Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
Patients with relapsed or progressive CLL are not considered curable except by allogeneic stem cell transplantation; all chemotherapy and antibody therapies are considered palliative (for the relief of symptoms). Relapsed CLL, however, remains highly responsive to a wide variety of treatments, and patients may survive for many years with repeated treatment.
Since patients with relapsed CLL are rarely curable, treatment strategies are currently directed at prolonging how long patients can live with their cancer. Clinical studies have documented that the response rate to first re-treatment can be 70-80% with patients surviving an average of 3-5 years following CLL recurrence. With each successive recurrence, the response rate is typically less and the duration of remission is shorter than that achieved with the prior treatment. A wide range of re-treatment options exist for recurrent CLL. Patients are usually, but not always, treated with an agent or agents not used for initial therapy. If the time to disease progression after initial therapy is prolonged, however, the drugs in the initial regimen can be successfully used again.
Single-agent Treatment of Recurrent CLL
Many patients with recurrent CLL are treated with single agents due to age and other health conditions. Single-agent therapy is given to palliate the disease (relieve symptoms) and improve the quality of life because toxicities are generally less severe than with combination therapy. Some of the most often used active agents are chlorambucil and Fludara® (fludarabine) and more recently, Rituxan® (rituximab) and Campath® (alemtuzumab). However, Rituxan is more commonly used in combination therapy than as single agent therapy.
Leukeran® (chlorambucil): Leukeran, 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 for initial treatment but many patients will receive this drug during some course of their palliative therapy.
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. One of the first studies of Fludara in patients with recurrent CLL showed this agent to be better than the combination of cyclophosphamide, doxorubicin and prednisone (CAP).1 Overall response rate to Fludara was 48% versus 27% in the CAP group. However, remission duration and survival were similar between the two groups. For elderly patients not receiving Fludara in induction, this would be an appropriate agent for retreatment.
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.
Researchers from Austria have reported data that confirm the efficacy and safety of Campath for the treatment of patients with CLL who have failed prior therapies.2 These authors analyzed data from 115 patients with CLL who were treated with Campath at 25 medical institutions within Austria. Patients had received approximately three prior treatment strategies, and 59% of patients had stopped responding to Fludara.
- 5% of patients achieved a complete response, 17% a partial response, and 36% had stable disease.
- Median survival was 11 months among patients whose cancer continued to progress while on Campath, nearly 30 months among patients who achieved disease stabilization on Campath, and even longer (median survival not yet reached) for patients who responded to treatment with Campath.
Severe infections occurred in 37% of patients and 26% developed grade 4 neutropenia (low white blood cell count). Grade 4 thrombocytopenia (low platelet count) occurred in 21. Fourteen percent of patients died during therapy or within two months of discontinuing therapy; half of these patients died of sepsis (infection). These data are consistent with other studies showing high activity of Campath. Infections due to Campath and pretreatment were major complications.
In another study, 93 patients with refractory CLL were treated with Campath in 21 centers worldwide.3 Overall response was 33%, with 2% being complete responses and 31% partial responses. The median time to response was 1.5 months and the median time to progression of disease was 4.7 months. Responders progressed at a median of 9.5 months. The median survival was 16 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to mild to moderate infusional toxicities occurring mainly in the first week. Moderate to severe infections were reported in 25 patients (26.9%). However, only 3 (9.7%) of 31 patients who responded to Campath® treatment developed severe infections. These authors concluded that Campath induced significant responses in patients refractory to alkylating agents and Fludara, with clinical benefit in the majority and with acceptable toxicity in a high-risk group.
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.
In a study of Treanda among 16 patients with refractory CLL, two patients achieved a complete remission and five patients achieved a partial remission.4
In another study, Treanda was combined with mitoxantrone for the treatment of 22 advanced CLL patients who had received prior treatment.5 The overall response rate was 86%, with six patients having a complete response. The average time to disease progression was 10 months and the median survival was 39 months.
In a third study, Treanda was combined with mitoxantrone and Rituxan for the treatment of 21 patients with CLL.6 Overall response rate was 96% with 41% having a complete response. The average time to disease progression was 17 months.
These data suggest that Treanda is very active and may replace cyclophosphamide and chlorambucil as the preferred alkylating agent for the treatment of CLL.
Fludara, Cytoxan and Rituxan: Previous studies from the M. D. 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.7 In a study of 177 patients with CLL who had failed initial therapies, a complete remission was achieved in 25% of patients and a partial remission in 48%. Thirty-two percent of patients achieving a complete response also achieved a molecular complete response. In a subsequent publication these same authors compared single agent Fludara, Fludara plus Cytoxan, and FCR.8 FCR was associated with the highest complete remission rate and the longest survivals.
The improved survival with the FCR regimen compared to Fludara alone or Fludara plus Cytoxan is most likely related to the increase in complete remissions.9 Researchers from the M.D. Anderson Cancer Center assessed 505 previously-treated patients enrolled in phase II studies. Results indicate higher complete and overall response rates for patients treated with FCR than for patients treated with Fludara alone or Fludara plus Cytoxan. The following table summarizes the results of these comparisons:
Fludara, Cytoxan and Campath: Researchers from Italy reported data on 25 patients with relapsed or refractory CLL treated with Fludara, Cytoxan, and Campath (FCC).10 They reported an overall response rate of 79% with 37% having a complete response. PCR negativity was achieved in 27% of evaluable patients. Major side effects were infectious complications. These researchers concluded that this was a safe and effective regimen for patients with relapsed or refractory CLL.
Rituxan and Campath: In one study , 48 patients with relapsed or refractory lymphoid malignancies, including 32 with CLL, were treated with combination Rituxan and Campath.11 Thirty-two patients had previously received Rituxan, one had received Campath and four had received both Rituxan and Campath. The overall response rate was over 50% and 8% of these refractory patients had a complete response. The median time to disease progression was six months and the median survival was 11 months. The major toxicities were infusion related and an increased incidence of infections. However, there were no fatal infections and no patient died of treatment. These authors concluded that “The combination of rituximab and alemtuzumab is feasible, has an acceptable safety profile, and has clinical activity with a short course in a group of patients with poor prognoses”.
Nipent® (pentostatin), Cytoxan and Rituxan (PCR): Researchers from Memorial Sloan-Kettering Cancer Center have reported that PCR has high activity in previously-treated patients with CLL or low-grade non-Hodgkin’s lymphoma (NHL).12 This trial included 46 patients: 32 with CLL and 14 with low-grade NHL who had failed prior treatments. The median age was 62 years with the oldest patient being 80 years old. The median number of prior chemotherapy regimens was two with a range of one to seven. Over 70% of patients received the full protocol-prescribed doses of drugs.
The complete response rate was 25% and the partial response rate was 50%. The response rate in Fludara-resistant patients was 75%. The median time to treatment failure was 17 months. Median survival of patients with CLL was 42 months. All patients with a complete or nodular response were alive at 36 months compared to an estimated 28% survival for the remaining patients. Grade 3-4 neutropenia occurred in half the patients treated. Fever of unknown origin occurred in 28%. Eight patients had pneumonia, with one death from progressive pneumonia.
These authors suggested that the outcomes of patients treated with PCR were superior to similar patients treated with Nipent and Cytoxan without Rituxan. They also suggested that when compared to Fludara, Cytoxan and Rituxan patients receiving PCR had less grade 3-4 neutropenia, fewer infections, and received more of the recommended drug dose. These data suggest that Nipent compares well with Fludara for the treatment of CLL and low-grade NHL with possibly less toxicity.
Allogeneic Stem Cell Transplantation
Patients with CLL have many palliative treatment options, but, ultimately, virtually all patients become refractory to treatment. Allogeneic stem cell transplantation is the most effective method of producing long-term disease-free survival and possible cure of patients with CLL. However, transplant-related mortality is high following conventional myeloablative treatment regimens. Allogeneic stem cell transplants can also be performed using reduced-intensity treatment regimens resulting in a lower treatment-related mortality while relying on a graft-versus tumor effect for the anti-lymphoma effect. However, there has been concern about the long-term effectiveness of this approach with very little long-term data available.
Researchers from Italy have previously reported that allogeneic stem cell transplantation using a reduced intensity regimen of thiotepa, fludarabine and cyclophosphamide resulted in a high rate of complete clinical and molecular remissions in 44 patients with relapsed or refractory CLL and follicular lymphoma.13
Researchers from the Fred Hutchinson Cancer Research Center (FHCRC) have presented long-term follow-up data showing that approximately 50% of patients receiving reduced intensity allogeneic stem cell transplants for advanced CLL are alive at 5 years.14 Results were available for 82 patients with a median age of 52 years (the oldest patient was 72 years old). Fifty-two of the patients received a transplant from a related donor and 30 received a transplant from an unrelated donor. The following table summarizes the main findings of this study:
One of the major complications was chronic graft-versus host disease (GVHD), which affected 7-14% of patients. The authors also reported that unfavorable cytogenetics had no impact on outcome.
Researchers associated with the European Bone Marrow Transplant (EBMT) group also reported that patients with CLL with a 17p deletion had a 48% survival following allogeneic stem cell transplantation.15 This study included 27 patients transplanted from a related donor and 17 transplanted from an unrelated donor. Eighty-nine percent received a reduced intensity allogeneic stem cell transplant and the remainder a conventional marrow ablative regimen. The median age was 54 years and the oldest patient was 64 years of age. All had received extensive prior therapies. With a median follow-up of 23 months 26 patients were alive and 18 were in complete remission. The estimated four-year overall survival was 48% and the progression-free survival was 37%. Non-relapse mortality was 27%.
These are promising data which suggest that a significant fraction of patients with advanced CLL can achieve long-term eradication of disease, and many appear to be living a normal life without GVHD. These data also support the concept that allogeneic stem cell transplantation may overcome the adverse prognosis associated with some cytogenetic abnormalities.
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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. Although bacterial infections are 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.16
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.17
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.18
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 Relapsed CLL
The progress that has been made in the treatment of 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 the treatment of CLL.
Leustat® (cladribine): Leustat is in the same class of drugs as Nipent and Fludara. Leustat has been evaluated as a single agent or in combination with other drugs for the treatment of patients with CLL. This drug has been extensively studied in Europe as an alternative to Fludara and has significant activity as a single drug or in combination with chemotherapy. For example, one study of Leustat with Rituxan with or without Cytoxan has shown significant activity in patients with refractory CLL.19 Overall response rates were 67% for Rituxan plus Leustat and 78% to Rituxan, Leustat and Cytoxan. Responses occurred in patients previously exposed to Leustat. Leustat has shown significant activity in the treatment of newly diagnosed patients with CLL and may be superior to Fludara.20
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).21
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.
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9 Wierda W, O Brien S, Faderl S, Ferrajoli A, et al. Improved Survival in Patients with Relapsed -Refractory Chronic Lymphocytic Leukemia (CLL) Treated with Fludarabine, Cyclophosphamide, and Rituximab (FCR) Combination. Proc Am Soc Hem, Blood 2003; 102(11):110a, Abstract #373.
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13 Farina L, Carrabba R, Milani R, et al. Molecular remission in relapsed/refractory chronic lymphocytic leukemia and follicular lymphoma treated with RIC-allogeneic stem cell transplantation correlates with a better disease-free survival. Bone Marrow Transplantation 2005;35 (supplement 2):S24, abstract number O138.
14 Sorror ML, Storer B, Sandmaier BM, et al. Long-term follow up of patients (pts) with high-risk chronic lymphocytic leukemia (CLL) given nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Blood 2007;110:496a, abstract 1662.
15 Schetelig J, van Biezen A, Caballero D, et al. Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia (CLL). Blood 2007;110:22a, abstract 47.
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17 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.
18 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.
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21 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.