It is well established that a variety of DNA-damaging agents can induce myeloid neoplasms, which are grouped together in the current World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues.1 In addition, there are now a number of distinct scenarios in which drugs used to treat or prevent certain diseases can lead to the development of abnormal lymphoproliferations, not all of which are overly neoplastic (Box 1).
However, the mechanisms leading to these secondary lymphoid disorders are more diverse than they are in myeloid neoplasms, as they are usually (but not always) unrelated to primary DNA damage by cytotoxic chemotherapy; therapy-related acute lymphoblastic leukemia (t-ALL) is an obvious exception. These lymphoid proliferations are perhaps best exemplified, and also best characterized, by the spectrum of posttransplant lymphoproliferative disorders (PTLDs). PTLDs have been well recognized for some time now, and have consequently been inculcated into contemporary classification schemes on hematologic malignancies.2
In this brief review, discussion will be restricted to only t-ALL, and those lymphoproliferations associated with the therapy of autoimmune and other immune-mediated diseases.
THERAPY-RELATED ACUTE LYMPHOBLASTIC LEUKEMIA
Any consideration of therapy-related acute leukemia is typically focused upon acute myeloid leukemias (t-AML). However, it is also apparent, albeit somewhat underemphasized, that therapy-related acute leukemias may also be ALLs. Thus, it has been suggested that although approximately 88% of all therapy-related acute leukemias are AML, a sizable minority, 12%, are t-ALL.3 The number of cases reported over the past 2 decades seems to be increasing, with at least 200 cases now described in the published literature.4–7
Of all adult AMLs, as many as 10% to 20% are considered to be t-AMLs,1 whereas only 1% to 4% of all adult ALLs are believed to be t-ALLs.6 Most of the t-ALLs are of B-cell lineage, and there is a nonrandom association with recurrent cytogenetic abnormalities. The most common abnormality, found in approximately 67% of cases, is a translocation affecting the MLL gene at 11q23,7 with approximately 65% of these cases (thus over 40% overall) showing the t(4;11) translocation.5 By contrast, 11q23 translocations are less common in t-AML, where they are observed in approximately 20% of cases. The second most common cytogenetic abnormality in t-ALL is t(9;22) occurring in nearly 13% of cases, whereas the third most common finding (nearly 8% of cases) is a normal karyotype.7
In t-AML, the major groups of drugs incriminated are the alkylating agents (such as melphalan, cyclophosphamide, and chlorambucil) and the topoisomerase II inhibitors (that include etoposide, daunorubicin, and mitoxantrone). Despite the presence of clinical, pathologic, and genetic differences between these 2 groups, they are understandably now no longer separated as different subtypes of t-AML, as many patients will have been treated with drugs from both the groups. However, as compared with topoisomerase II inhibitors, alkylators seem to be incriminated in a greater proportion of t-AMLs.1 By contrast, it appears that topoisomerase II inhibitors are most likely to be associated with the development of t-ALL, typically, but not exclusively, in the context of 11q23 translocations. Interestingly, there seems to be some differences (albeit mostly not statistically significant) in whether a t-ALL does, or does not, harbor an 11q23 translocation (Table 1). Of note, no matter what the cytogenetic association, the outcome of t-ALL is uniformly dismal with a median survival of only approximately 2.5 months.
The shorter latency associated with the use of topoisomerase II inhibitors and 11q23 translocations in t-ALL5–7 is akin to what is observed in t-AML that occurs with the use of these agents. It is not clear, however, if those cases not arising after topoisomerase II therapy and/or lacking 11q23 translocations are more likely to have a longer latency. It is not apparent that these cases are more likely to have arisen after alkylator therapy, and there does not seem to be an association with the cytogenetic abnormalities seen in such t-AML cases, for example abnormalities of chromosomes 5 and/or 7.
Not all patients treated with topoisomerase II inhibitors develop 11q23-positive ALLs; indeed, almost one-third of t-ALLs that develop in the setting of such agents lack 11q23 translocations. It is well established, at least in t-AML, that 11q23 is not the sole target of such drugs, with a number of other recurrent, nonrandom abnormalities seen in this therapeutic setting. It is nonetheless apparent that much more needs to be learned about t-ALLs, as it remains less well understood than the more frequent and better characterized t-AMLs.
ATYPICAL LYMPHOPROLIFERATIONS AND LYMPHOMAS ASSOCIATED WITH THERAPY FOR (AUTO)IMMUNE DISEASES
A number of different agents that are used to treat different (auto)immune diseases may induce a state of immunosuppression that is conducive to the development of a spectrum of lymphoid proliferations, including overt lymphoma. To some degree, this is analogous to the development of lymphoproliferations emerging in other states of immunosuppression, such as PTLDs, HIV/AIDS, and inherited syndromes associated with immunodeficiency. However, there are additional tiers of complexity in this group, which sometimes preclude the assignment of a direct cause-and-effect relationship. For example, some (auto)immune diseases themselves, even without therapeutic intervention, are associated with a baseline risk for the development of atypical lymphoid expansions and lymphoma. This varies between different autoimmune diseases in that some, such as rheumatoid arthritis (RA) seem to have a well-established (but variably reported) risk, whereas others, such as simple psoriasis, apparently do not. With regard to inflammatory bowel disease (IBD), there are essentially as many studies suggesting an increased baseline risk for the development of lymphoma as there are failing to show an association. There is also, in general, an association of increased risk of lymphoma with increasing (auto)immune disease severity8; whether this is due to the disease per se, or the need for more aggressive therapy, is unclear. An additional potential confounder is that different forms of therapy may have been used in individual patients, with this being administered previously or concomitantly. Hence, it is sometimes challenging to dissect out specific causality.
Description of Selected Drugs and Their Actions
Three drugs, or classes of drugs, will be discussed in some detail. These are methotrexate, thiopurines, and immunomodulators.
Methotrexate: Methotrexate (MTX) has been used for a number of decades, particularly for patients with RA. The mechanism of action of this drug as a chemotherapeutic agent is well characterized. It inhibits the enzyme dihydrofolate reductase, decreasing the production of thymidine (a pyrimidine), leading to impaired DNA synthesis and consequent cytotoxicity. By contrast, its action as an immunosuppressant is thought to be distinct from this mechanism, although it remains poorly understood. It may block other enzymes that are involved in purine metabolism, leading to the accumulation of adenosine. The downstream effects are primarily on T-cell function, including impairment of T-cell activation, decreased expression of adhesion molecules by T cells, increased numbers of regulatory T cells, and a shift from Th1 to Th2 cells and cytokines. Furthermore, the doses of this drug used to treat autoimmune diseases are 2 to 3 logs lower than those used to treat cancer.
Thiopurines: Azathioprine and 6-mercaptopurine are 2 commonly used thiopurines, with the former being a prodrug of the latter. They are converted into 6-thioguanine, leading to the inhibition of nucleotide synthesis. In addition, they appear to directly inhibit cytotoxic T-cell and natural killer cell function, as well as facilitating apoptosis of activated T cells. This leads to impaired cell-mediated immunosurveillance.
Immunomodulatory agents: A large number of unrelated therapeutic agents are seemingly variably included under this umbrella term, leading to the potential for terminologic confusion. These include compounds such as thalidomide and its derivative lenalidomide (immunomodulatory drugs or derivatives), used for the therapy of hematologic neoplasms such as myeloma and the myelodysplastic syndromes. Additional diverse groups of novel and some emerging immunomodulatory therapies include statins, curcumin, desferrioxamine, macrolide antibiotics, and even mesenchymal stem cells. However, none of these agents is the focus of discussion here. Rather, the term immunomodulator agents (IAs) in this context is used to cover agents that are typically, but not exclusively, monoclonal antibodies that inhibit soluble mediators and cellular receptors that are central to (auto)immune diseases, and which reflect a growing pharmaceutical wave of novel therapeutics. These agents will be detailed in a section below.
Of all lymphoproliferations arising in the setting of immunotherapy for an (auto)immune disease, the association is perhaps best described with the use of MTX, as it has been in use for this purpose for the longest time (over 4 decades). These lymphoproliferations and lymphomas have mostly, but not exclusively, been described in the setting of RA. The reasons for this association are unclear, and some not well-answered questions include (1) whether this reflects something specific about RA, (2) if this is because RA is especially common, or (3) if this is explained by the fact that, at least historically, most patients with RA were treated with MTX. Further complicating the issue is that patients with RA appear, in most studies, to have a baseline increased risk for the development of lymphoma, unrelated to any form of therapy. The reported increased risk, as compared with the general population, ranges from 2× to 20×. Typically, patients who develop lymphoma on MTX have been on long-term (median ∼3 y, sometimes up to ∼10 y) low-dose (5 to 25 mg/wk) therapy. As noted, the majority of reports (>80%) of MTX-associated lymphomas are in patients treated for RA; other less common underlying disorders include psoriasis and dermatomyositis.
The lymphomas seen with MTX are typically diffuse large B-cell lymphomas (DLBCLs) and classic Hodgkin lymphomas (CHLs), as well as mimics of the latter (see separate section below). It is worth noting that DLBCL and CHL appear to be disproportionately represented in the setting of MTX as compared with other immunodeficiency scenarios, such as PTLD and HIV/AIDS, as well as those seen with the use of immunomodulatory agents. Other less commonly reported lymphomas in the setting of MTX therapy include follicular lymphoma, Burkitt lymphoma, peripheral T-cell lymphoma, lymphoplasmacytic lymphoma, and small lymphocytic lymphoma. The frequency of MTX-associated lymphoproliferations is not well documented; however, over 100 cases have been reported in the literature. Approximately 40% are extranodal, including a recent unusual case of one developing at the site of subcutaneous injection of MTX.9
However, both here and indeed throughout this discussion, questions arise as to whether there really is a bona fide association, and if so is there direct evidence of causation, or is this merely coincidence. Although it is essentially accepted as dogma that patients with RA and treated with MTX are indeed at heightened risk for the development of lymphoma, it is sobering to note that large studies, involving a total of over 40,000 patients with RA treated with MTX,10,11 have failed to document a statistically significant increased risk for lymphoma! A smaller study, involving less than 500 patients, did however demonstrate a 5× increased risk for developing lymphoma12; however, the control group here was the general population, and not RA patients who were not treated with MTX. Indeed, a number of studies indicating an association seem to be flawed based upon the use of such inappropriate controls. Nevertheless, one very compelling point that supports the existence of MTX-associated lymphomas being quite distinct from those that occur in the absence of therapy is that the former tend to be Epstein Barr virus (EBV)-positive, whereas the latter are typically EBV-negative. These EBV-negative lymphomas, presumably unrelated to immunosuppressive therapy, actually account for the majority of lymphomas in RA patients.13
Hodgkin lymphoma and its mimics associated with methotrexate: Both bona fide CHL and lymphoproliferations that mimic CHL (Hodgkin-like lymphoproliferations; HLL) have been quite rarely but nevertheless quite well described in patients treated with MTX. It is essential to distinguish CHL from HLL, as the latter is much more likely to remit after the cessation of MTX, obviating the need for toxic therapy. Although these entities may superficially resemble one another histologically, there are a number of clues that may be helpful in determining which is the more likely consideration (Table 2).
Importantly, unambiguous and rigorous morphologic and immunophenotypic criteria must be applied when rendering a diagnosis of CHL in this scenario (or indeed in any situation in which there is known to be a background of immunosuppression). Although we have focused here on a discussion of CHL and HLL, it is important to appreciate that DLBCL occurs approximately twice as commonly as CHL in the setting of MTX therapy for autoimmune diseases. Overall, approximately 20% to 30% of MTX-associated lymphoproliferations will remit after cessation of therapy.14 Factors that might be predictive of remission, without the need for aggressive cytotoxic lymphoma therapy, include (1) DLBCL, as compared with CHL; (2) extranodal, as compared with nodal disease; and (3) EBV-positivity versus EBV-negativity. However, despite these correlations, the clinical behavior can be quite unpredictable, in that some traditionally aggressive lymphomas may regress spontaneously, whereas others that are not clearly malignant can be fatal. Nevertheless, and as noted above, it is important to distinguish bona fide CHL from HLL lesions, as the majority of the latter will indeed regress once MTX is withdrawn.13,15 If remission occurs, this happens quite rapidly and usually within 4 weeks. Given the unpredictable nature of this group of lymphoproliferations and lymphomas, a suggested therapeutic approach is a short period of observation, perhaps 4 to 8 weeks, off MTX, particularly if EBV is positive.16
Azathioprine and 6-mercaptopurine have been used most often in the therapy of IBD, in particular Crohn disease, and there are a number of studies assessing an association with lymphoma, with some of the original studies dating back to the 1980s. As is thematic throughout, many of the single center-based analyses might be confounded by ascertainment and referral bias. More rigorous studies yield data that suggest that the use of thiopurines for the therapy of IBD is associated with a 3× to 5× increased risk for the development of lymphoma, as compared with nontreated patients, with many of these being EBV-positive.17
Immunomodulatory Agent-related Lymphoproliferations
A number of biologically targeted agents have recently been developed for the treatment of a variety of autoimmune and related immunologically based diseases and have entered into clinical practice in the past decade (Table 3).18 These diseases include RA, IBDs, psoriasis, psoriatic arthritis, multiple sclerosis, and ankylosing spondylitis. Their use (and consequent association with lymphoproliferations) has been observed mostly in RA, IBD, and psoriatic arthritis; by contrast, lymphoproliferations are rather uncommon in the setting of multiple sclerosis, ankylosing spondylitis, and psoriasis. Within the IBDs, there is more of an association with Crohn disease than there is with ulcerative colitis. In general, and in contrast to what has been observed in MTX-related lymphomas, many different types of lymphoma have been reported in association with IAs, including a spectrum of both B-cell and T-cell lymphomas as well as NK-cell neoplasms and Hodgkin lymphoma. Furthermore, atypical but non-neoplastic lymphoproliferations have also been described, and hence these disorders tend to resemble what is seen in the context of PTLDs.
The epidemiology of IARLPDs is not well characterized and there are conflicting data in the published literature. Publications have evolved from anecdotal reports, to small series to meta-analyses.20–24 They are now recognized as a category of disorders by the WHO25; however, it is of some interest to note that the largest published series (an analysis of 18 cases) was a collaborative effort of 8 different institutions,18 suggesting that they are quite uncommon and/or underrecognized. It is also worth noting that there are now a growing number of studies that suggest the use of IAs, in isolation, may in fact not be significantly associated with a heightened risk of atypical lymphoproliferations and overt lymphomas.23,24,26,27 As with the other disorders discussed herein, this lack of clarity might be due to a number of potential confounders, allied to the multifactorial basis of these IARLPDs. Such factors include the specific types of therapy (what agent, duration of therapy, and, perhaps most importantly, what other drugs were used); the specifics of the underlying disease [for example, the inherent increased risk of lymphoma, the severity of the disease, and the curious association of hepatosplenic T-cell lymphoma (HSTCL) in the context of therapy for Crohn disease]; sex (suggestions that overt lymphoma may be seen more often in women, whereas atypical but non-neoplastic lymphoproliferations are more likely seen in men); as well an inherent constitutional genetic predisposition.
One of the major confounders to documenting definitive causation to a single agent, such as a specific IA, is the effect of other drugs such as MTX and/or thiopurines, which have frequently, if not invariably, been used in many of the patients studied and reported upon. As noted before, some of the underlying disorders are associated with a baseline increased risk for lymphoma development, unrelated to therapy. In addition, unintentional study flaws such as the use of suboptimal controls and referral/ascertainment bias are likely to limit the robustness of some studies' conclusions. However, as a counter to these concerns, a number of observations do indeed tend to legitimize these entities. Thus, and as with MTX, most lymphomas that develop in patients with these immune-mediated diseases unrelated to therapy are EBV-negative, whereas those seen in the context of therapy are typically EBV-positive. Furthermore, there are fairly compelling temporal associations that are difficult to dismiss. Hence, the short latency (as rapidly as 2 wk) between initiation of IAs and the development of IARLPDs is quite impressive, although somewhat contrary to conventional notions regarding the chronology of cancer development. Similarly, the reports of rapid regression of these lesions after withdrawal of therapy (as soon as 4 wk) are also noteworthy.
As with the MTX-associated disorders, the response to cessation of therapy may be unpredictable, as this has been observed with both atypical (but not overly neoplastic) lymphoproliferations, as well as bona fide lymphoma, with up to 30% to 40% of DLBCLs and CHLs apparently remitting off therapy. Also as with MTX, regression is more likely to occur in the context of EBV-positivity. In general, however, this favorable response to therapy withdrawal is more likely to occur in the setting of MTX than it is with IAs such as the tumor necrosis factor (TNF)-α inhibitors. The specific lymphoma type might also determine whether responses occur; for example, HSTCLs are usually rapidly fatal, regardless of cessation of immunomodulatory treatment.
In general in the setting of IAs, polymorphic lymphoproliferations are less common than overt lymphomas, accounting for approximately 10% and 90%, respectively. The polymorphic lymphoproliferations may be nodal (and include atypical follicular hyperplasia, atypical paracortical hyperplasia, aberrant T-cell phenotypes, and abnormal extrafollicular accumulations of B cells) or extranodal (as evidenced by atypical lymphoid infiltrates).18,25 As noted, a spectrum of different lymphoma types has been reported, albeit dominated by DLBCLs (∼45%) and CHL (∼20%). Follicular lymphoma (∼5% to 10%) and a spectrum of T-cell lymphomas (∼5%) are also seen; the T-cell lymphomas include HSTCL (see separate section below); peripheral T-cell lymphoma, not otherwise specified; angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma. Uncommon miscellaneous subtypes include Burkitt lymphoma, mucosa associated lymphoid tissue lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and NK-cell neoplasms. There is also a variable association with EBV among these different subtypes. Curiously, EBV is found less commonly in the polymorphic lymphoproliferations than it is in overt lymphomas,18 which is unlike the scenario in PTLDs and in MTX-associated lymphoproliferations.16,28 This suggests a somewhat different pathophysiology, and that this oncovirus might not be involved in the initiation of IARLPDs. Within specific lymphoma subtypes, EBV is most often seen in CHL (∼80%) and less so in DLBCL (∼25%). Interestingly, up to 25% of follicular lymphomas may be EBV-positive. HSTCL is never EBV-positive.
A number of interesting observations emerge from the recently reported largest series of IARLPDs. Of the 18 cases reported, 11 were lymphomas and 7 atypical lymphoproliferative disorders.18 Most of the lymphomas (8/11) were seen in female patients, all (8/8) on which data were available had not received IAs in isolation (MTX and/or thiopurines had been used), around 50% (6/11) were EBV-associated and a similar proportion (5/11) had RA. By contrast, all of the patients (7/7) with atypical lymphoproliferations were male, none (0/5) of whom with data had received MTX or thiopurines, a minority (1/6) was EBV-positive, and none (0/7) had RA. Some unusual features evident in the lymphomas include an EBV-positive follicular lymphoma, a primary cutaneous anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, a CHL that presented in the gastrointestinal tract, and a CD4-positive subcutaneous panniculitis-like T-cell lymphoma.
Do IAs really cause lymphoma? There are emerging data that seem to suggest that this might not be the case. These data emanate from a number of sources.23,24,26,27 A number of meta-analyses and pooled analyses performed on >10,000 patients treated with IAs failed to show an increased risk for lymphoma development. However, and again as alluded to before, disentangling the relative contributions of innate lymphoma susceptibility, the use of other immunosuppressive agents (previously or concomitantly), as well as the aggressiveness of the underlying immune disease (which is then almost invariably accompanied by more aggressive therapy) is virtually impossible. Nevertheless, it is difficult to ignore the noted temporal associations, with both the short latency to develop and brief time to regress. It is possible, however, that the short latency to development might reflect a reporting bias. There are also interesting anecdotal reports of patients with lymphoma unrelated to any prior underlying immune disease or therapy in remission, who subsequently—and presumably coincidentally—develop an (auto)immune disease.22 When this (auto)immune disease was treated with therapy directed at TNFα, the lymphomas rapidly recurred in a fulminant fashion.22
Hepatosplenic T-cell lymphoma: It remains unclear whether the presence of IBD, per se, without therapeutic intervention, is associated with a baseline increased risk for the development of lymphoma.29 Although several observational studies indicate an increased risk,30,31 the results of a number of population-based analyses have been variable, with some showing an association, and others not.32–35 Furthermore, the degree to which immunotherapy increases the risk is not well defined, although for thiopurines alone it appears to be of the order of 3 to 5 fold.
One specific lymphoma subtype that is tightly linked to the therapy of 1 group of immune-mediated disease is the association of HSTCL with IBD, and more so with Crohn disease than ulcerative colitis.36–38 HSTCL is a rare and highly aggressive form of T-cell lymphoma, comprising ∼5% of all T-cell lymphomas and <1% of lymphomas overall. However, although fewer than 200 cases have been reported in the literature (1996 to 2009), there is a disproportionate representation of patients with IBD on therapy (36 cases, 26 of whom had Crohn disease). Reporting bias may be a factor in these numbers, but it seems probable that there is indeed a link between HSTCL and IBD on therapy. All 36 received thiopurines, 16 alone and 20 in combination with anti-TNFα therapy.39 Most of these patients were young men (<35 years old), and none of the patients had been treated on anti-TNFα therapy alone. Thus, the available data more compellingly implicate thiopurines, as compared with anti-TNFα therapy, with the development of HSTCL. However, it is currently unclear to what degree the use of such biologic therapy adds to the risk imparted by thiopurines. Furthermore, the risk for developing HSTCL with thiopurines is not specific for IBD, as there are at least 20 reports of this lymphoma developing in solid organ transplant patients treated with azathioprine.40 Risk factors associated with the development of HSTCL in IBD seem to be young age (between 10 and 35 y) and male sex (men are 10× as likely as women to develop HSTCL). Accordingly, young men in particular should be monitored with enhanced vigilance. Although the absolute risk is very low, in that more than 99.9% of patients with IBD treated with thiopurines alone or in combination will not develop HSTCL (with the exception of men younger than 35), the relative risk for developing HSTCL is clearly much higher in patients with IBD as compared with the general population.
Lymphomas may not be the only hematologic neoplasm associated with the use of immunomodulatory agents: There has been a number of case reports in the past few years describing a variety of hematologic malignancies, other than lymphomas, in patients treated with anti-TNFα therapy. These include AML, ALL, myelodysplastic syndrome, and chronic myelogenous leukemia.41,42 It remains to be determined, of course, whether these cases are the smoke indicating a fire, or mere coincidence. Interestingly, some of these agents have been used in the therapy of a subset of myeloid neoplasms.43
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