Pocket Drug Guide

Posts Tagged ‘Emerging Therapies’

Following the entrance of the protein tyrosine kinase inhibitor imatinib (Novartis’ s Gleevec/Glivec) into the chronic myelogenous leukemia marketplace in 2001, the agent dramatically transformed the market, and protein tyrosine kinase inhibitors have dominated research and development in the field ever since. Since 2001, imatinib has entirely replaced interferon-a as the agent against which all potential newcomers are measured. Several agents that were trialed against interferon-a prior to the launch of imatinib have had to be reevaluated for synergism with imatinib or for activity in imatinib-refractory patients — indeed, the high and durable response rates imatinib has achieved have caused several companies to discontinue development of competing therapies. However, imatinib’s shortcomings define the nature and extent of unmet needs in the treatment of chronic myelogenous leukemia.

The leaders among the emerging therapies for chronic myelogenous leukemia are the protein tyrosine kinase inhibitors BMS-354825 and AMN-107, under development by Bristol-Myers Squibb and Novartis, respectively. Other novel promising agents include the heat-shock protein (HSP) inhibitors, peptide vaccines, farnesyl transferase inhibitors (FTIs), and hypomethylating agents. TABLE:Emerging Therapies in Development for Chronic Myelogenous Leukemia lists the emerging therapies’ stages of development.

Other drugs in development for the treatment of chronic myelogenous leukemia include rapamycin analogues, histone deacetylase inhibitors (HDACIs) such as suberoylanilide hydrox-amic acid (SAHA), and anti-bcl-2 antisense oligonucleotides.

A preclinical study has reported that the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, synergized with imatinib against BCR-ABL-positive myeloid and lymphoid cells and increased survival in a murine chronic myelogenous leukemia model. In addition, rapamycin + imatinib combinations inhibited imatinib-resistant mutants of BCR-ABL.

The possibility of combining HDACIs with the HSP-90 antagonist 17-AAG was raised in a recent study as a novel strategy against BCR-ABL-positive leukemias, including those resistant to imatinib.

Companies developing agents for chronic myelogenous leukemia may apply for orphan drug status for their molecule in any of the major markets. Orphan drug status was introduced in 1983 to give pharmaceutical companies a financial incentive to develop products to treat rare diseases. In the United States, a condition is considered rare if it affects fewer than 200,000 people in the country. Manufacturers of compounds with orphan drug status receive several benefits: seven years of market exclusivity if the product is subsequently approved, a federal tax credit for clinical research costs, exemption from the FDA registration fee, and protocol assistance. They may also be eligible for additional grants. The introduction of orphan drug status has dramatically increased the number of drugs being developed to treat rare conditions.

TABLE . Emerging Therapies in Development for Chronic Myelogenous Leukemia

Compound	Development Phase3	Marketing Company
Protein tyrosine kinase inhibitors
BMS-354825
United States	II	Bristol-Myers Squibb
Europe	II	Bristol-Myers Squibb
Japan	II	Bristol-Myers Squibb
AMN-107
United States	I	Novartis
Europe	I	Novartis
Japan	—	—
Heat-shock protein inhibitors
17-AAG
United States	lb	Kosan Biosciences/NCI/UK Institute of Cancer Research
Europe	—	—
Japan	—	—
Vaccines
AG-858 (HSPPC-70-C)
United States	II	Antigenics
Europe	II	Antigenics
Japan	—	—
PR1 peptide antigen
United States	II	M.D. Anderson Cancer Center
Europe	—	—
Japan	—	—
BCR-ABL fusion peptide vaccine
United States	II	Memorial Sloan-Kettering Cancer Center
Europe	—	—
Japan	—	—
Farnesyl transferase inhibitors
Tipifarnib (R-115777; Zarnestra)
United States	I	Janssen Pharmaceutica/Johnson & Johnson
Europe	—	—
Japan	—	—
Lonafarnib (Sch-66336; Sarasar)		Schering-Plough
United States	I
Europe	—	—
Japan	—	—
Hypomethylating agents
Decitabine (DAC)
United States	II	SuperGen/MGI Pharma
Europe	—	—
Japan	—	—
Antineoplastic agents
Homoharringtonine (Ceflatonin)
United States	II	ChemGenex
Europe	—	—
Japan	—	—
Apoptosis stimulators
Arsenic trioxide (Trisenox)
United States	II	Cell Therapeutics
Europe	—	—
Japan	—	—

^aAgent may be in later stages of development for other indications.

The long median survival of patients with chronic-phase chronic myelogenous leukemia means that initial response rates to investigational drugs are frequently used as surrogate measures of efficacy in clinical trials. These initial response rates have historically been the ability to achieve a complete hematologic response (a white blood cell count between 4,000 and 11,000 per mm³) or complete cytogenetic response (the absence of cells expressing the Philadelphia chromosome). However, because of the success of imatinib at achieving these endpoints, measuring molecular response (a reduction in quantities of BCR-ABL transcripts, as detected by polymerase chain reaction [PCR], is becoming increasingly important for evaluating novel therapies. A complete molecular response occurs when there is no evidence of BCR-ABL transcripts, indicating disease eradication.

Allogeneic stem-cell transplant (allo-Stem-cell transplantation) is the only potentially curative therapy for chronic myelogenous leukemia (chronic myelogenous leukemia). This aggressive approach is appropriate only for young (less than 55 years of age), fit patients with matched donors — a profile that accounts for less than one-third of the chronic myelogenous leukemia population.

Since its launch in 2001, the tyrosine kinase inhibitor imatinib (Novartis’s Gleevec/Glivec), alone or in combination with other agents, has been regarded as the treatment of choice for patients not destined for immediate allo-Stem-cell transplantation. Previously, the standard treatment for patients with newly diagnosed chronic-phase chronic myelogenous leukemia who were ineligible for allo-Stem-cell transplantation was interferon-alpha (interferon-a), either alone or in combination with low-dose cytarabine (LDAC) (Pfizer’s Cytosar-U, generics). interferon-a largely replaced hydroxyurea (Bristol-Myers Squibb’s Hydrea, generics) in the mid-1990s, when clinical trials demonstrated that it induces major cytogenetic responses in about one-third of patients and achieves an overall survival advantage of one to two years compared with hydroxyurea.

When disease progresses to the accelerated and blastic phases, more aggressive chemotherapeutic regimens may be employed (e.g., an anthracycline and cytarabine, high-dose cytarabine alone). In select cases, autologous transplantation is attempted. However, once chronic myelogenous leukemia starts to progress, no treatment is particularly effective. Purely palliative interventions include radiotherapy, splenectomy, and leukapheresis (the mechanical removal of white blood cells).

With the exception of the purely palliative interventions, which we do not discuss further in this report, the agents and procedures employed in the treatment of chronic myelogenous leukemia are described in the following sections. TABLE:Current Therapies Used for Chronic Myelogenous Leukemia lists brand names, marketing companies, dosage, and market availability of agents commonly used in the treatment of chronic myelogenous leukemia. TABLE:Current Therapies Used for Chronic Myelogenous Leukemia illustrates the achievements of current treatment modalities in various patient populations.

Because of the long median survival of patients in chronic-phase chronic myelogenous leukemia, primary endpoints in studies involving these patients are often hematologic and cytogenetic response rates. These response rates act as an indicator of length of survival. As novel drugs are achieving complete hematologic and complete cytogenetic responses, molecular response is becoming an increasingly popular trial end point owing to the fact that a complete molecular response indicates disease eradication. The following types of responses are generally measured:

TABLE. Current Therapies Used for Chronic Myelogenous Leukemia

Agent	Company/Brand	Daily Dose	Availability
Protein tyrosine kinase inhibitors
Imatinib	Novartis’s Gleevec, Glivec	400 mg	US ,France, Germany, Italy, Spain, UK, Japan
Interferons
lnterferon-alpha-2a	Roche’s Roferon-A	5x 106lU/m2	US ,France, Germany, Italy, Spain, UK, Japan
lnterferon-alpha-2b	Schering-Plough’s Intron-A	5x 106lU/m2	US ,France, Germany, Italy, Spain, UK, Japan
lnterferon-alpha-N1	Sigma -Tau’s Humoferon, GlaxoSmithKline’s Wellferon, Sumitomo’s Sumiferon	5x 106IU /m2	Italy, Spain, Japan
Interferon-alpha	Janssen-Cilag’s Cilferon-a, Otsuka’s Oif	5x 106IU /m2	Italy, Japan
Cytotoxic agents
Cytarabine	Pfizer’s Cytosar-U, generics	20 mg/m2	US ,France, Germany, Italy, Spain, UK, Japan
Hydroxyurea	Bristol-Myers Squibb’s Hydrea, generics	40-50 mg/kg	US ,France, Germany, Italy, Spain, UK, Japan
Busulfana	GlaxoSmithKline’s Myleran	0.1 mg/kgb	US ,France, Germany, Italy, Spain, UK, Japan

^aBusulfan is now rarely used in the treatment of chronic myelogenous leukemia but is included in the table for historical reasons. ^bWhen used in myeloablative regimens prior to allogeneic progenitor stem-cell transplantation, a dose of 8-16 mg/kg is given over four days.

TABLE. Achievements of Current Therapies Used for CML, 2005: Benchmarks for Evaluation of Emerging Therapies

Setting	Treatment	Four-Year Survival/ Ten-Year Survival (%)	CHR(%)	cytogenetic response(%)	PFS After 18 Months/ 42 Months (%)	Median Survival (months)
Late chronic-phase chronic myelogenous leukemia after failure with interferon-a therapy	Imatinib 400 mg dailya		95	41	89/—	—
Early chronic-phase chronic myelogenous leukemia	Imatinib 400 mg dailyb	—	97	76	97/90c	—
Early chronic-phase chronic myelogenous leukemia	interferon-a 5 MIU/m2 dailyd	—	80	26e	—	89
Chronic phase-chronic myelogenous leukemia	interferon-a 9 MIU/m2 dailyf	—/47g	—	10	—	104g
Early chronic-phase chronic myelogenous leukemia	interferon-a + LDAC (10 mg)h	70/—	92	50	—	—

A 42-month follow-up showed PFS of 90% for patients who had achieved cytogenetic response within 12 months of beginning therapy. For patients not achieving cytogenetic response, PFS was 75%.

^dKantarjian HM, 1996.

^e Five-year survival for patients who achieved cytogenetic response was 90%.

^fThe Italian Cooperative Study Group, 1998.

9 Data for Sokal’s low-risk patients.

^hKantarjian HM, 1999.

cytogenetic response = Complete cytogenetic response.

CHR = Complete hematologic response.

CML= Chronic myelogenous leukemia.

INF-α =interferon-a

LDAC = Low-dose cytarabine.

PFS = Progression-free survival.

•  Hematologic response. A complete hematologic response (CHR) is the absence of disease-related symptoms and splenic enlargement, normalization of the white blood cell count (i.e., a count between 4,000 and 11,000 per mm³), and a normal differential white blood cell and platelet count. If only some of these criteria are met, the response may be classed as partial.

•  Cytogenetic response. A complete cytogenetic response is the absence of detectable Ph-positive cells (cells expressing the Philadelphia chromosome) in metaphase. If a percentage of Ph-positive cells is detectable, the response may be classed as a major cytogenetic response (or partial cytogenetic response) (1-34% Ph-positive cells); minor cytogenetic response (35-94% Ph-positive cells); or no cytogenetic response (95-100% Ph-positive cells). Cytogenetic responses are clinically important because they are associated with better prognosis.

• Molecular response. A molecular response is the disappearance or reduction in quantities of BCR-ABL transcripts (i.e., amount of BCR-ABL oncoprotein). Monitoring the level of BCR-ABL is a way of predicting long-term patient outcomes. A thousandfold (>3 log) reduction in levels of BCR-ABL is defined as a major molecular response. The authors of a study (involving more than 1,000 chronic myelogenous leukemia patients) estimated that 100% of chronic myelogenous leukemia patients who have achieved a cytogenetic response and who achieve a major molecular response at 12 months will remain progression-free after another year. A complete molecular response is when there is no evidence of BCR-ABL transcripts, indicating disease eradication. The levels of BCR-ABL transcripts are usually measured by a quantitative real-time polymerase chain reaction (PCR) assay.

Rituximab (Rituxan, MabThera) is under development by Biogen Idee and Genentech in collaboration with Roche, Chugai, and Zenyaku Kogyo. This antibody is in Phase III clinical trials in the United States and Europe.

Rituximab is a mouse/human chimeric MAb directed against the cluster of differentiation (CD) 20 molecule. CD20 is a calcium channel that interacts with the B-cell immunoglobulinreceptor complex and is expressed on both normal and malignant B cells, making it an ideal target for monoclonal antibodies therapy in B-cell disorders. After binding to CD20, rituximab is thought to deplete B cells in a number of ways, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and alteration of calcium flux and factors involved in apoptosis. This antibody has been launched for the treatment of relapsed or refractory low-grade or follicular, CD20-positive B-cell non-Hodgkin’ s lymphoma (B-NHL).

Rituximab is under investigation in many chronic lymphocytic leukemia clinical trials both as a single agent and in combination with chemotherapy as well as in first- and subsequent-line settings.

The role for rituximab as a single agent in chronic lymphocytic leukemia is controversial. Previous studies showed an overall response rate of only 11% and 25%, comparing poorly with the rate of 40-60% reported for follicular NHL. However, a recent Nordic multicenter study yielded improved results. Twenty-four chronic lymphocytic leukemia patients of median age 57 (47-72) with active disease (3 Binet A, 7 Binet B, 14 Binet C) who had previously been heavily treated with a variety of chemotherapy regimens were given the standard dose of 375 mg/m² rituximab once weekly for four doses. The primary objectives this study addressed were response rate, quality, and duration; secondary objectives were to analyze the feasibility and tolerability of rituximab therapy.

Eight of 23 evaluable patients (35%) achieved a partial response (PR), with a median duration of 12.5 weeks. A drop of at least 50% in blood lymphocyte count occurred in 17/21 (81%) patients who had pretreatment lymphocytosis, and 10 patients achieved a normal blood lymphocyte count (< 3 x 10⁹ L^_1). Of the 15 patients who did not achieve a PR with rituximab, 9 had at least a 50% drop in lymphocyte count and 3 achieved a normal count.

TABLE. Emerging Therapies in Development for Chronic Lymphocytic Leukemia

Compound	Development Phase	Marketing Company
Monoclonal antibodies
Rituximab (Rituxan, MabThera)
United States	III	Biogen Idec/Genentech
Europe	III	Roche/Chugai/Zenyaku Kogyo
Japan	—	—
Lumiliximab (IDEC-152)
United States	II	Biogen Idee
Europe	—	—
Japan	—	—
Antisense oligonucleotides
Oblimersen (Genasense)
United States	Ill	Genta/Aventis
Europe	—	—
Japan	—	—
Cell-cycle inhibitors
Alvocidib (Flavopiridol)
United States	II	National Cancer Institute
Europe	III	—
Japan	—	—
Immunostimulatory therapies
Xcellerate
United States	I/I I	Invitrogen (formerly with Xcyte Technology)
Europe	—	—
Japan	—	—
ISF-154
United States	II	Tragen/University of California at San Diego
Europe	—	—
Japan	—	—
Immunotoxins
Denileukin diftitox (Ontak)
United States	II	Ligand Pharmaceuticals
Europe	—	—
Japan	—	—
Apoptosis inducers
SDX-101
United States	Ib/lla	Salmedix
Europe	—	—
Japan	—	—
Motexafin gadolinium (Xcytrin)
United States	II	Pharmacyclics
Europe	—	—
Japan	—	—
Selective apoptotic antineoplastic drugs
OSI-461
United States	Ila	OSI Pharmaceuticals
Europe	—	—
Japan	—	—

Seventy-five percent of patients experienced rituximab-related side effects, half of which were related to the first infusion only. The most common toxicities were World Health Organization (WHO) grade 1/2 chills and grade 2 fever. In previous studies, the severe infusion-related toxicities reported had been specifically linked to a high tumor burden. Mainly mild/moderate side effects were observed in this study, even in patients with extremely high lymphocytosis (223 x 10⁹ L^_1). This study demonstrates that single-agent rituximab does have some activity in heavily pretreated chronic lymphocytic leukemia patients, although the response is minor and of short duration.

The reasons rituximab is more effective in NHL than in chronic lymphocytic leukemia are unclear. Circulating soluble CD20 and a high tumor burden, both of which “mop up” rituximab, are potential mechanisms/states by which the antibody is rapidly cleared from the blood; this theory is supported by the observation of altered pharmacokinetics and increased response rates with higher doses of rituximab in chronic lymphocytic leukemia. In addition, chronic lymphocytic leukemia cells have a much lower density of surface CD20 than do NHL cells, although no correlation between density and response to therapy has been found.

Rituximab has been used as a first-line, single-agent therapy, and limited clinical data suggest it may be more effective than as second- or third-line therapy. In one trial, treatment-naive patients with stage II — IV small lymphocytic lymphoma or chronic lymphocytic leukemia received 375 mg/m² rituximab weekly for four doses. Patients who achieved an objective response (PR or complete response [CR]) or stable disease at reevaluation after six weeks continued maintenance courses of rituximab using the standard four-week schedule every six months for a maximum of four courses. Twenty-two of forty-three patients (51%) had an objective response at week 6, and the remaining patients had stable disease.

Twenty-eight patients (65%) went on to receive maintenance rituximab therapy. With a median follow-up of 24 months, the response rate was 58% (9% CR). Median progression-free survival (PFS) was 19 months with a one- and two-year actuarial PFS of 63% and 49%, respectively. Two patients had a reversible grade 3 infusion-related toxicity with the first course of rituximab. The increase in overall response rate is encouraging, but the small CR indicates that single-agent rituximab will not result in long-term survival in chronic lymphocytic leukemia.

Treatment for chronic lymphocytic leukemia is generally reserved for patients with symptoms of advanced disease, although rituximab therapy may be effective in early-stage disease for those at risk of progression. The overall response rate in 21 evaluable patients with Rai stage 0-11 and beta-2 microglobulin levels >2 mg/dL was 90% (19% CR, 19% nodular PR [nPR], 48% PR). The clinical significance of these results is unclear because a longer follow-up is required to analyze time to progression and long-term survival.

The dose and schedule of administration for single-agent rituximab therapy as both first and subsequent lines of therapy are under investigation in dose-escalation studies in an attempt to increase response rates. Researchers have reported using doses of up to 2,000 mg/m²/week in four patients. Such studies are ongoing to optimize clinical responses.

The most active area of research involving rituximab is in combination with chemotherapy. A randomized Phase II study of fludarabine in combination with concurrent rituximab versus sequential rituximab was conducted in 104 previously untreated chronic lymphocytic leukemia patients. The treatment schedule for sequential therapy involved patients receiving 25 mg/m² fludarabine for 5 days, repeated every 28 days for six cycles. Four weekly doses of 375 mg/m² rituximab were administered to patients who achieved stable disease or better, following a two-month rest period and restaging. The concurrent schedule followed the same pattern as the sequential schedule, with the addition of rituximab to each fludarabine cycle. It is important to note that patients receiving concurrent administration received 11 doses of rituximab (seven in combination with fludarabine and four as consolidation after this therapy) compared with only 4 doses in the sequential arm.

Concurrent administration of these two agents demonstrated superior response rates when compared with the sequential arm (47% CR versus 28% CR, 43% PR versus 49% PR, respectively). Neutropenia was more common in the concurrent arm, but infectious complications occurred at similar frequencies in both schedules. Additional data presented at the American Society of Hematology (ASH) meeting in 2003 determined that adding rituximab to fludarabine did not significantly increase the risk of infection.

This encouraging study establishes that concurrent administration of rituximab and fludarabine produces CR rates superior to those achieved with fludarabine alone. To date, the impact of rituximab on improving progression-free survival and overall survival compared with fludarabine monotherapy has not been analyzed in a randomized trial. A retrospective comparison with data from 179 patients enrolled in the North American Intergroup Study CALGB 9011 who received fludarabine monotherapy showed that CR, PR, and two-year performance-free and overall survival rates were significantly superior in the fludarabine/rituximab group.

The triple-drug regimen fludarabine/cyclophosphamide/rituximab (FCR) is also under intense investigation. In one study, 202 previously untreated chronic lymphocytic leukemia patients received FCR (25 mg/m²/day F for three days; 250 mg/m²/day C for three days; 375-500 mg/m² R on day 1). Results showed 68% CR, 18% nPR, and 14% PR. The study also analyzed patients for the presence of minimal residual disease (minimal residual disease) and found that the FCR regimen produced a high level of minimal residual disease-negative complete remissions. A longer follow-up will determine whether minimal residual disease-negative CR is more durable than minimal residual disease-positive CR.

At the 2003 ASH meeting, the results of a sequential FCR program also were presented. Thirty treatment-naive chronic lymphocytic leukemia patients received six cycles of standard fludarabine therapy, then 3 g/m² cyclophosphamide every three weeks for three cycles, and finally standard rituximab therapy. CR and PR rates of 57% and 29% (10% nPR and 19% PR), respectively, were achieved.

The FCR regimen has also succeeded in patients with relapsed or refractory chronic lymphocytic leukemia. In one trial, 179 patients who had already received between one and three courses of therapy were treated with FCR and achieved responses of 25% CR, 16% nPR, and 32% PR. Minimal residual disease (analyzed by polymerase chain reaction) was absent in 33% of CR patients. Therapy was well tolerated, and 62% of patients completed four or more cycles of this regimen. Forty-one percent of patients experienced fever and chills with the first rituximab infusion, and a minority experienced hypotension, nausea, and dyspnea (6%, 9%, and 3%, respectively). Hematologic toxicities included neutropenia in 30% of cycles and thrombocytopenia in 12%.

A comparative, retrospective analysis of patients treated with fludarabine (plus or minus prednisone), fludarabine/cyclophosphamide, or FCR demonstrated increased CR, overall response, and median survival in patients treated with FCR.

The purine analogue pentostatin (SuperGen Warner-Lambert’s Nipent) has shown significant activity and minimal toxicity when combined with cyclophos-phamide in chronic lymphocytic leukemia patients. In one trial, rituximab was added to this combination (known as the PCR regimen) and administered to previously untreated chronic lymphocytic leukemia patients. Preliminary data on 15 patients presented at ASH 2003 revealed 40% CR, 13% complete clinical response, and 47% PR. Most toxicities were grade 1 or 2, although eight patients suffered grade 3 anemia and hypotension and one patient developed grade 4 sinus bradycardia.

In another trial, 20 patients with relapsed or refractory disease were treated with the PCR regimen; the response rates were 20% CR, 10% nPR, and 50% PR. Grade 3/4 neutropenia occurred in 45% of patients, grade 3/4 thrombocytopenia in 5%, and infections in 15%. Preliminary data suggest this regimen is well tolerated, but further analysis is needed to determine both response rates and toxicity profiles compared with those associated with fludarabine-containing regimens.

The combination of rituximab and another MAb, alemtuzumab is under investigation for relapsed and refractory chronic lymphocytic leukemia. Nine patients underwent treatment with this combination, and preliminary data showed a 44% CR and 23% PR rate. Nonhematologic toxicities were grade 2 or less, and infection occurred in 44% of patients. Another study presented at ASH 2003 failed to show any complete or partial remissions in 11 patients with relapsed or refractory chronic lymphocytic leukemia who were treated with alemtuzumab and rituximab in combination. Further investigation into the combination of these antibodies is needed to determine their potential efficacy.

In an attempt to improve upon the success seen in FCR, the M.D. Anderson Cancer Center is pioneering a trial examining a regimen consisting of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (known as the CFAR regimen). Only two relapsed/refractory patients have completed all courses, and both achieved PRs. Four patients on continuing therapy were evaluated after three courses, and responses included one CR, one nPR, and two PRs. Seven patients came off therapy because of treatment failure (n = 2), infection (n = 1), noncompliance (n = 1), or at their own request (n = 2); one death occurred as a result of disease-related liver failure. Early analysis indicates good response with substantial but expected toxicities.

Rituximab enjoys extensive off-label usage in the United States, mainly in the first- and second-line chronic lymphocytic leukemia settings in combination with chemotherapy. In Europe, however, the use of rituximab is restricted by a lack of reimbursement owing to its experimental status and high cost.

Nonpharmacological Approaches

Currently, the only potentially curative option for chronic lymphocytic leukemia is stem-cell transplantation, which is still a highly experimental approach. There are two main types of stem-cell transplantation: autologous, in which the patient’s own stem cells are harvested and then returned to his or her body, and allogeneic, in which a related or unrelated donor is the source of stem cells.

Allogeneic stem-cell transplantation carries the risk of the patient developing graft-versus-host disease, a condition in which the donated stem cells trigger an immune response against the patient. This complication can be fatal; indeed, allogeneic stem-cell transplantation carries a high risk of mortality. However, allogeneic stem-cell transplantation also provides a higher chance of cure, partly because of the graft-versus-leukemia effect, where by the donor’s stem cells trigger an immune response against the patient’s own leukemia cells. There is no risk of graft-versus-host disease in autologous stem-cell transplantation, but neither does the beneficial graft-versus-leukemia occur. Another disadvantage of autologous stem-cell transplantation is that harvested and donated stem cells may be contaminated with tumor cells, which are then returned to the patient. The relapse rate for patients treated with autologous stem-cell transplantation is high.

Current research is investigating allogeneic stem-cell transplantation in a nonmyeloablative, rather than fully ablative, setting. Nonmyeloablative stem-cell transplantation uses less intensive conditioning regimens that rely on immunosuppression rather than cytotoxicity. In general, stem-cell transplantation is used in a minority of patients who are young and have poor prognostic factors or as a last-chance option for patients with advanced disease.

Emerging Therapies

The emerging therapy market for B-cell chronic lymphocytic leukemia (chronic lymphocytic leukemia) is extremely sparse. Only two agents are in Phase III development, and of the agents in Phase II development, data are available on only a minority. Further, progress on agents such as Novartis’s protein kinase inhibitor midostaurin (PKC412) and Bioenvision/Ilex’s antimetabolite clofarabine (Clofarex) has not been published. Two immunotherapeutic approaches are in Phase II development for chronic lymphocytic leukemia: the University of Southampton in the United Kingdom is developing a DNA vaccine that produces anti-idiotype antibodies conjugated to tetanus toxin, and Immuno-Designed Molecules is developing IDM-4, a macrophage-activated killer-cell bispecific antibody. No clinical data are available on either of these agents. The proteasome inhibitor bortezomib (Millennium’s Velcade) has been extremely successful in the treatment of multiple myeloma and is under investigation for non-Hodgkin’s lymphoma. However, clinical trial data demonstrating its effect in chronic lymphocytic leukemia have not been published. For now, the focus remains fixed on monoclonal antibodies (monoclonal antibodies) to improve both response and overall survival rates in chronic lymphocytic leukemia.

TABLE. Emerging Therapies in Development for Chronic Lymphocytic Leukemia summarizes drug therapies in development for chronic lymphocytic leukemia.