Chronic Leukemia

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This manual is not a substitute for consultation with an appropriate specialist.
The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.

Chronic Leukemia

Updated 15 November 2012

Treatment policies for patients with acute leukemia are formulated by the Leukemia/Bone Marrow Transplant (BMT) Program.

Chronic Myelogenous Leukemia

Treatment policies for chronic myelogenous leukemia can be found at Leukemia/Bone Marrow Transplant (BMT) Program .

Chronic Lymphocytic Leukemia (CLL)

Diagnosis

The diagnosis of CLL requires: > 5.0 x 109 /L B-lymphocytes in the peripheral blood; confirmation of clonality of the B-lymphocytes by flow cytometry; characteristic small mature lymphocytes, with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli and having partially aggregated chromatin, in the peripheral blood. These cells may be found admixed with larger or atypical cells, cleaved cells or prolymphocytes, which may comprise up to 55% of the blood lymphocytes. Finding prolymphocytes in excess of this percentage favours a diagnosis of prolymphocytic leukemia (B-cell PLL).

The diagnosis of monoclonal B-lymphocytosis, instead of CLL, requires the following: An absolute increase in the clonal B-lymphocytes (but < 5.0 x 109 /L) in the peripheral blood of an otherwise healthy adult; absence of lymphadenopathy or organomegaly (as defined by physical examination and CT scans), cytopenias, or disease related symptoms. 1% to 2% of patients with monoclonal B-lymphocytosis develop CLL per year.

The diagnosis of small lymphocytic lymphoma (SLL), which is the same disease as CLL except that SLL is not associated with a peripheral blood lymphocytosis > 5 x 109/L at diagnosis, requires biopsy proven involvement of lymphadenopathy and/or splenomegaly due to SLL.

Staging

The staging system used for treatment planning for CLL at BCCA is the modified Rai system (Hallek, Guidelines for the diagnosis and treatment of CLL, Blood 2008;111:5446-56). It identifies three risk groups.

1.	Definition of stages
	Modified Rai stage	Classical Rai stage	Findings
	Low risk	0	Peripheral blood lymphocyte count > 5.0 x 109/L. Bone marrow, if done, contains > 30% lymphocytes*
	Intermediate risk	1	Stage 0 + lymphadenopathy
	Intermediate risk	2	Stage 0 + hepatomegaly and splenomegaly
	High risk	3	Stage 0 + anemia (Hgb < 110 g/L)
		4	Stage 0 + thrombocytopenia (Platelets < 100 x 109/L)
2.	Staging procedures
	CBC with peripheral smear
	Serum creatinine, LDH, AST, alkaline phosphatase, bilirubin, serum protein electrophoresis, Hep B^surfaceAg, Hep B_core Antibody, Hep C Antibody
	Chest radiograph
	Physical examination for liver enlargement or splenomegaly; additional assessment with abdominal ultrasound or CT scanning is needed only if there is doubt about the liver or spleen involvement
	*Bone marrow biopsy and aspiration are not necessary unless: 1. the peripheral blood picture is not definitive for diagnosis of CLL or 2. they are required to explain abnormal blood cell counts
	Lymph node biopsy is seldom required unless doubt about the final diagnosis is present, or in the case of SLL.
	If findings suggestive of hemolysis are present a direct anti-globulin test can be useful
	Serum immunoglobulin G, M and A levels, particularly if recurrent infections.

Cytogenetics: Cytogenetic analysis should be performed prior to initiation of primary treatment for CLL to guide the choice of treatment.

The required specimen for FISH analysis is 10 mL of heparinized blood. A bone marrow specimen is not necessary but may be used. The minimal standard testing protocol should include:

FISH for deletion 13q
FISH for trisomy 12 (+12)
FISH for deletion of ATM (11q deletion)
FISH for deletion of TP53 (17p deletion)

Treatment

Treatment is not recommended for asymptomatic patients merely because of lymphocytosis, splenomegaly or lymphadenopathy. An elevated white blood cell count, even to markedly high levels, does not require treatment by itself as long as the hemoglobin and platelet count remain satisfactory, the patient does not become symptomatic and the lymphocyte doubling time remains greater than 6 months. Treatment should be considered for patients who develop one or more of the following, due to the CLL.

Anemia
Thrombocytopenia
Symptomatic splenomegaly
Symptomatic lymphadenopathy
Lymphocyte doubling time < 6 months
Autoimmune hemolytic anemia
Autoimmune thrombocytopenia
Otherwise unexplained fatigue or constitutional symptoms sufficient to interfere with work or normal daily activity

Treatment of advanced stage small lymphocytic lymphoma (SLL) is identical to that of CLL. Additional guidance on choice of treatment and integration of hematopoietic stem cell transplantation is available on the Leukemia/Bone Marrow Transplant (BMT) Program website.

All patients should receive the immunizations recommended in Appendix III.

1. Chemotherapy

The BC Cancer Agency maintains current Chemotherapy Protocols.

a) CLL without immune mediated hemolysis or immune mediated thrombocytopenia

1. CLL without 11q or 17p deletion: fludarabine + rituximab (LYFLUDR). Note that rituximab is not included in the initial 1-2 cycles if the total WBC is markedly elevated (see protocol).

The combination of fludarabine + rituximab provides the best balance of tolerability and improved progression free and overall survival (Byrd, Blood 2003;101:6-14; Byrd, Blood 2005:105:49-53).

2. CLL with 11q deletion: fludarabine + cyclophosphamide + rituximab (FCR) which may overcome the negative prognostic impact of this cytogenetic abnormality. (see review, Ding, ASH Education Book December 4, 2010 vol. 2010 no.1 p90-92)

CLL with 17p deletion: 17p deleted CLL is often resistant to both fludarabine + rituximab and fludarabine + cyclophosphamide + rituximab. A patient with CLL with 17p deletion should be discussed with a senior hematologist/oncologist in the Lymphoma Tumor Group and may be a candidate for early assessment for allogeneic hematopoietic stem cell transplantation.

b) CLL with immune mediated hemolysis or thrombocytopenia

Prednisone, given in high daily doses, > 40 mg/day, is the drug of choice for the initial two to four weeks of management of patients with CLL-associated hemolytic anemia or thrombocytopenia. The acute CLL-related immune mediated cell destruction should be stopped or at least well controlled before additional chemotherapy is started, usually after prednisone has been given for 2-3 weeks. After control of the immune mediated cell destruction is established the prednisone can be tapered and stopped and treatment with CVP + rituximab (LYCVPR) used for at least two cycles before switching to fludarabine + rituximab (LYFLUDR) to conclude the treatment. Folic acid supplementation should be given to patients with active hemolysis.

2. Supportive Measures
Allopurinol (300 mg/day by mouth) is necessary prophylactically only when a rapid lysis of large numbers of lymphocytes is anticipated (initial WBC >200.0 x 10 9 /L). It should also be employed in patients with chronic hyperuricemia, gout or significant renal dysfunction. Patients with hypogammaglobulinemia and repeated infections should be assessed for possible use of intravenous gammaglobulin.

3. Radiation
Involved field radiation is an effective treatment for localized SLL and for symptomatic or cosmetically disturbing focal lymphadenopathy for all stages of SLL/CLL. Radiation of the spleen is ordinarily not useful and may cause worsening of pancytopenia.

4. Splenectomy

Occasionally, removal of the spleen may prove helpful in CLL. The most common situations that may require elective splenectomy are symptomatic splenomegaly or hemolytic anemia or autoimmune thrombocytopenia uncontrolled by chemotherapy. This procedure should only be carried out with sophisticated hematologic support. Pneumococcal, hemophilus influenza and meningococcal vaccines should be given to patients as far in advance of splenectomy as possible (see Appendix III).

5. Secondary Chemotherapy
CLL which is refractory to fludarabine + rituximab may respond to agents such as chlorambucil, cyclophosphamide (with or without vincristine and prednisone) or bendamustine (bendamustine requires CAP approval). Rituximab can be added to secondary chemotherapy if the patient’s CLL has not demonstrated refractoriness to it (ie. non-response or progression within 6 months of receiving a rituximab-containing regimen). CLL that cannot be controlled with fludarabine, alkylating agents and rituximab and is free of bulky (> 5 cm) lymphadenopathy may respond well to alemtuzumab, a monoclonal antibody directed against the CD52 antigen. Its use should be discussed with a member of the Lymphoma Tumor Group and requires special authorization.

Reference:
Hallek, Guidelines for the diagnosis and treatment of LL, Blood 2008;111:5446-56

Hairy Cell Leukemia

This chronic B-cell leukemia, which is predominantly seen in older males, responds excellently to well tolerated doses of cladribine (LYCDA). Given the potential for long term remission all patients with hairy cell leukemia should be offered treatment at diagnosis. Because of very high efficacy, low toxicity, ease of administration and durability of response, cladribine is the treatment of choice. The complete response rate with cladribine exceeds 80% and durable responses are usual. However, most patients eventually relapse. The Lymphoma Tumor Group recommends four courses of fludarabine + rituximab (LYFLUDR) for relapsed hairy cell leukemia.

Prolymphocytic leukemia (PLL)

This aggressive variant of lymphocytic leukemia may be of B or T-cell lineage. It arises de novo and is distinct from prolymphocytoid transformation of chronic lymphocytic leukemia. The B-cell type of PLL typically presents with marked splenomegaly and minimal lymphadenopathy with a marked peripheral blood lymphocytosis. T-cell PLL presents similarly, but may be accompanied by more significant lymphadenopathy and serous effusions. Curative treatment has not been described. Younger, physiologically robust patients should be treated as for acute lymphoblastic leukemia with intensive chemotherapy and bone marrow transplantation if feasible. The usual patient is, however, elderly and is best treated with single agent chemotherapy and palliative measures. Fludarabine may be effective for this disease and should be tried if the patient does not respond well to chlorambucil or cyclophosphamide. Lymphophoresis may be useful for selected patients with extreme lymphocytosis.

T-cell Chronic Lymphocytic Leukemia

Less than 1% of cases of CLL are of T-cell origin. They are morphologically similar to B-cell CLL with the exception of marked nuclear irregularity. Distinction from the small cell variant of T-cell prolymphocytic leukemia is difficult. The behaviour is usually aggressive and similar to PLL as described above. These unusual cases should be discussed with a medical oncology member of the Lymphoma Tumour Group at one of the BCCA Centres.

Lymphoproliferative Disorder of Granular Lymphocytes (LDGL)

Also known as T-gamma leukemia, natural killer cell leukemia or large granular lymphocytosis. All of these diseases are characterized by a proliferation of lymphoid cells containing azurophilic granules. The most common presentation is as a chronic leukemia, however, it may present as lymphoma or acute leukemia. Two major phenotypic categories exist: 1) a "T-cell" variety expressing several T-cell markers including CD3 and CD8 and various NK markers including CD16, CD56 and CD57; 2) a true NK category with frequent expression of CD's 2,8,56 and 57 but lacking surface CD3. The T-cell variety is usually clonal for rearrangement of T-cell antigen receptor genes. The true NK variety lacks this clonal rearrangement.

The more common T-cell form of this disease has an indolent course and is associated with rheumatologic disease and neutropenia. Most patients do not require any treatment and as long as the peripheral blood counts remain at acceptable levels and the patient does not develop symptomatic splenomegaly intervention is not necessary. However, occasionally patients develop symptomatic or health-threatening fall in the erythrocyte, neutrophil or platelet count. These cytopenias are not due to tumour burden (filling of the marrow with leukemic cells) but rather to a poorly understood combination of peripheral destruction and cytokine-mediated inhibition of normal marrow cell production.

Until recently no treatment was known to be regularly effective for the cytopenias seen in LDGL. Several reports have now documented the effectiveness of cyclosporine A (Sood, Blood 1998;91:3372; Bible, Br J Haemat 1996;93:406). It is important to note that the improvement is not due to a cytotoxic effect of the cyclosporine A, but rather reduction of the destruction/inhibition effect. Cyclosporine A is ineffective at reducing tumour burden in this and other T-cell neoplasms. Thus, when symptomatic or threatening cytopenias develop in a patient with LDGL treatment should consist of oral cyclosporine A. A reasonable starting dose is 100 mg po twice daily. Doses should be reduced in the face of renal dysfunction (see product insert). The dose should be adjusted to the lowest that maintains an acceptable cell count and continued indefinitely. Cyclosporine A is available from BCCA for this treatment but requires submission of a class II drug request.

The true NK form of LDGL is rare, follows a more aggressive course and responds poorly even to intensive treatment. Consultation with a core member of the Lymphoma Tumour Group should be sought for help planning appropriate treatment.

Other Chronic Lymphoid Leukemias

A variety of other less common lymphoid leukemias have been recently recognized, including hairy cell leukemia variant and splenic lymphoma with villous lymphocytes. Recognition of these entities requires detailed clinical information, a careful morphologic review and immunophenotypic data as necessary. These unusual cases should be discussed with a medical oncology member of the Lymphoma Tumour Group at one of the BCCA Centres.

Malignant Lymphoma in Leukemic Phase

Many malignant lymphomas may have a leukemic phase, either late in the course of the disease or at presentation. In the past, these were referred to as lymphosarcoma cell leukemias, a term which specifically referred to small cleaved cell lymphoma in leukemic phase. Recognition of these cases requires careful morphologic and immunophenotypic assessment. Management should be as appropriate for that specific type of lymphoma. When the underlying lymphoma is low grade, no additional special measures are needed. When the lymphoma is an aggressive subtype, CNS prophylaxis is usually required.