28                                                                                              Chronic Lymphocytic Leukemia (CLL)                                             

4.    Chronic Lymphocytic Leukemia (CLL)

(especially B-cell CLL)

4.1       General considerations

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults which manifests with progressive accumulation of lymphocytes in the blood, bone marrow and lymphatic tissue. It varies substantially in both clinical presentation and biological characteristics. Analyses of immunoglobulin genes and gene expression pattern have defined at least two types of CLL, that differ in their tendency towards disease progression.: one arises from relatively less differentiated (immunologically naïve) B-cells with ummutated heavy-chain genes and has a poor prognosis; the other evolves from more differentiated (memory-type) B-cells with somatically mutated heavy-chain genes and has a good prognosis. The estimation of the prognosis and the choice of the treatment, therefore, depends not only on a determination of the disease stage but also of a number of cytogenetic and clinical risk factors.

   *  From Dighiero and Binet, 2000

   **  From Voliotis and Diehl , 2002

      Indolent early stage patients (particularly elderly ones) are eligible for a watch and wait strategy, whereas those with an increased progression risk may benefit from early treatment. For all patients who fulfill the criteria for initiating therapy,chlorambucil with or without prednisone has represented the gold standard of therapy for more than four decades. The purin analogs (mainly fludarabine)turned out to be effective for patients who failed to respond to, or relapsed after chlorambucil. In a number of randomized trials, fludarabine was also superior to chlorambucil as initial therapy with regard to rate and duration of remission but not to overall survival. Therefore, and because of its more distinct myelosuppression and suppression of CD4- lymphocytes, its use as frontline therapy is still seen controversially.

Several meta-analyses and randomized trials also compared chlorambucil-based therapy with more intensive combination regimens without fludarabine. Again the improved remission rates achieved with the latter ones did not translate into an increased overall survival.

Studies are therefore underway to evaluate novel treatment modalities, e.g. monoclonal antibodies, fludarabine- based combinations with other cytotoxic drugs or monoclonal antibodies, high-dose chemotherapy with autologous stem cell support, and allogeneic bone marrow transplantation (including nonmyeloablative procedures). It is still unclear whether these may result in an overall improvement of the therapy outcome, be it prolonged relapse- free or overall survival, or even cure.

Administration of immunoglobulins and erythropoietin are  important supportive measures for patients with CLL to restore hypogammaglobulinemia and disease related anemia, respectively.

Literature: for review e.g.

      BYRD et al. Semin. Oncol. 27 (2000): 587-597 (novel therapies)

            CLL TRIALISTS COLLABORATIVE GROUP. J. Natl. Cancer Inst. 91 (1999):

            861-865 (meta-analysis of randomized trials)

      D’ARENA et al, Leuk, Lymphoma 44 (2003): 223-228 (biological and clinical       

      heterogeneity of B-CLL)

   * DIGHIERO and BINET, N. Engl. J. Med. 343 (2000): 1799-1801

GILES et al, Semin. Oncol. 25 (1998): 117-125 (CLL in transformation)

JACOBS and WOOD, Hematology 7 (2002): 33-41

KEATING, Biomed , Pharmacother. 55 (2001): 524 – 528

KIPPS , Semin. Oncol. 29 (Suppl 2) (2002): 98 – 104

MONTSERRAT, Med. Oncol. 19 (Suppl) (2002): 11 – 19

PANGALIS et al, Hematol. Oncol. 20 (2002): 103-146

ROBAK and KASZNICKI, Leukemia 16(2002): 1015 – 1027 (role of alkylating anents and nucleoside analogs)

      ** VOLIOTIS and DIEHL, Semin, Oncol. 29 (Suppl 8) (2002): 30 – 39 (challenges in treating hematologic malignancies)

4.2             Chlorambucil + / - Prednisone

To be repeated every 4 weeks

High- dose chlorambucil, e.g. 15 mg/d up to CR followed by maintenance 5 – 15 mg twice a week for 18 months * , or 30 mg/d for 4 days per week for 4 weeks, followed by a further four courses at fortnightly intervals for 8 weeks**.

            The combination of chlorambucil + prednisone  does not appear to result in

            generally superior survival when compared to chlorambucil alone. It may be  

            preferable, however, in patients with

autoimmune phenomena (e.g. autoimmune hemolytic anemia or thrombocytopenia) associated with CLL.

The chlorambucil dose is to be raised by 0.1 mg/kg until the patient responds or develops toxic effects. To be repeated every 2 weeks

Literature:

          * JAKSIC et al, Cancer 79 (1997):  2107-2114

             KNOSPE et al, Cancer 33 (1974): 555-562

             MONTSERRAT and ROZMAN, Blood Rev. 7 (1993): 164-175

             MORRISON et al, J. Clin. Oncol. 19 (2001): 3611-3621 (impact of therapy  

             with chlorambucil, fludarabine, or their combination on the incidence and  

             spectrum of infections. Results from Intergroup study CALGB 9011)

             RAI et al, N. Engl. J. Med. 343 (2002): 1750-1757 (clinical outcome of              

             Intergroup study CALGR 9011)

        ** SUMMERFIELD et al, Br. J. Haematol. 116 (2002): 781-786

4.3             Purine nucleoside analogs

Literature : for review

            ROBAK, Leuk. Lymphoma 43 (2002): 537-548

4.3.1      Fludarabine

For patients not responding to or relapsing within 12 months after initial therapy or as initial therapy.

To be repeated every 3 – 4 weeks.

Literature:

            FRENCH COOPERATIVE GROUP ON CLL et al, Lancet 347 (1996): 1432-1438

            (randomized trial of fludarabine vs CAP)

            KEATING et al, Blood 92 (1998):1165-1171

            LEPORRIER et al, Blood 98 (2001): 2319-2325 (randomized comparison of fludarabine,

            CAP and ChOP performed  by the French Cooperative Group on Chronic Lymphocytic

 Leukemia )

LISO et al, Haematologica 86 (2001): 1165-1171 (response to fludarabine after chlorabbucil front-line therapy and a CHOP- like second- line therapy)

RAI et al. N. Engl. J. Med. 343 (2000): 1750-1757 (randomized comparison of chlorambucil, fludarabine, or their combination. Intergroup study CALGB9011)

4.3.2      Cladribine (2-chlorodeoxyadenosine)

To be repeated every 3 – 4 weeks. Cladribine can also be given subcutaneously (or orally; e.g. 10 mg/m² daily for 3 days, every 3 weeks)*

Chronic Lymphocytic Leukemia (CLL)                                                                                                  31

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            Literature:

                        BETTICHER et al, Ann. Oncol. 9 (1998): 711 – 726

                     * KARLSSON et al, Br. J. Haematol. 116 (2002): 538 – 548 (oral use)

                        ROBAK et al, Br. J. Haematol. 108 (2000):375 – 368 and Blood 96

                        (2000):2723-2729

                        SAVEN et al, J. Clin. Oncol. 13 (1995): 570 - 574

                        TALLMAN et al, J. Clin. Oncol. 13 (1995) : 983 – 988

4.4             Combination chemotherapy

4.4.1    Cop    

            To be repeated every 3 weeks

            Literature:

                        BAGLEY et al, Ann. Intern. Med. 76 (1972): 227 – 234

4.4.2      Chop (modified)

To be repeated every 3 – 4 weeks  ( later on 3 – monthly)

Literature:

            FRENCH COOPERATIVE GROUP ON CLL. Br. J. Haematol. 73 (1989):334 – 340

            LEPORRIER et al, Blood 98 (2001): 2319 – 2325 (randomized comparison of fludarabine,

            CAP, and ChOP performed by the French Cooperative Group on Chronic Lymphocytic

            Leukemia)

4.4.3      Fludarabine + cyclophosphamide

            To be repeated every 4 weeks

            Literature:

                        HALLEK et al, Br. J. Haematol. 114(2001): 342 – 348

                        O’BRIEN et al, J. Clin. Oncol. 19 (2001): 1414 – 1420

4.5           Monoclonal antibodies

4.5.1      Anti – CD 20 monoclonal antibody (Rituximab)

Rituximab has some activity in heavity pretreated patients with CLL.

  *  E.g. infusion of 50 mg on day 1, 150 mg on day 2, and the remainder of the dose  

      on day 3.

Infusion time for the first 50 mg at least 4 hours. Premedication with acetaminophen, diphenhydramine, and prednisone is recommended.

Literature:

            HEDGE et al, Blood 100 (2002): 2260 – 2262 (reversal of refractory  

            fludarabine- associated immune thrombocytopenia)

            HUHN et al, Blood 98 (2001): 1326 – 1331

            ITALA et al, Eur. J. Haematol. 69 (2002): 129 – 134

32                                                                                                         Chronic Lymphocytic Leukemia (CLL) ______________________________________________________________________________________

            Rituximab has also been successfully combined with chemotherapy e.g.  

            fludarabine ± cyclophosphamide.

            Literature:

            GARCIA-MANERO et al, Blood 96 (Suppl 1) (2000): 757a, abstr. 3275  

            (combination of

            fludarabine, cyclophosphamide and rituximab for refractory patients)

            SCHULZ et al, Blood 100 (2002): 3115 – 3120 (rituximab + fludarabine

            for untreated and relapsed patients)

4.5.2      Anti-CD 52 monoclonal antibody (Alemtuzumab)

Especially as salvage therapy for patients who have been treated with alkylating agents and have failed fludarabine therapy.

         *In the first week the dose is 3 mg, increased to 10 mg and then to 30 mg as soon as  

           infusion-related reactions are tolerated. Prophylactic medication against “ first-

           dose” reactions should be given 30 minuted prior infusion (e.g. with 50 mg  

           diphenhydramine and 650 mg acetaminophen, or with 1 g paracetamol orally and

           2 mg clemastine).

Literature:

            KEATING et al, Blood 99 (2002): 3554 – 3561

            OSTERBORG et al, Med. Oncol. 19 (Suppl) (2002): 21 – 26 (review)

            RAI et al, J. Clin. Oncol. 20 (2002): 3891 – 3897

Alemtuzumab has also been administered subcutaneously.

Literature:        

            LUNDIN et al, Blood 100 (2002): 768 – 773

Preliminary results indicate a high efficacy of alemtuzumab and fludarabine in combination.

Literature:

            KENNEDY et al, Blood 99 (2002): 2245 – 2247

4.6            Myeloablative therapy with hematopoietic stem cell support

Experimental approach , especially applicable for younger patients (< 50 years for allogeneic transplantation).

Allogeneic transplantation may induce prolonged remissions in young patients with relapsed or

refractory CLL, but the risk of treatment- related morbidity and mortality is high.

Autologous transplanttion also results in promising disease- free survival in less heavily pretreated patients, with late relapses remaining the major problem.

Literature: e.g.

                        ESTEVE et al, Leukemia 15 (2001): 445 – 451

            WASELENKO et al, Semin. Oncol, 26 (1999): 48 – 61 (for review)

4.7            Nonmyeloablative preparative regimens

A promising new strategy is the use of less toxic, nonmyeloablative preparative regimens (often based on fludarabine and cyclophosphamide ) to achieve engraftment and allow development of graft- versus-leukemia effects.

Literature:

CHAMPLIN et al, Curr. Oncol. Rep. 2 (2000):182 – 191 (review of the potential for nonmyeloablative preparative regimens in lymphoid malignancies)