Chapter 102: Burkitt Lymphoma

Burkitt lymphoma (BL) may present in three distinct forms: endemic (African), sporadic, and immunodeficiency-associated.¹ The endemic form (eBL) is the most common pediatric tumor in sub-Saharan Africa and other regions of the world where malaria is endemic. It typically presents in the jaw or maxilla, and is associated with Epstein-Barr virus (EBV) infection at an early age. Although there are reports dating to as early as 1910, it was Denis Burkitt who is credited with describing this malignancy in 1958 as a common tumor in children of Uganda.^2,3 Originally thought by Burkitt to be a sarcoma of the jaw, it was a pathologist named George O’Connor who, in 1960, concluded it was a lymphoma.⁴ In 1964, while studying BL samples by electron microscopy, Sir Michael Anthony Epstein, Yvonne Barr, and Bert Achong discovered EBV when they recognized viral particles were present in tumor cells,⁵ thus helping to launch the nascent field of tumor virology. Further studies of BL over many years led to epidemiologic associations with both EBV and malaria in Africa.^6,7 Tumors of a similar histologic appearance were subsequently identified in the United States, Middle East, and elsewhere (i.e., nonendemic regions) and termed sporadic BL. Sporadic cases were found to occur in older individuals, typically presented in the abdomen rather than the orofacial region, and were infrequently associated with EBV.⁸ In 1985, a third class of BL was identified in immunosuppressed patients, most commonly as a result of infection with HIV.⁹ BL was referred to as “small noncleaved cell lymphoma” according to the Kiel classification system proposed by Karl Lennert in 1977, but this designation is no longer used. In the mid-1970s, recurrent chromosomal translocations involving chromosomes 8 and 14 were described in BL,^10,11 paving the way for the identification of MYC as an important human oncogene when it was shown to be the translocation partner involved with immunoglobulin (Ig) heavy-chain and light-chain translocations.^12,13 Evolution in the diagnosis and treatment of BL has occurred over the past few decades. High cure rates are now achieved among pediatric and young adult populations in healthcare settings capable of delivering intensive combined chemotherapy regimens, both with and without B-cell–directed monoclonal antibody therapy (i.e., rituximab). In 2006, a “molecular signature” for BL was developed from gene-expression profiling (GEP) data,¹⁴ and in 2012 the first whole-genome sequences were published.¹⁵ Despite these scientific and technologic advances in our understanding of this historically important disease, translation of this information into specific targeted therapeutics for BL (i.e., inhibitors of known dysregulated pathways or mutated gene products) has yet to be realized.

The endemic form of BL is found in equatorial Africa (as well as Brazil, Papua New Guinea, and other malaria-endemic regions), with a peak age incidence at 4 to 7 years, and is nearly twice as frequent in boys as in girls. In Africa it accounts for 20 percent of cancers in newborns to 14-year-olds, and for the majority of non-Hodgkin lymphomas (NHLs) in all age groups.¹⁶ Infection by EBV is found in nearly 100 percent of patients with eBL, and higher titers are linked to increase risk of eBL.⁷ Although not as close, there is an epidemiologic association with malaria,¹⁷ in addition to other environmental factors.¹⁶ Sporadic BL, defined as cases outside of endemic African regions, accounts for 1 to 2 percent of NHL, is higher in males than in females, and has a median age of 30 years. In the United States, BL exhibits a primarily a bimodal age distribution, with at least two incidence peaks of approximately 10 and 75 years of age (median age of approximately 30 years), as compared to other NHLs, which generally increase from childhood through adulthood.¹⁸ Immunodeficiency-related BL increased in incidence during the AIDS epidemic; however, with improved antiretroviral therapy, the incidence has decreased in the United States and countries with access to effective therapy for HIV.

MOLECULAR GENETICS

Myc Overexpression and Gene-Expression Profiling

The unifying feature of all three types of BL is activation of the MYC gene via an Ig translocation leading to high levels of MYC protein, which activates transcription of a variety of genes involved in cell growth. Translocations are thought to occur via double-stranded DNA breaks that occur during normal class-switch reaction and somatic hypermutation in mature B-cell development, which, in turn, depends on activation-induced cytidine deaminase.¹⁹ In addition, somatic point mutation of growth-regulatory genes (such as MYC) which are also caused by activation-induced cytidine deaminase may also play an important role.²⁰ The dominant role of MYC activation in BL pathogenesis is emphasized by the results of multiple independent gene-expression studies. GEP analysis is capable of distinguishing BL from diffuse large B-cell lymphoma (DLBCL), and this finding is predicated on identifying cases with highly expressed target genes of MYC, as well as markers of germinal center B cells, and lower expression of target genes of the nuclear factor (NF)-κB pathway.²¹ In a separate study, a core group of eight cases of pediatric BL (fulfilling World Health Organization [WHO] criteria) were used to generate a molecular signature, and tumors that matched this expression pattern were termed “molecular BL” (mBL).²² Additional characteristics of this group included lower cytogenetic complexity (including near total absence of translocations involving BCL6 and/or IGH-BCL2) and the presence of MYC translocations involving Ig genes, rather than non-Ig partners, features which, again, distinguish BL from DLBCLs and other high-grade NHLs.

Next Generation Sequencing and ID3/TCF3 Mutations

Advanced sequencing analysis at the level of the whole genome, exome, and transcriptome has provided a more complete view of the spectrum of somatic mutations that occur in Burkitt lymphomagenesis and identified several recurring and previously unappreciated determinants of molecular pathogenesis. In addition to mutations in MYC, as many as 70 additional genes were found to be recurrently mutated in BL.²³ Mutations in ID3, TCF3, and CCND3 are among the most common seen in multiple independent studies.^23,24,25 ID3 is a member of the inhibitor of DNA binding (ID) protein family, and it is a negative regulator of transcription factor TCF3. The presence of biallelic inactivating mutations and/or deletions of ID3 suggests it serves as a tumor suppressor. TCF3, conversely, was shown to be essential for BL cell viability, and the presence of monoallelic mutations that result in substitutions among highly conserved amino acid residues suggests gain of function mutations in TCF3 may result. Overall, the mutational landscape for BL differs significantly from DLBCL. For example, relatively few ID3 mutations were found among other B-cell lymphomas, even in those with Ig-MYC translocations.²⁴ ID3 and/or TCF3 mutations were also common among all three epidemiologic subtypes of BL. CCND3 mutations were rare in eBL, but abundant in the other two subtypes.²⁵

ALTERED IMMUNE STATUS AND INFECTION

HIV-Associated and Endemic Disease

Underlying immune alteration likely plays a role in at least two epidemiologic subtypes of BL (endemic and immunodeficiency-associated), although teasing apart the precise role of immune function in BL pathogenesis has proven challenging. Immunodeficiency-associated BL occurs predominantly in HIV-positive patients. Its occurrence does not directly correlate with CD4+ T cell status, and BL only rarely occurs with other forms of immunosuppression. BL is different from other EBV-associated lymphoproliferative disorders that occur with advanced HIV, yet is otherwise comparable to EBV-positive posttransplantation lymphoproliferative disorders (PTLDs) that arise in severely immunosuppressed solid-organ allograft recipients.²⁶ Rather, the clinical course and pathogenesis of immunodeficiency-associated BL more closely parallels that of sporadic BL in the immunologically intact patient. In eBL, the underlying immune alteration is probably multifactorial, may be influenced by chronic malnutrition, and may stem from chronic immune activation to various stimuli including holoendemic malaria, EBV, and possibly other environmental agents.^27,28

Epstein-Barr Virus and Malaria

The clear epidemiologic and immunologic link to malaria and EBV-infection has led several investigators to characterize eBL as a “polymicrobial” disease.²⁹ Numerous biological mechanisms have been proposed to explain the etiologic link between eBL and each infection. For example, EBV may play a role prior to the MYC translocation event, simultaneously inducing proliferation (via Epstein-Barr nuclear antigen [EBNA]-2) and inhibiting apoptosis (via EBNA3A- and EBNA3C-induced epigenetic silencing of proapoptotic protein Bim [Bcl-2-interacting mediator of cell death], a key defender of MYC-induced tumorigenesis).³⁰ Alternatively, inhibition of apoptosis may be sustained in BL tumor cells as a result of EBNA-1 expression (the only latency-associated viral protein consistently expressed in BL), noncoding viral RNAs (including Epstein-Barr virus-encoded RNA [EBER] and microRNAs), or possibly as a result of epigenetic reprogramming.³¹ Precise mechanisms for the role of malaria in eBL are less clear, but it has been shown that Plasmodium species can stimulate B cells in a polyclonal fashion,^32,33 the effects of which may modulate EBV transcriptional programs within infected B cells.³⁴ Malaria infection also modulates virus-specific T-cell responses to EBV.³⁵ By simultaneously expanding EBV-infected B cells, which may dysregulate the activation induced cytidine deaminase function and thereby increase the chance of acquiring a MYC translocation, while at the same time perturbing the host’s antiviral immune response, malaria infection may serve as a critical facilitator that brings together these otherwise disparate pathologic events in a manner that predisposes specific populations to developing eBL.³⁶ Overall, these findings suggest that BL emerges in the setting of chronically altered but fundamentally intact immune system.

The endemic (African) form often presents as a jaw or facial bone tumor. It may spread to extranodal sites, especially to the marrow and meninges. Almost all cases are EBV-positive. The nonendemic or American form presents as an abdominal mass in approximately 65 percent of cases, often with ascites. Extranodal sites, such as the kidneys, gonads, breast, marrow, and CNS, may be involved. Involvement of the marrow and CNS is much more common in the nonendemic form. Patients with more than 25 percent marrow involvement with malignant cells often are referred to as having Burkitt cell leukemia (see Blood and Marrow below). In addition, in contrast to the endemic form, only 15 percent of the nonendemic cases are EBV-positive.

Immunodeficiency-related cases often involve the lymph nodes and are associated with EBV in 30 percent of the cases. Staging using the system modified for childhood BL (Murphy staging system, Table 102–1) may be used rather than the Ann Arbor system, given that BL is largely an extranodal lymphoma.

BLOOD AND MARROW

Patients with bulky disease may have Burkitt cells in marrow and blood with accompanying suppression of normal blood counts. Characteristic pathologic features of BL on smear preparation are intermediate-size cells with round nuclei, multiple nucleoli, strongly basophilic cytoplasm (a consequence of the abundant polyribosomes), and the presence of lipid-filled cytoplasmic vesicles, some of which overlie the nucleus (Fig. 102–1). Rare cases, more commonly in males, may present principally with marrow and blood involvement, so-called Burkitt cell leukemia variant (previously classified as acute lymphocytic leukemia–L3, according to the former French-American-British [FAB] classification).

The serum lactic dehydrogenase (LDH) is often elevated as a reflection of the high cell turnover, especially in patients with bulky disease.

HISTOPATHOLOGY AND CYTOLOGY

BL is characterized by monomorphic medium-size cells with round nuclei, multiple nucleoli, and basophilic cytoplasm.³⁷ Burkitt cells have a very high proliferative rate (≥95 percent as determined by Ki-67 staining) and frequent mitotic figures are usually present. BL has a diffuse pattern of growth comprised of intermediate-size B cells (12 μM diameter on a blood or marrow film) with a high nuclear-to-cytoplasmic ratio. Nuclear contours are round to oval without cleaves or folds, a key feature in the distinction from DLBCL. Nucleoli are typically multiple, small-to-intermediate in size, and the nuclear chromatin is relatively immature, being finely granular. Along with a high proliferation rate these cells are characterized by a high rate of spontaneous apoptosis leading to the characteristic “starry sky” pattern in marrow and lymph nodes—a monomorphic diffuse background of lymphoma cells that is interspersed with reactive macrophages engulfing cellular debris (so-called tingible-body macrophages) (see Fig. 102–1).

IMMUNOPHENOTYPE

BL cells are mature B cells, positive for CD19, CD20, CD22, and CD79a, and have monotypic surface IgM; they lack CD5 and CD23. BL cells also show immunologic similarity to germinal center cells of B-cell follicles rather than activated B cells, being positive for BCL6, CD10, Tcl1, and CD38, negative for Mum-1, CD44, CD138, TdT (terminal deoxynucleotidyl transferase), and importantly little to no expression of BCL2. However, germinal center cells markers are not specific for BL, since a significant proportion of DLBCL also has this germinal center cell signature.

EPSTEIN-BARR VIRUS STUDIES

Although EBV is associated with 98 percent of eBL, it is also seen in 20 percent of sporadic cases, and in 30 to 40 percent of HIV-associated cases.³⁸ It can be detected using in situ hybridization for EBER. Although EBV likely plays a key role in B-cell stimulation during a prelymphoma stage, the role for EBV after lymphoma development is unclear, as is whether EBV positivity is clinically meaningful. In EBV-positive endemic cases, CD21 (the EBV receptor) is expressed and is negative in most EBV-negative nonendemic BL cases. In contrast to primary effusion lymphomas and DLBCL, EBV-positive, HIV-associated BL does not express LMP1 or EBNA2.

CYTOGENETICS

Virtually all cases of BL have a translocation between the long arm of chromosome 8, the site of the MYC protooncogene (8q24), and one of three translocation partners: the Ig heavy-chain region on chromosome 14; the κ light-chain locus on chromosome 2; or the λ light-chain locus on chromosome 22. The translocations involving MYC can be detected by fluorescence in situ hybridization (FISH) using so-called MYC “break apart” probes: a set of two fluorescently tagged DNA probes of two different colors that hybridize to the upstream and downstream side of the gene. In an unperturbed gene, they hybridize together within interphase cells giving a composite color, whereas with translocation, the two fluorescently labeled probes are separated. A key feature of BL is the relative simplicity of their karyotype; in the majority of cases, the MYC translocation is the sole abnormality. This relatively limited degree of chromosomal change has been confirmed by microarray studies which can detect submicroscopic chromosomal alterations.^39,40 Among the few changes repeatedly seen by microarray, MYC amplification is found in mBL cases that lack Ig-MYC translocation. In general, this noncomplex cytogenetic profile for BL distinguishes it from DLBCL, which is among one of the primary considerations in the differential diagnosis with BL, as discussed below.

DIFFUSE LARGE B-CELL LYMPHOMA

The primary pathologic diagnosis in the differential diagnosis of BL is DLBCL.⁴¹ Since the publication of the 2008 WHO guidelines,¹ the diagnosis of BL has been refined and diagnostic criteria have been tightened. Although the majority of BL cases, even in the adult, possess all of the criteria for the diagnosis: high mitotic rate in an appropriate morphologic and immunophenotypic setting, together with an Ig-positive MYC translocation, significant overlap exists with DLBCL and a minority of cases do not fit neatly into the diagnosis of either. Typically, this arises because of the absence of key morphologic features in a lesion that otherwise resembles BL: a nonmonomorphic nuclear morphology; fewer tingible-body macrophages than is typical; or an abnormal immunophenotype. Terms that were once frequently used to describe such cases, such as “atypical” BL or “Burkitt-like lymphoma,” have fallen out of favor for diagnostic purposes, and these cases may be best classified as an intermediate or unclassifiable B-cell lymphoma (see “B-Cell Lymphoma, Unclassifiable” below). Consequently the term “Burkitt lymphoma” is now reserved for a more pathologically uniform tumor type, and thus BL now arguably comprises one of the most homogeneous subtypes of aggressive B-cell NHL.

B-CELL LYMPHOMA, UNCLASSIFIABLE

To address the spectrum of overlapping clinicopathologic features exhibited by some cases that fall outside BL, the WHO developed a mixed classifier, termed “B-cell lymphoma, unclassifiable, (BCL-U) with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma.”⁴² Although some propose that this category represents a distinct clinicopathologic entity, this designation is primarily reserved for cases with morphologic and/or immunophenotypic features that preclude more specific classification into either group. The BCL-U category is not intended simply to include otherwise conventional DLBCL that harbor a MYC translocation, or conversely BL for which a MYC translocation cannot be demonstrated.

DOUBLE-HIT LYMPHOMA

Another diagnostic term that has recently gained widespread use is “double-hit lymphoma” (DHL).⁴³ Although not a formal diagnostic category, DHL refers to a subset of aggressive mature B-cell (non-Burkitt) lymphomas that harbor translocations of MYC as well as at least one other protooncogene (most commonly BCL2 or BCL6). Distinction of such a subset is warranted given that DHL, empirically, has among the worst prognosis of any NHL and patients may benefit from more intensive chemotherapy. The prognostic implication for DLBCLs that overexpress both MYC and BCL2 (i.e., “double-hit” patterns of protein expression as determined by immunohistochemistry) is similar.⁴⁴ Whereas DHL most frequently exhibits histomorphologic features of DLBCL or BCL-U, and the importance of BCL2 activity clearly distinguishes it from BL, the clinical aggressiveness of these tumors and critical importance of MYC dysregulation have prompted comparisons to BL.

B-CELL LYMPHOBLASTIC LYMPHOMA

Despite the fact that B-cell lymphoblastic lymphoma (B-LBL; a.k.a. B-cell acute lymphoblastic leukemia [B-ALL]) is a malignant neoplasm of immature B-cell precursors, numerous features warrant its consideration in the differential diagnosis with BL, including: anatomic distribution (marrow, soft tissues, and nodes), high proliferation index, overlapping histomorphology (medium-size round-cell morphology, finely dispersed nuclear chromatin, high nuclear-to-cytoplasmic ratio, and occasional “starry sky” pattern), immunophenotype (CD10-positive/CD20-variable), and propensity to occur in young patients. Distinctive features include the expression of TdT, absence of mature B-cell markers (e.g., surface immunoglobulin expression and BCL6), and the distinctive cytologic and flow cytometric features of immature blasts.

GENERAL CONSIDERATIONS

BL is a highly aggressive tumor; however, therapy with multiagent chemotherapeutic programs results in excellent long-term remission rates and long-term survival of up to 85 percent of children. Applying the same chemotherapy regimens to adults has shown dramatically improved response rates.^45,46,47 Risk stratification allows patients with limited disease to be treated with less-intensive therapy than more advanced cases and still achieve very high responses, although the vast majority of patients present with advanced disease. Patients with extensive disease can achieve 80 percent long-term survival. The regimens employ multiple non–cross-resistant drugs used over a short period. These drugs include high-dose cyclophosphamide, methotrexate, vincristine, prednisone, high-dose methotrexate, high-dose cytarabine, etoposide, and sometimes ifosfamide. CNS prophylaxis therapy, either intrathecal or systemic, is given in almost all patients with BL. Radiation therapy does not play a role in the treatment of BL, and use of radiation therapy for limited-stage diseases is of no additional benefit.^48,49

TUMOR LYSIS SYNDROME

The tumor lysis syndrome is a serious metabolic complication of rapidly growing tumors, of which BL is a classic example. The syndrome is the result of the rapid destruction of tumor cells, highly sensitive to chemotherapy, and can result in hyperuricemia, hyperkalemia, hyperphosphatemia, secondary hypocalcemia, metabolic acidosis, and renal failure. In tumors such as BL the cell death rate (and proliferative rate) may be so substantial in patients with bulky disease that the tumor lysis syndrome may occur before therapy, so-called spontaneous tumor lysis.⁵⁰ Spontaneous tumor lysis is a highly morbid phenomenon with a poor prognosis for a salutary outcome from therapy and a complication with a high death rate. It occurs in patients with a high body burden of tumor, usually with abdominal disease, a common situation in BL. Its principal manifestation is the combination of hyperuricemia and azotemia. In BL a critical part of therapy is recognizing incipient or overt spontaneous tumor lysis rapidly or preventing chemotherapy-induced tumor lysis. LDH has been used as a surrogate marker for risk of tumor lysis with a serum level twice the upper limit of normal for the laboratory in question being the threshold for urgent concern. The usual prophylactic therapy for this situation is carefully monitored hydration of at least 3 L of saline per day and either allopurinol or rasburicase to decrease serum uric acid concentration and thereby hyperuricosuria. Rasburicase acts more quickly than allopurinol and should be used if risk is considered high or if evidence of spontaneous tumor lysis is present initially.^51,52 Continuous venovenous hemofiltration has also been very useful in allowing concomitant full-dose chemotherapy and preventing tumor lysis and renal failure.^53,54

SPECIFIC REGIMENS

The specific regimens that have been developed to treat BL have historically been adapted from pediatric experience; Table 102–2 depicts representative trial results, including adult patients. There are no studies directly comparing these regimens, and comparison among the single-arm studies is difficult because of lack of uniform diagnostic criteria, staging, and the heterogeneous patient populations studied. In general, shorter durations of chemotherapy (i.e., 6 months) are as good as longer (18 months) periods of treatment. Other studies have shown a dramatically improved response with use of four cycles of chemotherapy as opposed to 15 cycles. BL has a high proliferative rate, so subsequent chemotherapy cycles should be started as soon as hematologic recovery occurs. Waiting for a fixed period between cycles may lead to regrowth of resistant tumor cells between cycles.

Cyclophosphamide, doxorubicin, vincristine, methotrexate, ifosfamide, etoposide, and high-dose cytarabine, with intrathecal cytarabine and methotrexate (CODOX-M/IVAC) is among the most commonly used regimens in the United States for adults with BL, based upon an initial favorable publication from the National Cancer Institute (NCI) indicating extremely high response rates.⁴⁵ Two subsequent, small, phase II trials have used this regimen with minor modifications, and have successfully enrolled greater numbers of older patients, demonstrating cure rates of approximately 64 percent.^55,56 These cure rates are substantially less than the initial report,⁴⁹ but still better than historical data with standard-dose regimens. A modification of this regimen in patients with aggressive lymphomas and high proliferative rate as measured by Ki-67 fraction has been proposed.⁵⁷ BL was strictly defined as the following: germinal center phenotype, BCL2-negative, MYC-rearrangement–positive, and absence of the t(14;18) or abnormalities at chromosome 3q27. Overall survival of the subgroup defined as BL was 67 percent in this group of older patients. Treatment-related mortality was 8 percent. Outcomes were similar among all age groups with the exception of patients older than age 65 years who clearly had an inferior prognosis. These results likely reflect the true outcome of this regimen in practice. Several groups have further modified this regimen with the addition of rituximab, demonstrating superior outcomes compared with historical controls.^58,59,60 Based upon these findings and extrapolating from studies in other histologies of lymphoma, rituximab should be routinely incorporated in the treatment algorithms of BL.

The NCI has published an experience using a lower-intensity chemotherapy program consisting of infusional etoposide, vincristine and doxorubicin, with bolus rituximab, cyclophosphamide and steroids (dose-adjusted R-EPOCH). Nineteen patients with a median age of 25 years with generally favorable features (only 37 percent had elevated LDH, and only one patient had CNS disease) achieved a 95 percent rate of freedom from disease progression.⁶¹ Intrathecal methotrexate was administered to all patients for CNS prophylaxis.

Other regimens used for the therapy of BL include fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine.⁶² The outcome of patients at a single institution (M.D. Anderson Cancer Center) with BL treated with this regimen in combination with rituximab resulted in an overall survival of 89 percent with only one death.^63,64 The Cancer and Leukemia Group B has developed an intensive short duration regimen consisting of cyclophosphamide, ifosfamide, methotrexate, vincristine, cytarabine, etoposide and glucocorticoids. This regimen was combined with rituximab in a trial enrolling high risk patients with a median age of 43 years, with 74 percent event-free survival at 3 years.⁶⁵

No advantage of autologous stem cell transplantation in patients with BL has been observed, although incorporating planned autologous transplantation into the initial therapeutic algorithm has been used with reasonable results.⁶⁶

Historically, patients with HIV have been managed with less-intensive chemotherapy because of the concern of immunosuppression-related morbidity. In the highly active antiretroviral therapy (HAART) era, HIV-positive patients with BL should be treated similarly to nonimmunocompromised patients, and the dose-adjusted R-EPOCH regimen may be an excellent option for these patients. The rate of treatment failure in HIV-positive patients with BL was significantly lower with a highly aggressive protocol when compared with patients who were treated with less-aggressive chemotherapy. In addition, patients tolerated the aggressive protocol reasonably well, particularly when HAART therapy was incorporated into the regimen.⁶⁷

To better define optimal therapy and outcome of adults with BL, an international effort focused on with a group of adult patients with BL.⁶⁸ Authors of 12 large treatment series (10 prospective; two retrospective) provided outcome information of patients enrolled on their clinical trials who were older than age 40 years. In this pooled analysis, patients older than age 40 years were underrepresented in the published literature, and had significantly inferior outcomes in 10 of the 12 series. Despite this, the majority of adult patients were cured using these regimens.

According to data from the NCI’s Surveillance, Epidemiology, and End Results (SEER) program, up to 30 percent of BL diagnosis in the United States includes an “older” group of patients, age 60 years or older. Treatment options may be limited for this group of patients, as many older patients may not tolerate high-dose methotrexate and are not candidates for autologous transplantation. Although the number of older patients on the dose adjusted R-EPOCH trial was limited, this regimen has demonstrated safety in elderly patients with DLBCL. A confirmatory trial conducted in several centers is ongoing and enrolling older patients.

For patients with relapsed or refractory disease, autologous transplantation is best reserved for patients inadequately treated initially, as a consolidation procedure. Patients who relapse after appropriate therapy for BL tend to have highly treatment-resistant disease, with almost uniformly unfavorable outcome. These patients can be retreated with chemotherapy and considered for allogeneic stem cell transplantation because autologous transplantation is often not beneficial in these patients.⁶⁹