International CLL registry for spontaneous regression in CLL: Proposal

Background

The occurrence of a spontaneous regression of CLL in the absence of any previous treatment is exceptional. In the literature, there are only few papers in which this phenomenon has been reported. The clinical features of these cases have been described, but there is no information on the biologic markers of their disease or on the pathogenesis of this event.

Particularly, it is not known whether there are distinctive features which can identify among patients with good prognosis those who may experience over time a spontaneous regression of their disease and never require treatment.

In our Institution, we identified and reported on 9 CLL cases, who underwent a spontaneous regression of the disease after a median follow –up of 11 years (range: 3-28 years) from diagnosis (Del Giudice et al. Blood 2009).

They underwent an accurate clinical assessment and biologic evaluation of the residual clone, evident by peripheral blood immunophenotype. CD38 and ZAP-70 were negative in all cases. IGHV genes, mutated in all the 7 evaluable cases, belonged to VH3 family in 6, with the VH3-30 gene usage in 2. Light chain immunoglobulin variable region genes were mutated in 6/8 cases, with the Vk4-1 gene usage in 3. We could find neither recurrent associations between heavy and light chain genes nor characteristic HCDR3/LCDR3 aminoacidic motifs in this series.

Microarray analysis showed a peculiar gene profile of CLL cells with an over-representation of genes related to the BCR activity, ribosomal genes and regulators of signal transduction. Unfortunately, due to the lack of material, no cytogenetic analysis was performed. The amount of activated T lymphocytes expressing IFN-γ, TNF-α and IL-4 was similar between CLL in spontaneous regression and healthy individuals.

In this study, we concluded that spontaneous clinical regressions, which rarely occur in CLL, are characterized by the persistence of the neoplastic clone with negative CD38 and ZAP-70, mutated VH3-30 and Vk4-1. The peculiar gene profile suggested that BCR signaling may play an important role in this scenario as the most significant feature of the leukemic clone in regression (Del Giudice I, Chiaretti S, Tavolaro S, De Propris MS, Maggio R, Mancini F, Peragine N, Santangelo S, Marinelli M, Mauro FR, Guarini A, Foà R. Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood. 2009; 114:638-46).

Proposal

As the incidence of CLL spontaneous regression has been estimated about 1%, no single center will have many patients with this infrequent event. For this reason, it would be interesting to establish an international registry with the aim of pooling clinical data and biological informations of patients experiencing spontaneous regression and making them accessible to many researchers for future studies including immunological, cytogenetic, and molecular analyses to contribute to unfold the intriguing phenomenon of spontaneous regressions in CLL.

Goal

  1. To identify key differences with CLL cases which follow the usual natural history of the disease;
  2. To formulate hypothesis on the pathogenesis of this phenomenon and on mechanism of control of CLL progression to more advanced stages.

Inclusion criteria

Spontaneous clinical regression

  1. absence of any previous treatment for CLL or other radio/immuno/chemotherapy
  2. absence of superficial and deep lymphadenopathy, splenomegaly or constitutional symptoms
  3. peripheral blood lymphocytes < 4x109/l
  4. previous infections, vaccinations, second cancers are allowed
  5. persistence of CLL regression over time

Approach

The primary aims of establishing an international registry for the study of clinical and biologic features of CLL with spontaneous regressions can be summarized as follow:

  1. To collect clinical data to perform a characterization of CLL cases with the rare phenomenon of spontaneous regression (medical history, drug intake, etc.) in a dedicated » form (Excel)
  2. To collect available data on the biologic features of these cases in a dedicated form

Therefore, in the case peripheral blood samples can be obtained:

  1. To perform biologic studies on the residual CLL clone and on the T lymphocytes population (immunophenotype for the quantification and characterization of the neoplastic clone; IGHV mutational status, gene repertoire and sequencing; gene expression profiling by microarray, after CLL cells separation; cytogenetic and molecular genetic analysis; other molecular analysis i.e. miRNA)

Participants

The study will include the ERIC members and all the clinicians interested in CLL who have patients with a spontaneous regression of CLL.

Time-line

End of 2011

Coordination

Ilaria Del Giudice, MD PhD
Division of Hematology, Department of Cellular Biotechnologies and Hematology, “Sapienza” University, Rome (Italy)
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