Follicular Lymphoma

The genetic hallmark of FL is the t(14;18)(q32;q21) translocation, which is present in 80% to 90% of cases and places the BCL-2 oncogene under the control of the IgH enhancer. This leads to impaired cellular apoptosis and overexpression of the BCL-2 gene product.⁹¹ Inhibition of apoptosis by BCL-2, which occurs in normal germinal center cells, appears to play an important role in lymphomagenesis.⁹² However, constitutive BCL-2 expression is not necessarily required for survival because it may be turned off in FL cells that have undergone aggressive transformation.⁹³

Most indolent lymphomas are of follicular histology and classified into three grades based on the number of centroblasts. Grades 1 and 2 exhibit an indolent clinical course, but grade 3 FL is biologically diverse and includes both grade 3a and grade 3b, which has a follicular growth pattern but clinically behaves like DLBCL.⁹⁴ On the basis of multivariate analysis collected on more than 4000 patients, a five-variable prognostic index was constructed known as the Follicular Lymphoma International Prognostic Index (FLIPI) (see Table 106-5). The variables associated with outcomes included age older than 60 years, Ann Arbor stage III or IV, hemoglobin level less than 12 g/dL, abnormal serum LDH level, and involvement of five or more lymph node areas.⁶⁵ The scoring system of the FLIPI was found to predict outcomes in FL better than the IPI, but it is based on a cumbersome method of determining the number of nodal sites involved (Groupe d’Études des Lymphomes Folliculaires [GELF] criteria) and predated the use of rituximab, which may render its use obsolete. An international project, termed the F2 study, was conducted on more than 1000 patients with newly diagnosed FL and all treated with rituximab-based regimens using the PFS as the end point.⁶⁶ The F2 study identified three risk groups based on age, hemoglobin value, serum β₂-microglobulin, bone marrow involvement, and the longest diameter of the largest involved lymph node (see Table 106-5).⁶⁶ The high-risk group in this model had a 3-year PFS of 51%, whereas those with no risk factors had a 3-year PFS of 91% (Fig. 106-4). The F2 study uses clinical variables derived from patients treated with rituximab, but validation of its prognostic value with current treatment strategies will be required. Neither the FLIPI nor the F2 study defines which patients should be treated at the time of diagnosis.⁹⁵

Lymphoplasmacytic Lymphoma

Lymphoplasmacytic lymphoma (LPL) is treated like other indolent B-cell lymphomas. When these lymphomas have a significant IgM paraprotein, they are known as Waldenström macroglobulinemia (WM), which has a clinical picture that may be dominated by symptoms of hyperviscosity (e.g., dizziness, tiredness, and a propensity for bleeding from the mucous membranes) and symptoms of cryoglobulinemia and cold agglutinin anemia.¹¹⁸ In addition, some patients have peripheral neuropathy, renal disease, and amyloidosis. Patients with acute hyperviscosity symptoms require emergency plasmapheresis with frequent rapid resolution of symptoms.¹¹⁹ Alkylating agents, purine analogs, and rituximab monotherapy have all been used effectively in this disorder,¹¹⁹ but the proteasome inhibitor, bortezomib, in combination with rituximab and dexamethasone (BDR) has demonstrated impressive results with more rapid responses than with chemotherapy.¹²⁰ An important cautionary note is the paradoxical rise in IgM levels that is associated with rituximab treatment.¹²¹ Patients with signs of hyperviscosity should undergo plasmapheresis before initiating treatment with rituximab-containing regimens or when using rituximab as a single agent.¹²²

Marginal Zone Lymphomas

The treatment principles applied to FL do not apply to all indolent lymphomas. Some lymphomas such as extranodal MALT lymphomas have special treatment requirements. Maltomas are mucosa-associated lymphoid tumors that occur at multiple anatomic sites but predominantly involve the gastrointestinal tract (especially the stomach), the lungs, and the salivary glands. They are frequently antigen driven. Localized gastric MALT lymphoma is unique because of its association with Helicobacter pylori. In many cases, the MALT clone is indirectly dependent on H. pylori and resolves with appropriate antibiotic treatment. Approximately 70% of the cases of stage IE-gastric MALT regress after eradication of H. pylori with antibiotics.¹²³ However, the presence of t(11;18) in the tumor cells predicts a poor response to antibiotic therapy.¹²⁴ Patients with localized disease and persistent lymphoma despite antibiotics can be effectively treated with rituximab, chemotherapy such as fludarabine,¹²⁵ and/or radiation therapy,¹²⁶ depending on the clinical circumstances. Rituximab is particularly active in gastric MALT lymphomas, with overall responses in 64% and complete responses in 29% of patients.¹²⁷

Nodal marginal zone lymphomas (NMZL) are an extremely rare subtype of lymphoma and a disease mainly of older women. The relationship with MALT lymphomas is complex, and they may occur in the context of a MALT lymphoma (e.g., lymph node involvement secondary to a gastric or parotid MALT lymphoma) with an immunophenotype that is characteristically indistinguishable. NMZLs occur in the absence of extranodal disease and are often more aggressive than MALT lymphoma.¹²⁸ There is little consensus about treatment, and management is dictated by the site that is involved and the age of the patient. In general, however, the principles of therapy that were described for FL are usually applied to NMZL.

Splenic B-cell marginal zone lymphoma (SMZL) represents another special lymphoma that presents as splenomegaly and B cells with villous projections that can often be detected in the peripheral blood. Lymph nodes near the splenic hilum and bone marrow are often involved in these cases. SMZL is rare but represents most cases of chronic lymphoid leukemias that are CD5 negative as well as a large percentage of cases that present as splenomegaly as the dominant clinical feature.¹²⁹ SMZL is associated with disruptions in the nuclear factor-κB (NF-κB) pathway in up to one third of patients.¹³⁰ In patients with chronic hepatitis C, treatment of the infection with interferon-α alone or in combination with the antiviral agent ribavirin is associated with regression of disease in most patients.¹⁶ Many patients can be monitored without treatment for many years and should not be treated in the absence of symptoms.¹³¹ Historically, splenectomy was often required to establish the diagnosis and prolonged responses are often observed, but rituximab is highly effective and should be considered before splenectomy.¹³²

Relapsed Therapy for Indolent Lymphomas of B-Cell Origin

Relapsed indolent lymphomas can often be re-treated with the same regimen used for initial treatment. Multiple active regimens exist for patients with relapsed disease, with none clearly superior. Fludarabine can be safely combined with other agents and rituximab to achieve high responses. In a randomized phase III trial of 147 patients with relapsed or refractory low-grade lymphoma, patients were treated with fludarabine, cyclophosphamide, and mitoxantrone (FCM) versus FCM with rituximab (R-FCM). Both overall and complete response rates favored R-FCM and were 79% versus 58% and 33% versus 13%, respectively.¹³³ More recently, bendamustine-rituximab (BR) demonstrated a superior overall response rate, 83.5% versus 52.5%, and PFS, 30 versus 11 months, when compared with fludarabine-rituximab in 219 patients with relapsed FL in a multicenter, randomized phase III study.¹³⁴ Agents with novel mechanisms, such as bortezomib, have also demonstrated good activity in relapsed FL with tolerability that exceeded most chemotherapy agents.^135–138 Early activity of these agents led to the investigation of a novel combination therapy of bendamustine, bortezomib, and rituximab (BBR) in patients with relapsed indolent lymphomas.^139,140 In the first study, 29 evaluable patients were treated with BBR and 83% achieved an overall response rate with a complete response rate over 50% and a 2-year PFS of 47%.¹³⁹ A second study gave a similar dosing regimen to 73 patients and found an overall response rate of 88% with a complete response rate of 53% and a median PFS of almost 15 months.¹⁴⁰

RIT is highly active in relapsed indolent lymphomas and is indicated for this purpose. In one study, ¹³¹I-tositumomab was administered to 40 patients with low-grade or transformed lymphoma and showed a response rate of 65%, with particularly good responses in low grade FL cases with tumors less than 7 cm.¹⁴¹ Ibritumomab tiuxetan was assessed in rituximab failures as defined by no response or progression within 6 months.¹⁴² Among 57 patients with FL, overall and complete responses were observed in 74% and 15% of patients, respectively, and the median PFS was 6.8 months. The role of RIT is currently limited to use in patients who have experienced relapse and who have limited bone marrow involvement, but it is under investigation with chemotherapy for initial treatment.¹¹⁷

Multiple studies have demonstrated the feasibility of high-dose therapy with autologous stem cell transplantation (HD-ASCT) in patients with relapsed and transformed indolent lymphomas.145–145 Although patients who undergo HD-ASCT early in their disease course have the best outcome, relapses are almost universal. Once transformation occurs, prognosis is generally poor, with median survivals of 6 to 18 months. Long-term risks of this approach such as secondary malignancies are of concern for an approach that has not demonstrated to be curative.¹⁴⁶ Overall, these results indicate that autologous transplantation is feasible and active in indolent lymphomas but has a diminishing role in the era of rituximab and novel agents.

Several groups have investigated allogeneic transplantation in the hope that graft-versus-lymphoma effect may eradicate residual disease. In an effort to avoid the historical 40% treatment-related mortality (TRM) associated with myeloablative conditioning regimens, investigators have developed reduce intensity conditioning stem cell transplants. Khouri and coworkers reported 8-year results of the conditioning regimen using fludarabine, cyclophosphamide, and rituximab (FCR) in 47 patients with relapsed and refractory FL.¹⁴⁷ With a median of 60 months of follow-up, the PFS was 83% with the incidence of grade 2 or more graft-versus-host disease (GVHD) only 11% (Fig. 106-5). More recently, the same group tested the addition of ibritumomab tiuxetan to the FCR conditioning backbone in patients with both chemosensitive and chemorefractory disease and demonstrated 3-year PFS rates of 87% and 80% in those patients, respectively.¹⁴⁸ Larger clinical trials with longer follow-up and randomized study designs are needed to establish the role of allogeneic transplantation in the treatment of relapsed indolent lymphomas.

Burkitt Lymphoma

BL is an uncommon aggressive B-cell lymphoma composed of rapidly proliferating B cells; it is considered the most highly aggressive NHL, with doubling times of 24 to 48 hours in some cases.¹⁴⁹ It was the first tumor to be associated with a virus, one of the first to demonstrate a translocation that activates an oncogene, and the first lymphoma associated with HIV infection and the acquired immunodeficiency syndrome (AIDS).¹⁴⁹ Morphologically, BL is composed of small noncleaved cells arranged in a monotonous pattern with a “starry sky” appearance, and nearly 100% of cells are actively proliferating by Ki-67. Biologically, BL is derived from a mature post–germinal center B cell as indicated by its CD20+, CD10+, and terminal deoxynucleotidyl transferase (TdT)− immunohistochemical profile and gene expression profiling.^47,48 BL mostly occurs in the first 2 decades of life, and cases are often subdivided into endemic, sporadic, and those associated with underlying HIV/AIDS. Endemic BL typically manifests as jaw and facial bone disease, and is it virtually always associated with EBV. Sporadic BL usually presents as ileocecal disease and is associated with EBV in 30% to 50% of cases. Immunodeficiency-associated BL usually occurs in HIV-positive populations, associated with nodal disease, and is variably associated with EBV. Patients with disease involving the CNS or bone marrow have a worse prognosis than patients with limited-stage disease.

BL is characterized by a translocation between MYC on chromosome 8 and one of the three immunoglobulin chain loci. These translocations occur with a respective frequency of 80%, 15%, and 5% on chromosomes 14, 22 and 2, which encode in turn for the immunoglobulin heavy chain and λ and κ light chains.¹⁴⁹ Because these translocations bring the MYC oncogene into close approximation with the immunoglobulin gene inducible promoter, there is abnormal overexpression of the functionally intact MYC protein. The quantitative overexpression of MYC has been shown to result in deregulation of cellular growth and is capable of blocking phenotypic maturation. Hence, MYC overexpression appears to be central to the pathogenesis of BL.

BL tumor cells have the potential to spontaneously lyse even before the administration of combination chemotherapy, resulting in tumor lysis syndrome. Before the administration of chemotherapy, aggressive use of intravenous hydration and allopurinol reduces this risk by increasing the excretion of uric acid but does not directly address the serum uric acid levels already formed. Rasburicase is a recombinant version of a urate oxidase enzyme that rapidly reduces the preformed uric acid in the serum and can prevent or treat clinical signs of tumor lysis syndrome. Guidelines are available that address situations in which the use of rasburicase should be considered.¹⁵⁰

BL requires chemotherapy for all disease stages, but R-CHOP is inadequate. Several biological characteristics of BL have helped guide treatment strategies, including its high proliferative fraction. The high tumor proliferation rate led to the use of dose-intense regimens with a short cycle time to theoretically minimize tumor regrowth between cycles.151–156 Multiple drugs, typically administered in alternating combinations, are used, and the high rate of spread to the CNS has led to the standard use of CNS prophylaxis. Such high-intensity brief-duration regimens have been associated with very high rates of initial response and long-term DFS in most patients (Table 106-7). Toxicity is an important clinical limitation of these regimens in adults, particularly in older patients in whom severe morbidity occurs. Therefore, one of the major therapeutic challenges in BL is to develop therapies that are as effective in achieving high cure rates as “standard” regimens but that improve the therapeutic index and reduce toxicity complications. Preliminary results in a pilot study of dose-adjusted rituximab, cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (DA-EPOCH-R) in 29 patients with BL showed an EFS and OS of 97% and 100%, respectively, at a median follow-up of 57 months, with low toxicity compared with conventional regimens.¹⁵⁷

Diffuse Large B-Cell Lymphoma

DLBCL is the most common lymphoid neoplasm in adults, representing 30% to 40% of cases diagnosed. It is a disease of older adults, with a median presentation in the seventh decade, but it occurs at any age. Patients have localized or disseminated disease with nodal or extranodal involvement. Within DLBCL, there are several morphologic variants, including centroblastic, immunoblastic, T-cell rich/histiocyte rich, and anaplastic subtypes; and molecular profiling has further advanced this taxonomy.⁷¹ There are also several clinicopathological variants of DLBCL, such as primary mediastinal (thymic) large B-cell lymphoma (PMBL); intravascular large B-cell lymphoma; primary DLBCL of the CNS (PCNSL); primary cutaneous DLBCL, leg type; EBV-positive DLBCL of the elderly; DLBCL associated with chronic inflammation; ALK+ large B-cell lymphoma; plasmablastic lymphoma (PBL); primary effusion lymphoma (PEL); and large B-cell lymphoma arising in HHV-8–associated multicentric Castleman disease (see Table 106-3). These entities are considered distinct subtypes of DLBCL based on a combination of clinical, histologic, and molecular findings.

Initial Treatment of Advanced DLBCL

Anthracyclines have established themselves as the single most important drug class in the treatment of aggressive lymphomas, but a number of effective regimens exist (Table 106-8). Since it was first recognized in the 1970s that DLBCL could be cured with combination chemotherapy, the search for a perfect regimen has been ongoing.¹⁸⁰ The CHOP regimen is a first-generation regimen that became the standard after being studied extensively in national cooperative settings. In the 1980s, single-institution phase II studies of dose-intensive regimens reported impressive response rates compared with historical response rates seen with CHOP therapy. However, a landmark study in 1993 reestablished CHOP therapy as the backbone by which all challengers are to be compared in a randomized trial in which it was shown to be equally effective and less toxic.¹⁸¹ The fact that only 44% of patients achieved complete remissions with CHOP, however, left significant room for improvement and spawned multiple studies aimed at improving treatment outcome. Many of these studies have focused on modifications to the CHOP platform.

Table 106-8

Selected Regimens for Burkitt Lymphoma

Therapy	No. of Patients	Histology (Number)	Median Age in Years (Range)	Stage	EFS Rate	OS Rate
CODOX-M/IVAC	21 children, 20 adults	BL	12 (3-17) 25 (18-59)	III-IV: 78%	85% (children) and 100% (adults) at 2 yr	2 deaths
CODOX-M/IVAC155	52	BL	35 (16-60)	III-IV: 77%	65% at 2 yr	73% at 2 yr
R-hyper-CVAD153	32	BL and L3 ALL	46 (17-77)	N/A	80% at 3 yr	89% at 3 yr
DA-EPOCH-R157	29	BL	35 (16-88)	III-IV: 59%	97% at 5 yr	100% at 5 yr

ALL, acute lymphocytic leukemia; EFS, event-free survival; N/A, not available; OS, overall survival.

High tumor proliferation determined by Ki-67 or MIB-1 immunohistochemistry has been shown to be an adverse prognostic finding with CHOP chemotherapy, suggesting “kinetic failure” is a problem.¹⁸² One strategy to overcome kinetic failure is to increase dose density through frequent chemotherapy administration. The Deutsche Studiengruppe für Hochmaligne Non-Hodgkin Lymphome (DSHNHL) group evaluated the effect of dose density and etoposide in two four-arm studies of CHOP administered every 14 or 21 days, with or without etoposide (CHOEP), in patients older than age 60 years and low-risk patients 60 years and younger.^183,184 In younger patients, CHOEP-21 showed the best overall results, with a complete response rate of 88% versus 79% and an EFS of 69% versus 58% at 5 years compared with standard CHOP-21, respectively.¹⁸⁴ In older patients, however, dose-dense CHOP-14 showed the best outcome with a complete response rate of 76% versus 60% and EFS of 44% versus 33% at 5 years compared with standard CHOP-21.¹⁸³

An alternative strategy to dose density is to increase the fractional cell kill, thereby reducing the number of tumor cells that can survive and proliferate between cycles. Longer drug exposure may take advantage of the increased sensitivity of cycling cells, and in vitro studies have shown that prolonged low concentration exposure to vincristine and doxorubicin, compared with brief higher concentration exposure, can increase cytotoxicity by as much as 1 log.¹⁸⁵ This approach was translated into the pharmacodynamically derived DA-EPOCH regimen, which showed a promising PFS and OS of 70% and 73%, respectively, at 5 years median follow-up in newly diagnosed DLBCL.¹⁸⁶ Interestingly, high tumor proliferation was not found to be an adverse biomarker in this study.

It has been the development of rituximab, however, that has made the single greatest impact on the treatment of DLBCL since CHOP was first introduced almost 40 years ago. The first study to demonstrate the benefit of rituximab was a Groupe d’Études des Lymphomes de l’Adulte (GELA) study, in which patients older than 60 years were randomized to receive CHOP or CHOP with rituximab (R-CHOP).¹⁸⁷ In this study, the complete response rate (76% vs. 63%) and 5-year EFS (47% vs. 29%) were higher with R-CHOP than CHOP, respectively, making R-CHOP the “de-facto” standard in DLBCL.¹⁸⁷ Long-term follow-up of this study demonstrated a 10-year PFS of 36.5% with R-CHOP compared with 20% with CHOP alone with no late relapses or increased risk of secondary malignancies (Fig. 106-6).¹⁸⁸ In a similar patient population, this finding was validated in a U.S. Intergroup Study that additionally demonstrated the lack of benefit to maintenance rituximab.¹⁸⁹ The MabThera International Trial (MInT) studied the benefit of rituximab with CHOP-based treatment in younger patients (≤60 years) with favorable characteristics defined as low IPI risk.¹⁹⁰ Patients who received rituximab fared significantly better, with a 3-year EFS of 79%. As an interesting aside, the MInT study also showed that rituximab obviated the benefit of CHOEP in younger patients. Long-term results of the MInT study demonstrate a 6-year EFS still favoring the rituximab arm of the study, with 74% versus 56% without an increase in secondary malignancies despite the use of radiation therapy in nearly half of patients.¹⁹¹ The DSHNHL group also explored the question of whether there was a difference in outcome between six or eight cycles of treatment in a randomized study of six versus eight cycles of CHOP-14, with or without rituximab, in more than 1200 elderly patients with DLBCL. In that study, named the RICOVER-60 trial, the researchers found no difference in outcome with six versus eight cycles of treatment.¹⁹² Although there was an excellent 3-year EFS of 66% with R-CHOP-14 over six cycles, the superiority of R-CHOP-14 to standard R-CHOP-21 was not proven. A randomized comparison done in the United Kingdom of R-CHOP-14 did not demonstrate an advantage over R-CHOP-21 with respect to PFS or OS.¹⁹³

The GELA group reported outcomes with their ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) regimen used with rituximab (R-ACVBP) versus R-CHOP-21 for eight cycles in patients younger than 60 years old with low-risk IPI aggressive lymphomas. In this regimen, aggressive therapy for CNS disease, including both intrathecal and high-dose methotrexate, was used for a treatment duration of 30 weeks.¹⁹⁴ The R-ACVBP regimen demonstrated a 3-year PFS advantage over R-CHOP of 87% versus 73% but was associated with significant hematologic toxicity and is unlikely to be tolerated by patients older than the age of 60 years. Additionally, the need for intensive CNS prophylaxis in all patients with DLBCL, particularly those with low IPI, is unproven and likely results to result in overtreatment of many patients.

Rituximab has also been tested in combination with the DA-EPOCH regimen. In a single-institution study of 72 patients, 80% and 79% of patients were progression free and alive, respectively, at the median follow-up of 5 years.¹⁹⁵ Furthermore, 93% and 71% of patients in the low- and high-risk IPI groups, respectively, had not progressed. More recently, these findings were confirmed in a multicenter Cancer and Leukemia Group B (CALGB) cooperative group study of 69 patients with untreated DLBCL.⁷³ At a median follow-up of 62 months, the time to progression (TTP) and OS of the entire group were 81% and 88%, respectively.⁷³ Important differences were seen with respect to cell-of-origin phenotype, and the TTP and EFS in the GCB-like DLBCL cohort were 100% and 94%, respectively, whereas the TTP and EFS in the ABC-like DLBCL cohort were only 67% and 58%, respectively, at 62 months. A randomized, multicenter evaluation of DA-EPOCH-R versus R-CHOP in untreated DLBCL is ongoing in the CALGB cooperative group in conjunction with microarray analysis.

The role of high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) in the initial treatment of DLBCL remains controversial. Although some studies have suggested benefit, they were performed in the pre-rituximab era.¹⁹⁶ ASCT is also associated with late-stage toxicities, including leukemia and secondary myelodysplasia, which must be considered in the risk-benefit analysis of treatment.¹⁹⁷

Primary Mediastinal B-Cell Lymphoma

Primary mediastinal B-cell lymphoma (PMBL) represents a distinct clinicopathological variant of DLBCL with a readily distinguishable molecular profile and a favorable outcome with modern therapy.41,42 PMBL usually occurs in young women, remains localized to the mediastinum, and frequently invades adjacent structures. Involvement of extrathoracic nodal regions and the bone marrow is very uncommon, making the Ann Arbor staging system irrelevant in this disease. Clinically, the features seen in PMBL resemble those observed with NSHL.⁴⁵

In fact, it is now appreciated that the genetic and epigenetic makeup of PMBL shares more similarities with NSHL than other cases of de novo DLBCL.198,199 The genetic hallmark of PMBL is amplification of a region on chromosome 9p24 that encodes for Janus kinase 2 (JAK2), which can also be found in Hodgkin lymphoma but rarely in other DLBCLs.^200,201 PMBL and NSHL both arise from a thymic B cell, but PMBL arises from a mature B cell and NSHL does not.³² Overexpression of NFKB target genes and amplification of the REL locus are also frequently observed in PMBL and are likely important in pathogenesis.¹⁶⁴ These tumors, therefore, have many overlapping features and are bridged by MGZLs on a biological continuum between these two entities.⁴⁵

In the pre-rituximab era, patients with PMBL appeared to benefit from the use of dose-intense regimens, such as methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) and etoposide with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B), as well as 30 to 40 Gy of consolidative radiation therapy to the mediastinum.202,203 Thus, a precedent was set of six to eight cycles of R-CHOP followed by mediastinal irradiation, but the need for radiation therapy has not been validated in the rituximab era. Late complications of mediastinal irradiation in young women include an increased risk of second malignancies, particularly breast cancer, and the early onset of cardiovascular disease. Two groups have recently reported data on rituximab-based chemotherapy programs that largely omit consolidative irradiation. In a phase II study from the National Cancer Institute of 40 patients with PMBL uniformly treated with six cycles of DA-EPOCH-R, 100% and 95% are alive and event free at a median 47 months of follow-up, respectively; only two patients required radiation treatment, and no patient experienced relapse.²⁰⁴ Moskowitz and associates reported data on 54 patients treated with sequential dose-dense R-CHOP every 14 days for four cycles followed by three cycles of ifosfamide, carboplatin, and etoposide (ICE) without the use of mediastinal irradiation.²⁰⁵ Eighty-eight percent and 78% are alive and progression free at 3 years of follow-up, respectively. Taken together, these data suggest that when rituximab is added to dose-intense regimens, it may obviate the need for irradiation in most patients with PMBL.

Mantle Cell Lymphoma

MCL is an uncommon but distinct form of NHL derived from naïve small B lymphocytes. The median age of patients of newly diagnosed patients is older than 65 years and there is a male predominance.²⁰⁶ The genetic hallmark of MCL is the t(11;14)(q13;q32) translocation in which the coding region of cyclin D1 on chromosome 11 is juxtaposed to the immunoglobulin heavy-chain gene on chromosome 14.²⁰⁷ MCL has a remarkable tendency to disseminate, and almost all patients have advanced disease at presentation. It frequently involves extranodal sites such as the gastrointestinal tract (even with normal-appearing mucosa), bone marrow, and the CNS.²⁰⁸ A leukemic component can be found in 20% to 30% of patients, often in association with splenomegaly out of proportion to adenopathy.

Prognostic Factors

Historically, the prognosis of MCL has been the worst of all B-cell NHLs, with an OS of 3 to 5 years.²⁰⁸ Improvements have been achieved in the current era, with reports of OS in the 5- to 7-year range, yet a curative strategy remains elusive for most patients.²¹⁴ A clinical risk factor score modeled after the IPI was recently evaluated in MCL and is known as the Mantle Cell Lymphoma International Prognostic Index (MIPI).⁶⁷ Using the variables of age, performance status, serum LDH level, and white blood cell count (WBC) at diagnosis, the MIPI was able to identify three groups with separate outcomes (see Table 106-5). The MIPI has been validated in some series and appears to stratify risk better than the IPI²¹⁵ but requires further validation in other clinical settings and treatment paradigms.

Despite the overall poor prognosis, MCL demonstrates a striking variation in clinical behavior, and treatment can be deferred for as many as 15% of patients without an apparent impact on survival,216,217 although exact characterization of this “indolent subset” is not well defined. Angelopoulou and associates described a “splenic form” of MCL in which the clinical picture was dominated by splenomegaly, leukemia, and a minimal amount of nodal disease.²¹⁸ Ondrejka and associates more recently reviewed cases presenting as splenomegaly and leukemic-only disease and described these cases to have interstitial patterns of bone marrow involvement, simple karyotype, and a lack of staining for the transcription factor SOX11 on immunohistochemistry.²¹⁹ Fernandez and colleagues compared the gene expression profile of cases of MCL known to be indolent with more conventional cases and noted the indolent cases were frequently leukemic only, exhibited somatic mutations in the immunoglobulin heavy chain, and lacked complex karyotypes.²²⁰ The significance of these findings remains controversial, and other groups have found conflicting results with regard to SOX11 expression.^221,222 Recent characterization of “non-nodal MCL” revealed a three-gene signature that may identify patients who might benefit from deferred therapy.²²³ These findings will require validation in future trials.

The most powerful biological predictor of survival in MCL is tumor proliferation as measured by GEP. A quantitative score is derived based on the relative expression of 20 proliferation signatures genes known as the proliferation score (PS). The PS separates patients into four quartiles with a marked difference in survival during a 6-year period (Fig. 106-7).⁷⁵ The same study was able to demonstrate that higher expression of cyclin D1 mRNA correlated with increased proliferation and shorter survival time. Despite these provocative results, however, GEP is not routinely available to aid in clinical decision making, and surrogate markers for tumor proliferation are used. Similarly, the use of genome-wide microRNA profiling recently identified MCL cases with significantly higher proliferation signatures compared with a cluster of cases with signatures related to stromal elements.⁸⁶ GEP and miRNA profiling may be valuable clinical tools in the future for selecting MCL patients with a particularly poor prognosis.

Testicular Lymphomas

Primary testicular lymphoma (PTL) is a rare extranodal presentation of NHL, representing 3% to 5% of all NHLs, with a median age of 66 years,²⁴³ although patients with HIV infection may present at a younger age.²⁴⁴ PTL is the most common testicular tumor seen in men older than the age of 60 years. The majority of PTL cases are of intermediate- or high-grade histologic type such as DLBCL, and recent analyses suggest that the vast majority of these tumors are of the ABC-like subtype of DLBCL.^244,245 Other features include frequent overexpression of BCL-2 and marked proliferative activity as demonstrated by a Ki-67 typically in the 70% to 90% range.^244,245 These high-risk biological features explain why PTL has a worse prognosis than other DLBCL subtypes. PTL typically manifests as a unilateral testicular mass, but relapses occur frequently many years after therapy and often involve extranodal sites such as the contralateral testis, CNS, lung pleura, skin, and Waldeyer’s ring.^243,246 CNS involvement is observed in as many as 15% of cases at the time of relapse, with brain parenchymal lesions more common than leptomeningeal disease and detected as late as 14 years after presentation.^243,246

The standard management of PTL consists of surgical removal of the primary tumor, combination chemotherapy with rituximab, irradiation of the contralateral testis, and CNS prophylaxis. Relapse rates are as high as 80%, with the majority occurring within the first year after therapy even in patients with stage I disease.²⁴⁶ Thus, all patients without contraindication should be offered combination chemotherapy after primary orchiectomy. More difficult, however, is determining the best strategy to prevent CNS relapse, because the majority occur in the brain parenchyma. Vitolo and associates recently reported a uniformly treated group of patients with stage I and stage II PTL.²⁴⁷ Fifty-two patients aged 22 to 79 years were treated with R-CHOP for six to eight cycles with four doses of intrathecal methotrexate and 30 Gy of radiation to the contralateral testis and to regional lymph nodes for patients with stage II disease. These researchers reported a 5-year PFS and an OS rate of 74% and 85%, respectively.²⁴⁷ This should be considered the current standard of care, although strategies to reduce CNS relapse should be explored.

Primary CNS Lymphoma

PCNSL is a rare and highly aggressive lymphoma that arises in the intracerebral or intraocular spaces without systemic involvement. It is of B-cell origin in 95% of cases and is usually morphologically indistinguishable from systemic DLBCL. The majority of PCNSL cases demonstrate marked proliferative activity, with more than 90% of cells expressing the Ki-67 antigen. In patients with a known immunodeficiency such as HIV infection or AIDS or after transplantation, the majority of cases of PCNSL are in young patients and the lesions are more diffuse and multifocal; they are associated with an immunoblastic appearance on histology, and nearly all contain EBV.248,249 The diagnosis is made with direct tissue sterotactic-guided biopsy or with the demonstration of EBV DNA in the CSF, which is virtually diagnostic of CNS involvement by lymphoma. Increasingly, PCNSL is diagnosed in immunocompetent patients. These tumors are usually not associated with EBV and present as a solitary intracranial mass 60% to 70% of the time.²⁴⁹ The unique radiographic findings of PCNSL present challenges in evaluation, which have been addressed in a report of an international workshop to standardize criteria for baseline evaluation and response.²⁵⁰ If PCNSL is considered in the differential diagnosis of patients who have isolated brain lesions, it is important to attempt diagnostic studies before administration of corticosteroids because they cause rapid (but temporary) tumor lysis and can obscure diagnosis.

PCNSL has a worse prognosis than systemic DLBCL in any setting, but the presence of infection with HIV may portend an even worse outcome.²⁵¹ Combination antiretroviral therapy (CART) is frequently initiated or modified at the time of diagnosis of HIV-associated PCNSL, but the effect of immune reconstitution on lymphoma outcomes is not yet clear and requires prospective investigation.²⁵¹ Treatment with radiation therapy alone is not recommended for patients with PCNSL who are able to undergo more intensive therapies because the responses are brief. Another problem is the acute and long-term neurotoxicity of combined modality regimens of which patients older than the age of 60 years are particularly susceptible.²⁵² For this reason, regimens that obviate or defer the need for irradiation until relapse have been developed. Most promising are combinations of high-dose methotrexate alternating with systemic agents that cross the blood-brain barrier, such as cytarabine, vincristine, and ifosfamide.²⁵³ The Bonn group has reported results with chemotherapy and deferred radiation in younger patients.²⁵⁴ Additionally, the role of HD-ASCT has been explored in an attempt to reserve the use of whole-brain radiotherapy (WBRT) in patients who do not achieve complete remission.²⁵⁵ Ongoing studies are also addressing the role of immunochemotherapy with rituximab and other novel agents that promise to further improve the outcome of PCNSL.²⁵⁶

EBV-Associated Lymphomas

The loss of adequate EBV immune surveillance underlies the pathobiology of virtually all EBV-associated lymphomas in adults.¹¹ Management of EBV-associated lymphomas involves restoration of the host’s immune response to EBV in addition to therapy directed at the malignant cells. The type and duration of the host’s defect in EBV immune surveillance determines the clinical presentation, which is usually aggressive. EBV-associated lymphomas are well characterized in patients with known defects in cellular immunity such as occur after transplantation or with associated HIV infection or AIDS but are increasingly recognized in patients without overt immunodeficiencies. Thus, the term EBV-associated lymphomas encompasses a heterogeneous group of aggressive B-cell and NK-cell/T-cell lymphomas that arise in patients with and without overt impairments in cellular immunity.

It is useful to consider the origin of the immune suppression as it affects disease biology and treatment. The most commonly recognized diseases are associated with iatrogenic immunosuppression, as exemplified by PTLD and MTX-associated LPD.²⁵⁷ First-line therapy for iatrogenic-induced lymphomas is to withdraw the immunosuppressive agent if possible, because spontaneous regression has been seen with this maneuver alone. PTLDs are broadly defined as a heterogeneous group of lymphoproliferative diseases that occur in the setting of acquired immune deficiency after allogeneic transplantation of either solid organs or hematopoietic stem cells.²⁵⁸ PTLDs are associated with EBV reactivation in 60% to 70% of cases and are usually of B-cell origin; only 10% to 15% of PTLDs will be identified of T-cell/NK-cell origin.²⁵⁹ Strategies have been developed to detect EBV reactivation before the development of lymphoma, such as monitoring polymerase chain reaction (PCR) assay viral load and preemptively treating with rituximab when EBV DNA levels reach a predefined level.²⁶⁰ Immunotherapeutic strategies that generate EBV-specific T cells have shown tremendous promise.^261,262

EBV-positive DLBCL of the elderly is an aggressive B-cell neoplasm that occurs in patients without overt immunodeficiency and who usually are older than the age of 50 years, although not exclusively so.¹¹ It was first called “senile EBV-positive B-cell lymphoproliferative disorder” and has a median age of onset between 70 and 75 years.²⁶³ Characterization of this entity in elderly patients in the West described a wider spectrum of conditions, including cases with localized extranodal involvement of mucocutaneous ulcers.²⁶⁴ EBV infection is suspected to drive lymphomagenesis in this entity in conjunction with waning immunity that is part of the aging process. The prognosis of EBV-positive DLBCL of the elderly is poor compared with other DLBCL subsets, but the interplay between patient characteristics and tumor biology is unclear.

Lymphomatoid granulomatosis (LYG) is a rare angiodestructive EBV-driven lymphoproliferative disease composed of atypical clonal EBV-positive B cells in an inflammatory background. LYG mostly involves extranodal sites such as the skin and CNS, with the lung virtually always being involved. Patients usually do not have an overt immunodeficiency before diagnosis, but evidence of immune dysregulation can frequently be found, and patients with known immunodeficiency are at increased risk.²⁶⁵ EBV transformation of B cells and chemokine induction is at the center of all the pathological and clinical features of LYG.²⁶⁶ LYG can be divided into three grades on the basis of the proportion of large atypical EBV-positive B cells and necrosis. Low-grade LYG is best managed with strategies designed to enhance the host’s underlying immune system such as interferon-α2b, whereas high-grade LYG is best managed by combination chemoimmunotherapy.²⁶⁷

AIDS-Related Lymphomas

Among patients with HIV infection, 3% to 6% will develop NHL. Lymphomas associated with HIV include DLBCL, PCNSL, primary effusion lymphoma (PEL), plasmablastic lymphoma of the oral cavity, and BL and are collectively known as AIDS-related lymphomas. The relative risk of other lymphoid neoplasms such as Hodgkin lymphoma, extranodal marginal zone lymphoma, and certain T-cell lymphomas also appear increased in the setting of HIV infection, although they are not AIDS-defining illnesses.268,269 NHL is typically a late manifestation of HIV infection, with most cases occurring with CD4 counts less than 200 mm³, except for BL, which can occur with any CD4 count. In addition to the role of HIV, concomitant infection with HHV-8 and EBV also appear to play a role in pathogenesis.²⁷⁰ Patients with severe CD4 cell depletion display immunoblastic features with a plasmacytoid differentiation and have a poorer prognosis, whereas patients with higher CD4 cell counts develop centroblastic DLBCL and BL.^272–272 Hence, the decline in patients with low CD4 cell counts in the post-CART era is likely to lead to a shift in histologic subtypes.

The pathogenesis of AIDS-related lymphomas involves a complex interplay of factors and mechanisms. Among these are CD4-dependent immunodeficiency, chronic antigen stimulation, co-infecting oncogenic viruses such as EBV and HHV-8, cytokine dysregulation, and genetic abnormalities.²⁷⁰ Most AIDS-related lymphomas are of B-cell lineage and harbor clonal rearrangement of immunoglobulin genes. Plasmablastic lymphomas are a heterogeneous group of very aggressive B-cell lymphomas that arise most often in the setting of immunosuppression such as HIV infection and AIDS with profoundly low CD4 counts.²⁷³ Plasmablastic lymphomas were first described in AIDS patients with lesions that arose in the oral cavity and have a strong predilection for the sinonasal cavity, orbit, and other extranodal sites.²⁷⁴ Morphologically, plasmablastic lymphomas resembles DLBCL with large immunoblastic cells with a high expression of Ki-67, but the B-cell program is down regulated and CD45 and CD20 are usually negative; however, plasma cell markers such as MUM1, CD38, and CD138 are usually positive. MYC rearrangements can be found in as many as 50% of patients with plasmablastic lymphomas and are more common in cases positive for EBV, suggesting a possible mechanism of lymphomagenesis.²⁷⁵ Plasmablastic lymphomas are at an advanced stage at diagnosis and carry a poor prognosis compared with other aggressive lymphomas.

The introduction of CART in the mid 1990s had a dramatic and positive impact on the outcome of AIDS-related lymphomas. A comparison of median survival of the pre- and post-CART eras showed a significant improvement.²⁷⁶ Although the reasons for this are multifaceted, they can be ultimately attributed to salutary effects on CD4 cell counts. It was thus clinically predictable that the overall rise in CD4 cell count would improve the outcome of AIDS-related lymphomas based on the well-established association between poor outcome and low CD4 cell count. Most important is the more favorable biology associated with lymphomas that occur in patients with higher CD4 cells counts.²⁷⁷ These findings led to the assumption that CART during chemotherapy would be beneficial. Amid concerns about the risk of opportunistic infections, however, regimens in patients with ARL have been characterized by empirical dose reductions (such as half-dose or three-fourths-dose CHOP). Although studies show that CART does not excessively increase the toxicity of chemotherapy, there is no direct evidence that it improves outcome. CART also carries the potential for adverse pharmacokinetic and pharmacodynamic interactions related to hepatic metabolism and/or the multidrug-resistant pumps.²⁷⁸ Furthermore, CART drugs may inhibit multidrug resistance, increase hematologic toxicity, and decrease dose intensity, while conferring no benefit on tumor sensitivity.²⁷⁹ Of unknown significance are the inhibitory effects of some antiretroviral drugs on lymphoid cell apoptosis, which theoretically could antagonize chemotherapy effects.²⁸⁰ It is also possible that CART compliance could be compromised by chemotherapy and promote emergence of HIV viral mutations.

The National Cancer Institute investigated the effects of suspension of CART during all courses of DA-EPOCH in 39 patients with newly diagnosed AIDS-related lymphomas.²⁷⁷ After antiretroviral suspension during DA-EPOCH, the viral loads increased a median of 0.83 log₁₀; and after restarting antiretroviral treatment, the viral loads declined −0.61 log₁₀ below baseline. CD4 cells declined during chemotherapy treatment but recovered to baseline by 6 to 12 months after reinstitution of antiretroviral therapy. The treatment strategy was effective with complete remissions in 74% of patients; and at a median follow-up time of 53 months, DFS and OS were 92% and 60%, respectively. Indeed, the salutary effects of CART on immune function have led to the belief that this benefit exceeds any potential adverse effects on tumor control. Unfortunately, prospective randomized studies have yet to address this critically important question.

The finding that the addition of rituximab to CHOP chemotherapy significantly improves the survival of HIV-negative patients with DLBCL led to its testing in untreated AIDS-related lymphomas.¹⁸⁷ Pooled results from three phase II studies of rituximab and cyclophosphamide, doxorubicin, and etoposide (CDE) in ARL were first reported in 2004, demonstrating an apparent benefit compared with previously reported results with CDE alone.^281,282 In this study of 74 patients, 70% achieved a complete response; and at the median follow-up of approximately 2 years, the estimated failure-free rate and OS were 59% and 64%, respectively.²⁸¹ New opportunistic infections during or within 3 months of treatment occurred in 14% of patients, and death from infection occurred in 8% of patients.

To address the role of rituximab, Kaplan and colleagues performed a multicenter randomized phase III trial of CHOP with or without rituximab in untreated patients with AIDS-related lymphomas with concomitant CART administration.²⁸³ In this trial of 150 patients, disease control was significantly better in patients receiving R-CHOP with lower progression on treatment (P = .02) and death caused by lymphoma (P = .02). However, because there was no difference in OS or EFS, because of increased infectious deaths in patients receiving R-CHOP, the authors concluded that rituximab does not improve clinical outcome in AIDS-related lymphomas. It should not escape attention that most treatment-related infectious deaths occurred in patients with low CD4 cell numbers, a group enriched with tumors of ABC type and most likely to benefit from rituximab.^271,277

Employing a somewhat different strategy, the National Cancer Institute investigated the outcome of a short course of EPOCH with dose-dense rituximab (375 mg/m² days 1 and 5) (SC-EPOCH-R) to reduce treatment-related toxicity. In this study, patients with untreated AIDS-related lymphomas receive one cycle beyond maximum response, with a minimum of three cycles, compared with six cycles with DA-EPOCH alone.²⁸⁴ Thirty-three patients were treated and achieved a PFS and an OS of 84% and 68%, respectively, at 5 years median follow-up without any treatment-related deaths or new opportunistic infections during therapy.²⁸⁴ The patients with the GCB subtype of DLBCL had a much superior PFS than those with a non-GCB subtype (95% vs. 44%; P = .003). To help further define the role of rituximab, the AIDS malignancy consortium performed a randomized phase II trial comparing DA-EPOCH-R with DA-EPOCH alone followed by sequential rituximab weekly for 6 weeks in responding patients.²⁸⁵ They noted a significantly improved complete response with the concurrent arm and no different in toxicity. Additional evidence for the benefit of rituximab combined with chemotherapy comes from cohort studies that have demonstrated rituximab beneficial even in severely immunocompromised patients with CD4 counts less than 100 mm.²⁸⁶ All published data suggest high activity with the use of rituximab plus chemotherapy with historical controls of chemotherapy alone, even if there is a slight increase in the rate of infections.²⁸⁷

Although there has been an improvement in the collective outcome of HIV-associated lymphomas since CART, fewer advances in outcomes have been realized in the management of the BL subtype.²⁸⁸ Dose-intensive regimens typically used for BL in the non-HIV setting have been considered too toxic to warrant their general use in HIV-positive patients. Thus, the relatively poor outcome of HIV-associated BL may be due to the use of CHOP-based regimens, which are known to have a poor outcome in this disease.¹⁴⁹ Involvement of the CNS by BL may also contribute to reduced survival and highlights the need for CNS prophylaxis. Dose-intense regimens with agents that cross the blood-brain barrier, such as hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) have shown encouraging results in HIV-associated BL with complete remission rate of 92% but are often highly myelotoxic.²⁸⁹

Salvage Therapy for Aggressive Lymphomas

As initial therapy for aggressive lymphomas has improved, fewer patients experience relapse. Still, as many as one third of patients with DLBCL are not cured after initial therapy and will ultimately need second-line or “salvage” chemotherapy. The majority of relapses occur early, but 5% to 7% of relapses will occur after 5 years.290,291 As many as 17% of the patients with late relapses have an indolent NHL at the time of relapse.²⁹¹ Thus, it is essential to perform tissue biopsy at the time of suspected recurrence before initiating any therapy. The salvage treatment of relapsed aggressive lymphomas should be approached in an individual manner because the choice of treatment is influenced by the time to recurrence, prior therapy, medical condition, and the potential for cure. Although most relapsed aggressive lymphomas require combination chemotherapy for adequate disease control, it is important to recognize that patients with local disease may be successfully salvaged with radiation therapy alone.^204,292

The majority of patients with relapsed aggressive lymphoma will require systemic therapy. A variety of active salvage regimens exist for relapsed or refractory DLBCL.293,294 It is a commonly held notion that salvage treatment should include different agents from past treatment to avoid drug resistance. Recent evidence indicates, however, that sensitivity to apoptosis is a central cause of drug resistance and that drug-specific mechanisms are less important.²⁷⁹ It is standard to give rituximab with combination chemotherapy in the salvage setting even in patients who received it for initial therapy, although the responses are lower and survival is poor in this group.²⁹³ The most important prognostic factor in these patients is disease that remains sensitive to chemotherapy. Patients who are refractory to initial induction or do not achieve a response to initial salvage chemotherapy have a dismal prognosis and should be considered for novel approaches.²⁹⁵

Autologous Transplantation

Patients younger than 60 years without significant co-morbidities who have chemotherapy-sensitive disease (at least a partial remission) after two to three cycles of salvage chemotherapy are usually offered HD-ASCT with curative intent. The rationale for this approach predates the use of rituximab from a randomized study known as the Parma study, in which HD-ASCT was compared with chemotherapy alone in patients who achieved response to salvage chemotherapy.²⁹⁶ Both EFS and OS were improved in the HD-ASCT arm (46% and 53% vs. 12% and 32%), establishing it as the standard of care. However, it is important to consider, when assessing the effect of HD-ASCT in the modern era, that improvements in initial therapy from rituximab have biased the relapsed population toward greater resistance. Recently, the use of rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) was compared with the use of rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) before HD-ASCT in the CORAL study.²⁹⁴ Response rates were identical after three cycles of therapy (63.5% vs. 62.8%), and there were no differences in EFS or OS at 3 years.²⁹⁴ Importantly, patients who had been treated initially with rituximab-containing regimens derived much less benefit from HD-ASCT, which questions widespread use of this approach in the modern era (Fig. 106-8). Additionally, poor-risk subsets such as MYC+ DLBCL (17% of cases), demonstrated a 4-year EFS of only 18%.²⁹⁷ Subset analysis demonstrated that the group who derived the most benefit from HD-ASCT were patients who experienced relapse after 12 months, had a GCB-like phenotype, and were treated with R-DHAP.²⁹⁸ Indeed, if the benefit of HD-ASCT at relapse is to be maintained in the post-rituximab era, novel agents or radioimmunoconjugates introduced into conditioning regimens will likely be required.²⁹⁹

Anaplastic Large Cell Lymphoma

ALCL is a CD30+ T-cell lymphoma with an excellent prognosis and is often curable after treatment.³⁰⁵ It typically occurs in children and young adults and compromises approximately 3% of all lymphomas in adults. In the majority of cases, ALCL is associated with the t(2;5)(p23;q35) translocation, resulting in expression of ALK.³¹⁵ Although ALK+ ALCL has a significantly better prognosis than ALK− cases, patients with ALK− disease should still be approached with curative intent.³¹⁵ In adults, CHOP-based therapy is considered the standard of care and produces durable remissions in approximately 70% of ALK− and 50% of ALK− ALCL cases.³⁰⁵ Recently, the novel antibody-drug conjugate brentuximab vedotin demonstrated activity in patients with relapsed CD30+ lymphomas including ALCL.^316,317 Brentuximab vedotin is composed of the antitubulin agent monomethyl auristatin E (MMAE) attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker. In 58 patients with relapsed ALCL treatment with brentuximab vedotin demonstrated an 86% overall response rate with 57% of the responses complete. Importantly, the median duration of response was more 12 months and responses were similar between patients with ALK+ and ALK− disease.³¹⁷

Peripheral T-Cell: NOS

PTCL: NOS (not otherwise specified) makes up the largest group of PTCLs, representing 34% of cases diagnosed in the United States and Europe and 22% of cases diagnosed in Asia.³⁰⁵ Most patients have nodal disease in advanced stages with a median age of 60 years.³¹⁸ It is a heterogeneous category without unifying clinical or histologic features. The gene expression profile of PTCL: NOS is not surprisingly molecularly heterogeneous.³⁶ Importantly, however, a subgroup of cases of PTCL: NOS demonstrate the molecular phenotype of cytotoxic CD8+ T cells and carry a particularly poor prognosis.³⁶ Treatment principles are similar to those applied to ALCL, with CHOP being the most commonly used regimen, but outcomes are much worse, with a 5-year OS of only 32% and no demonstrable advantage to the use of an anthracycline.³¹⁸

Angioimmunoblastic T-Cell Lymphoma

AITL was first described in the 1970s and was originally known as “angioimmunoblastic lymphadenopathy with dysproteinemia.”³¹⁹ It is now characterized as a distinct PTCL with an association with EBV infection in almost all cases.³²⁰ The neoplastic T cells appear to be of germinal center origin, known as follicular B-helper T cells.³²¹ The malignant T cells are usually negative for EBV, and it is the background B cells that are infected.³²² AITL is the second most common PTCL in North America and the most common subtype diagnosed in Europe.³⁰⁵ The median age at diagnosis is 65 years, and it frequently manifests in patients as generalized lymphadenopathy in conjunction with features suggestive of an autoimmune disease such as fever, hypereosinophilia, hemolytic anemia, rash, organomegaly, hypergammaglobulinemia, arthralgias, and circulating immune complexes.¹¹ Paradoxically, patients also often exhibit some degree of immunodeficiency and are at high risk for infectious complications, which often result in death. Reports of expanded monoclonal B-cell clones that give rise to EBV-driven B-cell lymphomas (e.g., DLBCL) in patients with AITL are not uncommon.³²² The treatment of AITL is not standardized, but typical lymphoma chemotherapy regimens result in disappointing outcomes, owing to frequent relapses and a high incidence of opportunistic infections. The occurrence of B-cell dysregulation in AITL suggests a possible role for immunotherapy aimed at the EBV-positive B cells, such as with rituximab or the anti-CD52 monoclonal antibody alemtuzumab added to chemotherapy. At this point these therapies should be considered experimental because they have not yet demonstrated a clear effect on the natural history of AITL. Unfortunately, many patients succumb to infection or disease.

Extranodal NK-Cell/T-Cell Lymphoma, Nasal Type

Extranodal NK-cell/T-cell lymphoma, nasal type is a rare extranodal lymphoma of NK-cell or cytotoxic T-cell origin that usually affects immunocompetent middle-aged men of Asian, Native American, or Central/South American descent and is almost always associated with EBV.¹¹ In fact, the EBV viral load detected by PCR assay is intimately tied to prognosis, clinical course, and disease relapse.³²³ It frequently occurs in the midline such as the nasal cavity, nasopharynx, palate, skin, gastrointestinal tract, and testis, often with angiodestruction and necrosis in tissue specimens.¹⁰ Disease outside the nasal cavity is usually highly aggressive and associated with a poor prognosis. Hemophagocytic syndrome is a devastating event associated with this tumor type.³²⁴ Because of intrinsic chemotherapy resistance, the 5-year OS of extranodal NK-cell/T-cell lymphoma, nasal type is only 9%³⁰⁵; however, disease localized to the nasal cavity is often curative with radiation therapy alone.³²⁵ l-Asparaginase when used in combination chemotherapy regimens including methotrexate, ifosfamide, etoposide, and dexamethasone (SMILE) has demonstrated impressive results in patients with newly diagnosed and relapsed extranodal NK-cell/T-cell lymphoma, and such regimens are probably the treatment of choice for advanced disease.³²⁶