Guidelines for Clinical Trials

The CLL Guidelines also lay out special recommendations for clinical trials.

1 For patients who enter clinical trials it is recommended that a full range of prognostic marker tests is performed. This includes FISH for del 13q14, del 11q23. del 6q, del 17p13 and trisomy 12; IgVH mutations; CD38 and ZAP-70 by an agreed and valdated method, and serum tests for beta-2 microglobulin, CD23 and thymidine kinase. There are other prognostic markers under study, and these could with profit be evaluated at teh same time.

2 CT scanning of chest, abdomen and pelvis is encouraged especialy in trials where complete response is the aim. (Note however that these will not change the Rai of Binet stage).

3 Definitions of different types of response have been clarified. Complete remission (CR) requires all of the following for at least three months: absence of clonal lymphocytes in the blood; absence of lymph nodes > 1.5 cm in diameter by both physical examination and CT scan; no splenomegaly or hepatomegaly by both clinical examination and CT scan; absence of constitutional symptoms; neutrophils >1.5/microliter, platelets >100,000/microliter, Hb >11.0 g/dL (untransfused).

4 Bone marrow aspirate and trephine performed at least three months after last treatment should be free of clonal CLL B cells (by conventional imunophenotyping). In some bone marrow trephines lymphoid nodules could be detected; the term nodular PR was used. This term is now discarded; immunohistochemistry should be used to distinguish whether these are T cells, normal B cells or tumor B cells. If teh marrow is hypocellular it should be repeated after 4-6 weeks. The timing of a marrow might have to be delayed until the other criteria of a CR are fulfilled, but it should not be delayed after 6 months.

5. For patients who fulfill all teh other features of a CR, but fail to recover their blood counts, the term CR with incomplete bone marrow recovery (CRi) shopuld be used.

6 Partial remission requires the following: a decrease of blood lymphocytes by at least 50%; reduction of lymph node size (by CT scan) of at least 50% in the sum of the products of up to 6 lymph nodes or in the diameter of one lymph node if only one lymph node was present before treatment AND no new abnormal nodes and no increase in size of any nodes; a decrease in the size of liver and/or spleen by 50% or more; and at least one of teh following:- neutrophils at 1,500/microliter of a 50% improvement over baseline without G-CSF support, playelets at 100,000 or a 50% improvement over baseline, or Hb >11.0 g/dL or a 50% improvement without transfusion or Epo support.

7. Progressive disease (PD) is defined by the appearance of any new lesion such as a lymph node >1.5 cm in diameter, clinical splenomegaly, hepatomegaly or infiltration of any other organ; by the increase of >50% in the greatest diameter of any previously documented disease; an increase in spleen or liver size by 50%; an increase of lymphocyte count by at least 50%; transformation to Richter's syndrome (confirmed by lymph node biopsy); occurrence of any cytopenia attributed to CLL (as opposed to the treatment).

8. Stable disease refers to those who do not achieve CR or PR yet do not have PD.

9 Duration of response is measured from the date of the end of last treatment until evidence of PD. Progression-free survival is defined as the interval between the first day of treatment and the first sign of disease progression. event-free survival is defined as the time from the first day of treatment to the first sign of progression or treatment for relapse, or death. Overall survival is the interval from the first day of treatment until death.

10. Relapse is defined as evidence of disease progression after a period of 6 or more months after a CR or PR. Refractory is defined as failure to achieve a CR or PR within 6 months of the last anti-leukemic therapy.

11. The elimination of Minimal Residual Disease (MRD) may be a desirable treatment endpoint, though prospective clinical trials are needed to demonstrate that this has clinical benefit. he techniques for assessing MRD have been standardized. Either four-color flow cytometry or allele specific oligonucleotide PCR are reliably sensitive down to a level of one cell in 10,000 leukocytes. It is satisfactory to use blood for this estimate except within three months of treatment with monoclonal antibodies, in which case marrow must be used.