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This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. 97 patients (94 evaluable) with median age of 44 years (range, 20 - 60) and median WBC at presentation of 10 × 109/L (range, 1 - 410 × 109/L) were accrued. 83 (88%) patients achieved CR or CR with incomplete count recovery (CRi) and 41 underwent ASCT in CR1. Median follow-up is 36 months (range, 9 - 63). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT), showed statistically superior advantages for RFS and OS (p=0.038 and 0.037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing.

BackgroundThe role of day 14 (D14) bone marrow (BM) assessment in detecting increased blasts in patients undergoing induction for acute lymphoblastic leukemia (ALL) is not well defined.MethodsThis study evaluated 389 adolescent and adult patients with previously untreated Philadelphia chromosome-negative ALL who received frontline induction chemotherapy and for whom a D14 BM assessment was performed.ResultsA D14 BM blast proportion

A 61-year-old man with a history of chronic lymphocytic leukemia (CLL) presents with complaints of worsening fatigue and night sweats. He was diagnosed with CLL 3 years ago on routine blood count testing. He has no major medical comorbidities. On examination, he has several 2- to 3-cm lymph nodes in the cervical and axillary area. Spleen is palpable 5 cm below the costal margin. Blood counts show lymphocytosis with thrombocytopenia and anemia. Prognostic markers include deletion 13q by fluorescence in situ hybridization analysis and mutated IGHV You are asked by the hematology fellow you are supervising about the best treatment of this patient.

The advent of novel small-molecule inhibitors has transformed the treatment approaches for patients with chronic lymphocytic leukemia (CLL). These therapies are becoming increasingly used in patients with relapsed disease, patients with 17p deletion, and, as of recently, also in the frontline setting for previously untreated patients with CLL. Moreover, many of these are oral therapies that are significantly less myelosuppressive than chemoimmunotherapy. However, these agents have their own set of unique toxicities with which providers must gain familiarity. There is also ongoing development of second-generation agents which have the promise of less toxicity than the US Food and Drug Administration (FDA)-approved compounds. In addition, immunotherapy and the role of the microenvironment are becoming increasingly important and have therapeutic implications in the treatment of patients with CLL. Ultimately, investigators need to evaluate how to position these and other new exciting therapies and decide on the ultimate role for chemoimmunotherapy in modern times.

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612.

We sought to establish clinical practice recommendations to redefine the role of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with chronic lymphocytic leukemia (CLL) in an era of highly active targeted therapies. We performed a systematic review to identify prospective randomized controlled trials comparing allo-HCT against novel therapies for treatment of CLL at various disease stages. In the absence of such data, we invited physicians with expertise in allo-HCT and/or CLL to participate in developing these recommendations. We followed the Grading of Recommendations Assessment, Development and Evaluation methodology. For standard-risk CLL we recommend allo-HCT in the absence of response or if there is evidence of disease progression after B cell receptor (BCR) inhibitors. For high-risk CLL an allo-HCT is recommended after failing 2 lines of therapy and showing an objective response to BCR inhibitors or to a clinical trial. It is also recommended for patients who fail to show an objective response or progress after BCR inhibitors and receive BCL-2 inhibitors, regardless of whether an objective response is achieved. For Richter transformation, we recommend allo-HCT upon demonstration of an objective response to anthracycline-based chemotherapy. A reduced-intensity conditioning regimen is recommended whenever indicated. These recommendations highlight the rapidly changing treatment landscape of CLL. Newer therapies have disrupted prior paradigms, and allo-HCT is now relegated to later stages of relapsed or refractory CLL.

BackgroundThe clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial.MethodsThe authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between the cohorts.ResultsPropensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib.ConclusionsThe clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. © 2016 American Cancer Society.

PurposeTo learn whether an antecedent hematologic disorder (AHD) is associated with additional risk in patients with therapy-related acute myeloid leukemia (t-AML).Patients and methodsWe reviewed data of 301 patients with newly diagnosed t-AML who sought care from January 2000 to January 2014 (183 t-AML without AHD, 118 t-AML with AHD). Overall, median follow-up was 44 months.ResultsThe primary malignancy was non-Hodgkin lymphoma in 92 (31%), breast cancer in 80 (27%), and prostate cancer in 49 (16%). Median relapse-free survival (RFS) in t-AML without or with AHD was 10 months and 29 months, respectively (P = .032); median overall survival (OS) was 8 months and 8 months, respectively (P = .53). Multivariate analysis for OS identified older age, poor performance status, thrombocytopenia, nonfavorable cytogenetics, and lack of response as adverse factors.ConclusionThe favorable-risk cohort had better RFS and OS compared to the outcomes of patients in the intermediate- and adverse-risk cohorts; the RFS and OS did not differ between intermediate- and adverse-risk cohorts. The presence of AHD did not affect OS.

BCR signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined. We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells, a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases and promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and downregulation of BCL6, the transcriptional repressor of CCL3 In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization and failure to support downstream responses, including CLL cell survival and chemokine secretion. IgM and IgD receptor downmodulation, HS1 and ERK activation, chemokine secretion, and BCL6 downregulation were also observed when CLL cells were cocultured with nurselike cells. The Bruton's tyrosine kinase inhibitor ibrutinib effectively inhibited both IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.

Nucleoside analogues are highly active in patients with hairy cell leukaemia (HCL); however, patients continue to relapse. This phase II study evaluated the efficacy and safety of cladribine followed by rituximab in patients with untreated HCL (N = 59), relapsed HCL (N = 14) and HCL variant (HCLv, N = 7). Cladribine 5·6 mg/m(2) was given intravenously (IV) daily for 5 d and was followed approximately 1 month later with rituximab 375 mg/m(2) IV weekly for 8 weeks. Complete response rate in patients with untreated HCL, relapsed HCL and HCLv was 100%, 100% and 86%, respectively. With a median follow up of 60 months, 5-year failure-free survival (FFS) in patients with untreated HCL, relapsed HCL and HCLv was 95%, 100% and 64%, respectively. Median duration of response to the cladribine followed by rituximab was significantly longer than the first-line cladribine single agent in patients who received this treatment as second-line treatment (72 months vs not reached, P = 0·004). Almost all patients (94%) achieved negative minimal residual disease (MRD) after the treatment. Positive MRD during the follow up did not necessarily result in clinically relevant relapse. Cladribine followed by rituximab is highly effective even in patients with relapsed disease and HCLv, and can achieve durable remission.

BackgroundThe prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy.MethodsIn this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival.ResultsOf the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence interval {CI}, 72.1 to 87.7] vs. 29.4% [95% CI, 21.0 to 38.8], P

BackgroundMore active therapies are needed for older and unfit patients with chronic lymphocytic leukemia (CLL) who are not eligible for chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The phosphyotidylinositol-3-kinase δ inhibitor idelalisib is effective in patients with treatment-naive and relapsed/refractory CLL as monotherapy and in combination with rituximab, but it can be associated with treatment-limiting adverse events, particularly diarrhea/colitis. The outcomes for patients who cease treatment for adverse events have not been previously described.MethodsThe authors analyzed long-term follow-up data from 40 treatment-naïve patients aged ≥65 years who received treatment at The University of Texas MD Anderson Cancer Center on a phase 2 study of idelalisib plus rituximab for CLL.ResultsIn patients who permanently ceased treatment because of toxicity, the time to subsequent disease progression was analyzed according to baseline characteristics. Fifteen patients permanently ceased therapy (PCT) because of toxicity (PCTTOX ), most commonly diarrhea/colitis (n = 7), at a median of 11 months after commencing treatment. PCTTOX was associated with a higher risk of subsequent disease progression (hazard ratio, 6.61; 95% confidence interval, 1.77-16.15) relative to that observed in patients who remained on therapy. Ten patients subsequently progressed, and 7 required salvage therapy; 5 patients remained progression-free at a median of 23.3 months (range, 8.5-28.6 months). Patients who were positive for ζ-associated protein-70 had more rapid disease progression after treatment cessation (P = .048). There were no CLL-related deaths.ConclusionsPCTTOX is the major determinant of PFS in patients who receive first-line idelalisib-based treatment. However, a subgroup of patients with favorable biologic characteristics has prolonged PFS, even after PCTTOX . The absence of CLL-related deaths indicates that salvage treatment is generally successful after PCTTOX . Cancer 2016;122:2505-11. © 2016 American Cancer Society.

Several studies reported improved outcomes of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with pediatric-based ALL regimens. This prompted the prospective investigation of a pediatric Augmented Berlin-Frankfurt-Münster (ABFM) regimen, and its comparison with hyper-fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone (hyper-CVAD) in AYA patients. One hundred and six AYA patients (median age 22 years) with Philadelphia chromosome- (Ph) negative ALL received ABFM from October 2006 through March 2014. Their outcome was compared to 102 AYA patients (median age 27 years), treated with hyper-CVAD at our institution. The complete remission (CR) rate was 93% with ABFM and 98% with hyper-CVAD. The 5-year complete remission duration (CRD) were 53 and 55%, respectively (P = 0.98). The 5-year overall survival (OS) rates were 60 and 60%, respectively. The MRD status on Day 29 and Day 84 of therapy was predictive of long-term outcomes on both ABFM and hyper-CVAD. Severe regimen toxicities with ABFM included hepatotoxicity in 41%, pancreatitis in 11%, osteonecrosis in 9%, and thrombosis in 19%. Myelosuppression-associated complications were most significant with hyper-CVAD. In summary, ABFM and hyper-CVAD resulted in similar efficacy outcomes, but were associated with different toxicity profiles, asparaginase-related with ABFM and myelosuppression-related with hyper-CVAD. Am. J. Hematol. 91:819-823, 2016. © 2016 Wiley Periodicals, Inc.

In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse-free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30-125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi-parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known.

Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance.

PurposeWe evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment.Experimental designThirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3-6, and once every other course during courses 7-24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed.ResultsThe overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders.ConclusionsThe combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. Clin Cancer Res; 22(10); 2359-67. ©2016 AACR.

The tumor microenvironment is the cellular and molecular environment in which the tumor exists and with which it continuously interacts. In B-cell lymphomas, this microenvironment is intriguing in that it plays critical roles in the regulation of tumor cell survival and proliferation, fostering immune escape as well as the development of treatment resistance. The purpose of this review is to summarize the proceedings of the Second Annual Summit on the Immune Microenvironment in Hematologic Malignancies that took place on September 11-12, 2014 in Dublin, Ireland. We provide a timely overview of the composition and biological relevance of the cellular and molecular microenvironment interface and discuss the role of interactions between the microenvironment and neoplastic cells in a variety of B-cell lymphomas. In addition, we focus on various novel therapeutic strategies that target the tumor microenvironment, including agents that modulate B-cell receptor pathways and immune-checkpoints, chimeric antigen receptor T cells and immunomodulatory agents.

BackgroundLittle is known about outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA). The purpose of this study is to determine the characteristics and outcomes of AYA AML patients in comparison to older adult patients with AML.Patients and methodsWe retrospectively analyzed all AML patients treated at our institution from 1965 to 2009 who were aged 16 to 29 years.ResultsAmong 3922 adult AML patients treated during this period, 432 (11%) were identified as AYA. Median age was 23 years (range, 16-29 years); 73 (17%) patients had core binding factor (CBF)-AML [inversion (16), translocation (8:21)], and 51 (12%) had acute promyelocytic leukemia. Complete remission (CR) rates were 93% for CBF AML, 78% for APL, 77% with diploid karyotype, and 68% for other AML. Univariate analysis demonstrated higher rates of CR, CR duration, and overall survival (OS) in the AYA group compared with older patients. On multivariate analysis, AYA age group was independently associated with improved CR rate and CR duration, with a trend for longer OS (P = .085).ConclusionOutcome of AYA AML patients is overall better than for older adults with AML. Despite improvements in treatments and outcomes over time, there is still need for improvement in AYA with AML particularly for those with AML other than CBF and APL.

This study assessed the relevance of 2013 European LeukaemiaNet (ELN) response categories on patients treated with common frontline tyrosine kinase inhibitors (TKI) in chronic myeloid leukaemia in chronic phase (CML-CP). Four hundred and eighty-seven patients treated with imatinib (400 mg; IM 400, n = 70; 800 mg; IM800, n = 201), dasatinib (n = 107) or nilotinib (n = 109) were analysed. Intention to treat (ITT) analysis indicated that the proportion of patients falling into optimal, warning and failure ELN categories were 89%, 6%, 6% at 3 months, 78%, 17% and 6% at 6 months, and 75%, 13% and 13% at 12 months, respectively. Rates of optimal response at 3 months were 75% for IM400, 90% for IM800, 89% for dasatinib and 97% for nilotinib; 41%, 80%, 86% and 89% at 6 months; and 47%, 77%, 76% and 87% at 12 months, respectively. Patients achieving optimal response had longer eventfree (EFS), failurefree (FFS), transformationfree (TFS) and overall survival (OS) compared to warning and failure responses at all-time points. Treatment with imatinib 800, dasatinib or nilotinib predicted for achieving an optimal response. Optimal response predicted for significantly longer EFS, FFS, TFS and OS at 3, 6 and 12 months, irrespective of the TKI modality used. ELN response categories reliably predicted outcomes in CML patients receiving commonly used TKIs.

BackgroundLong-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting.Patients and methodsThe dose-escalation part of the study determined the selected dose of coltuximab ravtansine for the evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (≤ 8 weekly doses). The responding patients were eligible for maintenance therapy (biweekly administration for ≤ 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m(2). The primary endpoint was the objective response rate (ORR). The secondary endpoints included the duration of response (DOR) and safety.ResultsA total of 36 patients were treated: 19 during dose escalation and 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m(2) (grade 3 peripheral motor neuropathy); therefore, 70 mg/m(2) was selected for the dose-expansion phase. Five patients discontinued therapy because of adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of the 17 evaluable patients treated at the selected dose, 4 had a disease response (estimated ORR using the Bayesian method: 25.5% (80% confidence interval, 14.2%-39.6%). The DOR was 1.9 months (range, 1-5.6 months). Because of these results, the study was prematurely discontinued.ConclusionColtuximab ravtansine was well tolerated but was associated with a low clinical response rate in patients with relapsed or refractory ALL.

BackgroundThe safety and efficacy of front-line nilotinib and dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML-CP) with pre-existing liver and/or renal dysfunction are unknown.Patients and methodsWe analyzed the adverse event rates, response rates, and survival rates of 215 patients with CML-CP with or without renal and/or liver dysfunction who had been treated with front-line nilotinib (n = 108) or dasatinib (n = 107).ResultsThe overall median follow-up period was 49 months. At baseline, 6 dasatinib-treated patients (6%) had mild renal dysfunction and 13 (12%) had mild liver dysfunction. Also, 8 nilotinib-treated patients (7%) had mild renal dysfunction, 1 (1%) moderate renal dysfunction, and 9 (8%) mild liver dysfunction. No significant differences were found in the rate of complete cytogenetic response, major molecular response, or molecular response by a 4.5 log reduction on the international scale between the organ function cohorts. Dasatinib- or nilotinib-treated patients with baseline renal dysfunction had a greater incidence of transient reversible acute kidney injury (P = .011 and P < .001), and nilotinib-treated patients with renal dysfunction had a greater incidence of bleeding (P < .001).ConclusionPatients with CML-CP and mild to moderate renal or liver dysfunction can be safely treated with front-line dasatinib or nilotinib and can achieve response rates similar to those of patients with CML-CP without organ dysfunction.

BackgroundA high pretreatment β2 -microglobulin (B2M) level is associated with inferior survival outcomes in patients with chronic lymphocytic leukemia. However, to the authors' knowledge, the prognostic and predictive significance of changes in B2M during treatment have not been reported to date.MethodsThe authors analyzed 83 patients treated with ibrutinib-based regimens (66 with recurrent/refractory disease) and 198 treatment-naive patients who were treated with combined fludarabine, cyclophosphamide, and rituximab (FCR) to characterize changes in B2M and their relationship with clinical outcomes.ResultsB2M rapidly decreased during treatment with ibrutinib; on multivariable analysis, patients who received FCR (odds ratio, 0.40; 95% confidence interval [95% CI], 0.18-0.90 [P = .027]) were less likely to have normalized B2M at 6 months than patients treated with ibrutinib. On univariable analysis, normalization of B2M was associated with superior progression-free survival (PFS) from the 6-month landmark in patients treated with ibrutinib-based regimens and FCR. On multivariable analysis, failure to achieve normalized B2M at 6 months of treatment was associated with inferior PFS (hazard ratio, 16.9; 95% CI, 1.3-220.0 [P = .031]) for patients treated with ibrutinib, after adjusting for the effects of baseline B2M, stage of disease, fludarabine-refractory disease, and del(17p). In contrast, in patients treated with FCR, negative minimal residual disease status in the bone marrow was the only variable found to be significantly associated with superior PFS (hazard ratio, 0.28; 95% CI, 0.12-0.67 [P = .004]).ConclusionsNormalization of B2M at 6 months in patients treated with ibrutinib was found to be a useful predictor of subsequent PFS and may assist in clinical decision-making.

The prognostic value of minimal residual disease (MRD) assessed by multi-parameter flow cytometry (MFC) was investigated among 340 adult patients with B-cell acute lymphoblastic leukaemia (B-ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15-84). Median white blood cell count (WBC) was 9·35 × 10(9) /l (range, 0·4-658·1 ×1 0(9) /l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15-marker, 4-colour panel and subsequently a 6-colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease-free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P

BackgroundIrreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors.MethodsIn this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.ResultsThe median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred.ConclusionsIn this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

BackgroundTyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment.MethodsCumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction.ResultsA total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period.ConclusionsIn the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. © 2015 American Cancer Society.

BackgroundThe long-term efficacy of a combination of chemotherapy and dasatinib in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is not well established.MethodsPatients received dasatinib with 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and high-dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR.ResultsSeventy-two patients with a median age of 55 years (range, 21-80 years) were treated; 69 (96%) achieved CR. Among them, 57 (83%) achieved cytogenetic CR after 1 cycle, and 64 (93%) achieved a major molecular response at a median of 4 weeks (range, 2-38 weeks). Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. With a median follow-up of 67 months (range, 33-97 months), 33 patients (46%) were alive, and 30 (43%) were in CR; 12 underwent allogeneic SCT. Thirty-nine patients died (3 at induction, 19 after relapse, 7 after SCT performed during first CR, and 10 during CR). The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively. Seven relapsed patients had BCR-ABL kinase domain mutations, including 4 with T315I.ConclusionsA combination of chemotherapy with dasatinib is effective in achieving long-term remission for patients with newly diagnosed Ph + ALL.

B cell receptor (BCR) signalling is an important pathway in diffuse large B cell lymphoma (DLBCL). In response to BCR triggering, normal and malignant B cells secrete the chemokines CCL3 and CCL4 to attract accessory cells to the tissue microenvironment. We measured CCL3 and CCL4 serum concentrations in 102 patients with newly diagnosed DLBCL by enzyme-linked immunosorbent assay, investigated their prognostic impact and validated our findings in an independent cohort of 51 patient samples. We also tested CCL3 and CCL4 secretion by DLBCL cells, and the influence of BTK inhibitors on the secretion of these chemokines. High CCL3 (≥40 pg/ml) serum concentrations correlated with higher international prognostic index, lactate dehydrogenase and β2 microglobulin, as did CCL4 (≥180 pg/ml) with advanced Ann Arbor stages. High CCL3 levels correlated with significantly shorter progression-free and overall survival. The in vitro studies demonstrated that activated B cell-like, but not germinal centre B cell-like DLBCL cells, secrete high levels of CCL3 and CCL4 after BCR triggering, which was exquisitely sensitive to BCR pathway inhibition. These findings support CCL3 and CCL4 protein concentrations as biomarkers for BCR pathway activation and prognosis in DLBCL.

BackgroundChronic use of tyrosine kinase inhibitors (TKIs) may lead to previously unrecognized adverse events. This study evaluated the incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) in chronic-phase (CP) chronic myeloid leukemia (CML) patients treated with imatinib, dasatinib, and nilotinib.MethodsFour hundred sixty-eight newly diagnosed CP CML patients treated with TKIs were analyzed. The molecular and cytogenetic response data, creatinine, and glomerular filtration rate (GFR) were followed from the start of therapy to the last follow-up (median, 52 months). GFR was estimated with the Modification of Diet in Renal Disease equation.ResultsNineteen patients (4%) had TKI-associated AKI. Imatinib was associated with a higher incidence of AKI in comparison with dasatinib and nilotinib (P = .014). Fifty-eight patients (14%) developed CKD while they were receiving a TKI; 49 of these patients (84%) did so while they were being treated with imatinib (P

BackgroundCombination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial.MethodsIn this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982.Findings37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment.InterpretationThe first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes.FundingARIAD Pharmaceuticals Inc.

Little is known about outcomes of patients with chronic lymphocytic leukemia (CLL) with del(17p13.1) karyotype at diagnosis. We reviewed 114 de novo del(17p13.1) CLL patients seen at our institution. Using proportional hazards models to identify pretreatment clinical variables significantly associated with treatment-free survival (TFS) and overall survival (OS), we developed a simplified risk score for de novo del(17p13.1) CLL patients to predict TFS and OS based on these variables. These scores, particularly the very highest, can be utilized to identify high-risk patients for expedient enrollment on clinical trials. Our data support careful observation for low-risk patients, potentially preventing unnecessary use of aggressive therapies.

BackgroundFludarabine, cyclophosphamide, and rituximab (FCR) result in durable responses in patients with previously untreated chronic lymphocytic leukemia (CLL). Previous reports have suggested that in patients with relapsed CLL, a dose-intensified rituximab regimen increases response rates in comparison with standard-dose rituximab. It is unknown whether rituximab intensification of the FCR regimen will result in improved response rates and patient outcomes in patients with previously untreated CLL.MethodsA single-arm study was conducted to evaluate the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. The results were compared with those for a historical cohort treated with FCR.ResultsThe overall response rate to FCR3 was 97%, with 75% of the patients achieving a complete remission. Minimal residual disease negativity was achieved for 62% of the patients according to flow cytometry. The median time to progression (TTP) was 81 months, and the median overall survival (OS) was not reached, with 58% of the patients still alive at a median survivor follow-up of 9.7 years. Grade 3 or 4 neutropenia, grade 3 or 4 thrombocytopenia, and major infections were observed with 45%, 5%, and 1.9% of the FCR3 courses, respectively. Therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute myelogenous leukemia (t-AML) developed in 7 patients (11%; P < .01 vs the historical FCR cohort).ConclusionsIn patients with previously untreated CLL, FCR3 resulted in response rates, TTP, and OS similar to those of a historical cohort of patients treated with FCR. FCR3 was associated with an increased incidence of t-MDS/t-AML.

BackgroundIbrutinib is active in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). In patients treated with ibrutinib for R/R CLL, del(17p), identified by interphase fluorescence in situ hybridization (FISH), is associated with inferior progression-free survival despite equivalent initial response rates. Del(17p) is frequently associated with a complex metaphase karyotype (CKT); the prognostic significance of CKT in ibrutinib-treated patients has not been reported.MethodsThis study reviewed 88 patients treated for R/R CLL at The University of Texas MD Anderson Cancer Center with investigational ibrutinib-based regimens from 2010 to 2013. Pretreatment FISH and lipopolysaccharide-stimulated metaphase cytogenetic analysis were performed on bone marrow.ResultsAn adequate pretreatment metaphase karyotype was available for 56 of the 88 patients. The karyotype was complex in 21 of the 56 cases; 17 of the 21 had del(17p) according to FISH. The overall response rate, including partial remission with persistent lymphocytosis, was 94%; 18% had complete responses. In a multivariate analysis (MVA), only CKT was significantly associated with event-free survival (EFS; hazard ratio [HR], 6.6 [95% CI 1.7-25.6]; P = .006). Fludarabine-refractory CLL (HR, 6.9 [95% CI 1.8-27.1], P = .005) and CKT (HR 5.9 [95% CI 1.6-22.2], P = .008) were independently associated with inferior overall survival (OS) in MVA. Del(17p) by FISH was not significantly associated with EFS or OS in MVA.ConclusionsCKT is a powerful predictor of outcomes for ibrutinib-treated patients with R/R CLL and may be a stronger predictor of biological behavior than del(17p) by FISH. Because of their relatively poor outcomes, patients with CKT are ideal candidates for studies of consolidative treatment strategies or novel treatment combinations.

Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations for identification and management of idelalisib treatment-emergent diarrhea or colitis as well as a discussion of transaminitis and pneumonitis. For idelalisib-related diarrhea or colitis (including unresolved grade 2 and grade ≥ 3), after exclusion of infectious causes, the panel recommends individualized treatment with budesonide or oral or intravenous steroid therapy.

Bone marrow necrosis (BMN) is characterized by infarction of the medullary stroma, leading to marrow necrosis with preserved cortical bone. In reported small series, BMN in hematological malignancies is associated with poor prognosis. We sought to find the impact of BMN on clinical outcome in a relatively larger cohort of patients with acute leukemias. Overall we evaluated 1,691 patients; 1,051 with acute myeloid leukemia (AML) and 640 with acute lymphocytic leukemia referred to our institution between 2002 and 2013. Patients with AML and acute lymphoblastic leukemia (ALL) were evaluated separately to determine the incidence of BMN, associated clinical features and its prognostic significance. At initial diagnosis, BMN was observed in 25 (2.4%) patients with AML and 20 (3.2%) patients with ALL. In AML, BMN was significantly associated with French-American-British AML M5 morphology (32% vs. 10%, P = 0.002). The complete remission (CR) rate in AML with and without BMN was 32% and 59% respectively (P = 0.008). Likewise, CR rate in ALL with BMN was also inferior, 70% vs. 92% (P = 0.005). The median overall survival (OS) in AML with BMN was significantly poorer, 3.7 months compared to 14 months without BMN (P = 0.003). Similarly, the median OS in ALL with and without BMN was 61.7 and 72 months respectively (P = 0.33). BMN is not a rare entity in AML and ALL, but is infrequent. BMN in AML and in ALL is suggestive of inferior response and poor prognosis.

BackgroundPonatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML.MethodsWe did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (

BackgroundTrisomy 12 (+12) is detected by fluorescence in-situ hybridization (FISH) analysis in up to 20% of patients with chronic lymphocytic leukemia (CLL). Patients with +12 are known to have unique features and to carry an intermediate prognosis.Patients and methodsIn order to better define this large group, we reviewed the characteristics of 250 untreated patients with +12.ResultsWhen compared to 516 untreated patients negative for +12 by FISH, patients with +12 showed a higher incidence of thrombocytopenia, Richter transformation, and second malignant neoplasms (SMN), in addition to the expected increased rate of CD38 positivity and atypical immunophenotype. At a median follow-up of 51 months, 57% of patients needed first-line treatment; median time to first treatment was 38 months, and on multivariate analysis (MVA), it was found to be shorter in patients with advanced Rai stage, palpable splenomegaly, and deletion of 14q by conventional cytogenetic analysis. The overall response rate with first-line treatment was 94%. The median failure-free survival has not been reached, but on MVA, it was found to be shorter in patients whose disease responded in a manner other than complete remission or with FISH negativity for deletion 13q. The median overall survival for the entire group has not been reached, but MVA revealed it to be shorter in patients with an absolute lymphocyte count of > 30 × 10(9)/L or who developed SMN. Eighteen deaths have been observed so far, and Richter transformation and SMN were the leading causes of death (3 and 6, respectively).ConclusionPatients with +12 CLL show characteristic clinical and biologic features, and may benefit from increased surveillance for second cancers.

BackgroundRat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme.Patients and methodsWe report on a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1 to 21 of a 28-day cycle in a "3+3" dose escalation design.ResultsSeventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1-29). Three patients each were enrolled at a dose level of 100, 200, 400, 600, and 800 mg twice daily and 2 patients at a dose level of 900 mg twice daily. No dose-limiting toxicities were encountered. Grade 1/2 diarrhea was the only frequent nonhematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral antidiarrheal agents. Eight (47%) patients (4 with myelodysplastic syndrome, 2 with acute myeloid leukemia, 1 with chronic myelomonocytic leukemia, and 1 with chronic myeloid leukemia) had hematological improvement; 1 in 3 lineages, 1 in 2 lineages, and 6 in 1 lineage. None of the patients achieved complete remission. The responses lasted for a median of 10 weeks (range, 5-115). The study was discontinued because of financial constraints.ConclusionSalirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be used in combination therapy.

PurposeThe IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.Experimental design and resultsFirst, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.ConclusionsThese results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.

Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

PurposePrevious studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL).Experimental designTwenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD.ResultsThe median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders.ConclusionsThe combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL.

Patients with chronic lymphocytic leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving fludarabine, cyclophosphamide and rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety-three patients (40%) had other cancers before and 66 patients (28%) after FCR. Rates of therapy related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high, while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT, and as speculated the survival of affected patients is shorter.

We have analyzed patients with previously untreated chronic lymphocytic leukemia with del11q fluorescence in situ hybridization (FISH) abnormality (n = 196) in this study. Detection of the 11q22.3 used a multicolor FISH technique. Patients with del11q fell into two major FISH subsets-sole del11q (n = 64) and del11q with del13q (n = 132). FISH subsets were compared using the median del11q FISH% (>58%, high vs. ≤58%, low). Overall survival (OS) and time to first treatment (TTFT) were estimated using Kaplan-Meier plots (log rank). Multivariate analysis was performed to assess the association between FISH% of del11q and outcomes. Patients with sole del11q were similar to del11q with del13q in terms of TTFT and OS. Patients with high FISH% of del11q had significantly shorter OS and TTFT as compared with patients with low FISH%, particularly in sole del11q; this negative impact of high FISH% of del11q on OS and TTFT was diminished with coexistent del13q. In multivariate analysis, high FISH% of del11q was a significant predictor for shorter OS and TTFT. A comparison of these del11q subsets with a separate cohort of (n = 673) previously untreated patients with sole del13q showed that the high FISH% del11q cohort had a significantly shorter TTFT and OS. In addition, bulky disease by physical examination or computed tomography imaging was infrequent at presentation in patients with del11q. High FISH% of del11q can reliably discriminate higher risk patients with chronic lymphocytic leukemia. Presence of coexistent del13q should be accounted for while prognosticating patients with del11q.

PurposeAllogeneic stem-cell transplantation (SCT) induces long-term remission in a fraction of patients with high-risk chronic lymphocytic leukemia (CLL) or Richter's transformation (RT). Our purpose was to determine the outcomes of patients whose disease progressed after allogeneic SCT.Patients and methodsWe retrospectively analyzed the outcomes of 72 patients (52 with CLL and 20 with RT) who underwent allogeneic SCT between 1998 and 2011 and had documented progression after transplantation. Twenty-two (31%) never had a response, and 50 (69%) had a response but experienced relapse after a median of 7 months (range, 2 to 85 months). Forty-eight patients who were receiving or were candidates to receive post-SCT cell-based therapies were not included in this analysis.ResultsThe median age at time of transplantation was 58 years (range, 30 to 72 years). Sixty-two patients (86%) received more than two treatment regimens and 37 (51%) received more than three treatment regimens before SCT. Sixty-six patients (92%) had active disease at the time of transplantation. The 2- and 5-year survival rates were 67% and 38% (patients with CLL) and 36% and 0% (patients with RT). The patients who developed acute or chronic graft-versus-host disease had a longer overall survival (OS; P = .05). In a multivariable analysis, RT or low hemoglobin at the time of SCT predicted shorter OS. Chronic graft-versus-host disease and an initial response to SCT predicted longer OS.ConclusionPatients with CLL in whom allogeneic SCT fails may have a response to and benefit from salvage therapies, and their prognosis is relatively good.

UnlabelledWhile reviewing chronic lymphocytic leukemia (CLL) bone marrow slides, we identified cytoplasmic lipid vacuoles in CLL cells but not in normal B cells. Because lipoprotein lipase (LPL), which catalyzes hydrolysis of triglycerides into free fatty acids (FFA), is aberrantly expressed in CLL, we investigated whether LPL regulates the oxidative metabolic capacity of CLL cells. We found that unlike normal B cells, CLL cells metabolize FFAs. Because STAT3 is constitutively activated in CLL cells and because we identified putative STAT3 binding sites in the LPL promoter, we sought to determine whether STAT3 drives the aberrant expression of LPL. Transfection of luciferase reporter gene constructs driven by LPL promoter fragments into MM1 cells revealed that STAT3 activates the LPL promoter. In addition, chromatin immunoprecipitation confirmed that STAT3 binds to the LPL promoter. Furthermore, transfection of CLL cells with STAT3-shRNA downregulated LPL transcripts and protein levels, confirming that STAT3 activates the LPL gene. Finally, transfection of CLL cells with LPL-siRNAs decreased the capacity of CLL cells to oxidize FFAs and reduced cell viability.ImplicationsOur study suggests that CLL cells adopt their metabolism to oxidize FFA. Activated STAT3 induces LPL, which catalyzes the hydrolysis of triglycerides into FFA. Therefore, inhibition of STAT3 is likely to prevent the capacity of CLL cells to utilize FFA.