Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

BACKGROUND: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. METHODS: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. RESULTS: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. CONCLUSIONS: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

Early Generated B-1-Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma-like Neoplasia in Aged Mice.

In mice, fetal/neonatal B-1 cell development generates murine CD5+ B cells (B1a) with autoreactivity. We analyzed B1a cells at the neonatal stage in a VH11/D/JH knock-in mouse line (VH11t) that generates an autoreactive antiphosphatidylcholine BCR. Our study revealed that antiphosphatidylcholine B1a cells develop in liver, mature in spleen, and distribute in intestine/colon, mesenteric lymph node (mLN), and body cavity as the outcome of B-1 cell development before B-2 cell development. Throughout life, self-renewing B-1 B1a cells circulate through intestine, mesenteric vessel, and blood. The body cavity-deposited B1a cells also remigrate. In old age, some B1a cells proceed to monoclonal B cell lymphocytosis. When neonatal B-1 B1a cells express an antithymocyte/Thy-1 autoreactivity (ATA) BCR transgene in the C.B17 mouse background, ATA B cells increase in PBL and strongly develop lymphomas in aging mice that feature splenomegaly and mLN hyperplasia with heightened expression of CD11b, IL-10, and activated Stat3. At the adult stage, ATA B cells were normally present in the mantle zone area, including in intestine. Furthermore, frequent association with mLN hyperplasia suggests the influence by intestinal microenvironment on lymphoma development. When cyclin D1 was overexpressed by the Eµ-cyclin D1 transgene, ATA B cells progressed to further diffused lymphoma in aged mice, including in various lymph nodes with accumulation of IgMhiIgDloCD5+CD23-CD43+ cells, resembling aggressive human mantle cell lymphoma. Thus, our findings reveal that early generated B cells, as an outcome of B-1 cell development, can progress to become lymphocytosis, lymphoma, and mantle cell lymphoma-like neoplasia in aged mice.

Understanding the presence of mental fatigue in English academy soccer players.

Research has demonstrated that induced mental fatigue impairs soccer-specific technical, tactical and physical performance in soccer players. The findings are limited by the lack of elite players and low ecological validity of the tasks used to induce mental fatigue, which do not resemble the cognitive demands of soccer. The current study collected survey data from English academy soccer players (n = 256; age groups - U14 - U23), with questions comprising of five themes (descriptors of physical and mental fatigue, travel, education, match-play and fixture congestion). The survey consisted of multiple choice responses, checkboxes and blinded/unblinded (for duration based questions) 0-100 arbitrary unit (AU) slider scales. Listening to music (81.6% of players), using social media (58.3%) and watching videos (34.3%) were the most common pre-match activities. Pre-match subjective mental fatigue was low (18.7±18.8 AU), and most frequently reported at the end of a match (47±26 AU) and remained elevated 24-hours post-match (36±27 AU). Travel (29±24 AU), fixture congestion (44±25 AU) and education (30±26 AU) demonstrated a low to moderate presence of subjective mental fatigue. These findings provide an overview of activities performed by English academy soccer players pre-match, and demonstrate that mental fatigue is experienced as a result of match-play.

Dribble Deficit quantifies dribbling speed independently of sprinting speed and differentiates between age categories in pre-adolescent basketball players.

The aims of this study were to a) quantify the relationships between sprinting and dribbling speed measured using dribble time and Dribble Deficit and b) assess the difference between age categories in sprinting and dribbling speed in pre-adolescent basketball players. Pre-adolescent, male basketball players (Total, N = 81; Under-10, n = 32, Under-9, n = 49) completed two trials of different tasks including 20-m linear sprints without dribbling, 20-m linear sprints dribbling with dominant and non-dominant hands, and change-of-direction (COD) sprints with and without dribbling. Sprinting time, dribbling time and Dribble Deficit were then calculated for each trial. Spearman rank correlations were used to assess the relationships between outcome measures for Under-9 and Under-10 players separately and combined. The Mann-Whitney U test with effect sizes (ES) was used to assess differences in outcome measures between Under-9 and Under-10 players. Moderate-to-very large significant relationships (p <0.05) between linear and COD sprinting time and dribbling time using dominant and non-dominant hands were found in Under-9, Under-10 and all players combined. Trivial-to-moderate relationships were found between sprinting time and Dribble Deficit in all age categories across linear and COD paths. Quicker performance times (p <0.05) were found for Under-10 compared to Under-9 players in all outcome measures (ES: small-to-moderate), except for COD sprinting time (p >0.05; ES: small). Dribble Deficit measures dribbling speed independently of sprinting speed across linear and COD paths in pre-adolescent basketball players and differentiates between age categories.

Ibrutinib: a force with a dark side?

In this issue of Blood, Martin et al report poor outcomes for ibrutinib-refractory patients with mantle cell lymphoma (MCL). MCL, an uncommon B-cell lymphoma driven by dysregulated cyclin D1, responds well to initial therapy but is destined to relapse. Subsequent single-agent treatments had modest response rates and duration until the advent of ibrutinib. These data are important, given that ibrutinib is not curative, so clinicians will increasingly encounter patients with MCL who require therapy after ibrutinib.

Long-term outcomes, secondary malignancies and stem cell collection following bendamustine in patients with previously treated non-Hodgkin lymphoma.

Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Impact of comorbidities on outcomes of elderly patients with diffuse large B-cell lymphoma.

International prognostic index (IPI) has remained the primary prognostic tool in diffuse large B cell lymphoma (DLBCL) for more than 20 years. Even though the disease is more common in older population, the impact of comorbidities, dose reductions, and treatment-related adverse events (TAEs) on the outcome in elderly DLBCL patients has not been well established. We studied 413 consecutive patients aged ≥ 60 years who were treated at the Cleveland Clinic. The median age at diagnosis was 69 years, 58% of patients had high IPI score, and 85% had low Charlson comorbidity index (CCI). Forty percent of patients required dose reductions during treatment, 78% achieved CR, and 70% experienced at least one grade II-IV TAE. High IPI score, high CCI, reduced dose chemotherapy, TAE, and hospitalization were significant predictors of death and relapse. In multivariable analysis, high IPI and CCI were independent predictors of overall and progression free survival. A simple model combining IPI and CCI could reliably distinguish three prognostically separate risk groups. Our results suggest that incorporation of CCI in current prognostic models can improve prognostication of older DLBCL patients and CCI might be a valuable tool in evaluating the eligibility of older patients for clinical trial enrollment.

Is rituximab sub-optimally dosed in indolent B cell lymphoma?

Rituximab pharmacokinetics are affected by gender, age and weight and can affect outcomes in aggressive B cell lymphoma. Less is known about the pharmacokinetics of rituximab in indolent B cell lymphoma (iNHL). We analysed the effects of gender, age, weight and body surface area on the outcomes of 303 patients treated with first line rituximab-based regimens for iNHL. The patients were divided into 3 treatment cohorts: rituximab only, rituximab + chemotherapy (R-CTX) and R-CTX followed by rituximab maintenance; furthermore, each cohort was subdivided as follicular (FL) or non-FL, based on histology. Older males and patients with higher weight had worse outcomes when treated with R-CTX, probably due to faster rituximab clearance. Our results concur with studies of R-CTX for DLBCL. As this effect was not observed in patients treated with rituximab alone or R-CTX followed by rituximab maintenance, we hypothesize that higher rituximab levels reached with weekly rituximab and/or prolonged exposure achieved with maintenance therapy exceed the therapeutic threshold, even with faster clearance, which nullifies the negative effect of higher weight and male gender. In conclusion, under current practices, a subset of patients with iNHL, i.e., FL treated with R-CTX, may be sub-optimally dosed with rituximab.

Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.

Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t-AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.

Dual institution experience of nodal marginal zone lymphoma reveals excellent long-term outcomes in the rituximab era.

Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin lymphoma that arises from mature B-cells. We delineate outcomes, prognostic factors and treatment trends among a large cohort of patients with NMZL in the rituximab era. We identified 56 such patients treated at our institutions. The majority presented with advanced stage disease (78·6%). Over a median follow-up of 38·2 months, median progression-free survival (PFS) was 42·4 months and median overall survival (OS) was not reached. Kaplan-Meier estimates of OS at 120 months after diagnosis was 71·9%. High-risk follicular lymphoma international prognostic index (FLIPI) was associated with inferior PFS. Age >60 years and elevated serum lactate dehydrogenase (LDH) were associated with inferior OS. Transformation to diffuse large B-cell lymphoma occurred in 7 patients, 6 of who presented with advanced disease. OS was comparable to our previously reported extranodal MZL cohort. FLIPI score predicted for inferior PFS and OS when both cohorts were analysed together (n = 267). In summary, outcomes in NMZL are favourable with a large majority of patients surviving at 120 months. High risk FLIPI, age >60 years, and elevated serum LDH were associated with inferior outcomes.

Dual institution experience of extranodal marginal zone lymphoma reveals excellent long-term outcomes.

Extranodal marginal zone lymphoma (EMZL) is a B-cell lymphoma arising from mucosa-associated lymphoid tissue (MALT). The disease characteristics, clinical course and treatment vary considerably based on site of involvement. Because long-term outcome data for EMZL are limited, we sought to describe the clinical details of a large number of patients with EMZL evaluated at the Case Comprehensive Cancer Center over a 12-year period to identify prognostic markers including the impact of site of involvement. We identified 211 cases of EMZL involving the stomach (30%), ocular adnexa (19%), lungs (16%) and intestines (9%). Initial treatment included antibiotics (18%), radiation (21%), rituximab (20%), chemotherapy (3%), rituximab + chemotherapy (7%), surgery (17%) or observation (8%). After a median follow-up of 44·3 months (range 2·2-214·9), median progression-free survival (PFS) was 68·2 months (95% confidence interval [CI] 54·5-111·3) and median overall survival (OS) has not been reached. Age >60 years, elevated lactate dehydrogenase level (LDH), ≥4 lymph node groups involvement, and high follicular lymphoma international prognostic index (FLIPI) were associated with inferior PFS/OS. In summary, patients with EMZL have excellent prognosis with median OS in excess of 10 years. Age, elevated LDH, advanced disease, and high FLIPI score are associated with worse outcomes.

Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405).

Rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) were evaluated for efficacy and safety in Eastern Cooperative Oncology Group protocol E1405. Patients with previously untreated mantle cell lymphoma received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant-eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary end points were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n = 44) vs ASCT (n = 22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in mantle cell lymphoma. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials comparing MR against ASCT should be considered and randomized clinical trials evaluating bortezomib's contribution to conventional therapy are under way. This study was registered at www.clinicaltrials.gov as #NCT00433537.

Antibody Drug Conjugates (ADCs): Changing the Treatment Landscape of Lymphoma.

OPINION STATEMENT: While strides advancing cancer treatment have made it possible to cure some malignancies, the effort to strike an intricate balance between attaining higher efficacy and lower toxicity has been difficult to accomplish, especially with conventional chemotherapy agents. Introduction of antibody drug conjugates (ADCs) has brought us a step closer to this goal and made it possible to target the cancer cells and to minimize effects on normal tissue. Continued efforts have led to approval of two ADCs for cancer therapy, while many others are in various stages of clinical development. The design of ADCs allows them to be internalized into the cancer cells where the drug payload is released and leads to cell death. The key is to identify targets that are exclusively expressed on malignant cells with minimal or no expression on normal cells, which allows for selective killing of tumor cells. Development and approval of more potent ADCs could change the landscape of cancer therapy and possibly eliminate traditional chemotherapy agents from treatment algorithms. In this review, we discuss the ADCs that are being investigated in early and late stage clinical trials for the treatment of B cell non-Hodgkin lymphoma (NHL).

Mental fatigue impairs soccer-specific decision-making skill.

This study aimed to investigate the impact of mental fatigue on soccer-specific decision-making. Twelve well-trained male soccer players performed a soccer-specific decision-making task on two occasions, separated by at least 72 h. The decision-making task was preceded in a randomised order by 30 min of the Stroop task (mental fatigue) or 30 min of reading from magazines (control). Subjective ratings of mental fatigue were measured before and after treatment, and mental effort (referring to treatment) and motivation (referring to the decision-making task) were measured after treatment. Performance on the soccer-specific decision-making task was assessed using response accuracy and time. Visual search behaviour was also assessed throughout the decision-making task. Subjective ratings of mental fatigue and effort were almost certainly higher following the Stroop task compared to the magazines. Motivation for the upcoming decision-making task was possibly higher following the Stroop task. Decision-making accuracy was very likely lower and response time likely higher in the mental fatigue condition. Mental fatigue had unclear effects on most visual search behaviour variables. The results suggest that mental fatigue impairs accuracy and speed of soccer-specific decision-making. These impairments are not likely related to changes in visual search behaviour.

miR-377-dependent BCL-xL regulation drives chemotherapeutic resistance in B-cell lymphoid malignancies.

BACKGROUND: BCL-xL is an anti-apoptotic BCL-2 family protein that inhibits apoptosis and is overexpressed in many cancers. We have reported that acquired resistance to the BCL-2 inhibitor ABT-199 (venetoclax) is associated with increased BCL-xL expression. Yet, how BCL-xL mediates chemoresistance in hematopoietic malignancies is not clear. This finding may help in design of new strategies for therapeutic intervention to overcome acquired chemoresistance mediated by BCL-xL. RESULTS: We now show that the increased BCL-xL expression was inversely correlated with that of miR-377 in ABT-199-resistant cells. This finding was also extended to a panel of B-cell lymphoid lines and primary chronic lymphocytic leukemia (CLL) cells. miR-377 suppressed BCL-xL expression by recognizing two binding sites in the BCL-xL 3'-UTR. Mutation of these two miR-377 consensus-binding sites completely abolished its regulatory effect. Expression of a miR-377 mimic downregulated BCL-xL protein expression and significantly increased apoptotic cell death. Expression of a miR-377 inhibitor restored BCL-xL protein expression and limited cell death caused by the hypomethylating agent 5-azacytidine. Thus, miR-377-dependent BCL-xL regulation drives acquired therapeutic resistance to ABT-199. We further show that CLL patients who received a diverse array of chemotherapy regimens also had significantly higher BCL-xL and lower miR377 expression, indicating that exposure to chemotherapy might trigger transcriptional silencing of miR-377, which results in high levels of BCL-xL. Importantly, CLL patients with high BCL-xL/low miR-377 expression had an advanced tumor stage. Moreover, the high BCL-xL expression correlated with short treatment-free survival in 76 CLL patients. miR-377 is located at 14q32 in the DLK1-DIO3 region, which encodes the largest tumor suppressor miRNA cluster in humans. Examination of five additional 14q32 miRNAs revealed that the majority were significantly down-regulated in most CLL patients as well as in ABT-199-resistant cell lines. Remarkably, four of these miRNAs had significantly decreased expression in chemotherapy-treated CLL patients as compared to those untreated. These findings indicate a reduced expression of multiple miRNAs that may reflect a global silencing of this miRNA cluster in therapy-resistant lymphoid cells. CONCLUSIONS: These findings reveal a novel mechanism by which down-regulation of miR-377 increases BCL-xL expression, promoting chemotherapy resistance in B-cell lymphoid malignancies.

Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma: a multicentre phase II study.

There is a lack of published data examining non-cytotoxic options for the frontline treatment of patients with high-tumour burden (HTB) indolent non-Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty-two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n = 33, 79%). Patient characteristics included median age 62 years (40-86); 38% bulky disease; 19% malignant effusions; 91% advanced-stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent-to-treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50-month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four-year PFS for FLIPI 0-2 vs. 3-5 was 60% vs. 26% respectively (P = 0·02), with corresponding OS rates of 92% and 81% respectively (P = 0·16). Collectively, bortezomib/rituximab is a non-cytotoxic therapeutic regimen that was well tolerated and resulted in long-term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL.

Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS.

Reliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow-up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03-3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.

Comparison of the prognostic utility of the revised International Prognostic Scoring System and the French Prognostic Scoring System in azacitidine-treated patients with myelodysplastic syndromes.

The revised International Prognostic Scoring System (IPSS-R) was developed in a cohort of untreated myelodysplastic syndromes (MDS) patients. A French Prognostic Scoring System (FPSS) was recently reported to identify differential survival among azacitidine-treated patients with high-risk MDS. We applied the FPSS and IPSS-R to 150 patients previously randomized to azacitidine monotherapy or a combination of azacitidine with entinostat (a histone deacetylase inhibitor). Neither score predicted response but both discriminated patients with different overall survival (OS; median OS, FPSS: 9·7, 14·7, and 25·3 months, P = 0·018; IPSS-R: 12·5, 11·3, 20·8, and 36 months, P = 0·005). Statistical analysis suggested no improvement in OS prediction for the FPSS over the IPSS-R in azacitidine-treated patients.

Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) carries an unfavorable prognosis and requires new treatment strategies. The associated t(11:14) translocation results in enhanced cyclin D1 expression and cyclin D1-dependent kinase activity to promote cell-cycle progression. A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease, using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3-deoxy-3[(18)F]fluorothymidine (FLT) positron emission tomography (PET) to study tumor metabolism and proliferation, respectively, in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein (Rb) phosphorylation and markers of proliferation and apoptosis. Substantial reductions in the summed FLT-PET maximal standard uptake value (SUV(max)), as well as in Rb phosphorylation and Ki-67 expression, occurred after 3 weeks in most patients, with significant correlations among these end points. Five patients achieved progression-free survival time of > 1 year (range, 14.9-30.1+ months), with 1 complete and 2 partial responses (18% objective response rate; 90% confidence interval, 5%-40%). These patients demonstrated > 70%, > 90%, and ≥ 87.5% reductions in summed FLT SUV(max) and expression of phospho-Rb and Ki67, respectively, parameters necessary but not sufficient for long-term disease control. The results of the present study confirm CDK4/6 inhibition by PD0332991 at a well-tolerated dose and schedule and suggest clinical benefit in a subset of MCL patients. This study is registered at www.clinicaltrials.gov under identifier NCT00420056.