Christopher Melani and Mark Roschewski
INTRODUCTION
The term non-Hodgkin lymphoma (NHL) encompasses a diverse group of lymphoproliferative disorders of B-cell, T-cell, and NK-cell origin that together account for approximately 90% of all lymphomas diagnosed in the United States. Although unified in their histopathologic distinction from Hodgkin lymphoma, these disorders vary considerably in morphologic appearance, clinical behavior, therapeutic options, and prognosis. The past two decades have seen significant therapeutic advancements as well as progress in our understanding of the genetic and molecular basis of the different NHL subtypes.
EPIDEMIOLOGY AND RISK FACTORS
NHL is the seventh most common adult malignancy in the United States, with 72,580 new cases expected to be diagnosed in 2016. The overall incidence of NHL has increased substantially over the past several decades, almost doubling between 1975 and 1995. Since the mid-1990s, however, this trend has become progressively less pronounced, with overall incidence rates stabilizing between 2005 and 2009. Although incompletely understood, these changes in NHL incidence have been attributed to a variety of factors such as the emergence of (and subsequent advancements in therapy for) HIV/AIDS, improvements in detection and reporting of NHL, and reduction in mortality rates from other causes.
The risk of developing NHL increases with each decade of adult life. Certain subtypes of NHL, however, such as primary mediastinal B-cell lymphoma (PMBL) and Burkitt lymphoma (BL), tend to occur in younger patients. Although NHL occurs within all ethnic groups, it is most common in the Caucasian population. There is also considerable geographic disparity in NHL incidence, with the highest rates seen in North America, Australia, and Western Europe, and the lowest rates seen in Asia, South America, and the Caribbean.
Disorders of the immune system, often in conjunction with chronic viral infection, are also associated with increased risk of NHL. Higher rates of NHL are seen in patients with congenital and acquired immunodeficiencies as well as diseases of immune dysregulation. Though most of these lymphomas are of B-cell lineage, there are notable exceptions such as enteropathy-associated T-cell lymphoma (EATL), which occurs most commonly in patients with gluten enteropathy, and hepatosplenic T-cell lymphoma (HSTCL), which often occurs in patients with inflammatory bowel disease or post–solid organ transplantation.
Epstein-Barr virus (EBV) is an oncogenic driver in multiple subtypes of NHL, including some that arise in the setting of immunosuppression. Among HIV-related lymphomas, EBV is virtually always associated with both primary CNS lymphoma (PCNSL) and plasmablastic lymphoma, oral type. It is also seen in primary effusion lymphoma (PEL), plasmablastic lymphoma, and posttransplant lymphoproliferative disorder (PTLD). EBV is also associated with a number of NHL subtypes in immunocompetent patients. One oncogenic mechanism of EBV in NHL involves constitutive activation of the NF-κB pathway, although the entire spectrum of oncogenic mechanisms remain unknown.
Other infections have also been associated with the development of NHL subtypes, such as HHV-8 and HTLV-1, which are found in all cases of PEL and adult T-cell lymphocytic leukemia (ATLL), respectively. Marginal zone lymphoma (MZL) is also frequently driven by both viral and bacterial antigens. Hepatitis C virus (HCV) is found in some cases of splenic and nodal MZL variants, Helicobacter pylori in most cases of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and Chlamydia psittaci in some cases of ocular adnexal MALT lymphoma (OAML) (see Table 28.1).
TABLE 28.1Risk Factors Associated with NHL Development
Immunosuppression/Immunodeficiencies | Drugs | Environmental/Exposures | Infections | Other |
Congenital
Acquired
| Immunosuppressive agents Phenytoin Methotrexate TNF inhibitors | Radiation therapy Occupational exposures
Silicone breast implants | EBV HTLV-1 Helicobacter pylori HCV HHV-8 HIV Borrelia burgdorferi Chlamydia psittaci Chlamydia trachomatis Chlamydia pneumonia Campylobacter jejuni | Advanced age Male gender Previous history of NHL Family history of NHL |
SCID, severe combined immunodeficiency; CVID, common variable immunodeficiency; AIDS, acquired immunodeficiency syndrome; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; EBV, Epstein-Barr virus; HTLV-1, human T-cell lymphotropic virus type I; HCV, hepatitis C virus; HHV-8, human herpesvirus 8; HIV, human immunodeficiency virus.
PATHOGENESIS AND MOLECULAR CHARACTERIZATION
The process of lymphomagenesis in NHL involves a complex array of genetic aberrations that disrupt normal cellular pathways of proliferation, differentiation, and apoptosis. These genetic events are most commonly acquired and functionally result in activation of proto-oncogenes and/or inactivation of tumor suppressor genes. Balanced chromosomal translocations are early genetic events that initiate lymphomagenesis in certain types of NHL. As an example, up to 85% of patients with follicular lymphoma (FL) have a balanced translocation, t(14:18), while virtually every case of mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation. Newer methods using high-throughput genetic sequencing have revealed a broad genomic landscape in NHL including a long tail distribution of somatic mutations and heterogeneity across subtypes. Further molecular characterization of lymphomagenesis with emerging technologies promises more precision in diagnosis, prognosis, and treatment selection.
CLASSIFICATION
Individual NHL subtypes are defined in the World Health Organization (WHO) classification system, most recently updated in 2016. Initially established in 2001, this system constituted the first international consensus on diagnosis and classification of lymphoma. Within this system, NHL is classified primarily by cell lineage and maturity (B- vs. T/NK cell, mature vs. precursor cell of origin) and then further subcategorized according to a combination of morphologic, immunophenotypic, genetic, molecular, and clinical features. It is expected that the current classification system for NHL will continue to evolve as our knowledge of the genetic and molecular basis of these diseases continues to improve.
DIAGNOSIS
A properly evaluated and technically adequate excisional lymph node biopsy remains the gold standard for diagnosis of suspected lymphoma. In recent years, some centers have adopted the practice of obtaining a combination of core-needle biopsy and fine-needle aspiration as an alternative to surgical lymph node excision, reserving surgical biopsies for nondiagnostic cases. Although this approach is relatively sensitive and cost-effective, a definitive diagnosis is unobtainable in approximately 20% to 25% of patients. Consequently, perioperative risk, institutional experience with core-needle biopsy, and the harm of diagnosis delay are considerations when deciding the diagnostic approach.
The pathologic classification of NHL subtype relies on a combination of morphologic appearance and immunophenotyping using immunohistochemistry (IHC) and flow cytometry. Additional studies that confirm clonality and further sub-classify tumor include cytogenetic analysis and molecular studies.
WORKUP AND STAGING
Initial workup and staging evaluation of NHL should include a complete history and physical examination and laboratory assessment of organ function. The following tests should be performed:
Complete blood count with differential
Complete metabolic panel including serum lactate dehydrogenase (LDH)
Serologies for HIV, HBV, HCV (regardless of exposure history)
CT scan of the chest, abdomen, and pelvis
Whole-body FDG-PET scan
Bone marrow (BM) aspirate and biopsy
Lumbar puncture with CSF cytology and flow cytometry (in select cases only)
The Ann Arbor staging system, originally designed for Hodgkin lymphoma, also has prognostic and predictive utility in NHL, and its use is considered standard for newly diagnosed cases (see Table 28.2). Although this system has limited prognostic value due to the lack of contiguous orderly spread through lymph node regions, it nevertheless remains an integral component of the validated international prognostic indices for aggressive NHL (IPI) and FL (FLIPI).
TABLE 28.2Staging Classification of Lymphoma
Stage | Ann Arbor Classification | Cotswold Modification |
I | Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE) | Involvement of a single lymph node region or lymphoid structure |
II | Involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or with involvement of limited, contiguous extralymphatic organ or tissue (IIE) | Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is considered a single site, whereas the hilar lymph nodes are considered bilaterally); the number of anatomic sites should be indicated by a subscript (e.g., II3) |
III | Involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIS); a limited contiguous extralymphatic organ or site (IIIE); or both (IIIES) | Involvement of lymph node regions on both sides of the diaphragm: III1 (with or without involvement of splenic hilar, celiac, or portal nodes) and III2 (with involvement of para-aortic, iliac, and mesenteric nodes) |
IV | Multiple or disseminated foci of involvement of one or more extralymphatic organs or tissues, with or without lymphatic involvement | Involvement of one or more extranodal sites in addition to a site for which the designation E has been used |
Note: All cases are subclassified to indicate the absence (A) or presence (B) of the systemic symptoms of significant fever (>38.0°C [100.4°F]), night sweats, and unexplained weight loss exceeding 10% of normal body weight within the previous 6 months. The clinical stage (CS) denotes the stage as determined by all diagnostic examinations and a single diagnostic biopsy only. In the Ann Arbor classification, the term pathologic stage (PS) is used if a second biopsy of any kind has been obtained, whether negative or positive. In the Cotswold modification, the PS is determined by laparotomy; X designates bulky disease (widening of the mediastinum by more than one-third or the presence of a nodal mass >10 cm), and E designates involvement of a single extranodal site that is contiguous or proximal to the known nodal site.
Restaging for Response Evaluation
Upon completion of therapy, CT scans should be repeated to categorize the response. Bone marrow biopsy is required for the determination of complete response if it was involved prior to therapy. In accordance with the Revised Response Criteria for Malignant Lymphoma, FDG-PET is mandatory for the evaluation of residual masses at the completion of therapy. Response to therapy is determined based on changes in the sum of the product of the diameters of the masses as well as resolution of hepatosplenomegaly and bone marrow involvement. FDG-PET was formally incorporated into staging and response assessment with the Lugano classification with responses being assessed by changes in the lesion(s) 5-point Deauville score, which standardizes the lesion(s) FDG-uptake in relation to the mediastinal blood pool and liver. This classification was also recently refined to incorporate changes, such as tumor flare or pseudoprogression, that can occur with modern immunotherapy treatments. In cases of suspected disease relapse or refractoriness to initial therapy, repeat biopsy should be strongly considered for confirmation.
PROGNOSTIC FEATURES
The International Prognostic Index (IPI) is a clinical prognostic index that has been validated in aggressive lymphoma. Five clinical factors comprise the IPI and 1 point is assigned to each factor:
Age >60 years
Eastern Cooperative Oncology Group (ECOG) performance status 2 or higher
Two or more extranodal sites
Ann Arbor stage III or IV disease
Scores of 0 to 1, 2, 3, and 4 to 5 correspond to 5-year survivals of 73%, 51%, 43%, and 26%, respectively, in diffuse large B-cell lymphoma (DLBCL). A validated clinical prognostic index has also been applied to patients with untreated FL. The Follicular Lymphoma International Prognostic Index (FLIPI) is scored according to the following:
Age >60 years
Ann Arbor stage III or IV disease
LDH level greater than normal
Hemoglobin <12 g/dL
5 or more nodal areas involved
The FLIPI score has also been found to reliably predict survival in FL with scores of 0 to 1, 2, and 3 to 5 corresponding to 5-year survivals of 91%, 78%, and 53%, respectively. Gene expression profiling has emerged as a useful means of identifying molecularly distinct sub-classifications of NHL, and can be used to identify individuals who may benefit from treatment intensification or addition of novel agents given their poor prognosis with current standard therapies. Integration of somatic mutational profiles that correlate with individual subtypes has the potential to further refine these prognostic models. As an example, in FL patients receiving first-line chemoimmunotherapy, seven genes were incorporated into a clinico-genetic risk model, termed the m7-FLIPI, which identified a high-risk group more accurately than FLIPI or gene mutations alone. Such novel prognostic models that incorporate next-generation sequencing will undergo clinical validation in prospective trials before incorporation into clinical practice.
MANAGEMENT
Indolent B-Cell Non-Hodgkin Lymphoma
FL is the most common indolent lymphoma, constituting approximately 70% of cases, and is considered incurable. Patients are typically older (median age of 60) with widespread disease at diagnosis. Constitutional symptoms and extra-nodal involvement can occur, but are uncommon. Many patients are asymptomatic at diagnosis despite involvement of multiple lymph node regions. FL is graded (1–3) according to the number of centroblasts per high power field. Therapeutic approaches to grades 1 to 3A are similar, whereas grade 3B is considered a variant of DLBCL for the purposes of treatment.
A wide range of clinical behavior is observed in FL. While the median survival is currently greater than 10 years, approximately 20% of patients will progress within 2 years of initial therapy, and these patients have a much poorer prognosis compared to those without early progression. Histologic transformation to a more aggressive NHL subtype (typically DLBCL) occurs at an approximate cumulative rate of 3% per year and is generally associated with an inferior prognosis.
Even though FL is incurable in most patients, those who present with truly limited stage disease (stage 1) can achieve prolonged remissions and long-term survival with radiotherapy alone to the involved regions. Multiple studies have reported a 15-year overall survival rate of approximately 50% in these patients, and only a few relapses reported after 10 years. For the majority of patients with FL, however, radiotherapy alone is not an option since the disease is in advanced stage. For asymptomatic patients with advanced stages of FL, immediate therapy is not mandatory. Multiple randomized trials that have tested early initiation of therapy in advanced stage FL compared to observation alone have not shown an improvement in overall survival (OS). The anti-CD20 monoclonal antibody, rituximab, has demonstrated both safety and efficacy in FL with an overall response rate (ORR) of 72% in previously untreated patients with advanced-stage, low-grade disease. A recent randomized trial compared rituximab monotherapy to observation alone in 379 patients with asymptomatic advanced stage FL. Treatment with rituximab monotherapy was associated with an improvement in progression-free survival, but did not decrease rates of histologic transformation or improve OS.
Patients who require first-line therapy for FL and have a high tumor burden are usually offered therapy with combination chemotherapy with rituximab since rituximab monotherapy is less effective in this setting (see Table 28.3). Although no one particular chemoimmunotherapy regimen has demonstrated superior OS or the ability to cure patients with advanced FL, regimens such as bendamustine and rituximab (BR) or rituximab with cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) are considered the current standard of care. Due to less overall toxicity and an improvement in progression-free survival (PFS), many physicians consider BR as the regimen of choice. A randomized study in Germany recently compared BR to R-CHOP in patients with indolent NHL, including FL, and BR demonstrated an improvement in PFS compared to R-CHOP with less overall toxicity. A similar study was conducted in the United States testing BR versus both R-CHOP or R-CVP and determined similar response rates across all regimens tested. A newer first-line treatment option is also emerging that incorporates the novel immunomodulatory agent, lenalidomide, in combination with rituximab. The lenalidomide-rituximab regimen was recently tested in 46 patients with untreated FL and demonstrated an overall response rate of 98% including 87% of patients achieving complete remission (CR). Given the promising activity of this novel regimen, lenalidomide-rituximab is now being compared to standard combination chemo-immunotherapy in an ongoing randomized multicenter international study.
Another important clinical decision with first line therapy for FL includes the option of extended duration or “maintenance” therapy with rituximab. The RESORT trial addressed this question in patients with low tumor burden FL who were considered good candidates for rituximab monotherapy. Patients who responded to induction therapy with rituximab were then randomized to a planned schedule of rituximab maintenance or a schedule that initiated rituximab only at the time of disease progression. No advantage was observed with scheduled rituximab maintenance in this trial compared to the strategy of rituximab re-treatment. The benefit of maintenance rituximab was also assessed following induction chemoimmunotherapy (R-CHOP, R-CVP, or R-FCM) for patients with high tumor burden FL in the randomized phase III PRIMA trial. Following induction therapy, responding patients were randomized to 2 years of rituximab maintenance or observation. Although there was improvement in median PFS with rituximab maintenance, this did not translate into an overall survival benefit and was associated with increased toxicity and infections.
TABLE 28.3First-Line Treatment Regimens and Outcome for Follicular Lymphoma
First-Line Treatment Regimen | Number of Patients | Outcome | Study Reference |
BR vs. R-CHOP | 139 | Median PFS NR | Rummel et al. |
140 | Median PFS 40.9 months | ||
BR vs. R-CHOP/R-CVP | 154 | ORR 99% (CR 30%) | Flinn et al. |
160 | ORR 94% (CR 25%) | ||
R-CHOP vs. CHOP | 223 | 18-mo TTF 87% | Hiddemann et al. |
205 | 18-mo TTF 70% | ||
Rituximab induction | 37 | Median TTP 2.2 years | Witzig et al. |
Watchful waiting vs. rituximab induction vs. rituximab induction and maintenance | 187 | 3-y PFS 36% | Ardeshna et al. |
84 | 3-y PFS 60% | ||
192 | 3-y PFS 82% | ||
Rituximab induction + rituximab retreatment (RR) vs. maintenance rituximab (MR) | 143 | 3-y PFS 50% | Kahl et al. |
146 | 3-y PFS 78% | ||
Induction immunochemotherapy + observation vs. rituximab maintenance | 513 | 3-y PFS 74.9% | Salles et al. |
505 | 3-y PFS 57.6% | ||
Lenalidomide + rituximab (R2) | 50 | 3-y PFS 78.5% | Fowler et al. |
BR, bendamustine and rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CVP, rituximab, cyclophosphamide, vincristine, and prednisone; R2, rituximab and Revlimid (lenalidomide); PFS, progression free survival; NR, not reached; ORR, overall response rate; CR, complete response; TTP, time to progression; TTF, time to treatment failure.
Patients with relapsed/refractory FL can be treated with alternative chemoimmunotherapy regimens, single-agent rituximab, radioimmunotherapy (RIT), or novel agents that are currently under clinical development. RIT involves the delivery of targeted radiotherapy to tumor tissue by conjugating an anti-CD20 antibody to a radioactive isotope. In a randomized trial of relapsed or refractory follicular or transformed lymphoma, the ORR was better with ibritumomab tiuxetan than with rituximab (80% vs. 56%). However, a recently published phase III intergroup trial evaluating the role of RIT in newly diagnosed FL patients (R-CHOP vs. CHOP followed by 131Iodine tositumomab) demonstrated similar PFS and OS in both groups at median 5 years of follow-up.
Novel targeted therapies have now been FDA-approved in FL (see Table 28.4), and numerous others are in clinical development for relapsed and refractory FL. The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, idelalisib, is approved as monotherapy for patients with FL who have received at least two prior systemic therapies. In a multicenter, single-arm trial in relapsed indolent NHL, idelalisib monotherapy resulted in an ORR of 54% with median duration of response (DOR) that was not reached. In the phase I study of previously treated indolent NHL patients who failed to respond or relapsed within 6 months of rituximab and an alkylating agent, idelalisib resulted in a similar ORR of 57% with CR in 6% of patients. Median time to response was 1.9 months with a median DOR of 12.5 months and median PFS of 12.5 months. The CALGB 50401 study randomized patients with recurrent FL to rituximab monotherapy, lenalidomide monotherapy, or combination therapy with both and showed statistically better ORR and CR rates (76% vs. 53% and 39% vs. 20%, respectively) as well as an improved median time to progression (2 years vs. 1.1 year) favoring combination therapy. In rituximab refractory disease, the combination of obinutuzumab, a novel glycol-engineered type II anti-CD20 monoclonal antibody, was recently approved in combination with bendamustine followed by obinutuzumab maintenance. This approval was based on the GADOLIN study showing a significantly longer median PFS with combination therapy versus bendamustine alone (NR vs. 14.9 months). These targeted agents are currently being investigated in various combinations in the relapsed setting as well as front-line in combination with cytotoxic therapy.
TABLE 28.4Novel Targeted Treatment Regimens and Outcome for Follicular Lymphoma
Targeted Regimen | Number of Patients | Response Rate | Median TTR | Median DOR | Median PFS | Study Reference |
Idelalisib | 125 iNHL (72 FL) | ORR 57% CR 6% | 1.9 mo | 12.5 mo | 11 mo | Gopal et al. |
Lenalidomide vs. R2 | 45 | ORR 53% CR 20% | N/A | N/A | 1.1 years | Leonard et al. |
46 | ORR 76% CR 39% | N/A | N/A | 2 years | ||
Obinutuzumab + Bendamustine vs. Bendamustine monotherapy | 194 iNHL (150 FL) | ORR 69% CR 11% | N/A | NR | NR | Sehn et al. |
202 iNHL (166 FL) | ORR 63% CR 12% | N/A | 13.2 mo | 14.9 mo |
R2, rituximab and Revlimid (lenalidomide); iNHL, indolent non-Hodgkin lymphoma; FL, follicular lymphoma; ORR, overall response rate; CR, complete response; TTR, time to response; DOR, duration of response; PFS, progression free survival; NR, not reached; N/A, not available.
Lymphoplasmacytoid Lymphoma/Waldenström Macroglobulinemia
LPL is an indolent lymphoma composed of mature plasmacytoid lymphocytes that typically involves the bone marrow but may also involve the lymph nodes and spleen. When LPL is associated with a monoclonal IgM production it is termed Waldenström macroglobulinemia (WM). LPL/WM primarily affects older patients and is most common in the Caucasian population. Patients typically present with symptoms of increased tumor burden (cytopenias due to marrow involvement, hepatosplenomegaly, lymphadenopathy, constitutional symptoms) and/or symptoms attributable to the secreted monoclonal immunoglobulin (hyperviscosity syndrome, autoimmune neuropathy, mucocutaneous bleeding). Asymptomatic patients are considered to have “smoldering” WM and can be safely managed with an initial period of observation. Symptomatic disease requiring treatment occurs in approximately 50% of patients within 3 years of diagnosis, although up to 10% of patients managed with watchful waiting will not require treatment for 10 years or longer.
First-line treatment options for WM include single-agent rituximab, chemoimmunotherapy regimens such as BR, and rituximab combined with novel agents such as bortezomib and dexamethasone. When rituximab is used, the patient must be observed carefully for hyperviscosity symptoms, as serum IgM levels can initially increase abruptly with rituximab. Plasmapheresis prior to rituximab-containing therapy should be strongly considered for any patient presenting with symptoms of hyperviscosity or high baseline serum IgM.
Over the past several years, whole-genome sequencing has identified pathogenic mutations, which have aided in the diagnosis of WM. MYD88 (L265P) mutations that result in IRAK-mediated NF-κB signaling have been identified as a key genetic alteration in over 90% of cases. Warts, hypogammaglobulinemia, infection, and myelokathexis syndrome (WHIM) mutations have also been identified in the CXCR4 gene in 27% of cases, with this mutation only previously being described in germline DNA. Familial cases of WM have recently been described using whole-exome sequencing, with LAPTM5 and HCLS1 as potential candidate genes predisposing to familial WM development.
MYD88 mutations with resultant increased NF-κB signaling provide the scientific rationale for the use of inhibitors of Bruton’s tyrosine kinase (BTK) in treating this disease. In a prospective study of ibrutinib monotherapy in 63 patients with symptomatic WM who had received at least one prior therapy, ibrutinib was associated with an ORR of 90.5% with major responses in 73%. Higher responses were demonstrated in patients with mutated MYD88 (L265P) and wild-type CXCR4 with an ORR of 100% and major response rate of 91.2%. Based on this data, ibrutinib was granted breakthrough therapy designation by the FDA and approved for the treatment of patients with LPL/WM.
The spectrum of marginal zone lymphomas are all indolent lymphomas, comprising approximately 10% of NHL, that occur primarily in extranodal MALT (EMZL or MALT lymphomas), and to a lesser extent within the spleen (splenic MZL) and lymph nodes (nodal MZL). The majority of EMZL occurs within the gastrointestinal tract (most commonly the stomach), but can also occur in the parotid and salivary glands, thyroid, lungs, ocular adnexae, and breast, among others. Most patients present with localized disease, and 5-year survival is approximately 90%. EMZL is frequently antigen driven, and a history of chronic infection such as H.pylori-associated gastritis in gastric MALT lymphoma or Chlamydiphila psittaci in OAML is common. With current antibiotic regimens, approximately 62% of patients with early-stage gastric MALT lymphoma will achieve complete remission with bacterial eradication alone. Patients found to have a t(11;18) translocation detected by cytogenetics, FISH, or polymerase chain reaction (PCR) are less likely to respond to antibiotic therapy alone and should be considered for alternative treatment. In OAML, data indicate that eradication of C. psittaci with doxycycline can induce complete remission in approximately 22% of patients with partial remissions in another 22% and minimal responses (<50% regression) in 33%. For patients with advanced or antibiotic-refractory disease, or those with MALT subtypes not associated with known infectious agents, therapeutic options include rituximab, chemoimmunotherapy regimens similar to those used in FL, radiation, and surgical resection in sites amenable to complete resection.
Splenic MZL accounts for approximately 20% of MZL, and typically presents with splenomegaly and BM involvement. Five-year overall survival is approximately 80%. Splenectomy has been the historical standard of care; however, rituximab is increasingly being used as an alternative or adjunct to surgical therapy. In a retrospective trial of 43 patients with splenic MZL, rituximab monotherapy was as effective as combination chemoimmunotherapy with CR rates of 90% and 79%, respectively, and significantly less toxicity. Rituximab combined with splenectomy was associated with improved responses (CR 100% vs. 67%) compared to unsplenectomized patients and improved 3-year disease-free survival (DFS) was shown with rituximab therapy compared to splenectomy or chemotherapy alone (79% vs. 29% vs. 25%). Similar to EMZL, splenic MZL can also be antigen driven; approximately one-third of cases are associated with HCV, and many of these patients can enter remission with antiviral therapy alone.
Nodal MZL is the least common MZL, and is characterized by nodal disease in the absence of a mucosal component. The clinical course of nodal MZL tends to be more aggressive than its extranodal or splenic counterparts, and 5-year overall survival is slightly lower at approximately 76%. Although it can also be associated with HCV infection in up to 20% of cases, it is typically not associated with a known infectious etiology. A distinct pattern of genetic alterations was recently shown when comparing nodal MZL to its splenic counterpart, with a high prevalence of MLL2 (aka KMT2D), PTPRD, NOTCH2, and KLF2 mutations in nodal disease. Mutations in PTPRD, a receptor-type protein tyrosine phosphatase, resulted in cell-cycle deregulation and increased proliferation and was only seen in nodal MZL. This mutation provides further insight into the pathogenesis of disease and may serve as a novel marker in diagnosis. The therapeutic approach for nodal MZL generally follows that of FL.
Aggressive B-Cell Non-Hodgkin Lymphoma
DLBCL is the most common NHL subtype, accounting for approximately 30% of all cases. Although it is most commonly diagnosed in the seventh decade of life, DLBCL can occur at any age. DLBCL can occur either de novo or as a histologic transformation from an indolent NHL. Gene expression profiling classifies DLBCL into two major molecular subtypes, germinal center B cell (GCB) and activated B cell (ABC), with the latter being less curable with standard therapies. ABC-DLBCL is always associated with constitutive activation of the NF-κB pathway through a variety of mechanisms. One important and well-characterized mechanism involves chronic active B-cell receptor (BCR) signaling via activating mutations in the BCR subunits, CD79A and CD79B, as well as mutations in MYD88 and CARD11.
Patients with all stages of DLBCL are treated with systemic chemoimmunotherapy with curative intent (see Table 28.5). In multiple studies, R-CHOP given every 21 days (R-CHOP-21) has been shown to significantly improve response rates, PFS, and OS compared to CHOP alone in previously untreated patients with advanced disease, and consequently this regimen is now considered standard. The addition of Involved-field radiation therapy (IFRT) to an abbreviated course of systemic therapy is considered an option in patients with early-stage DLBCL, although such an approach introduces the risk of long-term complications of radiation treatment. The use of “dose-dense” R-CHOP every 14 days with myeloid growth factor support (R-CHOP-14) has failed to demonstrate superiority over standard R-CHOP-21. Dose intensity may still have a role in DLBCL, however, as the dose-intensive regimen of rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) (full chemo regimens in the legend with the table below) demonstrated superior 3-year PFS and OS in untreated DLBCL patients aged 18 to 59 with low-intermediate IPI compared to R-CHOP. Although serious adverse events were more than twice as common with R-ACVBP, it nevertheless remains a promising regimen that can be considered for younger patients. Dose-adjusted (DA) EPOCH-R is another alternative regimen that has shown promising results in phase II trials and is currently being evaluated against R-CHOP-21 in a randomized phase 3 study. In a multicenter, phase 2 study conducted by the CALGB in untreated DLBCL, 5-year time to progression (TTP) and event free survival (EFS) were 100% and 94% for GCB and 67% and 58% for non-GCB, respectively. This regimen is also associated with a lower observed incidence of cardiac toxicity compared to R-CHOP and can be considered for patients in whom this is a concern.
TABLE 28.5First-Line Treatment Regimens and Outcome for Diffuse Large B-Cell Lymphoma
First-Line Treatment Regimen | Number of Patients | Outcome | Study Reference |
R-CHOP vs. CHOP | 202 | 2-y EFS 57% | Coiffier et al. |
2-y OS 70% | |||
197 | 2-y EFS 38% | ||
2-y OS 57% | |||
R-CHOP-21 vs. R-CHOP-14 | 298 | 3-y EFS 60% | Delarue et al. |
3-y PFS 62% | |||
3-y OS 72% | |||
304 | 3-y EFS 56% | ||
3-y PFS 60% | |||
3-y OS 69% | |||
R-ACVBP vs. R-CHOP | 196 | 3-y EFS 81% | Recher et al. |
3-y PFS 87% | |||
3-y OS 92% | |||
183 | 3-y EFS 67% | ||
3-y PFS 73% | |||
3-y OS 84% | |||
DA-EPOCH-R | 69 | 5-y EFS 75% (94% GCB, 58% non-GCB) | Wilson et al. |
5-y PFS 81% (100% GCB, 67% non-GCB) | |||
5-y OS 84% (94% GCB, 68% non-GCB) |
R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; DA-EPOCH-R, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; R-ACVBP, rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone; EFS, event free survival; OS, overall survival; PFS, progression free survival; GCB, germinal center B-cell; non-GCB, non-germinal center B-cell.
Novel agents that target BCR signaling and reduce NF-κB activity are currently being tested as monotherapy in the relapsed/refractory setting as well as in combination with front-line cytotoxic therapy, especially in ABC-DLBCL. In a phase I/II study of 80 patients with relapsed or refractory DLBCL, a higher ORR was seen with ibrutinib monotherapy in ABC-DLBCL (37% vs. 5%) with a median response duration of approximately 5 months. Responses were enriched in patients with CD79B mutations compared to wild-type (ORR 55.5% vs. 31%) but were lower in those with isolated MYD88, CARD11, or TNFAIP3 mutations, given these mutations provide an alternative mechanism of NF-κB activation. The highest responses were seen in those patients with concomitant CD79B and MYD88 mutations with an ORR of 80%. When combined with R-CHOP in the front-line setting, all newly-diagnosed DLBCL patients who received the recommended phase II dose (560 mg daily) responded, with 100% CR rate in non-GCB subtype and 71% CR rate in GCB subtype.
The immunomodulatory agent, lenalidomide, through downregulation of IRF4 and SPIB, leads to decreased NF-κB activity and augmentation of INFβ production. Through these effects it has shown significant activity in ABC-DLBCL, both as monotherapy and in combination with cytotoxic therapy. In relapsed/refractory aggressive NHL, the majority DLBCL, lenalidomide monotherapy resulted in an ORR of 35% with CR rate of 12% and a median DOR and PFS of 6.2 and 4 months, respectively. This response was confirmed in a large international phase II study demonstrating an ORR of 28% with 7% CR and median duration of remission and PFS of 4.6 and 2.7 months, respectively. A retrospective study investigated responses based on molecular subtype and found significantly higher responses in non-GCB compared to GCB subtype, with ORR and CR rates of 52.9% vs. 8.7% and 23.5% vs. 4.3%, respectively. Combination with standard-dose R-CHOP on days 1 to 10 of each cycle in untreated DLBCL patients resulted in an ORR of 98% with a CR rate of 80%. Compared to historic controls treated with conventional R-CHOP alone, lenalidomide overcame the negative impact of non-GCB DLBCL showing no difference in 24-month PFS or OS in the R2-CHOP treated patients based on DLBCL subtype. These targeted therapies as well as other novel agents are currently being investigated in the front-line setting but are not yet commercially available for use outside of a clinical trial. Consequently, the GCB/ABC distinction cannot yet be used to guide choice of initial therapy for DLBCL.
Primary mediastinal B-cell lymphoma (PMBL) is a subtype of DLBCL that clinically and biologically more closely resembles classical Hodgkin lymphoma than other subtypes of DLBCL. Standard treatment approaches in the past have involved chemotherapy followed by mediastinal radiation. While combined modality therapy has been very effective in most patients, mediastinal radiation is associated with long-term sequelae and increased risks of cardiac disease and secondary tumors, particularly breast cancer in females. In a phase II study, DA-EPOCH-R demonstrated high efficacy in this disease with a 5-year EFS and OS of 93% and 97%, respectively, obviating the need for radiation in almost all patients.
Up to 10% of patients with DLBCL harbor t(8;14) with overexpression of MYC, and many of these patients are also positive for t(14;18) with overexpression of BCL2 (so-called “double-hit” lymphoma). Many of these tumors may fit into the WHO category of “B-cell lymphoma unclassifiable with features intermediate between BL and DLBCL.” In several retrospective studies, these patients have demonstrated inferior outcomes with standard therapies and benefit more from intensive treatment, similar to that used in Burkitt lymphoma. A multicenter study using DA-EPOCH-R in MYC-rearranged DLBCL is ongoing with encouraging preliminary results but at this time the optimal management of patients with “double-hit” lymphoma is unknown.
PCNSL is a rare and aggressive lymphoma that is confined to the CNS (brain parenchyma, meninges, cranial nerves, eyes, spinal cord). It is of DLBCL histology in over 95% of cases, and can occur in both immunocompetent and immunocompromised patients. It most commonly affects the brain parenchyma, although there can be concomitant or isolated leptomeningeal involvement in approximately 20% of cases. Intraocular involvement is also common and in some cases can predate the development of brain lesions by months.
PCNSL is not effectively treated by standard DLBCL chemoimmunotherapy regimens due to inability of the component agents to penetrate effectively through the blood–brain barrier. High-dose methotrexate (up to 8 g/m2) achieves therapeutic levels within the CSF and produces high response rates and 2-year OS of 50% to 70%. A randomized phase III study assessing the addition of whole brain radiation therapy (WBRT) to high-dose methotrexate failed to demonstrate an improvement in OS with the addition of WBRT. In a randomized phase II trial, the addition of high-dose cytarabine to high-dose methotrexate improved response rates (ORR 69% vs. 40%) and showed a trend toward improved OS (3-year OS of 46% vs. 32%, P=0.07). Consequently, this combination is now considered a standard first-line treatment option. The role of WBRT consolidation after chemotherapy remains controversial, as it is associated with significant and sometimes disabling neurotoxicity. Patients not achieving CR to chemotherapy have a poor prognosis and are generally offered WBRT. A study of salvage WBRT (median dose, 36 Gy) following initial high-dose methotrexate failure, resulted in a high ORR of 74% but median OS from initiation of WBRT was only 10.9 months. Relapsed and refractory PCNSL represents an unmet clinical need for effective salvage therapies and eligible patients should be considered for participation in clinical trials.
Approximately 96% of PCNSL tumors in immunocompetent individuals express an ABC immunophenotype by IHC. High-throughput sequencing has allowed for better characterization of the genomic landscape of PCNSL, leading to ongoing studies using novel targeted agents. Compared to systemic DLBCL, PCNSL has been shown to harbor more frequent mutations in the NF-κB pathway, including MYD88 and CD79B mutations, with often concurrent mutations at multiple sites in the same pathway. These mutations provide the scientific rationale for targeting the BCR pathway and BTK, and current studies with ibrutinib monotherapy and in combination with cytotoxic chemotherapy are ongoing. Ibrutinib was combined with a novel chemotherapy regimen DA-TEDDI-R (dose-adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib, and rituximab with intraventricular cytarabine) in untreated and relapsed/refractory PCNSL patients. In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone during a 14 day lead-in window period with 86% of evaluable patients achieving CR with DA-TEDDI-R. Programmed death 1 (PD-1) and/or programmed death ligand 1 (PD-L1) has been shown to be expressed on tumor cells, tumor infiltrating lymphocytes, or tumor-associated macrophages in 90% of PCNSL specimens from immunocompetent individuals. Frequent copy gains in 9p24.1, resulting in increased expression of PD-L1 and PD-L2, have been identified in 52% of EBV-negative PCNSL with 6% of PCNSL specimens having previously unidentified translocations involving the PD-L1 or PD-L2 loci. Studies using inhibitors of PD-1 in patients with PCNSL are currently ongoing.
BL is a highly aggressive but curable lymphoma, accounting for 1% to 2% of lymphomas in the United States. Most cases in the United States and Western countries are either sporadic or associated with immunodeficiency, typically affecting children and young adults and demonstrating EBV positivity in 30% to 50% of cases. Endemic BL, by contrast, is strongly associated with EBV infection and is highly prevalent in young children in equatorial Africa. Whereas endemic BL presents most commonly with jaw and facial bone disease, sporadic BL tends to present with bulky abdominal disease. Involvement of the BM, GI tract, and CNS are also common. All variants of BL are characterized by acute clinical onset and rapid disease progression without therapy.
Like DLBCL, the cell of origin for Burkitt lymphoma is presumed to be a normal germinal center B-cell. MYC is the most recurrently mutated gene in BL, found in up to 70% of the cases, but multiple other regulatory pathways are deregulated and cooperate with MYC in oncogenesis. Tonic BCR signaling is augmented through mutations in the transcription factor TCF3 or ID3, its negative regulator, and can be seen in up to 70% of sporadic BL cases. Frequent mutations in CCND3 stabilize cyclin D3 isoforms and drive cell cycle progression in approximately 38% of sporadic BL cases. These mutations provide insight into the underlying pathogenesis of disease as well as can serve as potential targets for novel therapies in the future.
Dose-intensive multiagent chemotherapy regimens incorporating high-dose methotrexate, high-dose cytarabine, and intrathecal chemotherapy (CODOX-M/IVAC, hyper-CVAD) are commonly used to treat BL, with approximately 60% to 80% of patients achieving long-term survival. The addition of rituximab to intensive chemotherapy was recently shown to improve EFS in a randomized phase III trial of 260 patients with untreated HIV-negative BL, and is now considered standard in most BL regimens. Additionally, treatment with DA-EPOCH-R appears to be an effective, less-toxic therapy for both HIV-negative and HIV-positive BL patients with freedom from progression (FFP) of 95% to 100% at the median follow-up. A confirmatory multicenter study of this regimen in BL and MYC+ DLBCL is ongoing.
MCL is an incurable and variably aggressive lymphoma. Median age at diagnosis is 60, and most those affected are men. Patients commonly present with advanced disease, splenomegaly, and involvement of the BM, peripheral blood, and GI tract. Virtually all cases of MCL harbor t(11;14) with resultant overexpression of cyclin D1, although a small minority of MCL can be negative for cyclin D1.
Although response rates to chemotherapy are high in MCL, remissions tend to be short-lived and historic median survival is approximately 3 to 6 years. The mantle cell IPI (MIPI) classifies patients into prognostic categories based upon age, performance status, LDH, and WBC count, and can aid in therapeutic decision making. Given that a subset of MCL behaves in an indolent manner, watchful waiting is a reasonable approach in asymptomatic patients with a low risk MIPI. For symptomatic patients or those with a high risk MIPI, therapeutic options include standard chemotherapy (R-CHOP, BR, DA-EPOCH-R) or dose-intensive chemotherapy such as R-hyper-CVAD/MA (see Table 28.6). Although the latter approach has recently yielded impressive results (median OS of 10.7 years), it has also been associated with considerable toxicity, especially in older patients. In younger patients, high-dose chemotherapy with autologous stem cell rescue (HDT/ASCR) in first remission after induction chemotherapy has been studied extensively and may extend PFS over chemotherapy alone, although it is not curative. A recent randomized study from the European MCL Network strongly suggested that induction regimens that utilize cytarabine during induction are superior to regimens without cytarabine in younger patients who undergo HDT in first remission. Such intensive regimens followed by HDT/ASCR are the standard of care in many regions, although this approach is not broadly applicable to all patients with MCL. Nonmyeloablative allogeneic stem cell transplantation (SCT) is still considered investigational, although currently it remains the only potentially curative option.
Since many patients with MCL are over the age of 65, a highly intensive treatment such as HDT/ASCR in first remission is associated with excessive toxicity. Thus, alternative strategies have been developed for patients considered unfit or those who wish to avoid dose intensive therapy in the front-line setting. In a randomized, non-inferiority trial of BR compared to R-CHOP in the first-line treatment of patients with MCL, BR was associated with improved PFS and less overall toxicity compared to R-CHOP in all histologic subtypes, including MCL (median PFS 35.4 vs. 22.1 months). The proteasome inhibitor, bortezomib, as well as the immunomodulatory agent, lenalidomide, have both shown activity in MCL and have been used as front-line therapy in combination with chemoimmunotherapy and rituximab, respectively. In a randomized, phase III study of R-CHOP vs. substitution of bortezomib for vincristine (VR-CAP), patients with newly-diagnosed MCL who received the bortezomib-containing regimen had improved PFS (median 24.7 vs. 14.4 months) with a trend toward improved OS (median NR vs. 56.3 months), but this was at the expense of increased hematotoxicity. Bortezomib was also combined with R-CHOP induction therapy followed by bortezomib maintenance in the phase II SWOG S0601 trial, and resulted in durable remissions in a subset of patients (5-year PFS 28% and OS 66%) with acceptable toxicity. In a multicenter, phase II study of lenalidomide and rituximab (R2), an ORR of 92% with CR rate of 64% was demonstrated in the up-front setting along with a 2-year PFS and OS of 85% and 97%, respectively. This regimen represents a promising chemotherapy-free approach with significant activity and acceptable safety, especially in patients unable to tolerate more aggressive cytotoxic regimens (see Table 28.6).
TABLE 28.6First-Line Treatment Regimens (non-HDT/ASCR) and Outcome for Mantle Cell Lymphoma
First-Line Treatment Regimen | Number of Patients | Outcome | Study Reference |
R-hyper-CVAD/MA | 97 | Median FFS 4.8 y Median OS 10.7 y | Chihara et al. |
BR vs. R-CHOP | 46 | Median PFS 35.4 mo | Rummel et al. |
48 | Median PFS 22.1 mo | ||
VR-CAP vs. R-CHOP | 243 | Median PFS 24.7 mo | Robak et al. |
244 | Median PFS 14.4 mo | ||
R-CHOP + Bortezomib induction and maintenance | 65 | Median PFS 29.5 mo | Till et al. |
R2 | 38 | 2-year PFS 85% 2-year OS 97% | Ruan et al. |
R-hyper-CVAD/MA, rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine; BR, bendamustine and rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R2, rituximab and Revlimid (lenalidomide); FFS, failure free survival; OS, overall survival; PFS, progression-free survival.
Multiple novel agents have demonstrated significant activity in MCL and are approved for use in the relapsed and/or refractory setting (see Table 28.7). In a multicenter phase II study, bortezomib monotherapy resulted in an ORR of 33% with a median DOR of 9.2 months. The phase II MCL-001 (EMERGE) study demonstrated an ORR of 28% with CR/CRu in 7.5% and median DOR of 16.6 months with lenalidomide monotherapy in MCL patients who relapsed after or were refractory to bortezomib. The randomized, phase II MCL-002 (SPRINT) study compared lenalidomide to investigator’s choice (rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine) and demonstrated a significantly improved PFS (8.7 vs. 5.2 months) in relapsed or refractory patients ineligible for intensive chemotherapy or stem-cell transplantation. In combination with rituximab, R2 demonstrated an ORR of 57% with a median DOR of 18.9 months. Durable responses with the BTK inhibitor, ibrutinib, have also been shown in relapsed or refractory MCL patients with an ORR of 68% (no difference comparing patients with prior bortezomib treatment) and a median DOR of 17.5 months. Extended follow-up of this study revealed a 2-year PFS and OS of 31% and 47%, respectively. Ibrutinib combined with rituximab resulted in increased response rates with ORR and CR rates of 88% and 44%, respectively, with acceptable toxicity. A randomized phase III study compared ibrutinib to temsirolimus and demonstrated a significant improvement in PFS with ibrutinib (14.6 vs. 6.2 months) with less treatment-emergent adverse events (68% vs. 87%) and reduced need for study drug discontinuation (6% vs. 26%). Bortezomib and ibrutinib monotherapy are both currently FDA approved for treatment of patients with MCL who have received at least one prior therapy with lenalidomide approved after two prior therapies, at least one including bortezomib.
TABLE 28.7Novel Targeted Treatment Regimens and Outcome for Mantle Cell Lymphoma
Targeted Regimen | Number of Patients | Response Rate | Median TTR | Median DOR | Median PFS | Study Reference |
Bortezomib | 155 | ORR 33% CR/CRu 8% | 1.3 mo | 9.2 mo | 6.2 mo | Fisher et al. |
Lenalidomide | 134 | ORR 28% CR/CRu 7.5% | 2.2 mo | 16.6 mo | 4 mo | Goy et al. |
Lenalidomide vs. single-agent investigator’s choice | 170 | ORR 40% CR 5% | 4.3 mo | 16.1 mo | 8.7 mo | Trneny et al. |
84 | ORR 11% CR 0% | NR | 10.4 mo | 5.2 mo | ||
R2 | 52 | ORR 57% CR 36% | 2 mo | 18.9 mo | 11.1 mo | Wang et al. |
Ibrutinib | 111 | ORR 68% CR 21% | 1.9 mo | 17.5 mo | 13.9 mo | Wang et al. |
Ibrutinib + Rituximab | 50 | ORR 88% CR 44% | 1.8 mo | NR | NR | Wang et al. |
Ibrutinib vs. Temsirolimus | 139 | ORR 72% CR 19% | N/A | NR | 14.6 mo | Dreyling et al. |
141 | ORR 40% CR 1% | N/A | 7 mo | 6.2 mo |
R2, rituximab and Revlimid (lenalidomide); ORR, overall response rate; CR, complete response; CRu, complete response unconfirmed; TTR, time to response; DOR, duration of response; PFS, progression free survival; NR, not reached; N/A, not available.
Peripheral T-Cell Lymphomas
The term “peripheral T-cell lymphoma” (PTCL) encompasses the various lymphomas derived from mature T and natural killer (NK) cells. T-cell lymphomas are less common than B-cell lymphomas, accounting for approximately 10% to 15% of NHL. Their behavior ranges from indolent to aggressive, although the majority are relatively aggressive lymphomas with poor response rates to chemotherapy and poor OS relative to B-cell lymphomas. There are notable exceptions, however, such as ALK-positive anaplastic large cell lymphoma (ALCL) and mycosis fungoides (MF) with limited skin disease, which have excellent prognoses. Although various distinct disease entities exist within the realm of PTCL, the most common subclassification remains “PTCL-not otherwise specified,” underscoring the need for further elucidation of the genetic and molecular basis of these diseases.
Anaplastic Large Cell Lymphoma
ALCL is a CD30-positive subtype of PTCL that encompasses two biologically distinct diseases: ALCL that overexpresses anaplastic lymphoma kinase (ALK), usually due to t(2;5), and ALK-negative ALCL. The former is typically a disease of children and young adults, while the latter tends to affect older individuals. Patients with both forms typically present with diffuse lymphadenopathy, extranodal disease, and systemic symptoms. ALK-positive ALCL has an excellent prognosis compared to most PTCL subtypes, with a 5-year OS of approximately 70% after anthracycline-based chemotherapy. ALK-negative ALCL has poorer outcomes, and the approach to therapy generally follows that of PTCL-NOS. DA-EPOCH-R has shown promising efficacy in a prospective study of 24 patients with newly-diagnosed ALCL with EFS rates of 72% and 62.5% and OS rates of 78% and 87.5% for ALK-positive and ALK-negative patients, respectively, at a median follow-up of 14.4 years. Additionally, the anti-CD30 monoclonal antibody/cytotoxic conjugate, brentuximab vedotin, was FDA approved for relapsed/refractory ALCL after demonstrating an ORR of 86% with a CR rate of 57% and median duration of overall and complete response of 12.6 and 13.2 months, respectively. This promising agent is being further evaluated in combination with chemotherapy and in the first-line setting.
Primary cutaneous ALCL is a separate disease entity characterized by indolent behavior, predominantly dermatologic involvement, and excellent long-term survival. Additionally, a recent phenomenon of primary breast ALCL occurring in women with breast implants has been reported over the past decade. A recent FDA analysis concluded that breast implants are potentially associated with an increased relative risk, but still very low absolute risk, of primary breast ALCL. A study of 87 breast implant-associated ALCL (BI-ALCL) patients showed a 3- and 5-year OS rate of 93% and 89%, respectively, with superior EFS and OS in patients who underwent a complete surgical excision (total capsulectomy and breast implant removal) compared to patients who had a partial capsulectomy, systemic chemotherapy, or XRT.
Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL-NOS)
This sub-classification includes all T-cell lymphomas not identified as clinicopathologically distinct by the WHO classification. They are generally aggressive lymphomas that affect men disproportionately, present with both nodal and extranodal disease, and respond poorly to CHOP-like chemotherapy, with 5-year OS of approximately 30% to 40%. Improved 3-year EFS (75.4% vs. 51.0%) was seen in younger (<60 years old) T-cell lymphoma patients with normal LDH levels with the addition of etoposide (CHOEP) to CHOP in patients treated on trials of the German High-Grade NHL Study Group (DSHNHL). PTCL-NOS patients had the worst outcome regardless of the regimen received with 3-year EFS and OS of 41.1% and 53.9%, respectively. Dose-intensive regimens such as hyper-CVAD have not been shown to improve outcomes over CHOP. A phase II study by the Nordic Lymphoma Group (NLG) of upfront HDT/ASCT in PTCL demonstrated good results, with 5-year PFS and OS of 44% and 51%, respectively. Although this approach is promising, randomized studies to assess the true benefit of HDT/ASCR are needed.
Several novel agents have demonstrated activity in relapsed/refractory PTCL in recent years, and are currently being evaluated in combination with chemotherapy and in the front-line setting (see Table 28.8). These include the histone deacetylase inhibitors, romidepsin and belinostat, and the novel antifolate, pralatrexate, which have all been FDA approved for relapsed/refractory PTCL. Romidepsin was approved based on a phase II trial showing an ORR of 25% with median DOR of 17 months, with responses seen independent of number of prior therapies or ASCT. PTCL patients treated on the phase II BELIEF (CLN-19) study with belinostat monotherapy had an ORR of 25.8% with median DOR of 13.6 months. The PROPEL study with pralatrexate demonstrated an ORR of 29% and median DOR of 10.1 months and led to its approval for PTCL in the relapsed setting. Other agents being studied include brentuximab vedotin for patients with relapsed PTCL-NOS who are CD30 positive. A phase II study of BV in 35 patients with CD30-positive PTCL (22 patients with PTCL-NOS) revealed an ORR for the entire cohort and PTCL-NOS patients of 41% and 33%, respectively. Median PFS was worse in the PTCL-NOS patients compared to those with angioimmunoblastic T-cell lymphoma (AITL) (1.61 vs. 6.74 months). Given the currently poor outcomes with these agents in patients with relapsed and/or refractory PTCL-NOS, enrollment in a clinical trial is preferred for eligible patients.
TABLE 28.8Novel Targeted Treatment Regimens and Outcome for PTCL
Targeted Regimen | Number of Patients | Response Rate | Median TTR | Median DOR | Median PFS | Study Reference |
Romidepsin | 130 | ORR 25% CR/CRu 15% | 1.8 mo | 16.6 mo | 4 mo | Coiffier et al. |
Belinostat | 120 | ORR 25.8% CR 10.8% | 5.6 weeks | 13.6 mo | 1.6 mo | O’Connor et al. |
Pralatrexate | 111 | ORR 29% CR 11% | 46 days | 10.1 mo | 3.5 mo | O’Connor et al. |
Brentuximab vedotin (CD30+ PTCL) | 34 All | ORR 41% CR 24% | N/A | 7.6 mo | 2.6 mo | Howitz et al. |
13 AITL | ORR 54% CR 38% | N/A | 5.5 mo | 6.7 mo | ||
22 PTCL-NOS | ORR 33% CR 14% | N/A | 7.6 mo | 1.6 mo |
CD30, cluster of differentiation 30; PTCL, peripheral T-cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; ORR, overall response rate; CR, complete response; CRu, complete response unconfirmed; TTR, time to response; DOR, duration of response; PFS, progression free survival; NR, not reached; N/A, not available.
Angioimmunoblastic T-cell Lymphoma
AITL is one of the more common subtypes of PTCL, accounting for 15% to 20% of cases. Median age at diagnosis is 65, and patients typically present with diffuse lymphadenopathy, hepatosplenomegaly, extranodal involvement, systemic symptoms, rash, and hypergammaglobulinemia. Autoimmune phenomena, both hematologic and nonhematologic, are also common. Response rates to anthracycline-based chemotherapy are relatively poor, and 5-year OS is approximately 30%. High-dose chemotherapy with autologous stem cell rescue as first-line therapy for AITL is being studied; however, currently the benefit of this approach remains unclear. The phase II study of brentuximab vedotin in relapsed/refractory PTCL showed a higher ORR of 54% and median PFS of 6.7 months in AITL patients compared to those with PTCL-NOS and represents an option for CD30-positive patients (see Table 28.8). Immunosuppressive therapy with cyclosporine has shown promising early results, and can be considered in select cases. The efficacy of cyclosporin A (CsA) in patients with recurrent AITL is being evaluated in a prospective study (ECOG 2402). Otherwise, the approach to treatment of AITL largely follows that of PTCL-NOS.
Rare Extranodal NK/T-cell Lymphomas
The two main subclassifications of NK/T-cell lymphoma are extranodal NK/T-cell lymphoma, nasal type (ENKL), and aggressive NK-cell leukemia (ANKL). These diseases are almost always EBV positive, and are extremely rare in North America and Europe but prevalent in Asia and Central/South America. ENKL typically involves the nasopharynx and nasal cavity, palate, and can also affect the skin, gastrointestinal tract, and testis. EBV viral load serves as a useful biomarker of disease in the blood and should be measured at diagnosis and followed throughout the course of treatment as a marker of possible persistent disease. A separate prognostic system involving four parameters (serum LDH >normal, B symptoms, LN involvement, N1-N3, not M1 and Ann Arbor Stage IV) comprises the NK/T-cell lymphoma prognostic index and divides patients into risk groups based on 0, 1, 2, or 3 to 4 risk factors with 5-year OS of 80.9%, 64.2%, 34.4% and 6.6%, respectively. Newer models exist for patients treated with non-anthracycline-based chemotherapies with or without concurrent chemoradiation or radiotherapy, termed the prognostic index of natural killer lymphoma, and another newer model incorporates EBV viral load. Patients with disease confined to the nasal cavity can be successfully treated using IFRT with or without chemotherapy (DeVIC, VIPD, SMILE, or GELOX), while those with extranasal disease and ANKL have a very poor prognosis. Encouraging results have recently been seen with L-asparaginase-based chemotherapy regimens, and further studies evaluating this agent in ENKL and ANKL are ongoing. The SMILE regimen in patients with newly diagnosed stage IV or relapsed/refractory disease yielded an ORR and CR rate of 79% and 45%, respectively, after 2 cycles of therapy with a majority of patients who completed the protocol proceeding to HSCT. A retrospective study of another regimen using pegaspargase with gemcitabine and oxaliplatin (P-GEMOX) in patients with newly-diagnosed stage III/IV or relapsed/refractory disease, demonstrated an ORR and CR rate or 80% and 51.4%, respectively, and represents and alternative option for therapy. Both of these regimens have been utilized alone as well as have been tested with sequential or sandwich radiotherapy.
These are rare and aggressive T-cell lymphomas that originate from gamma-delta lymphocytes. The WHO 2008 classification divided these lymphomas into two separate entities: hepatosplenic gamma-delta T-cell lymphoma (HSGDTL) and primary cutaneous gamma-delta T-cell lymphoma (PCGDTL). HSGDTL typically affects young men and involves the liver, spleen, and BM. Histologic diagnosis can often be difficult to obtain. Prognosis is poor regardless of choice of therapy, with a median OS of approximately 2 years. There is no standard of care, although most patients are treated with CHOP-like regimens with or without HDT/ASCR. PCGDTL is extremely rare and accounts for <1% of primary cutaneous lymphomas. Cutaneous disease is variable and clinical course is typically aggressive with poor long-term survival. Small single-center studies indicate brentuximab vedotin as a potential treatment option for chemotherapy-refractory patients whose tumors express CD30.
Enteropathy-Associated T-Cell Lymphoma
This is a rare and aggressive PTCL of the small intestine that typically affects older individuals with celiac disease, although many patients are diagnosed with EATL who have no known history of enteropathy. Patients typically present with abdominal pain and anorexia. A large, multicenter cohort study of 61 EATL patients showed overall poor prognosis with 1 and 5-year OS rates of 40% and 11%, respectively. Patients receiving the most aggressive treatments, including surgical resection, chemotherapy, and ASCT, showed the best outcomes with 1- and 5-year OS of 100% and 33%, respectively. Combination therapy appears to result in superior outcomes but the benefit of consolidative ASCT needs to be confirmed in larger randomized studies.
Cutaneous T-Cell Lymphoma/Mycosis Fungoides
CTCLs are typically mature T-cell neoplasms that originate within, and often remain confined to, the skin, with variable spread to the lymph nodes, BM, and peripheral blood. MF constitutes the majority of CTCL. Sezary syndrome (SS) is the much less common leukemic manifestation of MF, accounting for 3% of CTCL. MF is considered an indolent lymphoma, although behavior and prognosis are highly variable; patients with limited patch or plaque disease of the skin have excellent long-term survival, while prognosis is poorer for those with erythrodermal skin involvement and extracutaneous disease.
MF is staged per the revised MFCG staging system, which incorporates extent of skin, nodal, visceral organ, and peripheral blood involvement. Patients with limited skin disease are typically treated with topical corticosteroids, topical retinoids, topical chemotherapy, phototherapy, or local radiation. Patients with more extensive skin involvement can be treated with the same modalities or with total skin electron beam therapy (TSEBT). Patients with more advanced disease are treated initially with systemic therapies such as extracorporeal photopheresis (ECP), oral retinoids, interferon, or HDAC inhibitors, with chemotherapy being reserved for patients who progress on these agents or for those with aggressive disease with visceral organ involvement. Systemic chemotherapy agents used include alemtuzumab, brentuximab, bortezomib, doxil, gemcitabine, low-dose methotrexate, pentostatin, and temozolomide. A recent phase II study of brentuximab vedotin showed an ORR of 54% in patients with MF/SS, with responses seen independent of CD30 expression. A large, single-center study of allogeneic HSCT in advanced CTCL, after failure of standard therapy, reported long-term remissions in a subset of patients with 4-year OS and PFS of 51% and 26%, respectively, but at the risk of a cumulative incidence of non-relapse mortality of 16.7% at 2 years. The current role of allogeneic HSCT in the treatment of advanced and relapsed/refractory disease remains unclear at this time.
Treatment Approaches for Relapsed Aggressive Lymphomas
Treatment for relapsed aggressive DLBCL generally involves salvage chemotherapy followed by HDT/ASCR in fit patients who demonstrate chemosensitive disease. Commonly used salvage chemotherapy regimens include R-ICE, R-DHAP, R-ESHAP, and EPOCH-R. Patients with chemoresistant disease do not benefit from HDT/ASCR and should be enrolled into clinical trials, considered for allogeneic HSCT, or treated palliatively. Additionally, the results of the CORAL study indicate that the benefit of HDT/ASCR may be significantly limited in the rituximab era, as patients in this trial who were previously treated with rituximab had a 3-year EFS of only 21% after HDT/ASCR. This study also demonstrated a similarly poor 3-year EFS in patients who relapsed less than 12 months after initial diagnosis. Consequently, careful consideration of disease factors, as well as a frank discussion of treatment and available trial options, should precede referral for HDT/ASCR. Nontransplant candidates who are not eligible for a clinical trial can be treated palliatively with any of the aforementioned salvage regimens or with BR or lenalidomide.
The other aggressive B-cell lymphomas (MCL, BL) and most aggressive T-cell lymphomas are rarely, if ever, cured with conventional salvage chemotherapy or HDT/ASCR, although studies of HDT/ASCR in relapsed PTCL have demonstrated a 5-year OS of approximately 40% and patients with ALK-positive ALCL can be cured with this approach. HDT/ASCR is considered an option in patients with PTCL who demonstrate chemosensitivity to salvage chemotherapy, although again careful consideration should be given to investigational therapies to include allogeneic HSCT.
Novel Treatment Approaches and Future Directions
Genetically modified T-cells expressing the anti-CD19 chimeric antigen receptor (CD19 CAR T-cells) can be used to treat patients with advanced B-cell malignancies that express CD19. A small, single-center study of 15 patients with advanced, chemotherapy refractory DLBCL, indolent B-cell lymphoma, and CLL, resulted in CR in 8 patients with 4 of the 7 DLBCL patients in CR ranging from 9 to 22 months duration. CD19 CAR T-cell therapy represents a promising approach to the treatment of patients with chemotherapy-refractory disease and is currently being tested using autologous and allogeneic cells, prior to and following allogenic HSCT, respectively.
Immune checkpoint inhibition, with inhibitors of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), are currently being investigated in the treatment of NHL with promising safety and efficacy. The most robust data for PD-1 inhibition in hematologic malignancies is in the treatment of Hodgkin lymphoma, but several studies have indicated efficacy in NHL as well. Preliminary results of the phase I study with nivolumab, a humanized IgG4 PD-1 monoclonal antibody, in lymphoid malignancies demonstrated acceptable safety with an ORR of 28% and CR rate of 7% in B-cell NHL (ORR of 36% in DLBCL and 40% in FL) and an ORR of 17% in T-cell NHL (ORR of 40% in PTCL-NOS). The combination of pidilizumab, a humanized PD-1 monoclonal antibody, and rituximab was tested in a phase II study of rituximab-sensitive relapsed FL patients and was well tolerated with an ORR of 66% (CR 52% and PR 14%). Recent preclinical data suggest that ibrutinib, an inhibitor of both BTK and ITK, can enhance the effect of immune checkpoint inhibition through shifting from a Th2 to Th1 antitumor immune response. This provides scientific rationale for combination therapy and inhibitors of PD-1 and PD-L1 are currently being tested both as monotherapy and in combination with cytotoxic and targeted therapy in the treatment of NHL.
Novel methods have emerged over the past few years enabling the detection of small fragments of circulating-tumor DNA (ctDNA) in the peripheral blood. In a correlative biomarker study comparing ctDNA to CT scans in previously untreated DLBCL patients, interim monitoring of ctDNA revealed significantly improved 5-year TTP (80.2% vs. 41.7%) in patients with undetectable interim ctDNA and also detected early relapse 3.5 months prior to clinical disease when used in the surveillance setting. Beyond its use in interim and surveillance monitoring, ctDNA also has prognostic potential both at diagnosis and during MRD assessment following therapy. When used as a “liquid biopsy”, ctDNA can aid in non-invasive diagnosis and may eventually guide selection of targeted therapy in a precision-directed fashion. Further validation of this novel technique is needed in prospective studies, but ctDNA has the potential to transform our current methods of diagnosis, response assessment, and relapse detection in NHL.
Suggested Readings
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