Chronic Lymphocytic Leukemia and Hairy-Cell Leukemia
Chronic Lymphocytic Leukemia and Hairy-Cell Leukemia
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most common leukemia and one of the most common lymphoid malignancies in western countries. The pathobiology of CLL is a result of the failure of apoptosis rather than uncontrolled proliferation. By definition, CLL is B-cell–derived and is also referred to as small lymphocytic lymphoma when found in sites other than the blood and bone marrow. The prototypical CLL patient is an older, white man (2:1 male predominance, median age at diagnosis is 72 years) with lymphocytosis and possibly lymphadenopathy yet no other symptoms. The management for such a prototypical patient is observation, because early initiation of cytotoxic therapy will expose the patient to toxicities and to date has never been shown to improve survival. Therapy may ultimately be needed for such a patient and for an improvement in symptoms; disease control and improved overall survival are possible with modern CLL regimens. A fraction of CLL patients do not behave like the prototypical patient and have short remissions and resistance to therapy that will require aggressive therapeutic options, including an allogeneic hematopoietic progenitor cell transplant.
In the United States in 2014, there are an expected 15,270 new diagnoses of CLL and 4,600 CLL-related deaths. The age-adjusted incidence of CLL is 4.1/100,000 individuals. The median age at diagnosis is 72 years. The male to female ratio is 2:1, with little change as age increases. The incidence of the disease is higher in whites than in African Americans, and the diagnosis of CLL in Asian countries is infrequent. The shift in the global population has not changed the risk in any particular race or ethnicity.
Etiology and Risk Factors
Monoclonal B-cell lymphocytosis
Nearly all cases of CLL are preceded by a monoclonal B-cell lymphocytosis (MBL). MBL is defined as a B-cell population by flow cytometry that is not greater than 5 × 109/L and no symptoms consistent with a diagnosis of CLL, such as organomegaly. This disorder is discovered incidentally or when patients are being evaluated for a possible diagnosis of CLL. The monoclonal B cell will invariably have a phenotype analogous to CLL. It is estimated that about 3% of the US population meets the criteria for MBL, and this incidence increases with age. Studies have shown that the rate of progression to CLL from MBL is approximately 1% to 2% per year.
Up to 17% of patients with a diagnosis of CLL have a first-degree family member who has MBL, and 5% to 10% of CLL patients have a family member with CLL.
Exposure to herbicidal agents, such as “Agent Orange,” may be associated with CLL; however, this is not proven. Causality due to radiation exposure, alkylating chemotherapy, and other chemicals has not been confirmed.
Signs and Symptoms
In a prototypical patient, symptoms may be absent or there may be nonspecific, generalized complaints, such as weakness and fatigue. Classic B symptoms are uncommon at diagnosis, but their presence may signal transformation to large cell lymphoma. Patients may notice enlarged lymph nodes, and abdominal distention may relate to enlarged mesenteric adenopathy. Infections such as viral reactivation of herpes simplex virus are common.
Splenomegaly is a common finding in CLL and typically progresses as the disease matures and becomes refractory to therapy. Hepatomegaly may present in 15% to 25% of patients and is usually mild and nontender. Because these cells circulate freely in the blood and are attracted to sites of inflammation, CLL cells are often found in biopsy specimens from almost any organ. It is important to recognize that in the vast majority of cases, the CLL is a bystander, not an instigator, and such findings rarely require anti-CLL therapy.
Lymphocytosis is the hallmark finding in CLL, with a typical lymphocyte count between 30 and 50 × 109/L. Lymphocytes are small, mature-appearing cells with little cytoplasm and clumped chromatin. Smudge cells are frequently seen on peripheral blood smear; they may denote a more indolent course when present in high volumes. Larger cells, typically prolymphocytes, may also be seen on smear but they are usually less than 10% of the total lymphocyte pool. Diagnostic criteria for CLL defined by the National Cancer Institute and the International Workshop on Chronic Lymphocytic Leukemia are presented in Table 1.
A positive Coombs test is seen in as many as 30% of patients at some time during the disease course, although it is uncommon (< 5%) during early stages. Autoimmune phenomena are relatively frequent, with hemolytic anemia (lifetime risk, approximately 10% to 20%) and thrombocytopenia (lifetime risk, approximately 5% to 10%) occurring most commonly. Autoimmune neutropenia and other autoimmune sequelae are infrequent but more common than in the general population.
The marrow is usually hypercellular, and mature lymphocytes represent at least 30% of the marrow cellularity. Lymphocytic infiltration on the biopsy may be interstitial, nodular, mixed interstitial and nodular, or diffuse. The diffuse pattern was traditionally associated with a poor prognosis, but this is now less important with more modern therapies.
Other laboratory findings
A positive Coombs test is seen in as many as 30% of patients at some time during the course of the disease. Tests such as lactate dehydrogenase (LDH), indirect bilirubin, haptoglobin, and reticulocyte count are of help in diagnosing autoimmune hemolytic anemia, which is common in CLL. Progressive hypogammaglobulinemia is seen in more than 50% of patients, polyclonal gammopathy may be seen, and a monoclonal paraprotein is present in 5% to 10% of patients. Even patients with normal IgG levels have an impaired repertoire of antibodies and may still benefit from intravenous immunoglobulin replacement therapy. Elevated beta2-microglobulin levels are a poor prognostic marker.
Immunophenotyping by flow cytometry has become a common way to diagnose CLL, and since these cells are of B-cell origin, they commonly express CD19 and CD20. The expression level of CD20 is low compared with that of normal B cells. However, CLL is characteristically positive for CD5. Expression of CD23 helps differentiate CLL from mantle cell lymphoma. Expression of surface immunoglobulin is usually weak and lower than in normal B cells. CD38 expression is a poor prognostic marker in CLL.
Cytogenetic and Molecular Findings
Recurrent cytogenetic (karyotypic and more commonly on fluorescent in situ hybridization, FISH) abnormalities have been found in CLL and are useful in assigning prognosis and prescribing therapy. The proliferative rate of CLL cells is low and thus the standard karyotype is less helpful than the FISH studies. Chromosomal abnormalities using FISH can be identified in 70% to 80% of patients with CLL. The most frequent and significant abnormalities found on FISH are deletion 13q14 (45% to 55%), deletion 11q (17% to 20%), trisomy 12 (10% to 20%), and deletion 17p (5% to 10%). Some deletions are found primarily at diagnosis (or before treatment), such as deletion 13q14, while other genetic lesions may evolve after therapy or at the time of progression (clonal evolution), such as deletion 17p. The presence of multiple genetic aberrations is a poor marker even in the presence of favorable risk markers, such as deletion 13q14. The sole finding of deletion 13q14 is associated with the best median overall survival (113 months); the lowest median survival is that of patients with deletion 17p (32 months). Characteristics of patients harboring deletion 11q may include age less than 55 years, diffuse and bulky adenopathy, short disease remissions, and a median overall survival of approximately 79 months. A regimen combining a purine analog with cyclophosphamide may be particularly beneficial to patients with del11q.
No single gene has been implicated in the pathogenesis of CLL. However, several genetic abnormalities have biologic and/or prognostic implications.
The TP53 gene is located on the short arm of chromosome 17 and is deleted in the leukemia clone of up to 10% of patients with CLL. Mutations of TP53 occur in a similar proportion of CLL cases, usually in association with TP53 deletion in the other TP53 allele. The 17p deletion involving TP53 is considered the most significant negative prognostic factor in CLL. The TP53 protein normally responds to DNA damage by inducing cell cycle arrest and facilitating DNA repair. It can also induce apoptosis in cells with damaged DNA and in this way mediates the cytotoxicity of many anticancer agents. Resistance to treatment is a particular characteristic of TP53 deletion and has been observed for agents including purine analogs. Further investigation of the common 13q deletion has revealed the detection of specific micro-RNA genomic sequence abnormalities expressed in patients with CLL. Further analysis suggests a micro-RNA signature profile may be associated with ZAP-70 expression and mutational status of IGVH (immunoglobulin heavy-chain variable) as well as disease progression. Although the exact significance of this finding is not known with certainty, the specific micro-RNA signature may be relevant to the pathogenesis of CLL. In addition, germline mutations affecting these micro-RNAs may be a predisposing factor in familial CLL.
Overexpression of BCL2
Abnormalities of the long arm of chromosome 14 frequently involve region 14q32, the site encoding for the immunoglobulin heavy-chain gene. However, gene translocations such as t(11;14)(q13;q32) and t(14;18)(q32;q21), which juxtapose genes CCND1 and BCL2 to the heavy-chain immunoglobulin gene, are not typical and should prompt consideration of alternative diagnoses (mantle cell or follicular lymphoma). Nevertheless, increased expression of BCL2 mRNA and protein is typical in CLL. Because overexpression of BCL2 inhibits apoptosis, it is possible that this gene participates in the pathogenesis of CLL.
Staging and Prognosis
CLL continues to be staged by the Rai and Binet staging systems, which correlate with median overall survival (Table 2).
Other prognostic factors
Several markers have been associated with prognosis; however, only del 17p (and possibly 11q as indicated above) is predictive of therapeutic efficacy because it has been associated with relative resistance to purine analogs. TP53 is a crucial tumor suppressor gene located on chromosome 17p13, which can be compromised by deletion of 17p13 or by a somatic mutation within the gene. Popular (yet uneconomical) prognostic markers include IGVH mutation status, CD38 and ZAP-70 expression. Other prognostic markers, such as beta2-microglobulin (>3.5 mg/L), lymphocyte doubling time (<12 months), and diffuse versus a nodular or interstitial marrow involvement, are far less expensive. The authors find that lymphocyte doubling time to be one of the best predictors of time to first cytotoxic therapy. Transformation to another lymphoid malignancy is a poor prognostic sign and is usually a terminal event.
Somatic hypermutation of IGVH is a normal process in B-cell physiology and is responsible for the diverse immunoglobulin pool. CLL cells that retain this normal process have a better prognosis than those cells that lack this capability. Some studies suggest that for patients with an unmutated IGVH, the median survival is 5 to 10 years compared with 10 to 20 years for those who retain somatic hypermutation of the IGVH. These results, however, may overstate the longevity of these patients because they are based on retrospective analysis and are biased to patients who have already survived for some of time.
Zap-70 encodes a protein tyrosine kinase normally expressed by T cells and is involved in intracellular signaling. CD38 is a glycoprotein found on cell surfaces and is detectable by flow cytometry. Both ZAP-70 and CD38 are correlated with unmutated IGVH (approximately 70% for both) and thus their expression is a poor prognostic sign.
Lymphocyte doubling time with 12 months is associated with a worse prognosis. Such patients should have repeated FISH testing because clonal evolution may have occurred.
Prior to the 1990s, alkylating chemotherapeutic agents were the standard of care for symptomatic CLL. These agents were supplanted by the purine analogs in the 1990s; subsequently, combination chemoimmunotherapy was introduced in the 2000s, which has now become popular for young, fit patients with CLL. However, there is no standard front-line regimen for symptomatic or advanced-stage CLL. The choice of therapy depends on goals of therapy for the patient, the anticipated toxicities of the treatment regimen, and the biology of the CLL clone (deletion 17p13 positive or negative). Despite the cornucopia of new agents for CLL, there continues to be a paucity of head-to-head trials and those that have been done compare modern therapy with chlorambucil-based regimens. For patients able to tolerate aggressive modern combination chemoimmunotherapy, there is a higher complete response rate, including molecular remissions that were not observed previously with older treatment strategies.
Asymptomatic and early-stage disease
Despite the high frequency of complete responses achieved with modern CLL therapy, it has never been shown that treatment of early-stage or asymptomatic CLL improves overall survival. In fact, a recent study from the Mayo Clinic suggests that defining therapy may result in prolonged survival.
Although some have advocated that localized small lymphocytic lymphoma (SLL) may be treated with involved field radiation therapy, the authors believe that such therapy typically does not have a favorable risk/reward benefit. Patients with CLL or SLL who require treatment should receive systemic therapy in essentially all cases. Early-stage CLL, even in patients with high-risk markers, should be monitored until there is an indication for treatment. However, there are clinical trials that are evaluating whether a subset of these patients might benefit from earlier intervention.
Alkylator- and purine analog–based regimens
Single-agent chlorambucil and, less commonly, cyclophosphamide are still commonly used regimens in patients with CLL who may not tolerate aggressive chemoimmunotherapy. These agents may improve symptoms but rarely lead to complete responses and have not been associated with an improvement of survival. Eichhorst et al published the results of a phase III German CLL Study Group (GCLLSG) study that included 193 older patients with previously untreated symptomatic CLL, median age of 70, and Eastern Cooperative Oncology Group performance status of 2 or greater who were randomly assigned to receive single-agent fludarabine or chlorambucil. Despite the fact that patients assigned to fludarabine had higher response frequencies and higher complete response rates, grade 3-4 toxicities with fludarabine were high (myelosuppression) and, if anything, overall survival favored the chlorambucil arm (median 46 months for fludarabine and 64 months for chlorambucil). Several studies strongly suggested that fludarabine or fludarabine combinations do not benefit patients older than 65 to 70 years.
Chlorambucil may be prescribed in several schedules, including daily dosing (0.1 mg/kg) and pulse-intermittent dosing, which may be every 3 to 4 weeks (20 to 40 mg/m2 or 0.8 mg/kg). The dose of chlorambucil will need to be titrated based on myelotoxicity. Cyclophosphamide is an alternative to chlorambucil and is prescribed either alone or in combination with vincristine and prednisone. The common single-agent dose of cyclophosphamide is 0.5 to 1 g/m2 every 3 to 4 weeks. The addition of prednisone to either chlorambucil or fludarabine does not improve the frequency of response but does increase the risk of opportunistic infections.
Bendamustine is an alkylating agent (nitrogen mustard derivative) with a benzimidazole ring (purine analog) that demonstrates only partial cross-resistance (in vitro) with other alkylating agents. Knauf et al reported the results of a phase III randomized study of bendamustine compared with chlorambucil as frontline therapy in symptomatic CLL patients. The overall response rate (ORR), complete response (CR) rate, and progression-free survival for bendamustine versus chlorambucil were 68% vs 31% (P < .01), 31% vs 2%, and 21.6 months vs 8.3 months (P < .01), respectively. Fischer et al reported on the safety and efficacy of the combination of bendamustine and rituximab in 117 CLL patients. After a median follow-up of 27 months, the ORR, CR rate, and event-free survival were 88%, 23% and 33 months, respectively. The GCLLSG CLL10 trial has recently completed enrollment of physically fit patients randomized to receive the combination of fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR). Recently reported in abstract form by Eichhorst et al, FCR had more efficacy in terms of higher CR rate and longer progression-free survival and event-free survival than BR. But it was also noted that FCR was associated with a higher rate of severe adverse events, including neutropenia and infection, and authors concluded that there was no recommendation of one regimen over the other at this early point in the analysis. Bendamustine is FDA-approved for the treatment of previously untreated and relapsed CLL patients.
Rituximab has perhaps been one of the most important additions as part of modern therapy. As a single agent, it has modest activity, but when it is added to other treatments, it improves the quality and frequency of responses and, most importantly, improves survival. The Cancer and Leukemia Group B (CALGB) 9712 studied sequential versus the combination of rituximab and fludarabine in 104 patients with previously untreated CLL. With a median follow-up of 117 months, the ORR, CR rate, progression-free survival, and overall survival were 84%, 28%, 42 months, and 85 months, respectively. Investigators at MD Anderson evaluated FCR in a phase II study of 300 previously untreated patients. With a median follow-up of 6 years, the ORR, CR rate, and progression-free survival were 95%, 72%, and 80 months, respectively. These studies led to the GCLLSG CLL8 trial, which randomized 408 previously untreated patients to six cycles of either combination fludarabine and cyclophosphamide (FC) or FCR. The 3-year progression-free survival was 65% vs 45% (P <.01) and overall survival was 87% vs 83% (P=.01) in the FCR arm and FC arm, respectively. Adverse events were higher in the FCR arm and consisted primarily of neutropenia. Lamanna et al published the results of a sequential FCR regimen that produced a CR in 61%. Using a highly sensitive clonotypic polymerase chain reaction assay, the authors reported that 90% of patients achieving a molecular CR remained in a morphologic CR at 5 years. Other combinations, including pentostatin, cyclophosphamide, and rituximab (PCR) and cladribine, cyclophosphamide, and rituximab (CCR), may offer some advantages over FCR, with PCR perhaps being better tolerated and CCR possibly producing longer response durations.
Obinutuzumab is a humanized bioengineered monoclonal antibody to CD20 that has a higher binding affinity and leads to increased antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The FDA granted approval of obinutuzumab in 2013 for the treatment of patients with preexisting comorbidities in combination with chlorambucil. The CLL11 (BO21004) is a phase III trial that compared the combination of obinutuzumab and chlorambucil with the combination of chlorambucil and rituximab and chlorambucil alone in patients with previously untreated CLL and preexisting comorbidities. The overall response frequency, complete response frequency, and median progression-free survival with the combination of obinutuzumab and chlorambucil was higher than that of the combination of chlorambucil and rituximab, 75.5% vs 65.9%, 22.2% vs 8.3%, and 23 months vs 15.7 months, respectively. There were more grade 3-5 adverse events for the combination of obinutuzumab and chlorambucil, which mostly consisted of infusion reactions (21%) and neutropenia (34%). The FDA-approved dosing of obinutuzumab is 100 mg IV on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 for cycle one. For subsequent cycles, obinutuzumab is given on day 1 at 1000 mg IV on a 4-week schedule. The chlorambucil is given at 0.5 mg/kg PO on days 1 and 15 of each 4-week cycle.
Ofatumumab is a fully humanized antibody targeting CD20 that has been approved for CLL in fludarabine- and alemtuzumab-refractory patients. Current studies are investigating its role in frontline therapy.
Alemtuzumab is a recombinant, humanized monoclonal antibody against CD52 that is FDA-approved for treatment of upfront and relapsed CLL patients. Keating et al presented the results of alemtuzumab in 93 patients with relapsed CLL who were fludarabine-resistant. The ORR was 33%, CR was seen in only 2%, and 30% of patients died within 6 months of starting therapy. Hillmen et al studied alemtuzumab in a randomized study of 297 patients in the frontline setting in symptomatic CLL with chlorambucil as the control arm. The ORR, CR rate, and progression-free survival in the alemtuzumab and chlorambucil arms were 83% vs 55%, 24% vs 2%, and 14.6 months vs 11.7 months, respectively. Lozanski et al described their results with alemtuzumab in 36 patients with fludarabine-refractory CLL and either mutations or deletions of p53. The ORR was 40% and the response duration was 8 months. On the basis of these results, many believe that alemtuzumab may be the drug of choice for patients with CLL and del17p. Of particular note is the risk of cytomegalovirus reactivation in patients treated with alemtuzumab.
Lenalidomide, an agent with an unknown mechanism of action, characterized as an immunomodulatory agent, has important activity in CLL. Studies initially at Roswell Park and MD Anderson demonstrated the important clinical activity of lenalidomide alone or combined with rituximab. Interestingly the use of lenalidomide in CLL has been complicated by lethal tumor lysis and tumor flare. Accordingly, the typical starting dose is 5 mg and every dose increment needs very close initial follow-up to recognize and treat tumor lysis and tumor flare.
Novel agents under study
While the prior section describes the paradigm of CLL therapy for more than the past decade, the authors believe that in the next 5 years the treatment of CLL will shift dramatically. This will occur because of the introduction of 3 new classes of drugs: inhibition of signaling through the B-cell receptor, inhibition of BCL-2, and inhibition of PI3K-delta. While multiple agents are being developed, below we highlight the 3 most important agents.
BTK inhibitor: ibrutinib
Bruton tyrosine kinase (BTK) plays a role in signal transduction of the B-cell receptor, which is a necessary driver for CLL pathogenesis. Ibrutinib is a small-molecule inhibitor of BTK that may trigger apoptosis. In a study by Byrd et al, 85 CLL/SLL patients were treated with either 420 mg or 840 mg of ibrutinib once daily. The therapy was well tolerated, and although CR was infrequent (2%), overall response with disease control was seen in the vast majority of patients (>70%).
Bcl-2 inhibitor: ABT-199
The Bcl-2 family of anti-apoptotic proteins is a target in various B-cell malignancies. A phase I study by Seymour et al included 56 patients with refractory CLL. The dose-limiting adverse events were tumor lysis syndrome and neutropenia, and the ORR was 85%, with 13% CRs.
PI3k inhibitor: idelalisib
The class I PI3Ks regulate B-cell proliferation and survival. Idelalisib is an oral inhibitor of an isoform of the this enzyme that promotes apoptosis of CLL cells. A phase I study by Brown et al treated 54 refractory CLL patients with idelalisib with a resulting ORR of 56%; no dose-limiting toxicities; and mild adverse effects, including rash, fevers, fatigue, diarrhea, and respiratory infections. Recently reported in abstract form by Furman et al is a study of idelalisib plus rituximab compared with placebo plus rituximab in patients with relapsed/refractory CLL. This trial demonstrated an improved progression-free survival, ORR, and overall survival for patients receiving the idelalisib combination.
Importance of achieving a minimal residual disease state
Minimal residual disease (MRD) can be detected by multicolor flow cytometry (MFC) and real-time polymerase chain reaction (rt-PCR). With the popularization of chemoimmunotherapy and the resultant high rates of complete remissions, it now possible to achieve a depth of remission that is undectable by sensitive tests such as MFC and rt-PCR. Böttcher et al from the GCLLSG CLL8 trial concluded that MRD levels independently predict progression-free survival and overall survival in CLL. However, MRD is not a mandatory assessment for routine clinical practice. Furthermore, this may be more complicated than previously thought because an MRD negative state may be a biomarker of clinically favorable disease rather than a goal to be achieved through even more aggressive treatment.
Autologous transplant. An autologous progenitor cell transplant aims at delivering high-dose chemotherapy yet limits the associated duration of neutropenia by autologous progenitor cell rescue. Although autologous transplant is curative in some lymphomas, its role in CLL is less well defined. The European Bone Marrow Transplant Chronic Leukemia Working Party conducted a phase III randomized study offering an autologous transplant with conditioning with BEAM (BCNU, etoposide, cytarabine and melphalan) after first- or second-line therapy or observation. The event-free survival was doubled for patients in the autologous transplant arm versus the observation arm (51.2 months vs 24.4 months) and the 5-year event-free survival was 42% vs 24% (P<.01). Despite this impressive improvement in event-free survival, the overall survival was statistically similar in the two arms. A second randomized trial by Sutton et al confirmed this improvement in event-free survival yet no benefit in overall survival. Currently the authors believe there is no role for autologous transplant in CLL and that such transplants should not be offered outside of clinical trial.
Allogeneic transplant. Unlike the autologous transplant, allogeneic transplant not only offers higher-dose chemotherapy but also, more importantly, imparts a graft-versus-leukemia effect. Historically, the allogeneic transplant was preceded by a myeloablative conditioning regimen that only patients under the age of 55 to 60 years could tolerate. After the introduction of the reduced-intensity and nonmyeloablative conditioning regimens, older patients more representative of the CLL population were able to tolerate the transplant.
The largest prospective study using a nonmyeloablative conditioning regimen is by Sorror at al, who transplanted using either a matched related donor or matched unrelated donor in patients proved refractory to chemotherapy between 1997 and 2003. The 5-year incidence of treatment-related mortality, progression-free survival, and overall survival were 23%, 39%, and 50%, respectively. Similar results were reported by Dreger et al from the GCSG CLL3X study, which used a reduced-intensity conditioning, matched related donor, or matched unrelated donor in high-risk patients with CLL between 2001 and 2007. The 4-year treatment-related mortality, event-free survival, and overall survival were 23%, 42%, and 65%, respectively. These results support the utility of reduced-intensity transplants as treatment for CLL but also highlight the risks, thus requiring careful patient selection.
Chimeric antigen receptor T cells. Targeted cellular therapy is in its infancy, and recent patient case reports using chimeric antigen receptors (CARs) have generated tremendous excitement. Genetic modifications of T cells to identify and kill B cells form the basis of these therapeutic modalities. Porter et al reported the first successful cases in which three patients with CLL were given a conditioning regimen of bendamustine or pentostatin plus cyclophosphamide followed by the infusion of CAR-modified T cells. They described the immune reaction consisting of fevers, rigors, diarrhea, and even tumor lysis. Two patients achieved a CR and one had a partial response. To date, there is too little experience and follow-up data to decipher the duration of remission and the effects of overall survival from this expensive technology.
Hypersplenism. As the disease progresses and becomes more refractory to therapy, patients may develop an enlarging spleen that can be associated with worsening cytopenias. There are two methods for improving symptoms due to hypersplenism: irradiation of the spleen and splenectomy. Splenectomy is the more definitive choice; irradiation is a temporizing option in patients who are not surgical candidates. The mortality associated with splenectomy is variable. The procedure should be done in experienced centers. There are case series for which there have been reports of improvement in overall survival following splenectomy. Pre-surgical vaccination against pneumococcus, Haemophilus influenzae type B, and meningococcus should be administered. It should be noted that with more modern and effective therapies, the role of spleen-targeted therapy has been greatly reduced.
CLL is a hematological malignancy and as all such cancers is associated with multiple infections. The infectious complications may be due to either the underlying disease or the associated therapy. Patients have a quantitative and qualitative compromise in immunoglobulin that can be improved by the administration of immunoglobulin replacement therapy. Despite this beneficial treatment, it is projected that up to 50% of patients will die as a result of infection, which makes infection the leading cause of death in patients with CLL.
Autoimmune hemolytic anemia may occur in 5% to 10% or more of patients with CLL. The diagnosis is usually evident by a sudden worsening of anemia and an elevated indirect bilirubin level, LDH level, and reticulocyte count. However, the direct Coombs test may be negative in the vast majority of patients or results might be quite subtle; in this setting, a haptoglobin test result that is low to absent is the most sensitive clinical test. Patients with a sudden fall in hemoglobin level and a near absent reticulocyte count may have pure red cell aplasia. While most case of autoimmune hemolytic anemia will improve with corticosteroids or rituximab, pure red cell aplasia typically requires therapy with cyclosporine (3 to 6 mg/kg/d).
Transformation and secondary malignancies
The most common hematological malignancies encountered in patients who have received therapy for CLL include transformed disease, such as evolution to a large cell lymphoma, prolymphocytic leukemia (PLL), or Hodgkin lymphoma. Secondary malignancies include myelodysplastic syndrome and acute myeloid leukemia. There is some evidence that patients may also have a higher risk of developing secondary solid malignancies, perhaps related to the immune dysfunction inherent in CLL.
Large-cell lymphoma. Maurice Richter initially described transformation to large cell lymphoma in 1928. Typically this is diffuse large B-cell lymphoma (DLBCL) and rarely Hodgkin and even T-cell lymphomas. Although not always included under the umbrella term of "Richter transformation," PLL represents a biologically similar event and should be viewed as “transformed disease.” The incidence of Richter transformation is approximately 0.5% to 1% of patients per year, and presenting symptoms include fever and other B symptoms and accelerated enlargement of adenopathy. Laboratory signs include a sharp rise in serum LDH level, hypercalcemia, and the discovery of a monoclonal protein. Positron emission tomography may be very helpful in diagnosing Richter transformation, but biopsy of an enlarged hypermetabolic lymph node is the diagnostic procedure. If the biopsy proves DLBCL, therapy with the combination of rituximab, cyclophosphamide, donorubincin, vincristine, and prednisone (R-CHOP) should be considered. Patients who have had significant prior therapy may not respond to this regimen. Patients who have not had cytotoxic therapy often respond to R-CHOP and may have durable remissions.
PLL and Hodgkin lymphoma. PLL is characterized by more than 55% prolymphocytes in the peripheral blood, which is accompanied by a rapidly enlarging spleen and, thus, cytopenias that prove refractory to additional therapy. The Hodgkin lymphoma associated with CLL is typically more aggressive than de novo Hodgkin lymphoma and is typically resistant to tranditional Hodgkin lymphoma treatment. The authors recommend that all patients with transformed disease be treated with R-CHOP regardless of the histologic subtype. Consolidation with allogeneic transplant should be considered for patients with transformation to Hodgkin lymphoma and for any patient who received chemotherapy for their CLL before transformation.