Abstract

Chemoimmunotherapy has resulted in high complete remission rates and long remission duration in patients with chronic lymphocytic leukemia (CLL) but relapses occur and curative strategies still need to be developed. A wealth of new agents with a wide variety of mechanisms of action against CLL are currently in clinical trials. Twelve of these agents, which are in various stages of development varying from Phase I to Phase III trials, will be discussed. These include alkylating agents, monoclonal antibodies, immune modulators, cyclin-dependent kinase (CDK) inhibitors, BCL-2 family member inhibitors, protein kinase C (PKC) inhibitors, SRC inhibitors, HSP-90 inhibitors and small modular immune pharmaceutics (SMIP).

Introduction

The development of chemoimmunotherapy regimens has resulted in an increase in complete remission (CR) rates achieved with frontline therapy of chronic lymphocytic leukemia (CLL) to 40% to 70% with correspondingly durable remission durations of 3 to 7 years.1,3 Such lengthy remission durations clearly represent a major advance for patients with CLL, although no randomized trial has shown a benefit in terms of survival. Nevertheless, two retrospective analyses have suggested an improvement in survival with chemoimmunotherapy. The CALGB compared data with fludarabine and rituximab to historical data with single agent fludarabine in previous CALGB trials and showed a significant difference in survival.4 In multivariate analyses controlling for pretreatment characteristics the patients receiving fludarabine and rituximab had a 2-year disease-free survival of 67% versus 45% with fludarabine alone and a 2-year overall survival of 93% versus 81% with fludarabine alone. MD Anderson data indicated a 4-year survival with fludarabine, cyclophosphamide, and rituximab (FCR) of 85% versus 70% with fludarabine and cyclophosphamide in the historical control population. Analyzing survival in frontline trials is also complicated by the fact that expecting a survival difference implies that no subsequent therapies the patients receive will have any impact on their survival. Although improvement in survival may be occurring with chemoimmunotherapy, patients continue to relapse and require retreatment, and refractoriness eventually ensues. The unfortunate fact is that patients who reach the point of requiring therapy for CLL are likely to die of their disease. Thus, new agents for the treatment of CLL are clearly needed. The good news is that there are a large number of novel agents under investigation for the treatment of CLL (Table 1 ). In addition, the variety in the mechanism of action of these agents is encouraging, as the disease is being targeted at various levels. Types of drugs being studied include: monoclonal antibodies, microenvironmental modulators, BCL-2 family antagonists, cyclin-dependent kinase inhibitors, PKC inhibitors, HSP90 inhibitors, tyrosine kinase inhibitors, small modular immune pharmaceuticals, nucleoside analogs, and others. This review will necessarily be unable to discuss all the drugs that are currently being investigated but will focus on agents currently being explored in clinical trials.

Participation in a clinical trial is always a reasonable option for a patient since even when a good initial outcome is expected, such as in frontline trials, patients will relapse and toxicities are not insignificant, so improvements can still be made. However, participation in a clinical trial becomes even more important at the time of relapse. There are currently a limited number of FDA-approved agents available to treat CLL. Patients treated initially with fludarabine-based regimens such as fludarabine and rituximab (FR) or FCR usually have durable remissions and can be retreated with the same or a similar regimen, albeit with less likelihood of CR and shorter remission durations. However, once patients fail retreatment, or have short first remissions with chemoimmunotherapy, options are limited. Frequently these patients are treated with lymphoma-type regimens with or without rituximab such as CHOP, ICE, and DHAP, which are often associated with a significant degree of myelosuppression; previously treated patients often have poor bone marrow reserve. Unfortunately most patients currently participating in trials of investigational agents have often failed 4 to 5 prior regimens or are in poor condition and are at a point where the potential benefit from an investigational agent may not be seen because of the refractory nature of the patient population. Thus, consideration should be given earlier in the course of therapy to investigational agents, certainly at the time of second relapse or even at the time of first relapse in patients who had effective frontline regimens with short remission durations.

Alkylating Agents

Bendamustine was developed in the 1960s as a bi-functional anticancer agent having an alkylating group and also potential antimetabolite properties associated with benzimidazole ring. It has been used extensively in Germany since the 1970s particularly in the treatment of hematologic malignancies. It has been shown to have clinical activity in patients with disease refractory to conventional alkylating agents, and in a recently published article Leoni et al indicated that it had a distinct pattern of activity unrelated to other DNA alkylating agents.5 It had multiple mechanisms of action including activation of DNA damage stress response and apoptosis, inhibition of mitotic check points and induction of mitotic catastrophe. Similarly to other alkylating agents bendamustine activates a base excision DNA repair pathway. This drug was recently approved by the FDA for treatment of CLL based on a randomized study comparing it to chlorambucil.6 Previously untreated patients (n = 305) were randomized to receive bendamustine 100 mg/m2 IV for 2 days every 4 weeks or chlorambucil 0.8 g/kg orally day 1 and 15 of each 28-day cycle. CR rate and overall response rate with bendamustine were 29% and 68%, respectively, compared to less than 1% and 39% with chlorambucil. The myelo-suppression was somewhat greater in the bendamustine arm but the incidence of infections was the same. Medium progression-free survival (PFS) was 18 months with bendamustine compared to 6 months with chlorambucil. Bendamustine has also been shown to have increased efficacy when used in combination with rituximab.

An important question is where bendamustine would be utilized in the treatment of CLL. As mentioned, the currently available frontline treatments such as FCR provide high CR rates and durable remission durations that are significantly better than seen with single-agent bendamustine. Nevertheless, patients having inferior responses to fludarabine-based therapy are reasonable candidates for treatment with this agent. The German CLL Study Group is initiating a large randomized frontline trial of FCR versus bendamustine and rituximab that will provide important information. Another consideration that should be explored in a clinical trial, is the substitution of bendamustine for cyclophosphamide in the FCR regimen; such a trial is being pursued in the relapsed population.

Monoclonal Antibodies

Lumiliximab

Lumiliximab is a macaque-human primatized monoclonal antibody targeting the CD23 antigen. Preclinical studies showed that lumiliximab induced apoptosis of CD23+ lymphoid cell lines and prolonged survival of SCID mice inoculated with CD23-bearing lymphoblastic cell lines.7 This drug was previously explored in patients with allergies and showed a favorable safety profile without significant infusion-related toxicities or immunosuppression.8 A Phase I study utilizing this antibody to treat CLL was published in 2007.9 Forty-six patients were treated over 6 cohorts and received lumiliximab at 125, 250, or 375 mg/m2 weekly for 4 weeks; 500 mg/m2 weekly for 3 weeks or 500 mg/m2 thrice weekly for 4 weeks. The median number of prior regimens was 4; no partial or complete responses were observed. Clinical benefit was observed; 17 of 33 (52%) had a decrease in lymph node bulk and 42 of 46 (91%) had some reduction in lymphocytosis with a median maximum decrease in ALC of 32% (5.2%–84.3%) by day 29. The median duration of each infusion was 2 hours and all side effects were grade 1–2 except for 1 patient who withdrew due to a grade 4 headache. Combination studies with lumiliximab and fludarabine or rituximab in preclinical models have shown synergy. These preclinical findings along with the excellent safety profile of lumiliximab led to a Phase II trial in patients with relapsed/refractory CLL where lumiliximab was added to the FCR regimen. The results were compared with historical control data published by MD Anderson using FCR in the relapsed setting. The doses of FCR were standard and lumiliximab was administered at 375 mg/m2 on the first cycle and 500 mg/m2 on subsequent cycles. The overall response rate in this trial of 31 patients was 65%, compared with 73% seen with FCR alone. However, the historical data showed a CR rate of 25%; the addition of lumiliximab to FCR produced a CR rate of 52%.10 The median PFS for all patients was 19.3 months; this was 30.4 months for responders. The toxicity profile was identical to that seen with FCR; this led to a pivotal randomized trial comparing FCR with and without lumiliximab to FCR alone in patients with relapsed CLL that is underway internationally.

Ofatumumab

Ofatumumab (huMAX CD20) is a fully humanized anti-CD20 monoclonal antibody binding to a different CD20 epitope than rituximab.11 At low levels of CD20 expression (particularly relevant to CLL) complement-related killing of cells was significantly higher with this agent than with rituximab. The increased efficacy may be due to a lower off rate and more stable CD20 binding. In 2008 results from a Phase I/II study utilizing this agent were published in Blood.12 Three cohorts of 3 (A), 3 (B), and 27 (C), patients received 4 weekly infusions of ofatumumab at the following doses: (A) 1 × 100 mg dose and 3 × 500 mg doses; (B) 1 × 300 mg dose and 3 × 1,000 mg doses; (C) 1 × 500 mg dose and 3 × 2,000 mg dose. Maximum tolerated dose was not achieved, and the majority of side effects occurred during the first infusion. These usually occurred within the first few hours after starting the infusion and the most common symptoms were transient chills, fever, rash, and sweating. Only 1 patient enrolled on the trial could not receive all 4 infusions. The response rate in cohort C was 50% (13 of 26); 1 patient achieved a nodular partial response (nPR) and 12 patients achieved partial response (PR). The median PFS was 106 days, but the median time to next treatment was 1 year. A multicenter pivotal trial assessing ofatumumab in patients who are refractory to fludarabine and alemtuzumab is almost complete.

Immune Modulators

Lenalidomide, a thalidomide analog, is an immuno-modulating drug with antitumor activity in hematologic disorders including multiple myeloma and myelodys-plastic syndrome.13,14 While the mechanism of action of lenalidomide is unclear, it has been shown to inhibit tumor necrosis factor alpha (TNF alpha), has anti-angiogenic effects, and activates T cells and NK cells. It also upregulates tumor suppressor genes such as SPARC.15,16 Two different dose schedules of lenalidomide have been employed to treat patients with relapsed CLL. The Roswell Park group gave the drug at 25 mg on days 1 through 21 of a 28-day cycle.17 The overall response rate was 47%, with 9% of the patients achieving a CR. The median PFS was not reached and the estimated probability of PFS at 1 year was 81%. The main toxicities were fatigue and myelosuppression. Two patients developed tumor lysis. In addition, a flare reaction was seen in 58% of patients. This typically involved painful swelling of the lymph nodes, fever, and rash and could usually be controlled with the use of non-steroidal anti-inflammatory agents. In a clinical trial performed at MD Anderson Cancer Center the drug was given at 10 mg daily continuously.18 Forty-four patients with relapsed/refractory CLL were enrolled. The overall response rate was 32%, with 7% of patients achieving a CR; follow-up in this trial was significantly shorter than that in the Roswell Park trial. The most common toxicity was myelosuppression, but the grade 3–4 myelosuppression rate was significantly less with this lower dose, as was the incidence of tumor flare. Recently Ohio State published their experience with 4 patients with relapsed CLL who were treated on the 25 mg dose schedule.19 All had serious adverse events, including tumor flare, which was seen in 3 patients and resulted in hospitalization of 2 with 1 fatal outcome. Another patient developed sepsis and renal failure. This group concluded that a starting dose of 25 mg was too high in patients with CLL. There is currently an ongoing multi-center Phase I/II trial evaluating starting doses of 2.5 mg daily and allowing for gradual dose escalation.

Cyclin-Dependent Kinase Inhibitors

Flavopiridol

Flavopiridol is a synthetic flavone that inhibits cyclin-dependent kinase (CDK) 1, 2, and 9 and effectively induces apoptosis in CLL cells in vitro at clinically achievable concentrations; the antileukemic activity is p53 independent.20 A variety of different schedules of administration were explored with flavopiridol including 72-hour continuous infusion, 24-hour continuous infusion, and 1-hour bolus. Toxicities included neutropenia, diarrhea, cytokine release syndrome and fatigue. No significant clinical activity was observed in Phase II testing.21,22 The lack of clinical activity in these studies was partly due to increased binding of flavopiridol to human serum proteins; this led to an underestimation of the dose required to induce apoptosis in CLL cells. Pharmacokinetic modeling resulted in a Phase I study using a 30-minute loading dose followed by a 4-hour infusion administered weekly.23 Forty-two patients were enrolled on 3 cohorts and the dose-limiting toxicity was hyper-acute tumor lysis. The response rate was 45% (all PR) with a median response duration exceeding 12 months. Responses were seen in patients with high-risk disease including 5 of 12 (42%) with 17p deletions and 13 of 18 (72%) with 11q deletion. A Phase II trial presented at ASCO 2008 confirmed these results in 62 patients. Thirty patients (48%) responded with 6.5% achieving CR. A multicenter Phase II trial is ongoing to explore the activity of flavopiridol in patients with CLL that is refractory to fludarabine.

SNS-032

SNS-032, an aminothiazole, is a small-molecule inhibitor of CDK 2, 7, and 9. CDK2 is a cell cycle–dependent kinase that controls the entry into and progression through the cell cycle. CDK7 and CDK9 are involved in transcriptional control, particularly of short half-life (T1/2) mRNAs, many of which encode antiapoptotic and growth regulatory genes. CDK9 may play a role in survival of B-cell malignancies: CDK9 and its partner, cyclin T1, are highly expressed in some lymphomas and other B-cell malignancies. A Phase I study of SNS-032 using 3 weekly infusions in patients with refractory solid tumors did not identify an MTD at doses up to 16 mg/m2.24 The experience with flavopiridol in patients with CLL prompted development of an alternate schedule currently being explored in patients with CLL and multiple myeloma. A multicenter Phase I trial using a loading dose followed by a 6-hour infusion weekly for 3 weeks is ongoing.

BCL-2 Family Member Inhibitors

Oblimersen

Oblimersen sodium is an antisense oligonucleotide that downregulates BCL-2 in a concentration- and time-dependent manner. BCL-2 is highly expressed in virtually all patients with CLL.25 In a Phase I trial this agent was administered as a 5-day continuous infusion. The starting dose of 7 mg/kg/day was found to be too high based on dose-limiting reactions including hypotension and fever, and the maximum tolerated dose for Phase II dosing was established at 3 mg/kg/day.26 Two (8%) of 26 assessable patients achieved a PR. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (7/17; 41%), complete disappearance of hepatomegaly (2/7; 29%), ≥ 50% reduction of lymphadenopathy (7/22; 32%) and ≥ 50% reduction in circulating lymphocyte counts (11/22; 50%). Subsequently a Phase III trial was conducted in patients with relapsed or refractory CLL.27 All patients received chemotherapy with fludarabine plus cyclophosphamide and were randomized to chemotherapy alone or chemotherapy with the addition of oblimersen 3 mg/kg/day as a 7-day continuous infusion. CR/nPR was achieved in 17% of 120 patients in the oblimersen group and 7% of 121 patients in the chemotherapy-only group (P = .025). Most of the benefit was seen in patients with fludarabine sensitive disease (i.e., those who had a PR lasting at least 6 months after fludarabine based therapy). Among these patients the CR/ nPR rate was 25% in the oblimersen group and 6% in the chemotherapy only group (P = .016). Overall response rates were not different between the two arms. The median time to progression in patients achieving a CR/nPR on chemotherapy alone was 22 months but was not reached in the oblimersen arm. A recent 5-year update of this trial presented at ASCO 2008 showed no difference in overall survival, but in patients achieving any response (CR/nPR/ PR) the median survival was 38 months in the chemotherapy arm and 56 months in the oblimersen arm (log rank P = .04).28 In addition, the fludarabine-sensitive patients continued to show the most benefit. The median survival was 33 months on the chemotherapy arm and 46 months in the oblimersen arm (log rank P = .004). Approval for this drug was not given by the FDA based on the initial data and recent submission of the 5-year data was pending review.

Obatoclax

The BCL-2 family of antiapoptotic proteins share a conserved binding site for the BH-3 domain of BH-3-only or multidomain pro-apoptotic proteins whose sequestration prevents the initiation of the apoptotic cascade through the mitochondrial pathway. Small molecule mimics of the BH-3 peptidic domain can inhibit these protein-protein interactions and facilitate initiation of programmed cell death. In addition to high levels of BCL-2, CLL cells also express high levels of other anti-apoptotic proteins including BCL-XL and MCL-1. Obatoclax methylate (GX15-070) is a novel small molecule pan-BCL-2 inhibitor which inhibits several anti-apoptotic BCL-2 family proteins including BCL-XL, BCL-2, BCL-W, BCL-B, A-1 and MCL-1. It induces apoptosis of human B CLL cells treated ex-vivo and was additive with fludarabine and chlorambucil. It also induces apoptosis of human AML samples.29 Recently in a phase I trial in patients with CLL obatoclax was administered at doses ranging from 3.5 to 40 mg/m2 as a short infusion every 3 weeks.30 Dose limiting toxicities were neurological (somnolence, euphoria, ataxia) and temporally associated with the infusion. The MTD was 28 mg/m2 over 3 hours every 3 weeks. One (4%) of 26 patients achieved a partial response. Interestingly, patients with anemia (3/11) or thrombocytopenia (4/14) experienced improvements in hemoglobin and platelet counts; circulating lymphocyte counts were reduced in 18/26 patients. Activation of BAX and BAK was demonstrated in peripheral blood mononuclear cells and induction of apoptosis was related to overall obatoclax exposure, as assessed by the plasma concentration of oligonucleosomal DNA/histone complexes. A recent article in Neurophysiology suggests a potential explanation for the toxicity profile; BCL-XL acts locally to modulate synaptic transmission without regulating apoptosis of the cell because the synapse is isolated from the nucleus.31 In vitro, another BCL-XL inhibitor, ABT-737, slowed recovery of synaptic responses after repetitive synaptic activity indicating that endogenous BCL-XL was necessary for timely recovery of rapidly firing synapses.

ABT-263

ABT-263 is a small molecule BCL-2 family protein inhibitor that binds with high affinity to several anti-apoptotic BCL-2 family proteins including BCL-XL, BCL-2, BCL-W, and BCL-B but not MCL-1 or A-1.32 Preclinical experiments with CLL samples showed that treatment with ABT-737, a first generation inhibitor, induced significant and concentration-dependent apoptosis in 47 of 50 CLL specimens. The primary toxicological finding was a decrease in circulating platelets in mouse, rat and dog that was concentration dependent and is expected to be the dose-limiting toxicity for ABT-263 in humans. This thrombocytopenia appeared to be an effect on peripheral circulating platelets and not on bone marrow production. A limitation of ABT-737 was that it was not orally bioavailable, whereas ABT-263 has an oral bioavailability in preclinical animal models of 20% to 50% depending on the formulation. A Phase I/IIa trial is being conducted in patients with lymphoid malignancies and there is a separate trial in patients with CLL. Data from the lymphoid malignancy trial was presented at ASH in 2007.33 The drug was given orally for 14 days of a 21-day cycle. The Phase IIa component will evaluate up to 40 patients with both indolent and aggressive lymphoma. At the time of the presentation 17 patients had been enrolled starting at doses of 10 mg. A grade 3 DLT (infection) occurred in the 160 mg dose cohort and the cohort was expanded to 6. Two patients with bulky small lymphocytic leukemia/CLL in the 40 and 160 mg cohorts had 95% and 64% tumor reduction, respectively, and were continuing on treatment. Data from the CLL trial have not been presented yet.

Protein Kinase C Inhibitor

Enzastaurin HCl, an oral serine/threonine kinase inhibitor, targets the protein kinase C (PKC) and PI3K/AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis.34 Enzastaurin inhibits PKCβ (IC50 ~6 nM), as well as other PKC isoforms (for example, α, γ, ε, IC50S 40 to 100 nM). At plasma concentrations achieved clinically, enzastaurin and its active metabolite(s) can suppress signaling through the PI3K/AKT pathway. PKC activation has been implicated in the malignant progression of human cancers, notably B-cell lymphomas, malignant gliomas, and colorectal carcinomas.35,37 Multiple PKC isoforms are expressed in CLL including PKCβ, γ, and δ (as well as variable expression of isoforms α and ε). Several studies have described constitutive activation of PKCs in CLL cells.38 In addition, activators of PKC such as the phorbol esters TPA and bryostatin act as inhibitors of spontaneous and chemotherapy-induced apoptosis in B-CLL lymphocytes. These data suggest a potential role of PKC in survival and activation of CLL cells. A Phase I study of enzastaurin was conducted in patients with advanced cancers. The drug was given orally continuously at a starting dose of 20 mg. No MTD was identified at doses of up to 700 mg/day.39 Steady-state enzastaurin exposures increased with increasing doses of up to 240 mg but were similar at 525 and 700 mg. This steady state is achieved within 2 weeks of daily oral dosing and is produced by the 525 mg dose, which was then chosen as the recommended Phase II dose. Functional inhibition of PKCβ and PI3K/AKT pathways can be measured through a decrease in phosphorylation of pGSKβ. Currently a multicenter Phase 1a trial of enzastuarin in patients with CLL is being conducted. The primary goal of this study is to determine if the inhibition of pGSK3β can serve as a pharmacodynamic marker of enzastaurin activity in CLL and to see if this inhibition is correlated with antitumor activity.

Hsp90 Inhibitors

BIIB021 (formerly CNF2024) is an inhibitor of Hsp90 (heat shock protein). Hsp90 is a ubiquitous molecular chaperone protein that is involved in folding, activation, and assembly of many proteins, including key mediators of signal transduction, cell cycle control, and transcriptional regulation. Identification of a novel Hsp90 client that plays an important role in the course of a malignancy is of great interest for clinical development of Hsp90 inhibitors. One such client is the tyrosine kinase ζ-associated protein of 70 kD (ZAP-70). ZAP-70 is normally expressed in T cells, where it plays a key role in transducing mitogenic signals from the T-cell receptor complex, but it is also expressed aberrantly in 40% to 50% of cases of B CLL, particularly those cases with unmutated VH genes. ZAP-70+ CLL is more aggressive than ZAP-70 CLL, indicating that ZAP-70 may be a driver of malignancy in this disease. ZAP-70 is physically associated with Hsp90 in B-CLL cells and the protein expression is ablated by treatment with 17-AAG.40 Furthermore, ZAP-70 is not associated with Hsp90 in normal T cells, and its expression is unaffected by 17-AAG in T cells, showing that the protein is a tumor-specific Hsp90 client. Taken together, these data suggest that Hsp90 inhibitors may be beneficial in ZAP-70+ B-CLL by virtue of their ability to induce degradation of this poor prognosis associated kinase. A Phase I multicenter trial with this agent, the first in humans, is underway.

SRC Kinase Inhibitors

Dasatinib is a tyrosine kinase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of CML in patients failing imatinib since it has potent anti-BCR-ABL activity.41,42 In addition it is a SRC kinase inhibitor. Increased SRC kinase activity is present in multiple tumors including CLL. B-cell receptor engagement leads to the phosphorylation of ITAMs located in the cytoplasmic tails of the B-cell receptor. This is accomplished by the Src-related tyrosine kinase Lyn. Recent data has shown that in B-CLL, as compared to normal B cells, the Lyn protein is upregulated and shows a different subcellular localization.43 This upregulation resulted in increased expression in 40 of 40 samples examined and ranged from 2.5- to 5-fold higher than in normal B lymphocytes. Whereas Lyn is concentrated in membrane lipid rafts in normal B cells, the enzyme was present all over the cell surface membrane in CLL cells. This upregulation displayed significant constitutive activity, which led to increased basal tyrosine protein phosphorylation. In addition, the activity of Lyn was decreased by drugs that induced apoptosis in cultured B-CLL cells; Lyn inhibitors reduced the survival of leukemia cells. Researchers recently showed that the use of a potent and selective inhibitor of the Src family tyrosine kinases, PP2, led to cell death in murine B-cell leukemia.44 A Phase II study of dasatinib in relapsed/refractory CLL was presented in a poster at ASH 2007.45 The starting dose of dasatinib was 140 mg daily orally. Nine patients were enrolled and the major toxicity encountered was myelosuppression with grade 3-4 neutropenia in 7 patients and grade 3/4 thrombocytopenia in 5 patients. One patient developed a grade 2 pleural effusion. Evidence of biologic activity was noted with shrinkage in lymph nodes and reduction in lymphocyte counts, although no responses were seen by NCI criteria. Given the ability of this agent to sensitize CLL cells to fludarabine-mediated apoptosis, combination regimens may prove beneficial.

Small Modular Immune Pharmaceutics

TRU16 represents a new type of agent called small modular immune pharmaceutics (SMIP); these contain variable regions derived from specific antibodies and engineered constant regions encoding human IgG-1 domains. Two SMIPs under clinical development include one targeting CD20 (TRU15) and another targeting CD37 (TRU16). CD37 is a heavily glycosylated 40–52 kDa glycoprotein and is a member of the tetraspan transmembrane family. It is strongly expressed on the surface of B cells and mature B-cell leukemia and lymphoma cells. It’s either absent or only minimally expressed on T cells, monocytes, and granulocytes and is absent on NK cells, platelets, and erythrocytes. CLL appears to be a good target for CD37-based therapy because the expression of CD37 is relatively high, particularly when compared with the expression of CD20.46 In vitro CD37 SMIP mediates caspase independent apoptosis against primary CLL cells as well as a variety of B-cell lymphoma lines. This agent effectively mediates ADCC but not CDC and this is primarily effected through NK cells. Apoptosis by CD37-SMIP was directly proportional to CD37 antigen expression and partly dependent on signal transduction and tyrosine phosphorylation of certain proteins. In addition there was synergy between rituximab and CD37 SMIP in lymphoma xenograft models. This encouraging data has led to the initiation of a Phase I trial in CLL.

Conclusions

Given the wealth of new agents in clinical trials physicians could reasonably ask how to decide what trial might be most beneficial to their patient. There is really no simple answer to this. In many cases proximity to centers conducting the trial is, in fact, the most commonly used method of choosing a new agent for a patient. In addition, eligibility can vary widely particularly if the expected side effects of the drugs are different. Thus, drugs expected to be myelo-suppressive might be avoided in patients with baseline cytopenias. In addition, some of the agents that are further along in development have also shown activity in patients traditionally poorly responsive to standard agents such as those with 17p deletions. In particular, flavopiridol produced a 50% response rate in this population. Thus, knowing characteristics of the disease may also help in choosing trials.

In summary, the wealth of new agents being investigated in the treatment of CLL can only lead to further improvements in outcome for such patients, and an increased likelihood of developing curative strategies.

Table 1.

New agents in clinical trials for treatment of chronic lymphocytic leukemia (CLL).

Agent Type Route Doses/schedule Stage of development in CLL 
Abbreviations: FCR, fludarabine, cyclophosphamide, rituximab 
Bendamustine Alkylating agent nucleoside analog? IV 70–100 mg/m2 d x 2 q 4 wks Approved by FDA 3/08 
Lumiliximab Primatized antibody to CD23 IV 500 mg/m2 q 4 weeks with chemotherapy Pivotol trial ongoing FCR ± lumiliximab 
Ofatumumab Humanized antibody to CD20 IV Dose 1: 500 mg/m2
 Doses 2–7: 2000 mg/m2 51% response rate in fludarabine/ alemtuzumab refractory CLL, to be submitted to FDA 
Lenalidomide IMID PO 5–25 mg daily continuously or 3 of 4 weeks Dose finding study nearing completion 
Flavopiridol Cyclin-dependent kinase (CDK) inhibitor IV 30 mg/m2 IV bolus
 30–50 mg/m2 IV for 4 hrs Pivotal trial in fludarabine-refractory CLL ongoing 
SNS-032 CDK inhibitor IV Loading dose then 6-hr infusion
 q 3 weeks Phase I ongoing 
Oblimersen BCL-2 antisense IV 3 mg/kg/d as continuous infusion
 7 days with chemotherapy Pivotal randomized trial of FCR ± oblimersen completed, under FDA review 
Obatoclax BH3-mimetic IV 60 mg over 24 hrs, 1–4 days 45 mg over 3 hrs weekly or days 1, 4, 8, 11 Fludarabine, rituximab and obatoclax trial ongoing 
ABT-263 BH3-mimetic PO Daily Phase I ongoing 
Enzastaurin Protein kinase C inhibitor PO 500 mg daily Phase IA ongoing 
BIIB021 HSP-90 inhibitor PO 21 of 28 days Phase I ongoing 
Dasatinib SRC-inhibitor PO 50–140 mg daily Phase II trials ongoing 
TRU16 Small modular immune pharmaceutic anti-CD37 IV Weekly x 4 Phase I ongoing 
Agent Type Route Doses/schedule Stage of development in CLL 
Abbreviations: FCR, fludarabine, cyclophosphamide, rituximab 
Bendamustine Alkylating agent nucleoside analog? IV 70–100 mg/m2 d x 2 q 4 wks Approved by FDA 3/08 
Lumiliximab Primatized antibody to CD23 IV 500 mg/m2 q 4 weeks with chemotherapy Pivotol trial ongoing FCR ± lumiliximab 
Ofatumumab Humanized antibody to CD20 IV Dose 1: 500 mg/m2
 Doses 2–7: 2000 mg/m2 51% response rate in fludarabine/ alemtuzumab refractory CLL, to be submitted to FDA 
Lenalidomide IMID PO 5–25 mg daily continuously or 3 of 4 weeks Dose finding study nearing completion 
Flavopiridol Cyclin-dependent kinase (CDK) inhibitor IV 30 mg/m2 IV bolus
 30–50 mg/m2 IV for 4 hrs Pivotal trial in fludarabine-refractory CLL ongoing 
SNS-032 CDK inhibitor IV Loading dose then 6-hr infusion
 q 3 weeks Phase I ongoing 
Oblimersen BCL-2 antisense IV 3 mg/kg/d as continuous infusion
 7 days with chemotherapy Pivotal randomized trial of FCR ± oblimersen completed, under FDA review 
Obatoclax BH3-mimetic IV 60 mg over 24 hrs, 1–4 days 45 mg over 3 hrs weekly or days 1, 4, 8, 11 Fludarabine, rituximab and obatoclax trial ongoing 
ABT-263 BH3-mimetic PO Daily Phase I ongoing 
Enzastaurin Protein kinase C inhibitor PO 500 mg daily Phase IA ongoing 
BIIB021 HSP-90 inhibitor PO 21 of 28 days Phase I ongoing 
Dasatinib SRC-inhibitor PO 50–140 mg daily Phase II trials ongoing 
TRU16 Small modular immune pharmaceutic anti-CD37 IV Weekly x 4 Phase I ongoing 

Disclosures
 Conflict-of-interest disclosure: The author receives research funding from Genta, Genentech, Berlex, Biogen Idec, Eli Lilly, Novartis, GeminX, and Bristol-Myers Squibb; serves as a consultant for Genta; and serves on advisory committees for Biogen Idec, Eli Lilly, and GeminX.
 Off-label drug use: The use of every drug discussed is off-label with the exception of bendamustine; lenalidomide is the only drug that has been approved by the FDA so far.

References

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Author notes

1

University of Texas M.D. Anderson Cancer Center, Houston, Texas