free survival (EFS) rates or similar [6–10], only a single trial using intensive chemotherapy and interferon maintenance has shown a difference in overall survival (OS) rates in favor of a certain front-line chemotherapy regimen [11]. In addition, up-front intensification with high-dose chemotherapy with or without stem cell support does not seem to improve OS, but significantly increases toxicity [12–15]. This is reflected in the well-known results of long-term follow-up of patients with FL treated with different chemotherapy regimens at Stanford University, CA, USA, which shows equivalent survival rates over a 30-year period [16]. Therefore, measures other than OS rates should be used in deciding upon the best front-line treatment for a patient with disseminated indolent NHL.

[AU: Peer review comment: “The information included is related to CHOP but many have adopted the addition of rituximab along with most of the chemotherapy regimens used to treat low-grade lymphomas. Therefore, you may wish to consider adding the data that is available regarding R-CHOP along with your data on CHOP.”

Response: The disucssion above relates to chemotherapy only, not to a combination of chemotherapy and immunotherapy. I believe that this is clear from the text, but if it isn't, please feel free to add this statement.]
Follicular lymphoma (FL): the big guy on the block [H1]

FL is the most frequent indolent B-NHL accounting for approximately 30% of all NHL cases [2]. FLs are divided into three grades (I, II, and III) depending on the number of large cells (“centroblasts”) per average high-power field of a microscope. FLs are divided into three groups (follicular, mixed, and diffuse) based on their growth pattern. While grade I and II FLs are generally regarded as indolent and grade III FLs as aggressive, there is no consensus on the distinction between small cells (“centrocytes”) and centroblasts making the grading irreproducible and of doubtful clinical significance. In addition, growth pattern does not seem to be of major clinical importance except for type IIIB. Those are grade III FLs with a predominantly diffuse growth pattern. Their biological and clinical characteristics are indistinguishable from diffuse large B-cell lymphoma (DLBCL) and should be regarded and treated as such. Some patients, mostly with grade I FL, experience spontaneous remissions, usually of short duration.


Starting treatment: “watchful waiting” versus “waiting and worrying” [H2]

Most academic hematologists, especially in Europe, advocate the concept that patients with disseminated indolent NHL, including FL, should not be treated unless they are symptomatic, have a rapidly growing or high tumor burden, or have signs of suppression of normal hematopoiesis [1]. An academic minority and a somewhat larger percentage of practicing hematologists disagree, occasionally leading to heated debates. Arguments in favor of “watchful waiting” come from trials that have used chemotherapy that is not standard today and have not included immunotherapy [3–5]. Therefore, it is possible to argue that treating these patients with a more effective therapy such as R-CHOP (combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) might result in a different outcome. An argument in favor of watchful waiting is that in most trials there was no evidence at all of an improvement in the early treatment arm. Another argument in favor of this strategy comes from results of long-term follow-up of FL patients from Stanford University, which showed no improvement in results from different treatment regimens over a period of 3 decades [16]. This would indicate that early treatment with more aggressive chemotherapy does not improve the most important outcome measure, the OS rate. Unfortunately, the latter argument can be a double-edged sword, because cohort studies from other groups show an improvement in event-free survival (EFS) rates and somewhat less pronounced, but still significant, improvement in OS rates over different treatment periods [17].

This question can be addressed in a slightly different way, by asking whether there could be another reason, besides an increase in the tumor mass, that delaying treatment might be harmful. For example, are tumor cells expected to acquire mutations that will make them less sensitive to treatment? Knowing the biology and indolent course of the disease, the answer is most probably not. Therefore, it seems safe, prudent, and in accordance with evidence-based medical principles to delay treatment of disseminated FL until one of the criteria for beginning treatment is fulfilled. However, it should also be remembered that early treatment is not detrimental and that there will be patients and physicians for whom watchful waiting will be waiting and worrying. For these patients, early treatment might be a more acceptable alternative.
Rituximab: the gold standard [H2]

The only drug shown to significantly improve OS rates, when used as part of a front-line treatment regimen, is rituximab. Trials comparing cyclophosphamide, vincristine, and prednisone (CVP) with rituximab (R)-CVP; CHOP with R-CHOP; mitoxantrone, chlorambucil, and prednisone (MCP) with R-MCP; and cyclophosphamide, doxorubicin, etoposide, prednisone, and interferon-α (CHVP) with R-CHVP have all shown that the addition of rituximab improves not only complete remission and EFS rates but also the rate of OS (Table 1) [18–21]. The improvement is remarkably similar across the trials, and amounts to approximately 2.5% per year of follow-up (that is, 2.5% at 1 year, 5% at 2 years etc.), at least during the limited published follow-up period of about 4 years [22]. The addition of rituximab to chemotherapy does not lead to an increase in the incidence and severity of side effects. Therefore, rituximab should definitely be part of any front-line treatment for FL.


Choosing rituximab’s partners: “speaking softly” versus “carrying a big stick”[H2]

Should front-line rituximab treatment be given as monotherapy or in combination with chemotherapy? In the latter case, what is the most appropriate chemotherapy regimen? What is there to base our answers on, given that the lack of randomized clinical trials reporting differences in OS rates? In practice, there are multiple answers to these questions. Results of more frequently used front-line regimens are presented in Table 2. Rituximab monotherapy with a short maintenance results in outcomes similar to those achieved with R-CVP or R-chlorambucil without maintenance [18,23,24]. Rituximab monotherapy is somewhat less toxic but more expensive. Response rates to R-CHOP are >90%, and the EFS is 5–6 years, more than twice that observed with R-CVP [19]. Data are emerging suggesting that fludarabine-based combinations, such as fludarabine and mitoxantrone (FM) result in even slightly better outcomes [25]. All these treatments are generally well tolerated, with CHOP having more hematological toxicity and fludarabine-based combinations resulting in more infectious toxicity.

There are two opposing approaches for deciding on the optimal front-line treatment, although various compromises between them are possible. The first approach is to start with the mildest possible treatment regimen and then, when the patient stops responding, switch to another, more aggressive regimen. With this approach, financially conscientious healthcare systems most frequently choose to use R-CVP (although it might be rituximab combined with chlorambucil and steroids), and those not limited by tight budgets tend to prefer rituximab monotherapy. When patients stop responding, they can be switched either to R-CHOP, a rituximab and fludarabine containing combination, such as R-FND (fludarabine, mitoxantrone, dexamethasone) or R-FCM (fludarabine, cyclophosphamide, mitoxantrone), or to radioimmunotherapy.

The second approach is to give the most aggressive therapy that still enables the patient to continue with his routine daily activities. The thinking behind this is that being in complete remission and having a long EFS are important favorable outcomes. As there are at least two different treatment classes that are not cross-resistant, giving one of them up-front does not jeopardize the outcome of later salvage treatment followed by an intensive consolidation such as transplantation or radioimmunotherapy. There is financial argument in favor of this approach which, to my knowledge, has not previously been raised. For patients receiving R-CHOP the median time to next anti-lymphoma treatment is approximately 6 years and in those receiving R-CVP 3.5 years [18,19]. This means that with R-CHOP there is an average delay of second-line treatment for approximately 2.5 years. As salvage treatments also contain rituximab, this delay results in a substantial financial gain for the healthcare system. Of course, this argument is only valid for patients able to tolerate more aggressive treatment without significant side effects who do not have substantial comorbidity that might reduce their life expectancy and QoL, irrespective of the outcome of FL treatment. On the other hand, there is a possibility that patients treated with front-line CHOP might have a higher frequency of serious late side-effects such as cardiac failure or secondary leukemias, than those treated with CVP. Unfortunately, there are no randomized trials comparing R-CVP with R-CHOP to prove or disprove these arguments although one such trial is being planned in Poland.

Regarding more aggressive protocols, essentially there is a choice between CHOP and fludarabine-based regimens. Other treatment types (for example MCP, CHVP, or bendamustine-containing combinations) are not widely used outside of certain cooperative groups or geographic regions. Available data from comparative trials suggest that the superiority of rituximab and fludarabine combinations in comparison with R-CHOP is mainly related to increased complete remission but probably not EFS rates [25]. There is a dearth of data on outcomes of patients receiving first a fludarabine-containing regimen and then CHOP. Therefore, for the time being it seems safer to give CHOP first and reserve the fludarabine regimens for later than vice-versa.

[AU: Peer review comment: “While there are those who use R-CHOP frontline in the management of low-grade lymphomas, there are many oncologists in academic settings who would disagree with the use of R-CHOP frontline and do not feel it should be front-line therapy in the management of low-grade lymphomas. We certainly have many patients with follicular lymphoma who live >10 years and therefore, long term effects of therapy must be considered. Although, I can not disagree that R-CHOP is used as front-line, it is not a panacea and you may want to consider the pros and cons of this therapy as frontline.”]

Response: As requested, I have added a sentence (in green) related to the possible late side-effects of CHOP.
Non-FL indolent NHL: the orphans [H1]

Small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL) are non-FL indolent NHLs [3]. If extranodal and splenic MZLs are excluded, these entities are infrequent and represent approximately 10% of all NHL cases. Before the era of rituximab treatment, their prognosis was inferior to FL, with approximately 60% of patients remaining alive after 5 years and an average life expectancy of 6–7 years [26]. During this time and that of the widespread use of the REAL and WHO classifications, this patient population was usually grouped with FL patients and treated similarly [6,7]. Since the distinction between different indolent lymphoma types became more important to researchers, many cooperative groups stopped enrolling patients with these diseases into randomized clinical trials; therefore, it has been extremely difficult to collect enough cases to achieve sufficient statistical power. Even in groups that continued to perform randomized trials within the whole indolent NHL population, the number of patients with specific non-FL types has been too small to reach statistically firm conclusions specific to that lymphoma type [8,9,12,24,27]. For this reason, there are no solid data regarding treatment efficacies in this patient population and little hope of finding some in the near future. Phase II trials indicate that non-FL indolent lymphomas respond to rituximab, although possibly less favorably than FLs [24,28–31]. This difference seems to be more pronounced in patients with relapsed or refractory disease than in previously untreated cases [28,32]. However, indolent non-FL lymphomas also respond less well to other treatment modalities, as evidenced by the inferior survival rates of patients with SLL, MZL, and LPL in comparison with FL during the pre-rituximab era [26]. Given that none of the currently available treatments specifically targets one type of NHL only, it seems reasonable to accept the conclusions that are emerging from Phase II trials and assume that non-FL indolent lymphomas behave similarly to FL, albeit not quite so favorably. This means that patients with SLL, nodal MZL, and LPL should be treated in the same way as patients with FL, that is, with watchful waiting until an indication for treatment emerges upon which treatment with rituximab alone or in combination with chemotherapy is advised [AU: Words added to the above sentence to incorporate peer review comments. Is this OK? And the sentence below has been reworded]



Response: Yes, it’s perfectly OK. R-CHOP is the author’s recommendations (see FL: the big guy on the block, pXX) except for those for whom age and comorbidity significantly reduce the expected advantages of a more aggressive approach.
Splenic marginal zone lymphomas [H2]

Splenic marginal zone lymphomas infrequent lymphomas seem to respond less well to chemotherapy than their nodal counterparts. Splenectomy can be a effective treatment and improve the rate of response to other types of treatment, even in patients with disseminated disease and a leukemic presentation [33].


Localized indolent NHL: the lucky few [H1]

Occasionally, patients with indolent NHL are identified while still in stage I. Approximately 65% of these patients are disease free 10 years after involved-field (IF) radiotherapy, most are cured [34–36]. Available evidence suggests that adding chemotherapy, prior to or after radiation, does not improve OS rates [37,38]. This is not surprising in view of the lack of effect of chemotherapy on the OS rate in disseminated disease. There are no data on the effect of rituximab in this setting. Therefore, current evidence suggests that IF radiotherapy is still the optimal treatment in these patients. However, there is no consensus about the most effective dose of radiotherapy. Many radiotherapists would opt for a full 40-Gy dose, although there is a trial, indicating that a reduction to 24 Gy is safe [39]. Patients with a systemic relapse after IF irradiation seem to have an inferior prognosis than previously untreated patients with primary disseminated disease [40].


Localized extranodal (stage IE) marginal-zone lymphomas – mucosal-associated lymphoid tissue lymphomas: the goodies [H1]

Extranodal MZLs or mucosal-associated lymphoid tissue (MALT) lymphomas differ from other types of NHLs in that many of them are antigen-driven and regress once the causative antigen is eliminated. The stomach is most frequently affected and the tumor is usually caused by chronic Helicobacter pylori infection. Controlled clinical trials have shown that treatment directed against H. pylori leads to MALT lymphoma regression in approximately two-thirds of cases, even if the bacteria cannot be identified in gastric biopsies [41–43]. Another possibility is to use gastric irradiation in H. pylori-negative patients. The addition of low-intensity chemotherapy does not improve outcomes. Localized gastric MALT lymphoma has a very favorable prognosis, the disease-specific mortality was 0 in a randomized trial. Therefore, even in patients who initially fail anti-H. pylori therapy, aggressive treatment does not seem to be indicated.

Ocular adnexa are another frequent localization of MALT lymphomas. Some, but not all studies suggest Chlamydia psittaci to be the culprit [44,45]. The observed differences might result from variations in exposure to infectious agents in different geographical areas. While these discrepancies are being resolved, it seems reasonable to add a course of antibiotics (azitromycin or tetracyclines) to the treatment directed against lymphoma, at least for patients coming from geographical areas with unknown or high C. psittaci positivity rates. Patients with localized ocular MALT lymphomas are routinely treated with radiotherapy but uncontrolled studies suggest that similar results can be obtained with low-intensity chemotherapy, such as CVP or chlorambucil [46,47]. As the prognosis of these patients is excellent, aggressive front-line treatment is not indicated.
Future directions: the crystal globe [H1]

The PRIMA (Primary Rituximab and Maintenance) trial, investigating the role of rituximab maintenance after front-line immunochemotherapy in disseminated FL has recently been closed for accrual. First results are expected in the second half of 2008. Most hematologists expect results to be positive, although few would expect that the combination of induction immunochemotherapy and rituximab maintenance to result in a cure. A randomized trial of consolidation with radioimmunotherapy has also recently been closed; results from the Phase II trials are encouraging [48]. The combination of these two approaches might have a more profound effect on indolent NHL than either method alone, but this should first be tested in later disease phases; one such trial is to begin shortly.



Other monoclonal antibodies are also under investigation for the treatment of NHL, such as those targeting CD22 and CD80, in addition to enhanced versions of anti-CD20 [AU: this sentence has been added to incorporate peer review comments. Is this OK?]. Response: Yes, it’s perfectly OK. Another interesting alternative could be adding lenalidomide, or less optimistically bortezomib, to rituximab maintenance. And while in this era of targeted therapy cytotoxic agents seem to be old-fashioned, interesting data are emerging to suggest that bendamustine will be a better alternative to cyclophosphamide in combination chemotherapy regimens in the years to come [49].
Conclusion [H1]

As disseminated indolent NHLs are incurable with standard treatment, the choice of front-line regimen for each patient must take into account factors that might influence the need and possibilities for subsequent therapies, primarily age and comorbidity, as well as economic factors. Rituximab is the only drug shown to increase the OS rate in this patient population and should be part of every front-line regimen. Pending more experience with front-line fludarabine-containing regimens, in comparison with other frequently used therapies, indirect evidence suggests that R-CHOP may result in better EFS rates and longer delays in time to next treatment, thus reducing total treatment costs [AU: Words have been added to the above sentence to incorporate peer review comments. Is this OK?]. Response: Yes, it’s perfectly OK. Unfortunately, evidence for this is only indirect. In elderly and unfit patients in whom CHOP is expected to significantly reduce QoL or whose life expectancy makes it unlikely that they will require multiple treatment lines, less intensive regimens, such as R-CVP or R-chlorambucil with or without steroids, may be more useful. If, in such patients, treatment costs are not an issue, rituximab monotherapy may result in comparable results with even less toxicity.

Splenectomy should be considered in patients with splenic MZL in need of treatment. Localized indolent nodal NHLs should be treated with IF radiotherapy, gastric MALT lymphomas with treatments directed against H. pylori without the addition of chemotherapy and ocular MALT lymphomas with radiotherapy or low-intensity chemotherapy, possibly with the addition of antibiotics that are active against C. psittaci.
Address for correspondence: Dr Igor Aurer, Division of Hematology, University Hospital Center Rebro, Kispaticeva 12, 10000 Zagreb, Croatia. Email: aurer@mef.hr
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Table 1. Results of randomized trials comparing chemotherapy alone with chemotherapy + rituximab.

Reference

Regimen

n

RR (%)

CR + CRu (%)

EFS / TTP

OS

[18]

CVP

159

57

11

median

15 mo

at 30 months

85%

R-CVP

162

81

41

32 mo

89%

[19]*

CHOP

205

90

17

at 2 years

63%

at 2 years

90%

R-CHOP

223

96

20

82%

95%

[20]**

MCP

96

75

25

median

29 months

at 4 years

74%

R-MCP

105

92

50

Not reached

87%

[21]**

CHVP

175

85

49

at 30 months

62%

Patients alive after median follow-up 30 months

145

R-CHVP

184

94

76

78%

169

.
CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; CR: complete remission; CRu: unconfirmed complete remission; CVP: cyclophosphamide, vincristine, and prednisone; CHVP: cyclophosphamide, doxorubicin, etoposide, prednisone, and interferon-α; EFS: event-free survival; OS: overall survivalMCP: mitoxantrone, chlorambucil, and prednisone; Mo: months; R: rituximab; RR: response rate; TTP: time to progression.



* Responding patients <60 years of age were randomized between interferon maintenance and autografting, while responding older patients received interferon maintenance.

** All responding patients received interferon maintenance



RR includes CR, unconfirmed CRu, and partial remissions

CR only, CRu not reported

Table 2 Results of front-line treatment in patients with disseminated follicular lymphoma

Reference

Regimen

RR (%)

CR + CRu

EFS

OS

[23]

R  8

67

9%

36 months

not reported

[18]

R-CVP

81

41%

32 months

89% at 2.5 years

[19]

R-CHOP*

96

25%

82% at 2 years

95% at 2 years

[25]

R-FM

96

90%

63% at 3 years

94% at 3 years

CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP: cyclophosphamide, vincristine, and prednisone; EFS: event-free survival; FM: fludarabine and mitoxantrone; MCP: mitoxantrone, chlorambucil, and prednisone; OS: overall survival; R: rituximab.


* Responding patients <60 years old were randomized between interferon maintenance and autografting, while responding older patients received interferon maintenance.

RR includes CR, unconfirmed CRu, and partial remissions

CR only, CRu not reported


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