ABSTRACT: Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease with significant variation in clinical presentation, time to disease progression, survival, and aggressiveness of clinical course. A subgroup of patients who have been repeatedly identified as having a poor response to therapy are those with del(17p13.1)—identified by either interphase cytogenetics or other comparable strategies. Although there has been much progress over the past few years in the development of new therapeutic targets for CLL patients, this subgroup has continued to lag behind others. Because of the poor response or significant therapy-related toxicity experienced by patients with del(17p13.1)—and the small number of these patients included in clinical trials—current guidelines are unable to provide suggestions for the care of newly diagnosed, symptomatic but untreated patients (as well as relapsed patients) in this subgroup on account of the modest amount of evidence. However, novel agents are on the horizon that appear to be significantly more effective in this patient population, and these will likely shape the standard of care for these patients in the future.
Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease with significant variation in clinical presentation, time to disease progression, survival, and aggressiveness of clinical course. Multiple ongoing laboratory-based studies are attempting to better understand the pathophysiology of this disorder, identify risk factors that portend poor survival, and provide targets for future therapeutic agents. A subgroup of patients who have repeatedly been identified as having a poor response to therapy are those with del(17p13.1) on interphase cytogenetics. Although there has been much progress in CLL therapeutics over the past few years, progress in this patient subgroup has continued to lag behind that seen in other populations. This review will discuss the pathophysiology associated with the del(17p13.1) interphase cytogenetic abnormality, the current generally poor outcomes in affected patients, currently approved therapeutic agents, and new agents now undergoing investigation.
The chemotherapy resistance observed in del(17p13.1) patients is likely related to malfunction of the tumor suppressor protein p53. In humans, the gene that regulates this protein (TP53) is located on the short arm of chromosome 17 (17p13.1). Patients with deletion of 17p have a homozygous TP53 gene, which becomes inactivated by mutation in the vast majority of these patients,[2-4] leading to total lack of function of the p53 pathway (Figure 1). To date, studies have indicated that ~80% of patients with del(17p13.1) also have TP53 gene mutations, and only 4% to 18% of patients studied have TP53 mutations but do not have del(17p13.1).[2,4] However, the region deleted is large, and loss of other genes in this area or associated genomic instability could also be a driver of poor outcomes in these individuals. In response to cellular DNA damage caused by radiation or therapeutics, a normal cell responds by up-regulating the level of p53 protein. Cell-cycle arrest is then induced by p21WAF1 (wild-type p53-activated fragment) through inactivation of cyclin-dependent kinase 2 (CDK2), which blocks the transition of the cell cycle from the G1 phase to the S phase.[6,7] Then cellular and DNA repair enzymes can repair DNA lesions before DNA replication, preventing perpetuation of potentially harmful mutations.[5,8] However, if DNA damage is extensive and irreparable, p53 induces apoptosis of the cell, a process mediated by BAX (BCL-2
[B-cell lymphoma 2]–associated protein X) and down-regulated by BCL-2, and the damaged cell is eliminated.[7,9] The function of p53 is therefore paramount to cellular response to cytotoxic chemotherapies—yet p53 is defective in CLL patients with del(17p13.1) or TP53 mutations.
With the advent of interphase fluorescence in situ hybridization (FISH) and its heightened diagnostic sensitivity, the del(17p13.1) aberration was detected in ~7% of a large group of mostly untreated patients. Rates of detection of del(17p13.1) following fludarabine therapy have been reported as being as high as 30%, indicating clonal evolution of the disease to withstand chemotherapy. Because the abnormal p53 clones are resistant to chemotherapy, they initiate a negative selection process that slowly increases the number of cells that carry these abnormalities, causing subsequent adverse clinical repercussions. These patients have consistently demonstrated poor survival and a shorter interval from diagnosis to therapy.[7,10,13] The landmark study using interphase FISH for cytogenetic classification of CLL predicted that patients with del(17p13.1) typically require therapy within 1 year of diagnosis and have a meager median overall survival (OS) of only 32 months. Additionally, the landmark trial that established fludarabine, cyclophosphamide(Drug information on cyclophosphamide), and rituximab(Drug information on rituximab) (Rituxan) (FCR) as standard-of-care front-line therapy for CLL patients resulted in improved progression-free survival (PFS) and OS when the patients were evaluated all together, but demonstrated that expression of del(17p13.1) was the strongest negative predictive factor for these variables. For the del(17p13.1) patient group, the rate of complete response (CR) was only 5%, 3-year PFS was 18%, and 3-year OS was 38%—compared with rates of 44%, 65%, and 87%, respectively, for the group as a whole. The del(17p13.1) group did not benefit from the addition of rituximab.
In contrast to the majority of historical data, a recent study by Tam et al reviewed 99 treatment-naive (TN) CLL patients with del(17p13.1) and discovered that there is significant clinical heterogeneity within this group. The researchers cautioned against making therapeutic choices solely on the basis of the presence of this cytogenetic abnormality. In the published results of this study, several attempts were made to document this heterogeneity, including by means of short follow-up. Also, patients with del(17p13.1) who also had unmutated IGVH and Rai stage (Rai) ≥ 1 demonstrated worse survival. Another study indicated that a loss of TP53 of ≥ 10% conferred a markedly inferior prognosis, compared with the prognosis in patients with < 10% loss of TP53. Rossi et al used quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to evaluate a series of patients with and without del(17p13.1) cytogenetics. This study identified a microRNA (miR) fingerprint typically expressed in del(17p13.1) patients. It also identified higher levels of miR-21 and low levels of miR-181 in these patients. Many other ongoing research studies attempt to risk-stratify patients within this high-risk group, with the goals of better understanding disease pathology and discovering new and effective therapeutic targets.
As described above and documented in a large number of previous trials, current available treatments have demonstrated discouraging efficacy in the high-risk group of patients who express del(17p13.1). In addition, the small overall number of patients in this group has thwarted progress in the improvement of therapy, with most clinical trials including a very limited number of patients with this cytogenetic feature (Table). In this section of the article, we describe the current guidelines for therapy. In subsequent sections, we describe prior trials and promising agents currently under investigation.
In general, the clinical spectrum of CLL at initial presentation is very heterogeneous. Therefore, a patient usually needs to meet specific criteria prior to initiation of therapy, since some patients can be observed for years without change in clinical condition. Some investigators have proposed that CLL patients who have del(17p13.1) may require earlier therapy because of their known poor prognosis. However, recent trials (described in detail above)[14-16] have suggested heterogeneity even within this group, with some early-stage patients demonstrating a reasonable treatment-free survival. Thus, the indications for therapy in a patient with del(17p13.1) remain the same as for a CLL patient without this deletion. Indications for consideration of treatment that have been established by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) include the presence of any one of the following:
• Clinical symptoms (fevers, night sweats, weight loss, or painful lymphadenopathy or splenomegaly).
• Cytopenias (hemoglobin < 11 g/dL or platelets < 100 × 1012/L) without other causes.
• Autoimmune hemolytic anemia or thrombocytopenia (idiopathic thrombocytopenia purpura [ITP]) poorly responsive to standard therapy.
• Rapidly progressive disease (lymphocyte count rising to > 300 ×109/L, or rapidly enlarging lymph nodes, spleen, and liver).
Isolated mild thrombocytopenia (platelets 70–100 × 1012/L) can often represent chronic ITP and can be followed closely if no other symptoms are present. A bone marrow biopsy can sometimes help determine whether disease or a combination of disease and ITP is driving this isolated thrombocytopenia.
Once the necessity of treatment has been established, most clinicians turn to the National Comprehensive Cancer Network (NCCN) guidelines for recommendations regarding choice of therapy. Straightforwardly, the NCCN guidelines indicate that there is no set standard-of-care for patients with del(17p13.1) cytogenetics; if eligible, these patients should be enrolled in a clinical trial. Per these guidelines, if a patient achieves a CR or a partial response and is a candidate for transplant, allogeneic stem-cell transplant (alloSCT) should be considered. However, the currency of the NCCN guidelines is limited by the amount of time and strict regulations required to update these recommendations. Research in the field of CLL is constantly bringing new therapeutic options to the fore, and guidelines can become outdated quickly. That being said, the NCCN guidelines are updated as expeditiously as possible based on new published data and represent the most comprehensive and up-to-date source for treatment suggestions. Below, the therapeutic options for patients who are ineligible for a clinical trial will be discussed—for the front-line setting, for the relapsed/refractory (RR) setting, and for the elderly patient population. Figures 2 and 3 depict the treatment algorithms used for patients with del(17p13.1) in the front-line and RR settings, respectively, at our institution.