bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of ipilimumab (ipi) in patients (pts) with myelodysplastic syndromes (MDS) after hypomethylating agent (HMAs) failure.
Authors: Zeidan Amer M , Knaus Hanna , Robinson Tara M. , Zeidner Joshua F. , Blackford Amanda L. , Rizzieri David , Frattini Mark G. , Levy Moshe Yair , Schroeder Mark A. , Ferguson Anna K. , Sheldon Katherine , Dezern Amy Elizabeth , Gojo Ivana , Gore Steven , Streicher Howard , Luznik Leo , Duffield Amy , Smith B. Douglas
Published: September 2018

7010

Background: Pts with HR-MDS after HMA failure have a poor overall survival (OS) of < 6 months. Immune escape is associated with resistance to HMAs in MDS. We hypothesized that CTLA-4 blockade in these pts would be tolerable and lead to clinical responses. Methods: This investigator-initiated, CTEP-sponsored, multi-center phase 1b study enrolled pts after failure of HMAs. In dose-escalation, ipi monotherapy was given at 2 dose levels (DL): 3 and 10mg/kg. Four doses (every 3 weeks) were administered followed by a maintenance phase (4 doses every 3 months) for non-porgressors. Toxicities and responses were evaluated with CTCAE4 and IWG2006 criteria, respectively. OS was estimated using the Kaplan-Meier method. The impact on T-cells were studied by flow cytometry and TCR sequencing. Results: 29 pts from 7 centers were enrolled. Mean age (SD) was 67 (8) years. Most had IPSS high/int-2 (55%), 45% had int-1. Three of 6 pts in DL1 and 4 of 5 pts in DL2 experienced grade [G]2-4 immune-related adverse events [IRAEs] that were reversible with drug discontinuation or systemic steroids. The DL1 (3mg/kg) was expanded with no G2-4 IRAEs reported in the 18 additional pts. A total of 15 deaths occurred due to disease progression or other complications but none attributed to ipilimumab. In total, 52% received all 4 induction doses, and 24% received ≥1 maintenance dose. Best objective responses were 2 marrow complete responses (mCR, 7%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 6 pts (21%) and for ≥54 weeks in 3 pts (10%). Five pts (17%) subsequently underwent allogeneic transplantation (alloSCT) without evidence of excessive toxicity. Median OS (censoring at alloSCT) was 294 days (95%CI, 240-671+) and 400 days (95%CI, 240-671+) for those who received maintenance (n = 7). Pts who achieved PSD and mCR had significantly increased expression of ICOS, a marker of T-cell activation. Conclusions: Immune checkpoint blockade with ipi is tolerable and can lead to PSD/mCR in a proportion of pts. However, ipi monotherapy efficacy is limited after HMA failure and combination-based approaches should be considered. Increased frequencies of ICOS expression might predict clinical benefit. Clinical trial information: NCT01757639.
Dose escalation results of a phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML).
Authors: Erba Harry Paul , Becker Pamela S. , Shami Paul J. , Grunwald Michael Richard , Flesher Donna L. , Zhang Yilong , Rasmussen Erik , Henary Haby A. , Wang Eunice S.
Published: September 2018

7027

Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, MDM2 inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity of the investigational oral, selective MDM2 inhibitor AMG 232 as monotherapy or combined with the MEK kinase inhibitor trametinib in pts with r/r AML. Methods: Pts with r/r AML received AMG 232 for 7 days every 2 weeks (7 days on/7 days off) at 60, 120, 240, 480, and 960 mg PO QD as monotherapy (Arm 1) or combined with trametinib 2 mg PO QD (Arm 2). Primary endpoints were the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), and PK. Additional endpoints included best response (revised IWG) and serum MIC-1 level (increased MIC-1 suggests p53 activation). p53 target gene ( P21, BAX, and PUMA) expression in bone marrow was assessed by microarray. Results: In total, 35 pts (Arm 1, n = 26; Arm 2, n = 9; median age, 68 y; range, 26–86) were treated. Arm 1 enrolled AMG 232 at 60 mg (n = 4), 90 mg (n = 4), 180 mg (n = 5), 240 mg (n = 3), and 360 (n = 10). Twenty-two (85%) pts in Arm 1 had treatment-related AEs; the most common were nausea (n = 14), diarrhea (n = 14), and vomiting (n = 6). No DLTs occurred; one pt is still on treatment. The MTD was determined as 360 mg based on tolerance of gastrointestinal toxicity. Arm 2 enrollment is ongoing at a fixed AMG 232 dose of 60 mg plus trametinib (n = 9). AMG 232 plasma exposure increased with dose escalation; PK was unaffected by trametinib. Trametinib PK was as expected. Increases from baseline (BL) to day 10 in serum MIC-1 were dose dependent. Evidence of increased P21, BAX, and PUMA expression (BL to day 7 or 8) was seen (n = 3). One pt (Arm 2) had complete remission (CR); three pts (Arm 1) achieved CRi/MLFS. Median response duration was 66 days [range, 21–377+]). Conclusions: AMG 232 monotherapy was tolerable in pts with r/r AML at doses up to 360 mg on a 7 days on/7 days off schedule with expected PK, on-target biological effects, and early evidence of antileukemia activity. Clinical trial information: NCT02016729.
Overall survival (OS) with CPX-351 versus 7+3 in older adults with newly diagnosed, therapy-related acute myeloid leukemia (tAML): Subgroup analysis of a phase III study.
Authors: Lancet Jeffrey E. , Rizzieri David , Schiller Gary J. , Stuart Robert K. , Kolitz Jonathan E. , Solomon Scott R. , Newell Laura F. , Erba Harry Paul , Uy Geoffrey L. , Ryan Robert , Chiarella Michael , Louie Arthur Chin , Cortes Jorge E.
Published: September 2018

7035

Background: tAML may occur as a late complication of cytotoxic therapy and is associated with a poor prognosis. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). In a randomized, open-label, controlled phase III trial in patients (pts) aged 60-75 years with newly diagnosed, secondary AML (tAML or after MDS), CPX-351 significantly improved OS versus 7+3. The current analysis of this phase III study evaluated outcomes in the subgroup of pts with tAML. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 cycles of consolidation therapy. The study was not powered for this subgroup analysis. Results: 304 pts were enrolled and received study treatment, including 62 (20%) pts with tAML; demographics of tAML pts were similar between study arms. Pts with tAML had typically received prior non-anthracycline chemotherapy alone (25%), radiation alone (25%), or non-anthracycline chemotherapy + radiation (32%). CPX-351 was associated with an OS benefit versus 7+3 in older tAML pts and numerically longer event-free survival (EFS) and remission duration (Table). A greater proportion of tAML pts achieved CR+CRi (47% vs 36%, respectively) and proceeded to stem cell transplantation (37% vs 27%) with CPX-351. The safety profile of CPX-351 was comparable to that of 7+3. Conclusions: CPX-351 is associated with improved outcomes in older pts with newly diagnosed tAML. Outcomes in the tAML subgroup mirrored the overall study population, indicating CPX-351 may represent a new therapeutic option for this difficult to treat population. Clinical trial information: NCT01696084. [Table: see text]
Idarubicin and cytarabine with clofarabine or fludarabine in adults with newly diagnosed acute myeloid leukemia: Updated results of a randomized phase II study.
Authors: Issa Ghayas C. , Kantarjian Hagop M. , Short Nicholas James , Ravandi Farhad , Huang Xuelin , Garcia-Manero Guillermo , Plunkett William , Gandhi Varsha , Pemmaraju Naveen , Daver Naval Guastad , Borthakur Gautam , Jain Nitin , Konopleva Marina , Estrov Zeev , Kadia Tapan M. , Dinardo Courtney Denton , Brandt Mark , O'Brien Susan Mary , Cortes Jorge E. , Jabbour Elias
Published: September 2018

7037

Background: The purine nucleoside analogues fludarabine and clofarabine are effective agents in the treatment of acute myeloid leukemia (AML). This study evaluated the efficacy and safety of combining idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Methods: Using a Bayesian adaptive design, patients (pts) deemed suitable for intensive chemotherapy were randomized to receive CIA (n = 106) or FIA (n = 76). All pts received idarubicin 10 mg/m2 IV daily on Days 1-3 and cytarabine 1 g/m2 IV daily on Days 1-5. Clofarabine and fludarabine were given at 15 mg/m2 and 30 mg/m2, respectively, IV daily on Days 1-5. Pts with FLT3 mutations could receive sorafenib. Up to 6 cycles of consolidation were allowed for responding pts. Results: Baseline characteristics were similar comparing CIA to FIA with a median age of 53 years (range, 20-66) vs 49 years (range, 18-66) respectively and ELN risk intermediate-2/adverse of 57% and 58% respectively. With a median follow-up of 27 months (range, 1-58), the CIA and FIA arms had a similar CR/CRp rate (80% and 82%, respectively). MRD negativity rate by multiparameter flow cytometry at the time of CR/CRp was higher comparing CIA to FIA (80% vs. 65%, respectively, P = 0.07). The median EFS were 13 months and 12 months, respectively (P = 0.91), and the median OS were 24 months and not reached, respectively (P = 0.23). There were more adverse events (all grades) associated with CIA, particularly AST/ALT elevation (29% vs 4%), hyperbilirubinemia (26% vs 9%) and rash (31% vs 9%). Early mortality was similar in the 2 arms (60-day mortality: 4% for CIA vs 1% for FIA; P = 0.32). Comparing the 2 arms to a historical cohort of pts treated with IA showed similar response rates, EFS and OS excluding pts with FLT3 mutations from this analysis. However, in pts < 50 years of age, FIA was associated with improved survival compared with IA (2-year EFS rate: 58% vs 30%, P = 0.05; 2-year OS rate: 72% vs 36%; P = 0.009). Conclusions: CIA and FIA have similar efficacy in younger pts with newly diagnosed AML. FIA is associated with a better toxicity profile and may improve survival compared to IA in pts < 50 years of age. Clinical trial information: NCT01289457.
Allogeneic stem cell transplant (AHCT) in the eighth decade: Age is just a number.
Authors: Narra Ravi Kishore , Chhabra Saurabh , Narayana Swapna , Shah Nirav Niranjan , Hamadani Mehdi , Szabo Aniko , Pasquini Marcelo C. , Hari Parameswaran
Published: September 2018

7045

Background: Allogeneic hematopoietic cell transplant (AHCT) is a curative treatment for hematological malignancies but older adults ( > 70 years) have been historically excluded due to age-related comorbidities and concern for increased non-relapse mortality (NRM). Reduced intensity conditioning (RIC) regimens, and improvements in supportive measures have broadened AHCT to older adults. Limited data exist regarding AHCT in their eighth decade ( > 70). Methods: We evaluated 24 consecutive pts aged > 70 years receiving AHCT for various hematological malignancies between 2012 and 2016 at the Medical College of Wisconsin. Results: Median age was 72 (range, 70-76), and 62% were male. Disease indications included 11 AML, 6 CMML, 1 MDS, 1 NHL, 1 MM with only 11 patients (46%) in CR at transplant. 15 patients (62%) had normal karyotype, while other 9 had complex karyotype (n = 4), trisomy 11 (n = 1), trisomy 8 (n = 1). 6 patients (26%) had low-risk DRI score, 9 (39%) intermediate and 8 (35%) had high-risk score. Median HCT-CI score was 1.5 (range, 0-5) and 79% patients had a score of ≤2. Donors were related in 50% cases (3 haploidentical, 7 matched siblings and 2 syngeneic). Conditioning was RIC in 23 pts and all peripheral blood grafts. Median follow up was 14.2 months (range, 1.5-42.3). At day 28, 92% had neutrophil engraftment and 87% platelet engraftment. 2 patients had primary graft failure. 4 patients had acute GVHD, 4 had chronic GVHD,1 had both. Median CD3 chimerism was 99% (range, 74-100), CD33 was 100% (range, 78-100). Median of hospital-free days in the first 100 days was 80 and 160 days in the first 6 months after AHCT. 4 pts (17%) underwent AHCT entirely in outpatient setting. 6 patients relapsed at a median of 145 days (range 40-195). Survival at 2 years was 67% with relapse-free survival of 56% and NRM of 14%. Causes of death included sepsis (n = 1), fungal pneumonia (n = 1), cardiac (1), IPS (1), relapse (3). Conclusions: This experience with septuagenarians undergoing AHCT demonstrated an excellent 2 yr survival of 67% and that they can receive AHCT in the outpatient setting with a median hospital-free period of 80 days within the first 100 days. In carefully selected patients NRM with AHCT is manageable. Age alone should not determine eligibility for AHCT.
Allogeneic transplant leads to markedly improved survival in older patients with AML.
Authors: Lachowiez Curtis Andrew , Cook Rachel J. , Meyers Gabrielle
Published: September 2018

7048

Background: AML is a disease of the elderly, and outcomes with standard treatment are dismal. Allogeneic transplant is the only curative therapy for most patients with AML. Recent work has shown age is not a factor in transplant outcomes, and should not be a limiting factor for transplant. The treatment pathway for older patients with AML should take into account their disease risk, comorbidities, and treatments with a proven survival advantage. We investigated our institutional experience to help guide the establishment of optimal pathways for patients. Methods: We conducted a retrospective analysis of 118 patients over age 65 with AML treated at our institution between 2010-2015. Patients receiving therapy (n = 90) were categorized into two groups: intensive induction therapy (7+3 based) or induction therapy with a hypomethylating agent. The groups were well matched in regard to comorbidities. Results: In poor risk patients, complete remission (CR) was achieved in 42% (n = 30/71). Select patients up to age 75 proceeded to allogeneic transplant if they achieved CR. Survival in CR1 was higher in the transplant (n = 22, median 719 days, 95% CI: 366-1071 days), than in the non-transplant group (n = 8, median 257 days, 95% CI: 92-421 days, p-value < .001). In analyzing all risk groups, overall survival was superior in transplant (median 1188 days) versus non-transplant recipients (median 185 days) (see 1, 2, and 3 year survival in table). No difference in median survival occurred based on age at induction (older than 70: n = 9, younger than 70: n = 16, p-value = 0.316). There was no difference in median survival based on chemotherapy regimen without transplant: intensive induction (n = 24, survival 250 days, p-value 0.179) compared to hypomethylating agents (n = 22, survival 139 days). Conclusions: We confirm that transplant can be safely performed in patients over 70 years of age, and highlight the survival advantage of transplant to chemotherapy alone. Additionally, our data found no survival benefit of hypomethylating agents in elderly patients with poor risk AML.[Table: see text]
Clinical relevance of mutations in patients with myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with normal karyotype.
Authors: Montalban-Bravo Guillermo , Alfonso Pierola Ana , Takahashi Koichi , Konopleva Marina , Jabbour Elias , Borthakur Gautam , Daver Naval Guastad , Dinardo Courtney Denton , Estrov Zeev , Kadia Tapan M. , Pemmaraju Naveen , Ravandi Farhad , Bueso-Ramos Carlos E. , Kantarjian Hagop M. , Patel Keyur , Garcia-Manero Guillermo
Published: September 2018

7053

Background: Clinical outcomes of patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are heterogeneous. Specific mutations and mutation patterns are known to define prognostic groups in normal karyotype acute myeloid leukemia. Whether this is the case in MDS and MDS/MPN remains unknown. Methods: We evaluated 325 previously untreated patients with MDS or MDS/MPN with normal karyotype evaluated from 2012 to 2016. Next generation sequencing (NGS) on whole bone marrow DNA analyzing a panel of 28 or 53 genes was performed at the time of diagnosis. Results: A total of 225 (69%) patients had MDS and 100 (31%) had MDS/MPN including 77 (24%) patients with chronic myelomonocytic leukemia (CMML). Median age was 69 years (31-92). Among patients with MDS, 189 (84%) had lower-risk and 36 (16%) had higher-risk based on IPSS. NGS data was obtained by 53-gene panel in 93 (29%) patients and by 28-gene panel in 232 (71%). A total of 202 (62%) patients had detectable mutations. Median number of mutations was 1 (range 0-6). Detected mutations are detailed in Table 1. A total of 111 (34%) patients, 70 with MDS and 41 with MDS/MPN, received therapy with hypomethylating agents. Median follow up was 12 months (0-167). By univariate analysis, NRAS (HR 3.28, CI 1.25-8.62, p=0.016) and TP53 (HR 4.9, CI 1.44-16.67, p=0.011) predicted for shorter overall survival (OS) among MDS patients. After multivariate analysis including IPSS-R, only TP53retained its impact in OS (HR 5.25, CI 1.44-19.13, p=0.012). Among MDS/MPN patients, no mutation was found to significantly impact OS. Conclusions: With the exception of TP53mutations, no other identified mutation seemed to independently define prognosis of patients with MDS or MDS/MPN with normal karyotype. In view of the high proportion of lower-risk patients, longer follow up is required to better define prognostic impact of mutations in this population. [Table: see text]
Phase I clinical trial on pomalidomide and dexamethasone in treating patients with relapsed/refractory primary central nervous system lymphoma (PCNSL) or primary vitreoretinal lymphoma (PVRL).
Authors: Tun Han W. , Johnston Patrick B. , Grommes Christian , Reeder Craig B. , Omuro Antonio Marcilio Padula , Menke David M , Copland John A. , DeAngelis Lisa Marie , Witzig Thomas E.
Published: September 2018

7516

Background: PCNSL is a diffuse large B cell lymphoma confined to the CNS. Pomalidomide (POM) is a novel immunomodulatory agent with excellent CNS penetration (~40%) based on CNS PK analysis in rats and pre-clinical therapeutic activity against CNS lymphoma. Methods: A Phase I clinical trial was undertaken to determine the maximal tolerated dose (MTD) of POM, safety profile and overall response rate (ORR). Treatment consists of POM daily for 21 days every 28 days in combination with dexamethasone 40 mg PO weekly for two cycles followed by POM alone in subsequent cycles until progression or intolerance. 4 dose escalation levels of POM (3mg, 5mg, 7mg, and 10 mg) were planned. Thromboprophylaxis with oral anticoagulant or aspirin was required. MTD determination has been completed and expansion of the MTD cohort is ongoing. Therapeutic responses were evaluated per the international PCNSL collaborative group (IPCG) criteria after 2 cycles of treatment. The trial is registered with ClinicalTrials.gov (#NCT01722305). Results: 21 of 25 patients accrued were eligible for assessment. The MTD was determined to be 5 mg qd for 21 days every 28 days. Two DLTs were seen at dose level 3 (Grade 3 dyspnea and grade 4 thrombocytopenia). One DLT was seen in the expanded MTD cohort (Grade 4 neutropenia and lymphocytopenia). ORR for the study (9/21) was 43% (95% CI- 22%, 66%) with 4 CR, 1 CRu and 4 PR. 3 responders completed 2, 4, and 6 cycles before progression. 6 responders have completed 4, 5, 6, 10, 12, and 32 cycles and remain on treatment. ORR for the MTD dose level was (5/12) 42% (95% CI- 15%, 72%) with 3 CR and 2 PR. 2 patients had stable disease (SD). Pseudo-progression was seen in 1 patient. Overall, grade 3/4 toxicity was hematologic (neutropenia, anemia, and thrombocytopenia) in 38.1% and non-hematologic in 33.3% (fatigue, pneumonia, sepsis, syncope, dyspnea, hypoxia, respiratory failure and maculo-papular rash). Percent CSF/blood ratio of POM was determined to be 19% in 1 patient. Conclusions: Pomalidomide treatment is feasible with therapeutic activity against relapsed/refractory PCNSL and should be further developed. Clinical trial information: NCT01722305.
Persistence of ibrutinib-associated hypertension in CLL pts treated in a real-world experience.
Authors: Gashonia Lisa M. , Carver Joseph R. , O'Quinn Rupal , Clasen Suparna , Hughes Mitchell E. , Schuster Stephen J. , Isaac Krista , Kennard Kaitlin , Svoboda Jakub , Daniel Catherine , Tsai Donald Edward , Fanning Molly J , Nasta Sunita , Landsburg Daniel Jeffrey , Nabhan Chadi , Mato Anthony R.
Published: September 2018

7525

Background: Cardiovascular (CV) complications associated with ibrutinib (Ibr) include hypertension (HTN) and atrial fibrillation (AFIB) (incidence 26% and 9%, OBrien, ASH 2016). Unlike clinical trials, Ibr toxicities are the most common reasons for its discontinuation in clinical practice. The incidence of HTN in pts treated with Ibr outside of clinical trial setting and its impact on outcomes is unknown. Methods: Retrospective, cohort study of Ibr-treated CLL pts to estimate HTN incidence. Baseline CLL characteristics and co-morbidities were recorded. Blood pressure (BP) measurements were recorded prior to Ibr and sequentially following exposure at specific time points. CV meds were reviewed during a 12 mo follow-up period. The association between Ibr exposure and BP was tested. Results: 153 consecutive CLL pts treated with Ibr at a dose of 420 mg/day were identified. Med age was 57 yr (range: 34-87), relapsed CLL (69%), follow-up 14.5 mo. CV pre-Ibr characteristics included: smoking hx (49%), HTN (42%), hyperlipidemia (39%), diabetes (17%), CAD (12%), AFIB (6.8%). Proportion of pts on ≥1 anti-HTN med increased from 44% pre-Ibr (20% ≥ 2) to 57% during Ibr (30% ≥ 2). Med pre-Ibr BP was 127/70 mmHg (range 90-182/48-95mmHg). At 1, 3, 6, 9, 12 mo, med BPs were 137/73, 141/75, 143/76, 140/75, 142/77 (7 mo to peak BP). There was a significant association between Ibr exposure and increased BP (p<.01). New HTN was observed in 40% of pts and 36% HTN pts had BP increased above baseline (med baseline 135/70 vs peak 161/80). Incidence of new AFIB was 8.1%. In UV analyses, predictive clinical factors for HTN were not identified. Pre-Ibr HTN (OR 3.0, p .05), CAD (OR 4.3, p .03), prior AFIB event (OR 10.8, p.001), hyperlipidemia (OR 3.4, p.05) were associated with post-Ibr AFIB. Conclusions: In the largest real-world series focused on BP in Ibr treated pts, we demonstrate a clear association between Ibr and HTN. Nearly 40% of pts developed HTN within 12 mo of Ibr exposure (vs. 26% in clinical trials over 5 yr). Despite aggressive management (multiple agents), Ibr associated HTN was persistent. These data underscore the critical need for monitoring and management strategies for HTN and follow-up data on future CV events.
Phase 1B of ibrutinib and high-dose methotrexate for recurrent/refractory CNS lymphoma.
Authors: Grommes Christian , Stone Jacqueline , Nolan Craig , Tsyvkin Elina , Wolfe Julia , Mellinghoff Ingo K. , DeAngelis Lisa Marie
Published: September 2018

7533

Background: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). In this phase 1B trial, we investigate the toxicity of ibrutinib in combination with high-dose methotrexate (HD-MTX) in r/r PCNSL/SCNSL. Methods: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses. To minimize adverse events, ibrutinib was stopped on days of HD-MTX infusion and was restarted 5 days after MTX infusion or after completion of MTX-clearance, if clearance of MTX required more than 5 days. Ibrutinib was continued daily after completion of 8 doses of MTX. Results: Six patients have been enrolled; 3 received 560mg and 3 received 840mg ibrutinib in combination with HD-MTX. Median age was 62 (range 43-74); median ECOG 1 (0:2; 1:3; 2:1). Two had r/r PCNSL and 4 SCNSL. Three had brain disease, one isolated cerebrospinal fluid (CSF) involvement and two parenchymal and CSF involvement. Three patients had recurrent (2 PCNSL; 1 SCNSL), two refractory (both SCNSL), and one newly diagnosed disease (SCNSL). There were no grade 4 adverse events. Grade 3 events were observed in 5 patients (lymphopenia in 3, ALT elevation in 2, diarrhea in 1, electrolyte changes in 1, hypertension in 1). The most common adverse events were hypokalemia, low WBC, hyperglycemia, ALT and AST elevation. There was no dose reduction of methotrexate or ibrutinib in any patient. After a median follow-up of 130 days, all patients were evaluated for response after 4 doses of HD-MTX, with 4/6 (67%) showing a response: 2 CR, 2 PR, and 1 SD, 1 PD; both non-responders were refractory SCNSL. Ibrutinib concentrations were measured in plasma and CSF. Conclusions: Patients with CNS lymphoma tolerate the combination of HD-MTX and Ibrutinib (at 560 and 840mg) well. Continued enrollment into a combination arm that includes rituximab, methotrexate and ibrutinib is ongoing. Clinical trial information: NCT02315326.
Oncogenic activation of STAT3 pathway drives PD-L1 expression in natural killer/T cell lymphoma.
Authors: Lim Soon Thye , Song Tammy , Lim Jing Quan , Laurensia Yurike , Pang Jane Wan Lu , Nagarajan Sanjanaa , Claresta Giovanni , Jing Tan , Tang Tiffany Pooi Ling , Nairismagi Maarja-Liisa , Ong Choon Kiat
Published: September 2018

7549

Background: Natural killer/T-cell lymphoma (NKTL) is a rare type of non-Hodgkin lymphoma that occurs more frequently in East Asia and Latin America and is associated with Epstein–Barr virus infection. Recent whole-exome sequencing studies in NKTL have reported recurrent somatic mutations in genes associated with JAK-STAT pathway, however the role of aberrant JAK-STAT signaling in tumor immune escape through PD-L1 regulation is unclear. Methods: To determine the prevalence of JAK-STAT pathway alteration in NKTL, we performed targeted sequencing of 188 genes associated with JAK-STAT pathway in 109 NKTL (22 Singapore cases, 79 China cases and 8 cell lines). Single nucleotide variants and micro-indels were called using Freebayes and candidate variants annotated using ANNOVAR. Ba/F3 model system was used to test the transformation capacity of identified variants. Cell lines were evaluated for PD-L1 expression by immunoblotting and flow cytometry. Tissue microarrays were examined for p-STAT3 and PD-L1 expression by immunohistochemistry. Results: We identified a total of 284 non-synonymous somatic mutations candidates in 114 genes, including 243 missense, 10 nonsense, 4 splice-site and 27 indel mutations. Recurrent mutations were most frequently located in STAT3 (25/109 cases, 23%) followed by TP53 (16/109 cases, 16%) and JAK3 (8/109 cases, 7%). A total of 18 STAT3 variants were identified including known hotspot mutations and novel mutations in the SH2, coiled coil and DNA-binding domains. Characterization of novel E616K mutant residing in the SH2 domain showed that E616K conferred IL3 independent growth to Ba/F3 cells, increased STAT3 phosphorylation and PD-L1 expression. Consistent with these findings, PD-L1 was over expressed in cell lines harboring STAT3 mutations. A positive correlation between PD-L1 and p-STAT3 expression was also observed in tumor tissue (R = 0.51, P = 0.02). Conclusions: We characterized a novel activating STAT3 mutant and demonstrated its ability to drive PD-L1 expression, which may promote tumor evasion from the antitumor immune response. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising and novel therapeutic approach for NKTL in the future.
Allogeneic hematopoietic stem cell transplantation for mantle cell lymphoma in a heavily pretreated patient population.
Authors: Kobrinski Daniel Allen , Smith Scott E. , Al-Mansour Zeina , Tsai Stephanie Bochen , Martin Brendan , Stiff Patrick J.
Published: September 2018

7558

Background: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only potential curative treatment option for patients with MCL due to its potent graft-versus-lymphoma (GVL) effect. Survival following allo-SCT for MCL is variable due to high rates of non-relapse mortality (NRM). Methods: We retrospectively identified all patients who were treated with an allo-SCT for MCL at Loyola University Medical Center between January 1, 1999 and January 1, 2016. Probability estimates for overall survival (OS) and non-relapse mortality (NRM) at 5 years were calculated from the date of allo-SCT to the date of patient death or last known follow-up. Significance was determined using a cox proportional hazard (CPH) model. Rates of acute graft-versus-host disease (aGVHD) and relapse were also reported. Results: Patient characteristics (n = 29) are listed in Table. Median follow-up in surviving patients is 10 years (range 5-14 years). A majority of patients (n = 23, 79%) had 3 or more lines of treatment prior to allo-SCT. The 5 year rates of OS and NRM for all patients are 42% and 53%, respectively. Univariate analysis showed a lower risk of death in patients who received TBI-based conditioning (HR: 0.19, 95 CI: 0.04 – 0.81, p = 0.03), and those who had HLA-matched related donor (MRD) transplants (HR: 0.29, 95 CI: 0.11 – 0.79, p = 0.02). Patients who received more than 3 lines of prior treatment had a higher risk of death (HR: 2.77, 95% CI: 1.05-7.34, p = 0.04). Low rates of grade III/IV aGVHD (n = 4) and relapse (n = 4) occurred in our patient population. Two patient deaths were attributable to aGVHD, and the majority of other deaths were due to treatment-related toxicities. Conclusions: In an era of numerous effective non-curative salvage therapies, the optimal timing of allo-SCT for MCL needs further clarification. Our data supports early opposed to delayed allo-SCT for select high-risk patients with MCL who have a MRD. [Table: see text]
Replacement of ixazomib for relapsed/refractory multiple myeloma patients refractory to a bortezomib or carfilzomib-containing combination therapy.
Authors: Berenson James R. , Cohen Alexa , Spektor Tanya M. , Bitran Jacob D. , Chen Gigi Qiqi , Moezi Mehdi M. , Bessudo Alberto , Ye Joseph Z. , Hager Steven Jeffrey , Moss Robert A. , Cartmell Alan D. , Coleman Teresa A. , Hrom John Stewart , Eshaghian Shahrooz , Maluso Tina , Swift Regina A. , Lim Stephen
Published: September 2018

8013

Background: The proteasome inhibitor (PI) ixazomib (Ixz) is the first orally administered PI approved for treating multiple myeloma (MM). It has shown clinical activity as a single agent and when used in other combinations. In this phase 1/2 trial, we evaluated Ixz as a replacement therapy for bortezomib or carfilzomib for MM patients who were refractory to a bortezomib- or carfilzomib-containing combination regimen. Methods: This was a phase 1/2, intra-patient, multicenter, open-label trial evaluating the replacement of ixazomib for bortezomib or carfilzomib for MM patients who were refractory in combination with the other agents that the patients had received and failed. Patients received Ixz on days 1, 8 and 15 on a 28-day schedule and the other drugs were administered using the same doses and schedules as they were receiving during their prior regimen. If the Ixz maximum tolerated dose (MTD) for a particular combination regimen was previously determined, then patients were enrolled directly into Phase 2 (PhII). If not, MTD was determined during the Phase 1 (PhI) portion of the trial. Results: To date, a total of 40 patients have been enrolled; 37 patients (21 were enrolled in PhI and 16 in PhII) had completed at least one cycle of this treatment. Patients received a median of 5 prior treatments (range, 1-22). The median follow-up time for all patients was 1.6 months (range, 0.1-10.7 months), whereas that of PhII was 2.2 months (range, 0.2-10.7 months). There was no clinical benefit (CBR; 0%) nor any overall response rate (ORR; 0%) for patients receiving Ixz 3 mg (PhI). Nine patients (43%) showed stable disease (SD) while 12 (57%) exhibited disease progression (PD). In PhII (4mg Ixz) portion of the trial, ORR and CBR were both 18.7% with 16 (43.2%) patients showing SD, and 18 (48.6%) patients displaying PD. Common ≥ Gr3 adverse events were anemia (11%), thrombocytopenia (5.4%), hyponatremia (5.4%), dehydration (5.4%) and neutropenia (2.7%). Conclusions: Replacement of bortezomib or carfilzomib with Ixz infrequently leads to responses among RRMM patient who have progressed while on proteasome inhibitor -containing combination regimens. Clinical trial information: NCT02206425.
Phase 3 ELOQUENT-2 study: Extended four year follow-up (FU) of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM).
Authors: Lonial Sagar , Dimopoulos Meletios A. , Weisel Katja C. , White Darrell , Moreau Philippe , Mateos Maria-Victoria , San Miguel Jesus , Anderson Kenneth Carl , Shpilberg Ofer , Grosicki Sebastian , Spicka Ivan , Walter-Croneck Adam , Magen Hila , Belch Andrew , Reece Donna Ellen , Beksac Meral , Mekan Sabeen , Sy Oumar , Singhal Anil K. , Richardson Paul G.
Published: September 2018

8028

Background: Elotuzumab, an immunostimulatory monoclonal antibody, has a dual mechanism of action: directly activating NK cells and tagging myeloma cells for recognition/death via antibody-dependent cell-mediated cytotoxicity. In a 3-y FU, ELOQUENT-2 (NCT01239797) showed a sustained 27% reduction in risk of disease progression/death for ELd vs Ld and OS trend in favor of ELd (Dimopoulos et al, ASH 2015). Here we present extended 4-y FU data (median FU 46 mo). Methods: RRMM patients (pts) were randomized 1:1 to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity. Coprimary endpoints: PFS, ORR. Secondary endpoint: OS. Results: Of 646 RRMM pts, 321 were randomized to ELd, 325 to Ld; ~ twice as many pts remain on therapy in ELd vs Ld (17 vs 9%) at data cut-off (Oct 18, 2016). Discontinuation was mainly due to disease progression (both arms 54%). At 4-y FU, ELd had 29% reduction in risk of progression/death vs Ld (HR 0.71, 95% CI 0.59–0.86) and relative improvement of 50% in PFS (21 vs 14%). Pts with ≥VGPR (ELd 112 [35%], Ld 95 [29%]) had greatest reduction in risk of progression/death (HR 0.65, 95% CI 0.46–0.94). ORR was 79% (ELd) vs 66% (Ld). OS will be presented. G3–4 AEs in ≥5% of pts included second primary malignancies (SPMs), vascular diseases, cardiac disorders and infections (ELd vs Ld: 9 vs 6%, 10 vs 8%, 5 vs 8%, 33 vs 26%). Overall rate (any grade) of infection and SPMs was 84 vs 75% and 17 vs 11% for ELd vs Ld. However, pts had longer exposure to ELd vs Ld (median [Q1, Q3] treatment cycles (19 [9, 42] vs 14 [6, 25]). There were fewer deaths with ELd vs Ld (165 vs 186), mainly due to disease progression and infection in both arms. Conclusions: Elotuzumab in combination with Ld consistently met its efficacy objectives at 4-y FU. ELd showed durable, clinically relevant improvement in PFS, with 29% reduction in risk of progression/death, consistent with 2-y (30%) and 3-y FU (27%). Safety, including rate of SPMs, was consistent with previous findings, with minimal incremental AEs with addition of elotuzumab to Ld. These data represent the longest median FU of an immuno-oncology agent in MM. Study funding: BMS. Writing support: C Tomas, Caudex, funded by BMS. Clinical trial information: NCT01239797.
Nivolumab (nivo) ± ipilimumab (ipi) in advanced small-cell lung cancer (SCLC): First report of a randomized expansion cohort from CheckMate 032.
Authors: Hellmann Matthew David , Ott Patrick Alexander , Zugazagoitia Jon , Ready Neal E. , Hann Christine L. , De Braud Filippo G. , Antonia Scott Joseph , Ascierto Paolo Antonio , Moreno Victor , Atmaca Akin , Salvagni Stefania , Taylor Matthew H. , Amin Asim , Camidge D. Ross , Horn Leora , Calvo Emiliano , Cai Weiguo , Fairchild Justin P. , Callahan Margaret K. , Spigel David R.
Published: September 2018

8503

Background: Patients (pts) with advanced SCLC after first-line platinum-based chemotherapy (PLT-CT) have a poor prognosis and limited treatment options. CheckMate 032 is a phase I/II trial evaluating multiple regimens of nivo ± ipi in solid tumors, including advanced SCLC. Tolerability and efficacy of nivo ± ipi were demonstrated in early results from the initial treatment arms (Antonia, Lancet Oncol 2016), prompting long-term follow-up and the addition of a randomized expansion cohort to further evaluate nivo ± ipi in advanced SCLC. Methods: In the initial treatment arms, pts with advanced SCLC and disease progression after prior PLT-CT were assigned to nivo (3 mg/kg Q2W; n = 98) or nivo 1 + ipi 3 (1 mg/kg and 3 mg/kg Q3W x 4, then nivo 3 Q2W; n = 61); safety/efficacy was assessed with a follow-up of ~18 mo. In the subsequent SCLC expansion cohort, pts were randomized 3:2 to nivo vs nivo 1 + ipi 3 and stratified by number of prior therapies. The primary endpoint was objective response rate (ORR). Results: Updated efficacy/safety results from the initial (non-randomized) nivo and nivo 1 + ipi 3 arms are summarized in the table. Responses were durable and occurred regardless of PD-L1 expression or PLT-sensitivity; safety was consistent with prior nivo ± ipi studies. In the expansion cohort, 247 pts were randomized to nivo or nivo 1 + ipi 3. The presentation will contain the first report of efficacy/safety results and subgroup analyses from this randomized expansion cohort. Conclusions: Durable responses are observed with nivo and nivo + ipi in pts with previously treated SCLC. The expansion cohort represents the first randomized evaluation of combined immune checkpoint blockade in SCLC. Clinical trial information: NCT01928394. [Table: see text]
Outcomes of anti-PD-1 therapy in mesothelioma and correlation with PD-L1 expression.
Authors: Rivalland Gareth , Kao Steven Chuan-Hao , Pavlakis Nick , Hughes Brett Gordon Maxwell , Thapa Bibhusal , Pal Abhijit , Walkiewicz Marzena , Zimet Allan Solomon , White Shane , O'Byrne Ken , Mitchell Paul , John Thomas
Published: September 2018

8514

Background: Early phase trials of anti-programmed death 1 (PD-1) antibodies have demonstrated important responses in malignant mesothelioma (MM). Expression of the ligand, PD-L1, is a potential biomarker for PD-1 directed therapy use and is expressed in a significant proportion of MM. We present results for a cohort treated with PD-1 inhibitory antibodies and assessed for PD-L1 expression. Methods: Patients (pts) with unresectable pleural or peritoneal mm treated with anti-PD-1 antibodies were included. Data was collected retrospectively. Radiological response was assessed using RECIST 1.1. Overall survival (OS) and progression-free survival (PFS) were evaluated. PD-L1 expression was assessed with IHC clone E1L3N (Cell Signaling Technology). PD-L1 positivity was defined as membranous expression on tumour cells: > 5% for PD-L1+ and > 50% for PD-L1hi. Results: Forty-six pts were treated between July 2015 and January 2017. Median age was 66.5 years, ECOG PS was 0/1 in 3/46 (7%) and 35/46 (76%) respectively. Most were male (83%), and 43/46 (93%) had ≥1 prior therapy, with a median of 2 (range 0 - 5). The predominant histology was epithelioid (n = 32/46; 70%). Pembrolizumab was used in 45/46 and BGB-A317 (a PD-L1 antibody) in 1 pt. Of the 46 pts, the overall response rate (ORR) was 15% (7 PR) with 15/46 (33%) achieving stable disease, giving a DCR of 44%. Progression was seen in 24/46 (52%). Median OS for the entire cohort was 8.0 months (95% CI: 2.3 – 11.9). Median duration of response was not yet reached (range 1.5 -19.8). PD-L1 testing was performed in 14 samples, with PD-L1+ in 5 (36%) and PD-L1hi in 4 (29%). The ORR was 40% (2 PR, 3 SD) with PD-L1+, 50% (2 PR, 2 SD) with PD-L1hi and 22% (2/9 patients) with negative expression. PFS and OS were greater with both PD-L1+ (PFS HR: 0.26, 95% CI 0.05 – 1.32, p = 0.10) and PD-L1hi(PFS HR: 0.17, 95% CI 0.02 – 1.47, p = 0.11). PD-L1+ positivity remained a borderline predictor of improved survival on multivariate analysis (p = 0.06). Complete PD-L1 analysis will be presented at the meeting. Conclusions: PD-1 targeted therapy demonstrated a clinically significant response rate in this cohort of mm patients. Initial analysis suggests PD-L1 expression is correlated with improved response and survival.
Trilaciclib (G1T28): A cyclin dependent kinase 4/6 inhibitor, in combination with etoposide and carboplatin (EP) for extensive stage small cell lung cancer (ES-SCLC)—Phase 1b results.
Authors: Rocha Lima Caio Max S. , Roberts Patrick J. , Priego Victor M. , Divers Stephen G. , Thomas Melanie B. , Boccia Ralph V. , Stabler Katie , Andrews Elizabeth , Malik Rajesh K. , Aljumaily Raid , Hamm John Turner , Chiu Vi Kien , Richards Donald A. , Nikolinakos Petros , Hussein Maen A. , Schuster Steven Robert , Hoyer Robert John , Shapiro Geoffrey , Dragnev Konstantin H. , Owonikoko Taofeek Kunle
Published: September 2018

8568

Background: Chemotherapy (chemo) has significant clinical utility, however consequent damage to hematopoietic stem and progenitor cells (HSPCs) and the immune system may limit activity. If chemo-mediated anti-tumor activity was maximized, while minimizing myelosuppression and immunosuppression, patient outcomes would be improved. Trilaciclib (T) is an intravenous CDK4/6 inhibitor in development to reduce myelosuppression and preserve immune system function during chemo. HSPCs are dependent on CDK4/6 for proliferation. Preclinical data demonstrated that transient T-induced G1 cell cycle arrest renders HSPCs resistant to chemo cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of anti-tumor immunity and activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess dose limiting toxicities (DLTs), safety, tolerability, hematological profile, PK, and anti-tumor activity of T administered prior to EP. Phase 1b was open-label, dose-finding, and the ongoing Phase 2a is randomized (1:1), double-blind. Eligible pts had confirmed diagnosis of ES-SCLC, adequate organ function, ECOG PS 0-2, no prior chemo, and no symptomatic brain metastases. Results: 19 pts were enrolled in the Phase 1b: 10 pts received T 200 mg/m2 + EP and 9 pts received T 240 mg/m2 + EP. T + EP was well tolerated. 2 pts at T 200 mg/m2 and 1 pt at T 240 mg/m2 experienced asymptomatic DLTs in cycle 1. 2 pts (1 at each dose) had an ANC < 1500 on cycle 2 day 1, delaying the start of cycle 2, and 1 pt at the T 200 mg/m2dose had grade 4 thrombocytopenia. There were no cases of febrile neutropenia or bleeding. PK analysis showed no drug interactions between T and EP. 17/19 pts were evaluable: 1 pt had CR, 14 had PR (confirmed ORR = 88%); 1 pt had SD (clinical benefit rate = 94%). Conclusions: In the Phase 1b part of the study, T + EP was well tolerated. Early activity results are promising with a confirmed objective response rate of 88%. This novel approach allowing the administration of chemotherapy while preserving HSPC and immune system function could potentially improve treatment outcomes for SCLC pts. Clinical trial information: NCT02499770.
Histology determination of lung cancers: A report on genomic profiling of lung cancer of mixing histology.
Authors: Tang Ming , Kalhor Neda , Ramineni Maheshwari , Fujimoto Junya , Zhang Jianhua , Li Jun , Chow Chi-Wan , Mao Xizeng , Song Xingzhi , Little Latasha , Gumbs Curtis , Behrens Carmen , William William N. , Weissferdt Annikka , Lee J. Jack , Swisher Stephen , Heymach John , Wistuba Ignacio Ivan , Futreal Andrew , Zhang Jianjun
Published: September 2018

8570

Background: Histopathology, largely determined by morphology, plays a critical role in choosing appropriate treatment for lung cancer. The understanding of molecular determination of lung cancer histology is rudimentary. Our recently published data (Zhang, Science, 2014 and Liu, Nature Communications, 2016) have demonstrated that within the same patients with identical genetic background and identical exposure, tumor regions with different morphologic appearances may have very similar genomic profiles while tumors with the same morphology may have distinct genomic landscape. Methods: We collected 12 lung cancers of mixing histology with 2 to 4 histologic components within each tumor. In total, 26 tumor regions including 9 adenocarcinomas, 6 large-cell neuroendocrine carcinoma, 6 small cell carcinomas and 4 squamous cell carcinomas and one poorly differentiated lung carcinoma were microdissected and subjected to whole exome sequencing. Results: A substantial number of identical mutations were shared between different histologic components within the same tumor in all 12 patients. However, the proportion of shared mutations varies in different patients ranging from as little as 4% to as much as 99%. Mutation spectrum is also similar between different histologic components within the same tumors suggesting similar mutational process in place. Identical canonical cancer gene mutations including TP53, KRAS, PIK3CA, SOS1 and STK11 are generally shared between different histologic components within the same tumors. Canonical mutations in FBXW7 and MTHFR were detected in squamous component, but not small-cell component in one patient. Conclusions: Different histologic components of lung cancers of mixing histology are likely derived from the same progenitor cells, but the molecular timing of branch separation of subclones giving rise to different histologic components varies in different tumors. Although genomic aberrations may play a role in a subset of tumors, histologic features may not be determined at genomic level for most lung cancers. Gene expression and methylation analyses from these tumors are underway.