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Cytokines in lymphoma

Commentary on: Fabre-Guillevin et al. Aggressive non-Hodgkin's lymphoma: Concomitant evaluation of interleukin-2, soluble interleukin-2 receptor, interleukin-4, interleukin-6, interleukin-10 and correlation with outcome. Leuk Lymphoma 2006;47:603 – 611.

DAVID JOSKE

Sir Charles Gairdner Hospital and University of Western Australia Department of Medicine, WA, Australia

With our deepening understanding of the immune system, and the clinical success of monoclonal antibodies, tumour immunology is undergoing a revival of scientific interest. Cytokines are secreted or membrane-bound proteins that regulate the growth, differentiation and activation of immune cells. Inevitably then, research is also gaining pace into the role played by cytokines in cancer, especially lymphomas, which are, after all, cancers of the immune system. In this issue of Leukemia and Lymphoma, Fabre-Guillevin et al. [1] report their finding that serum levels of soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) are of prognostic significance in aggressive lymphomas. How important is this finding? How far have we come in our understanding of the role of cytokines in the pathogenesis and treatment of cancer?

Although each cytokine differs in its cell of origin and effects, collectively as a group, like growth factors, they have some biological redundancy and pleiotropism. Moreover, the overall cytokine environment significantly alters the overall effect of individual cytokines. Simplistically they “hunt in packs” and certain cytokines are associated with skewing of the adaptive immune response in one of two principal directions: the so-called Th1 and Th2 responses. Activation of CD4+ Th1 cells leads to release of IL-2, IFN-γ, IL-12, and IL-18 and activation of cytotoxic T lymphocytes (CTL). The Th2 response, leading to enhancement of antibody secretion, involves the B-cell tropic cytokines IL-4, IL-6, IL-10, and IL-13.

Fabre-Guillevin et al. [1], using commercially available ELISA kits, measured serum levels of IL-2, sIL-2R, IL-4, IL-6, and IL-10 in 116 previously untreated patients with aggressive non-Hodgkin's lymphoma (NHL). The patient group (median age 60 years) did not include any cases of diffuse large B cell NHL and 56% had IPI scores of 0 or 1. Potentially importantly, details of treatment are not provided. In univariate analysis, sIL2R and IL-6 levels were predictive of complete remission, overall survival (OS), and failure-free survival. For example, median OS in those with a high level of sIL-2R was 22 months, compared to 95 months in those with a low level. What this means in biological terms is a fascinating question; sIL2R is a marker of lymphocyte activation and IL-6 is tropic for neoplastic B cells. The apparent prognostic impact of any cytokine, however, was lost in multivariate analysis suggesting other biological factors are also at play in determining outcome.

In those with low- and high-intermediate IPI scores of 2 and 3, small differences in clinical outcomes were also found according to sIL-2R and IL-6 levels, and the authors posit that measuring these may aid stratification of patients for treatment of higher intensity. That time has probably not yet arrived. Prognostication in lymphoma using cytokine levels remains a controversial area ([1] includes an excellent summary of published results to date). This is partly because of the difficulty in interpreting serum levels of cytokines clinically. In this study, the authors established reference ranges in 204 lymphoma patients including 88 with low-grade NHL. We may ultimately require reference ranges for each nosological lymphoma entity and for the normal population. We also know little about how cytokine levels may fluctuate diurnally, and change longitudinally during treatment. Whilst these might be a useful marker of disease resistance, early positron emission tomography (PET) scanning is already emerging as a powerful and more readily available measure (discussed by Sweetenham [2]).

Cytokines could affect cancer development in several ways (see [3] for a review). Firstly, they may have a profound effect upon the tumorigenic microenvironment. A probable example is chronic gastritis due to Helicobacter pylori and the subsequent development of gastric mucosal-associated lymphoid tissue (MALT) lymphoma. Secondly, they may directly or indirectly promote tumor cell growth. With regard to lymphomas, IL-2, IL-6, and IL-10 have been shown to individually and additively stimulate the proliferation of normal and neoplastic B cells (IL-4 is tropic for normal B-cells only). Cytokines may also mediate an interaction between tumor cells and the microenvironment that is essential for tumor growth [4].

Thirdly, they may abrogate the immune response to the tumor cell population within the microenvironment. Although tumor cells typically lack important co-stimulatory molecules such as B7 family members, both Th1 and Th2 responses are thought to be important in the anti-tumor immune response. Two examples of the clinical importance of this can be given. A recent meta-analysis concluded that IFN-α (leading to Th1 response augmentation), given with chemotherapy, prolongs survival in low grade NHL [5]. A microarray approach has shown that the presence of a T-cell immune response signature in the diagnostic tissue biopsy is predictive of prognosis in follicular NHL, independent of established prognostic markers [6]. Recently, differences in immune responses to localised versus metastatic colorectal cancers have been shown [7].

Fourthly, cytokine polymorphisms—genetic versions of cytokines with varying ability to respond to stimuli—can predispose to disease. We and others have shown an association between polymorphisms of IL-10 and the development of aggressive NHL [8],[9]. Very recently this has been confirmed and extended to also implicate a tumor necrosis factor (TNF) polymorphism by the InterLymph Consortium in a study of 3586 cases of NHL [10]. Fifthly, cytokines may provide important markers of prognosis in lymphoma, as in the paper [1] under discussion here. Finally, cytokines can be administered therapeutically (IFN, IL-2), and used to generate ex-vivo CTL (as in melanoma and NHL vaccine trials).

Ultimately the main research problem in this area remains that of understanding and recreating the complexities of the tumor microenvironment. Fabre-Guillevin et al. [1] provide a fresh impetus to study the role of cytokines in lymphomagenesis and disease progression.

David Joske

Sir Charles Gairdner Hospital

Hospital Avenue, Nedlands WA 6009, Australia

Tel: [phone], Fax: [phone]

E-mail: [email protected]

Dendritic cells in leukemia and lymphoma

Commentary on: Fiore et al. Dendritic cells are significantly reduced in non-Hodgkin's lymphoma and express less CCR7 and CD62L. Leuk Lymphoma 2006;47:613 – 622.

DEREK HART & DEON VENTER

Mater Medical Research Institute, South Brisbane, Queensland, Australia

Dendritic cells (DC) are specialized antigen presenting cells (APCs), which are present in almost every tissue in the body. They are derived from both myeloid and lymphoid hematopoietic progenitors and have been further sub-divided into an increasing number of sub-sets [1]. Some, such as Langerhan's cells, have unique characteristics, particularly relevant to their specific environment. Myeloid (CD11c + ) DC (MDC) act as surveillance cells, which respond to environmental influences and pathogens, discriminating between self and non-self to generate an effective immune response. MDC use a range of receptors to take up potential antigenic material and direct it to specialized antigen processing pathways. These include microbial-directed lectin-like molecules, notably the macrophage mannose receptor (MMR), DC-SIGN, langerin and an increasing number of novel lectins such as DCL-1 [2]. The lymphoid-derived DC (CD 123hi/BDCA-2+) or plasmacytoid DC (PDC) have very different characteristics to MDC, notably their capacity to produce large amounts of interferon-α. PDC enter lymph nodes by the high endothelial venule as opposed to the afferent lymphatics. Both types of DC show remarkable plasticity in their responses, but differ in their expression of the Toll-like receptors (TLR), which act as sensors for pathogenic exposure and initiate activation of DC. The migration of DC through the tissues and central immune system is regulated by the expression of adhesion molecules (e.g. CD62L) and chemokine receptors (e.g CCR7). DC also produce chemokines that recruit the appropriate lymphocytes into their cellular/cytokine micro-environment.

Studies of fundamental APC biology have begun to provide insights as to how to initiate immune reactions and suppress them for the benefit of the patient, as well as to provide at least partial answers to the patient's question ‘why doesn't my immune system protect me against the cancer?’. The answer is that it probably does, but that, like viruses, cancers evolve many mechanisms to evade the immune system. One of their most effective methods of frustrating appropriate immune responses is to compromise the biology of DC. Thus, deficiencies in bone marrow DC production, migration, antigen uptake, activation and costimulation/cytokine release have all been described in cancers [1]. Active immunotherapy, using DC loaded in vitro with tumor-associated antigens (TAA) to vaccinate the patient may reverse these defects, particularly in a minimal residual disease environment. This approach has provided initial encouraging results in metastatic melanoma and the lymphoproliferative disorders [1].

To fix a problem first define it. Discriminating between the DC sub-sets and counting these cells accurately in blood is now possible [3]. Markers such as CD83 and CMRF-44 provide an indication as to whether the DC have been activated [4]. Studies on malignant tissue have been more difficult because many of the antibodies used to distinguish DC sub-sets recognize molecular epitopes that are damaged by formalin fixation and paraffin embedding and resist current antigen retrieval protocols. Given the interest in DC, one can anticipate that better immunohistochemical reagents will soon emerge and reagents such as the anti-restin (p55) antibodies that work well on paraffin sections will have great currency. The current interest in identifying biomarkers using contemporary proteomic technologies should provide additional markers for DC activation and competence.

The existing literature reflects variable degrees of alterations to DC biology in the leukemias and lymphomas: MDC production is compromised in the acute leukemias, whilst DC do not seem to be directly involved in chronic myelomonocytic leukemia [5]. The new entity of CD4 + CD56 + lineage negative leukemia/lymphoma appears to be derived from malignant early PDC [6]. DC numbers decline in advanced multiple myeloma and defects in DC activation are related to the stage of the disease [7]. The studies in non-Hodgkin lymphoma (NHL) by Fiore et al. [8] are, therefore, timely for what they reveal about DC biology in response to the lymphoma. They used immunohistological techniques and flow-cytometry to analyse DC in 55 NHL and 33 reactive lymph nodes. Although absolute quantitative counts were not available to compare with blood DC counts, it does appear that DC numbers are proportionately reduced in NHL but, as the authors acknowledge, this may be a dilutional phenomenon. Both MDC and PDC sub-sets were involved but their relative ratios were not altered. BDCA-1 (CD1c) was confirmed to identify a sub-set of MDC and BDCA-2, the greater proportion of PDC; both of these markers showed significant co-expression with S100 cytoplasmic staining in frozen sections. DC were prominent around high endothelial venules and in the peri-follicular areas in NHL but lesser numbers were noted in tumor tissue of the two cases with partial nodal involvement. There was minimal evidence of activation, perhaps indicative of a relatively defective response. Perhaps most significant was the reduction in density of the CCR7 and CD62L on MDC on the PDC. These changes may cause reduced DC homing to lymph nodes and, by compromising the effectiveness of this aspect of DC function, contribute to the lack of immunological control of NHL.

Can this be reversed to any effect? Probably not specifically, but it may be improved by therapies that modify the immune environment. However, given the success of passive immunotherapy in NHL it begs the question as to how can we exploit active DC immunotherapy, perhaps in conjunction with passive antibody (and cytotoxic T-cell) therapy to eradicate the disease long-term.

Professor Derek Hart

Mater Medical Research Institute

Level 3, Aubigny Place

Raymond Terrace

South Brisbane, Q 4101

Australia

E-mail: [email protected]

Defining the cost of cure: Infertility among female survivors of lymphoma

Commentary on: Elis et al. Fertility status among women treated for aggressive non-Hodgkin's lymphoma. Leuk Lymphoma 2006;47:623 – 627.

CATHARYN J. STERN¹ & JOHN F. SEYMOUR²

¹Reproductive Services, Melbourne IVF, The Royal Women's Hospital, Melbourne, Australia, and ²Haematology Department, Peter MacCallum Cancer Centre, Victoria, Australia

The likelihood of cure for patients with lymphoproliferative disorders, particularly Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) has increased steadily over recent decades, and for the most favorable sub-groups, now exceeds 90%. Simultaneously, there has been increasing recognition of the spectrum, frequency, and severity of the late adverse effects of the therapies utilized to achieve cure, including neuropsychological, endocrine, cardiac, hematological, and a heightened risk of a range of subsequent malignancies [1]. Thus it is an appropriate time to pause and count the cost of cure.

One of these costs is impaired female fertility. While not life-threatening, as are some other late effects of therapy, and at times not given high priority by treating physicians [2], infertility is a very important late effect, as it has a substantial adverse impact on the quality of life of survivors, and is considered a major issue by many patients themselves [3].

There are many reasons why it is essential to be able to provide female patients with lymphoma with accurate data on the likelihood of impaired fertility associated with a proposed treatment program. Firstly, the patient has an intrinsic right to balance their personal risks and benefits with any proposed therapy. Secondly, as stated above, cure is the likely outcome for most patients, hence irreversible adverse effects, such as infertility are important to minimize. Thirdly, and most importantly, there are a number of potentially effective methods available to address the risk of infertility in such patients, as recently reviewed in detail elsewhere [4]. This includes the option of harvesting and cryopreservation of ovarian tissue, given the recent reports of successful human pregnancies following reimplantation [5]. In the context of lymphomas, the issue of potential disease contamination of harvested tissue needs to be considered [6]. Obviously these issues are very complex, and it is highly desirable for each unit which treats such patients to have an identified referral path to a fertility specialist with an interest in the area, and ensure involvement early in the process of staging and treatment planning.

It is in this context that we must consider the analysis of Elis et al. (this edition of Leukemia & Lymphoma) [7]. This group of investigators from Israel have made major contributions to the field of fertility preservation in female cancer patients and on this occasion they retrospectively evaluated the fertility status of 36 women aged <40 treated for histologically aggressive lymphoma with anthracycline-based regimens, mainly CHOP and VACOP-B. While most current patients with aggressive NHL will be treated with CHOP-R, possibly at 14, rather than 21-day intervals, the impact on fertility is most likely influenced by the total dose of genotoxic drugs, rather than dose density, and Rituximab is unlikely to adversely impact fertility. Thus the reported results are probably indicative of outcomes with contemporary regimens. However, there are five cautions we must consider. Firstly, 92% of the cohort of Elis et al. had localized disease, and some may have received abbreviated chemotherapy, although the mean total number of chemotherapy cycles was 5.6. Secondly, there is ample data from patients with breast cancer suggesting that there is a strong gradient of risk of infertility according to age at treatment, even within the relatively narrow range of 30 – 40 years [8]. The mean age at diagnosis of patients analyzed in the current report was relatively young at 28 years, but the distribution was not provided. Thirdly, three analyzed patients received GnRH analogs during therapy, which these authors have previously reported to reduce the risk of infertility with chemotherapy [9]. Fourthly, the ovarian function was only assessed by descriptions of cyclicity, rather than by the more accurate methodologies of serum FSH, inhibin and AMH levels and ultrasound assessment of ovarian volume and antral follicle counts. Lastly the assessment of ovarian function was performed early, often only 12 months after completion of chemotherapy. This assessment would necessarily be of acute versus more permanent ovarian failure, so the low prevalence of amenorrhea is reassuring.

While cognisant of these issues, 63% of patients resumed spontaneous menses within 3 months of discontinuation of therapy, 50% conceived naturally, and only two patients developed amenorrhea (5.5%; 95% confidence intervals 0.7 – 18.7%), both of whom were 40 years old. Importantly, resumption of menses is not equivalent to maintaining normal fertility, and it is probable that a proportion of women who do maintain fertility in the short-term, are destined to suffer premature menopause [10], making family planning issues even more complex for survivors.

The authors conclude that the low rate of gonadal dysfunction they have described, suggests that “fertility-preserving techniques should be reserved for high-risk sub-groups such as older women”. However, the limitations described above, make the broad acceptance of such a conclusion somewhat premature. In particular, larger studies with more comprehensive evaluation of ovarian function are needed to better define the risk for more precise age cohorts, and to evaluate the infertility risk for more recently developed intensive therapies [11]. Ultimately, within the resource limitations of the treating institution and society more broadly, the individual woman's wishes should be respected, and for some, even a 10% risk of permanent infertility may be unacceptable [12].

Dr. John F. Seymour

Department of Haematology

Peter MacCallum Cancer Centre

St. Andrew's Place

East Melbourne, Vic 3002, Australia

Tel: [phone], Fax: [phone]

E-mail: [email protected]

Something old, something new …

Commentary on: Di Renzo et al. Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) as salvage therapy in relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL): Results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi. Leuk Lymphoma 2006;47:473 – 479

SONALI SMITH

Lymphoma Program, University of Chicago, Chicago, USA

There is an unmet clinical need for new and effective treatments for patients with aggressive lymphomas who either are ineligible for transplantation or who relapse after autologous stem cell transplantion. In this issue of Leukemia and Lymphoma, the Gruppo Italiano per lo Studio dei Linfomi (GISL) describe their results using a novel combination of vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) in a group of patients with both relapsed and refractory aggressive NHL. Their regimen is based on the premise that an effective, outpatient treatment is needed for this group of patients and that these agents do not generally overlap with chemotherapeutics typically used in the front-line setting.

Given the multitude of new and old drugs being tested in relapsed NHL, it is worthwhile to pause and evaluate this regimen carefully. Modern salvage regimens are typically either ifosfamide-based (ICE, IE, MINE) or platinum-based (ESHAP, DHAP). As the current body of literature reflects, there appears to be significant interest in developing gemcitabine-based regimens. Gemcitabine is an attractive agent based on its tolerability, outpatient ease of administration and non-overlapping mechanism of action with CHOP-like regimens. Despite this enthusiasm, single-agent gemcitabine has only modest activity in aggressive NHL with overall response rates of ∼20 – 30% and only rare complete remissions [1],[2]. Combinations of gemcitabine with other agents may be more promising. The largest series is reported by the NCI Canada in which 51 patients with relapsed and refractory aggressive NHL were treated with the GDP regimen (gemcitabine, dexamethasone and cisplatin) [3]. There were eight complete responses and 17 partial responses for an overall response rate of 49%.

Others have combined gemcitabine with vinorelbine and show quite similar results to the GISL study. The Hellenic Cooperative Oncology Group demonstrated an overall response rate of 50% using gemcitabine 1000 mg/m² with vinorelbine 30 mg/m² on days 1 and 8 of a 21 day cycle [4]. A German group used the same regimen and added prednisone 100 mg per day on days 1 – 8 and again had an approximate 50% response rate [5]. The current regimen increases the gemcitabine to 800 mg/m² on days 1, 8 and 15 and intensifies the regimen by adding yet another cytotoxic, procarbazine. Despite this intensification, the overall response rate remains in the 50% range and it is not clear that ViGePP differs substantially from the other permutations of gemcitabine and vinorelbine. The median time to progression in all three studies is similar, ranging from 4 months in the German study to 6 months in the current series, to 8.1 months in the Hellenic Cooperative Oncology Group study.

Of the four agents in the ViGePP regimen, perhaps the one that is most unusual to include is procarbazine. Procarbazine has long been recognized as an effective alkylator that is unfortunately limited by its lengthy side effect profile that includes high leukemogenicity, sterilization and rare hyper-sensitivity reactions. In addition, procarbazine's need for extensive hepatic metabolism leads to significant interactions with other drugs and with foods [6]. Despite these limitations, procarbazine is an active agent in NHL and was an important component of several regimens historically designed for NHL such as C-MOPP and COPP. Furthermore, there are hints of activity in patients with refractory NHL recently reported [7]. Whether or not the added toxicity of procarbazine improves patient outcome will remain unknown until prospective randomized studies can be performed.

The authors propose that elderly patients or those not eligible for transplant be considered as the population of choice for ViGePP. The main advantage of this regimen is its outpatient administration and acceptable toxicity profile. The addition of rituximab may also improve its efficacy and there is emerging in vitro data supporting synergy between rituximab and gemcitabine. The relatively long relapse free survival of 40% at 3 years is encouraging and suggests that there may be a sub-set of patients with relapsed disease for whom high dose chemotherapy and autologous stem cell transplant can be successfully avoided with acceptable outcomes. On the other hand, 39% of patients progressed on therapy and the vast majority of deaths (82%) were due to lymphoma progression, thus showing that patients with chemorefractory disease continue to be a population in need of better therapies.

Where will the ViGePP regimen fit in the current generation of salvage regimens? Should it be utilized as a bridge to transplant or as a ‘definitive’ treatment? Is the addition of the older drug procarbazine warranted in light of similar response rates using gemcitabine and vinorelbine without other cytotoxics? Whether or not the ViGePP combination is more effective than other commonly used salvage regimens will certainly require prospective randomized clinical trials. In the meantime, the combination of new and old drugs in ViGePP offers yet another reasonable choice for patients with relapsed aggressive lymphomas.

Sonali Smith, MD

Lymphoma Program

University of Chicago

5841 S. Maryland Avenue MC2115

Chicago, IL 60637, USA

E-mail: [email protected]

Finding the best way to train the immune system against lymphoma

Commentary on: Ritchie et al. Autologous dendritic cells pulsed with eluted peptide as immunotherapy for advanced B-cell malignancies. Leuk Lymphoma 2006;47:675 – 682.

LEO LUZNIK

Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA

Recent insight into the mechanisms involved in the immune-mediated recognition of B-cell malignancies provides a strong basis for using the immune system as a therapeutic tool against these diseases. An especially attractive strategy is the development of therapeutic cancer vaccines [1],[2]. The advantages of cancer vaccine-induced immune responses in the treatment of B-cell malignancies are several: malignancies can be eradicated systemically beyond the state of minimal residual disease; responses can be specific, without generalized toxicities; and vaccination can lead to the induction of immunological memory, which may be long-lasting. Early clinical studies of idiotype vaccines for B-cell lymphomas have shown promising immune responses and clinical outcomes with very little toxicity [3],[4]. The number of promising new cancer vaccines against human B-cell malignancies is increasing rapidly [5]. Phase III trials using this strategy and involving large numbers of patients are under way. Other strategies, such as DNA idiotype vaccines or complexes of peptides and heat-shock proteins (HSPs), are undergoing clinical tests [5],[6]. Several groups have reported impressive results in preclinical models using whole tumor cell-based vaccines genetically engineered to express immunostimulatory molecules, such as CD40 ligand, granulocyte-macrophage colony-stimulating factor (GM-CSF) and costimulatory molecules [1],[2].

In the current issue of the journal, Ritchie et al. [7] report the results of an early phase clinical trial in which 10 patients with advanced B-cell malignancies were immunized with a vaccine comprising autologous dendritic cells (DCs) pulsed with peptides eluted from surgically retrieved lymphomatous tissue. This formulation had induced effective immunity in several murine tumor models [8]. The processing of the vaccine itself is simple. Autologous DCs are obtained from peripheral blood monocytes grown with interleukin-4 and GM-CSF and loaded with eluted peptides and keyhole limpet hemocyanin (KLH). The resulting cellular product is then injected first subcutaneously as a test dose and then intravenously. Although this was a pilot trial and its results must be interpreted with caution, one clear-cut partial response (PR) and one minor response were seen. In all vaccinated patients, T-cell responses were measured against tumor, eluted peptides and KLH. Only two patients (including the one with a PR) exhibited immunological responses against tumor and KLH. No treatment-related toxicities other than mild myalgias were observed.

When looking for the best way to train the immune system against B-cell malignancies, it is important to keep in mind the lessons that have been learnt from these early trials. First, the choice of tumor antigen and the strategy of vaccine formulation is important. At this point, cancer vaccines can be divided into two major categories: (i) vaccines formulated with purified defined antigens and (ii) those based on undefined antigen mixtures derived from the tumors themselves [1],[2]. The idiotype vaccines, representing earlier formulations of cancer vaccines, have been well studied in patients with B-cell malignancies. Inherent difficulties in preparing such vaccines are increasingly being resolved, and their limitations, such as the loss of antigen and/or the development of antigen-escape tumor mutants, are well recognized [5]. The main reason for using vaccine formulations containing undefined antigens derived from the tumors themselves is to elicit broad immune responses against the widest possible range of tumor antigens [1],[2]. Various vaccine strategies using the patient's primary tumor as the source of immunogen, including whole cell-based vaccine, eluted peptides, tumor lysates, tumor RNA, and HSP-complexes, are being tested against a variety of malignancies [1],[2]. The main difficulty in using such vaccine formulations lies in obtaining enough tumor tissue. However, Ritchie et al. [7] did not encounter this difficulty because the tumor tissue can be acquired fairly easily from peripheral lymph nodes, blood or bone marrow. B-cell malignancies may have an advantage in this regard. A second difficulty lies in maximizing the immunogenicity of injected ex vivo generated and antigen loaded DCs. This is especially relevant to the study by Ritchie et al. [7], given that 80% of patients vaccinated did not elicit responses to KLH. The maturation status of injected DCs is critical in determining whether they prime immune response or induce tolerance [9]. The best strategy to induce optimal DC maturation is unknown. Approaches that can augment their maturation in vivo have several advantages [10] because such steps can also enhance their migration and homing to the lymph nodes, where T-cell responses must be initiated.

In conclusion, the study by Ritchie et al. [7] demonstrates the feasibility of antigen retrieval from primary tumors and loading it to autologous DCs. Deciding how to improve the immunogenicity of the vaccine and whether to test the vaccine as an immunotherapeutic adjunct after salvage or high-dose chemotherapy will be important for the future development of this vaccine strategy.

Dr Leo Luznik

Division of Hematologic Malignancies

Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

1650 Orleans Street, Room 290

Baltimore MD 21231-1000, USA

E-mail: [email protected]

Treatment of acute myeloid leukemia in older adults: Time to reflect?

Commentary on: Abou-Jawde et al. The role of post-remission chemotherapy for older patients with acute myelogenous leukemia. Leuk Lymphoma 2006;47:689 – 695.

FARHAD RAVANDI

Department of Leukemia, The University of Texas – MD Anderson Cancer Center, Houston, TX, USA

In this issue of the journal, Abou-Jawde and colleagues [1] compare the outcome of two cohorts of older elderly patients with acute myeloid leukemia (AML): 40 patients aged 60 years and older who were treated solely with their induction regimen of cytarabine and mitoxantrone and a historical group of 30 patients with similar pre-treatment characteristics who received the same induction regimen followed by post-remission therapy (PRT) with two cycles of intermediate dose cytarabine. The disease-free survival (DFS) and overall survival (OS) did not differ significantly between the two groups and the authors conclude that elderly patients in complete remission (CR) should not be routinely treated with PRT.

The role of PRT in treating younger adults (patients ≤60 years of age) has been long established [2-4]. However, this strategy has failed to produce a significant benefit for prolongation of DFS or OS in studies designed specifically for the older adults (generally patients >60 years of age) [5],[6]. This study, despite its limitations, namely its non-randomized and retrospective nature comparing two small groups of patients, is in agreement with the notion of futility of PRT in the specified patient age group.

However, there are several assumptions that have to be carefully dissected. The first assumption is that age is a dichotomous entity with 60 (or sometimes 55) being the cut-off point above and below which patients have a disparate outcome. Clearly, older age has been established to be associated with a poorer response to initial therapy and shorter survival in all studies published to date [7]. This is a reflection of patient-related factors with older patients tending to have co-morbidities, reduced tolerance to chemotherapy and a poorer performance status. Furthermore, disease-related and biological factors such as a higher incidence of unfavorable cytogenetic and molecular abnormalities in the elderly and more frequent association with genes that mediate drug resistance in the older age group contribute to the poorer outcome [8-10]. However, it is also clear that a particular older patient may have favorable co-existing covariates that may mitigate the age effect and may, therefore, be a candidate for ‘standard’ therapy including PRT.

It may also be true that this poor outcome is a function of drugs that may be inappropriate for septa- and octogenarians. The role of PRT in elderly patients with AML has to be further evaluated using newer and less toxic strategies that may allow continuation of therapy without a significant risk of toxicity. Advances in molecular biology of AML have led to the identification of a number of potential targets for therapeutic intervention [11]. Several of these agents are undergoing evaluation in ongoing clinical trials and a number of them have limited toxicity and can potentially be investigated in the setting of CR to potentially prolong its duration and to eliminate the residual disease responsible for relapse.

Prior studies have generally suggested a benefit of a more intensive induction therapy in the older adults, despite a higher incidence of early mortality [7],[12],[13]. This suggests that anti-leukemia therapy, when effective, is likely to be beneficial and the benefits are only diminished by the attendant toxicity and any inherent resistance to the applied treatment. Similar principals are likely to apply to the PRT; that is the limitations of PRT in the elderly are related to the associated toxicity as well as the limited efficacy of the hitherto available cytotoxic agents in an inherently more resistant disease. As such, current strategies of PRT using available DNA-targeted agents are unlikely to lead to meaningful improvements in the outcome of the elderly patients with AML. Further understanding of the biology of the disease with development of less toxic, more specific and more effective therapeutic agents that can be safely used during the remission is likely to be the way forward in the treatment of elderly patients with AML.

Therapeutic intervention, when available and safe, is generally advocated in all branches of medicine, irrespective of the patient's age. Advances in science and technology have allowed extension of therapeutic procedures to advance the life expectancy in the Western societies to previously unimaginable levels. Similar progress has been hampered in oncology due to the limitations of cytotoxic chemotherapy with regards to toxicity and resistance. Such limitations have been partly overcome by advances in supportive care, but we may have reached or are close to the ceiling of DNA-targeted therapy. Further progress in the understanding of the molecular basis of leukemogenesis will hopefully lead to agents that will seek and eliminate only the neoplastic cells. Perhaps this will pave the way to a time when therapeutic stratification will only be based on the disease biology and characteristics and not solely on age.

Farhad Ravandi, MD

Department of Leukemia

Unit 428

The University of Texas –

MD Anderson Cancer Center

1515 Holcombe Boulevard

Houston, TX 77030, USA

Tel: -713-745-0394, Fax: -713-794-4297

E-mail: [email protected]

Vitamin D and acute promyelocytic leukemia

Commentary on: Wu-Wong et al. Vitamin D receptor (VDR) localization in human promyelocytic leukemia cells. Leuk Lymphoma 2006;47:727 – 732.

LEONIDAS C. PLATANIAS

Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Northwestern University Medical School, Chicago, IL, USA

It is well established that vitamin D analogs are capable of inducing differentiation of acute leukemia cells [1]. There is also emerging evidence that the co-operative action of vitamin D and all-trans-retinoic acid in acute promyelocytic leukemia cells results from enhanced activation of the retinoic acid-transcriptional activity through a RARβ promoter [2]. In addition, recent evidence has suggested that the anti-leukemic properties of vitamin D can be enhanced by combinations with anti-oxidants or pharmacological inhibitors of the p38 Map kinase [3]. Despite such recent advances in this research area, the precise mechanisms by which vitamin D analogs induce differentiation of acute promyelocytic leukemia cells are not known.

In this issue, Wu-Wong et al. [4] report on the localization of the vitamin D receptor (VDR) in human promyelocytic leukemia cells. The authors examined the distribution of VDR in the HL-60 acute leukemia cell line that has promyelocytic futures. Using confocal microscopy, they were able to establish that VDR is primarily localized in the cytoplasm at baseline. After binding of VDR ligands, the complex moved into the nucleus. Such an effect was dose- and time-dependent, further establishing the specificity of the process. Altogether, the findings of the authors strongly suggest that the binding of various vitamin analogs to VDR results in translocation of the receptor into the nucleus and its stabilization.

These findings address a potentially important mechanism by which vitamin D analogs may promote differentiation of acute promyelocytic leukemia cells. As the authors point out, this mechanism appears to be reminiscent of the ones seen in the case of the estrogen and glucocorticoid receptor systems. Nevertheless, the precise role of this pathway in the induction of differentiation of acute leukemia cells by vitamin D analogs remains to be established. In future studies, it will be important to determine whether VDR translocates to the nucleus in promyelocytic leukemia cells that have the t(15;17) translocation and express PML-RARα, such NB-4 cells or primary leukemia cells from acute promyelocytic leukemia (APL) patients. Further studies to determine the effects of retinoids on the production VDR and its translocation to the nucleus may also provide important additional hints on the mechanisms by which vitamin D analogs synergize with retinoids to induce leukemia cell differentiation. Altogether, this report forms the basis for future studies to better understand the mechanisms of action of vitamin D analogs. Such future efforts will be important and may ultimately form the basis for clinical-translational studies towards the development of novel approaches for the treatment of APL.

Leonidas C. Platanias

Robert H. Lurie Comprehensive Cancer Center

Northwestern University Medical School

710 North Fairbanks Street

Olson 8250, Chicago

IL 60611, USA

Tel: [phone], Fax: [phone]

E-mail: [email protected]