New Agents
As detailed in this review, standard therapies have had consistently disappointing outcomes in the population of CLL patients with abnormalities of del(17p13.1) or TP53 mutations. The future of this subgroup depends heavily on the development of innovative therapies that act with a p53-independent mechanism. There are several promising therapies currently in clinical trials.
Lenalidomide
Lenalidomide (Revlimid) is an immunomodulatory drug that may work in part by stimulating the host’s own immune system via an increase in the activity of T cells and natural killer cells, which directly induces apoptosis in tumor cells.[42] Additionally, lenalidomide activates CLL cells, making them more recognizable to the immune system; it also increases CD154 expression, thereby activating pro-apoptotic pathways (eg, p73) that can bypass p53.[43] A number of other mechanisms have also been proposed that have recently been reviewed.[44] Eighty RR CLL patients, including patients with high-risk cytogenetic features and bulky lymph nodes, were treated in two phase II studies that demonstrated clinical efficacy. PR was achieved in 29% of the del(17p13.1) patients (n = 14).[45] One of these studies used a higher dose (25 mg/d) for 21 days of a 28-day cycle, but 3 patients experienced severe tumor lysis syndrome (TLS) and 58% had a tumor flare reaction (TFR) (8% had grade 3/4 reactions).[46] The other study used a continuous lower dose (10 mg/d), which resulted in no TLS and TFR in 30%.[47] A subsequent phase I study tested starting at a low dose (2.5 mg/d), with titration up to 20 mg/d to minimize TLS and TFR. In this study, 11.5% (n = 6) achieved PR, and 55.7% (n = 30) achieved stable disease (SD), with a median PFS of ~24 months.[48] Due to lenalidomide’s success, there are ongoing trials evaluating its efficacy as front-line single-agent therapy and in combination with chemoimmunotherapy. One of these studies treated CLL patients over age 65 with lenalidomide and demonstrated clinical efficacy (ORR = 65%, 2-year PFS = 60%) and tolerability in this subset of patients.[49] The six patients with del(17p13.1) did not respond; however, the total number of patients in the study was quite small. Notable efficacy and tolerability have been shown with the combination of lenalidomide and rituximab(Drug information on rituximab), both in the front-line[50] and relapsed settings. In the relapsed setting, the ORR of del(17p13.1) patients (n = 15) was 53%, with 13% (n = 2) achieving CR.[51] Registration studies are ongoing with lenalidomide to establish the use of this agent with or without rituximab as one alternative therapy for relapsed del(17p13.1) CLL patients.
B-cell receptor (BCR) antagonists
B-Cell Receptor Stimulation
Ibrutinib (formerly PCI-32765) and GS-1101 (formerly CAL-101) are two of the most successful of these new therapies; they have been especially effective in refractory/relapsed CLL (recently reviewed by Woyach et al[52]). These drugs work by targeting the BCR signaling pathway (Figure 4), which has been found to be aberrantly activated in CLL and to promote CLL cell survival and proliferation.[52] Ibrutinib is an oral, irreversible inhibitor of Bruton’s tyrosine kinase (BTK); it promotes apoptosis and inhibits proliferation, migration, and adhesion in CLL cells.[53,54] A phase Ib/II trial evaluated single-agent ibrutinib in RR CLL patients (n = 61) and TN CLL patients (n = 31), all over age 65; the study participants included 24 patients with del(17p13.1) (RR = 22, TN = 2). At the recommended phase I dose (420 mg/d), the ORR was 67% and 73% in the RR and TN groups, respectively, and estimated 12-month PFS was 88% and 93.3%, respectively. An additional 22% of the RR group achieved a nodal response, with residual lymphocytosis. The initial lymphocytosis was likely due to CLL cell mobilization from the bone marrow, and most patients returned to baseline with a break in treatment or longer-term continuation of the drug. The ORR was independent of high-risk factors, including del(17p13.1). The majority of toxicities were less than grade 2, making this a very tolerable as well as an efficacious regimen.[55] Multiple ongoing studies are investigating ibrutinib in combination with various immunochemotherapy regimens, such as bendamustine and rituximab or ofatumumab.
GS-1101 is an isoform-selective inhibitor of phosphatidylinositol 3-kinase (PI3K) δ; it inhibits PI3K signaling and induces apoptosis of CLL cells in vitro.[56] A phase I trial using GS-1101 in relapsed CLL patients (n = 54) demonstrated that 84% achieved a ≥ 50% decrease in lymph node and spleen size. However, a > 50% increase in lymphocytosis (temporary in some—similar to the reaction seen with ibrutinib) was seen in 58%, and this resolved in only a subset of patients, thereby lowering the ORR by the IWCLL criteria.[17] The response rate seen in this study was independent of typical high-risk CLL features, notably the presence of del(17p13.1) (n = 19) and bulky adenopathy (n = 44). Median PFS had not been reached at the time of presentation but was > 11 months. Notably, del(17p13.1) patients had a shorter PFS in this study than did other groups. The compound was well tolerated, with limited toxicity reported.[57] Multiple combinations involving GS-1101 are currently in phase II trials, including combinations with rituximab, ofatumumab, and bendamustine and rituximab. Multiple other agents that target the BCR signaling pathway are currently under investigation in clinical trials in lymphoid malignancy, including fostamatinib, dasatinib(Drug information on dasatinib) (Sprycel), AVL-292, GDC-0941, and XL147.
CDK inhibitors
Another promising group of agents that have shown efficacy in the del(17p13.1) population are the CDK inhibitors, most notably flavopiridol and dinaciclib. CDKs are a family of proteins that control most of the steps in the cell cycle and also other functions, such as transcription (among the proteins in this family are CDK7, CDK8, and CDK9). The mechanism by which CDK inhibitors promote cell death in nonproliferating CLL cells has long been an enigma, although recent evidence with flavopiridol suggests endoplasmic reticulum stress is a major mechanism of action.[58] Clinical trials have indicated clinical efficacy for flavopiridol in the RR CLL population. A review of the major phase I[59] and phase II trials[60] involving flavopiridol noted that ORR and PFS were not significantly different between cytogenetic groups, with a 48% ORR and an estimated PFS of 10.1 months in the del(17p13.1) population.[61] Combinations of this drug with chemoimmunotherapy agents have been studied in the phase I setting, with successful results.[62,63] Dinaciclib is a small-molecule inhibitor of multiple CDKs that has been studied in a phase I trial in RR CLL. This trial demonstrated an ORR of 53% in patients with del(17p13.1) (n = 17).[64] Although the CDK inhibitors are efficacious, both flavopiridol and dinaciclib demonstrated increased risk of TLS in their early trials. However, this toxicity has been minimized by alteration of the dosing regimens and aggressive inpatient supportive care during the first two doses of the drug, when the tumor burden is at its highest. Neither of these drugs are currently commercially available.
BCL-2 antagonists
Another novel group of agents are the BCL-2 antagonists navitoclax (ABT-263) and ABT-199. Navitoclax binds to BCL-2, BCL-x1, and BCL-w, thereby halting suppression of BAX and BAK and allowing these proteins to oligomerize and trigger apoptosis of the tumor cells (see Figure 1). In a phase I trial in RR CLL, navitoclax has shown promise by reducing lymphocytosis by more than 50% in 19 of 21 patients (with baseline lymphocytosis). In patients treated with doses ≥ 110 mg/d (n = 26), 35% achieved PR and 33% maintained SD for > 6 months. Similar responses were shown in high-risk groups, including PR in 3 of 9 patients with del(17p13.1), with PFS not yet reached at time of publication. The major limiting side effect in this trial was dose-dependent thrombocytopenia, thought to be related to inhibition of BCL-x1.[65] Based on these promising data with navitoclax, another BCL-2 inhibitor, ABT-199, is currently under investigation in phase I trials. ABT-199 is an agent with more specific inhibition of BCL-2; it is hoped that it will be able to limit the thrombocytopenia toxicity while maintaining the clinical efficacy seen with navitoclax.
Conclusion
In summary, the population of CLL patients with del(17p13.1) or other defects in the p53 pathway has consistently demonstrated a poor response to therapy. The p53 defect impairs the CLL cell’s ability to respond to DNA damage inflicted by cytotoxic chemotherapy. Although progress has been made since the clinical significance of this abnormality was discovered, the currently available regimens are substandard, with poor response or unacceptable toxicity. Exciting new agents, which are designed to function in the absence of a functional p53 pathway, are showing much promise, as demonstrated in early clinical trial results. New therapies are clearly needed for the high-risk population of patients with del(17p13.1). Until such therapies are available, we would emphasize the importance of referring these individuals for clinical trials.
Financial Disclosure: Dr. Byrd has received funding for clinical support for trials from Pharmacyclics. Dr. Stephens has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
A hematologically stable CML patient developed a solitary, exquisitely painful ulceration, 7 cm × 5 cm, located on the mid-medial foreleg. There was never any evidence of venous insufficiency. The patient denied the possibility of a spider bite. What is the likely cause of this lesion?
