Diagnosis and Treatment Guidelines

Authors: C. Schweighofer, M. Hallek, Universität Köln, GermanyInformation Letter No.5, August 2008

Introduction

Since publication of the first two versions of guidelines on diagnosis and treatment of CLL in 1988 and 1996, notable progress has been made in CLL research with regard to prognostic and diagnostic parameters and new treatment options. Recently, the IWCLL (International workshop on CLL ) -sponsored working group summarized these achievements in a new release of guidelines, which have been e-published in Blood in January 2008 ¹. Members of the European Research Initiative on CLL (WP7) have been involved in their development, discussion and validation. The following article gives a short overview about the most important 5 new aspects of the up-dated IWCLL -guidelines in comparison to the 1996-version published by the National Cancer Institute Working Group (NCI-WG) ²:

Diagnosis of CLL versus MBL versus SLL

The requirement of ≥5000/μl lymphocytes in peripheral blood for the diagnosis of CLL is still valid with more accentuation of the lymphocytes being identified as “Blymphocytes” by immunophenotyping. The minimum duration of pathologic lymphocytosis is now defined at 3 months (former guidelines: 4 weeks). The presence of > 5000 B-lymphocytes without further clinical pathologic signs and symptoms is separately named as “monoclonal B-lymphocytosis (MBL)” according to Marti et al.³ with an increased risk of development of CLL . Notably, a heavy bone marrow infiltration with consecutive peripheral cytopenia annuls the criterion of 5000 B-cells in the peripheral blood. Then the diagnosis of CLL via bone-marrow is sufficient. The diagnosis of SLL (small lymphocytic lymphoma) has to be diagnosed via lymph node histology and is clinically defined by the presence of lymphadenopathy, less than 5000/μl peripheral Blymphocytes and the absence of cytopenias caused by bone marrow infiltration. The criteria for the immunophenotypic definition of CLL have been similarly formulated to the 1996 criteria. In addition to the co-expression of CD5, CD19, CD20 and CD23, low surface immunoglobuline and kappa or lambda light chain expression, the low surface expression of CD79b on CLL cells is noted.

Role of cytogenetics and FISH analysis

Molecular cytogenetic analysis via fluorescent in situ hybridization (FISH) for the detection of unfavourable prognostic factors like deletions on chromosome 17p or 11q is recommended as a diagnostic procedure prior first-line treatment. The usage of unmutated VH status, VH 3.21 usage, ZAP70- and CD38 expression, serum markers like CD23, thymidine kinase and ß2-microglobuline for routine assessment is not advised. Further clinical trials are requested to standardize these prognostic markers and develop them to useful instruments in clinical practice.

Indication for computed tomography (CT ) scans

CT scans are recommended to assess lymphadenopathy in CLL patients only within clinical trials, in order to allow an optimal response assessment. Further clinical trials are demanded to investigate the necessity and efficiency of CT scans for response evaluation. Outside of clinical trials CT scans are considered not to be required, neither for initial staging nor for follow-up. Positron emission tomography
(PET) scans are regarded as useful only in cases of Richter’s syndrome.

Definition of remission status and progressive disease

The criteria for the definition of a complete remission (CR) have been changed as follows: Staging examinations to assess the remission status after any therapy are recommended to be performed not earlier than 3 months (former criteria: 2 months) and not later than 6 months (in case of persistant cytopenias) after treatment completion. The absence of clonal lymphocytes in the peripheral blood is added as one of the major criteria. Pathologic lymphadenopathy is defined at a lymph node diameter of greater than 1.5 cm. For the confirmation of a complete remission after treatment within clinical trials a bone marrow biopsy is recommended, which should be additionally analyzed with flow cytometry or immunohistochemistry. In case of residual CLL cells by conventional flow or immunohistochemistry a partial remission has to be ascribed. The use of the definition “nodular PR” is no longer recommended. For patients with persistant cytopenias not caused by marrow infiltration and otherwise fulfilling all criteria for a CR, a new remission term is defined by “CR with incomplete bone marrow recovery (CRi)”.
The outcome of such patients in comparison to non-cytopenic CRs has to be assessed within future trials. The definition of a partial remission has been changed as follows: The required 50% reduction of lymphadenopathy is now specified as a decrease in the “sum products of up to 6 lymph nodes” and extended by a complete lack of newly emerging or increasing lymph nodes. In case of a single enlarged lymph node the calculation with one diameter is allowed. The criteria for progressive disease have not been widely changed but are also outlined in more detail with regard to the required 50% increase in lymphadenopathy: e. g. small lymph nodes in the size of > 1 cm to 1.5 cm must increase up to a size to at least 1.5 cm or by 50% to be clinically relevant. Lymph nodes with a diameter of > 1.5 and > 2 cm must increase to a size of > 2 cm to be considered as significant. Importantly, it is advised that treatment related cytopenias must be excluded for the judgement of the CLL remission status.

Minimal residual disease (MRD) assessment

Due to its potential impact on long-term prognosis and survival of CLL patients, the assessment of MRD is highly recommended to be included into clinical trials, in order to further investigate the achievement of MRD eradication and duration of MRD negative complete remissions. As a current standard, four-colour flow cytometry (MRD flow) or allele-specific oligonucleotide PCR are considered as reliable techniques sensitive enough to track one single CLL cell in 10.000 leukocytes of peripheral blood or bone marrow ⁴. In patients with peripheral cytopenia the latter has to be preferably assessed for MRD. In summary, the most important changes in the new CLL guidelines concern the following 5 aspects: 1. the approval of MBL as a subclinical disease entity with an increased risk of CLL development, 2. the recommendation of fish analysis prior firstline treatment to exclude chromosomal high-risk features, 3. the basic incorporation of MRD testing into clinical trials, 4. the referral of CT scan assessment solely within clinical trials and 5. the definition of a new remission status, the "complete remission with incomplete bone marrow recovery (CRi)". The new IWCLL - guidelines should be the basis for future scientific and clinical studies in CLL , but also deliver expert advice for daily clinical practice.

References

1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute- Working Group (NCI-WG) 1996 guidelines. Blood. 2008 Jan 23.
2. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990-7.
3. Marti GE, Rawstron AC, Ghia P, Hillmen P, Houlston RS, Kay N, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005 Aug;130(3):325-32.
4. Rawstron AC, Villamor N, Ritgen M, Bottcher S, Ghia P, Zehnder JL, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia. 2007 May;21(5):956-64.