Clearly defined response criteria evaluating treatment of CLL patients in clinical research trials

To the editor:

The treatment of chronic lymphocytic leukemia (CLL) has dramatically improved over the past decade using chemotherapy regimens combined with rituximab. However, the optimal regimen has yet to be defined and clearly defined response criteria are critical for evaluating CLL patients who are treated on clinical research trials. The Guidelines from the International Workshop on CLL were first published in Blood in June 2008, but was replaced by an updated corrected version online on December 8, 2008.¹  These Guidelines were published to update and replace the 1996 National Cancer Institute (NCI)–sponsored Working Group Guidelines.²  However, while this online updated manuscript is otherwise outstanding, some important issues were not clearly defined regarding response criteria in clinical research trials.

The 2 issues that require clarification include examination of the bone marrow aspirate and biopsy and computed axial tomography (CT) scans. The published version¹  redefined the 1996 bone marrow criteria guidelines for a complete response (CR) by waiting “3 months after the last treatment” to perform the marrow and requiring standard flow cytometry or immunohistochemistry negativity for a CR. It also eliminated nodular partial responses (nPRs). These criteria for CR differ from the criteria from the guideline published in 1996, which only required less than 30% lymphoma cells in the marrow for a CR.²  The online updated version required a bone marrow examination within 2 months after the last treatment and changed the CR criteria back to the 1996 guidelines including reinstating nPR. However, it suggested that clinical trials aiming to maximize CR should assess the bone marrow for minimal residual disease (MRD) using standard flow and immunohistochemistry (1 in 10 leukocyte sensitivity) and 4-color flow or allele-specific oligonucleotide polymerase chain reaction (1 in 10 000 leukocyte sensitivity).

In the online version, Section 5.1.2, titled “Absence of significant lymphadenopathy (eg, lymph nodes > 1.5 cm in diameter) by physical examination,” states: “CT scans are desirable if previously abnormal. Lymph nodes should not be larger than 1.5 cm in diameter.” Section 5.2.2 in the online version is titled “Reduction in lymphadenopathy (by CT scans in clinical trials or by palpation in general practice).”

It is not clear whether CT scans are mandatory for clinical trials with contradicting statements in the same online revised version. It is also not clear whether there are differences in the minimal residual disease bone marrow criteria for a CR between the published and online versions. These issues are critical for clinical trial evaluation, as CRs are highly predictive of progression-free survival and in many trials responses are the primary endpoint. It would be helpful if the authors could clarify these issues.