Originally published as JCO Early Release 10.1200/JCO.2009.23.9731 on October 5 2009

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Time to Treatment Does Not Influence Overall Survival in Newly Diagnosed Mantle-Cell Lymphoma

Department of Hematology, Derriford Hospital, Plymouth, United Kingdom

To the Editor:

We read with interest the recent article by Martin et al¹ describing their retrospective cohort study comparing early treatment with observation in patients with newly diagnosed mantle-cell lymphoma (MCL). In their study, 66 patients received systemic therapy within 3 months of diagnosis, whereas treatment was deferred beyond this time point for the remaining 31 patients until clinically indicated. Although time to treatment (TTT) did not predict overall survival (OS) in multivariate analysis, the median OS of the observation group was statistically longer than that of the early treatment group (not reached v 64 months; P = .004). This confirms that in selected patients who are clinically well despite their diagnosis of MCL, a "watch and wait" policy is an acceptable management strategy. Similar to the approach followed by Martin et al, it has been standard practice in our institution for many years to observe asymptomatic patients with MCL until treatment is considered necessary. The decision to initiate therapy is made on the basis of the same principles described in the report by Martin et al.

Using a clinical database held within our hematology department, 52 patients consecutively diagnosed with MCL between 1994 and 2008 were identified. Diagnosis was made by histologic examination of representative tissue, together with characteristic immunophenotyping and presence of cyclin D1 and/or t(11:14). After diagnosis, the decision on whether treatment was required immediately or could be deferred was made at the discretion of the patient's consultant hematologist. For the purpose of this analysis, patients were divided into early treatment and observation groups on the basis of time from diagnosis to first therapy (chemotherapy, radiotherapy, or splenectomy) of less than 3 months and 3 months or more, respectively. OS was defined as time from MCL diagnosis to death as a result of any cause or date of last follow-up and was estimated with the Kaplan-Meier method.

Of the 52 patients identified, three were excluded from analysis because of missing data. Using the TTT cutoff of 3 months or more, 16 patients (33%) were included in the observation group and 33 patients (67%) in the early treatment group. Patient characteristics are summarized in Table 1. Although formal statistical analysis was not performed, there was a trend in the observation group toward lower median age (59 v 68 years) and European Cooperative Oncology Group performance score of 0 to 1 (94% v 72%) as well as a higher percentage of patients with lymphocytosis (50% v 24%). Median TTT in the observation group was 11.1 months (range, 3.7 to 131.1 months), with 12 patients (75%) observed for at least 6 months, eight patients (50%) for at least 12 months, and one patient (6%) for more than 5 years.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival of observation versus early treatment groups.

Comparing our results with those of Martin et al,¹ there are a number of similarities that stand out. First, although the number of patients included in our analysis was roughly half of their number, an almost identical proportion (33%) were identified as having asymptomatic disease at diagnosis and were suitable for a "watch and wait" management strategy. These patients were generally younger and had lower European Cooperative Oncology Group performance scores than those requiring early treatment, presumably reflecting the less aggressive behavior of their underlying disease. Observation for at least 12 months before therapy was indicated was possible for exactly half of the patients within this group, enabling them to have a period of time free from treatment schedules or adverse effects.

In contrast to the original report,¹ our survival analysis failed to demonstrate a significant difference between the two patient groups. However, our results provide additional confirmation that initial observation in asymptomatic patients is an acceptable course of action to take. Despite failing to demonstrate a superior survival profile with this approach, we found no evidence that deferring treatment has a detrimental effect on outcome in appropriately selected patients. Because MCL remains an incurable disease in the vast majority of patients, our results (and those originally presented by Martin et al) support a management strategy similar to that which has been widely adopted for other incurable lymphoproliferative disorders, such as follicular lymphoma (ie, initiation of treatment only when clinically indicated). One likely benefit of this practice is avoidance of treatment-related toxicities for a potentially prolonged period of time after diagnosis, which will surely have a favorable impact on quality-of-life measures.

At present, there are no biologic markers available that have been validated for use in MCL to differentiate between those patients who require immediate treatment and those who could be expectantly observed. Until this situation changes, clinical judgment alone must be relied on at initial diagnosis to identify those patients who have no apparent disease-related symptoms or complications requiring intervention. Given the noninferiority of a "watch and wait" policy in this setting, our current recommendation is that this strategy be adopted. Patients should then be evaluated at regular intervals to ensure that if symptoms, signs, or laboratory abnormalities develop, they are detected in a timely fashion, and therapy is implemented in an appropriate manner.

AUTHORS' DISCLOSURES of POTENTIAL CONFLICTS of INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCE

1. Martin P, Chadburn A, Christos P, et al: Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 27:1209–1213, 2009.[Abstract/Free Full Text]

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