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The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p

PURPOSE Commonly used first-line (1L) treatments for mantle cell lymphoma include high-dose cytarabine-based induction followed by autologous stem-cell transplant (ASCT) for younger patients and several chemoimmunotherapy regimens for older patients. Continuous debates exist on the role of ASCT in younger patients and maintenance rituximab (MR) after bendamustine plus rituximab (BR). METHODS Retrospective data from 4,216 patients with mantle cell lymphoma in the Flatiron Health electronic record-derived deidentified database diagnosed between 2011 and 2021, mostly in US community oncology settings, were evaluated for treatment patterns and outcomes. The efficacy findings with ASCT and MR were validated in an independent cohort of 1,168 patients from 12 academic centers. RESULTS Among 3,614 patients with documented 1L treatment, BR was the most used. Among 1,265 patients age < 65 years, 30.5% received cytarabine-based induction and 23.5% received ASCT. There was no significant association between ASCT and real-world time to next treatment (hazard ratio [HR], 0.84; 95% CI, 0.68 to 1.03; P = .10) or overall survival (HR, 0.86; 95% CI, 0.63 to 1.18; P = .4) among ASCT-eligible patients. Among MR-eligible patients, MR after BR versus BR alone was associated with a longer real-world time to next treatment (HR, 1.96; 95% CI, 1.61 to 2.38; P < .001) and overall survival (HR, 1.51; 95% CI, 1.19 to 1.92; P < .001). The efficacy findings were consistent in the validation cohort. CONCLUSION In this large cohort of patients treated primarily in the US community setting, only one in four young patients received cytarabine or ASCT consolidation, suggesting the need to develop treatments that can be delivered effectively in routine clinical practice. Together with the validation cohort, data support future clinical trials exploring regimens without ASCT consolidation in young patients, whereas MR should be considered for patients after 1L BR and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 24% of new cases of B-cell non-Hodgkin lymphoma in the US each year. Up to 50% of patients relapse or are refractory (R/R) to the standard first-line treatment option, R-CHOP. The anti-CD19 monoclonal antibody tafasitamab, in combination with lenalidomide (LEN), is an NCCN preferred regimen for transplant-ineligible patients with R/R DLBCL and received accelerated approval in the US (July 2020) and conditional marketing authorization in Europe (August 2021) and other countries, based on data from the L-MIND study. The recommended dose of tafasitamab is 12 mg/kg by intravenous infusion, administered in combination with LEN 25 mg for 12 cycles, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. Tafasitamab + LEN is associated with durable responses in patients with R/R DLBCL. The majority of clinically significant treatment-associated adverse events are attributable to LEN and can be managed with dose modification and supportive therapy. We provide guidelines for the management of patients with R/R DLBCL treated with tafasitamab and LEN in routine clinical practice, including elderly patients and those with renal and hepatic impairment, and advice regarding patient education as part of a comprehensive patient engagement plan. Our recommendations include LEN administration at a reduced dose if required in patients unable to tolerate the recommended dose. No dose modification is required for tafasitamab in special patient populations.

PURPOSE Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent (c) BTKi pre-treated mantle cell lymphoma (MCL), a population with poor prognosis. PATIENTS AND METHODS Patients with cBTKi pre-treated relapsed/refractory MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 trial (BRUIN, NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. RESULTS Median patient age was 70 years (range, 46-87), median prior lines of therapy 3 (range, 1-8), 82.2% had discontinued a prior cBTKi due to disease progression, and 77.8% had intermediate or high risk sMIPI score. The ORR was 57.8% (95% CI, 46.9-68.1), including 20.0% complete responses (n=18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5-not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n=164), the most common treatment-emergent adverse events (TEAE) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAE of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib due to a treatment-related AE. CONCLUSION Pirtobrutinib is a first-in-class novel non-covalent (reversible) BTKi, and the first BTKi of any kind to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated relapsed/refractory MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity.

Mantle cell lymphoma (MCL) is a rare, incurable hematological malignancy with a heterogenous presentation and clinical course. A wide variety of chemotherapy-based regimens are currently utilized in untreated patients. Several targeted or small molecule therapies have shown efficacy in the relapsed/refractory (R/R) setting over the last several years and have since been explored in the frontline setting. Lenalidomide plus rituximab was explored in a phase II study of 38 untreated patients with MCL ineligible for transplant, where the combination produced durable remissions. We looked to build upon this regimen by adding venetoclax to the combination. We conducted a multi-center, open-label, non-randomized, single arm study to evaluate this combination. We enrolled 28 unselected patients with untreated disease irrespective of age, fitness or risk factors. Lenalidomide was dosed at 20 mg daily on days 1-21 of each 28-day cycle. The dose of venetoclax was determined using the TITE-CRM model. Rituximab was dosed at 375 mg/m2 weekly starting on cycle 1 day 1 until cycle 2 day 1. No DLTs were noted. All patients were treated with venetoclax at the maximum tolerated dose of 400 mg daily. The most common Adverse Events noted were neutropenia and thrombocytopenia. The overall and complete response rates were 96% and 86% respectively. 86% of patients achieved minimal residual disease undetectability by NGS. The median overall and progression-free survivals were not reached. The combination of lenalidomide, rituximab and venetoclax is a safe and effective regimen in patients with untreated MCL. Clinical trial # NCT03523975.

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Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

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Chronic lymphocytic leukemia (CLL) exhibits high remission rates after initial chemoimmunotherapy, but with relapses with treatment, refractory disease is the most common outcome, especially in CLL with the deletion of chromosome 11q or 17p. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment. Auranofin (Ridaura) is approved for use in treating rheumatoid arthritis, but it exhibited preclinical efficacy in CLL cells. By inhibiting thioredoxin reductase activity and increasing intracellular reactive oxygen species levels, auranofin induced a lethal endoplasmic reticulum stress response in cultured and primary CLL cells. In addition, auranofin displayed synergistic lethality with heme oxygenase-1 and glutamate-cysteine ligase inhibitors against CLL cells. Auranofin overcame apoptosis resistance mediated by protective stromal cells, and it also killed primary CLL cells with deletion of chromosome 11q or 17p. In TCL-1 transgenic mice, an in vivo model of CLL, auranofin treatment markedly reduced tumor cell burden and improved mouse survival. Our results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL. Cancer Res; 74(9); 2520–32. ©2014 AACR.

Supplemental Figure 1: Chemical structures of the molecules utilized in this study. Supplemental Table 1: Characteristics of the primary CLL cells utilized in these studies. Supplemental Figure 2: Apoptosis of CLL cells with AF and NAC. Supplemental Figure 3: AF effects on nurse-like cells (NLCs). Supplemental Table 2: Leukemia cell burden in TCL-1 mice pre and post treatment with AF. Supplemental Table 3: Gene expression changes in CLL cells after 8 hrs of AF treatment. Supplemental Table 4: Ingenuity Pathway Analysis of perturbed networks in Primary CLL cells after AF treatment. Supplemental Figure 4: IPA analysis of connected networks in CLL cells. Supplemental Figure 5: Synergy of AF with BSO or Zn-BG in CLL cells. Supplemental Figure 6: Hydrogen peroxide mediated effects on ROS, ER stress and apoptosis in CLL cells.

The improved understanding of lymphoma biology and recent advances in the field of cancer immunology have paved the way for the development of many effective small molecule inhibitors and immunotherapies in B cell non-Hodgkin’s lymphomas. This article reviews novel treatments that have been approved recently by the US Food and Drug Administration and are now routinely used in clinical practice. It discusses their mechanisms of action, efficacy and safety, current therapeutic roles, and future directions in the treatment paradigm of different types of B cell non-Hodgkin’s lymphoma. It also reviews other exciting novel treatments that are not yet approved but have unique mechanisms of action and have shown encouraging early results.

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.

Low-grade CD5-negative B-cell lymphoproliferative disorders (CD5- LG B-LPD) encompass several entities that often show mutations in different growth regulatory pathways. These include MYD88 (TLR signaling), CD79A/B (BCR complex), CARD11 (CBM signalosome), CXCR4 (chemokine receptor), and NOTCH1/2 and are complemented by KLF2 mutations and BCL6 and MALT1 overexpression. Using targeted, next-generation sequencing (NGS) for 50 B-cell associated growth regulators and epigenetic modifiers (>1000X depth) and cytogenetic/FISH data, we sought to delineate the complementary mutation and gene amplification patterns in 45 consecutive cases of CD5- LG B-LPD. In mutation-negative cases, a 572-gene NGS panel was used to interrogate these pathways more completely. WHO diagnostic criteria were used, without reliance on molecular data, emphasizing morphology features, paraprotein level and type to distinguish lymphoplasmacytic lymphoma (LPL) from marginal zone lymphoma (MZL). As expected, MYD88 L265P mutations were seen in the majority of LPL (11/17, 65%), but also in CD5- chronic lymphocytic leukemia (CLL) (3/9, 33%) and splenic (S) MZL (1/6, 17%) but not in nodal MZL. In 4 LPL cases lacking MYD88 L265P, extra copies of chromosome 3 (BCL6), 6 (IRF4), 12 and/or 18 (MALT1) were seen, with CARD11 mutations in the other 2. NOTCH1/2 mutations were mostly associated with SLL/CLL (3/9, 33%). Mutations in epigenetic regulators (see Table) were seen in the majority of nodal MZL (8/13, 62%) but only few LPL (2/17, 12%) and SMZL (1/6, 17%). CXCR4 inactivating mutations were seen with MYD88 and CD79B mutations and +3/BCL6 alteration. CARD11 mutations were seen with KLF2, MYD88 and NOTCH1/2 mutations. Less common mutations targets included PTPRC and PLCG2 (pre-ibrutinib treatment). The higher rate of mutation in epigenetic regulators (along with loss of KLF2-mediated BCR signaling) supports a distinct pathogenesis for nodal MZL in contrast to other CD5- B-LPD. Calls per gene in MYD88 negative cases; *TP53, TET2, ASXL1, DNMT3A, BCORCD79BCARD11NOTCH1/2CXCR4KLF2Epigenetic gene set*LPL023000010000000010CD5- CLL000002001001001000001000000001sMZL011010010000000001nMZL000002000022000001010011000101000001000001000001012010000200 Citation Format: Sophia Shaddy, Weiqiang Zhao, Huolin Tu, Brianna Sisson, Rongqin Ren, Sean Caruthers, Susan Long, Peng Ru, Narendranath Epperla, Lynne Abruzzo, Kami Maddocks, Dan Jones. Distinct and overlapping patterns of B-cell growth pathway mutations in CD5-negative B-cell lymphoproliferative disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 481.

Purpose Paclitaxel therapy often result in a unique subacute pain syndrome, commonly termed "myalgia" or "arthralgia." The pathophysiology of this syndrome is unknown and has not been demonstrated to be associated with any structural alteration of muscles or joints. We hypothesized that this syndrome was caused by a neuropathic nerve injury from paclitaxel. Herein, we characterize the clinical characteristics of this syndrome using detailed patient interviews and consider the putative mechanism(s) for these symptoms. Methods Oncology patients who were treated with paclitaxel and developed a subacute pain syndrome were questioned using a detailed structured interview. Data were tabulated descriptively. Results Eighteen patients were interviewed. The symptoms (ie, pain) typically began 1-2 days after the infusion and lasted for a median of 4-5 days. Pain was most commonly located in the back, hips, shoulders, thighs, legs, and feet, with the most common descriptors used being "aching" or "deep pain." Commonly used adjectives to describe the pain were radiating, shooting, aching, stabbing, and pulsating. Some patients described increased pain with weight bearing, walking, or tactile contact. When asked directly whether the pains appeared to be specifically localized to either joints or muscles, 15 of 18 patients denied localization. Discussion Based on the nature and temporal occurrence of the paclitaxel acute pain syndrome symptoms, we infer that the paclitaxel acute pain syndrome occurs as a result of sensitization of nociceptors, their fibers, or the spinothalamic system. This proposed neurologic etiology of this pain may also explain the subsequent development in some patients of a symmetric length-dependent sensorimotor polyneuropathy. The mechanism of this syndrome needs further study.

Previous studies suggested that patients with chronic lymphocytic leukaemia (CLL) are at a three- to fivefold increased risk of developing a second lymphoproliferative disorder (LPD). This observational cohort study used the Mayo Clinic CLL Database to identify factors associated with developing a second LPD. A second LPD was identified in 26 (2.7%) of 962 CLL patients during a median follow-up of 3.3 years. Diffuse large B-cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Patients previously treated for CLL had a trend toward higher prevalence of second LPD (4%) compared with previously untreated patients (2%; P = 0.053). More strikingly, patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5.2%) compared with patients who had not received PNA (1.9%; P = 0.008). No statistically significant association was observed between risk of second LPD and other CLL characteristics (ZAP-70, CD38, IgV(H) mutation status or cytogenetic abnormalities). In this series, prior treatments with PNA or anthracyclines were the only significant factors associated with risk of developing a second LPD in patients with CLL. Physicians should strictly adhere to established criteria to initiate treatment for CLL patients who are not participating in clinical trials.

Mantle cell lymphoma (MCL) is a distinct B-cell non-Hodgkin's lymphoma (NHL) defined by the translocation t(11;14). MCL combines characteristics of both indolent and aggressive lymphomas, and it is incurable with conventional chemoimmunotherapy but has a more aggressive disease course. Minimal data exist on treatment of patients diagnosed with early-stage disease (stage I-II non-bulky), as this represents only a small portion of the patients diagnosed with MCL, but therapeutic options evaluated in retrospective studies include radiation or combination radiation and chemotherapy. There is a subset of patients with newly diagnosed MCL that can be observed without treatment, but the majority of patients will require treatment at diagnosis. Treatment is often based on age (≤65-70 years of age), comorbidities, and risk factors for disease. The majority of patients who are younger and without significant comorbidities are treated with intensive induction using combination chemoimmunotherapy regimens, many which include consolidation with autologous stem cell transplant (ASCT). Several regimens have been studied that show improved median progression-free survival (PFS) to 3-6 years in this population of patients. The majority of older patients (≥65-70 years of age) are treated with combination chemoimmunotherapy regimens with consideration of rituximab maintenance, with enrollment on a clinical trial encouraged. Therapy for relapsed disease is dependent on prior treatment, age, comorbidities, and toxicities but includes targeted therapies such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, the immunomodulatory agent lenalidomide, the proteasome inhibitor bortezomib, combination chemoimmunotherapy, ASCT, and allogeneic stem cell transplant in selected cases. Several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed setting.

Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg m(-2) intravenous bolus (IVB) + 30 mg m(-2) continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg m(-2) IVB + 50 mg m(-2) CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.

Previous studies suggested that patients with chronic lymphocytic leukaemia (CLL) are at a three- to fivefold increased risk of developing a second lymphoproliferative disorder (LPD). This observational cohort study used the Mayo Clinic CLL Database to identify factors associated with developing a second LPD. A second LPD was identified in 26 (2.7%) of 962 CLL patients during a median follow-up of 3.3 years. Diffuse large B-cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Patients previously treated for CLL had a trend toward higher prevalence of second LPD (4%) compared with previously untreated patients (2%; P = 0.053). More strikingly, patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5.2%) compared with patients who had not received PNA (1.9%; P = 0.008). No statistically significant association was observed between risk of second LPD and other CLL characteristics (ZAP-70, CD38, IgV(H) mutation status or cytogenetic abnormalities). In this series, prior treatments with PNA or anthracyclines were the only significant factors associated with risk of developing a second LPD in patients with CLL. Physicians should strictly adhere to established criteria to initiate treatment for CLL patients who are not participating in clinical trials.

Complexity has been associated with an adverse outcome in CLL (Kujawski et al. Blood 2008, 112:1993), and cytogenetic complexity often evolves as the patient progresses (Blood 2013, 121:1403). We sought to determine whether the degree of complexity as determined by cytogenetic analyses correlated with time-to-treatment (TTT) or with overall survival (OS) and its relationship with del(17p). Patients (pts) with CLL who had cytogenetic analyses completed between December 2006 and May 2011 were identified from The Ohio State University Wexner Medical Center (OSU) databases. The first cytogenetic analysis evaluated within one year of diagnosis and prior to treatment was considered the diagnostic sample. All but one cytogenetic analyses were performed using CpG +/- pokeweed mitogen and phorbol 12-myristate 13-acetate stimulation. Cytogenetic methods and analyses were by standard laboratory protocols. Fluorescence in situ hybridization (FISH) was performed on all cases. For these analyses, probes for ATM (11q22.3) and TP53 (17p13.1) (Abbott Molecular, Des Plaines, IL) were used according to the manufacturer's recommendations. Complex karyotype (CK) was defined as ≥3 independent aberrations. Associations between CK and clinical or molecular characteristics were tested using Fisher's exact or Wilcoxon rank sum tests. TTT was calculated from the date of diagnosis until the date of treatment, censoring pts who had not started treatment at the date last seen. OS was calculated from the date of diagnosis until the date of death or last follow-up. Estimates of TTT and OS were calculated using the Kaplan-Meier method, and differences in survival distributions were compared using the log-rank test. Diagnostic samples meeting the above criteria were identified in 143 pts. Median age was 58 (range 33-85), 38% were female, and 44% had Rai stage 0. Twenty pts (14%) had del(11q) and 16 (11%) had del(17p), 10 of which were identified by both FISH and karyotype, 4 by FISH alone, and 2 by karyotype alone. CK was detected in 22 pts (15%, 95% CI: 0.10-0.22). CK tended to be more prevalent in males (20% vs 7% in females, p=0.05) and in those with Rai stage ≥ I (20% vs 8% with Rai stage 0, p=0.06), but there was no significant association with age (p=0.98). Only 5 CK pts (23%) had del(11q) compared to 12% without CK (NCK; p=0.20). CK was strongly associated with del(17p), where 41% of CK pts harbored this typically high-risk aberration versus only 6% in NCK pts (p TTT was significantly shorter in pts with CK compared to NCK (p=0.0005), with 12 mos estimates of 55% (95%CI=0.31-0.74) and 83% (95%CI=0.75-0.89), respectively (Figure 1A). In the subsets of pts with and without del(17p), the negative impact of CK persisted as shown in Figures 2A-B. In a proportional hazards model for TTT, CK remained significantly associated with shorter TTT independent of del(17p) and Rai stage (hazard ratio=2.20, 95%CI=1.03-4.71; p=0.04). With a median follow-up of 32 months for OS, there have been only 14 events. Still, early deaths tended to occur more often in those with CK than NCK; five deaths occurred in the first 12 mos following diagnosis, 3 in the CK group (13.6%) and 2 in the NCK group (1.7%), and hence there was a significant difference in OS (p=0.015; Figure 1B). The limited information prevented meaningful comparisons between CK and NCK by del(17p) subgroups. In summary, CK is indicative of both shorter TTT and OS. Although there is a strong correlation of del(17p) with CK, presence of CK appears to predict TTT independent of del(17p). Complexity should be evaluated in a larger, prospective series to further clarify its role in clinical outcome. Disclosures: No relevant conflicts of interest to declare.

Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults. While the breadth of therapies for this incurable disorder has increased recently, patients afflicted with high risk disease have few and predominantly unsatisfactory options. Cyclin-dependent kinase (CDKs) inhibitors, such as Flavopiridol, have demonstrated clinical activity in CLL, though have been associated with significant therapy associated tumor lysis (TLS). Dinaciclib is a selective inhibitor of CDKs 1, 2, 5, and 9 that exhibits activity in CLL, including high risk subtypes. We performed a phase 1 dose escalation trial in relapsed and refractory CLL in order to determine the recommended phase 2 dose and maximum administered dose of dinaciclib. Patients received treatment as a 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle. The initial starting dose, determined based on preclinical data, was 5 mg/m2. Other dosing cohorts of 7 mg/m2, 10 mg/m2, 14 mg/m2 and 17mg/m2 were included in the dose escalation schema. An expansion cohort of patients utilizing an intra-patient dose escalation of 7mg/m2 on day 1, 10mg/m2 on day 8 and 14mg/m2 on day 15 during cycle 1 and 14mg/m2 on days 1, 8, and 15 of each subsequent cycle was further employed. Patients continued on treatment until there was disease progression, unacceptable toxicity or subject’s refusal to continue. In total, 52 patients have been enrolled on this trial. The median age is 62.4 years (range 43-79), with 46% of patients ≥65 years. The majority of patients have advanced Rai stage (65%) and/or bulky disease (69%) and 46% with del(17p13.1). The median number of prior therapies is 4 (range 1-12) with 92% having received prior fludarabine and 31% having received prior flavopiridol. One episode of a dose limiting toxicity (DLT) was noted at 7mg/m2 (sepsis/death) and two at dose level of 17mg/m2 (hyperacute tumor lysis syndrome and pneumonia). One further DLT of TLS occurred at the recommended phase II dose level of 14mg/m2 during cohort expansion for a total of 18 patients treated at 14mg/m2. The most common serious adverse events included leucopenia, anemia, thrombocytopenia and metabolic evidence of tumor lysis, which occurred in 15% of patients. Clinical response was assessed utilizing the 1996 NCI-WG CLL criteria. The overall response rate of evaluable patients was 58% (28 of 48), while 57% patients with del(17p13.1) and 63% with del(11q22) achieved at least a partial response. The median progression free survival was 481 days (95% CI, 253 – 481). For responders, the median treatment duration was 214.5 days (range, 79 – 470 days). In conclusion, Dinaciclib is clinically active in this population of relapsed and refractory CLL. Importantly, patients with high risk disease, such as del(17p13.1) demonstrated impressive overall responses. Utilizing a dose escalation treatment model, Dinaciclib is well tolerated, safe and associated with typical toxicities which are readily managed. The use of this agent in combination with other efficacious agents, especially in the high risk CLL population is warranted. Disclosures: Jones:Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Small:Merck: Employment. Im:Merck: Employment. Zhou:Merck: Employment.

Background: Monoclonal B-cell lymphocytosis (MBL) is characterized by the presence of a circulating population of clonal B-cells where the total B-cell count is Methods: After IRB review and approval, we reviewed the hematopathology records of 2292 patients seen at Mayo Clinic between August 1998 and May 2006 who had a clonal B-cell population on flow cytometry phenotypically consistent with CLL and fewer than Results: A total of 118 patients meeting the criteria for MBL were identified. Median age at the time of MBL diagnosis was 69.4 years (range 39.0 – 91.4). A slight male preponderance was observed (54% male). CD38 status was available for 106 (90%) patients of whom 20% were CD38 positive using the 30% threshold to classify CD38. Cytogenetic analysis by fluorescent in situ hybridization (FISH) was available in 58 (49%) patients. Using the hierarchical classification system of Dohner and colleagues, 26 (44.8%) were 13q-, 10 (17.2%) were trisomy 12, 2 (3.4%) were 11q-, 1 (1.7%) was 17p-, and 19 were (32.8%) no defect was detected. ZAP-70 status was available for 32 patients of whom 22% were ZAP-70+ positive. IgVH gene mutation status was only available for 15 (12.7%) patients of whom 40% were unmutated. Time from MBL diagnosis to treatment is shown in Figure 1. Survival free of treatment was 92.7% (95%CI: 86.8–99.1%) at 1 year, 90.9% (95%CI: 84.2–98.2%) at 2 years, and 87.5% (95% CI: 78.7–97.4%) at 5 years. While age (p=0.68) and gender (p=0.14) were not found to be associated with time to treatment (TTT), CD38 status showed a strong relationship with TTT (p Conclusion: The distribution of prognostic parameters (e.g. CD38, FISH) in patients with MBL appears similar to that of patients with early stage CLL. We observed a low rate of progression, with 5 year survival free of treatment greater than 87%. TTT among newly diagnosed MBL patients was associated with the CD38 status of clonal B-cells. Figure Figure

BACKGROUND: Studies have suggested that patients with CLL are at a significantly increased risk of developing other lymphoid malignancies. Whether the risk of developing a 2nd lymphoproliferative disorder (LPD) is more strongly related to characteristics of the leukemia cell or to other factors such as prior chemotherapy is unknown. This distinction is important given increasing momentum to pursue early treatment of CLL patients based on recently identified prognostic markers, e.g. ZAP-70, IgVH mutation status. We used the Mayo Clinic CLL Database (DB) to conduct an observational cohort study to evaluate the relationship between clinical, biologic, and treatment characteristics and the risk of secondary LPD. METHODS: The Mayo Clinic CLL DB was established in 1999 and included 962 patients at the time of the present analysis. Clinical information regarding date of diagnosis, prognostic parameters, treatment history, disease-related complications, and co-morbidities was abstracted from clinical records on all patients at the time of study enrollment and maintained on an ongoing basis. For the present study, cases of secondary LPD were identified by chart review and cross referencing patient clinic numbers from the CLL DB with the Mayo Clinic Lymphoma and Leukemia/Myelodysplasia databases. Additionally, all clinic numbers were cross-referenced with an electronic hematopathology database that has recorded results of all bone marrow and lymph node biopsies of all Mayo Clinic patients since 1992. RESULTS: A second LPD was identified in 26 (2.7%) of the 962 CLL patients during a median follow-up of 7.12 years (range 0.1–21.0). The median time from diagnosis to development of secondary LPD was 4.4 years (range 0–19 years). Diffuse large B-cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Gender was associated with increased risk of developing 2nd hematologic cancer where 1% of women compared to 3.4% of men (p=0.051) developed a 2nd LPD. Treatment history was also related to development of a 2nd LPD. 2nd LPD developed among 4% of previously treated CLL patients compared to 2% of untreated patients (p=0.08). Among the 362 patients who were treated for CLL prior to developing a second LPD, the median time to first treatment was shorter for those who developed a 2nd LPD (2.43 years vs. 6.22 years; p CONCLUSIONS: In this observational cohort study, prior treatment demonstrated a stronger correlation with the risk of developing a 2nd LPD than did leukemia cell characteristics including IgVH gene mutation status, FISH, ZAP-70, B2M, and CD38. This finding suggests Richter’s transformation may relate more to therapy than characteristics of the leukemia cell itself. Until the results of clinical trials evaluating the role of early treatment based on prognostic parameters are available, this result underscores the importance of delaying administration of chemotherapy until patients meet established criteria for treatment.