Treatment of Chronic Lymphocytic Leukemia

Cancer Connect - Treatment of Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia

by Dr. C.D. Buckner M.D. Medically reviewed by Dr. C.H. Weaver M.D. 8/2018

Chronic lymphocytic leukemia (CLL) is a disease characterized by high numbers of circulating abnormal lymphocytes (B-Cells) in the peripheral blood. The disease often involves enlargement of lymph nodes in various parts of the body as well as enlargement of the spleen. In CLL the marked elevation of lymphocytes in the blood is partially due to a prolonged survival of abnormal lymphocytes compared to normal lymphocytes.

CLL typically occurs in individuals between 65 and 70 years of age. Historically, it has been diagnosed at an advanced stage that typically involves the lymph nodes and bone marrow. More recently, however, the disease has frequently been detected in routine blood tests, allowing for earlier diagnosis. As a result, more patients are presenting with early-stage asymptomatic disease.

CLL is the most common adult leukemia with over 15,000 new cases per year in the United States and almost 5,000 deaths. CLL is not a rapidly growing cancer, but the abnormal cells accumulate in blood, bone marrow, lymph nodes and spleen, resulting in enlargement of these organs and decreased bone marrow and immune function. This disease interferes with the normal production of antibodies and immunoglobulins, so the body cannot properly fight infections.

Chronic lymphocytic leukemia has unique features that are not present in other kinds of leukemia, such as immune-mediated destruction of red blood cells and platelets. These are referred to as autoimmune-mediated cytopenias. Patients with CLL may also experience repeated infections from low levels of normal immunoglobulin production.

CLL is a heterogeneous disease with survival times measured in months or many years depending on risk factors at the time of diagnosis. The diagnosis of CLL is usually confirmed by tests for specific characteristics of B-cells in individuals with an absolute lymphocyte count above 5,000.

Monoclonal B-Cell Lymphocytosis

Some individuals will have all the characteristics of CLL in a blood test but have a lymphocyte count of less than 5,000. This is known as monoclonal B-cell lymphocytosis.[1] Such low levels of CLL cells are detected in approximately 3% of the general population. Chromosomal abnormalities are frequently detected in this group of apparently normal patients. It is estimated that 1-2% of patients per year with monoclonal B-cell lymphocytosis will progress to CLL and require treatment. Monoclonal B-cell lymphocytosis occurs predominantly in elderly individuals and requires periodic monitoring but not necessarily treatment.

Staging of CLL

There are two staging systems in use: Rai and Binet.

The Rai system has five stages:

  • Stage 0: Stage 0 CLL is characterized by absolute lymphocytosis (high lymphocyte count) without lymphadenopathy (enlarged lymph nodes), hepatosplenomegaly (enlarged liver and spleen), anemia (low red blood cell count), or thrombocytopenia (low platelet count).
  • Stage I: Stage I CLL is characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
  • Stage II: Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
  • Stage III: Stage III CLL is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
  • Stage IV: Stage IV CLL is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

The Binet staging system has three stages:

  • Clinical Stage A*: Clinical Stage A CLL is characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai Stages 0, I, and II).
  • Clinical stage B*: Clinical Stage B CLL is characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai Stages I and II).
  • Clinical Stage C: Clinical Stage C CLL is characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai Stages III and IV).

*Lymphoid areas include cervical, inguinal and spleen.

The original staging systems were based on clinical examination and blood tests which may not be accurate enough for determination of need for treatment. For instance, researchers have found that 27% of patients with RAI Stage 0 will have abnormal abdominal computed tomography (CT) scans.[2] These authors found that an abnormal abdominal CT correlated with increased bone marrow infiltration, higher lymphocyte count, increased ZAP-70 expression (a marker for poor prognosis) and a short lymphocyte doubling time. Patients with an abnormal CT also had a median time to disease progression of 3.5 years while for patients without an abnormal CT scan the median time to disease progression was longer.

One of the most important factors that affects the decision to treat or not to treat is whether or not patients with CLL have symptoms of their disease. Some of the symptoms of CLL include: fever, frequent infections, night sweats, swollen and painful lymph nodes and significant weight loss.

Although all patients should be accurately staged with one of the above staging systems, for treatment purposes patients are divided into two groups: asymptomatic patients with early-stage disease (usually Binet Stage A and RAI Stage 0, I, and II) and symptomatic patients who usually have advanced-stage disease (Binet Stage B and C and RAI Stage III and IV). The goal of staging is to determine which patients have early and which have advanced-stage CLL.

There have been tremendous advances in the treatment of CLL over the past decade, especially over the past five years. CLL was once described as a chronic disease with treatment being predominantly palliative (with the exception of allogeneic stem cell transplantation). Now, complete molecular remissions and long-term disease-free survival can sometimes be achieved with one of several combination treatment regimens. It has therefore become important to determine when patients should be treated and how aggressively. A comprehensive approach to treating patients with CLL now involves risk stratification for newly diagnosed patients, adherence to supportive care guidelines, attention to quality of care issues specific to patients with CLL and consideration of age, other health conditions, and quality of life in selection of therapy and disease management.

In order to learn more about the most recent information available concerning the treatment of CLL, click on the appropriate stage:

Early Asymptomatic CLL (usually Binet Stage A or RAI Stage 0-II)

Symptomatic CLL (usually Binet Stages B and C or RAI Stage III-IV)

Relapsed/Refractory CLL (the cancer has persisted or returned following treatment)

Early-stage Asymptomatic CLL

Patients with early-stage CLL have Binet Stage A or RAI Stage 0-II disease and no symptoms. In general, patients with asymptomatic early-stage CLL should not be treated unless they are participating in a clinical trial evaluating the effects of therapy on patients with adverse prognostic features.

The following is a general overview of the treatment of early-stage asymptomatic CLL. The specific characteristics of your cancer and circumstances unique to your situation may ultimately influence how these general treatment principles are applied.

The major dilemma regarding treatment of CLL is when to initiate treatment and whether earlier more aggressive treatments can improve a patient’s outcome. However, these are research questions and patients with asymptomatic early stage CLL should not be treated outside a clinical study as there is no definitive data that such treatment prolongs survival or improves the chances for cure.

When to Initiate Treatment?

In contrast to past experience many patients will present with early-stage asymptomatic CLL. It is clear that patients with early-stage CLL are a heterogenous group; approximately 30-50% will develop progressive disease within a short period of time, while the remainder may live for decades and not require therapy. It should also be remembered that patients with early-stage CLL can become symptomatic without a change in the stage of their cancer. In this case, patients with symptomatic Binet stage A or RAI stage I-II are treated the same as more advanced patients with symptomatic CLL.

Accepted indications for the treatment of CLL:

  • Anemia (hemoglobin level less than 11.0 g/dL)
  • Thrombocytopenia (platelet count less than 100,000/mm3)
  • Massive or progressive enlargement of lymph nodes
  • A lymphocyte doubling time of less than 6 months
  • Fever, weight loss, night sweats or profound fatigue

Patient Information

Patients with newly diagnosed asymptomatic CLL should be informed about the potential for disease progression and the need for close monitoring. Patients with early-stage CLL are at risk for developing infections, autoimmune diseases and transformation to a diffuse lymphoma called Richter transformation. Delay of therapy is more important for elderly patients who may have other diseases which could increase the toxicities of therapy. Younger patients without significant other health problems may opt for earlier treatment in the hope of prolonging survival.

Treatment of Symptomatic Advanced CLL

Chronic lymphocytic leukemia is a heterogenous disease with some patients progressing rapidly and others living for years without treatment. Nevertheless, most patients with symptomatic advanced CLL receive treatment.

There have been tremendous advances in the treatment of CLL over the past decade. Complete molecular remissions and long-term disease-free survival can be achieved with one of several treatment regimens. With a curative potential possible it becomes more important to determine when patients should be treated and how aggressively. A comprehensive approach to treating patients with CLL now involves risk stratification for newly diagnosed patients; adherence to supportive care guidelines; attention to quality of care issues specific to patients with CLL and consideration of age, other health conditions, and quality of life.

Recent studies have suggested that patients with CLL who achieve a complete remission will have a longer survival than patients who do not achieve a complete remission. Furthermore, a complete molecular remission is associated with the best survival. Complete remission is usually defined as absence of abnormal lymphocytes in blood and bone marrow, no enlarged lymph nodes, and normal blood counts. A complete molecular remission is determined by performing polymerase chain reaction (PCR) tests on blood and bone marrow which can detect CLL that cannot be seen under the microscope.

Currently available standard treatment includes the following:

Single Agent Therapy

Many patients with CLL are treated with single agents due to age and other health problems. Single agent therapy is given to relieve symptoms and improve quality of life because toxicities are generally less severe than with combination therapy. Some of the most often-used agents are Leukeran® (chlorambucil) and Fludara® (fludarabine) and, more recently, Rituxan® (rituximab), Campath® (alemtuzumab), and Treanda® (bendamustine). However, Rituxan is more commonly used in combination therapy than as single agent therapy.

  • Leukeran® (chlorambucil), an oral alkylating agent, was the primary initial treatment of for CLL for 40 years, before the development of newer agents such as Fludara and Rituxan. This drug has, in general, been replaced with newer agents called purine antagonists, such as Fludara, for initial treatment of CLL. [1] A recent randomized trial suggested that chlorambucil was better than Fludara for the initial treatment of patients older than 64 years of age.[2] Thus, the sequence of treatment of patients with CLL may be important since most available drugs will be used a some point in management of the disease.
  • Fludara® (fludarabine): Fludara is a type of chemotherapy and is the first of a new class of drugs (purine analogs) active in the treatment of CLL. Researchers in Germany treated 81 previously untreated patients with Fludara alone.[3] They reported an overall response rate of 72% with complete remissions in 37%. The average time to disease progression was 841 days.
  • Venclexta (ventoclax) The BCL-2 protein is a type of protein that contributes to a cancer cell’s survival. Over expression of the BCL-2 protein in lymphoma cells is associated with increased survival time of the cancer cells as well as resistance to standard chemotherapy. Venclexta is an agent that binds to the BCL-2 protein, thereby disabling its ability to keep cancer cells alive.
  • Gazyva (obinutuzumab) Gazyva is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain types of B-cells. It is thought to work by attacking targeted cells both directly and together with the body’s immune system. The FDA approved Gazyva based on a clinical trial comparing chemotherapy with Rituxan or Gazyva. The progression-free survival was significantly improved with Gazyva compared to Rituxan.
  • About Aliqopa(copanlisib) Aliqopa is a precision cancer medicine that inhibits several key cell-signaling pathways in lymphoma cell lines resulting in cancer cell death by apoptosis and inhibition of the growth of primary malignant B cell lymphoma cell lines.
  • Keytruda® (pembrolizumab) belongs to a new class of medicines called PD-1 inhibitors that help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 may enhance the ability of the immune system to fight cancer. Keytruda® works by blocking PD-1.
  • Revlimid® (lenalidomide) This oral immunomodulatory therapy is being used in combination with Rituxan.2
  • Campath® (alemtuzumab): Campath is a fully human monoclonal antibody that selectively targets the CD52 antigen, which is expressed more prominently on malignant lymphocytes than other cells. The binding of Campath stimulates destruction of the malignant lymphocytes and reduction or elimination of cancerous cells throughout the bone marrow, blood and lymph system. An international phase III trial demonstrated that Campath provides significantly superior responses with a favorable toxicity profile when compared with chlorambucil as initial therapy of CLL.[4] Further studies also confirmed that specific “bad” cytogenetics in CLL were associated with superior responses to Campath compared to chlorambucil.[5]
  • Treanda® (bendamustine): Treanda is a chemotherapy drug that has both alkylator and purine-like activity. One advantage of Treanda is that it is not cross-resistant with other alkylating agents such as chlorambucil. Treanda has been marketed and used clinically in Germany for many years in patients with non-Hodgkin’s lymphoma (NHL), CLL, multiple myeloma, breast cancer and other solid tumors such as lung cancer.

The study that led to FDA approval of Treanda was a multicenter trial that included 301 patients with previously untreated CLL.[6] Symptomatic patients requiring treatment received initial therapy with either Treanda or chlorambucil, an alkylating agent that is FDA approved for the treatment of CLL as well as several types of lymphoma.

  • Overall response rates among patients treated with Treanda were 59% compared with 26% among the chlorambucil-treatment group.
  • Additionally, complete response rates were seen in 8% of the patients treated with Treanda compared with less than 1% of those treated with chlorambucil.
  • The average progression-free survival period for the Treanda treatment group was 18 months, 12 months longer than for those treated with chlorambucil.
  • 79% of patients treated with chlorambucil experienced side effects compared with 89% of patients treated with Treanda. Side effects included the need for red blood cell transfusions and were more likely among patients treated with Treanda (20%) compared with those treated with chlorambucil (6%).

Researchers concluded that Treanda should replace chlorambucil for the treatment of CLL, as has been done in some European countries. Future research may investigate the use of Treanda within the United States for treatment of non-Hodgkin’s Lymphoma, multiple myeloma, breast cancer, and other solid tumors such as lung cancer.

Combination Therapies

Combination regimens are increasingly being used in younger, more healthy patients with CLL. The strategy that is commonly used is to attempt to produce a complete remission with induction therapy, to administer consolidation therapy after complete or partial remission to produce a molecular remission, and then to administer maintenance therapy to prevent recurrences. Rituxan® (rituximab) is the main drug that has been added to chemotherapy in the past decade to treat patients with CLL and is utilized in most up-front treatment regimens. Studies show that in patients with advanced indolent NHL, maintenance Rituxan after chemotherapy significantly prolongs progression-free survival to a far greater extent than has been achieved by any previous strategy.3

Fludara plus Cytoxan (FC): A randomized trial has shown that the addition of Cytoxan to Fludara improves the overall and complete response rates of previously untreated patients with CLL.[7] The overall response rate was 74% for combination therapy and 60% for Fludara alone. Combination therapy also increased progression-free survival from 19 to 32 months. There did not appear to be an increase in infectious complications or a decrease in quality of life measurements.

Fludara, Cytoxan, and Rituxan (FCR): Previous studies from the MD Anderson Cancer Center showed that a regimen of Fludara, Cytoxan, and Rituxan (FCR) produced results superior to any previously tested regimens for treatment of refractory or newly diagnosed CLL.[8][9] The study in 224 previously untreated patients with CLL showed a complete remission rate of 70%, a partial remission rate was 25% for an overall response rate of 95%. Flow cytometry studies showed that two-thirds of the patients had less than 1% CD5- and CD19-positive cells in the bone marrow. At two years, over 90% of patients were alive and over 80% had not progressed; all complete responders were alive. Infectious episodes occurred in a third of all patients. 10,11

Fludara, Cytoxan and Mitoxantrone (FCM) with or without Rituxan: The combination of Fludara, Cytoxan and mitoxantrone (FCM) was a common regimen for CLL prior to the use of Rituxan. Subsequent studies have shown that adding Rituxan to this regimen improves outcomes of patients with CLL. Recently, researchers from the UK presented the results of a randomized phase II study comparing FCM with and without Rituxan in patients with previously treated CLL.[12]

Cytoxan, Fludara and Campath (FCC): Researchers affiliated with CALGB Study 10101 reported that consolidation therapy with Campath resulted in severe toxicity in previously untreated patients who achieved a complete response after Cytoxan and Fludara therapy.[13] These researchers reported a high rate of infectious complications in patients in complete response receiving Campath consolidation although they continue to evaluate this approach in patients not achieving a complete response. Infectious complications occurred both during and after the administration of Campath.

Cytoxan, Fludara, Campath and Rituxan (CFAR) Researchers from the M. D. Anderson Cancer Center have reported that CFAR shows promising results for the treatment of high-risk CLL.[14] The CFAR regimen was evaluated in 40 patients with newly diagnosed CLL. All patients were 69 years of age or younger with a median age of 63 years. All patients received Neulasta® (pegfilgrastim) and prophylaxis against cytomegalovirus and pneumocystis carinii pneumonia. The researchers reported that adding Campath to the FCR regimen did not increase toxicity compared to previous experience with the FCR regimen. The complete remission rate was 69% and the partial response rate was 27%. Five patients were classified as partial responders due to persistent low blood cell counts. They also reported that 83% of patients with a complete hematological response had complete molecular remissions. It would appear that high-risk patients with CLL benefit from the CFAR regimen.

Nipent, Cytoxan and Rituxan (PCR): Researchers from Ohio State University and the Mayo Clinic have reported that the treatment combination consisting of Nipent® (pentostatin), Cytoxan and Rituxan (PCR) demonstrates high activity in previously untreated patients with CLL with high-risk factors.[15] This study evaluated PCR in 64 patients with previously untreated high-risk CLL. The median age was 63 years, with the oldest patient being 80 years old. The treatment regimen consisted of 21 day cycles of PCR for a projected six cycles with prophylaxis against cytomegalovirus and Pneumocystis carinii. The median follow-up of this study was 26 months. These authors reported an overall response rate of 91% with a median duration of response of 34 months. The complete response rate was 41% and the partial response rate was 50%. Progression-free survival was 32.6 months. Eighty-six per cent of patients are alive at the time of this report, and 38% have progressive disease.

The death rate during treatment was 3.2%. Forty percent of patients had grade 3-4 neutropenia and 20% had grade 3-4 thrombocytopenia. Six patients had upper respiratory infections and one had fever without neutropenia. Life-threatening infections did not appear to be a major problem.

These results appear to be comparable to Fludara-based regimens with possibly fewer infectious complications. Only a direct comparison can determine relative effectiveness and determine if there are fewer infections with Nipent-based versus Fludara-based regimens.

Rituxan and Campath: A study from the M. D. Anderson Cancer Center has shown that the co-administration of Rituxan and Campath results in significant responses in patients with refractory CLL. Toxicities associated with these two agents were not excessive. A recent small study evaluated Rituxan and Campath in 10 patients with previously untreated poor-risk CLL.[16] Patients were treated with Campath three times a week and Rituxan was given every two weeks for eight doses. All patients received antibiotic prophylaxis and were monitored for the development of cytomegalovirus infection. The median age for these patients was 52 years, the median white blood cell count was 48,000 and the follow-up was 10 months. All ten patients achieved a complete response in the peripheral blood and bone marrow. Seven of the 10 patients achieved a clinical complete response in lymph nodes. The main side effects were lymphopenia in all patients and neutropenia in six patients. Four patients developed cytomegalovirus infection and were treated with ganciclovir. This appears to be a very active antibody combination for the treatment of CLL. Infectious side effects appear to be manageable.

Supportive Care

Infections remain a major cause of morbidity and mortality in patients with CLL. These infections are related to immune defects inherent to CLL as well as to therapy-related immunosuppression. Infectious complications are increased with the use of Fludara and monoclonal antibodies such as Rituxan and Campath compared to treatment with chemotherapy alone. Although bacterial infections are the most common; fungal and herpesvirus infections are also seen with use of these agents. Infections such as Pneumocystis carinii and cytomegalovirus pneumonias are due to reactivation of these organisms already present in the body.

Several steps can be taken to improve the survival and well being of patients with CLL:

Intravenous Immunoglobulin: Intravenous immunoglobulin should be administered to patients with low levels of gamma globulin for infection prevention.[17]

Pneumocystis carinii: Pneumocystis carinii (now called jiroveci) is a common lung infection in immunosuppressed patients caused by a fungus. Pneumonia due to this infection can be prevented by the prophylactic administration of cotrimoxazole or another appropriate drug.

Cytomegalovirus: Cytomegalovirus causes pneumonia in immunosuppressed patients and can be prevented by the prophylactic administration of valganciclovir or another appropriate drug.[18]

Bacterial Infections: The prophylactic administration of a systemic broad-spectrum antibiotic is indicated for CLL patients receiving combination therapy. Patients should also be vaccinated with pneumococcal vaccine.[19]

Fungal Infections: Antifungal agents are used to prevent or treat fungal infections which are common in CLL.

Neutropenia: Neulasta® (pegfilgrastim) or Neupogen® (filgrastim) are frequently administered prophylactically to patients receiving combination chemotherapy and antibody therapy for CLL to hasten recovery of granulocytes in the blood.

Anemia: Anemia due to chemotherapy can be prevented or treated with Aranesp® (darbepoetin alfa) or Epogen® (epoetin alfa).

Strategies to Improve Treatment of CLL

The progress that has been made in the treatment of advanced-stage CLL has resulted from the incorporation of new anti-cancer agents into treatment regimens and the performance of clinical trials. Future progress will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving treatment.

Leustat® (cladribine): An international randomized study has shown that Leustat (cladribine, CdA) may be superior to Fludara or chlorambucil for the initial treatment of patients with chronic lymphocytic leukemia (CLL).[20] Leustat is used primarily to treat hairy cell leukemia, but has also been evaluated as a single agent for the treatment of mantle cell lymphoma (MCL) with significant activity. A recent study evaluated Leustat and Rituxan for the initial treatment of CLL.[21] Patients received Neupogen® (filgrastim) or Neulasta® (pegfilgrastim) due to significant neutropenia in the first patients treated. The median age of the patients in this study was 70 years with the oldest being 86 years old. The complete response rate was 52% with only one of these patients relapsing. Four patients achieved a partial response. Most patients received further therapy after failure to respond or progression, but 90% were alive at the time of this report. These authors concluded that Leustat and Rituxan were well tolerated and produced durable remissions in half the patients treated.

Another study involved 229 previously untreated symptomatic patients with CLL who were randomly allocated to receive treatment with Leustat, Fludara or high-dose intermittent chlorambucil. The results of this trial are shown in table 4.

Table 4: Leustat vs Fludara vs chlorambucil for newly diagnosed CLL.

There were more infections in patients receiving Fludara or Leustat than in patients receiving chlorambucil. Survival was equivalent in all three groups, reflecting the efficacy of second-line therapy. These authors concluded that Leustat prolonged time to disease progression and time to second-line therapy for symptomatic CLL patients. These are interesting results and could mean more trials of Leustat in B-cell diseases where Fludara has been the drug of choice for over a decade.

Genasense® (oblimersen): Genasense is being evaluated for the treatment of multiple myeloma, acute myeloid leukemia, CLL, melanoma, and acute lymphoid leukemia. Genasense down-regulates a protein known as Bcl-2. Bcl-2 is a potent inhibitor of apoptosis (programmed cell death). Over-expression of this protein in patients with a variety of malignancies is associated with resistance to chemotherapy. Genasense has been investigated in several hematologic malignancies where Bcl-2 has been implicated in disease resistance.

Researchers involved in a multicenter trial have reported that the addition of Genasense® (oblimersen, Bcl-2 antisense) to Fludara and Cytoxan improves the survival of patients with relapsed or refractory CLL who achieve a complete remission (CR) or near complete remission (nCR).[22]

In a previous report on 241 patients with advanced CLL treated with Fludara and Cytoxan with or without Genasense, the addition of Genasense increased the proportion of patients who achieved CR/nCR from 7% in the Fludara/Cytoxan only arm to 17% in the Genasense arm. Responses were also more durable in the patients receiving Genasense. Overall response rates were not different between the two groups. Maximum benefit was observed in Fludara-sensitive patients, who had a four-fold increase in the complete or near-complete response rate. The estimated median survival was 33.8 months in the Genasense group and 32.9 months in the chemotherapy-only group. The estimated three-year survival rate was 46% for the Genasense group and 37.5% for the chemotherapy only group.

Based on these results and the results of a follow-up analysis, it was concluded that the addition of Genasense to Fludara and Cytoxan increased the complete response rate, complete response duration, and survival of patients achieving complete response. These results indicate that Genasense is active in patients with CLL. Further studies will be needed to determine if this agent should be tested for initial therapy of CLL.

References:

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[2] Muntanola A, Bosch F, Arguis P, Abdominal computed tomography predicts progression in patients with RAI stage 0 chronic lymphocytic leukemia. Journal of Clinical Oncology. 2007;25:1576-1580.

[1] Shanafelt TD, Byrd JC, Call TG, et al. Narrative review: Initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Annals of Internal Medicine 2006;145:435-447.

[2] Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. New EnglandJournal of Medicine. 2004; 351: 893-901.

[3]Bergmann MA, Eichhorst BF, Busch R, et al. Prospective evaluation of prognostic parameters in early stage chronic lymphocytic leukemia (CLL): Results of the CLL1-protocol of the German CLL Study Group (CCLLSG). Blood 2007;193a, abstract 625.

[4] Muntanola A, Bosch F, Arguis P, Abdominal computed tomorgraphy predicts progression in patients with RAI stage 0 chronic lymphocytic leukemia. Journal of Clinical Oncology 2007;25:1576-1580.

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[2] Eichhorst BF, Busch R, Stauch M, et al. No significant clinical benefit of first line therapy with fludarabine (F) in comparison with chlorambucil (Clb) in elderly patients (pts) with advanced chronic lymphocytic leukemia (CLL): Results of a phase III study of the German CLL Study Group (GCLLSG). Blood 2007;194a, abstract number 629.

[3] Rossi JF, van Hoof A, de Boeck K, et al. Efficacy and safety of oral fludarabine phosphate in previously untreated patients with chronic lymphocytic leukemia. Journal of Clinical Oncology 2004;22:1260-1267.

[4] Hillmen P, Skotnicki A, Tobak T, et al. Preliminary Phase III Efficacy and Safety of Alemtuzumab vs Chlorambucil as Front-Line Therapy for Patients with Progressive B-Cell Chronic Lymphocytic Leukemia (BCLL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 6511.

[5] Dmoszynska A, Fetni R, Wang Y, et al. Cytogenetic Correlation with Efficacy on Alemtuzumab (Campath®, Mabcampath®) (CAM) vs Chlorambucil (CHLO) as Front-Line therapy for Patents with Progressive B-Cell Chronic Lymphocytic Leukemia (BCLL). Proceedings from the 42 annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 6601.

[6]Cephalon. Cephalon Receives FDA Approval for TREANDA, a Novel Chemotherapy for Chronic Lymphocytic Leukemia. Available at: Accessed April 2008.

[7] Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. Journal of Clinical Oncology 2007;25:793-798.

[8]Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of Fludara, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. Journal of Clinical Oncology. 2005;23:4079-4088.

[9] Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. *Journal of Clinical Oncology.*2005;23:4070-4078.

[10] Tarhini AA, Land S, Pietragallo A, et al. Final results of lower dose fludarabine (F) and cyclophosphamide (C), and high dose rituximab (R), (FCR-lite) for patients with untreated chronic lymphocytic leukemia (CLL). Blood 2007;110:606a, abstract 2037.

[11] Egle A, Weiss L, Russ G, et al. Planned first efficacy and safety analysis of de-intensified induction with fludarabine, cyclophosphamide plus rituximab (FCR) followed by fludarabine plus rituximab (FR) and remission maintenance with rituximab in previously untreated B-cell chronic lymphocytic leukemia (B-CLL). Blood 2007;110:609a, abstract number 2045.

[12] Hillman P, Popcock C, Cohen D, et al. NCRI CLL201 Trial: A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated CLL. Blood2007;231a, abstract number 762.

[13] Lin TS, Donahue KA, Lucas MS, et al. Consolidation therapy with subcutaneous (SC) alemtuzumab results in severe infections toxicity in previously untreated CLL patients who achieve a complete response (CR) after fludarabine and rituximab (FR) induction therapy. Blood 2007;110:232a, abstract number 755.

[14] Wierda WG, O’Brien S, Ferrajoli A, et al. Combined cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR), an active frontline regimen for high-risk patients with CLL. Blood 2007;194a, abstract number 628.

[15] Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B-chronic lymphocytic leukemia. Blood First Edition Paper, prepublished online September 28, 2006:DOI 10.1182/blood-2006-07-033274

[16] Frankfurt O, Hamilton E, Rosen ST. Pilot Trial of Alemtuzumab/Rituximab for CLL. Oral presentation by Dr. Rosen at the 14th Annual Meeting of the Chemotherapy Foundation Symposium. New York, NY. November 8-11, 2006.

[17] Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized controlled clinical trial. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. New EnglandJournal of Medicine 1988;319:902-907.

[18] O’Brien S, Ravandi F, Riehl T, et al. Valganciclovir prevents CMV reactivation in patients receiving alemtuzumab based therapy. Blood 2007; e-pub ahead of print November 2007.

[19] Sinisalo M, Vilpo J, Itala M, et al. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukemia. Vaccine 2007;26:82-87.

[20] Karisson KA, Stromberg M, Jonsson V, et al. Cladribine (CdA) gives longer response duration than fludarabine (F) and high-dose intermittent chlorambucil (Chl) as first-line treatment of symptomatic chronic lymphocytic leukemia (CLL). First results from the international randomized phase III trial. Blood2007;110;194a, abstract 630.

[21] Inwards DJ, Hillman DW, Fishkin PA, et al. Phase II study of rituximab and cladribine (2-CDA) in newly diagnosed mantle cell lymphoma (MCL) (NO189). Blood 2006;108777a, abstract 2746.

[22] O’Brien S, Moore J, Ding L, et al. Addition of Oblimersen (Bcl-2 antisense) to fludarabine/cyclophosphamide for relapsed/refractory chronic lymphocytic leukemia extends survival in patients who achieve CR/nCR: Results from a randomized phase 3 study. Blood. 2007;110:231a. Abstract 751.

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