Management of High-Grade Lymphomas

ABSTRACT: High-grade non-Hodgkins lymphomas generally refer to immunoblastic lymphoma, lymphoblastic lymphoma, and small-noncleaved-cell lymphoma, three histological subtypes that were associated with the worst prognosis at the time of categorization 16 years ago in the Working Formulation for Clinical Usage. Small-noncleaved-cell lymphoma was classified further into Burkitts lymphoma and non-Burkitts lymphoma. The treatment of high-grade lymphomas in adults remains somewhat unfavorable today. In children, however, survival rates of 80% to 90% are being achieved with intensive short duration protocols. In this article, the management of Burkitt, Burkitt-like, and lymphoblastic lymphomas is discussed as is the possibility of improved survival in adults using treatment strategies developed for pediatric patients.[ONCOLOGY 12(Suppl 8):40-48, 1998] Introduction In the United States high-grade non-Hodgkins lymphomas generally refer to three histological subtypes of lymphoma categorized in the Working Formulation for Clinical Usage, published over 16 years ago.[1] The classification into low-, intermediate- or high-grade lymphomas was mainly based on differences in survival, and the three histological subtypes with the worst prognosis were defined as high-grade (immunoblastic lymphoma, lymphoblastic lymphoma, and small-noncleaved-cell lymphoma, which were associated with 5-year survival rates of 32%, 26%, and 23%, respectively). Small-noncleaved-cell lymphoma was further classified into Burkitts and non-Burkitts lymphomas. High-Grade Non-Hodgkins Lymphoma The decision to label immunoblastic lymphoma, lymphoblastic lymphoma, and small-noncleaved-cell lymphoma as high-grade has been criticized on a number of grounds. First, the term grade is usually used in the context of specific histopathological criteria rather than clinical outcome. Second, in the study that led to the Working Formulation for Clinical Usage, there was little or no attempt to take into consideration either the treatment used (although most patients received an anthracycline-containing regimen), or the prognostic factors that we know to be critically important to the outcome of therapy. Even in 1982, better results than those recorded in the study that led to the Working Formulation for Clinical Usage had been reported, at least in children, for small-noncleaved-cell and lymphoblastic lymphoma [2-6], so that the present, paradoxical situation in which the survival rates of these high-grade lymphomas are much better than the survival rates of either low-grade or intermediate-grade lymphomas were, even then, beginning to become apparent. Third, although differences in survival among the three grades defined in the study that led to the Working Formulation for Clinical Usage were statistically significant, there was clear overlap in the survival rates of lymphomas classified as high and intermediate grades, overlap that was not always reflected accurately by the survival rates at 5 years. Clearly, the decisions as to where to draw the line between high-grade and intermediate-grade was somewhat arbitrary, as indeed, is the histological distinction between small-noncleaved-cell lymphoma of non-Burkitts type and large-cell lymphoma.[7] Chromosomal translocations 8;14(q24;q32) (which might be considered defining characteristics of Burkitts lymphoma), are also observed in subsets of Burkitt-like lymphoma and large-B-cell lymphoma, particularly in children.[8] Identifying High-Grade Lymphomas The problem of the definition of a high-grade lymphoma has been compounded by the identification, with the help of immunohistochemical and molecular analyses, of new entities, some of which (or some histological variants of which) would be classified as high-grade in the Working Formulation for Clinical Usage. And, finally, immunoblastic lymphoma cannot be reproducibly separated from large-B-cell lymphoma, and there is disagreement among pathologists as to whether it constitutes a separate entity.[9] The identification of prognostic groups has been greatly refined since the early 1980s, particularly by the detailed analysis leading to the International Prognostic Index, and such prognostic factors work for all histologies. However, there is an increasing recognition that each entity that can be precisely defined behaves differently, and that the tendency to lump tumors together for treatment purposes may not be wise. Certainly there is no a priori reason to suppose that different biological entities will respond similarly to the same therapythe reverse is often the case, particularly in children. Unfortunately, while histology remains the dominant means of making diagnoses, distinctions between biological entities within a histological category will remain difficult at best, and the hypothesis that genetically different tumors require different therapies for optimal results will remain untested. Thus, the use of broad risk groups that encompass multiple entities as a continuing basis for the determination of therapy is of increasingly questionable validity. There can be little doubt that the biological nature of the tumor cell, in addition to the molecular genetic lesions that have modified normal cellular behavior during the process of lymphomagenesis, are the primary determinants of treatment outcome, although research is urgently needed to determine whether molecular genetic markers (particularly those that influence proliferation and apoptosis) provide a more effective basis for treatment decisions than histology (other factors, such as tumor burden and effective drug concentrations will, doubtless, remain of significance, too). Moreover, as novel therapies are introduced, (eg, monoclonal antibody therapy such as anti-CD20 (rituximab [Rituxan]), or therapies targeted towards specific molecular lesions or viral proteins present in the tumor cells), the identification of the presence of specific therapeutic targets is likely to become at least as important as histology as a basis for therapeutic decisions. With these considerations in mind, this article will deal with the management of the three tumors, 1) Burkitts lymphoma, 2) the B-cell tumors from the Working Formulation for Clinical Usages category of non-Burkitts lymphoma (renamed in the more recent Revised European American Lymphoma (REAL) classification [10] Burkitt-like lymphoma), and 3) lymphoblastic lymphoma. These tumors were defined on exclusively histological grounds in the Working Formulation for Clinical Usage, but are specified as B-cell neoplasms (in the case of Burkitts lymphoma and Burkitt-like lymphoma), or neoplasms of precursor T or B cells in the case of lymphoblastic lymphoma, in the REAL classification. It is important to recognize that Burkitt-like lymphoma overlaps considerably with both Burkitts lymphoma and large-B-cell lymphoma and indeed, the dividing lines between these three entities cannot be reproducibly made. It seems probable that Burkitt-like lymphoma is not truly a separate diesease, but is composed of a mixture of Burkitts lymphoma and large-B-cell lymphoma, the relative proportion of large-B-cell lymphoma increasing with age. However, Burkitt-like lymphoma appears, in general, to have a clinical behavior pattern and response to therapy similar to Burkitts lymphoma (and will be included with Burkitt's lymphoma for the purposes of this article) such that its large-B-cell lymphoma element is likely to consist predominantly of a subtype of large-B-cell lymphoma. For therapeutic purposes it may remain appropriate to separate this category from large-B-cell lymphoma in some way. However, in children, large-B-cell lymphoma has a similar prognosis to Burkitts lymphoma and Burkitt-like lymphoma when treated with the same chemotherapy regimens.[2-4] Whether this would apply to the large-B-cell lymphomas of adults is not known. All three of the neoplasms dealt with in this article have a peak incidence in the first 2 decades of life and are the predominant non-Hodgkins lymphomas of childhood and adolescence, but account for only a few percent of cases of adult non-Hodgkins lymphoma. Management of Burkitts and Burkitt-like Lymphomas Perhaps the most important point to recognize in the management of Burkitts lymphoma is that it is among the most rapidly growing of human tumors. At least some Burkitt-like lymphomas have a high, essentially 100%, proliferative index, although this has not been formerly examined, and Ki-67 or MIB-1 expression may be an appropriate way to define such tumors for treatment purposes. The presence of an 8;14(q24;q32) chromosomal translocation may be an equally appropriate means of defining tumors that should be treated as Burkitts lymphoma, although detection is not possible by simple histochemical examination, as is the case for Ki-67/MIB-1. The correlation between the presence of an 8;14(q24;q32) translocation and proliferative index has also not been formally examined and is clearly worthy of further investigation. Interestingly, although it is a poor prognostic factor in large-cell lymphomas treated with standard therapeutic approaches such as CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone) [11], a high proliferative index may be a factor in the good response of Burkitts lymphoma and Burkitt-like lymphoma to chemotherapy, at least when treated with the kind of intensive treatment regimens used in children with these diseases. The rapid growth rate is certainly the reason that patients with these tumors usually succumb within a matter of months if left untreated (rare patients with very limited disease may be exceptions). This, coupled to the high rate of apoptosis, also explains the frequent complication of uricosemic renal failure that is present at the time of diagnosis in patients with large tumor burdens. The extremely high sensitivity of these rapidly proliferative tumors to chemotherapy also results in a high potential for additional metabolic and renal problems, in patients with substantial tumor burdens, during remission induction. Both pretreatment uricosemia and the renal consequences of rapid tumor lysis are compounded in the presence of renal outlet tract obstruction, or, occasionally, by massive renal involvement. This leads to two important principles of therapy: 1) patients must be assessed as rapidly as possible, so that definitive therapy can be instituted at the earliest time (within a few days at the most, regardless of tumor burden at presentation), and 2) during the initial few days of chemotherapy, at least in patients with moderate to large tumor burdens, careful management designed to avoid the precipitation of acute oliguric renal failure is essential. The key to the latter is hydration. It is important to correct uricosemia prior to the commencement of therapy, and alkaline diuresis with administration of allopurinol or uricase (not yet approved in the United States) is usually adequate for this purpose. In the presence of renal outflow tract obstruction, other therapeutic measures (preferably hemodialysis), may be necessary prior to the initiation of specific chemotherapy. Allopurinol is continued during the first week or so of therapy, but it is important not to over-alkalinize patients because this reduces the solubility of phosphate, which becomes a major potential cause of renal microtubular obstruction once tumor lysis commences. If a good urine flow is not established prior to therapy, the risk of post-chemotherapy renal failure from rapid tumor lysis with consequent microtubular obstruction by solutes that exceed their solubility product (oxypurines and phosphorus) is extremely high. In this circumstance, the most immediate risk is death from acute hyperkalemia, although hypocalcemia may precipitate cardiac arrhythmias. In French and German pediatric cooperative group protocols (both of which are now used in many other countries) a prephase of low-intensity chemotherapy (cyclophosphamide, vincristine, and corticosteroid) is given during the first week of therapy [3,4] based on the hypothesis that this will reduce the rate of response, and thereby lessen the risk of acute tumor lysis. In some patients (ie, those recovering from major surgery), such an approach may have additional advantages, although the value of a prephase has not been subjected to study by randomized clinical trial. Patients with large pleural or peritoneal effusions may have difficulty tolerating the high hydration rates (ie, 4.5 L/m²) required prior to and during the first few days of chemotherapy. Liberal diuretics are recommended for these patients, along with appropriate monitoring of central venous and/or wedged pulmonary arterial pressures. Clearly, all patients at significant risk for a tumor lysis syndrome are best monitored in an intensive care unit. Other complications that may be encountered at the time of presentation or during tumor regression include major gastrointestinal bleeding or perforation (rarely, the development of visceral fistulae). Surprisingly, given the frequent involvement of the bowel in Burkitts lymphoma and Burkitt-like lymphoma, neither of these problems are common, although perforation does appear to occur more frequently in Latin America. The reason for this is unknown, but in one Mexican series, perforation appeared to be associated with malnutrition and previous surgery.[12] Specific Chemotherapy The primary therapeutic modality for patients with Burkitts lymphoma and Burkitt-like lymphoma is chemotherapy. An advantage to the addition of radiation in any setting has not been demonstratedindeed it has been shown, by randomized clinical trial, to be of no benefit in children with limited disease.[13] Even in patients who present with central nervous system involvement, including cranial nerve palsies or extradural tumor with cord compression, the response to chemotherapy is so universal, while radiation is of questionable benefit [14] and can certainly have deleterious late effects, that the best course of action is to initiate immediate chemotherapy, unless there is a reason that this cannot be done (eg, uricosemic renal failure). In view of the excellent results of modern chemotherapy, attempts at tumor debulking are no longer recommended [15], although in circumstances in which such chemotherapy cannot be given (ie, in the poorest developing countries), this may still be a reasonable consideration, at least when essentially all of the tumor can be easily resected. Complete resection of tumor in technologically advanced countries is most often performed in patients who present with small tumor volumes, and an acute abdomen due either to tumor in the appendix, causing a syndrome resembling appendicitis, or in the small bowel, causing intussusception. Excisional biopsy is performed as the remedy for the acute problem, and usually necessitates only appendicectomy or excision of a short segment of bowel. In children and adolescents, several recent clinical trials have demonstrated that excellent overall results (approximately 90% prolonged disease-free survival) can be achieved with intensive drug combinations delivered over the course of a few months (Table 1).[2-4] Although only a few randomized studies have been conducted, including the comparison of a 10-drug combination leukemia-like therapy versus a four-drug combination lymphoma-like therapy (the latter was clearly superior)[16], and studies of the role of radiation and maintenance therapy in low risk patients (neither of which was shown to be of benefit), [17] there is little doubt, on the basis of the similarly improved results achieved in several countries, that multiple effective drugs, (ie, more than five), are necessary to the achievement of such excellent results in all except patients with the most limited disease.[2-4] Cyclophosphamide, methotrexate, and vincristine have been used since the early days of chemotherapy in African Burkitts lymphoma, and are highly effective agents, but the role of other generally used drugs, such as Adriamycin and corticosteroids is unclear. The latter is not included in the National Cancer Institute protocol.[2] The addition of drugs and drug combinations initially explored in patients with recurrent tumor to these basic drug regimens has been associated with improved survival rates.[18,19] Such drugs include epipodophyllotoxins, high-dose cytarabine, and ifosfamide. Methotrexate, in the most successful protocols, is usually given at high dosage (ie, above 5 g/m² for patients with more extensive disease). Such high dosages, in addition to demonstrated efficacy in patients with recurrent disease [20] have been associated, at least retrospectively, with an improved event-free survival rate in patients with extensive stage III disease compared to patients who received similar therapy but with 0.5 g/m² of methotrexate.[3] The optimal duration of methotrexate infusions is presently under study. Intrathecal therapy is needed to prevent the development of central nervous system disease which, although uncommon at presentation, except in African patients, has a high likelihood of subsequent development in the absence of central nervous system prophylaxis in all patients except those with completely resected, small volume gastrointestinal disease. Thus, all except the latter patients should receive intrathecal drugs. Usually both cytarabine (Cytosar) and methotrexate are given, but central nervous system radiation has not been shown to be effective in this context, and in view of the potential for significant central nervous system toxicity when used in conjunction with high-dose S-phase agents, should be avoided. In the context of conventional chemotherapy, refinements in the division of patients into risk groups, such that chemotherapy intensity is adapted as well as possible to tumor burden (which appears to be the most important indicator of outcome), continue to be made. Patients who present with a small tumor volume (a few centimeters), particularly if it is completely resected, have the best prognosis. Such small tumor volumes are likely only to result in diagnosis when the tumor is visible (ie, it presents as lymphadenopathy or tonsillar enlargement), or when it produces a major problem because of its location (ie, orbital tumor, intussusception, or appendicitis). Such patients can be effectively treated (ie, with survival rates of 95% to 100%) with as few as two cycles of chemotherapy and only three or four drugs).[4,21] It is possible that a single cycle of therapy would suffice for the majority of such patients, because long-term survivors have been reported in a small fraction of African patients treated with a single dose of cyclophosphamide.[22] This issue may not be sufficiently important to study, however, given the low toxicity of present therapy and the potential negative impact if the hypothesis proves to be wrong. For patients with greater tumor burdens, however (ie, patients with non-resected stage II disease), such minimal therapy is probably not adequate by todays standards. The Pediatric Oncology group (POG), for example, recently reported 94% survival at 10 years in patients with gastrointestinal stage II disease treated with a CHOP variant [23] and a survival rate only just in excess of 80% for other patients with limited disease, whereas Societe Francaise dOncologie Pediatrique (SFOP, or French Society of Pediatric Oncology), Berlin, Frankfurt, Munster group (BFM), and National Cancer Institute patients with limited disease (other than the completely resected primary in SFOP trials) receive more intensive therapy and achieve survival rates of 95% to 100% for non-GI stage II patients.[3,4,21] Patients with extensive disease, most often manifested as extensive intra-abdominal disease, with or without the involvement of other sites, require intensive therapy, although therapy need not be prolonged. Therapy durations of approximately 12 weeks, if sufficiently intensive and containing enough drugs, can produce event-free survival rates of 80% to 90%, depending upon the total tumor burden.[2] Patients with bone marrow involvement have had a poor prognosis in the past, usually because bone marrow disease is associated with extensive tumor (although, surprisingly, this is an uncommon site of involvement in the African child). Most pediatric oncologists refer to Burkitts lymphoma or Burkitt-like lymphoma in which there is greater than 25% of bone marrow involvement as acute B-cell leukemia. This can be confusing to the uninitiated, and is an entirely arbitrary designation. There is, at present, no evidence that the presence of bone marrow involvement connotes a biological difference in the disease, at least, any more so than does involvement of other anatomical sites. In adults, however, since the range of B-cell neoplasms is much broader than in children, there are more likely to be diagnostic difficulties in patients with acute B-cell leukemia. Immunohistochemistry (ie, to assess proliferative index) and chromosomal or molecular genetic analysis will help to increase the precision of diagnosis. Marrow involvement increases the likelihood of central nervous system involvement which, at one time, was associated with a very poor prognosis. Patients with central nervous system disease have been reported to have event-free survival rates in excess of 70% in several series (predominantly children).[2,4,24-26] Burkitts Lymphoma and Burkitt-like Lymphoma in Adults At the present time, many adult patients with Burkitts lymphoma or Burkitt-like lymphoma are treated with identical or similar chemotherapy regimens to those used in patients with so-called diffuse aggressive lymphomas, a category comprised predominantly of large-cell lymphomas.[27,28] Results are clearly inferior to those obtained in children and adolescents. Even the few studies reported in which treatment regimens have been designed for adult patients with Burkitts lymphoma or Burkitt-like lymphoma [29-31] do not appear to give results as good as those obtained in children (Table 1). However, preliminary studies with French, German, and United States protocols have demonstrated that with some treatment protocols, similar results may be observed in adults to those obtained in children (Figure 1).[2,21,32-34]. Patients above 60 to 65 years of age, depending upon their general health, are likely to be less tolerant of such intensive therapy. Burkitts lymphoma and Burkitt-like lymphoma occur predominantly in younger adults and there is, as yet, insufficient data to determine tolerance of these successful regimens in the elderly. Management of Lymphoblastic Lymphomas Lymphoblastic lymphoma is also a very rapidly growing tumor, although the fraction of cells in S phase is lower than that of Burkitts lymphoma. This, coupled to the frequent presentation with tumor in the anterior superior mediastinum (related to the frequent origin of lymphoblastic lymphoma from immature T cells), with the potential for tracheal, bronchial, or esophageal obstruction, as well as the development of pleural and pericardial effusions, indicate that patients with lymphoblastic lymphoma, like those with Burkitts lymphoma or Burkitt-like lymphoma, require rapid assessment and the early initiation of therapy. Once again, although radiotherapy was frequently used in the past, there is no evidence that radiation improves the outcome in patients treated with optimal chemotherapy regimens, and this, coupled to the risk of late effects, particularly late second malignancies and ischemic heart disease in this, on average, young group of patients, argues strongly against its routine use. Moreover, as with Burkitts lymphoma, because response to therapy is almost universal (many patients will have a significant response even to corticosteroids alone), it is difficult to justify the use of radiation even in patients who require urgent treatment because of compression of tumor-adjacent structures. One potential use, however, may be in the patient in whom there is an isolated mediastinal mass and tracheal compression prevents administration of an anesthetic for a biopsy. In some of these patients, carefully designed fields may permit relief of life-threatening mass effect while leaving some unirradiated tumor for subsequent biopsy. It is, of course, always essential to ensure that there is no other accessible tumor, for example, peripheral lymph nodes, bone marrow, or a serous effusion, before attempting such a course of action. Specific Chemotherapy A primary consideration in the management of lymphoblastic lymphoma is the borderline between this disease and acute lymphoblastic leukemia. Since histologically and cytologically these entities are indistinguishable, the point at which one ends and the other begins is an arbitrary determination. It is not unreasonable to assume that they represent different manifestations of the same disease, although whether some molecularly characterized subtypes are more or less likely to involve the bone marrow remains to be determined. Of interest in this regard is the fact that localized lymphoblastic lymphoma usually has a phenotype indistinguishable from precursor B-cell acute lymphoblastic leukemia. In some of these cases, subtle analyses of the bone marrow (eg, flow cytometric analysis), may reveal the submicroscopic presence of the malignant clone. Most pediatric oncologists use a cutoff of 25% blasts in the bone marrow to distinguish leukemia from lymphoma, while in adult oncology there is more variability in the definition such that results in children and adults are sometimes difficult to compare from the published literature. Whether lymphoblastic lymphoma and acute lymphoblastic leukemia are different facets of the same disease, or a family of diseases, is of practical importance only insofar as it influences the treatment approach. This tends to be much more varied in adults with lymphoblastic lymphoma than in children. In the mid 1980s, the Childrens Cancer Group showed that patients with extensive lymphoblastic lymphomas (approximately 85% to 90% of all patients) have a better outcome when receiving treatment based on acute lymphoblastic leukemia therapy than when treated with repeated cycles of a four-drug regimen containing cyclophosphamide, vincristine, prednisone, and methotrexate (the opposite was true when treated with Burkitts lymphoma and lymphoblastic lymphoma).[16] While this should not, perhaps, be interpreted as indicating that variations, or intensifications, of the latter approach would not result in a better outcome [35], there can be no doubt that treatment of lymphoblastic lymphoma in children and young adults with acute lymphoblastic leukemia therapy is highly effective (Table 2). In a French study, where high dose methotrexate was added to the LSA2L2 protocol used by the Childrens Cancer study group, an event-free survival of 75% (median follow up 57 months) was achieved.[36] The German BFM group recently reported an event-free survival rate of 92% at 5 years in T-cell lymphoblastic lymphoma, using a protocol essentially identical to that used for childhood acute lymphoblastic leukemia.[37] Because an acute lymphoblastic leukemia-like approach is used by most pediatric oncologists, the distinction between acute lymphoblastic leukemia and lymphoblastic lymphoma becomes unimportant, at least from the perspective of the therapeutic decision. In most of these protocols, bone marrow involvement is not a poor prognostic sign, as might be expected in protocols designed for acute lymphoblastic leukemia. In contrast, many oncologists still treat adult patients with drug combinations used for diffuse aggressive lymphomas, namely, CHOP or later-generation variants [38,39] of CHOP that have not been shown to have an advantage over CHOP, and results of treatment are considerably worse in adults than in children. This is consistent with the poor results in children with the lymphoma-like COMP (cyclophosphamide, vincristine, methotrexate, prednisone) protocol which included methotrexate instead of Adriamycin.[16] However, even protocols designed specifically for the treatment of adult lymphoblastic lymphoma, most of which incorporate some of the principles of the treatment of acute lymphoblastic leukemia, appear to give worse results (Table 2) [40-43] than those obtained in children treated with standard, highly effective protocols for the treatment of childhood acute lymphoblastic leukemia (particularly in patients with bone marrow involvement). It is possible that adult patients may have a different spectrum of subtypes of lymphoblastic lymphoma (ie, subtypes defined by the molecular lesions present in the tumor), or that they have simply not received adequate therapy. While acute lymphoblastic leukemia therapy has been highly successful in children, it cannot be assumed that all acute lymphoblastic leukemia protocols are equal and that all that is necessary to cure adults with lymphoblastic lymphoma is to use such a protocol. Indeed, LSA2L2 is not considered an optimal protocol for the treatment of children with T-cell acute lymphoblastic leukemia [44] and appears to be inferior to more recent acute lymphoblastic leukemia protocols in the treatment of lymphoblastic lymphoma. Patients With Limited Lymphoblastic Lymphoma Patients with extrathoracic, limited lymphoblastic lymphoma (ie, isolated nodal or bony sites) are uncommon, and tend frequently to have a precursor B-cell phenotype. How are they best treated? In children, one issue that appears to be of importance is the length of therapy. Treatment with the POG CHOP-like regimen for 9 weeks produced a poorer outcome than this regimen followed by 24 weeks of maintenance therapy with 6-mercaptopurine/MTX (methotrexate).[17] In the French and German cooperative group protocols, such patients receive the same therapy as patients with more extensive disease and have an excellent outcome.[3] Because such patients are few in number there remains uncertainty regarding their optimal treatment. It is unlikely to be resolved in the near future, since, for the same reason, clinical trials in this subgroup are difficult to perform. Bone Marrow Transplantation in First Remission A consequence of these relatively poor results achieved with most protocols used to date for Burkitts lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma in adults has been to explore the use of bone marrow transplantation or another form of stem-cell support for high-dose chemotherapy. However, only about 60% of patients treated with standard therapy to induce remission will achieve remission, and therefore be eligible for bone marrow transplantation. This means that even if all patients who achieve remission were subjected to transplantation and all were cured, the maximum overall survival rate would still only be 60%clearly inferior to results obtained in children. If allogeneic bone marrow transplantation were to be used (rather than autologous), donors would be obtainable in perhaps only one-third of patients although the potential for an advantageous graft-versus-tumor effect would exist. In practice, published survival rates of patients with Burkitts lymphoma or lymphoblastic lymphoma who receive bone marrow transplantation in first remission are at best 70% to 80%, and often significantly worse.[45-49] Thus, it would appear more rational to attempt to improve remission induction rates rather than increase the intensity of therapy only for the fraction of patients that achieve remission. Short intensive regimens have considerable promise in Burkitts lymphoma and Burkitt-like lymphoma, and it appears that higher induction rates can be obtained in adults with lymphoblastic lymphoma with at least some acute lymphoblastic leukemia-type induction regimens.[47] It has yet to be seen if in lymphoblastic lymphoma in adults, whether transplantation in remission will ultimately prove better than continuation with intensive acute lymphoblastic leukemia-type therapy but, based on present results, it is unlikely that the use of bone marrow transplantation as consolidation therapy will give survival rates as good as those being achieved in children treated with chemotherapy alone. Challenges for the Future While with some regimens, the majority of children with Burkitts lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma can be cured, and at least in the B-cell tumors there is promising evidence that regimens used in children may be equally successful in most adults, it will be important to confirm these results, and if confirmed, to ensure that such regimens become standard in adults as well as children. Even the excellent results obtained in children with Burkitts lymphoma, Burkitt-like lymphoma, and lymphoblastic lymphoma leave room for improvement, both with respect to patients with very extensive disease and to toxicity, whether acute or late. Randomized clinical trials do not represent an appropriate research tool in this context, even if restricted to patients with extensive disease, since to demonstrate small improvements in event-free survival would require very large numbers of patients, which are not feasible in these uncommon diseases, while there is an added disadvantagea high proportion of patients entered into trials of this kind would have disease curable with presently available therapy. Since the possibility of doing harm with modified therapy exists, it may even be considered unethical to randomize all patients to a different, presumably, more intensive therapy. Indeed, further intensification could lead to higher toxic death rates with no net benefit. Thus, improved means of detecting patients destined to achieve only partial response (which is a more important cause of failure than relapse) are warranted. Such patients may be recognized by careful measurement of the rate of response of their tumor to chemotherapy, although in making such measurements, the problem of nonviable tumor residua must not be overlooked. An alternative approach is to attempt to identify the molecular genetic correlates of chemotherapy resistance. In patients destined to achieve only a partial response, a significant fraction of the cells present at the time of initiation of therapy can be expected to be resistant, making this prospect feasible. There are many mechanisms that lead to drug resistance; one approach to the identification of such patients would be microarray technology. This technology allows the expression of thousands of genes to be simultaneously examined in tumor cells. Although dealing only with expression, functional changes caused by point mutation or major structural changes in one gene are likely to result in modifications in the expression of other genes in the downstream pathway. Mutations can be directly assessed by similar techniques, but this approach is presently limited by the need to seek specific mutations or structural changes in selected genes. Even before treatment, once a means is found to identify patients destined to do badly, either before treatment or shortly after its initiation, modifications in the therapeutic approach could then be made this subset of patients. Such modifications might include: additional chemotherapeutic agents or very high dose therapy with stem-cell rescue (although salvage of partial responders by this means is very unlikely after modern intensive chemotherapy [50]); potentiating agents (ie, those which may influence specific biochemical pathways relevant to tumor cell apoptosis); immunotherapy, including immunotoxin and immunoradiopharmaceuticals; and therapy targeted at the genetic changes relevant to pathogenesis. A number of novel, targeted approaches are presently being studied, and although some of these show promise, they remain highly experimental (the majority are still in preclinical phases of development).[51-55] If such approaches can be shown to be beneficial in the highest risk patients, their use in other patients may be justified if toxicity can be shown to be less than that of conventional therapy. Summary and Conclusions Considerable progress has been made in the treatment of Burkitts lymphoma, Burkitt-like lymphoma, and lymphoblastic lymphoma in children and young adults. Today, 80% to 90% of all such patients are cured with intensive short duration protocols for Burkitts lymphoma and Burkitt-like lymphoma, and effective acute lymphoblastic leukemia protocols for lymphoblastic lymphoma. Unfortunately, all too many adults with these diseases are still treated with CHOP or second- and third-generation protocols used for patients with so-called diffuse aggressive lymphomas, a strategy that is clearly less effective, with anticipated cure rates of some 50% at best. Preliminary results in these diseases (particularly for Burkitts lymphoma and Burkitt-like lymphoma), suggest that the type of protocols used in children give better results in adults than standard protocols for diffuse aggressive lymphomas. One problem that must be addressed if results of therapy are to be improved is that of diagnosis. Burkitt-like lymphoma in children may have a much narrower spectrum than Burkitt-like lymphoma in adults, and it is possible that only a fraction of Burkitt-like lymphomas in adults, depending upon the definition used, will have similar outcomes to children or adults with Burkitts lymphoma when treated with the same regimens. Those with a high proliferative index may be the most likely to respond to such therapies. In the case of lymphoblastic lymphoma, it is unclear whether the approaches used in children will be as beneficial in adults (although this has yet to be put to the test in a similarly defined patient group), and it is possible that there are biological differences between childhood and adult lymphoblastic lymphoma. Finally, resort to bone marrow transplantation in first remission has tempted many, but in Burkitts lymphoma and lymphoblastic lymphoma, even the best reported results (including all patients, not just those who undergo transplantation) fall far short of those achieved in several series of young patients with chemotherapy alone. This approach clearly cannot lead to improved overall survival rates unless improved rates of remission induction can be achieved. It would seem likely that in addition to the extent of disease, its biology (ie, the sum of the genetic changes that have given rise to it), is a more important determinant of treatment outcome than age. The latter is likely to be of importance only in the very young and the elderly, in which pharmacokinetics, co-morbidities, and tolerance to therapy, may differ. References: 1. National Cancer Institute-sponsored study of the classifications of non-Hodgkins lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49: 2112-2135, 1982. 2. Adde M, Shad A, Venzon D et al: Additional chemotherapy agents improve treatment outcome for children and adults with advanced B-cell lymphomas. Semin Oncol 2(Suppl 4):33-39, 1998. 3. Reiter A, Schrappe M, Parwaresch R, et al: Non-Hodgkins lymphomas of childhood and adolescence: Results of a treatment stratified for biologic subtypes and stagea report of the Berlin-Frankfurt-Munster Group. J Clin Oncol 2:359-372, 1995 4. Patte C, Michon J, Frappaz D, et al: Therapy of Burkitt and other B-cell acute lymphoblastic leukaemia and lymphoma: Experience with the LMB protocols of the SFOP(French Paediatric Oncology Society) in children and adults. Baillieres Clin Haematol 2:339-248, 1994. 5. Brecher ML, Schwenn MR, Coppes MJ, et al: Fractionated cylophosphamide and back to back high dose methotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (SNCCL): A randomized trial of the Pediatric Oncology Group.Med Pediatr Oncol 6:526-533, 1997. 6. Magrath IT: The treatment of pediatric lymphomas: paradigms to plagiarize? Ann Oncol 8(Suppl 1):7-14, 1997. 7. Magrath IT: Introduction: Concepts and controversies in lymphoid neoplasia. In The Non-Hodgkins Lymphomas, second edition. Ed, Ian Magrath. Arnold, London, pp 3-46, 1997. 8. Siebert R, Matthiesen P, Harder S, et al: Application of interphase fluorescence in situ Hybridization for the detection of the Burkitt translocation t(8;14)(q24;q32) in B-cell lymphomas. Blood 91:984-990, 1998. 9. Engelhard M, Brittinger G, Huhn D, et al: Subclassification of diffuse large B-cell lymphomas according to the Kiel classification: Distinction of centroblastic and immunoblastic lymphomas is a significant prognostic risk factor. Blood 89:2291-2297, 1997. 10. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994. 11. Miller TP, Grogan TM, Dahlberg S, et al: Prognostic significance of the Ki-67-associated proliferativeantigen in aggressive non-Hodgkins lymphomas: a prospective Southwest Oncology Group trial. Blood 83:1460-1466, 1994. 12. Rivera-Luna R, Martinez-Guerra G, Martinez-Avalos A, et al: Treatment of non-Hodgkins lymphoma in Mexican children. The effectiveness of chemotherapy during malnutrition. Am J Pediatr Hematol Oncol 9:356-366, 1987. 13. Link MP, Donaldson SS, Berard CW, et al: Results of treatment of childhood localized non-Hodgkins Iymphoma with combination chemotherapy with or without radiotherapy. N Engl J Med 322:1169-1174, 1990. 14. Wong ET, Portlock CS, OBrien JP, et al: Chemosensitive epidural spinal cord disease in non-Hodgkins lymphoma. Neurology 46:1543-1547, 1996. 15. Miron I, Frappaz D, Brunat-Mentigny M, et al: Initial management of advanced Burkitt lymphoma in children: is there still a place for surgery? Pediatr Hematol Oncol 14:555-561, 1997. 16. Anderson JR, Jenkin RD, Wilson JF, et al: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkins lymphoma: A report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11:1024-1032, 1993. 17. Link MP, Shuster JJ, Donaldson SS, et al: Treatment of children and young adults with early-stage non-Hodgkins lymphoma. N Engl J Med 337:1259-1266, 1997. 18. Magrath I, Adde M, Sandlund J, et al: Ifosfamide in the treatment of high-grade recurrent non-Hodgkins lymphomas. Hematol Oncol 9:267-274, 1991. 19. Gentet JC, Patte C, Quintana E: Phase II study of cytarabine and etoposide in children with refractory or relapsed non-Hodgkins lymphoma: A study of the French Society of Pediatric. Oncology.J Clin Oncol 8(4):661-665, 1995. 20. Patte C, Bernard A, Hartmann O, et al: High-dose methotrexate and continuous infusion Ara-C in childrens non-Hodgkins lymphoma: phase II studies and their use in further protocols. Pediatr Hematol Oncol 3:11-18, 1986. 21. Magrath I, Adde M, Shad A, et al: Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol 14:925-934, 1996. 22. Burkitt D: Long-term remissions following one and two dose chemotherapy for African lymphoma. Cancer 20:756-59, 1967. 23. Link MP, Shuster JJ, Hutchison RE, et al: Minimizing therapy for children with localized non-Hodgkins lymphomas of hte gastrointestinal tract. Proc Am Soc Clin Oncol 17:528a (A2030), 1998. 24. Reiter A, Schrappe M, Ludwig WD, et al: Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood 80:2471-2478, 1992. 25. Bowman WP, Shuster JJ, Cook B, et al: Improved survival for children with B-cell acute lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: A pediatric oncology group study. J Clin Oncol 14:1252-1261, 1996. 26. Waits TM, Greco FA, Greer JP, et al: Treatment of poor prognosis non-Hodgkins lymphoma with intensive, inpatient combination chemotherapy of brief duration: long-term follow-up. Leuk Lymphoma 10:453-459, 1993. 27. Lepage E, Gisselbrecht C, Haioun C, et al: Prognostic significance of received relative dose intensity in non-Hodgkins lymphoma patients: application to LNH-87 protocol. The GELA (Groupe dEtude des Lymphomes de lAdulte). Ann Oncol 4:6510-656, 1993. 28. Lopez TM, Hagemeister FB, McLoughlin P, et al: Small noncleaved cell lymphoma in adults: Superior results for stages I-III disease. J Clin Oncol 8:615-622, 1990. 29. McMaster ML, Greer JP, Greco FA, et al: Effective treatment of small noncleaved cell lymphoma with high-intensity, brief duration chemotherapy. J Clin Oncol 9:941-946, 1991. 30. Mazza JJ, Hines JD, Andersen JW, et al: Aggressive chemotherapy in the treatment of Burkitts and non-Burkitts undifferentiated lymphoma. Leukemia and Lymphoma 18: 289-96, 1995. 31. Soussain C, Patte C, Ostronoff M, et al: Small noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the LMB pediatric protocols. Blood 85:664-674, 1995. 32. Pees HW, Radtke H, Schwamborn J, et al: The BFM-protocol for HIV-negative Burkitts lymphomas and L3 acute lymphoblastic leukemia in adult patients: a high chance for cure. Ann Hematol 65:201-205, 1992. 33. Todeschini G, Tecchio C, Degani D, et al: Eighty-one percent event-free survival in advanced Burkitts lymphoma/leukemia: No differences in outcome between pediatric and adult patients treated with the same intensive pediatric protocol. Ann Oncol 8(Suppl 1):77-81, 1997. 34. Tubergen DG, Krailo MD, Meadows AT, et al: Comparison of treatment regimens for pediatric lymphoblastic non-Hodgkins lymphoma: A Childrens Cancer Group study. J Clin Oncol 13:1368-1376, 1995. 35. Patte C, Kalifa C, Flamant F, et al: Results of the LMT81 Protocol, a modified LSA2L2 protocol with high dose methotrexate, on 84 children with non-B-cell (lymphoblastic) lymphoma. Med Pediatr Oncol 20:105-113, 1992. 36. Schrappe M, Tiemann M, Ludwig WD, et al: Risk-adapted therapy for lymphoblastic T-cell lymphoma: Results from trials NHL-BFM 86 and 90. Med and Ped Oncol 29:356(A-0-141), 1997. 37. Vose JM, Armitage JO: The present status of therapy for patients with aggressive non-Hodgkins lymphoma. Ann Oncol 2(Suppl 2):171-176, 1991. 38. Colgan JP, Andersen J, Habermann TM, et al: Long-term follow-up of a CHOP-based regimen with maintenance therapy and central nervous system prophylaxis in lymphoblastic non-Hodgkins lymphoma. Leuk Lymphoma 15:291-296, 1994. 39. Coleman CN, Picozzi VJ Jr, Cox RS, et al: Treatment of lymphoblastic lymphoma in adults. J Clin Oncol 11:1628-1637, 1986. 40. Slater DE, Mertelsmann R, Koziner B, et al: Lymphoblastic lymphoma in adults. J Clin Oncol 1:57-67, 1986. 41. Bernasconi C, Brusamolino E, Lazzarino M, et al: Lymphoblastic lymphoma in adult patients: Clinicopathological features and response to intensive multiagent chemotherapy analogous to that used in acute lymphoblastic leukemia. Ann Oncol 1:141-146, 1990. 42. Morel P, Lepage E, Brice P, et al: Prognosis and treatment of lymphoblastic lymphoma in adults: A report on 80 patients. J Clin Oncol 7:1078-1085, 1992. 43. Cherlow JM, Steinherz PG, Sather HN, et al: The role of radiation therapy in the treatment of acute lymphoblastic leukemia with lymphomatous presentation: A report from the Childrens Cancer Group. Int J Radiat Oncol Biol Phys 27:1001-1009, 1993. 44. Sweetenham JW, Pearce R, Taghipour G, et al: Adult Burkitts and Burkitt-like non-Hodgkins lymphoma-outcome for patients treated with high-dose therapy and autologous stem-cell transplantation in first remission or at relapse: results from the European Group for Blood and Marrow Transplantation. J Clin Oncol 14:2465-2472, 1996. 45. Pettengell R, Radford JA, Morgenstern GR, et al: Survival benefit from high-dose therapy with autologous blood progenitor-cell transplantation in poor-prognosis non-Hodgkins lymphoma. J Clin Oncol 14:586-592, 1996. 46. Bouabdallah R, Xerri L , Bardou V-J, et al: Role of induction chemotherapy and bone marrow transplantation in adult lymphoblastic lymphoma: a report on 62 patients from a single center. Ann Oncol 9:619-625, 1998. 47. Sweetenham JW, Liberti G, Pearce R, et al: High-dose therapy and autologous bone marrow transplantation of adult patients with lymphobastic lymphoma: Results of the European Group for Bone Marrow Transplantation. J Clin Oncol 12:1358-1365, 1994. 48. Santini G, Congiu AM, Coser P, et al: Autologous bone marrow transplantation for adult advanced stage lymphoblastic lymphoma in first CR. A study of the NHLSCG. Leukemia 5(Suppl 1):42-45, 1991. 49. Ladenstein R, Pearce R, Hartmann O, et al: High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitts lymphoma: A report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 90:2921-2930, 1997. 50. Khanna R, Cooper L, Kienzle N, et al: Engagement of CD40 antigen with soluble CD40 ligand up-regulates peptide transporter expression and restores endogenous processing function in Burkitts lymphoma cells. J Immunol 159:5782-5785, 1997. 51. Judde JG, Spangler G, Magrath I, et al: Use of Epstein-Barr virus nuclear antigen-1 in targeted therapy of EBV-associated neoplasia. Hum Gene Ther 7:647-653, 1996. 52. Gutierrez MI, Judde JG, Magrath IT, et al: Switching viral latency to viral lysis: A novel therapeutic approach for Epstein-Barr virus-associated neoplasia. Cancer Res 56:969-972, 1996. 53. Smith JB, Wickstrom E: Antisense c-myc and immunostimulatory oligonucleotide inhibition of tumorigenesis in a murine B-cell lymphoma transplant model. J Natl Cancer Inst 90:1146-1154, 1998. 54. French RR, Penney CA, Browning AC: Delivery of the ribosome-inactivating protein, gelonin, to lymphoma cells via CD22 and CD38 using bispecific antibodies. Br J Cancer 71:986-994, 1995. 55. Sang BC, Shi L, Dias P, et al: Monoclonal antibodies specific to the acute lymphoblastic leukemia t(1;19)-associated E2A/pbx1 chimeric protein: Characterization and diagnostic utility. Blood 89:2909-2914, 1997.