Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 73, No. 7 ( 1989-05-15), p. 1963-1967

Abstract: Approximately one fourth of children with newly diagnosed acute lymphoblastic leukemia (ALL) have hyperdiploid (greater than 50 chromosomes) blasts and a relatively favorable prognosis. Nonetheless, a substantial proportion of these patients fail therapy. We studied 138 children (70 male, 68 female) with hyperdiploid greater than 50 ALL to assess initial clinical and cytogenetic features that might predict treatment failure. In 85 of these cases (62%), structural chromosomal abnormalities were also present; clinical and laboratory features in this group did not differ from those of the 53 cases with only numeric abnormalities. However, of the 28 failures seen at a median follow-up of 4 years, 22 occurred in cases with structural chromosomal abnormalities (P = .03 by Breslow test). In a multivariate analysis, only the presence of structural chromosomal abnormalities and male gender were independently associated with treatment failure. Structural chromosomal abnormalities in cases of ALL with greater than 50 chromosomes may define a biologically different form of leukemia characterized by increased likelihood of drug resistance.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V73.7.1963.bloodjournal7371963

Language: English

Publisher: American Society of Hematology

Publication Date: 1989

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 831-831

Abstract: Introduction Btk is a kinase involved in B-cell receptor (BCR) signal transduction and a critical target in chronic lymphocytic leukemia (CLL). ACP-196-a potent, second generation Btk inhibitor that is more selective than the first-in-class Btk inhibitor, ibrutinib (Covey AACR2015)-has demonstrated antitumor activity in preclinical CLL models (Niemann AACR2014). Here, we present preliminary data from patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL) enrolled in an ongoing Phase 1/2 study of single-agent ACP-196 (ClinicalTrials.gov NCT02029443). Methods and Patients This first-in-human study was designed to evaluate the safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics and efficacy of orally administered ACP-196 in patients with R/R CLL/SLL. Patients were continuously treated with ACP-196 at dosages ranging from 100 to 400 mg once daily (QD) as part of the dose-escalation portion of the study (4 cohorts of 6-8 patients per cohort), and 100 mg twice daily (BID) and 200 mg QD as part of the expansion portion of the study (2 cohorts). Of note, CLL patients with any degree of pancytopenia and prior exposure to PI3K inhibitors were allowed. CLL responses were investigator assessed per IWCLL criteria (modified Hallek 2008). SLL responses were investigator assessed per IWG criteria (Cheson 2007). Patients had a median age of 62 years (range 44-84), bulky lymph nodes ≥ 5 cm (47%) and median of 3 prior therapies (1-13). High-risk prognostic factors included del(17)(p13.1) 31% (18/58), del(11)(q22.3) 29% (17/58) and unmutated IGVH genes 75% (38/51). Results Results are presented through 01 June 2015 for the first 61 R/R patients, including 60 evaluable for response. The median time on study (N=61) was 10.3 (0.5-15.9) months. ACP-196 has been well tolerated with 93% (57/61) of patients continuing on study drug. Of the 4 patients who discontinued, 1 patient each discontinued due to withdrawal of consent, physician decision, unrelated AE (pre-existing, active autoimmune hemolytic anemia) and related AE (Grade 3 dyspnea). To date, no dose-related effect has been observed in frequency or severity of AEs or serious adverse events. No dose-limiting toxicities have occurred, and most AEs were Grade ≤ 2. The most common Grade 1/2 AEs (≥ 15%) were headache (39%), diarrhea (33%) and URI (16%). Grade 3/4 AEs that occurred in ≥ 3 patients were anemia (7%), pneumonia (7%) and hypertension (5%). No major hemorrhage (including subdural hematomas), atrial fibrillation, tumor lysis syndrome or pneumonitis have occurred suggesting an improved safety profile compared with other BCR and BCL-2-targeted therapies. Clinical activity has been observed in patients with R/R CLL/SLL at all doses evaluated. All patients experienced rapid reductions in lymphadenopathy. Treatment-related lymphocytosis (defined as ≥ 50% increase from baseline and above absolute lymphocyte count [ALC] of 5 K/µL) occurred in 61% (37/61) of patients and resolved in 81% (31/37) of these patients. In general, lymphocytosis peaked at a median of 3 weeks and resolved by a median of 19 weeks (range 1 to 58 weeks). The rapid decrease in lymphadenopathy and treatment-related lymphocytosis along with concurrent improvement in baseline cytopenias has led to a high proportion of partial responses (PRs) early in treatment (Figure 1). Best overall response rate including PR and PR with lymphocytosis (PR+L) was 93% (PR=70%, PR+L=23%, SD=7%, PD=0%). For patients with del(17)(p13.1), the response rate was 100% (PR=72%, PR+L=28%). In the 4 patients with prior idelalisib therapy, the response rate also was 100% (PR=75%, PR+L=25%). To date, no disease progression or Richter's transformation has occurred (Figure 2). Pharmacokinetic results showed exposure of ACP-196 was dose proportional with no drug accumulation. At dosages as low as 100 mg QD, pharmacodynamic results showed low intra-patient variability, high Btk occupancy ( 〉 90% over 24 hr) and high phospho-Btk inhibition ( 〉 90% over 24 hr). Conclusion ACP-196 is a highly potent and selective oral Btk inhibitor with a favorable safety profile. Responses occur early in treatment with no disease progression to date either in heavily pretreated patients or those with high-risk prognosis factors. ACP-196 is currently in Phase 3 trials for TN (ClinicalTrials.gov NCT0247568) and R/R high-risk CLL (ClinicalTrials.gov NCT02477696). Disclosures Byrd: Acerta Pharma BV: Research Funding. Jones:Acerta Pharma BV: Research Funding. O'Brien:Acerta Pharma BV: Research Funding. Schuh:Acerta Pharma BV: Research Funding. Hillmen:Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Acerta Pharma BV: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Stephens:Immunomedics: Research Funding; Acerta Pharma BV: Research Funding. Ghia:Pharmacyclics: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Acerta Pharma BV: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Devereux:Acerta Pharma BV: Research Funding. Chaves:Acerta Pharma BV: Research Funding. Barrientos:Acerta Pharma BV: Research Funding. Wang:Acerta Pharma BV: Employment, Equity Ownership. Huang:Acerta Pharma BV: Employment, Equity Ownership. Covey:Acerta Pharma BV: Employment, Equity Ownership, Patents & Royalties. Navarro:Acerta Pharma BV: Employment, Equity Ownership. Rothbaum:Acerta Pharma BV: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties. Hamdy:Acerta Pharma BV: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.831.831

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1362-1362

Abstract: Historically, reported outcomes in patients with mantle cell lymphoma (MCL) have been poor, with a median overall survival cited in the range of 2 to 4 years. As a consequence, recent approaches to first-line treatment have become more aggressive. Single- and oligo-center non-randomized studies with R-Hyper-CVAD and/or autologous stem cell transplant in first remission have produced 3-year overall survival 〉 80%, prompting many to consider them as optimal standard of care. However, a substantial fraction of MCL patients are ineligible to receive these regimens due to age and comorbidities. To determine whether these interesting results might be affected by patient referral/selection biases rather than a true superiority of therapy, we evaluated outcomes from our MCL patient cohort, a group potentially shaped by similar biases but largely managed in a more conservative fashion. As progression-free survival is likely improved by aggressive treatments, our focus is on overall survival given the central importance of this endpoint. Methods: We used pathology records to identify all patients with a diagnosis of MCL evaluated at the Weill Cornell Medical Center since 1997. Patients were considered eligible for inclusion if a date of diagnosis could be identified. In the subset where clinical records were limited, an online social security database was used to verify survival. Median overall survival was calculated according to the Kaplan-Meier method. Results: We identified 181 patients with the diagnosis of MCL established by standard hematopathologic criteria. Forty-eight of these cases were outside consults to our pathology department without available clinical data. Of the remaining 133 patients, date of diagnosis was identified in 111 subjects. Median age at diagnosis was 64 years (range: 37–88). For the subset of patients with available prognostic information, 81% were stage IV, 75% had bone marrow involvement, 52% had an IPI of ≥3. The median overall survival (N=111) was 7.1 years (85 months with 95% C.I. 63 to 98 mo.). Three-year overall survival was 86% (95% C.I. 78% to 92%). Adequate information on therapy was available for 75 patients. Most patients were treated with CHOP-like regimens. Only 5 were treated with (R)-Hyper-CVAD or autologous stem cell transplant in first remission while an additional 4 patients received one of these regimens as subsequent therapy, Five patients survived longer than 10 years—one patient is alive at 15.4 years—despite never receiving Hyper-CVAD or autoSCT. Univariate analysis of treatment type revealed no significant effect on overall survival. Conclusions: Our data demonstrate that single-center outcomes with conservative approaches in MCL can yield similar overall survival to that achieved with more intensive approaches at other single-centers. Therefore patient referral/selection biases may substantially account for the perceived superiority of aggressive strategies. Intensive treatment approaches for MCL should not be considered superior with respect to overall survival in the absence of long-term data from multicenter randomized trials comparing them to more conservative strategies.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.1362.1362

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2970-2970

Abstract: Introduction. Recent research in lymphoma has resulted in better outcomes for clinical trial populations. Population studies have suggested that some real-world patients (pts) have not benefited. We hypothesized that one reason for this discrepancy is the difference between trial participants and real-world pts. We aimed to: 1) Compare demographics and baseline clinical characteristics of real-world and clinical trial pts receiving first-line therapy for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL); and 2) Compare demographics and baseline clinical characteristics of real-world DLBCL, FL, and MCL pts with clinical trial eligibility criteria. Methods. Using ClinicalTrials.gov, we identified all phase 2 and 3 clinical trials that opened between 2002-2017 and included pts with DLBCL, FL, MCL. Published trials that included front-line immunotherapy and chemotherapy were selected, and eligibility criteria recorded. We reviewed publications and recorded pt numbers and characteristics. Using the Weill Cornell Medicine (WCM) Lymphoma Database, an IRB-approved, prospective cohort which started in 2010, we identified all pts diagnosed with DLBCL, FL, and MCL and recorded baseline characteristics. Descriptive statistics were used to describe clinical trial eligibility and pt characteristics. Fisher's exact test was used to compare pt characteristics. Results. We identified 642 phase 2 and 3 trials on Clinicaltrials.gov, 37 of which met predefined criteria. The most frequent exclusion criteria were HIV infection (n=33), pregnancy (n=25), HBV infection (n=21), history of non-lymphoma cancer (n=19), ECOG 〉 2 (n=16), HCV infection (n=16), serum creatinine 〉 2 mg/dL or 〉 2x ULN (n=15), active infection (n=12), history of MI (n=11), serum bilirubin 〉 2 mg/dL or 〉 2x ULN (n=7), congestive heart failure (n=4), hemoglobin (Hb) 〈 10g/dL (n=4). A total of 5614 pts were enrolled in 37 trials. Pt characteristics are listed in Table 1. Of 3690 enrolled in the 23 trials that reported the number of patients screened for eligibility, 502 (14%) were excluded based on eligibility criteria. We identified 652 pts in the WCM Database with newly diagnosed DLBCL, FL, and MCL (Table 1). Key differences between clinical trial and Database populations for DLBCL included proportion of pts with stage 3-4 disease (79% vs 60%, p 〈 0.001), presence of B symptoms (40% vs 25%, p 〈 0.001) or bulky disease (23% vs 15%, p=0.016), and intermediate or high IPI (85% vs 66%, p 〈 0.001); 36% of Database pts were age 〉 70. Among FL pts, key differences between trial and Database populations included proportion with stage 3-4 disease (98% vs 56%, p 〈 0.001), presence of B symptoms (36% vs 8%, p 〈 0.001) or bulky disease (21% vs. 5%, p 〈 0.001), and intermediate or high FLIPI (83% vs 58%, p 〈 0.001). All FL trials had a median age between 50-60, whereas 30% Database pts varied in age from 27-93 years and 30% were age 〉 70. Clinical trial vs. Database MCL pts differed in proportion with presence of B symptoms (29% vs 18%, p=0.022) or bulky disease (18% vs 5%, p=0.025), and intermediate or high MIPI (63.5% vs 79%, p=0.002); 42% of Database pts were age 〉 70. Of all 652 pts from the Database, 190 (29%) had characteristics that may have excluded them from clinical trial participation. The most common reasons for exclusion included history of cancer (11%), cardiac arrhythmias (7%), MI (6%), active infections (6%) and Hb 〈 10g/dL (5%). Only 19 might have been excluded due to serum creatinine 〉 2mg/dL (1.4%), serum bilirubin 〉 2 mg/dL (0.9%) and ECOG 〉 2 (0.6%). Conclusions. These data suggest that real-world lymphoma pts are considerably more heterogeneous than clinical trial populations. While the average pt in WCM Database had a lower stage and/or lower prognostic risk score than a typical trial population, over 30% of database pts were 〉 70, a group that was uncommon in clinical trials. Likewise, almost 30% of Database pts had medical conditions that may have excluded them from clinical trial participation. Future research should focus on better defining the characteristics and outcomes of pts that either are underrepresented on clinical trials, both intentionally due to eligibility criteria and unintentionally for less clear reasons. It is likely that some eligibility criteria have little impact on treatment and outcomes and may be eliminated from prospective trials, while other trials may focus on pts that remain poorly understood. Disclosures Allan: Acerta: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Furman:Verastem: Consultancy; Loxo Oncology: Consultancy; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Genentech: Consultancy; Incyte: Consultancy, Other: DSMB; Gilead: Consultancy. Leonard:ADC Therapeutics: Consultancy; BMS: Consultancy; Celgene: Consultancy; United Therapeutics: Consultancy; Biotest: Consultancy; Gilead: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy; Genentech/Roche: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Sutro: Consultancy. Martin:AstraZeneca: Consultancy; Janssen: Consultancy; Kite: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113872

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 983-983

Abstract: Abstract 983 Introduction: Btk is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally-administered irreversible inhibitor of Btk which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. An early analysis of the phase Ib/II study PCYC-1102 showed PCI-32765 to be highly active and tolerable in patients with CLL (Byrd, ASCO 2011). Here we report longer-term follow-up of this multicenter phase Ib/II trial. Methods and Patients: Two cohorts of CLL patients (previously untreated ≥65 years old and relapsed/refractory [R/R] disease following at least 2 prior therapies, including fludarabine) were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease. Doses of 420mg (previously untreated and R/R) and 840mg daily (R/R) were examined. The patients with R/R disease are the subject of this report. Results: Sixty-one R/R CLL/SLL patients were enrolled (420mg cohort n=27, 840mg cohort n=34). The median follow-up time for the 420mg cohort is 10.2 months and for the 840mg cohort is 6.5 months. The median number of prior treatment regimens for the 420mg cohort was 3 (2–10) and for the 840mg cohort was 5 (1–12). Seventy-two percent of patients had at least one poor-risk molecular feature: del(17p) 31%, del(11q) 33%, IgVH un-mutated 57%. Treatment has been well tolerated. Two patients have discontinued for adverse events (AE); 6 patients have required reduction of PCI-32765 dose (420mg cohort 2/27, 840mg cohort 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported AEs. Serious AEs (SAEs) have occurred in 38% of patients; SAEs considered potentially related to PCI-32765 have occurred in 10% of patients. Grade ≥3 AEs considered potentially related to PCI-32765 occurred in 21% of patients. A characteristic pattern of response, with a transient phase of lymphocytosis typically peaking within the first 2 months of Rx, followed by resolution over time, has been observed in the majority of patients. Objective response (ORR; PR + CR) by IWCLL criteria in the 420mg cohort cohort, previously reported as 48% with 6.2 months median follow-up (Byrd, et al ASCO 2011), is now 70% with 10.2 months median follow-up. ORR in the 840mg cohort is 44% at 6.5 months median follow-up. An additional 19%, and 35% of patients in these cohorts, respectively, have a nodal PR ( 〉 50% reduction in aggregate lymph node size) with residual lymphocytosis. ORR appears to be independent of molecular risk features. Eighty-two percent of patients (50/61; 420mg cohort 22/27, 840mg cohort 28/34) remain on PCI-32765. Only 8% (5/61) of patients have had progressive disease (PD); 6-month PFS is 92% in the 420mg cohort and 90% in the 840mg cohort. Treatment cessation not related to PD or AE includes: death (n=2) or investigator discretion (n=3). Conclusions: The potent Btk inhibitor PCI-32765 is well tolerated and is associated with high rates of 6-month PFS in R/R CLL/SLL. Phase III trials of PCI-32765 in CLL/SLL are planned. Disclosures: O'Brien: Pharmacyclics, Inc: Research Funding. Burger:Pharmacyclics, Inc: Research Funding. Blum:Pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Coutre:Pharmacyclics, Inc: Research Funding. Sharman:Pharmacyclics, Inc: Research Funding. Flinn:Pharmacyclics, Inc: Research Funding. Grant:Pharmacyclics, Inc: Research Funding. Heerema:Pharmacyclics, Inc: Research Funding. Johnson:Pharmacyclics, Inc: Research Funding. Navarro:Pharmacyclics, Inc: Employment, Equity Ownership. Holmgren:Pharmacyclics, Inc: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Byrd:Pharmacyclics, Inc: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.983.983

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 71, No. 4 ( 1988-04-01), p. 1135-1137

Abstract: The clinical significance of interleukin 2 receptor (IL2R) concentrations in serum was determined for 344 children with newly diagnosed acute lymphoblastic leukemia (ALL). Serum levels of IL2R in patients (267 to 80,000 U/mL, median 2,007 U/mL) were significantly higher than normal control values (170 to 738 U/mL, median 347 U/mL) (P less than .0001). Measurements in cases of T cell ALL were lower than in the non-T, non-B cases (P = .02). Among the 264 patients with non-T, non-B ALL, but not in those with T cell disease, higher serum IL2R levels (greater than 2,000 U/mL) were associated with a poorer treatment outcome (P = .04). In a multivariate analysis, serum IL2R level contributed independent prognostic information beyond that conveyed by leukocyte count, race, and age (P = .04). One explanation for these results is that soluble IL2R competes with normal lymphocyte- integrated IL2R for the ligand and thus could suppress host antitumor immunity.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V71.4.1135.1135

Language: English

Publisher: American Society of Hematology

Publication Date: 1988

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3045-3045

Abstract: Ribavirin, an antiviral drug used to treat infections including respiratory syncytial virus (RSV), inhibits the eukaryotic translation initiation factor 4E (eIF4E). EIF4E exports key mRNA transcripts from the nucleus and is a critical factor for translation of mRNAs into protein. Prospective trials of patients treated with ribavirin indicate that the drug has clinical activity and expected molecular effects of eIF4E inhibition in AML including relocalization of eIF4E to cytoplasm and decrease in eIF4E levels (Assouline Blood 2009 and Assouline Haematologica 2015). We demonstrated in pre-clinical models including a PDX triple hit lymphoma that eIF4E is also implicated in the pathogenesis of lymphomas (Culjkovic-Kraljacic Blood 2016). To elucidate the mechanism of action of ribavirin in DLBCL, we conducted eIF4E-immunoprecipitation followed by RNA-sequencing (RIP-seq) in OCI-Ly1 cells to identify RNAs that bind to eIF4E. We integrated this data with the RNA-sequencing of ribavirin-treated OCI-Ly1 cells (vs. vehicle) to further characterize RNAs that are more likely to be decreased by ribavirin. We performed pathway analysis with this data and found several lymphomagenic eIF4E transcripts to be significantly reduced by ribavirin treatment including the BCR, epigenomic regulators, interleukin signaling (IL-6, IL10), DNA damage response elements, and components of the splicing machinery. This suggests that ribavirin interferes with critical pathways in proliferating DLBCL cells and may be active in lymphoma patients. After observing a patient with an aggressive, refractory transformed lymphoma (CLL to HL) demonstrate an objective response on imaging following administration of ribavirin for RSV in absence of concurrent chemotherapy, we retrospectively analyzed (with IRB approval) outcomes of lymphoma patients undergoing autologous or allogeneic SCT who received ribavirin for antiviral indications. We searched our institutional electronic record system and SCT database for lymphoma patients meeting prospectively defined criteria as receiving ribavirin within 6 months prior to or any time after SCT. Ten patients were identified including 5 DLBCL (1 transformed from CLL and another from FL), 2 HL (1 transformed from CLL), 2 FL, and 1 MCL. All were male and median age at lymphoma diagnosis was 54 years (range 35-64). Median number of treatments received prior to SCT was 4 (2-8). Four were deemed to have inadequate response (3 with PD and 1 with insufficient PR) after salvage therapy and were treated with bendamustine prior to proceeding to SCT (3 with an investigational high dose regimen). Responses to therapy immediately prior to SCT included 4 CR, 5 PR, and 1 SD. Six underwent allo SCT and 4 auto SCT. All patients received ribavirin for RSV (4 inhalational, 6 oral) with a median length of treatment of 10 days (5-15). Median interval between SCT and ribavirin was 5 months (-1 to 23). Nine of 10 patients are currently alive with no evidence of lymphoma with a median OS of 17.8 months (4.6-85.5) and median PFS of 11.1 months (2.4-63.8). These retrospective data from patients with refractory lymphomas treated with ribavirin as antiviral therapy (just prior to or soon following SCT) demonstrate lymphoma-related outcomes superior to those expected based on disease risk profiles (9 of 10 with ongoing CRs). We recognize the limitations of this analysis, as well as potential selection biases and other possible explanations for these findings. However, our observations, in conjunction with preclinical data on eIF4E inhibition, raise the intriguing possibility that ribavirin may have clinically meaningful anti-lymphoma activity. Further assessment of larger numbers of patients, and rationally designed prospective clinical studies of ribavirin are justified and planned. Table Table. Disclosures Martin: Acerta: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Teva: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3045.3045

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

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In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 964-964

Abstract: Abstract 964 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk. We have previously reported initial efficacy and safety data with this agent in various B-cell malignancies (ASCO 2010 abstract # 8012). We now report updated efficacy and safety of PCI-32765 in patients (pts) with long-term dosing. Pts and Methods: Pts on the Phase 1 study were treated with escalating doses over 6 cohorts. Cohort 1 was dosed at 1.25 mg/kg/day with subsequent dose escalation (2.5, 5.0, 8.3, 8.3 continuous dosing, and 12.5 mg/kg/day) based on safety evaluation. Pts were analyzed according to histology, pretreatment clinical and laboratory characteristics, PCI-32765 dose levels, overall response (OR), and response duration. Results: Responses and time on study (≥ 6 months) are summarized in Table 1. Of 47 pts enrolled in the Phase 1 study, 20 pts (43%) achieved an OR including 3 complete remissions (CR) and 17 partial remissions (PR). Fourteen of 47 pts have been on study ≥ 6 months; of these 8 pts demonstrated a PR or better and 6 pts maintained stable disease (SD). Responses were observed irrespective of pretreatment risk factors such as performance status, lactate dehydrogenase (LDH) levels, or disease burden. Durable responses were seen at all dose levels and across various histologic subtypes (Table 1) and currently 9 of 14 pts with treatment ≥ 6 months are still on study. Study-drug related Grade ≥ 3 toxicities were reported in 9/47 pts (19%). Five of 47 pts discontinued study drug due to adverse events: neutropenia (Grade 3) lasting 〉 7 days, hypersensitivity reaction (Grade 3), small bowel obstruction (Grade 3), anemia (Grade 2), and exacerbation of chronic obstructive pulmonary disease (Grade 3). No evidence of cumulative hematologic toxicity or long-term safety signals have been observed. No treatment-related deaths have been reported. Conclusion: PCI-32765 is a novel oral Btk inhibitor that induces durable objective responses in various relapsed or refractory B-cell malignancies. The favorable safety profile and lack of cumulative hematologic toxicities support further studies of both monotherapy and combination treatment with PCI-32765. Disclosures: Fowler: Pharmacyclics: Consultancy, Research Funding. Off Label Use: This phase I trial describes the results of a first in human Phase I trial. This drug is not FDA approved for the treatment of malignancy. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Smith:pharmacyclics: Research Funding. Boyd:pharmacyclics: Research Funding. Grant:pharmacyclics: Research Funding. Kolibaba:pharmacyclics: Research Funding. Furman:Pharmacyclics, Inc: Research Funding. Buggy:pharmacyclics: Employment. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:pharmacyclics: Employment. Advani:Pharmacyclics, Inc: Honoraria, PI grant.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.964.964

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 55-55

Abstract: Abstract 55 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B cell proliferation and survival. In chronic lymphocytic leukemia (CLL) the PI3K pathway is constitutively activated and dependent on PI3Kδ. CAL-101 is an isoform-selective inhibitor of PI3Kδ (EC50 of 62 nM in a whole-blood assay with 〉 200-fold selectivity relative to other PI3K isoforms) that inhibits PI3K signaling and induces apoptosis of CLL cells in vitro. Methods and Patients: This Phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics and clinical activity of CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally one or 2 times per day (QD or BID) continuously for 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Clinical response was evaluated according to standard criteria. Results: At data cutoff, the study had enrolled 37 patients with CLL. Patients included: males/females n=31 (84%)/6 (16%) with median age of 65 [range 37–82] years, refractory/relapsed disease n=24 (65%)/13 (35%), bulky disease n= 29 (81%), and adverse cytogenetics of del(17p), del(11q) or both n=22 (63%). The median number of prior therapies was 5 [range 2–14] . The number (%) of patients with specific prior therapies included: rituximab n=37 (100%), purine analog n=37 (100%), alkylating agent n= 31 (84%), and alemtuzumab n=12 (32%). CAL-101 dose levels were 50 mg BID (n=1), 100 mg BID (n=4), 150 mg BID (n=11), 200 mg BID (n=10), 350 mg BID (n=7) and 300 mg QD (n=4). The median number of treatment cycles was 9 [range 1–13], with 21 (57%) patients continuing on treatment (11 on study and 10 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL-101-related. Grade ≥3 pneumonias occurred in 9 (24%) patients. Grade ≥3 hematological laboratory abnormalities included neutropenia n=9 (24%), thrombocytopenia n=4 (11%) and anemia n=3 (8%) that were not usually considered CAL-101-related. A pharmacokinetic analysis of dose-proportionality showed minimal increases in plasma Cmax and AUC at CAL-101 doses 〉 150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2–3 dose selection. Flow cytometry of CLL cells from patients showed that CAL-101 reduced constitutive expression of phospho-AKT to background levels when measured after 1 week of treatment (p 〈 0.0001), demonstrating pharmacodynamic inhibition of activated PI3K signaling. Plasma concentrations of chemokines CCL3, CCL4, and CXCL13 were elevated at baseline and decreased significantly within 1 cycle of CAL-101 administration (p 〈 0.001 for all comparisons). CAL-101 reduced lymphadenopathy in all 32 (100%) patients with at least 1 post-treatment tumor assessment; 29/32 (91%) achieved a lymph node response (≥50% reduction in target nodal lesions). An initial increase in peripheral absolute lymphocyte counts of 〉 50% from baseline was observed in 21/35 (60%) patients; increases were maximal during the first 2 cycles and decreased thereafter; the pattern suggested drug-mediated lymphocyte redistribution. Considering nodal and peripheral blood changes together, partial responses were observed in 11/33 (33%) of patients. The median duration of response had not been reached; 7 patients had response durations of ≥6 months. Of 20 patients with CLL-related thrombocytopenia (baseline platelet counts 〈 100,000/μ L), 15 (75%) had either an improvement to 〉 100,000/μ L or a 〉 50% increase from baseline. Conclusions: CAL-101, an oral PI3Kδ isoform-selective inhibitor, shows acceptable toxicity, positive pharmacodynamic effects, and favorable clinical activity in heavily pretreated patients with CLL, including patients with refractory disease, bulky lymphadenopathy, and poor-prognosis cytogenetics. The high level of lymph node regression and prolonged duration of symptomatic tumor control strongly support evaluation of CAL-101 alone and in combination with other chemo/immunotherapy approaches to CLL management. Disclosures: Byrd: Calistoga Pharmaceuticals: Consultancy, Equity Ownership. Brown:Calistoga: Consultancy. Kahl:Calistoga Pharmaceuticals: Consultancy, Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Giese:Calistoga Pharmaceuticals: Equity Ownership. Webb:Calistoga Pharmaceuticals: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment. Yu:Calistoga Pharmaceuticals: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.55.55

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 123, No. 22 ( 2014-05-29), p. 3398-3405

Abstract: This clinical study assessed idelalisib, a selective PI3Kδ inhibitor, in 40 patients with relapsed/refractory MCL. In a dose-escalation trial in heavily pretreated patients, an overall response rate of 40% was observed with an acceptable safety profile.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2013-11-537555

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7