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Low-grade lymphoma 1993: State of the art
Annals of Oncology 5 (Suppl. 2): S23-S27, 1994. O 1994 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Low-grade lymphoma 1993: State of the art S. J. Horning Stanford University Medical Center, Palo Alto, California, USA
Introduction
Background
Radiotherapy alone induces prolonged remissions in a significant proportion of patients with limited follicular low-grade lymphoma [8-10]. Age at the time of treatment correlated with progression-free survival in a previous Stanford series [8]. In a current update of 158 consecutive patients with Ann Arbor stage I—II FSC or FM lymphoma managed at Stanford, the actuarial
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The low-grade lymphomas continue to present a considerable challenge to clinicians in 1993. Despite a wide array of therapies which induce an initial response, these lymphomas follow a continuous remitting course and no treatment is known to be curative. The difficulties in managing these lymphomas relate to decisions as to when to treat, how to treat, and the strategy to be used in investigational therapies. The hallmark: of the low-grade lymphomas is a relatively long natural history, such that they are not immediately life-threatening but will be fatal for the majority within 10 to 12 years of diagnosis. The Working Formulation defined three subtypes of low-grade lymphoma: small lymphocytic (SL), follicular small cleaved cell (FSC), and follicular mixed small cleaved and large cell (FM) [1]. Additional histologic subtypes have since been recognized and others in the formulation have been reclassified. These include diffuse intermediate lymphocytic lymphoma (mantle-zone lymphoma), which is considered to have a relatively low-grade natural history, and monocytoid B-cell lymphoma [2-5]. Recent publications have emphasized the difficulty in the cytologic subtyping of the follicular lymphomas [6,7]. This may explain reports of the natural history of intermediate-grade follicular large-cell lymphomas, which are very similar to follicular low-grade lymphomas [8]. This discussion will be focused primarily on the follicular lymphomas because they are histologically distinctive and share the cytogenetic and molecular biologic features of the t(14; 18) karyotypic abnormality.
freedom from progression (FFP) is 40% between 10 to 20 years after definitive radiotherapy (unpublished observation). Median survival in this series is 14 years. However, the occurrence of relapses beyond 15 years indicates the extreme indolence of this disease. Of note, a recent series suggests that lymphoma cells can be detected in the bone marrow and the peripheral blood with equal frequency in limited- and advanced-stage follicular lymphoma [11]. A variety of treatments, including single-agent chemotherapy, combination chemotherapy, combined modality approaches, and whole body irradiation, results in 80%-90% overall response rates in extensive follicular low-grade lymphoma [12-14]. From 1971 to 1978 a group of 131 patients with Ann Arbor stage ni-IV low-grade lymphoma and age less than 65 years participated in randomized clinical trials which tested the efficacy of CVP (cyclophosphamide, vincristine, prednisone) alone or in combination with total lymphoid irradiation (TLI), oral cyclophosphamide or chlorambucil alone, or whole body irradiation with boosts to involved sites [12]. With follow-up currently in excess of 15 years, the median FFP is 4 years and median overall survival is 10 years. By 20 years, the actuarial FFP is just 10%, and the overall survival is 22%. When assessed for the effect of histology there are no significant differences in FFP, overall survival, or lymphoma-specific survival among the 87 patients with FSC histology, the 31 patients with FM histology, or the 13 patients with SL histology. Similarly, no significant differences are seen among the four treatment programs described above. Overall, 77% of patients achieved a complete response to treatment as determined by standard restaging procedures in the era that preceded computerized tomography. The lymphomaspecific survival of the 101 complete responders is significantly greater than the 31 patients with less than a complete response, 45% compared to 10% at ten years (p < 0.0001). Age at treatment is also a significant variable. While no difference in FFP is seen according to age, the median lymphoma-specific survival for patients under age 50 is 15 years, significantly longer than the 10-year lymphoma-specific survival of patients age
24
50 or greater. These data may serve as a historical reference to current clinical investigations in the lowgrade lymphomas.
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grade lymphoma. It is important to remember that patients managed with no initial therapy by definition have a lower tumor burden and therefore a more favorable prognosis. The concept of watchful waiting is being assessed in Histologic transformation an important clinical trial conducted at the National Cancer Institute [17]. Patients are randomly assigned to Histologic transformation from a low-grade to an inter- receive immediate treatment with ProMACE-MOPP mediate- or high-grade Lymphoma, usually follicular (prednisone, methotrexate, Adriamycin, cyclophosphasmall cleaved cell or follicular mixed to diffuse large- mide, etoposide, mustard, Oncovin, and procarbazine) cell, occurs with increasing frequency over time. The plus TLI to involved sites, or therapy is deferred until actual incidence is difficult to quantitate because of dif- there is tumor progression which cannot be managed ferences in clinical acumen, biopsy policy, and the with local radiotherapy in the watch and wait group, at accessibility of diagnostic tissue. In the Stanford series which time ProMACE-MOPP/TLI is instituted. The of 131 patients participating in randomized trials dis- rates of complete response (CR) in this study are incussed above, the actuarial incidence of transformation structive of the heterogeneity of low-grade lymphoma reaches 45% 18 years after diagnosis. The risk of histo- and the importance of tumor burden. Immediate treatlogic transformation is essentially identical between ment with ProMACE-MOPP results in a 75% comthese patients and a group of 83 patients who were ob- plete response rate for the 64 patients randomized to served without initial therapy [15]. Some of the latter that arm. However, the CR rate is only 57% among the group never received cytotoxic therapy prior to trans- 23 patients who could not be randomized because they formation. A group of 64 patients with histologic trans- were judged to require immediate treatment with formation from a follicular low-grade lymphoma to a ProMACE-MOPP. Thirty-five patients initially randiffuse large-cell, mixed, or immunoblastic lymphoma domized to watch and wait have required systemic has recently been analyzed at Stanford [16]. The time to treatment; the CR rate with ProMACE-MOPP in this transformation in this group ranges from 8 months to group is just 43%. 25 years. In multivariate analysis, significant prognostic The acceptance of deferred therapy for selected pafactors for survival include the extent of disease at tients and the heterogeneity of the low-grade lymphotransformation, the use of chemotherapy prior to trans- mas may partially explain the apparent reduction in CR formation, and the response (complete or less than rates in clinical trials conducted in the 1980s compared complete) to therapy at transformation. The median to earlier reports. The CR rates in four recent multisurvival of all 64 patients is 33 months. Median sur- institutional trials have ranged from just 23% to 48%, vival for the 27 complete responders is 103 months compared to historical series in which CR rates ranged and median lymphoma-free survival in this group is from 65% to 83% [18-22]. Several of the recent cliniabout 4 years. Among those relapsing after CR, two- cal trials restricted accrual to patients with unfavorable thirds were transformed lymphoma, and the original features or to patients judged to require immediate follicular low-grade lymphoma comprises the remain- treatment. Alternative explanations for the lower reing third. sponse rates include the larger patient numbers in multi-institutional trials compared with early singleinstitutional trials, more sensitive methods, and/or Heterogeneity of low-grade lymphoma more precise definitions employed in restaging patients in the recent trials, and the abbreviated overall duration Stanford investigators made the original observation of treatment of current studies. On this basis, historical that asymptomatic patients with advanced disease controls may not provide a valid comparison for curmanaged expectantly, with 'no initial therapy,' had an rent low-gTade lymphoma treatments. overall survival that was no worse than patients treated A number of authors have described prognostic facimmediately after diagnosis [15]. Important observa- tors at diagnosis for the follicular low-grade lymphotions on the natural history of low-grade lymphoma, in- mas [23-28]. In each of these, tumor burden as detercluding the incidence and characteristics of sponta- mined by factors such as stage, bone marrow involveneous regression and histologic transformation, have ment, B2 microglobulin, and number of extranodal been made on this group of untreated patients. Cur- sites; host factors such as age, systemic symptoms, and rently, therapy has been deferred for a period of two hemoglobin; and response to treatment emerge as progmonths or longer after referral in more than 300 pa- nostic factors. Prognostic indices have been described tients seen at Stanford. Their median actuarial time to based on these features. A complete response to initial treatment is 3.5 years, and their median survival is 12 treatment, duration of response >1 year and age <60 years. By 10 years, 85% of patients have received treat- have been identified as favorable prognostic features ment for lymphoma. This should not be interpreted as upon relapse [29]. These features should be considered a demonstration of the superiority of a 'watch and wait' in the assessment of novel treatments at diagnosis or policy; rather, it points out the heterogeneity of low- after relapse.
25
Myeloablative therapy
Alpha interferon (IFN) has modest activity in lowgrade lymphoma CR rates are relatively low whether IFN is administered as primary therapy or subsequent to relapse [30-32]. Murine leukemia-lymphoma models demonstrating the synergistic effects of interferonchemotherapy combinations provide the basis for current clinical trials. The Eastern Cooperative Oncology Group reported the use of COPA (cyclophosphamide, Oncovin, prednisone, Adriamycin) alone or with alpha interferon in 249 patients with unfavorable low-grade lymphoma or the follicular large-cell or diffuse small cleaved subtypes [19]. Although there are no differences in response rates, patients managed with chemotherapy plus interferon induction have a significantly longer remission duration (p < 0.001). The Groupe d'Etude des Lymphomes de lAdulte is treating follicular low-grade lymphoma patients with unfavorable features with CHVP (cyclophosphamide, Adriamycin, vindesine, prednisone) alone or with induction and adjuvant interferon alpha [20]. Preliminary analysis indicates a highly significant event-free survival in favor of the interferon arm (p < 104) and significance is retained at three years. This study stands alone in demonstrating an overall survival advantage for the interferon arm at three years, 86% vs. 69% (p - 0.02). However, although remission duration is lengthened with interferon in this study, the familiar pattern of lymphoma progression over time is observed. Three other large clinical trials with alpha interferon are under investigation. The design of the U.S. Intergroup study with cyclophosphamide ± interferon and the United Kingdom multi-institutional trial with chlorambucil ± interferon is a double randomization for induction and adjuvant interferon [22, 33]. The European Organization for the Research and Treatment of Cancer (EORTC) trial randomizes patients to adjuvant interferon or no further therapy following eight courses of CVP and RT [21]. The duration of adjuvant interferon in these trials ranges from seven months to two years. Preliminary data from the first randomization demonstrate no advantage for adjuvant interferon in the US study. The EORTC study shows a significant increase in median progression-free survival for patients receiving adjuvant interferon, but this is no longer observed by three years. Remission duration is significantly longer when interferon is given adjuvantly in the UK trial. The ability of interferon in combination with chemotherapy to prolong remission duration is reminiscent of that conferred with maintenance chemotherapy [34]. It is debatable whether an advantage of 50-100 weeks of disease-free survival justifies the cost and inconvenience. Many physicians and patients would demand a survival advantage as well.
Intensive chemotherapy and total body irradiation provide long-term survival in a subset of patients with otherwise incurable leukemia and lymphoma. The rationale for applying this strategy to the follicular lowgrade lymphomas rests in their sensitivity to repeated courses of alkylating agents and the possible curative effect of radiotherapy applied to selected lymphoid regions. In either case, myelotoxicity is dose-limiting. At the Dana Farber Cancer Institute (DFCI) and St. Bartholomew's Hospital, London, patients in second or subsequent remission with minimal disease receive high-dose cyclophosphamide and fractionated TBI prior to rescue with autologous marrow [35]. Autografts are purged with one or more monoclonal antibodies directed against B-cell antigens and baby rabbit complement Recurrence rates have been lower than expected compared with historical series: with a median follow-up of 27 months, 43 relapses have been noted in 121 patients. At the University of Nebraska, patients with follicular low-grade lymphoma, recurrent after anthracycline therapy, receive one of two highdose regimens followed either by unpurged marrow or peripheral blood stem cells [36]. With a short median follow-up, a subset of patients is alive without recurrent lymphoma. Results in these two studies are difficult to interpret because, historically, patients may not be treated immediately upon recurrence or they have received treatment only in a palliative manner. While both studies have shown an acceptably low morbidity and mortality to date, a significant prolongation of survival compared with the expected median of five to six years will be required. Myeloablative therapy and stem-cell rescue is also being assessed in follicular low-grade lymphoma patients in first remission. Patients at the DFCI are cytoreduced with CHOP (cyclophosphamide, Adriamycin, Oncovin, prednisone) chemotherapy to a minimal disease state prior to high-dose cyclophosphamide and TBI. Bone marrow is purged with monoclonal antibodies and antibody as described above. In a similar study at Stanford University, patients receive CVP to a minimal disease state before ablation with TBI, highdose etoposide, and high-dose cyclophosphamide. Autologous bone marrow is treated in vitro with a panel of monoclonal antibodies directed against B-cell antigens and complement before reinfusion. Both of these trials are in progress with a median follow-up of less than two years. It remains to be seen whether this dose-intense approach favorably alters the natural history of low-grade lymphoma and provides a survival advantage which offsets the cost, morbidity, and mortality of this procedure. As stated earlier, because historical controls may be invalid, it is imperative that treatment results are evaluated with respect to prognostic factors. Perhaps of nearly equal importance to efficacy data, patients participating in these bone marrow transplant studies are providing information re-
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Alpha interferon
26 garding the utility of molecular markers as surrogates for relapse. Molecular remission
Korsmeyer and colleagues have conducted an elegant series of studies of bcl-2, which they propose as one of a new category of oncogenes which affect programmed cell death [42]. The overexpression of bcl-2 in B-cell lymphoma results in decreased death, and the accumulated cells may go on to acquire secondary genetic abnormalities. This is consistent with the initial indolent behavior of low-grade lymphoma followed by more refractory disease and histologic transformation. Only 40%-70% of patients with advanced-stage low-grade lymphoma achieve complete remission with current therapy. Fewer achieve molecular remission, and virtually none appear to be cured. The findings of Reed and colleagues that bcl-2 inhibits the death of cells following a variety of chemotherapeutic agents and radiation provides insight into the incurability of low-grade lymphomas with combination chemotherapy and irradiation [43]. Interference with the expression or activity of bcl-2 or the development of cytotoxic strategies which utilize different death pathways should be further investigated. In addition to the myeloablative approaches and the use of interferon alpha described above, a number of new modalities are under investigation in the low-grade lymphomas. These include radiolabeled antibodies, immunotoxins, monoclonal antibodies, idiotype vaccines, and idiotype-specific peptides. Results of phase II studies and the initiation of phase HI studies with promising strategies are eagerly anticipated. In 1993, management of the low-grade lymphomas continues to challenge clinicians. The progress in understanding the basic biology of these lymphomas lends optimism that new insights can be exploited therapeutically. It is imperative that patients with lowgrade lymphoma continue to participate in clinical trials.
References 1. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project Cancer 1982; 49: 2112-35. 2. Jaffe ES, Bookman MA, Longo DL. Lymphocytic lymphoma of intermediate differentiation-mantle zone lymphoma: A distinct subtype of B-cell lymphoma. Hum Pathol 1987; 18: 877-80. 3. Richards MA, Hall PA, Gregory WM et al. Lymphoplasmacytoid and small-cell centrocytic non-Hodgkin's lymphoma - a retrospective analysis from St. Bartholomew's Hospital 19721986.Hematol Oncol 1989; 7: 19-35. 4. Sheibani K, Burke JS, Swartz WG et al. Monocytoid B-ceU lymphoma: Clinicopathologic study of 21 cases of a unique type of low-grade lymphoma. Cancer 1988; 62:1531-8. 5. Ngan BY, Warnke RA, Wilson M et al. Monocytoid B-cell lymphoma: A study of 36 cases. Hum Pathol 1991; 22:409-21. 6. Metter GE, Nathwani BN, Burke JS et al. Morphological subclassification of follicular lymphoma: Variability of diagnoses among hematopathologists, a collaborative study between the
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The long natural history of the low-grade lymphomas precludes anything but the most tentative conclusions regarding preliminary data and presents an obstacle to the effective study of the disease. Recent advances in molecular biology, including the cloning of the t(14; 18) breakpoints involving the bcl-2 proto-oncogene and the development of sensitive techniques for monitoring follicular lymphomas, promise to alter this circumstance in follicular lymphoma. Amplification by the polymerase chain reaction (PCR) technique permits the detection of one lymphoma cell in 10 5 -10 6 normal cells. A series of studies conducted at the DFCI by Gribben and Nadler on bone marrow from B-cell lymphoma patients undergoing high-dose therapy and stem-cell transplant has provided important clinical correlations with this technique. DNA from lymphomatous tissue can be amplified with primers for the major and minor breakpoint regions on chromosome 18 in about 80%-85% of patients with follicular low-grade lymphoma [37]. This technique has been used to assess the efficacy of marrow purging. Prior to autologous marrow purging, bone marrow from each of 74 patients was PCR+ after treatment with CHOP chemotherapy. About hah0 of these marrow harvests converted to PCR~ after purging, and these patients have a markedly more favorable diseasefree survival two years post-transplant [38]. The DFCI group also reported early results using this technique to monitor patients after BMT [39]. The majority of patients have a consistent PCR pattern after transplant, and those who are persistently positive have a high relapse rate, while no relapses have occurred among those who are persistently negative. However, potential false positives occur in the form of patients who convert from positive to a repeated negative status, and false negatives occur among patients who are initially negative and became positive with follow-up. Furthermore, a mixed pattern of positive and negative results has been seen in individual patients. Cabanillas and colleagues have recently presented data using this technique following chemotherapy [40]. These results, while highly interesting, must be considered to be preliminary and should be correlated with routine diagnostic tests. Apparently contradictory data, such as the report of PCR+ peripheral blood in six patients in remission for more than 10 years by the group from St. Bartholomew's Hospital, suggest that it is still too early to assess the predictive accuracy of PCR for t(14; 18) as a surrogate for persistent or recurrent disease [41]. However, the emerging data with good laboratory technique suggest that patterns of molecular detection of residual disease have prognostic value.
Future directions
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Correspondence to: Sandra J. Horning, MD. Stanford University Medical Center Suite 202 1000 Welch Road Palo Alto, California 94304-1811 USA
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13.
Repository Center and Pathology Panel for Lymphoma Clinical Studies. J Clin Oncol 1985; 3: 25-38. Nathwani BN, Mctter GE, Miller TP et al. What should be the morphologic criteria for the subdivision of follicular lymphomas? Blood 1986; 68: 837-45. Paryani SB, Hoppe RT, Cox RS et al. Analysis of nonHodgkin's lymphomas with nodular and favorable histologies, stages I and II. Cancer 1983; 52: 2300-7. Sutcliffe SB, Gospodarowicz MK, Bush RS et al. Role of radiation therapy in localized non-Hodgkin's lymphomas. Radiother Oncol 1985; 4: 211-23. Lawrence TS, Urba WJ, Steinberg SM et al. Retrospective analysis of stage I and n indolent lymphomas at the National Cancer Institute. Int J Radiat Oncol Biol Phys 1988; 14:417-24. Berinstein N, Reis MD, Ngan BY et al. Detection of occult lymphoma in the peripheral blood and bone marrow of patients with untreated early and advanced stage follicular lymphoma. Proc Am Soc Clin Oncol 1993; 12:1251 (abstract). Hoppe RT, Kushlan P, Kaplan HS et al. The treatment of advanced stage favorable histology non-Hodgkin's lymphomas: A preliminary report of a randomized trial comparing single agent chemotherapy, combination chemotherapy, and whole body irradiation. Blood 1981; 58: 592-8. Lister TA, Cullen MH, Beard ME et al. Comparison of combined and single-agent chemotherapy in non-Hodgkin's lymphoma of favourable histological type. Br Med J 1978; 1: 533-7. Mendenhall NP, Noyes WD et al. Total body irradiation for stage II-IV non-Hodgkin's lymphoma: Ten-year follow-up. J Clin Oncol 1989; 7: 67-74. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med 1984; 311:1471-5. Yuen AR, Horning SJ. Long-term survival after histologic transformation of low-grade lymphoma. Proc Am Soc Clin Oncol 1993; 12:1236 (abstract). Young RC, Longo DL, Glatstein E et al. The treatment of indolent lymphomas: Watchful waiting v aggressive combined modality treatment. Sem Hematol 1988; 25:11-6. Portlock CS. Management of the low-grade non-Hodgkin's lymphomas. Sem Oncol 1990; 17: 51-9. Smalley RV, Andersen JW, Hawkins MJ et al. Interferon alfa combined with cytotoxic chemotherapy for patients with nonHodgkin's lymphoma. N Engl J Med 1992; 327:1336-41. Solal-Celigny PH, Lepage E, Brousse N et al. Alpha-interferon and chemotherapy in patients with high-tumor burden follicular lymphoma: Preliminary results of the 'Groupe D'etude des Lymphomes Folliculaires.' Proc Am Soc Clin Oncol 1991; 10: 955 (abstract). Hagenbeek A, Carde P, Somers R et al. Maintenance of remission with human recombinant alpha-2 interferon (Roferon-A) in patients with stages III and IV low-grade malignant nonHodgkin's lymphoma: Results from a prospective, randomized phase QI clinical trial in 331 patients. Blood 1992; 74a: 288 (abstract). Peterson BA, Petroni G, Okan MM et al. Cyclophosphamide versus cyclophosphamide plus interferon alpha-2b in follicular low-grade lymphomas: A preliminary report of an intergroup trial (GALGB 8691 and EST 7486). Proc Am Soc Clin Oncol 1993; 12:1240 (abstract). Romaguera JE, McLaughlin 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. Litam P, Swan F, Cabanillas F et al. Prognostic value of serum beta-2 mlcroglobulin in low-grade lymphoma. Ann Intern Med 1991; 114: 855-60. Leonard RC, Hayward RL, Prescott RJ et al. The identification of discrete prognostic groups in low-grade non-Hodgkin's lymphoma. The Scotland and Newcastle Lymphoma Group Therapy Working Party. Ann Oncol 1991; 2: 655-62. Soubeyran P, Eghbali H, Bonichon F et al. Low-grade follicular lymphomas: Analysis of prognosis in a series of 281 patients. Eur J Cancer 1991; 27:1606-13. Gallagher CJ, Gregory WM, Jones AE et al. Follicular lym-
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Original article Low-grade lymphoma 1993: State of the art S. J. Horning Stanford University Medical Center, Palo Alto, California, USA
Introduction
Background
Radiotherapy alone induces prolonged remissions in a significant proportion of patients with limited follicular low-grade lymphoma [8-10]. Age at the time of treatment correlated with progression-free survival in a previous Stanford series [8]. In a current update of 158 consecutive patients with Ann Arbor stage I—II FSC or FM lymphoma managed at Stanford, the actuarial
Downloaded from http://annonc.oxfordjournals.org/ at Carleton University on June 25, 2015
The low-grade lymphomas continue to present a considerable challenge to clinicians in 1993. Despite a wide array of therapies which induce an initial response, these lymphomas follow a continuous remitting course and no treatment is known to be curative. The difficulties in managing these lymphomas relate to decisions as to when to treat, how to treat, and the strategy to be used in investigational therapies. The hallmark: of the low-grade lymphomas is a relatively long natural history, such that they are not immediately life-threatening but will be fatal for the majority within 10 to 12 years of diagnosis. The Working Formulation defined three subtypes of low-grade lymphoma: small lymphocytic (SL), follicular small cleaved cell (FSC), and follicular mixed small cleaved and large cell (FM) [1]. Additional histologic subtypes have since been recognized and others in the formulation have been reclassified. These include diffuse intermediate lymphocytic lymphoma (mantle-zone lymphoma), which is considered to have a relatively low-grade natural history, and monocytoid B-cell lymphoma [2-5]. Recent publications have emphasized the difficulty in the cytologic subtyping of the follicular lymphomas [6,7]. This may explain reports of the natural history of intermediate-grade follicular large-cell lymphomas, which are very similar to follicular low-grade lymphomas [8]. This discussion will be focused primarily on the follicular lymphomas because they are histologically distinctive and share the cytogenetic and molecular biologic features of the t(14; 18) karyotypic abnormality.
freedom from progression (FFP) is 40% between 10 to 20 years after definitive radiotherapy (unpublished observation). Median survival in this series is 14 years. However, the occurrence of relapses beyond 15 years indicates the extreme indolence of this disease. Of note, a recent series suggests that lymphoma cells can be detected in the bone marrow and the peripheral blood with equal frequency in limited- and advanced-stage follicular lymphoma [11]. A variety of treatments, including single-agent chemotherapy, combination chemotherapy, combined modality approaches, and whole body irradiation, results in 80%-90% overall response rates in extensive follicular low-grade lymphoma [12-14]. From 1971 to 1978 a group of 131 patients with Ann Arbor stage ni-IV low-grade lymphoma and age less than 65 years participated in randomized clinical trials which tested the efficacy of CVP (cyclophosphamide, vincristine, prednisone) alone or in combination with total lymphoid irradiation (TLI), oral cyclophosphamide or chlorambucil alone, or whole body irradiation with boosts to involved sites [12]. With follow-up currently in excess of 15 years, the median FFP is 4 years and median overall survival is 10 years. By 20 years, the actuarial FFP is just 10%, and the overall survival is 22%. When assessed for the effect of histology there are no significant differences in FFP, overall survival, or lymphoma-specific survival among the 87 patients with FSC histology, the 31 patients with FM histology, or the 13 patients with SL histology. Similarly, no significant differences are seen among the four treatment programs described above. Overall, 77% of patients achieved a complete response to treatment as determined by standard restaging procedures in the era that preceded computerized tomography. The lymphomaspecific survival of the 101 complete responders is significantly greater than the 31 patients with less than a complete response, 45% compared to 10% at ten years (p < 0.0001). Age at treatment is also a significant variable. While no difference in FFP is seen according to age, the median lymphoma-specific survival for patients under age 50 is 15 years, significantly longer than the 10-year lymphoma-specific survival of patients age
24
50 or greater. These data may serve as a historical reference to current clinical investigations in the lowgrade lymphomas.
Downloaded from http://annonc.oxfordjournals.org/ at Carleton University on June 25, 2015
grade lymphoma. It is important to remember that patients managed with no initial therapy by definition have a lower tumor burden and therefore a more favorable prognosis. The concept of watchful waiting is being assessed in Histologic transformation an important clinical trial conducted at the National Cancer Institute [17]. Patients are randomly assigned to Histologic transformation from a low-grade to an inter- receive immediate treatment with ProMACE-MOPP mediate- or high-grade Lymphoma, usually follicular (prednisone, methotrexate, Adriamycin, cyclophosphasmall cleaved cell or follicular mixed to diffuse large- mide, etoposide, mustard, Oncovin, and procarbazine) cell, occurs with increasing frequency over time. The plus TLI to involved sites, or therapy is deferred until actual incidence is difficult to quantitate because of dif- there is tumor progression which cannot be managed ferences in clinical acumen, biopsy policy, and the with local radiotherapy in the watch and wait group, at accessibility of diagnostic tissue. In the Stanford series which time ProMACE-MOPP/TLI is instituted. The of 131 patients participating in randomized trials dis- rates of complete response (CR) in this study are incussed above, the actuarial incidence of transformation structive of the heterogeneity of low-grade lymphoma reaches 45% 18 years after diagnosis. The risk of histo- and the importance of tumor burden. Immediate treatlogic transformation is essentially identical between ment with ProMACE-MOPP results in a 75% comthese patients and a group of 83 patients who were ob- plete response rate for the 64 patients randomized to served without initial therapy [15]. Some of the latter that arm. However, the CR rate is only 57% among the group never received cytotoxic therapy prior to trans- 23 patients who could not be randomized because they formation. A group of 64 patients with histologic trans- were judged to require immediate treatment with formation from a follicular low-grade lymphoma to a ProMACE-MOPP. Thirty-five patients initially randiffuse large-cell, mixed, or immunoblastic lymphoma domized to watch and wait have required systemic has recently been analyzed at Stanford [16]. The time to treatment; the CR rate with ProMACE-MOPP in this transformation in this group ranges from 8 months to group is just 43%. 25 years. In multivariate analysis, significant prognostic The acceptance of deferred therapy for selected pafactors for survival include the extent of disease at tients and the heterogeneity of the low-grade lymphotransformation, the use of chemotherapy prior to trans- mas may partially explain the apparent reduction in CR formation, and the response (complete or less than rates in clinical trials conducted in the 1980s compared complete) to therapy at transformation. The median to earlier reports. The CR rates in four recent multisurvival of all 64 patients is 33 months. Median sur- institutional trials have ranged from just 23% to 48%, vival for the 27 complete responders is 103 months compared to historical series in which CR rates ranged and median lymphoma-free survival in this group is from 65% to 83% [18-22]. Several of the recent cliniabout 4 years. Among those relapsing after CR, two- cal trials restricted accrual to patients with unfavorable thirds were transformed lymphoma, and the original features or to patients judged to require immediate follicular low-grade lymphoma comprises the remain- treatment. Alternative explanations for the lower reing third. sponse rates include the larger patient numbers in multi-institutional trials compared with early singleinstitutional trials, more sensitive methods, and/or Heterogeneity of low-grade lymphoma more precise definitions employed in restaging patients in the recent trials, and the abbreviated overall duration Stanford investigators made the original observation of treatment of current studies. On this basis, historical that asymptomatic patients with advanced disease controls may not provide a valid comparison for curmanaged expectantly, with 'no initial therapy,' had an rent low-gTade lymphoma treatments. overall survival that was no worse than patients treated A number of authors have described prognostic facimmediately after diagnosis [15]. Important observa- tors at diagnosis for the follicular low-grade lymphotions on the natural history of low-grade lymphoma, in- mas [23-28]. In each of these, tumor burden as detercluding the incidence and characteristics of sponta- mined by factors such as stage, bone marrow involveneous regression and histologic transformation, have ment, B2 microglobulin, and number of extranodal been made on this group of untreated patients. Cur- sites; host factors such as age, systemic symptoms, and rently, therapy has been deferred for a period of two hemoglobin; and response to treatment emerge as progmonths or longer after referral in more than 300 pa- nostic factors. Prognostic indices have been described tients seen at Stanford. Their median actuarial time to based on these features. A complete response to initial treatment is 3.5 years, and their median survival is 12 treatment, duration of response >1 year and age <60 years. By 10 years, 85% of patients have received treat- have been identified as favorable prognostic features ment for lymphoma. This should not be interpreted as upon relapse [29]. These features should be considered a demonstration of the superiority of a 'watch and wait' in the assessment of novel treatments at diagnosis or policy; rather, it points out the heterogeneity of low- after relapse.
25
Myeloablative therapy
Alpha interferon (IFN) has modest activity in lowgrade lymphoma CR rates are relatively low whether IFN is administered as primary therapy or subsequent to relapse [30-32]. Murine leukemia-lymphoma models demonstrating the synergistic effects of interferonchemotherapy combinations provide the basis for current clinical trials. The Eastern Cooperative Oncology Group reported the use of COPA (cyclophosphamide, Oncovin, prednisone, Adriamycin) alone or with alpha interferon in 249 patients with unfavorable low-grade lymphoma or the follicular large-cell or diffuse small cleaved subtypes [19]. Although there are no differences in response rates, patients managed with chemotherapy plus interferon induction have a significantly longer remission duration (p < 0.001). The Groupe d'Etude des Lymphomes de lAdulte is treating follicular low-grade lymphoma patients with unfavorable features with CHVP (cyclophosphamide, Adriamycin, vindesine, prednisone) alone or with induction and adjuvant interferon alpha [20]. Preliminary analysis indicates a highly significant event-free survival in favor of the interferon arm (p < 104) and significance is retained at three years. This study stands alone in demonstrating an overall survival advantage for the interferon arm at three years, 86% vs. 69% (p - 0.02). However, although remission duration is lengthened with interferon in this study, the familiar pattern of lymphoma progression over time is observed. Three other large clinical trials with alpha interferon are under investigation. The design of the U.S. Intergroup study with cyclophosphamide ± interferon and the United Kingdom multi-institutional trial with chlorambucil ± interferon is a double randomization for induction and adjuvant interferon [22, 33]. The European Organization for the Research and Treatment of Cancer (EORTC) trial randomizes patients to adjuvant interferon or no further therapy following eight courses of CVP and RT [21]. The duration of adjuvant interferon in these trials ranges from seven months to two years. Preliminary data from the first randomization demonstrate no advantage for adjuvant interferon in the US study. The EORTC study shows a significant increase in median progression-free survival for patients receiving adjuvant interferon, but this is no longer observed by three years. Remission duration is significantly longer when interferon is given adjuvantly in the UK trial. The ability of interferon in combination with chemotherapy to prolong remission duration is reminiscent of that conferred with maintenance chemotherapy [34]. It is debatable whether an advantage of 50-100 weeks of disease-free survival justifies the cost and inconvenience. Many physicians and patients would demand a survival advantage as well.
Intensive chemotherapy and total body irradiation provide long-term survival in a subset of patients with otherwise incurable leukemia and lymphoma. The rationale for applying this strategy to the follicular lowgrade lymphomas rests in their sensitivity to repeated courses of alkylating agents and the possible curative effect of radiotherapy applied to selected lymphoid regions. In either case, myelotoxicity is dose-limiting. At the Dana Farber Cancer Institute (DFCI) and St. Bartholomew's Hospital, London, patients in second or subsequent remission with minimal disease receive high-dose cyclophosphamide and fractionated TBI prior to rescue with autologous marrow [35]. Autografts are purged with one or more monoclonal antibodies directed against B-cell antigens and baby rabbit complement Recurrence rates have been lower than expected compared with historical series: with a median follow-up of 27 months, 43 relapses have been noted in 121 patients. At the University of Nebraska, patients with follicular low-grade lymphoma, recurrent after anthracycline therapy, receive one of two highdose regimens followed either by unpurged marrow or peripheral blood stem cells [36]. With a short median follow-up, a subset of patients is alive without recurrent lymphoma. Results in these two studies are difficult to interpret because, historically, patients may not be treated immediately upon recurrence or they have received treatment only in a palliative manner. While both studies have shown an acceptably low morbidity and mortality to date, a significant prolongation of survival compared with the expected median of five to six years will be required. Myeloablative therapy and stem-cell rescue is also being assessed in follicular low-grade lymphoma patients in first remission. Patients at the DFCI are cytoreduced with CHOP (cyclophosphamide, Adriamycin, Oncovin, prednisone) chemotherapy to a minimal disease state prior to high-dose cyclophosphamide and TBI. Bone marrow is purged with monoclonal antibodies and antibody as described above. In a similar study at Stanford University, patients receive CVP to a minimal disease state before ablation with TBI, highdose etoposide, and high-dose cyclophosphamide. Autologous bone marrow is treated in vitro with a panel of monoclonal antibodies directed against B-cell antigens and complement before reinfusion. Both of these trials are in progress with a median follow-up of less than two years. It remains to be seen whether this dose-intense approach favorably alters the natural history of low-grade lymphoma and provides a survival advantage which offsets the cost, morbidity, and mortality of this procedure. As stated earlier, because historical controls may be invalid, it is imperative that treatment results are evaluated with respect to prognostic factors. Perhaps of nearly equal importance to efficacy data, patients participating in these bone marrow transplant studies are providing information re-
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Alpha interferon
26 garding the utility of molecular markers as surrogates for relapse. Molecular remission
Korsmeyer and colleagues have conducted an elegant series of studies of bcl-2, which they propose as one of a new category of oncogenes which affect programmed cell death [42]. The overexpression of bcl-2 in B-cell lymphoma results in decreased death, and the accumulated cells may go on to acquire secondary genetic abnormalities. This is consistent with the initial indolent behavior of low-grade lymphoma followed by more refractory disease and histologic transformation. Only 40%-70% of patients with advanced-stage low-grade lymphoma achieve complete remission with current therapy. Fewer achieve molecular remission, and virtually none appear to be cured. The findings of Reed and colleagues that bcl-2 inhibits the death of cells following a variety of chemotherapeutic agents and radiation provides insight into the incurability of low-grade lymphomas with combination chemotherapy and irradiation [43]. Interference with the expression or activity of bcl-2 or the development of cytotoxic strategies which utilize different death pathways should be further investigated. In addition to the myeloablative approaches and the use of interferon alpha described above, a number of new modalities are under investigation in the low-grade lymphomas. These include radiolabeled antibodies, immunotoxins, monoclonal antibodies, idiotype vaccines, and idiotype-specific peptides. Results of phase II studies and the initiation of phase HI studies with promising strategies are eagerly anticipated. In 1993, management of the low-grade lymphomas continues to challenge clinicians. The progress in understanding the basic biology of these lymphomas lends optimism that new insights can be exploited therapeutically. It is imperative that patients with lowgrade lymphoma continue to participate in clinical trials.
References 1. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project Cancer 1982; 49: 2112-35. 2. Jaffe ES, Bookman MA, Longo DL. Lymphocytic lymphoma of intermediate differentiation-mantle zone lymphoma: A distinct subtype of B-cell lymphoma. Hum Pathol 1987; 18: 877-80. 3. Richards MA, Hall PA, Gregory WM et al. Lymphoplasmacytoid and small-cell centrocytic non-Hodgkin's lymphoma - a retrospective analysis from St. Bartholomew's Hospital 19721986.Hematol Oncol 1989; 7: 19-35. 4. Sheibani K, Burke JS, Swartz WG et al. Monocytoid B-ceU lymphoma: Clinicopathologic study of 21 cases of a unique type of low-grade lymphoma. Cancer 1988; 62:1531-8. 5. Ngan BY, Warnke RA, Wilson M et al. Monocytoid B-cell lymphoma: A study of 36 cases. Hum Pathol 1991; 22:409-21. 6. Metter GE, Nathwani BN, Burke JS et al. Morphological subclassification of follicular lymphoma: Variability of diagnoses among hematopathologists, a collaborative study between the
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The long natural history of the low-grade lymphomas precludes anything but the most tentative conclusions regarding preliminary data and presents an obstacle to the effective study of the disease. Recent advances in molecular biology, including the cloning of the t(14; 18) breakpoints involving the bcl-2 proto-oncogene and the development of sensitive techniques for monitoring follicular lymphomas, promise to alter this circumstance in follicular lymphoma. Amplification by the polymerase chain reaction (PCR) technique permits the detection of one lymphoma cell in 10 5 -10 6 normal cells. A series of studies conducted at the DFCI by Gribben and Nadler on bone marrow from B-cell lymphoma patients undergoing high-dose therapy and stem-cell transplant has provided important clinical correlations with this technique. DNA from lymphomatous tissue can be amplified with primers for the major and minor breakpoint regions on chromosome 18 in about 80%-85% of patients with follicular low-grade lymphoma [37]. This technique has been used to assess the efficacy of marrow purging. Prior to autologous marrow purging, bone marrow from each of 74 patients was PCR+ after treatment with CHOP chemotherapy. About hah0 of these marrow harvests converted to PCR~ after purging, and these patients have a markedly more favorable diseasefree survival two years post-transplant [38]. The DFCI group also reported early results using this technique to monitor patients after BMT [39]. The majority of patients have a consistent PCR pattern after transplant, and those who are persistently positive have a high relapse rate, while no relapses have occurred among those who are persistently negative. However, potential false positives occur in the form of patients who convert from positive to a repeated negative status, and false negatives occur among patients who are initially negative and became positive with follow-up. Furthermore, a mixed pattern of positive and negative results has been seen in individual patients. Cabanillas and colleagues have recently presented data using this technique following chemotherapy [40]. These results, while highly interesting, must be considered to be preliminary and should be correlated with routine diagnostic tests. Apparently contradictory data, such as the report of PCR+ peripheral blood in six patients in remission for more than 10 years by the group from St. Bartholomew's Hospital, suggest that it is still too early to assess the predictive accuracy of PCR for t(14; 18) as a surrogate for persistent or recurrent disease [41]. However, the emerging data with good laboratory technique suggest that patterns of molecular detection of residual disease have prognostic value.
Future directions
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Correspondence to: Sandra J. Horning, MD. Stanford University Medical Center Suite 202 1000 Welch Road Palo Alto, California 94304-1811 USA
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