Favorable Outcome in CLL Patients Not Treated Despite Presenting Iwcll Criteria: A Retrospective Analysis of the Brazilian CLL Group
Authors: Marques Fernanda de Morais , Pfister Verena , Parra Flavia , Yamamoto Mihoko , Santucci Silva Rodrigo , Bellesso Marcelo , de Molla Vinicius Campos , Da Fonseca Ana Rita , Novis Yana , Fortier Sérgio Costa , Silveira Talita , Amarante Guilherme Brasil Duffles , Buccheri Valeria , Vescovi Matheus , Chiattone Carlos Sérgio , Arrais Celso 
Published: November 2020

Introduction: Some patients with CLL will require treatment at diagnosis, but many other will remain untreated under observation for several years. In 2008, the International Workshop on Chronic Lymphocytic Leukemia(IWCLL) defined the criteria for treatment indications, which have been widely used in daily practice and in clinical trials. We have observed that many patients tolerate several of these clinical manifestations without treatment need, especially in public hospitals were resources and treatment options are scarce. We identified 5 reference centers for CLL that share the same profile of being more conservative in indicating treatment for CLL patients. We decided to analyze if more conservative local criteria for treatment indication impacts on patients' outcomes.
Objective: To describe the outcomes of a series of CLL patients treated according to locally defined more conservative criteria for initiating treatment.
Methods: The Brazilian Registry of CLL was started in 2004 as a prospective observational data collection tool. Inclusion criteria for enrollment followed the IWCLL guidelines. We retrospectively evaluated all patients with CLL in the Brazilian Registry of CLL who were followed between January 2013 and April 2020 at the 5 reference centers (3 public and 2 private). The following local criteria were used for treatment indications to all patients included: 1) persistent and progressive symptomatic cytopenias (no predefined minimum levels), 2) Massive or symptomatic lymphadenopathy, 3) Massive or symptomatic splenomegaly, 4) Disease-related symptoms, only if persistent and if other causes were excluded, and 5) Autoimmune complications including anemia or thrombocytopenia non-responsive to steroids. Progressive lymphocytosis and extranodal manifestations were not considered for treatment indication.
Results: A total of 581 patients were followed during the observation period of 7 years (median follow-up was 40 months (range: 3-86). Median age was 65 years (range: 32-98) and most patients were male (57%). Binet stage was A in 67%, B in 14% and C in 19% of cases. FISH, performed in only 199 patients (34%), was normal in 47%, and showed del13q in 22%, trisomy 12 in 17%, del11q in 8% and del17p in 7%. According to IWCLL criteria, 257 (44%) presented indication for treatment over the time: 140 (55%) at diagnosis and 117 (45%) during follow-up. Based on the local criteria, 148 (25%) patients met criteria for indication of treatment. Therefore, 109 patients with IWCLL indication were not treated to date according to the local criteria. The IWCLL indications for these untreated patients were: cytopenias in 50 patients (48%), constitutional symptoms in 37 patients (35%), progressive lymphocytosis in 9 (9%), and lymphadenopathy or splenomegaly in 8 (8%). The median observation time for these untreated patients from the time of indication of treatment by IWCLL until the analysis was closed was 39 months, ranging from 3 to 86 months. Of the 109 untreated patients, 12 (13%) died during follow-up: 4 from infections probably unrelated to CLL (all patients were elderly, Binet A, non-neutropenic and non-hypoglobulinemic), 2 from cardiac causes, 1 from a car accident and 5 of unknown causes (lost follow-up after at least 2 years). No deaths were attributable to LLC. Overall survival at 4 years was 90% for the patients who were treated versus 89% for the patients who were not treated (P=0.85).
Conclusion: Our data suggest that it is feasible and safe to adopt more conservative criteria to indicate treatment in a CLL patient. A more restrict approach may not only reflect in a significant financial impact to the health care system but also avoid premature exposition to prolonged and/or potentially toxic treatments. This finding might be of special interest to low-income countries.

Disclosures
No relevant conflicts of interest to declare.