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The treatment of low grade lymphoma
Clinical Oncology (1994) 6:385-390 © 1994 The Royal College of Radiologists
Clinical Oncology
Review Article The Treatment of Low Grade Lymphoma D. A. Cameron and R. C. F. Leonard ICRF Department of Medical Oncology, Western General Hospital, Edinburgh, UK
INTRODUCTION
Table 1. Low grade lymphomas, as defined by the Working Formulation [2] and NCI clinical schemata [3]
Th e prognosis for a patient with non-Hodgkin's lymphoma is dependent in a large part on the grade of disease, as well as its stage and the general condition of the patient. It was traditionally thought that patients with low grade lymphoma (LGL) had a generally good prognosis, with many series reporting 5-year survivals in the order of 60%-80%. However, in his Karnofsky Memorial Lecture, Rosenberg highlighted the fact that this population has a continual decline in survival over the subsequent years, so that, by 15 years, they fare worse than patients with high grade disease [1]. Reflecting this recognition that there is a substantial long term mortality from LGL, the treatment polices adopted are wide, from no initial treatment to autologous bone marrow transplant in first remission. There is continuing interest in both the use of newer agents such as purine analogues, as well as radical chemotherapy or radiotherapy. We discuss below some of the treatments that have been and are still being used, and attempt to define patient groups for whom each approach may be justified.
Working Formulation Rappaport
CLASSIFICATION Before we can define the grade of a lymphoma, it has to be borne in mind that the various classifications of non-Hodgkin's lymphoma are based on different criteria. The Working Formulation, which was created to permit clinicians to 'translate' between the various schemata in use by pathologists, including Rappaport, Kiel and Lukes-Collins, defined groups in terms of the histology as well as the clinical outcome [2]. Therefore one would expect a Working Formulation LGL to have a reasonable medium term survival; using this approach to patient selection for trials can be self-fulfilling. However, the Rappaport approach is essentially that of defining the histology; no account is taken of clinical outcome. Table 1 Correspondence and offprint requests to: R. C. F. Leonard, Consultant Medical Oncologist, Department of Oncology, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
Small lymphocytic, consistent with CLL plasmacytoid Follicular, predominantly cleaved cell (small cleaved) Follicular, mixed, small cleaved and large cell Diffuse small cleaved cell (intermediate grade)
NCI clinical
Lymphocytic, well differentiated
Small lymphocytic
Nodular, poorly differentiated lymphocytic
Follicular small
Nodular, mixed lymphocytichistiocytic Diffuse lymphocytic, poorly differentiated
Follicular mixed Diffuse, small cleaved Diffuse, intermediately differentiated (mantle zone) Cutaneous T-cell
defines roughly approximate categories for the traditional LGLs; it can be seen that the Working Formulation does not easily accommodate mantle zone cell lymphomas, which are generally considered to be of low grade [3]. There is also a somewhat grey area between the subtypes of follicular lymphoma, which fall into the Working Formulation definitions of LGL or intermediate grade lymphoma, which, for many pathologists, result from arbitrary and unproven prognostic attributes. LGLs are therefore of two main types: small lymphocytic and follicular. Within each histological subtype there is a wide range of behaviours and prognoses. We must also consider the more recently defined types of mantle zone cell lymphoma~ because, even if they are not included in many historical series, they may be biologically different [41.
EXPECTANT POLICIES It is well recognized that patients may remain for years in a stable clinical condition, despite obvious widespread disease. This has prompted many clini-
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cians only to offer treatment at evidence of disease progression or for symptoms. That this expectant approach is not detrimental to ultimate survival has been clearly shown [5]; indeed, O'Brien et al. [6], in a review that included a group of patients randomized to observation versus initial chemotherapy, found a statistically significant survival advantage for 'no initial therapy'. This was felt probably to reflect the fact that more indolent disease is compatible with a better survival, even if the recognized prognostic factors are taken into consideration. In another randomized trial of such an approach involving 84 evaluable patients, there was no detriment to deferring therapy in terms of overall survival, although the disease free survivals were different [7]. However, all analyses of prognostic factors in LGL define patient subgroups with poor medium term survival; our own data from the Scottish and Newcastle Lymphoma Group identified substantial cohorts of patients (up to 25% of an unselected population) whose median survival was less that 2 years [8,9]. Thus, to follow an expectant policy requires some knowledge about the natural history of the disease as manifest at presentation. Simply noting the patient to be asymptomatic at presentation is insufficient to predict an indolent course.
RADIOTHERAPY Lymphomas are often extremely radiosensitive tumours, and up to 25% of patients with LGL can have localized disease. For these patients, radical radiotherapy, often using 3500-4000 cGY over 4 weeks, offers a good chance of complete remission (CR) from disease [10]. Many reports claim cures in such localized disease, but, given the propensity for late relapse, such claims must be examined in the light of long term follow-up. The series from Stanford [11] had no plateau in the survival curve, even after 15 years, with 42% overall survival at this point, but, when updated by Homing 10 years later [12], there was 40% freedom from progression at 20 years, suggesting that this proportion of,Stage I and II patients may be cured by radical radiotherapy. Gospodarowicz et al.'s series [13] again had no plateau in the survival curve at 15 years, but they were able to identify a subgroup of good prognosis patients with Stage I and II disease having 92% overall survival and 72% relapse free survival at 12 years. There were few, if any, relapses beyond 10 years in these series, but, equally, there were few patients at risk. Encouraged by this, several workers have given total central nodal radiotherapy to patients with Stage III disease [14-16], sometimes combining it with some chemotherapy [17], presumably in adjuvant mode for subclinical metastatic or bone marrow disease, since the drugs do not seem to have been used as radiation enhancers. Again the follow-up is too short for a plateau to be confirmed, but amongst Paryani et al.'s patients there were no relapses or deaths due to disease beyond 10 years. McLaughlin et al. combined B-CHOP with involved field radiotherapy, and, although there was no pla-
D . A . Cameron and R. C. F. Leonard
teau in survival, using a 'log-logistic' model they obtained the best fit of the observed survival curve if 55% of the low grade follicular lymphomas had been cured (95% CI 40-69). This is also one of the few series to report response, with an impressive 81% CR rate. Total body irradiation, using 150 cGy fractionated over 5 weeks has been tried in the treatment of Stage III and IV disease [18], but, although the results are comparable, randomized trials against single and combination chemotherapy showed no benefit [19]. The main toxicity was thrombocytopenia, with 40% of patients requiring treatment delay. There is controversy over whether patients should be treated with involved or extended fields when using radical radiotherapy. There is no doubt that the former is less toxic, both in terms of marrow suppression and local acute and delayed radiation effects, which can be quite severe, for example, in the extended field of treatment of Waldeyer's ring [10]. The fact that long term cure of these diseases is difficult should be remembered, and indeed there is a role for palliative treatment with doses of around 2500 cGy; many clinicians have good anecdotal experience of complete responses to single fractions of only 200-400 cGy. These series suggest that there may be a definite cure rate of around 40% for radiotherapy in Stage IIII low grade lymphoma, although the numbers are small, particularly for types other than follicular lymphoma. A recent retrospective analysis of almost 400 patients entered into British National Lymphoma Investigation (BNLI) trials, using a 'cure prediction model', suggests that 30%-40% Stage I and II patients may be considered to be cured [20].
CHEMOTHERAPY FOR STAGE III-IV DISEASE Single alkylating agents were shown to induce responses in the 1970s [21]. Daily administration seemed to be the most effective, and the time to response could vary enormously, with CRs still being obtained after 40 months of therapy. However, there has been concern expressed about the risk of leukaemiagenesis with chronic oral alkylating therapy, which appears to arise even after cessation of therapy [22]. Following the model of successful multiagent chemotherapy in leukaemias, several groups tried the same approach with LGLs [23-26]. The title of De Vita et al.'s report [26] reflected the belief of many that this was the way to cure patients. Certainly the response rates were increased, up to 90%-100% [23], and a short term survival advantage was found for the responders. However, the median survival did not rise much above 6-9 months in responders [21], although there was a small group of long term survivors (up to 9 years) [25]. When, however, such regimens were compared with single agent akylators [19, 27-30], they merely confirmed the improved response rate, as well as time to response, but in general there was no signifi-
The Treatment of Low Grade Lymphoma
cant survival advantage seen. These were all small series, with under 100 patients in each. Hoppe et al. [19] therefore included in the survival analysis an earlier group [27] of patients also randomized between similar treatments, and this confirmed the lack of survival benefit. Maintenance chemotherapy after induction was also tried [23,24,31]; it helped to maintain remission, but again conferred no survival benefit. The next step was to try to increase survival with more intensive chemotherapy, in particular by the addition of adriamycin. Dana et al. [32] recently published an overview of 415 patients treated with adriamycin-containing regimens in randomized trials, all of which also had a group randomized to maintenance therapy. Overall there was no benefit for using adriamycin, or for maintenance therapy, whether chemotherapy or immunotherapy with BCG. The CR rate was 64%, but median survival was 6.9 years, no better than any of the three groups in Hoppe et al.'s randomized study of single versus multiagent chemotherapy versus total lymphoid irradiation [19]. Dana et al.'s study [32] again highlights the importance of long follow-up in this disease. Many of these patients had been reported on earlier by Cabanillas et al. [33]. They found that after 5 years of follow-up, patients treated with CHOP did better than those without the adriamycin (COP); the CR rates were 53% against 83%, and a survival benefit was seen for those patients in CR after adriamycin who were the given BCG maintenance immunotherapy. A recent report has shown a similar lack of survival benefit for adriamycin, despite a short term survival gain for patients in CR [34].
INTENSIFIED CHEMOTHERAPY This was first tried by Portlock et al. [35] with 'high dose' pulsed chlorambucil, using 80 mg/mZ/month, but the early promising results have not been maintained with longer follow-up. Autologous bone marrow transplantation is now performed more for non-Hodgkin's lymphoma than any other disease [36], and it is not surprising that it has been tried in the treatment of low-grade lymphomas in a further search for their elusive cure. A recent review of this subject by Armitage [37] discusses some of the problems, particularly the lack of consensus about the timing and the regimen to be used, and summarizes the current published experience. The longest follow-up for patients treated in relapse is from the Dana-Farber and St Bartholomew's Hospital groups [38], which was updated at the Fifth International Lymphoma Meeting in 1993 [39]. Median follow-up is still only 2.5 years, and only 60% remain in remission. Comparison with a historical series shows an advantage for transplantation only in terms of freedom from relapse, not survival. The treatment related mortality was quoted as 3 %, which was not much worse than for conventional regimens such as CHOP [40]. There are two small series of patients treated
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either in first remission [41] or as consolidation of first remission [42]. There were two treatment related deaths in Freedman et al.'s [41] group of 66 patients; the smaller series of Fouillard et al. [42] had no toxic deaths, but only seven of the nine patients have remained in CR for 15-43 months. Increasingly, such high dose chemotherapy regimens are now supported with peripheral blood stem cells, which reduce the duration of neutropenia and thrombocytopenia [43], though, whether this translates into reduced toxic mortality is unknown. However, we cannot judge the true cure rate from this intensive approach until the follow-up is a lot longer. Looking at the survival curves for all patients with low-grade lymphoma we see a continuous decline of about 5% per annum up to at least 15 years. It will therefore be well into the next century before we know whether autologous bone marrow transplantation can produce cures.
NEW DRUGS It was always clear that new approaches were needed to LGLs, and this had to include the development of new agents. Perhaps the most promising area is that of the new purine analogues. Fludarabine was synthesized in an attempt to develop an effective, stable and slowly metabolized variant of cytosine arabinoside. It soon became apparent that, despite a lack of efficacy in solid tumours, it induced lymphocytopenia [44], and so interest developed in the application of this drug to lymphoid malignancies. Its activity has been confirmed in several studies, with overall response rates of 50%-60% for previously treated patients [45,46], rising to 69% in previously untreated patients [47]. However, as well as causing myelosuppression, this agent depletes CD4 lymphocytes [44,48], and this may be partly the reason for the high incidence of infections in patients treated with fludarabine [46,47], even if not all infections are 'opportunistic'. Indeed, in the series of patients from St Bartholomew's Hospital, London, the treatment related mortality was higher in patients treated with fludarabine, compared with those treated with autologous bone marrow transplantation! Another synthetic purine analogue, 2-chlorodeoxyadenosine, is active in lymphoid malignancies. The experience in LGL is more limited, with a 43% response rate amongst 40 previously treated patients [49]. More recently, from the Royal Marsden, six of eight patients with LGL responded, including three complete responses ]50]; the primary toxicity was myelosupression. However, Keating points out in a recent editorial [51] that similar falls in CD4 lymphocytes have been noted with this drug as well as fludarabine. Other newer agents have been tried in LGL, including 2'-deoxycoformycin (with a response rate of at most 16% in previously treated patients) [52], and idarubicin [53]; but, as Cheson points out in a recent review of newer agents [54], none alone will cure LGL, and both multiagent and multimodality approaches need to be tried.
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BIOLOGICAL A G E N T S Interferon-or was first used to treat LGLs in the 1970s, and many Phase I and II studies have confirmed its activity, with response rates up to 50% and complete responses occurring in 5%-10% of patients. The optimum dose remains unknown, and the toxicity profile is of flu-like symptoms, with some patients developing weight loss and fatigue with chronic usage [55]. Since it was clear that this agent alone was not going to cure LGL, it has been combined both with single agent [56] and multiagent chemotherapy. The recently published MD Anderson study has one of the longest follow-ups when combining interferon with polychemotherapy [57]. The design was slightly complicated, with some patients receiving interferon before chemotherapy with B-CHOP. Interferon was then given thrice weekly (for up to 2 years) to all patients in CR, even if radiotherapy, or even additional daily interferon, was required to achieve CR. In comparison with historical controls, there is an increase in failure free survival, but the gain appears to be less than the 2 years' duration of the interferon therapy. Recently, two European randomised trials were reported. The E O R T C administered interferon-ol to patients with LGL who had responded after CVP chemotherapy and radiotherapy [58]. Those patients who received interferon for 1 year appeared to have 1 year's gain in progression free survival, with no data yet available for overall survival. The GELA group administered concomitant interferon-o~ for 18 months with polychemotherapy, with approximately 18 months' gain in event free survival [59]. Clearly interferon-o~ has efficacy in the treatment of LGL, but it is not without toxicity, and so far the studies have merely demonstrated a gain in progression free survival for, at most, the duration of therapy with the interferon. As with all studies in LGL, where the median survival is 6-8 years, a few more years' follow-up will be necessary before we can be sure of any survival benefit. Perhaps one of the most interesting developments is the use of monoclonal antibodies in conjuction with autologous bone marrow transplantation, using the polymerase chain reaction (PCR) to detect subclinical residual disease. The significance of a 'molecular CR', as defined by a negative PCR, to look for residual t(14, 18) translocation in patients with follicular lymphoma, is not yet clear, but Gribben and Nadler, in a recent review [60], reported on their own, and colleagues', data that PCR positive harvested bone marrow, and PCR positive bone marrow taken post-transplant are both associated with increased risk of relapse [61,62]. Monoclonal antibodies have therefore been used both to purge the harvested bone marrow [61] and be given adjuvantly post-transplant to treat minimal residual disease [63]. In the latter study, administering anti-B-blocked ricin after autologous bone marrow transplantation resulted in three patients being converted from PCR positive to PCR negative; but one patient to whom the antibody was administered whilst PCR negative subsequently converted to
D . A . Cameron and R. C. F. Leonard
PCR positive, and was the only patient to have clinical relapse to date! As with all research into these diseases, definite survival gains will not be seen until the studies are more mature. Other biological agents have been tried in the treatment of LGL, and recent reviews has been done by Parkinson et al. [64], and, for anti-B-cell monoclonal antibodies, by Grossbard et al. [65].
O N G O I N G TRIALS Given the difficulty in defining cure in LGL, and consequently the length of time it takes to discover that a new treatment has or has not influenced the long term survival, what issues are being addressed by current trials? The Scotland and Newcastle Lymphoma Group are looking at an entirely oral polychemotherapy regimen, to be followed by randomization to two different doses of interferon-0l, in order to determine the minimum effective dose required. The chemotherapy consists of dexamethasone and chlorambucil, but, in addition, half the patients are randomized also to receive oral idarubicin. Whether benefit from administration of another anthracycline will be shown is uncertain, but a pilot study in 35 patients has shown that the regimen is well tolerated (Taylor and Proctor, personal communication), with no grade IV neutropenia, a complete response rate of 34%, and an overall response rate of 77%. The BNLI are joining the E O R T C multicentre study comparing fludarabine and CVP as first line treatment. Several centres continue to be involved in the chlorambucil/interferon trials and other fludarabine studies. St Bartholomew's Hospital continues its autologous bone marrow transplant programme for relapsed follicular lymphoma and the Royal Marsden continues to treat patients with 2-CdA [50] and alpha-calcidol [66].
PROGNOSTIC FACTORS Most workers report that achieving a response to treatment is a good prognostic factor. This is particularly true if it is maintained for at least 1 year [67]. However, it is important to determine the likely long term outcome in advance of any treatment. Tumour related biological prognostic factors are few in low grade lymphomas, and the observation that a follicular lymphoma with additional cytogenetic abnormalities as well as the t(14, 18) translocation [68] is associated with a worse prognosis has not been translated into clinical practice. The literature abounds with studies on composite prognostic models. The two largest such series [9,13] both identify that, for patients with follicular lymphoma, disease stage, the presence of Bsymptoms, and age are all important. However, even amongst Stage IV disease, groups with significantly differing prognoses can be determined [69]. A recent
The Treatment of Low Grade Lymphoma
review analysed the reported data for follicular lymphoma, and concluded that the prognostic factors are not in general very different from other types of lymphoma, but also pointed out that transformation to high grade lymphoma may also increase early mortality [70]. The same group looked for prognostic factors for transformation, which generally occurs within 10 years of presentation, and found that they are similar to those for a poor prognosis [71]; thus, separating the two is difficult.
CONCLUSIONS Almost 10 years after Rosenburg's Karnofsky Memorial Lecture [1], we seem no nearer a cure for low grade lymphomas; neither do we know the impact of any of our therapies on the natural history of these diseases. Clearly, there are patients with an exceptionally good prognosis, at least in the short to medium term; they are usually young, fit and without advanced disease. Some of these may indeed be cured by radiotherapy; others, even with more advanced disease, may not need any initial treatment until symptoms become problematic, but equally there are patients who at presentation have a poor prognosis. Some of them are old, ill and with advanced disease for which palliation is required. There is little evidence that anything other than oral alkylating agents are necessary, unless a rapid response to relieve specific symptoms is required. Whatever prognostic model is used, however, young and/or fit patients who have a poor prognosis can be identified at the outset. Aggressive treatments should be confined to this group, whether they be high dose chemotherapy, experimental approaches based on CHOP and/or immunotherapy, or monoclonal antibodies. The newer cytotoxics should also be examined in this group, either initially or at relapse. It would appear to be a reasonable policy to restrict experimental therapies to those 'poor prognosis' patients and extend their use in a carefully controlled way to the larger population of patients with chronic disease only when their improved therapeutic ratio has been established.
Acknowledgements. The authors would like to thank Dr L. M. Matheson for her helpful comments on the section on radiotherapy.
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sine treatment of low grade lymphomas. J Clin Oncol 1992;10:371-7. Hickish T, Serafinowski P, Cunningham D, et al. 2'-cholorodeoxyadenosine: Evaluation of a novel predominantly lymphocyte selective agent in lymphoid malignancies. Br J Cancer 1993;67:139-43. Keating MJ. Immunosuppression with purine analogues - the flip side of the gold coin. Ann Oncol 1993;4:347-8. Duggan DB, Anderson JR, Dillman R, et al. 2'-deoxycoformycin (pentostatin) for refractory non-Hodgkin's lymphoma: A CALGB Phase II study. Med Pediatr Onco11990;18:203-6. Case DC, Hayes DM, Gerber M, et al. Phase II study of oral idarubicin in favorable histology non-Hodgkin's lymphoma. Cancer Res 1990;50:6833-5. Cheson BD. New drugs for low-grade NHL. Semin Oncol 1993;20: Suppl 5: 96-100. McLaughlin P. The role of interferon in the therapy of low grade lymphoma. Leukemia Lymphoma 1993;10 Suppl:l% 20. Rohatiner AZS, Richards MA, Barnet MJ, et al. Chlorambucil and interferon for low grade non-Hodgkin's lymphoma. Br J Cancer 1987;55:225-6. McLaughlin P, CabinaUas F, Hagemeister FB, et al. CHOPBleo plus interferon for Stage IV low-grade lymphoma. Ann Oncol 1993;4:205-11. Hagenbeek A, Carde P, Somers R, et al. On the influence of human recombinant alpha-2 interferon (Roferon-A) on remission duration in patients with Stages III and IV low grade non-Hodgkin's lymphoma: Results from a prospective, randomised Phase III clinical trial [abstract]. Fifth International Conference on Malignant Lymphoma, Lugano, Switzerland. 1993: 54. Solal-G61ignyP, Lepage E, Brousse N, et al. for 'GELA'. A concomitant treatment with interferon alfa and a doxorubicincontaining regimen improves survival in high-tumour burden follicular non-Hodgkin's lymphomas [abstract]. Fifth International Conference on Malignant Lymphoma, Lugano, Switzerland. 1993: 54. Gribben JG, Nadler LM. Monitoring minimal residual disease. Semin Oncol 1993;20 (Suppl 5):143-55. Gribben JG, Freedman AS, Neuberg D, et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Eng J Med 1991 ;325:1525-33. Gribben JG, Neuberg D, Freedman AS, et al. Detection by polymerase chain reaction of residual cells with the bcl-2 translocation is associated with increased risk of relapse after autologous bone marrow transplantation for B-cell lymphoma. Blood 1993;81:3449-57. Grossbard ML, Gribben JG, Freedman AS, et al. Adjuvant immunotoxin therapy with anti-B-blocked ricin after autologous bone marrow transplantation for patients with B-cell non-Hodgkin's lymphoma. Blood 1993;81:2263-71. Parkinson DR, Snzol M, Cheson BD. Biologic therapies for low-grade lymphomas. Semin Oncol 1993;20 Suppl 5:111-7. Grossbard ML, Press OW, Appelbaum FR, et al. Monoclonal antibody-base therapies of leukemia and lymphoma. Blood 1992;80:863-78. Raina V, Cunningham D, Gilchrist N, et al. Alfacalcidol is a nontoxic, effective treatment of follicular small-cleaved lymphoma. Br J Cancer 1991;63:463-5. Weisdoff D J, Anderson JA, Glick JH, et al. Survival after relapse of low-grade non-Hodgkin's lymphoma: Implications for marrow transplantation. J Clin Oncol 1992;10:942-7. Yunis J J, Frizzera G, Oken MM, et al. Multiple recurrent genomic defects in folicular lymphoma; A possible model for cancer. N Engl J Med 1987;316:79-84. Romaguera JE, MeLaughlin P, North L, et al. Multivariate analysis of prognostic factors in Stage IV follicular low-grade lymphoma: A risk model. J Clin Oncol 1991;9:762-9. Coiffier B, Bastion Y, Berger F, et al. Prognostic factors in follicular lymphomas. Semin Oncol 1993;20 Suppl 5:89-95. Bastion Y, Berger F, Sebban C, et al. Incidence, predictive factors and prognosis of histologic transformation (HT) in follicular lymphoma [abstract]. Fifth International Conference on Malignant Lymphoma, Lugano, Switzerland 1993:47.
Received for publication July 1994 Accepted July 1994
Clinical Oncology
Review Article The Treatment of Low Grade Lymphoma D. A. Cameron and R. C. F. Leonard ICRF Department of Medical Oncology, Western General Hospital, Edinburgh, UK
INTRODUCTION
Table 1. Low grade lymphomas, as defined by the Working Formulation [2] and NCI clinical schemata [3]
Th e prognosis for a patient with non-Hodgkin's lymphoma is dependent in a large part on the grade of disease, as well as its stage and the general condition of the patient. It was traditionally thought that patients with low grade lymphoma (LGL) had a generally good prognosis, with many series reporting 5-year survivals in the order of 60%-80%. However, in his Karnofsky Memorial Lecture, Rosenberg highlighted the fact that this population has a continual decline in survival over the subsequent years, so that, by 15 years, they fare worse than patients with high grade disease [1]. Reflecting this recognition that there is a substantial long term mortality from LGL, the treatment polices adopted are wide, from no initial treatment to autologous bone marrow transplant in first remission. There is continuing interest in both the use of newer agents such as purine analogues, as well as radical chemotherapy or radiotherapy. We discuss below some of the treatments that have been and are still being used, and attempt to define patient groups for whom each approach may be justified.
Working Formulation Rappaport
CLASSIFICATION Before we can define the grade of a lymphoma, it has to be borne in mind that the various classifications of non-Hodgkin's lymphoma are based on different criteria. The Working Formulation, which was created to permit clinicians to 'translate' between the various schemata in use by pathologists, including Rappaport, Kiel and Lukes-Collins, defined groups in terms of the histology as well as the clinical outcome [2]. Therefore one would expect a Working Formulation LGL to have a reasonable medium term survival; using this approach to patient selection for trials can be self-fulfilling. However, the Rappaport approach is essentially that of defining the histology; no account is taken of clinical outcome. Table 1 Correspondence and offprint requests to: R. C. F. Leonard, Consultant Medical Oncologist, Department of Oncology, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
Small lymphocytic, consistent with CLL plasmacytoid Follicular, predominantly cleaved cell (small cleaved) Follicular, mixed, small cleaved and large cell Diffuse small cleaved cell (intermediate grade)
NCI clinical
Lymphocytic, well differentiated
Small lymphocytic
Nodular, poorly differentiated lymphocytic
Follicular small
Nodular, mixed lymphocytichistiocytic Diffuse lymphocytic, poorly differentiated
Follicular mixed Diffuse, small cleaved Diffuse, intermediately differentiated (mantle zone) Cutaneous T-cell
defines roughly approximate categories for the traditional LGLs; it can be seen that the Working Formulation does not easily accommodate mantle zone cell lymphomas, which are generally considered to be of low grade [3]. There is also a somewhat grey area between the subtypes of follicular lymphoma, which fall into the Working Formulation definitions of LGL or intermediate grade lymphoma, which, for many pathologists, result from arbitrary and unproven prognostic attributes. LGLs are therefore of two main types: small lymphocytic and follicular. Within each histological subtype there is a wide range of behaviours and prognoses. We must also consider the more recently defined types of mantle zone cell lymphoma~ because, even if they are not included in many historical series, they may be biologically different [41.
EXPECTANT POLICIES It is well recognized that patients may remain for years in a stable clinical condition, despite obvious widespread disease. This has prompted many clini-
386
cians only to offer treatment at evidence of disease progression or for symptoms. That this expectant approach is not detrimental to ultimate survival has been clearly shown [5]; indeed, O'Brien et al. [6], in a review that included a group of patients randomized to observation versus initial chemotherapy, found a statistically significant survival advantage for 'no initial therapy'. This was felt probably to reflect the fact that more indolent disease is compatible with a better survival, even if the recognized prognostic factors are taken into consideration. In another randomized trial of such an approach involving 84 evaluable patients, there was no detriment to deferring therapy in terms of overall survival, although the disease free survivals were different [7]. However, all analyses of prognostic factors in LGL define patient subgroups with poor medium term survival; our own data from the Scottish and Newcastle Lymphoma Group identified substantial cohorts of patients (up to 25% of an unselected population) whose median survival was less that 2 years [8,9]. Thus, to follow an expectant policy requires some knowledge about the natural history of the disease as manifest at presentation. Simply noting the patient to be asymptomatic at presentation is insufficient to predict an indolent course.
RADIOTHERAPY Lymphomas are often extremely radiosensitive tumours, and up to 25% of patients with LGL can have localized disease. For these patients, radical radiotherapy, often using 3500-4000 cGY over 4 weeks, offers a good chance of complete remission (CR) from disease [10]. Many reports claim cures in such localized disease, but, given the propensity for late relapse, such claims must be examined in the light of long term follow-up. The series from Stanford [11] had no plateau in the survival curve, even after 15 years, with 42% overall survival at this point, but, when updated by Homing 10 years later [12], there was 40% freedom from progression at 20 years, suggesting that this proportion of,Stage I and II patients may be cured by radical radiotherapy. Gospodarowicz et al.'s series [13] again had no plateau in the survival curve at 15 years, but they were able to identify a subgroup of good prognosis patients with Stage I and II disease having 92% overall survival and 72% relapse free survival at 12 years. There were few, if any, relapses beyond 10 years in these series, but, equally, there were few patients at risk. Encouraged by this, several workers have given total central nodal radiotherapy to patients with Stage III disease [14-16], sometimes combining it with some chemotherapy [17], presumably in adjuvant mode for subclinical metastatic or bone marrow disease, since the drugs do not seem to have been used as radiation enhancers. Again the follow-up is too short for a plateau to be confirmed, but amongst Paryani et al.'s patients there were no relapses or deaths due to disease beyond 10 years. McLaughlin et al. combined B-CHOP with involved field radiotherapy, and, although there was no pla-
D . A . Cameron and R. C. F. Leonard
teau in survival, using a 'log-logistic' model they obtained the best fit of the observed survival curve if 55% of the low grade follicular lymphomas had been cured (95% CI 40-69). This is also one of the few series to report response, with an impressive 81% CR rate. Total body irradiation, using 150 cGy fractionated over 5 weeks has been tried in the treatment of Stage III and IV disease [18], but, although the results are comparable, randomized trials against single and combination chemotherapy showed no benefit [19]. The main toxicity was thrombocytopenia, with 40% of patients requiring treatment delay. There is controversy over whether patients should be treated with involved or extended fields when using radical radiotherapy. There is no doubt that the former is less toxic, both in terms of marrow suppression and local acute and delayed radiation effects, which can be quite severe, for example, in the extended field of treatment of Waldeyer's ring [10]. The fact that long term cure of these diseases is difficult should be remembered, and indeed there is a role for palliative treatment with doses of around 2500 cGy; many clinicians have good anecdotal experience of complete responses to single fractions of only 200-400 cGy. These series suggest that there may be a definite cure rate of around 40% for radiotherapy in Stage IIII low grade lymphoma, although the numbers are small, particularly for types other than follicular lymphoma. A recent retrospective analysis of almost 400 patients entered into British National Lymphoma Investigation (BNLI) trials, using a 'cure prediction model', suggests that 30%-40% Stage I and II patients may be considered to be cured [20].
CHEMOTHERAPY FOR STAGE III-IV DISEASE Single alkylating agents were shown to induce responses in the 1970s [21]. Daily administration seemed to be the most effective, and the time to response could vary enormously, with CRs still being obtained after 40 months of therapy. However, there has been concern expressed about the risk of leukaemiagenesis with chronic oral alkylating therapy, which appears to arise even after cessation of therapy [22]. Following the model of successful multiagent chemotherapy in leukaemias, several groups tried the same approach with LGLs [23-26]. The title of De Vita et al.'s report [26] reflected the belief of many that this was the way to cure patients. Certainly the response rates were increased, up to 90%-100% [23], and a short term survival advantage was found for the responders. However, the median survival did not rise much above 6-9 months in responders [21], although there was a small group of long term survivors (up to 9 years) [25]. When, however, such regimens were compared with single agent akylators [19, 27-30], they merely confirmed the improved response rate, as well as time to response, but in general there was no signifi-
The Treatment of Low Grade Lymphoma
cant survival advantage seen. These were all small series, with under 100 patients in each. Hoppe et al. [19] therefore included in the survival analysis an earlier group [27] of patients also randomized between similar treatments, and this confirmed the lack of survival benefit. Maintenance chemotherapy after induction was also tried [23,24,31]; it helped to maintain remission, but again conferred no survival benefit. The next step was to try to increase survival with more intensive chemotherapy, in particular by the addition of adriamycin. Dana et al. [32] recently published an overview of 415 patients treated with adriamycin-containing regimens in randomized trials, all of which also had a group randomized to maintenance therapy. Overall there was no benefit for using adriamycin, or for maintenance therapy, whether chemotherapy or immunotherapy with BCG. The CR rate was 64%, but median survival was 6.9 years, no better than any of the three groups in Hoppe et al.'s randomized study of single versus multiagent chemotherapy versus total lymphoid irradiation [19]. Dana et al.'s study [32] again highlights the importance of long follow-up in this disease. Many of these patients had been reported on earlier by Cabanillas et al. [33]. They found that after 5 years of follow-up, patients treated with CHOP did better than those without the adriamycin (COP); the CR rates were 53% against 83%, and a survival benefit was seen for those patients in CR after adriamycin who were the given BCG maintenance immunotherapy. A recent report has shown a similar lack of survival benefit for adriamycin, despite a short term survival gain for patients in CR [34].
INTENSIFIED CHEMOTHERAPY This was first tried by Portlock et al. [35] with 'high dose' pulsed chlorambucil, using 80 mg/mZ/month, but the early promising results have not been maintained with longer follow-up. Autologous bone marrow transplantation is now performed more for non-Hodgkin's lymphoma than any other disease [36], and it is not surprising that it has been tried in the treatment of low-grade lymphomas in a further search for their elusive cure. A recent review of this subject by Armitage [37] discusses some of the problems, particularly the lack of consensus about the timing and the regimen to be used, and summarizes the current published experience. The longest follow-up for patients treated in relapse is from the Dana-Farber and St Bartholomew's Hospital groups [38], which was updated at the Fifth International Lymphoma Meeting in 1993 [39]. Median follow-up is still only 2.5 years, and only 60% remain in remission. Comparison with a historical series shows an advantage for transplantation only in terms of freedom from relapse, not survival. The treatment related mortality was quoted as 3 %, which was not much worse than for conventional regimens such as CHOP [40]. There are two small series of patients treated
387
either in first remission [41] or as consolidation of first remission [42]. There were two treatment related deaths in Freedman et al.'s [41] group of 66 patients; the smaller series of Fouillard et al. [42] had no toxic deaths, but only seven of the nine patients have remained in CR for 15-43 months. Increasingly, such high dose chemotherapy regimens are now supported with peripheral blood stem cells, which reduce the duration of neutropenia and thrombocytopenia [43], though, whether this translates into reduced toxic mortality is unknown. However, we cannot judge the true cure rate from this intensive approach until the follow-up is a lot longer. Looking at the survival curves for all patients with low-grade lymphoma we see a continuous decline of about 5% per annum up to at least 15 years. It will therefore be well into the next century before we know whether autologous bone marrow transplantation can produce cures.
NEW DRUGS It was always clear that new approaches were needed to LGLs, and this had to include the development of new agents. Perhaps the most promising area is that of the new purine analogues. Fludarabine was synthesized in an attempt to develop an effective, stable and slowly metabolized variant of cytosine arabinoside. It soon became apparent that, despite a lack of efficacy in solid tumours, it induced lymphocytopenia [44], and so interest developed in the application of this drug to lymphoid malignancies. Its activity has been confirmed in several studies, with overall response rates of 50%-60% for previously treated patients [45,46], rising to 69% in previously untreated patients [47]. However, as well as causing myelosuppression, this agent depletes CD4 lymphocytes [44,48], and this may be partly the reason for the high incidence of infections in patients treated with fludarabine [46,47], even if not all infections are 'opportunistic'. Indeed, in the series of patients from St Bartholomew's Hospital, London, the treatment related mortality was higher in patients treated with fludarabine, compared with those treated with autologous bone marrow transplantation! Another synthetic purine analogue, 2-chlorodeoxyadenosine, is active in lymphoid malignancies. The experience in LGL is more limited, with a 43% response rate amongst 40 previously treated patients [49]. More recently, from the Royal Marsden, six of eight patients with LGL responded, including three complete responses ]50]; the primary toxicity was myelosupression. However, Keating points out in a recent editorial [51] that similar falls in CD4 lymphocytes have been noted with this drug as well as fludarabine. Other newer agents have been tried in LGL, including 2'-deoxycoformycin (with a response rate of at most 16% in previously treated patients) [52], and idarubicin [53]; but, as Cheson points out in a recent review of newer agents [54], none alone will cure LGL, and both multiagent and multimodality approaches need to be tried.
388
BIOLOGICAL A G E N T S Interferon-or was first used to treat LGLs in the 1970s, and many Phase I and II studies have confirmed its activity, with response rates up to 50% and complete responses occurring in 5%-10% of patients. The optimum dose remains unknown, and the toxicity profile is of flu-like symptoms, with some patients developing weight loss and fatigue with chronic usage [55]. Since it was clear that this agent alone was not going to cure LGL, it has been combined both with single agent [56] and multiagent chemotherapy. The recently published MD Anderson study has one of the longest follow-ups when combining interferon with polychemotherapy [57]. The design was slightly complicated, with some patients receiving interferon before chemotherapy with B-CHOP. Interferon was then given thrice weekly (for up to 2 years) to all patients in CR, even if radiotherapy, or even additional daily interferon, was required to achieve CR. In comparison with historical controls, there is an increase in failure free survival, but the gain appears to be less than the 2 years' duration of the interferon therapy. Recently, two European randomised trials were reported. The E O R T C administered interferon-ol to patients with LGL who had responded after CVP chemotherapy and radiotherapy [58]. Those patients who received interferon for 1 year appeared to have 1 year's gain in progression free survival, with no data yet available for overall survival. The GELA group administered concomitant interferon-o~ for 18 months with polychemotherapy, with approximately 18 months' gain in event free survival [59]. Clearly interferon-o~ has efficacy in the treatment of LGL, but it is not without toxicity, and so far the studies have merely demonstrated a gain in progression free survival for, at most, the duration of therapy with the interferon. As with all studies in LGL, where the median survival is 6-8 years, a few more years' follow-up will be necessary before we can be sure of any survival benefit. Perhaps one of the most interesting developments is the use of monoclonal antibodies in conjuction with autologous bone marrow transplantation, using the polymerase chain reaction (PCR) to detect subclinical residual disease. The significance of a 'molecular CR', as defined by a negative PCR, to look for residual t(14, 18) translocation in patients with follicular lymphoma, is not yet clear, but Gribben and Nadler, in a recent review [60], reported on their own, and colleagues', data that PCR positive harvested bone marrow, and PCR positive bone marrow taken post-transplant are both associated with increased risk of relapse [61,62]. Monoclonal antibodies have therefore been used both to purge the harvested bone marrow [61] and be given adjuvantly post-transplant to treat minimal residual disease [63]. In the latter study, administering anti-B-blocked ricin after autologous bone marrow transplantation resulted in three patients being converted from PCR positive to PCR negative; but one patient to whom the antibody was administered whilst PCR negative subsequently converted to
D . A . Cameron and R. C. F. Leonard
PCR positive, and was the only patient to have clinical relapse to date! As with all research into these diseases, definite survival gains will not be seen until the studies are more mature. Other biological agents have been tried in the treatment of LGL, and recent reviews has been done by Parkinson et al. [64], and, for anti-B-cell monoclonal antibodies, by Grossbard et al. [65].
O N G O I N G TRIALS Given the difficulty in defining cure in LGL, and consequently the length of time it takes to discover that a new treatment has or has not influenced the long term survival, what issues are being addressed by current trials? The Scotland and Newcastle Lymphoma Group are looking at an entirely oral polychemotherapy regimen, to be followed by randomization to two different doses of interferon-0l, in order to determine the minimum effective dose required. The chemotherapy consists of dexamethasone and chlorambucil, but, in addition, half the patients are randomized also to receive oral idarubicin. Whether benefit from administration of another anthracycline will be shown is uncertain, but a pilot study in 35 patients has shown that the regimen is well tolerated (Taylor and Proctor, personal communication), with no grade IV neutropenia, a complete response rate of 34%, and an overall response rate of 77%. The BNLI are joining the E O R T C multicentre study comparing fludarabine and CVP as first line treatment. Several centres continue to be involved in the chlorambucil/interferon trials and other fludarabine studies. St Bartholomew's Hospital continues its autologous bone marrow transplant programme for relapsed follicular lymphoma and the Royal Marsden continues to treat patients with 2-CdA [50] and alpha-calcidol [66].
PROGNOSTIC FACTORS Most workers report that achieving a response to treatment is a good prognostic factor. This is particularly true if it is maintained for at least 1 year [67]. However, it is important to determine the likely long term outcome in advance of any treatment. Tumour related biological prognostic factors are few in low grade lymphomas, and the observation that a follicular lymphoma with additional cytogenetic abnormalities as well as the t(14, 18) translocation [68] is associated with a worse prognosis has not been translated into clinical practice. The literature abounds with studies on composite prognostic models. The two largest such series [9,13] both identify that, for patients with follicular lymphoma, disease stage, the presence of Bsymptoms, and age are all important. However, even amongst Stage IV disease, groups with significantly differing prognoses can be determined [69]. A recent
The Treatment of Low Grade Lymphoma
review analysed the reported data for follicular lymphoma, and concluded that the prognostic factors are not in general very different from other types of lymphoma, but also pointed out that transformation to high grade lymphoma may also increase early mortality [70]. The same group looked for prognostic factors for transformation, which generally occurs within 10 years of presentation, and found that they are similar to those for a poor prognosis [71]; thus, separating the two is difficult.
CONCLUSIONS Almost 10 years after Rosenburg's Karnofsky Memorial Lecture [1], we seem no nearer a cure for low grade lymphomas; neither do we know the impact of any of our therapies on the natural history of these diseases. Clearly, there are patients with an exceptionally good prognosis, at least in the short to medium term; they are usually young, fit and without advanced disease. Some of these may indeed be cured by radiotherapy; others, even with more advanced disease, may not need any initial treatment until symptoms become problematic, but equally there are patients who at presentation have a poor prognosis. Some of them are old, ill and with advanced disease for which palliation is required. There is little evidence that anything other than oral alkylating agents are necessary, unless a rapid response to relieve specific symptoms is required. Whatever prognostic model is used, however, young and/or fit patients who have a poor prognosis can be identified at the outset. Aggressive treatments should be confined to this group, whether they be high dose chemotherapy, experimental approaches based on CHOP and/or immunotherapy, or monoclonal antibodies. The newer cytotoxics should also be examined in this group, either initially or at relapse. It would appear to be a reasonable policy to restrict experimental therapies to those 'poor prognosis' patients and extend their use in a carefully controlled way to the larger population of patients with chronic disease only when their improved therapeutic ratio has been established.
Acknowledgements. The authors would like to thank Dr L. M. Matheson for her helpful comments on the section on radiotherapy.
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Received for publication July 1994 Accepted July 1994