© Borgis - Postępy Nauk Medycznych 6/2011, s. 490-498
*Tadeusz Robak1, Paweł Robak2
Przewlekła białaczka limfocytowa: rokowanie i leczenie
Chronic lymphocytic leukemia: prognosis and treatment
Departments of Hematology1 and Experimental Hematology2, Medical University of Łódź and Copernicus Memorial Hospital
Head of Department: prof. dr hab. med. Tadeusz Robak
Przewlekła białaczka limfocytowa (CLL) jest klonalną chorobą limfoidalną charakteryzującą się proliferacją i akumulacją małych limfocytów Bofenotypie CD5+/CD19+/CD23+ we krwi obwodowej, węzłach chłonnych, wątrobie, śledzionie i szpiku kostnym. Klasyfikacje kliniczne opracowane w latach osiemdziesiątych przez Rai’a i Bineta są do dziś przydatne w ustalaniu rokowania chorych na CLL. Ponadto, w ostatnich latach wprowadzono szereg nowych, biologicznych czynników prognostycznych, np. stan mutacji genów immunoglobulinowych (IgVH), anomalie cytogenetyczne, ekspresję ZAP-70 i szereg markerów surowiczych, w tym stężenie kinazy tymidynowej (TK), β2-microglobuliny (β2M) i rozpuszczalnego receptora CD23. Leczenie CLL nie jest zwykle wskazane we wczesnym, bezobjawowym okresie choroby. Chemioterapia lub chemioimmunoterapia jest natomiast stosowana w progresywnej, objawowej CLL. Przez wiele lat lekiem z wyboru był chlorambucyl. Obecnie jest on stosowany głównie u starszych pacjentów z współistniejącymi innymi chorobami. U młodszych chorych stosuje się analogi puryn, fludarabinę lub kladrybinę, w skojarzeniu z cyklofosfamidem i rytuksymabem. U opornych chorych może być celowe leczenie alemtuzumabem lub ofatumumabem.
Chronic lymphocytic leukemia (CLL) is a clonal lymphoid disease characterized by the proliferation and accumulation of small CD5/CD19/CD23-positive lymphocytes in the blood, lymph nodes, spleen, liver and bone morrow. Clinical staging systems proposed in the early 1980s by Binet and Rai have been the longest used for prognostic scoring in patients with CLL. Within the past few years, several biological markers, including serum markers, immunoglobulin heavy chain variable region (IgVH) mutation status, some cytogenetic abnormalities, P53 mutations, cell membrane expression of CD38 and intracellular expression of zeta associated protein-70 (ZAP-70), have become important prognostic factors. Chemotherapy is usually not indicated in the early and stable disease. Widely accepted guidelines for the initiation of chemotherapy in CLL patients have been proposed by the National Cancer Institute Sponsored Working Group (NCISWG). Chlorambucil (Chl), with or without prednisone, was used for many years in the first line treatment of patients with advanced and progressive CLL. More recently, purine nucleoside analogs (PNA), have been introduced and chlorambucil is not longer the leading standard everywhere. Subsequently, higher efficacy of the fludaraine and cyclophosphamide (FC) protocol than fludaraine alone has been confirmed in a phase III trials of treatment naive patients with advanced CLL. Cladribine (2-CdA) in combination with cyclophosphamide (CC regimen) has been also investigated in patients with previously untreated CLL in phase II and III trials. The results of a randomized study comparing the activity and toxicity of CC versus FC in previously untreated progressive or symptomatic CLL indicate that both combinations give similar efficacy and toxicity. Currently rituximab combined with FC or CC is becoming the first-line choice for younger patients.
Chronic lymphocytic leukemia (CLL) is a clonal disease characterized by proliferation and accumulation of small CD5 positive B-cells. It is the most common leukemia in the western world accounting for approximately 30% of all leukemias in Europe and North America with an incidence of 4:100.000/year (1). The disease is diagnosed most commonly in the elderly. The median age at diagnosis is 65-70 years with 80% of patients diagnosed over 60 years of age. The natural clinical course of CLL is highly variable and chemotherapy is usually not indicated in an early and stable disease. However, patients with progressive and more advanced disease require treatment (2).
Clinical staging systems proposed in the early 1980’s by Binet et al.(3) and Rai et al (4) are still the most common and validated prognostic factors in the patients with CLL. Within the past few years, several biological markers, including serum markers, immunoglobulin heavy chain variable region (IgVH) mutation status, some cytogenetic abnormalities, P53 mutations, cell membrane expression of CD38 and intracellular expression of zeta-associated protein-70 (ZAP-70), have become important prognostic factors (5). A correlation between the immunoglobulin gene mutational status and prognosis has shown that the median survival for stage A patients with unmutated IgVH genes was 8 years, compared with approximately 25 years for patients with mutated IgVH genes.
Deletion of 11q22-q23 and deletion of 17p13 are independent prognostic factors identifying patients with a rapid disease progression and a short survival time in a multivariate analysis (6). The deletion 17p affecting the TP53 gene has been associated with failure after treatment with alkylating agents, purine analogs, and rituximab (7). In contrast, deletion of chromosome band 13q14 is associated with a favourable outcome. Moreover, patients with trisomy 12 have a shorter survival than those with 13q deletion. Deletion of 17p and deletion of 11q predominate among advanced stages of CLL and among patients with unmutated IgVH genes. In patients with CLL deletion 17p13 is independent prognostic factor identifying patients with rapid disease progression and short survival time. Furthermore, ZAP-70 expression and CD38 expression on leukemic lymphocytes have been found to correlate with IgVH mutations and a shorter patient survival . Recent data may indicate that a prognostic score constructed using modified Rai stage, cellular CD38 and serum lactate dehydrogenase (LDH) significantly predict time to treatment failure and survival in patients at the time of diagnosis, and perform as well or better than models using the newer markers. The expression of ZAP-70 remains constant over the course of the disease as opposed to CD38. ZAP-70 expression can be evaluated using flow cytometric techniques, immunohistochemistry, western blotting or reverse transcriptase-polymerase chain reaction techniques. The cut-off to classify patients as ZAP-70 positive or ZAP-70 negative remains controversial and arbitrarily varies between 10% and 20%. Standardization of its measurement at the messenger RNA (mRNA) or protein level needs further investigation. Several serologic parameters such as thymidin kinase (TK), β2-microglobulin (β2M) and soluble CD23 (sCD23) provide also valuable information about the disease progression and survival.
Indications for treatment
There is no evidence that cytotoxic therapy has beneficial effects in patients with the indolent form of the disease (9, 10). However, patients with symptomatic and/or progressive disease should be immediately treated.
Widely accepted guidelines for the initiation of chemotherapy in CLL patients have been proposed by the National Cancer Institute Sponsored Working Group (NCI-WG) (11, 12). According to these guidelines the criteria for the initiation of therapy may not be identical for routine clinical practice and for patients included in clinical trials. In the routine clinical practice, therapy should not be initiated in patients who have asymptomatic CLL, including those with Rai stage 0 or Binet stage A until disease progression or unless disease-related symptoms are evident. Laboratory results supporting deferred therapy include a non-diffuse pattern of bone marrow involvement, serum haemoglobin concentration > 13 g/dL, peripheral blood lymphocytes < 30 × 109/L, and lymphocyte doubling time longer than 12 months. The criteria for treatment initiation include disease-related symptoms, especially fever, body weight loss and extreme fatigue, increasing bone marrow failure, autoimmune anaemia and/or thrombocytopenia responding poorly to corticosteroid treatment, massive or progressive splenomegaly and/or lymphadenopathy, progressive lymphocytosis and recurrent infections.
For many years, chlorambucil has been considered the drug of choice in previously untreated patients. Higher response rates were obtained when higher doses of chlorambucill were used (13). Chlorambucil is still acceptable as the first line treatment of progressive CLL in frail, elderly patients with comorbidities, because of the apparent increase in toxicity of purine nucleoside analogs (PNAs) in this group of patients. The recent results of the German CLL study group (GCLLSG) support such a recommendation (14).
Bendamustine (Treanda; Cephalon), is a bifunctional alkylating agent composed of an alkylating nitrogen mustard group and a purine like benzimidazole ring. This agent seems to have a low cross-resistance with alkylating agents and fludarabine. Bendamustine have been investigated in several clinical trials (15). Various doses and treatment schedules have shown significant efficacy and acceptable toxicity in previously treated patients. The dose of 70 mg/m2 on days 1 and 2 every 4 weeks is suggested in heavily pretreated and treatment-refractory patients. Bendamustine was also investigated in an open-label, randomized, comparative trial (16). Previously untreated patients were randomly assigned to receive either bendamustine (100 mg/m2 i.v. on days 1 and 2) or chlorambucil (0.8 mg/kg p.o. on days 1 and 15). An overall response rate and a CR rate were significantly higher in patients treated with bendamustine. Moreover, the median duration of response was longer after treatment with bendamustine (21.7 months) than after chlorambucil (9.3 month, p < 0.0001). Other alkylating agents have been less extensively investigated than chlorambucil and mainly in combination therapy. Cyclophosphamide (CY) has a similar activity to chlorambucil and is usually used when chlorambucil is poorly tolerated. Cyclophosphamide was more frequently used in combination therapy with vincristine and prednisone (COP, CVP) or with doxorubicin, vincristine and prednisone (CHOP) (10).
Purine nucleoside analogs
In the past 20 years the purine nucleoside analogs (PNA) – fludarabine (FA), cladribine (2-CdA, 2-chlorodeoxyadenosine) and pentostatin (DCF, 2’-deoxycoformycin) have been introduced for treatment of CLL (10,13). Significantly higher OR, CR, and longer progression free survival (PFS) in patients with CLL treated with FA or 2-CdA have been confirmed in randomized, multicenter trials and more recently in meta-analysis. However, the median survival time did not differ between patients treated with PNA and alkylating agents. Combination therapies with PNA and CY are more active than monotherapy in terms of OR, CR and PFS. However, higher overall response (OR), CR and PFS do not translate for longer overall survival. Over the last few years several monoclonal antibodies (mAbs) and immunotoxins have been investigated in clinical trials in patients with CLL Recently, we performed a randomized study that compared the activity and toxicity of 2-CdA and CY (CC programe) versus FA and CY (FC programe) in previously untreated progressive or symptomatic CLL (2). We did not observe any significant differences in CC and FC efficacy and toxicity across different patient prognostic subgroups (17).
Over the last few years several monoclonal antibodies (mAbs) and immunotoxins have been investigated in clinical trials in patients with CLL (18). The most important clinical value in the patients with CLL have at present two antibodies. The first is human mouse antibody rituximab that targets CD20 antigen. The second is alemtuzumab, a humanized form of a rat antibody active against CD52.
Rituximab (Rituxan, Mabthera, F. Hoffmann-La Roche) is an IgG1 kappa immunoglobulin containing murine light – and heavy-chain variable region sequences and human constant region sequences (18, 20). The Fab domain of the rituximab binds specifically to the CD20 antigen, expressed on normal and malignant B-lymphocytes. The Fc domain recruits immune effect or functions to mediate B-cell lysis in vitro and in vivo.
The precise mechanism of rituximab cytotoxicity remains unclear. However, several mechanism by which rituximab may be cytotoxic are suggested. These include complement-dependent cytotoxicity (CDC), which involves fixation of the complement by the Fc portion of immunoglobulin and the subsequent activation of the complement cascade. Moreover, rituximab induces antibody-dependent cell mediated cytotoxicity (ADCC) in vitro. These two mechanisms are categorized into “immune-mobilizing” mechanisms or direct effects. However, accumulating evidence suggests that rituximab can also directly induce apoptosis.
Rituximab in conventional doses of 375 mg/m2 weekly for 4 doses has rather low efficiency in CLL. In the study performed by Byrd et al. 83 previously treated CLL patients were treated with different doses of rituximab (250 mg/m2-375 mg/m2) 3 times weekly for 4 weeks (20). The OR rate was 45% (3% CR and 42% PR). Responses were noted in all groups of patients including those with bulky lymphadenopathy and those for which alkylator and/or FA based therapy had failed. However, some studies suggest that higher doses are more effective than standard doses, used routinely in other lymphoid malignancies O’Brien et al. treated CLL patients with an initial dose of rituximab 375 mg/m2 which was then increased to a fixed dose of between 500 and 2250 mg/m2 once weekly for 4 weeks (21). The OR rate was 36% and ranged between 22-75%. All responses were partial responses (PR). Median time to progression in responded patients was 8 months with the longest remission duration 15 + months.
Several recent reports suggest that in patients with CLL, rituximab combined with PNA can increase the OR and CR rates and prolonge PFS as compared with PNA or rituximab alone with acceptable toxicity. The addition of rituximab to a variety of chemotherapy regimens for the treatment of patients with CLL has yielded promising results in phase II and III trials (22-24). The combination of rituximab with FC (R-FC regimen) demonstrated particularly high rates of overall response, CR, PFS, and overall survival in previously untreated and relapsed/refractory CLL. In order to validate this concept the German CLL study group (GCLLSG) initiated a multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and tolerability of R-FC versus FC for the first-line treatment of pts with advanced CLL (23). In this study 817 patients were randomly assigned to receive 6 courses of either FC of R-FC. The overall response rate was significantly higher in the R-FC arm (95%) compared to FC (88%) (p = 0.001). The complete response rate of the R-FC arm was 52% as compared to 27.0% in the FC arm (p < 0.0001). PFS was 76.6% at 2 years in the R-FC arm and 62.3% in the FC arm (p < 0.0001). There was a longer OS in the R-FC arm.
In the REACH trial 552 relapsed or refractory patients from 17 countries were randomized (1:1) to receive either R-FC or FC (24). A median of one prior treatment had been administered, consisting of single-agent alkylator therapy (66%), purine-analogs (16%), or combination treatments (CHOP, COP, F-containing, 18%). Patients with prior FC combination treatment or prior rituximab were not eligible. Median observation time was 25 months.The primary endpoint PFS was significantly prolonged by median 10 months in the R-FC arm (30.6 months) compared to FC (20.6 months, p = 0.0002). Secondary endpoints showed similar results. Overall response rate was higher for R-FC vs. FC (70% vs. 58%, p = 0.0034), due to superior CR rates (24% vs. 13%, p = 0.0007). Grade 3/4 adverse events were higher in the R-FC arm (80%) vs. FC (74%), but serious adverse events were similar (50% vs. 48%, respectively). Grade 3/4 neutropenia and febrile neutropenia were only marginally increased for R-FC (42% and 15%) vs. FC (40% and 12%, respectively), the same was seen for thrombocytopenia (R-FC 11% vs. FC 9%). Grade 3/4 infections (R-FC 18%, FC 19%) were similar, and there was no difference in bacterial, viral, or fungal infections between the two arms. Grade 3/4 anemia was slightly increased in the FC arm (R-FC 2%, FC 5%).
Chemoimmunotherapy combining rituximab with FA and cyclophosphamide is becoming the first-line choice for younger CLL patients. Moreover, several studies have confirmed significant activity of these agents in relapsed or refractory CLL (25). In recent years, four drug combination therapies with R-FC and other agents including mitoxantrone, lumiliximab or alemtuzumab, have been investigated in CLL patients and showed that these regimens are highly effective in previously untreated CLL. However, at present it is unclear whether these regimens have an advantage over R-FC immunochemotherapy olone.
We investigated efficacy and toxicity of the combined therapy consisting of rituximab and 2-CdA (RC protocol) or 2-CdA, CY and rituximab (RCC protocol) in patients with refractory or relapsed CLL (26). The RC regimen consisted of a 6-hour infusion of rituximab 375 mg/m2 on day 1 and 2-hour infusion of 2-CdA 0.12 mg/kg on days 2-6. The RCC protocol consisted of rituximab at a dose of 375 mg/m2 on day 1, 2-CdA at a dose of 0.12 mg/m2 on days 2 through 4, and intravenous CY at a dose of 250 mg/m2 per day on days 2 to 4. The RC/RCC courses were repeated at 4-week intervals. Forty-six patients entered the study. Three patients (6.5%) achieved a CR and 31 (67%) patients achieved a PR. According to the particular regimen, the overall response rate was obtained in 12 (67%) patients treated with RC and in 22 (78%) treated with RCC. Hypersensitivity to rituximab occurred in 16 (33%) patients, mostly during the first infusion of the drug. Grade 3/4 neutropenia was seen in six (13%) patients, grade 3/4 thrombocytopenia in three (9%) patients, and grade 3/4 infections were observed in 10 (28%) patients.
Combinations of high dose methyl prednisolone (HDMP) with rituximab were investigated in previously untreated and relapsed/refractory patients with CLL (25). HDMP and rituximab were well tolerated and had promising activity when used in combination to treat patients with fludarabine-refractory CLL. These results demonstrate that in combination with rituximab it is a useful treatment strategy in refractory CLL including patients with p53 abnormalities. Further studies of this regimen in controlled trials are warranted.
Alemtuzumab (MabCampath, Genzyme) is an unconjugated recombinant DNA-derived humanized IgG1 mAb directed against the CD52 antigen. The CD52 antigen is expressed on normal and neoplastic lymphocytes, monocytes and natural killer cells but not on hematopoietic stem cells. In 2001, alemtuzumab was approved in the US and Europe to treat patients with CLL refractory to FA. Alemtuzumab is highly active in previously treated patients with CLL (19, 27, 28).
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