Refractory Anaplastic Large Cell Lymphoma Research Articles

Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology Group phase I consortium study.

9500 Background: Genetic aberrations in the anaplastic lymphoma kinase (ALK) gene are found in anaplastic large cell lymphoma (ALCL), neuroblastoma (NB) and other tumors.Crizotinib,a small molecule inhibitor of ALK and c-Met, is active in non-small cell lung cancers (NSCLC) harboring an ALK translocation. We performed a phase 1 dose-escalation and pharmacokinetic (PK) trial of crizotinib in patients (pts) with refractory solid tumors and ALCL. Methods: Crizotinib was administered bid without interruption in 28 day cycles using the rolling-six design. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2/dose) have been evaluated (A1). Pts with confirmed ALK fusion proteins, mutations or amplification (A2) could enroll at one dose level lower than part A1 and those with NB could enroll on a separate stratum (A3). PK studies were performed on day 1 and at steady state (SS). ALK genomic status in tumor tissue was evaluated and qPCR was used to measure NPM-ALK fusion transcript in bone marrow and blood samples of ALCL pts. Results: 70 pts were enrolled, 57 fully evaluable for toxicity, [median (range) age 9.9 yrs (1.1–21.3)]: 29 on A1, 18 on A2, and 10 on A3. In A1, 2/7 pts developed DLT (grade 3 dizziness, grade 5 intra-tumoral hemorrhage) at 215 mg/m2 and 1/6 pts developed DLT (grade 4 liver enzyme elevation) at 365 mg/m2. In A2, 1 grade 4 DLT (neutropenia) occurred at 165 mg/m2; in A3, no DLTs occurred. Mean (±SD) Cave (=AUC0-12h/12h) of crizotinib at SS was 466±114 ng/mL at 215 mg/m2/dose (n=5), 443±121 ng/mL at 280 mg/m2/dose (n=8), and 720±230 ng/mL at 365mg/m2/dose (n=4). Response data for pts with ALCL (six at 165 mg/m2, two at 280 mg/m2) approved for release by the Data Safety Monitoring Committee demonstrates 7/8 (88%) complete response (CR) rate to date. RT-PCR data for 6 of these pts at 57 time points was obtained and will be described. In addition, 2 pts with NB have had CRs, one with a documented ALK mutation. One patient with an inflammatory myofibroblastic tumor and one with NSCLC had PRs. Conclusions: Inhibition of ALK in pediatric pts with ALK-driven tumors occurs with minimal toxicity and is associated with objective anti-tumor activity.

Brentuximab vedotin in systemic T-cell lymphoma

Introduction: Brentuximab vedotin is an antibody–drug conjugate which consists of the anti-CD30 monoclonal antibody cAC10 conjugated with the cytotoxic agent monomethyl auristatin E (MMAE). Brentuximab vedotin has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory Hodgkin's lymphoma (HL) and anaplastic large cell lymphoma (ALCL). The efficacy of brentuximab vedotin in other CD30+ lymphomas is currently being investigated.Areas covered: In this paper, we review the currently available treatment options for systemic peripheral T-cell lymphomas (PTCL) and the role of brentuximab vedotin in relapsed or refractory ALCL. In addition, ongoing clinical trial of brentuximab vedotin in relapsed PTCL and combination therapy with other chemotherapies for initial treatment of CD30 lymphoma will also be reviewed.Expert opinion: Brentuximab vedotin has established its role in the treatment of relapsed or refractory HL and ALCL. In the next few years, the efficacy of this agent in other CD30+ lymphomas will be described. The safety and efficacy of several brentuximab-based combination regimens, including use as frontline chemotherapy is under investigation.

Brentuximab Vedotin: A New Age in the Treatment of Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma

To review the clinical trial data, pharmacology, pharmacokinetics, and adverse effects of brentuximab vedotin. A literature search was performed using MEDLINE and PubMed (both 1966-October 2011), as well as the American Society of Hematology abstracts (2000-January 2012), using the primary search terms brentuximab vedotin, SGN-35, Hodgkin lymphoma (HL), and anaplastic large cell lymphoma (ALCL). Published and ongoing clinical studies and abstracts in the English language that detail the pharmacology, pharmacokinetics, safety, and clinical efficacy of brentuximab vedotin in the treatment of HL and ALCL were included in this review. Brentuximab vedotin is an antibody drug conjugate that combines the anti-CD30 antibody, cAC10, with the synthetic tubulin disrupting agent monomethyl auristatin E. A Phase 1 trial in patients with relapsed and refractory HL or systemic ALCL supported a dose of 1.8 mg/kg every 3 weeks. The drug was well tolerated, with the majority of adverse reactions being grade 1 or 2 in severity. Common toxicities included fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. Phase 2 studies in the same patient populations illustrated objective response rates of 73-86% with an acceptable toxicity profile. Based on results of these Phase 2 trials, the Food and Drug Administration granted approval of brentuximab vedotin in August 2011 for the treatment of relapsed and refractory HL or ALCL. Phase 1 and 2 clinical trial data indicate that brentuximab vedotin is efficacious and safe in patients with relapsed and refractory CD30-positive lymphomas. This agent is being investigated in combination with chemotherapy to further elucidate its role in lymphoma therapy.

Brentuximab vedotin: its role in the treatment of anaplastic large cell and Hodgkin's lymphoma

Brentuximab vedotin is being developed in a joint collaboration between Seattle Genetics and Millennium: The Takeda Oncology Company. In August 2011, it was approved by the FDA for the treatment of patients with Hodgkin's lymphoma (HL) and anaplastic large cell lymphoma (ALCL). Brentuximab vedotin is an antibody-drug conjugate that specifically targets the TNF receptor superfamily member 8 (CD30) antigen on the surface of cancer cells to induce cell death. Brentuximab vedotin has shown efficacy in inducing apoptosis in HL and ALCL cell lines that express CD30 and reducing tumor size in preclinical models. Brentuximab vedotin is under clinical evaluation for the treatment of relapsed or refractory HL and ALCL in both adults and children. It is being investigated for use as a combination agent with pre-existing frontline chemotherapies and as a stand-alone salvage therapy for use prior to autologous stem cell transplant. Treatment with brentuximab vedotin is generally well tolerated although it is associated with grade 1-2 adverse reactions such as neutropenia and there have been reports of grade 3-4 serious adverse events. In particular its use with chemotherapy regimens that include bleomycin is contraindicated because of adverse pulmonary effects.

Long‐term survival of a child with refractory anaplastic large cell lymphoma following therapy with an antisense oligonucleotide, topotecan, and vinblastine

Anaplastic large cell lymphoma includes a subset of highly aggressive tumours and has a relapse rate of 30% at 2 years. Relapsed patients often have poor clinical outcome. The use of antisense oligonucleotides to down-regulate Bcl-2 protein can reverse chemotherapy resistance. The authors describe an 11-year-old boy with recurrent anaplastic large cell lymphoma who had received double high-dose chemotherapy followed by autologous haematopoietic stem-cell transplantation, had refractory disease and then had achieved long-term remission with the use of an antisense oligonucleotides in combination with vinblastine and topotecan.

Evaluation of the Pharmacokinetics, Immunogenicity, and Safety of XmAb®2513 in the Ongoing Study XmAb2513-01: A Phase 1 Study of Every Other Week XmAb2513 to Evaluate the Safety, Tolerability, and Pharmacokinetics in Patients with Hodgkin Lymphoma or Anaplastic Large Cell Lymphoma

XmAb2513 is a novel second-generation humanized monoclonal antibody (mAb) directed against the human cell surface antigen CD30, with an Fc region engineered to enhance cell killing activity via recruitment of effector cells through increased binding affinity to Fcγ receptors (FcγRs). The CD30 antigen (Ki-1) is a member of the tumor necrosis factor superfamily and was originally identified as a cell surface antigen on primary and cultured Reed-Sternberg cells of Hodgkin Lymphoma (HL). Expression of CD30 is a hallmark for the identification of HL and a subset of T-cell lymphomas, including Anaplastic Large Cell Lymphoma (ALCL). Preclinical in vitro data demonstrated XmAb2513 to be more potent with regards to antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) than the first generation anti- CD30 antibodies MDX-060 and SGN-30. Studies in cynomolgus monkeys demonstrated that XmAb2513 exposure was proportional to dose with half-lives (t½) ranging from 5 to 9 days in single dose studies and 12 to 17 days in repeat dose studies. The exposure and t½ data from these cynomolgus monkey studies supported an every other week dosing interval in clinical trials. Based on these favorable features, a Phase 1 study has been initiated to examine the safety and efficacy of XmAb2513 in patients with relapsed and refractory classical HL and ALCL. This ongoing Phase 1 Study is currently evaluating every other week dosing of XmAb2513 using a dose-escalation study design to establish the maximum tolerated dose (MTD). The dose levels under evaluation are 0.3, 1.0, 3.0, 6.0, 9.0, and 12.0 mg/kg, given intravenously over two hours. To date, seven patients are enrolled on the study in the first three dose levels. Pre-study simulation of human exposure based on the pharmacokinetic (PK) parameters obtained from cynomolgus monkeys predicted that 0.3 mg/kg XmAb2513 in humans would result in serum trough levels of 1–1.5 μg/mL after four infusions given every other week. Interim PK and immunogenicity results from the treated patients have been analysed and the results observed thus far are on track with these simulations. Additionally, immunogenicity assessment for human anti-XmAb2513 (HAHA) showed that the treated patients are so far negative for HAHA. Importantly XmAb2513 was well tolerated. As dose escalation continues, results for human PK, immunogenicity, and safety for additional dose cohorts of HL patients, and preliminary safety and response assessment data will be presented.

Successful Allogeneic Stem Cell Transplantation for an Adult with Refractory Anaplastic Lymphoma Kinase—Positive Anaplastic Large Cell Lymphoma

Anaplastic lymphoma kinase (ALK) expression exists in approximately 60% of anaplastic large cell lymphoma (ALCL) cases. Compared with the ALK-negative cases, ALK-positive cases are usually characterized by a good response to chemotherapy and a good prognosis. In the relapsed or refractory ALCL cases, high-dose chemotherapy followed by autologous stem cell transplantation has been widely used as a salvage therapy. However, 40% of patients who received transplants after more than 2 complete remissions eventually experienced disease progression, despite receiving autologous stem cell transplantation. Allogeneic stem cell transplantation has been proposed as a therapeutic option in refractory ALCL cases, but clinical reports of adult patients are rare. Herein, we report the case of an adult with refractory ALK-positive ALCL who was successfully treated with salvage high-dose chemotherapy followed by allogeneic stem cell transplantation.

SGN-30 (Anti-CD30 mAb) Has a Single-Agent Response Rate of 21% in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma (ALCL).

SGN-30 is a monoclonal antibody directed against the CD30 antigen expressed on some hematologic malignancies. Based on encouraging phase I data, a multicenter phase II study was conducted treating patients with refractory or recurrent CD30-positive ALCL with an ECOG performance status of ≤ 2. Thirty-nine patients (24M, 15F) with ALCL were enrolled, with a median age of 57 (range 23–82) and a median of 3 prior therapies (range 2–5). Nine patients had previously received a stem cell transplant. Eighty-five percent of tumors were negative for ALK, a poor prognostic factor. SGN-30 was administred at 6 mg/kg/wk (90 minute infusion, premedications were not required) for 6 consecutive weeks. After 24 patients were enrolled, the dose was escalated to 12 mg/kg/wk in subsequent patients. (Patients with stable disease or objective response were eligible to receive additional cycles of SGN-30. Five patients received ≥ 2 cycles of SGN-30.) Response assessments, as determined by CT scans, were performed 2 weeks after the last infusion. Best response is shown below:CRPRSDPDPending EvalORR2*6**5***24221%*Both CRs have ongoing durations of >365 days; both patients received additional cycles of SGN-30.**PRs had durations of 27, 53, 139 and 167 days; two additional patients have ongoing durations of 86+ and 25+ days.***Three SDs have ongoing durations of 96+, 365+, and 365+ days. Two additional patients had SD for 71 and 174 days.Three drug-related toxicities ≥ Grade 3 were reported (each was considered possibly related to SGN-30): 1) lymphopenia, 2) catheter related infection and 3) urticaria. No other significant hematologic or biochemical toxicities have been observed. There was one definitely related serious adverse event (Grade 2) in a patient who experienced a transient exacerbation of his cutaneous lesions after 2 doses of SGN-30 but achieved a partial response after continuing on study. This phase II study represents one of the largest prospectively designed trials in relapsed/refractory ALCL and demonstrates good tolerability and clinically meaningful antitumor activity of SGN-30, especially in ALK negative patients who have a particularly poor prognosis.

Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents – a Berlin–Frankfurt–Münster group report

Patients with refractory or early relapsed anaplastic large cell lymphoma (ALCL) have a poor chance of survival. We report 20 children and adolescents with high-risk relapsed or refractory ALCL who underwent allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively analysed 20 patients who relapsed between December 1991 and April 2003 during (six patients) or soon after first-line Berlin-Frankfurt-Münster-type chemotherapy (14 patients) and underwent allogeneic HSCT. Nine patients received allogeneic HSCT after the first relapse and 11 after multiple relapses. Eight patients received their transplants from matched sibling donors, eight from unrelated donors and four from haploidentical family donors. The conditioning regimen was based on total body irradiation in 15 patients. Two patients relapsed after allogeneic HSCT and died. Three patients died of transplant-related toxicity. Event-free survival at 3 years after allogeneic transplant was 75 +/- 10%. There was no influence of donor type or conditioning regimen on outcome. Two of six patients with progressive disease during frontline therapy survived compared with 13/14 patients with a first relapse after frontline therapy. Two of three patients who were transplanted with active lymphoma and all five patients who received allogeneic HSCT for relapse following autologous HSCT survived disease-free. Allogeneic HSCT is effective and has acceptable toxicity as rescue therapy for high-risk ALCL relapse. It even offers cure for patients refractory to chemotherapy, suggesting a graft-versus-ALCL effect.

SGN-30 (Anti-CD30 Monoclonal Antibody) Is Active and Well Tolerated in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma (ALCL).

SGN-30 is a chimeric monoclonal antibody (mAb) directed against the CD30 antigen expressed on hematologic malignancies, notably Hodgkin's disease and ALCL. SGN-30 was well tolerated in phase I studies and objective responses were seen. In this multicenter phase II study, refractory or recurrent CD30-positive ALCL patients, ECOG performance status 0–2, are treated with SGN-30 at 6 mg/kg administered by IV over a 90 minute infusion weekly for 6 consecutive doses. A two stage statistical design provides a 90% power to detect an objective tumor response rate of at least 30%. Twenty patients (11M, 9F) with ALCL have been enrolled, with a median age of 53 (range 33–78) and 3 median prior therapies (range 2–5). Eighteen of 20 patients were Anaplastic Lymphoma Kinase (ALK) negative. Response evaluations demonstrate that one patient achieved a complete response and remains in remission more than one year after therapy. Three patients achieved a partial response, of which two had a lasting response of 27 and 53 days respectively. The third patient is currently still on treatment. Of the other 16 patients, 3 had stable disease, 10 progressed and 3 are not yet evaluable. SGN-30 has been well tolerated. Drug-related adverse events have been typically mild and consistent with the phase I experience. There were 2 grade 3/4 toxicities possibly related to SGN-30. No significant hematological or biochemical toxicities have been observed. One patient had a catheter related infection and another experienced urticaria. There was 1 definitely related grade 3/4 event in a patient who experienced an exacerbation of his cutaneous lesions after 2 doses of SGN-30 and followed by a partial response. The requisite number of responses have now been obtained to allow the study to continue.

Unrelated bone marrow transplantation for high‐risk anaplastic large cell lymphoma in pediatric patients: a single center case series

The use of allogeneic stem cell transplantation in NHL patients is not yet clearly defined, especially in children and adolescents, but this option offers the advantages of a tumor-free graft and the possible induction of a graft-vs.-tumor effect. We report the results of four consecutive pediatric patients affected by anaplastic large cell lymphoma (ALCL) and treated with allogeneic stem cell transplantation from an unrelated donor. The conditioning regimen was based on total body irradiation given in association with etoposide in three patients, and with thiotepa and cyclophoshamide in one patient. Graft-vs.-host disease (GVHD) prophylaxis consisted of cyclosporin, a short course of methotrexate and rabbit antithymocyte globulin. All patients had rapid engraftment within 3-4 wk for neutrophils and platelets, and achieved a stable full donor chimerism that has been maintained to the last follow-up visit. One patient later developed a restrictive pneumonopathy. This patient had been heavily pretreated during the course of the disease having suffered four relapses and had received a cumulative dose of bleomycin of 160 mg/m(2). After a follow-up of 11-42 months, all patients are alive in complete hematological and molecular remission; and three of them without any chronic GVHD. The increasing number of volunteer bone marrow donors and the reduced toxicity of unrelated stem cell transplantation, especially in children, make this therapeutic option worth more extensive investigation in the treatment of high-risk failure ALCL, although more data is needed to evaluate the long-term benefits. In this regard, the presence of factors predictive of worst outcome such as an early relapse (within 12 months from diagnosis), a refractory or relapsing ALCL and the persistent detection on blood or bone marrow of nucleophosmin-anaplastic lymphoma kinase protein (NPM-ALK) transcript may help select the patients eligible to allogeneic related or unrelated stem cell transplantation.

SGN-30 (Anti-CD30 Monoclonal Antibody) Is Active and Well Tolerated in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma.

SGN-30 is a chimeric mAb which recognizes the CD30 antigen found on tumor cells from patients (pts) with Hodgkin's disease (HD) and anaplastic large cell lymphoma (ALCL). In preclinical experiments, SGN-30 was shown to have antitumor activity in both in vitro and in vivo models of HD and ALCL. The results of a multi-dose phase I study showed minimal toxicity associated with doses of 2–12 mg/kg as six weekly IV infusions. One complete response (CR) was seen in the three non-Hodgkin's lymphoma patients (2 ALCL, 1 diffuse large B-cell lymphoma) accrued to the study and two patients demonstrated stable disease (SD) over time. A phase II multi-dose study was initiated to further evaluate the safety, antitumor activity and pharmacokinetics of six weekly IV infusions of 6 mg/kg of SGN-30 in pts with relapsed or refractory HD or systemic ALCL (sALCL). Five patients (2M, 3F) with ALCL have been enrolled, with a median age of 52 (range 33–75) and 3 median prior therapies (range 2–5). Multiple doses of SGN-30 have been well tolerated in all of the pts. Drug-related adverse events have been typically mild and consistent with mAb administration. No drug-related grade 3/4 events have been observed. Two patients have had objective responses with one patient achieving a CR. The patient's baseline CT scan showed a 5.1 x 2.0 cm chest wall mass in the lower left anterior lateral chest wall representing local lymphoma recurrence. After six doses of SGN-30 the mass disappeared completely with some edema in the chest wall but no obvious residual mass. The duration of response is pending at this time, and it will be presented in the meeting. Another patient experienced a partial response. The patient, who entered the study with constitutional symptoms and extensive cutaneous and nodal disease, had resolution of all skin lesions, significant reduction in adenopathy and improvement in constitutional symptoms after completion of her SGN-30 therapy. The patient progressed after discontinuation of therapy. Of the other three patients, one had SD and two progressed. These early results are promising and accrual to the trial continues.

Phase II Study of SGN-30 (Anti-CD30 Monoclonal Antibody) in Patients with Refractory or Recurrent Hodgkin's Disease.

SGN-30 is a chimeric monoclonal antibody which recognizes the CD30 antigen found on tumor cells from patients with Hodgkin's disease (HD) and anaplastic large cell lymphoma (ALCL). Preclinical studies with this agent have demonstrated anti-lymphoma effects in both in vitro cell line assays and in vivo murine model systems. The results of a multi-dose phase I study showed minimal toxicity associated with doses from 2 to 12 mg/kg administered as six weekly IV infusions over 120 minutes each. Of the 21 patients with Hodgkin's Disease accrued to the phase I study, four patients had stable disease (SD). A phase II multi-dose study is currently underway to further evaluate the safety, antitumor activity and pharmacokinetics of six weekly IV infusions of 6 mg/kg of SGN-30 in patients with relapsed or refractory HD or systemic ALCL (sALCL). Fifteen subjects (6M, 9F) with HD have been enrolled, with baseline data as follows: median age 34 (range 20–65), median number of prior therapies 3 (range 1–5), and 11 patients (73%) have disease which progressed after prior high-dose chemotherapy and stem cell transplant. Multiple doses of SGN-30 have been well tolerated in all subjects. Drug-related adverse events have been typically mild and consistent with monoclonal antibody administration. The most common drug-related adverse event has been fatigue. No grade 3/4 events have occurred. Twelve patients are currently evaluable for response, with 6 having had stabilization of their disease. Assessment of duration of disease stabilization and response is continuing. While the acceptable safety profile and frequency of stable disease following therapy in this heavily pretreated patient population are encouraging, a 12 mg/kg/dose regimen is now being tested in subsequent subjects to further explore the dose-response relationship of SGN-30 in Hodgkin's Disease. Further evaluation of this novel immunotherapy in additional HD patients is ongoing.

Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms.

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.

ALK-negative systemic anaplastic large cell lymphoma: differential diagnostic and prognostic aspects--a review.

Anaplastic large cell lymphoma (ALCL) can be divided into two major groups. The first is a spectrum of CD30+ T-cell lymphoproliferative disorders including primary cutaneous ALCL and lymphomatoid papulosis, usually affecting older patients but characterized by an excellent prognosis. The second is systemic nodal ALCL, which on the basis of genetic and immunophenotypic features combined with clinical parameters can be divided into two subgroups: anaplastic lymphoma kinase (ALK)-positive and ALK-negative systemic ALCL. ALK expression, usually the result of a t(2;5) translocation, correlates with the expression of other markers such as EMA and a cytotoxic phenotype, and is strongly related to younger age groups, lower international prognostic index (IPI) risk groups, and a good prognosis. ALK-negative ALCL, however, shows a more heterogeneous immunophenotype and clinical behaviour, and prognostic parameters are needed to determine treatment strategies in individual patients. Besides clinical parameters included in the IPI, recent studies have pointed out several biological prognosticators of potential value, such as the percentage of tumour-infiltrating activated cytotoxic T-lymphocytes. The expression of proteins involved in the execution or regulation of apoptosis, such as activated caspase 3, Bcl-2, and PI9, was also found to be strongly related to clinical outcome. These studies indicate that inhibition of the apoptosis cascade in particular is an important mechanism that can explain the poor clinical outcome in therapy refractory ALCL. Functional studies are required to investigate whether disruption of one or more of the apoptosis pathways is the major factor in the fatal outcome of the disease and whether apoptosis resistance based on inhibition of one pathway can be overcome by activating another pathway that is still intact.