Chlorambucil

In 2003, an estimated 7,300 new cases of chronic lymphocytic leukemia (CLL) and 4,300 new cases of chronic myeloid leukemia (CML) will occur in the United States.1 For 2003, the number of deaths due to CLL and CML are estimated at 4,400 and 1,600, respectively. In Rhode Island, 30-40% of an estimated 100 new cases of leukemia will be chronic leukemias.

CHRONIC MYELOID LEUKEMIA

The World Health Organization (WHO) defines CML as "a myeloproliferative disease that originates in an abnormal pluripotential bone marrow stem cell and is consistently associated with the Philadelphia (Ph) chromosome and/or the bcr-abl fusion gene". The hallmark of this disease is the 9:22 translocation, which results from the bcr gene (on chromosome 22) being juxtaposed to the abl gene (on chromosome 9). The bcr-abl oncogene product is a 240 kD protein, which is a constitutively active tyrosine kinase and is a causative factor. Most patients present in the chronic phase of the disease but later develop an accelerated phase or go directly into a blast crisis, a phase similar to acute leukemia. Average survival in chronic phase disease is approximately 5 years and less than a year in accelerated phase or blast crisis.

TRADITIONAL TREATMENT APPROACHES

Interferon alpha

Until recently, interferon (IFN)-based therapy has been a first-line option for newly diagnosed patients in chronic phase CML. Approximately 50-80% of patients experience hematologic responses (improvement in blood counts and appearance of the bone marrow). Major (reduction to fewer than 50% Philadelphia (Ph1) chromosome positive metaphases in the marrow) and complete (no evidence of Ph1 chromosome in the marrow) cytogenetic response rates are 10-40% and 5-25%, respectively. Lack of major hematologic responses after 3 months or major cytogenetic responses after 9-12 months should prompt alternative therapeutic approaches. IFN[alpha]^sub 2b^ is given as a single-agent or in combination with cytarabine (Ara-C). Two randomized trials comparing IFN with IFN plus Ara-C showed higher hematologic and cytogenetic responses with combination therapy and also increased survival in one trial. Median survival with IFN-based therapy is 6-7 years and high long-term survival rates (> 10 years) are seen in patients with complete cytogenetic responses.

Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation (SCT) is the only curative option for CML. Long term remission is believed to be mainly due to the immunologic 'graft versus leukemia' (GVL) effect that is successful in controlling or eliminating minimal residual disease obtained after high dose chemotherapy. Widespread applicability is limited by donor availability, patient age and general health, and major acute and chronic toxicities. Outcomes are better for patients undergoing transplantation early in the course of their disease, with 5-year survival rates of 75%, 40%, and 10% for chronic, accelerated and blast crisis phases, respectively. The consensus after meta-analysis is that there is no major difference in major transplant associated outcomes between chemotherapy-only preparative regimens and total body irradiation (TBI)-containing regimens. The use of improved anti-infective therapy (antifungal and anticytomegaloviral) has contributed to improved survival of chronic phase patients. Younger patient age at transplantation and a shorter time from diagnosis to transplantation are associated with superior outcomes.

The lack of matched related donors can be obviated with matched-unrelated donor (MUD) transplants. However, lack of available donors, especially in the minority populations and increased toxicity of this approach, mostly due to graft versus host disease (GVHD), remain problematic issues. Outcomes m younger patients with chronic-phase CML undergoing MUD-transplants approach those undergoing related donor transplants.

Autologous Stem Cell Transplantation

Autografting is useful in the setting of patients with incomplete responses to frontline therapy and who lack matched donors. The curative potential is limited by lack of the immunologic GVL effect and the potential contamination of autograft with residual CML cells. As in allogeneic transplants, success is heavily dependent on phase of disease and in a multicenter review, the 3-year survival rates for patients transplanted in chronic, accelerated and blast crisis phase were 60%, 30%, and 0%, respectively. Recent data indicate better survival in chronic phase patients but few patients enter complete cytogenetic remission with this approach. It is unclear presently whether purging (depletion of tumor cells) from the autologous stem cell graft is beneficial or necessary in this setting. One method of prolonging remission status involves the use of post-transplant consolidation using specific immunologic therapies such as interleukin 2 (IL-2) or IFN.

RECENT TREATMENT ADVANCES

Imatinib Mesylate (Gleevec(TM)).

Imatinib mesylate is a small molecule targeted to disrupt bcr-abl function and works by preventing phosphorylation of the tyrosine kinase residue. In phase II studies, imatinib was shown to have major responses in all phases of CML. Results of an 1100-patient randomized trial comparing imatinib to IFN plus Ara-C showed that major and complete cytogenetic responses at 12 months were 83% and 68% with imatinib versus 29% and 7% with IFN plus Ara-C (p=0.001).2 Similarly, one-year progression free survival rates were 97% and 80% for imatinib and combination therapy, respectively (p=0.001). Based on these results, the FDA has approved imatinib for first-line therapy in chronic phase CML. Higher doses of imatinib (up to 800 mg/day) may be associated with improvements in responses, especially in patients who have less than a complete response at standard doses of 400 mg/day. Major and complete cytogenetic response rates in patients with accelerated phase CML were 24% and 17%, respectively and were 16% and 7%, respectively in blast crisis patients.

The toxicity profile of imatinib is favorable and commonly includes mild to moderate fluid retention, nausea, muscle cramps, rashes, fatigue and diarrhea. Myelosuppression is more commonly seen with accelerated or blast crisis cases. The significantly lower disease progression seen with imatinib (1.5% vs. 7% for IFN plus Ara-C) may translate into a survival benefit with longer follow up. Impressive cytogenetic responses in all phases of CML, lack of major toxicities and easy oral administration make imatinib the treatment of choice in most settings. There has been a reduction of upfront allogeneic SCT even though the durability of cytogenetic responses with imatinib is unclear at present. Moreover, the frequency and persistence of molecular (bcr-abl negative) complete remissions is unknown. Currently, studies are examining the role of imatinib use in combination with IFN and Ara-C. Imatinib is also being incorporated in transplantation strategies.

Reduced Dose Intensity Transplantation

Reduced dose intensity conditioning regimens ('mini-transplants') are less myeloablative in nature and obviate the acute toxicites associated with high dose chemotherapy and standard doses of TBI. Originally targeted for elderly and organ function-compromised patients, this approach has demonstrated major responses in a variety of hematologic malignancies, including CML. In a recent review of seven reports in CML, actual 1-year survival rates of 65-83% were seen in a heavily pre-treated patient population.3 The major anti-leukemia effect stems from the GVL phenomenon. This approach also utilizes donor lymphocyte infusions in order to induce full chimerism in the recipient and maximize the GVL effect. It is possible that somewhat more myelosuppressive regimens may add to the efficacy of the GVL effect and result in improved outcomes by providing more disease debulking. Though acute toxicities are lower, major GVHD seems to be no less common or problematic than with standard transplantation.

CHRONIC LYMPHOCYTIC LEUKEMIA

CLL is an accumulative disorder of malignant small B lymphocytes commonly seen in the elderly. As the disorder advances, there is increasing immune impairment, including hypogammaglobulinemia and T cell abnormalities. The increased WBC count is reflective of the impaired apoptosis of CLL cells. This is the commonest leukemia among Caucasians. Staging of CLL identifies risk groups. The median survival from diagnosis for early (stages 0 and I), intermediate (stage II), and advanced disease (stages III and IV) patients is approximately 10 years, 7 years and 1-2 years, respectively. Early stage patients are usually asymptomatic and treatment is offered in the setting of advanced or bulky disease and rapidly progressive or symptomatic early disease stages.

TRADITIONAL TREATMENT APPROACHES

Alkylating Agents

Alkylating agents such as cyclophosphamide or chlorambucil, often in combination with corticosteroids, have been traditionally used in frontline CLL therapy. Comparisions have been conducted for the use of single agent chlorambucil versus combination chemotherapy regimens such as CVP (cyclophosphamide, vincristine, prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Even though response rates were higher with combination regimens, a survival advantage could not be demonstrated. Initiation of treatment in early stage CLL has not proven to confer survival benefit when compared to delayed treatment initiated upon disease progression to advanced stages. Thus, multiagent chemotherapy is not usually offered to patients in general practice.

Purine Analogs

The advent of the purine analogs (fludarabine and cladaribine) increased the therapeutic options for this disease in the 1980s. Initial studies demonstrated that these agents were active as salvage therapy in patients previously treated with alkylating agents. Response rates for fludarabine and cladaribine as second line therapy were in the range of 30-50% with more complete responses seen with fludarabine. Fludarabine as first-line therapy has shown response rates of 75-80% with a 25-30% complete response rate. The North American Intergroup randomized trial showed complete response rates of 20% and 4% and overall response rates of 70% and 43%, respectively, for fludarabine and chlorambucil. Time to disease progression was superior with fludarabine but no survival advantage was seen. Other studies have examined fludarabine in comparison to regimens such as CHOP or CAP (cyclophosphamide, doxorubicin, prednisone); all of them showed no significant survival advantage with combination chemotherapy. Recent attempts to combine fludarabine with cyclophosphamide have resulted in superior response rates without survival benefits. The Food and Drug Administration (FDA) has approved single agent fludarabine as first line therapy for CLL.

RECENT TREATMENT ADVANCES

Monoclonal Antibodies

Most of the recent advances are in the development of monoclonal antibodies directed against lymphocyte cell surface antigens. Alemtuzumab (CAMPATH-1H(TM)) is a chimeric humanized murine antibody directed against the CD52 antigen, which is present in high density on B and T lymphocytes in CLL. In refractory patients who have failed alkylators and fludarabine, the response rate with alemtuzumab was 33%, with median survival of 16 months for all patients and 32 months for responding patients.4 An increased incidence of severe infections, especially cytomegalovirus (CMV) reactivation and Pneumocystis carinii pneumonia (PCP) was seen in 27% patients. Prophylaxis for PCP is recommended with early treatment for CMV with ganciclovir or foscarnet upon suspicion of reactivation.

Rituximab (Rituxan(TM)) is a chimeric humanized murine antibody directed against the CD20 antigen, which is present in lower density on B lymphocytes in CLL as compared to lymphoma. As a result, traditional dosing of rituximab has resulted in low response rates. Thrice weekly dosing or high-dose scheduling of this agent obtains more impressive response rates in the 40-50% range,5,6 Recent data indicate that concurrent use of combination fludarabine and rituximab7 or fludarabine, cyclophosphamide, rituximab (FCR) are associated with complete response rates over 50% and overall responses in the 80-90% range. Both these novel therapies hold the promise of improving the outcome for CLL patients, especially when used in combination regimens.

Stem Cell Transplantation.

Allogeneic SCT approaches in CLL have been limited mostly by the elderly patient population and high mortality rates. Allogeneic SCT is an option for young patients (

Difficulty in obtaining sufficiently cleared blood or bone marrow for harvesting stem cells for autologous SCT has been an issue that is likely to recede with the impressive marrow clearance rates obtained with the use of monoclonal antibody and fludarabine combinations. In a recent review,8 4-year disease free survival rates over 65% were reported. Autografting is noncurative in CLL as evidenced by late relapses even after 5 years post transplant.

NEW TRANSPLANT APPROACHES

The Blood and Marrow Transplant Program at the Roger Williams Medical Center has initiated several novel protocols for patients with CLL and CML. In chronic phase CML, patients

In high-risk, relapsed or refractory CLL patients (

SUMMARY

Recent developments with targeted therapies have expanded the therapeutic armamentarium (Table 1) for patients with both CLL and CML. Significant advances in allogeneic and autologous donor transplantation have increased the patient eligibility pool and reduced the toxicities while improving upon long term survival results.

REFERENCES

1. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003, CA Cancer J Clin 2003;53:5-26.

2. Larson R, IRIS Study Group. Imatinib as initial therapy for Ph+ chronic myeloid leukemia: results of a randomized phase III study ve interferon-alfa plus cytarabine. Blood 2002;100(11):4a

3. Barrett J. Allogeneic stem cell transplantation for chronic myeloid leukemia. Semin Hematol 2003;40:59-71

4. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:3554-61.

5. Byrd JC, Murphy T, Howard RS, et al. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 2001;19:2153-64.

6. O'Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001;19:2165-70.

7. Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712(CALGB 9712). Blood 2003;101:6-14.

8. Dreger P, Montserrat E. Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Leukemia 2002;16:985-92.],

Ritesh Rathore, MD, and Gerald J. Elfenbein, MD

Ritesh Rathore, MD, is Clinical Director, Cancer Immunotherapy, Roger Williams Medical Center, and Assistant Professor of Medicine, Boston University School of Medicine.

CORRESPONDENCE:

Ritesh Rathore, MD

Adele R. Decof Center

Roger Williams Medical Center

825 Chalkstone Avenue

Providence, RI 02908

phone: (401)456-2077

Fax: (401) 456-5765

E-mail: rrathore@rwmc.org

Copyright Rhode Island Medical Society Aug 2003
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