Trials In Lymphoma Research Articles

Reply to K. Tay et al

The well-established International Prognostic Index (IPI) developed by Shipp et al over many years allowed a widely accepted risk stratification of patients with aggressive lymphoma worldwide and guaranteed the international comparability of clinical trial results. The IPI, developed in the prerituximab era, was confirmed in many analyses comparing different treatment regimens in different lymphoma entities. Recently, marked improvement of treatment outcomes has been achieved by adding rituximab to chemotherapy. Prognostic factors may change with novel treatment strategies; we, therefore, checked whether the IPI score is valid also when rituximabcontaining regimens are used. Robust prognostic factors should reflect important biologic features of the tumor and therefore— against the statement from Tay et al—should be effective largely independent from therapy. We investigated the validity of IPI score pooling the data from three prospective clinical trials. Data was included for patients 60 years from the RICOVER-60 (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab [R-CHOP] for patients older than age 60 years) trial (n 610), patients 60 years with a good prognosis from MInT (Mab-Thera International Trial; n 380), and patients 60 years with a poor prognosis from MegaCHOEP (dose-escalated regimen of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) trial (n 72). All of these studies used rituximab and chemotherapy and confirmed that the IPI score is valid also in rituximab era. We analyzed the data of all three trials separately and demonstrated that the IPI was similarly effective in separating individual risk groups. Within each of the three populations we found significant differences between IPI score groups (see Fig 1 of our article). In the MInT and the RICOVER-60 trial (see Figs 2 and 3) we showed that a shift to better treatment results occurs within each IPI group if rituximab is used. The different patient numbers representing our three populations, in particular the low number of young poor-prognosis patients, do not invalidate our results; they only reflect the relative scarcity of young high-risk patients in the population at large. Furthermore, we illustrated by a simulation that analyses of a prognostic factor system distinguishing four ordered groups requires larger samples sizes than reported by Sehn et al in a retrospective analysis of data from only 365 patients or as mentioned by Tay et al (data not shown). Their sample sizes are too small to draw reliable conclusions as they are prone to random effects leading to overlays between different patient groups. In conclusion, the statements raised by Tay et al are not useful to make a case that the classical IPI system should be replaced. It should be used further on to allocate patients to risk groups and to report clinical trials in lymphomas as the reference.

The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells

IntroductionThe aim was to determine the effect of the Bruton tyrosine kinase (Btk)-selective inhibitor PCI-32765, currently in Phase I/II studies in lymphoma trials, in arthritis and immune-complex (IC) based animal models and describe the underlying cellular mechanisms.MethodsPCI-32765 was administered in a series of murine IC disease models including collagen-induced arthritis (CIA), collagen antibody-induced arthritis (CAIA), reversed passive anaphylactic reaction (RPA), and passive cutaneous anaphylaxis (PCA). Clinical and pathologic features characteristic of each model were examined following treatment. PCI-32765 was then examined in assays using immune cells relevant to the pathogenesis of arthritis, and where Btk is thought to play a functional role. These included proliferation and calcium mobilization in B cells, cytokine and chemokine production in monocytes/macrophages, degranulation of mast cells and its subsequent cytokine/chemokine production.ResultsPCI-32765 dose-dependently and potently reversed arthritic inflammation in a therapeutic CIA model with an ED50 of 2.6 mg/kg/day. PCI-32765 also prevented clinical arthritis in CAIA models. In both models, infiltration of monocytes and macrophages into the synovium was completely inhibited and importantly, the bone and cartilage integrity of the joints were preserved. PCI-32765 reduced inflammation in the Arthus and PCA assays. In vitro, PCI-32765 inhibited BCR-activated primary B cell proliferation (IC50 = 8 nM). Following FcγR stimulation, PCI-32765 inhibited TNFα, IL-1β and IL-6 production in primary monocytes (IC50 = 2.6, 0.5, 3.9 nM, respectively). Following FcεRI stimulation of cultured human mast cells, PCI-32765 inhibited release of histamine, PGD2, TNF-α, IL-8 and MCP-1.ConclusionsPCI-32765 is efficacious in CIA, and in IC models that do not depend upon autoantibody production from B cells. Thus PCI-32765 targets not only B lymphocytes but also monocytes, macrophages and mast cells, which are important Btk-expressing effector cells in arthritis.

Long‐term results of AIEOP‐8805 protocol for acute B‐cell lymphoblastic leukemia of childhood

Acute B-cell leukemia (B-ALL) is a rare form of pediatric leukemia characterized by a very high-proliferation index, rapid clinical progression, and a high frequency of central nervous system (CNS) involvement. Commonly, it is treated in the clinical trials for Burkitt lymphoma, of which it represents the leukemic counterpart. Children with B-ALL diagnosed between 1988 and 1999 were enrolled in the AIEOP-8805 protocol. Treatment included six high-dose chemotherapy courses. No prophylactic CNS irradiation was administered. Sixty-five consecutive patients were enrolled in the study. L3 morphology was observed in 57 of 65 patients (88%). Twenty-five children (38%) had tumor mass in addition to massive bone marrow infiltration; 11 children (17%) had CNS disease at diagnosis. Sixty-two patients obtained complete morphological remission of which 13 suffered a relapse, including 3 with initial CNS involvement. Ten-year overall survival and event-free survival were 77% and 75%, respectively. Neither relevant long-term toxicity nor second malignancies were observed. The AIEOP-8805 confirmed that short high-dose chemotherapy is highly effective for the treatment of B-ALL without significant long-term adverse sequelae. Therapy modifications to reduce relapse rate, such as the use of anti-CD20 monoclonal antibody and more effective CNS treatment, are being tested.

Hodgkin Lymphoma Patients with Stage II B or Stage II Bulky Disease Have Advanced Disease and Should Not Be Included In Limited Stage Trials

AbstractAbstract 417 Background:Trials enrolling patients with limited stage Hodgkin lymphoma conducted by European cooperative groups including EORTC, GELA and the GHSG frequently include patients with stage II B or stage II bulky (≥ 10 cm) disease in either “favorable” or “unfavorable” subgroups. Similar patients are usually excluded from North American trials of limited stage disease and rather are included in trials of advanced stage lymphoma. We sought to clarify the appropriateness of these approaches. Methods:All adult (age > 15 but < 66 y) HIV antibody negative patients with stage II A bulky, II B non-bulky or II B bulky Hodgkin lymphoma treated in British Columbia since 1981, when ABVD-type chemotherapy became standard, were identified using the BC Cancer Agency Lymphoid Cancer Database. Characteristics: n=416; male 54%; age range 16–64 y (median = 30); histologic subtype nodular sclerosis 86%, mixed cellularity 5%, not subclassifiable 6%, other 3%; subdiaphragmatic 3%; stage II A bulky 32%, II B non-bulky 32%, II B bulky 36%; localized extranodal extension (E lesion) 35%; largest mass diameter non-bulky range 1–9 cm (median 6 cm), bulky range 10–25 cm (median 12 cm); IPFP prognostic score 0, 9%; 1, 33%; 2, 32%; 3, 19%; 4, 6%; 5, 1% (data missing 36%). Results:Planned treatment consisted of 6–8 cycles of ABVD-type chemotherapy followed by radiation for a persistent residual mass (only if PET positive since 2005). 50% of patients received radiation (extended field 24%, involved field 76%). Thus, patients were treated with the same approach that is used for stage III or IV. Patients with bulky disease were much more likely to receive radiation: II A bulky 72%; II B non-bulky 11%; II B bulky 65%. For all 416 patients, with a median follow-up of 8 y, 5 and 10 y progression free survivals (PFS) were 81% and 76%; time-to-progression (TTP) estimates 83% and 81% (Fig. 1); and overall survivals (OS) were 94% and 90%. Although there is some variation, survivals were very similar across the three stage groups.Stage groupnPFS%TTP%OS%5-y10-y5-y10-y5-y10-yII A bulky135858585859493II B non-bulky134807080779588II B bulky147787282799490All patients416817683819490This experience is instructive and indicates that when patients with stage II B bulky or non-bulky or stage II A bulky Hodgkin lymphoma are treated with the same approach as is used for advanced stage disease at least 20% of patients relapse. Conclusion:It is inappropriate to include patients with stage II B or stage II A bulky Hodgkin lymphoma on trials designed for limited stage disease. With an estimated relapse rate of at least 20% inclusion of these patients can grossly distort outcomes and compromise interpretation of the results of the trial since the expectation for the rest of the patients (stage I A and II A, low bulk) is that no more than 5% of patients will relapse. Patients with stage II B or stage II A bulky Hodgkin lymphoma should be included in trials for patients with advanced stage disease. [Display omitted] Disclosures:Klasa:Seattle Genetics, Inc.: Research Funding.

PILLAR-1: Preliminary Results of a Phase II Study of mTOR Inhibitor Everolimus In Patients with Mantle Cell Lymphoma (MCL) Who Are Refractory or Intolerant to Bortezomib

AbstractAbstract 3963 Introduction:MCL remains incurable with current therapeutic approaches. Bortezomib is approved for patients with relapsed MCL, though the duration of response is limited. As such, there is a critical need for novel therapeutic strategies and targeted agents. The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in many hematologic malignancies. Studies of monotherapy everolimus, an oral inhibitor of mTOR, have shown substantial antitumor activity in relapsed aggressive non-Hodgkin's lymphoma and other types of relapsed or refractory lymphomas, including MCL. Methods:PILLAR-1 (PIvotaL Lymphoma triAls of RAD001-1) is an open-label, US-based, multicenter, single-arm, phase II study (clinicaltrials.gov: NCT00702052) of oral everolimus (RAD001) 10 mg/d in patients with pathologically confirmed MCL who are bortezomib refractory (defined as radiological progression ≤12 months after the last bortezomib-containing combination or monotherapy) or intolerant (defined as requiring discontinuation due to toxicity). Study treatment with everolimus continued until disease progression, unacceptable toxicity, death, or study discontinuation. Eligible patients have received ≥1 prior antineoplastic agent other than bortezomib either separately or in combination with bortezomib. The primary endpoint is objective response rate (ORR including complete response [CR] and partial response [PR]). Secondary endpoints include progression-free survival, overall survival, duration of response, and safety. A Simon two-stage design was used and was based on ORR among 34 treated patients in Stage 1. If ≥3 CR or PR occurred in Stage 1, an additional 23 patients would be treated in Stage 2; otherwise, the study would be stopped. Results presented here are based on a data cut-off of April 26, 2010. Results:A preliminary analysis of efficacy and safety included 26 patients (65% male) with the following baseline characteristics: median age 65 y (range, 50–83); 77% were >2 y post initial diagnosis; 72% had previously received ≥3 therapies; 89% had previously relapsed ≤6 months before enrollment; 73% were stage IV at initial diagnosis; 73% had prior bone marrow involvement; 92% had ECOG performance status ≤1; 85% were refractory and 12% were intolerant to bortezomib. Median duration of exposure to everolimus was 58 days (range, 13–221). Efficacy analysis of best overall disease response revealed no CR, 3 PR (12%), 14 SD (54%), 3 PD (12%), and 6 unknown (23%). ORR (CR+PR) was 12% (95% CI, 2–30) and met the requirement for full recruitment in Stage 2 of the study ahead of the Stage 1 enrollment target. A total of 19 patients discontinued from the study, 7 (27%) due to adverse events, 9 (35%) due to PD, and 3 (12%) withdrew consent. In the safety analysis, grade 3 or 4 adverse events suspected to be related to study treatment in ≥2 patients (>7%) were anemia, thrombocytopenia (including 1 grade 4), diarrhea, hyperglycemia (including 1 grade 4), and pneumonitis. Conclusion:Early analysis from this ongoing phase II study (stage I) shows that oral everolimus 10 mg/d has promising single-agent activity with 12% PR and 54% SD and good tolerability in bortezomib-refractory and intolerant MCL. The efficacy results support continuing to stage II enrolling more patients into this study. Disclosures:O'Connor:SAB-Pharma: Research Funding. Winter:Novartis Pharmaceuticals: Consultancy, Research Funding. Yuan:Novartis Pharmaceuticals: Employment, Equity Ownership. Robeva:Novartis Pharmaceuticals: Employment, Equity Ownership. Cauwel:Novartis Pharmaceuticals: Employment, Equity Ownership. Chau:Novartis Pharmaceuticals: Employment, Equity Ownership. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

Emerging role of the histone deacetylase inhibitor romidepsin in hematologic malignancies

Importance of the field: Histone acetylation plays a crucial role in chromatin modification and the regulation of gene expression. Histone deacetylase inhibitors (HDACi) are a novel class of antitumor agents with pleiotropic effects; they are under active clinical investigation. The HDACi romidepsin is being evaluated in a variety of tumors and was recently approved for the treatment of cutaneous T-cell lymphomas (CTCL).Areas covered in this review: This review focuses on the findings from early Phase trials involving romidepsin, and the Phase II trial results that led to the approval of romidepsin in CTCL.What the reader will gain: Mechanisms of action of HDACi, including romidepsin, are described in this review and the pharmacodynamic and pharmacokinetic properties of romidepsin are summarized. The efficacy and safety profile of romidepsin in clinical trials in T-cell lymphoma is reviewed, and emerging data on single-agent and combination strategies in myeloid and B-lymphoid malignancies is outlined.Take home message: Romidepsin has significant activity and an acceptable safety profile in CTCL and peripheral T-cell lymphomas. Its use in rationally designed combination approaches is under active investigation in B-lymphoid malignancies.

Biopharmaceuticals and monoclonal antibodies in oncology trials--a cross-sectional analysis

Protein engineering has led to a significantly improved understanding of the biophysical properties of proteins and, importantly, of the molecular mechanisms of disease. Moreover, it has enabled scientists to modify the molecular characteristics of peptides and proteins, leading to improved pharmacokinetics and pharmacodynamics of protein therapeutics. Consequently, biopharmaceuticals, such as monoclonal antibodies (mAbs), interferons/cytokines or vaccines, contribute increasingly to clinical practice. Some of these new treatments have dramatically changed the outcome of specific diseases. However, treatment options remain limited in many conditions, particularly in malignant disease, despite a much-improved understanding of the molecular mechanisms underlying cancer. With the successful pre-clinical development of therapeutic biomolecules, the most significant barrier prior to implementation into clinical practice is proof of concept in humans. This is in part addressed by clinical trials that evaluate the toxicology, dose response and efficacy of the molecules. This observational study summarises the current state of biopharmaceuticals in clinical trials and provides a particular focus on oncology trials. It identifies those cancer types that are most likely to benefit from the efforts made in pre-clinical protein science and establishes evidence that engineered proteins and peptides are set to play a growing role in clinical practice. This study was based on the 95,254 trials registered on the National Institute of Health Clinical Trials Database by 31 August 2010. Of these, 25,525 trials assigned to cancer conditions, including leukaemia and lymphoma, were further analysed, with a particular focus on the 3653 interventional trials that were based on biological interventions. The inclusion criterion for the analysis was registration on the Clinical Trials Database by the above date. No other trials were included. Biopharmaceuticals were the more prevalent intervention in cancer trials (14%) compared with trials in non-cancer conditions (6%). Further subgroup analysis based on the 20 cancer subtypes with the highest mortality revealed that biological therapeutics comprise 43% in malignant melanoma trials and more than 20% in five other cancer types. Two-thirds of all monoclonal antibody are registered in cancer trials (1033, 4.6% of all cancer trials). The subgroup analysis demonstrated a predominance of lymphoma and leukaemia trials for antibody interventions, with 204 and 163 trials registered, respectively. In non-cancer conditions only 503 (0.9%) trials investigate monoclonal antibody interventions. A retrospective longitudinal analysis of the trials demonstrated that monoclonal antibody trials are increasingly frequently registered in non-cancer as well as cancer conditions. However, biopharmaceutical trials continue to be registered more frequently only in non-cancer conditions, but have come to a plateau in cancers. This study is limited by analysis of data from one database only. While the NIH Clinical Trials Database used is the most comprehensive and internationally recognised of its kind, it is possible that the results may have been modified if other databases were also included. Protein engineering has paved the way for biopharmaceutical clinical interventions. A cross-sectional analysis of trials registered on the NIH Clinical Trial Database shows that biological interventions are increasingly entered into clinical trials. While oncological diseases used to lead this effort, biotherapeutic trials in non-cancer conditions have now become more frequent in comparison. Monoclonal antibodies, however, are still mainly investigated in oncological conditions. Haemato-oncological diseases are most frequently investigated for mAb interventions, although they are not among the eight most common causes of cancer mortality. This may reflect the fact that pre-clinical research, understanding of molecular mechanisms and target identification in other malignancies and diseases is less developed.

A study design with conditional, serially assessed co-primary endpoints: An application to a single-arm, pilot non-Hodgkin's lymphoma trial

Optimizing study designs is an important responsibility for applied statisticians supporting clinical trials. We describe the study design for an early-phase non-Hodgkin's lymphoma trial with two co-primary endpoints; however, evaluation of the second endpoint on a subject is conditional on a positive response to the first endpoint. Thus, these dichotomous measures are collected conditionally and in series. We present the probability density function for this study design selected and derive the parameters that describe this distribution. We also derive the maximum likelihood estimates for the unknown parameters of interest to the trial investigator. We compare the theoretical operating characteristics (type I and type II error rates) to a simulation study for the motivating example. Using this report as a guide, others designing studies with similarly measured co-primary endpoints can utilize these formulas to calculate the operating characteristics and analyze their resulting study data. Drug Dev Res 71: 395–403, 2010. © 2010 Wiley-Liss, Inc.

Selected Clinical Trials in Hodgkin Lymphoma

Tabled 1 Phase III Trials in the United States Official Title A Phase III Randomized, Double Blind, Placebo Controlled Multi-center Study of Panobinostat for Maintenance of Response in Patients With Hodgkin Lymphoma Who Are at Risk for Relapse After High-Dose Chemotherapy and Autologous Stem Cell Transplant Sponsor Novartis Pharmaceuticals Primary Endpoint Disease-free survival Contact Information Novartis Pharmaceuticals; Ph: 1-800-340-6843 Study Director Novartis Pharmaceuticals Clinicaltrials.gov ID NCT01034163; study start: April 2010 Official Title ASI-HDOOO 0109: Phase III Randomized, Multi-center Study to Evaluate the Effect of Rituximab in Patients With Lymphocytic Predominant Hodgkin Lymphoma Primary Endpoint Response rates by Kaplan-Meier at 3, 6, 12, and 18 months Contact Information Ph: 732-981-8686; e-mail: [email protected] Study Chair Ratna Grewal, MD Clinicaltrials.gov ID NCT00816959; study start: April 2010 Official Title AETHERA: A Randomized, Double Blind, Placebo-Controlled Phase III Study of SGN-35 and Best Supportive Care (BSC) Versus Placebo and BSC in the Treatment of Patients at High Risk of Residual Hodgkin Lymphoma Following Autologous Stem Cell Transplant Sponsor Seattle Genetics, Inc. Primary Endpoint Progression-free survival Contact Information Terri Lowe; ph: 866-333-7436; e-mail: [email protected] Study Director Eric Sievers, MD Clinicaltrials.gov ID NCT01100502; study start: April 2010 Official Title A Phase III Multicenter, Randomized Trial Comparing Tacrolimus/Sirolimus/Methotrexate Versus Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma Factor Sponsor Dana-Farber Cancer Institute Primary Endpoint 2-year overall survival Contact Information Philippe Armand, MD, PhD; ph: 617-632-2305; e-mail: [email protected] Study Director GSK Clinical Trials Clinicaltrials.gov ID NCT00928018; study start: June 2009 Phase II Trials in the United States Official Title CALGB-100601: Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation as Second Transplantation for Patients With Disease Relapse or Myelodysplasia After Prior Autologous Transplantation Primary Endpoint Event-free survival Sponsor Cancer and Leukemia Group B Contact Information Ph: 404-255-1930 Principal Investigator Asad Bashey, MD, PhD Clinicaltrials.gov ID NCT01118013; study start: not yet recruiting Official Title Phase II Trial of Response-Adapted Therapy Based on Positron Emission Tomography (PET) for Bulky Stage I and Stage II Classical Hodgkin Lymphoma (HL) Sponsor Cancer and Leukemia Group B Primary Endpoint Progression-free survival at 36 months from enrollment Contact Information Ph: 617-632-5959; 866-790-4500 Principal Investigator Ann LaCasce, MD Clinicaltrials.gov ID NCT01118026; study start: September 2010 Open table in a new tab

Selected Clinical Trials in Diffuse Large B-Cell Lymphoma and T-Cell Lymphoma

Status for All Trials, July 2010: RecruitingTrials Open in the United States Official Title: PILLAR-2 trial: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase III Study of RAD001 Adjuvant Therapy in Poor-Risk Patients With Diffuse Large B-Cell Lymphoma (DLBCL of RAD001 Versus Matching Placebo After Patients Have Achieved Complete Response With First-line Rituximab-Chemotherapy) Primary Endpoints: Disease-free survival; incidence of adverse events; incidence of noninfectious pneumonitis Sponsor: Novartis Pharmaceuticals Study Chair: Novartis Pharmaceuticals Contact Information: Novartis Pharmaceuticals; Ph: 800-340-6843 Clinicaltrials.gov ID: NCT00790036 Study Start: July 2009 Official Title: CALGB 50303: Phase III Randomized Study of R-CHOP V. Dose-Adjusted EPOCH-R With Molecular Profiling in Untreated De Novo Diffuse Large B-Cell Lymphomas Primary Endpoint: Event-free survival Sponsors: Cancer and Leukemia Group B; National Cancer Institute Study Chair: Wyndham H. Wilson, MD, PhD Contact Information: Ph: 301-435-2415; e-mail: wilsonw@mail.nih.gov Clinicaltrials.gov ID: NCT00118209 Study Start: May 2005Selected International Trials of Interest Official Title: DSHNHL 2006-1B/ACT-2: Phase III Study of CHOP-14 Plus or Minus Alemtuzumab in Peripheral T-Cell Lymphoma of the Elderly Primary Endpoint: Event-free survival Sponsors: University of Göttingen; German High-Grade Non-Hodgkin's Lymphoma Study Group; Nordic Lymphoma Group Study Chair: Lorenz H. Trümper, MD Contact Information: Ph: 49-551-398535, ext. 8535; e-mail: lorenz.truemper@med.uni-goettingen.de Clinicaltrials.gov ID: NCT00725231 Study Start: February 2008 Official Title: ACT-1: A Randomized Phase III Study to Evaluate the Efficacy of Chemoimmunotherapy With the Monoclonal Antibody Campath-1H (Alemtuzumab) Given in Combination With 2-weekly CHOP Versus 2-weekly CHOP Alone and Consolidated by Autologous Stem Cell Transplant, in Young Patients With Previously Untreated Systemic Peripheral T-Cell Lymphomas Primary Endpoint: Event-free survival Sponsor: Aarhus University Hospital Study Chair: Francesco d’Amore, MD Contact Information: Ph: 45-8949-7567; e-mail: frandamo@rm.dk Clinicaltrials.gov ID: NCT00646854 Study Start: November 2007 Official Title: MAYO-LS0881: Phase III Study of the Interest of Radiotherapy After 4 or 6 Cycles of CHOP 14 Rituximab Regimen of Chemotherapy, Patients With Aggressive Localized Lymphoma Primary Endpoints: Event-free survival; progression-free survival Sponsor: Groupe Ouest Est d’Etude des Leucémies et Autres Maladies du Sang (GOELAMS) Study Chair: Thierry Lamy, MD, PhD Contact Information: Ph: 33-2-99-28-42-91; e-mail: thierry.lamy@univ-rennes1.fr Clinicaltrials.gov ID: NCT00841945 Study Start: April 2005 Official Title: UNFOLDER 21/14 Study: Randomized Study Comparing an Immuno-Chemotherapy With 6 Cycles of the Monoclonal Anti-CD20 Antibody Rituximab in Combination With 6 Cycles of Chemotherapy With CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) at 21-Day Intervals or 14-Day Intervals, Both With or Without Consolidating Radiotherapy or Large Tumour Masses (= 7.5 cm) and/or Extranodal Involvement in Patients With Aggressive CD20 B-Cell Lymphoma Aged 18 to 60 Years With Age-Adjusted IPI = 1 (All) or IPI = 0 With a Large Tumour Mass (≥ 7.5 cm) Primary Endpoint: Time to treatment failure Sponsor: German High-Grade Non-Hodgkin's Lymphoma Study Group Study Chair: Michael G. M. Pfreundschuh, MD Clinicaltrials.gov ID: NCT00278408 Study Start: November 2005 Official Title: Double-Blind Randomized Phase III Study of Lenalidomide Maintenance Versus Placebo in Responding Elderly Patients With DLBCL and Treated With R-CHOP in First Line Primary Endpoints: Progression-free survival Sponsor: Groupe d'Etude des Lymphomes de l'Adulte - Recherche Clinique Principal Investigator: Bertrand Coiffier Contact Information: Tel: 33-478-86-4301; e-mail: bertrand.coiffier@chu-lyon.fr Clinicaltrials.gov ID: NCT01122472 Study Start: April 2009

Interim PET in lymphoma: a step towards standardization

In this issue, Barrington et al. propose well-defined criteriafor interim PET/CT reporting in lymphoma [1]. Thesecriteria, based on a five-point scale, introduce two mainconcepts which are highly relevant for interim PETanalysis: (1) the intensity of the residual uptake frequentlyobserved at interim is graded relative to various levels ofreference background (RB)—mediastinal blood pool(MBP) and liver—and (2) this grading process is indepen-dent of the size of the residual tumour. Furthermore, theauthors reported that this five-point scale assessed on asample of 50 patients with advanced stage Hodgkin’slymphoma (HL) by 4 pairs of experts from 4 Europeancentres: (1) seems a reproducible tool for guiding thera-peutic strategy after 2 cycles of ABVD (Adriamycin,bleomycin, vinblastine, dacarbazine) when liver is chosenas an RB and (2) is robust enough to be used in multicentretrials for interim PET reporting.The authors have decided to use this scale in theResponse Adapted Treatment in Hodgkin Lymphoma(RATHL) trial, an interim PET-driven therapeutic strategyin patients with advanced stage HL. Although manytrials are ongoing worldwide in HL and non-Hodgkin’slymphoma (NHL) to test whether the results of an interimPET performed after one to four cycles of chemotherapycan tailor a response-adapted therapy, standardized interimPET criteria are still missing. Interim PET requires indeedspecific criteria which should be different from thosedefined for end treatment by the International Harmoniza-tion Project (IHP) in Lymphoma [2]. In the context of drugdevelopment and survival improvement observed inlymphoma, the rationale of interim PET is to define ana posteriori prognostic index reflecting tumour chemo-sensitivity during first-line therapy, allowing earlychanges of therapy (escalation or de-escalation) adaptedto specific situations. In many trials the strategy can bemodified according to the results of two interim PETexams performed at different times during inductiontreatment. As a matter of fact, depending on thecharacteristics of tumour growth and histological typethe evolution of PET under treatment is different. Indiffuse large B-cell lymphoma (DLBCL) neoplastic cellsconstitute more than 90% of the total cell population.The metabolic activity during therapy decreases in acontinuous mode, with cell killing. Interim PET after oneor two cycles of chemotherapy evaluates the response ofthe cells with the highest mitotic index, thereby providingan early evaluation of chemosensitivity and identifyingresponders and non-responders [3, 4]. On the other hand,after three or four cycles of therapy, FDG uptake is moredependent on the tumour regrowth [5]. In HL, the Reed-Sternberg (RS) cells account for less than 1% of the tumour.Bystander, lymphomononuclear cells work, throughcytokines, as an amplifier of the PET detection power. Thesecells are switched off very early (one to two cycles) bychemotherapy [6]. Therefore, the amount of residual activityat interim varies with the kinetics of tumoral destruction, thehistology of lymphoma, the tumoral microenvironment, thetreatment and the time point (two cycles or more) at whichPET is performed. These variations are better described by aquantitative analysis by reference to the baseline PET thanby using a visual dichotomous analysis (positive or negative)which results in a loss of information [3, 5]. In this regard thefive-point scale proposed by Barrington et al. is goingtowards the right direction by giving the possibility to grade

Pralatrexate: basic understanding and clinical development

Importance of the field: Pralatrexate (PDX; 10-propargyl 10-deazaaminopterin), is an exciting new chemotherapeutic agent that is approved for the treatment of relapsed and refractory peripheral T-cell lymphomas (PTCL). This is the only approved therapy for patients with PTCL.Areas covered in this review: This review describes the clinical development of PDX from its synthesis to its FDA approval. It details the biochemical basis of the differences between PDX and other antifolates that form the basis of the superiority of its activity. This is followed by a description of the preclinical data that led to early-phase clinical trials in lung cancer and lymphoma and, finally, the definitive trial that led to its approval in PTCL. The review also describes how PDX is being combined with other agents in both the preclinical and clinical arenas.What the reader will gain: These trials have been instrumental in defining a safe dose as well as the safety profile of the agent. FDA approval for the use of PDX in PTCL has been granted based on the results of the pivotal Phase II trial of this agent in relapsed and refractory PTCL patients.Take home message: PDX is a unique antifolate that has been rationally designed to have a high affinity for the reduced folate receptor (RFC-1) and the enzyme folylpolyglutamy synthetase. It is active in T-cell lymphomas and non-small-cell lung cancer. It is now being studied in combination with other chemotherapeutic and targeted agents for the treatment of hematological malignancies.

Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma

To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries. Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively. The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.

A phase II trial of fludarabine and cyclophosphamide followed by thalidomide for angioimmunoblastic lymphoma.

TPS302 Background: The best treatment for AITL is not known. Some 30% of patients achieve long term remissions but for the majority AITL is an aggressive disease with profound immune dysfunction (Mourad, Blood 2008;111:4463; Dunleavy, Curr Opin Hematol 2007;14:348). Histological subtyping does not aid prognostication, and even though registry data of high dose chemotherapy (HDC) is encouraging, AITL survival in a series of randomised lymphoma trials did not correlate with treatment intensity (Mourad, Blood 2008; 111:4463;Kyriakou, JCO 2008;26:218). We therefore set up a multicenter phase II study to (1) estimate response of AITL to FluCy chemotherapy, and (2) assess incremental anatomical, flow cytometric and molecular response to consolidation with Thal. Methods: Eligible are patients with a first diagnosis of AITL and performance status 0–2. FluCy is given as 4 cycles of Flu 40mg/m2 and Cy 250mg/m2 od po for 3 days every 4 weeks. Thal is given to maximal tolerated dose for 6 months. The two-stage trial aims at recruiting 37 patients in 3 years. It opened in February 2009. Novel aspects of this trial are (1) first prospective trial in AITL investigating two immune interventions-ablation followed by cytotoxic T and NK cell stimulation (Hayashi, BJH 2005;128:192); (2) investigation of two therapeutic interventions sequentially; (3) definition of an incremental response rate for the second intervention based on the frequent presence of circulating lymphoma cells in AITL (Baseggio, Leukemia 2005;20:296). In the first year, only 5 patients were enrolled. Difficulties encountered were (1) protracted set up due to changes in regulatory status of Thal; (2) low pick up rate among trial centers because of high administrative work for low recruitment rate; (3) perception in many larger centers that younger patients should be offered HDC in first remission; (4) drop out rate during first phase of trial higher than expected because of skewing of the patient population toward the elderly (not fit for HDC) so that Thal question, which needs 26 patients, may not be answered; (5) lack of facilities for storage of fresh frozen tissue in most prospective trial centers , precluding linkage of trial data to gene expression profiling. No significant financial relationships to disclose.

Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma

Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza) is a histone deacetylase inhibitor with clinical activity in cutaneous T-cell lymphoma (CTCL). A phase I trial of oral vorinostat was conducted in Japanese patients with malignant lymphoma. Vorinostat 100 or 200 mg was administered twice daily for 14 consecutive days followed by a 1-week rest interval. Of 10 patients enrolled, four had follicular lymphoma (FL), two mantle cell lymphoma (MCL), two diffuse large B-cell lymphoma, and two CTCL (median age, 60 years; median number of prior regimens, 3). Vorinostat was well tolerated up to 200 mg with only one of six patients developing a dose-limiting toxicity (DLT; Grade 3 anorexia/hypokalemia). Common Grade 3 events were reversible neutropenia (30%), thrombocytopenia, and hypermagnesemia (20% each). The median number of treatment cycles was five (range, 1-36); two patients were continuing treatment. The overall response rate was 40%, with two complete responses/unconfirmed (CRu) and one partial response among FL patients and one CRu among MCL patients. One FL patient maintained CRu for 18.0 months. The median time to achieve CRu among the three patients was 8 months. These data suggest that further investigations of vorinostat in non-Hodgkin lymphoma, focusing on FL and MCL, are warranted.

“Limiting Anthracycline-Induced Cardiotoxicity Using Amrubicin in Leukemia Systems”.

Abstract 3760Poster Board III-696The overall survival of pediatric cancer patients has greatly improved over the last forty years in part due to the introduction of anthracyclines into therapeutic regimens. However, a significant limitation of anthracyline use is cardiotoxicity by this class of drugs. The mechanism most often cited as contributing to anthracycline cardiotoxicity is the production of reactive oxygen species (ROS) and subsequent damage to mitochondria, resulting in activation of the apoptotic cascade. Because heart tissue contains more mitochondria than other organ sites, this mechanism is particularly damaging to this organ site. Newer, less toxic anthracyclines are being developed and amrubicin, a completely synthetic anthracycline with potent topoisomerase II inhibition, is one such compound and is approved in Japan for the treatment of small cell and non-small cell lung cancer. In animal studies amrubicin has demonstrated decreased cardiotoxicity compared to doxorubicin, and in Phase I/II clinical trials in lymphomas and solid tumors has demonstrated single agent activity and an improved early cardiotoxicity profile. Our goal was to elucidate the role of ROS in the decreased cardiotoxicity observed with amrubicin exposure and to test the ability of amrubicin to promote cell death in leukemia cells.We used a rat cardiomyocyte cell line model (H9c2 cells) to quantify oxidative stress after exposure to amrubicin or other anthracyclines. Flow cytometry was used to evaluate superoxide levels after the cells were treated for 24 hours and stained with hydroethidium (HE). Interestingly, at equimolar doses (500 nM, 1 μM, 2 μM and 3 μM), cardiomyocytes treated with amrubicin produced less superoxide than cells treated with an equivalent dose of daunorubicin. These results suggest that ROS-mediated damage to cardiomyocytes is less after amrubicin exposure as compared to daunorubicin. The anti-leukemia efficacy of amrubicin was also evaluated as compared to other anthracyclines. Apoptosis induction in three different acute lymphocytic and myelocytic leukemia cell lines; Jurkat, ML-1 and KG-1 was measured using propidium iodide staining followed by flow cytometric analysis to yield cell cycle distributions. The percentage of the population with subdiploid amounts of DNA were representative of cells undergoing apoptotic DNA fragmentation. Using this method, we found that all three anthracyclines caused cell death after 24 hours of exposure. In order to assess the role of oxidative stress in anthracycline mediated cell death in leukemia cells, we measured ROS levels using equipotent doses of the drugs that elicited a 50% increase in the subdiploid population at 24 hours. In Jurkat and ML-1 cells both daunorubicin and doxorubicin significantly increased superoxide levels compared to control. Amrubicin also increased superoxide levels in Jurkat cells compared to cells treated with diluent alone. To establish a relationship between the observed oxidative stress and DNA fragmentation, we treated Jurkat cells with daunorubicin and doxorubicin with and without pretreatment with NAC (N-acetyl-cysteine), an antioxidant. NAC pretreatment significantly decreased superoxide levels, but did not abrogate the anthracyclines' promotion of apoptotic DNA fragmentation.These results suggest that ROS may not be essential for anthracycline cytotoxicity in leukemia cells. Since ROS are promoting cardiotoxic effects, yet appear dispensible for anti-leukemia effects, anthracyclines that cause less ROS, such as amrubicin, may prove to be better treatment options in pediatric cancer patients for whom anthracycline exposure is indicated. Furthermore, our data raises the possibility that amrubicin's decreased cardiotoxicity could be enhanced by administering antioxidants to patients without compromising the drug's anti-tumor effects. Disclosures:Chandra:Pharmion Corporation: Research Funding.

Impact of Physician to Physician Interactions Utilizing Case Based Learning Workshops to Accelerate Accrual to Lymphoma Trials.

Abstract 1418Poster Board I-441 Introduction:Seventy percent of clinical trials in the United States are delayed by one to six months due to enrollment challenges. Barriers to accrual are site specific as well as protocol specific. Site specific challenges include perceptions of patient ineligibility and cumbersome screening processes. Protocol barriers include complexity of inclusion and exclusion criteria. Coomis et al (J Onc Prac 2009; 5:50) reported that 73% of overall clinical trial awareness was generated by physician interest. Therefore, the familiarity of investigators with each trial is crucial to optimizing patient accrual. The standard protocol initiation process relies on investigators and staff to attend an investigator's meeting. However, this approach does not focus on actual clinical patient presentations to determine trial eligibility or exclusion. As a result, many investigators may overlook key criteria for eligibility thus losing patients to enrollment. We have previously shown that interventions directly with PIs to increase PI awareness of inclusion/exclusion criteria of a clinical trial results in improved trial accrual (ASCO 2009, abs 6613). Methods:Investigator focused Accrual Workshops (AW) are used to increase patient enrollment to oncology clinical trials. While a standard investigator meeting includes protocol review, AW first create a compelling scientific story to re-engage the investigators in the trial. The key to these AW is the use of case-based learning to highlight the clinical and scientific rationale of the trial as opposed to general protocol review. Results:Between May 2008 and May 2009, 14 AW were conducted for 5 separate studies including 2 lymphoma trials. The AW with less than 120 days of follow up (n=5) show no significant impact although there was a trend toward increased accrual. In those with more than 120 days of follow up (n=9), the mean increase in accrual was 108% with increased accrual following every AW (Figure 1). After those 9 AW, patient accrual per month increased 1.65 fold on average. Analysis of the 2 lymphoma clinical trials demonstrates a significant increase in accrual following AW of 230% and 40%, respectively. Conclusion:AW using physician to physician clinical case-based learning provide an effective means of educating investigators and research staff in the identification of patients who meet the criteria for participation in clinical trials. The impact of AW on clinical trial accrual is best seen over time and they are effective in lymphoma clinical trials as well as others. After every AW with more than 120 day follow up, accrual was accelerated. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Pharmacodynamic (PD) Biomarker Assay Validation for SB1518, a Novel Oral JAK2 Inhibitor in Phase 1 Clinical Trials for Advanced Leukemias, Myeloproliferative Diseases and Lymphoma.

Abstract 1888Poster Board I-911 Introduction:Abnormalities in JAK2 and FLT3 kinases are reported in various hematological malignancies and may underlie the pathogenesis of these diseases. An activating mutation of JAK2, namely JAK2V617F is the most common mutation in bcr-abl-negative chronic myeloproliferative disorders (MPDs). Activation of wild type JAK2 has been reported in Hodgkin lymphoma (HL) and primary mediastinal large cell Non-Hodgkin lymphomas (NHL) due to loss of Suppressor of Cytokine Signaling (SOCS)-1 gene. Abnormalities in FLT3 are present in ∼30% of acute myelogenous leukemias (AML). SB1518 is a potent inhibitor of both JAK2 (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) as well as FLT3 (IC50 = 22 nM) and it mutant D835Y (IC50 = 6 nM). As a consequence, SB1518 inhibits the proliferation of human leukemia and lymphoma cell lines dependent on either JAK2 or FLT3 activation (IC50 =35–240 nM), and has antitumor activity in nude mouse models of FLT3- (MV4-11) or JAK2-dependent (BaF3-JAK2V617F) leukemia. SB1518 is currently being evaluated in Phase 1 clinical trials for advanced leukemias, MPDs and lymphoma. We describe here the development and assessment of biochemical biomarkers to assess the pharmacodynamic (PD) efficacy of SB1518 in the phase I clinical trials. Methods and Results:Sensitive flow cytometric and quantitative Western-blot assays were developed for measuring downstream JAK2 and FLT-3 signaling; namely STAT5/3 phosphorylation in tumor tissue, fixed cells from whole blood or lysed PBMCs. These assays were validated by demonstrating target inhibition after ex vivo treatment of PBMCs from healthy human donors and in blood cells and tumor tissue after oral dosing of normal and tumor bearing nude mice with SB1518. Initial data obtained from analysis of whole blood and PBMCs from patients treated with SB1518 in the ongoing Phase 1 clinical trials demonstrate target inhibition even at the lowest dose level of 100 mg/day on the first day of oral dosing. Conclusion:In summary, we have developed and quantitative biomarker assays and applied them to demonstrate PD target efficacy of SB1518 in animal tumor models as well as patients in ongoing phase 1 clinical trials. Disclosures:Hart:S*BIO PTE LTD: Employment, Equity Ownership. Goh:S*BIO PTE LTD: Employment. Tan:S*BIO PTE LTD: Employment. Chithra:S*BIO PTE LTD: Employment. Wood:S*BIO PTE LTD: Employment.

Identification of Potential Surrogate Endpoints in Randomized Clinical Trials of Aggressive Non-Hodgkin Lymphoma: Correlation of Complete Response, Time-to-Event and Overall Survival Data.

Abstract 3699Poster Board III-635 BackgroundAggressive histology non-Hodgkin lymphomas (NHLs) are generally treated with curative intent. Establishing appropriate surrogate endpoints for overall survival (OS) may permit more rapid evaluation and approval of new agents for aggressive NHL. Treatment failure endpoints including event-free survival (EFS) or progression-free survival (PFS) permit earlier reporting of results, but their ability to predict OS is unknown. The purpose of this study is to correlate different efficacy endpoints with the goal of identifying an appropriate surrogate endpoint for OS. MethodsRandomized controlled trials (RCTs) of previously untreated aggressive histology NHL published between 1990-2009 were identified through a systematic literature search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases. Eligible RCTs included at least 2-arms comparing different systemic treatments with ≥100 patients/arm. Studies investigating the effect of autologous stem-cell transplant and those exclusively involving T-cell lymphoma, mantle cell lymphoma or HIV-associated lymphoma were excluded. Baseline characteristics, design, treatment arms, efficacy endpoints, and results were extracted from each published RCT. Reported survival endpoints were defined as PFS, EFS, or OS according to established (ie: per protocol) definitions in the International Working Group Revised Response Criteria for Lymphoma. Absolute differences in efficacy endpoints were determined and nonparametric Spearman rank correlation coefficients were calculated to determine the association between differences in: 1) CR and each of EFS, PFS and OS and 2) EFS or PFS and OS. ResultsThirty-eight RCTs were identified representing 85 treatment arms and 16,103 patients. The median follow up was 55 months (range 20-108). The most commonly used primary endpoint was OS (55%) followed by EFS (32%), but use of CR as a primary endpoint was infrequent (5%). Differences in CR strongly correlated with differences in 3-yr EFS with a Spearman rank correlation coefficient of 0.88 (95% CI: 0.57 to 0.97). The Spearman rank correlation coefficients between differences in CR and differences in 3-yr PFS and 5-yr OS were 0.62 (95% CI: 0.21 to 0.84) and 0.50 (95% CI, 0.23 to 0.74), respectively. Differences in intermediate endpoints, 3-yr PFS or EFS, were high correlated with differences in 5 yr OS with a Spearman rank correlation coefficient of 0.90 (95%CI, 0.73-0.96). Similarly strong correlations were noted when 3-yr PFS and 3-yr EFS were each correlated with 5-yr OS separately. Linear regression determined that a 10% improvement in CR is estimated to correspond with a 9±1% improvement in 3-yr EFS and that a 10% improvement in 3-yr EFS or PFS would predict for a 7±1% improvement in 5-yr OS. ConclusionsIn RCTs of initial treatment for aggressive NHL, improvements in 3-yr EFS/PFS are highly correlated with improvements in 5-yr OS. Changes in CR rates are a strong predictor for changes in 3-yr EFS, but not for changes in 5-yr OS. This may inform future trial design since EFS or PFS appear to be appropriate surrogate endpoints for OS in this patient population. Disclosures:No relevant conflicts of interest to declare.

Selective inhibition of CDK4/CDK6 sensitizes bone marrow myeloma cells for killing by proteasome inhibitors carfilzomib and PR-047 through cell cycle-dependent expression of pro-apoptotic Noxa and Bim.

Abstract 2854Poster Board II-830Targeting the cell cycle in combination with cytotoxic killing is a rational approach to cancer therapy. Progression in multiple myeloma (MM) stems from both loss of apoptotic control in the bone marrow (BM) microenvironment and dysregulation of the cyclindependent kinases (CDK)4 and CDK6, which precedes uncontrolled proliferation of myeloma cells in vivo in particular during relapse. This reinforces the critical importance of targeting CDK4/CDK6 in MM. Through selective and reversible inhibition of CDK4/CDK6 with PD 0332991, the only known CDK4/6-specific inhibitor, we have recently developed a novel strategy to sensitize primary myeloma cells for cytotoxic killing by diverse cytotoxic drugs. These include carfilzomib (PR-171), an irreversible selective inhibitor of the chymotrypsin-like activity of the proteasome, and PR-047, an orally bioavailable analog of carfilzomib. We showed that induction of prolonged early G1 arrest following inhibition of CDK4/CDK6 markedly enhances cytotoxic killing of primary BM myeloma cells by either carfilzomib or PR-047 despite protection by BM stromal cells. The enhancement of cytotoxic killing is further augmented during synchronous S phase entry upon removal of PD 0332991 subsequent to induction of prolonged G1 arrest in myeloma cell lines. In both cases, the enhancement in carfilzomib (or PR-047) mediated killing is not associated with cell cycle regulation of the proteasome activity. It is caspase-dependent, requiring only a brief (one hour) exposure to the proteasome inhibitor at concentrations as low as 30 nM. This killing is mediated by synergistic and rapid induction of mitochondrial membrane depolarization and activation of downstream caspase-9. Further, it is apparently initiated by cell cycle-dependent expression of the pro-apoptotic BH3-only proteins, which neutralize the anti-apoptotic Bcl-2 family proteins upstream of mitochondrial depolarization. Bim is upregulated during early G1 arrest to neutralize the anti-apoptotic MCL-1 and Bcl-2. By contrast, Noxa is silenced in G1 but dramatically upregulated in S phase, in particular when combined with carfilzomib. Importantly, targeting CDK4/CDK6 with PD 0332991 in combination with either carfilzomib or PR-047 leads to complete eradication of myeloma cells ex vivo, in contrast to the combination of PD 0332991 with other proteasome inhibitors. Selective inhibition of CDK4/CDK6 in combination with carfilzomib (or PR-047), therefore, not only halts tumor cell proliferation but also potently induces synergistic killing that is likely to profoundly inhibit cell cycle reentry and self-renewal in MM. PD 0332991 is a small molecule with bio-availability and proven tumor suppressing activity in both human myeloma xenograft and immunocompetent mouse myeloma models. It is well tolerated in humans as indicated by the ongoing Phase I/II clinical trials in myeloma and previous phase I trials in mantle cell lymphoma and solid tumors. Evidence from Phase 2 trials of carfilzomib indicates that it is also well tolerated, in fact, the peripheral neuropathy that is commonly observed with the proteasome inhibitor bortezomib appears to be less severe and possibly less frequent. Mechanism-based targeting of CDK4/6 in combination with selective proteasome inhibitors, like carfilzomib and PR-047, thus represents a new and promising therapeutic strategy for multiple myeloma and potentially other hematopoietic malignancies. Disclosures:Off Label Use: PD 0332991 is going to be used as a CDK4/6-specific inhibitor. Parlati:Proteolix, Inc.: Employment, Equity Ownership. Aujay:Proteolix, Inc.: Employment, Equity Ownership. Niesvizky:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics, Inc: Research Funding; Proteolix: Research Funding, data monitoring committee.