Background

D, a human CD38 IgGκ mAb, induces deep, durable responses in pts with relapsed/refractory MM, as monotherapy and combined with other regimens. Infusion-related reactions (IRRs) occur in ∼50% of D-treated pts, are generally mild to moderate, and usually occur during the 1^st infusion. The median duration of the 1^st infusion is ∼7 hours. To determine if splitting the first dose would reduce IRRs and infusion times, split-dose D was evaluated in two K-based regimens (MMY1001: NCT01998971).

Methods

Pts received D plus K and dexamethasone (d; DKd) or DKd and lenalidomide (R; DKRd). Pts in the DKd arm had 1-3 prior therapies; pts in the DKRd arm were newly diagnosed. 28-day cycles comprised K 20 mg/m² intravenously (IV) over 30 minutes on Cycle 1 Day 1 (C1D1) and 70 mg/m² over 30 minutes weekly, thereafter; and weekly d 40 mg (20 mg if > 75 years). In the DKRd arm, R 25 mg was given orally on Days 1-21. Pts received IV D as a single or split dose (Table). If C1D1 and C1D2 D infusions were not well-tolerated, C1D8 was given in 1000 mL. Pts received treatment until progression (DKd) or for ≤13 cycles (DKRd). To mitigate IRRs, d (20 mg) was given ≤3 hours before dosing on C1D1 and C1D2, and ≤3 hours before and the day after subsequent infusions. Paracetamol and diphenhydramine were given ≤3 hours before infusion. Montelukast was given prior to first D dose (optional thereafter).

Results

Thirty-two pts received split-dose D. Median age (range) was 61 (34-76) years. Median number of D cycles received was 12 (1-14). Median first infusion time was 4.2 (4.0-10.3) hours. Among pts who received split-dose D, 9 (28%) pts had an IRR. Five (16%) and 4 (13%) pts had grade 1 and grade 2 IRRs, respectively. No grade 3/4 IRRs occurred. IRRs reported in ≥ 2 pts were cough, throat irritation, nausea, and headache (2 pts [6%] each). Data will be updated.

Conclusions

A split first dose of D was associated with shorter infusion times and reduced incidence and lower grade of IRRs.Table:

997PD

Clinical trial identification

NCT01998971

Legal entity responsible for the study

Janssen Research & Development, LLC

Funding

Funding provided by Janssen Research & Development

Disclosure

S.Z. Usmani: Research Funding: Onyx, Janssen, Sanofi, Array Biopharma, Pharmacyclics, Takeda, Celgene, Bristo-Myers Squibb. Speakers Bureau: Celgene, Amgen, Takeda. Advisory Board: Celgene, Skyline, Onyx, Millennium, Sanofi, Janssen. A. Jakubowiak: Consultancy & Advisory Committee: Janssen. A. Chari: Consultancy & Research Funding & Advisory Committee: Amgen, Array Biopharma, Celgene, Janssen, Millenium/Takeda, Novartis. S. Lonial: Advisory Committee: Millennium, Celgene, Novartis, Bristol-Myer Squib, Onyx, Janssen. Research Funding: Janssen. M-V. Mateos: Consultancy & Honoraria: Janssen, Celgene, Takeda, Amgen. L. Benboubker: Honoraria: Takeda, Celgene, Janssen, and Amgen. K. Wu, N.Z. Khokhar: Employment: Janssen. J. Wang: Employment & Stock Ownership: Janssen. P. Doshi: Employment & Royalties & Stock Ownership: Janssen. P. Moreau: Honoraria & Consultancy: Celgen, Takeda, Janssen, Novartis, Amgen. Speakers Bureau: Janssen, Celgene.

Background

Daratumumab (D), a CD38-targeted monoclonal antibody, reduced the risk of MM progression or death by > 60% when combined with standard-of-care regimens in the phase 3 studies CASTOR (bortezomib [V] and dexamethasone [d] vs DVd; NCT02136134) and POLLUX (lenalidomide [R] and d vs DRd; NCT02076009). This analysis evaluated the management of D-related IRRs in the DVd and DRd arms of CASTOR and POLLUX.

Methods

Pts had MM and had received ≥1 line of therapy. In CASTOR, pts were given 8 21-day cycles of Vd (V 1.3 mg/m² subcutaneously on Days 1, 4, 8, and 11; d 20 mg per os [PO]/intravenously [IV] on Days 1-2, 4-5, 8-9, and 11-12) ± D (16 mg/kg IV, weekly [QW] for Cycles 1-3, every 3 weeks [Q3W] for Cycles 4-8, then every 4 weeks [Q4W] thereafter). In POLLUX, pts were given 28-day cycles of Rd (R 25 mg PO on Days 1-21; d 40 mg QW) ± D (16 mg/kg IV QW for Cycles 1-2, every 2 weeks for Cycles 3-6, then Q4W thereafter). In addition, pre-infusion medication consisted of 20 mg d (or equivalent) IV/PO, 650-1000 mg paracetamol, and 25-50 mg diphenhydramine (or equivalent). Pts with high-risk respiratory complications received diphenhydramine on Days 1 and 2, a short-acting β2 adrenergic receptor agonist and control medications for lung disease after D infusion.

Results

All pts receiving D were given pre-infusion medication. In CASTOR and POLLUX, 31 (13%) and 21 pts (7%) received post-infusion medications, respectively. In both trials, the median duration of D infusion was ∼7.0, 4.3, and ∼3.4 hours for the first, second, and subsequent infusions, respectively. IRRs occurred in 45% and 48% of pts and 98% and 96% of IRRs occurred during the first infusion in CASTOR and POLLUX, respectively. Most IRRs were grade 1/2 and no grade ≥4 IRRs were reported. The median time to onset of IRRs after starting the first D infusion was 84 minutes in CASTOR and 90 minutes in POLLUX. In CASTOR, 2 pts discontinued treatment due to IRRs; in POLLUX, 1 pt discontinued D due to a grade 3 IRR, but continued Rd.

Conclusions

Most D-related IRRs occurred during the first infusion and were grade 1/2. D-related IRRs were easily managed with pre- and post-infusion medications.

Clinical trial identification

NCT02136134 and NCT02076009

Legal entity responsible for the study

Janssen Research & Development, LLC

Funding

Funding provided by Janssen Research & Development

Disclosure

P. Moreau: Honoraria & Consultancy: Celgen, Takeda, Janssen, Novartis, Amgen. Speakers Bureau: Janssen, Celgene. N. Rabin: Consultancy: Janssen, Amgen, Novartis, Takeda, Bristol-Myers Squibb. Honoraria: Janssen, Takeda. Speakers Bureau: Janssen, Celgene. T. Plesner: Consultancy: Janssen, Takeda. Research Funding: Janssen. Advisory Committee: Janssen, Genmab. K. Weisel: Consultancy & Honoraria: Amgen, Bristol-Myers Squib, Celgene, Janssen, Novartis, Takeda, Onyx. Research Funding: Janssen, Celgene, Amgen, Sanofi. P. Sonneveld: Consultancy & Research Funding & Honoraria: Amgen, Celgene, Janssen, Karyopharm, Takeda. M-V. Mateos: Consultancy & Honoraria: Janssen, Celgene, Takeda, Amgen. J.M. Schecter: Employment & Equity: Janssen. H. Amin, S. Trivedi: Employment: Janssen. M.A. Dimopoulos: Consultancy & Honoraria: Celgene, Janssen, Takeda, Amgen.

Background

Multiple myeloma is a disease of age. With all of the new myeloma drugs being developed, there are number of treatment options for relapsed and refractory multiple myeloma (RRMM). However, in our knowledge, few data are available in patients older than 65 or 75 years. We performed a meta-analysis to compare the efficacy of new drugs to treat RRMM between younger and older patients.

Methods

PubMed and the Cochrane databases were searched up to April 2016. We included phases III randomized controlled trials (RCTs) of monoclonal antibodies (mAbs) targeting CD38 or SLAMF7 (daratumumab, elotuzumab), second generation proteasome inhibitors (carfilzomib, ixazomib) and histone deacetylase (HDAC) inhibitors (vorinostat, panobinostat) reporting subgroups comparison of progression-free survival (PFS) based of aged cut-offs. The summary hazard ratio (HR) and 95% confidential interval (CI) were calculated.

Results

A total of 5241 patients from eight RCTs of RRMM new therapies were included (CASTOR, POLLUX, ELOQUENT-2, ASPIRE, ENDEAVOR, TOURMALINE-MM1, PANORAMA-1 and VANTAGE-088). When patients are dichotomized into younger and older groups with an age cut-off of 65-75 years, RRMM new therapies improved PFS in both younger (HR, 0.62; 95% CI, 0.56–0.70) and older (HR, 0.67; 95% CI, 0.60–0.74) groups. An improvement in PFS with mAbs was observed in younger (HR, 0.57; 95% CI, 0.46–0.72) and older (HR, 0.52; 95% CI, 0.42–0.64) patients. An improvement in PFS with HDAC inhibitors was also observed in both younger (HR, 0.67; 95% CI, 0.56–0.80) and older (HR, 0.78; 95% CI, 0.63–0.97) as well as with second generation proteasome inhibitors (HR, 0.61; 95% CI, 0.52–0.73 and HR, 0.70; 95% CI, 0.60–0.81 respectively).

Conclusions

A benefit in PFS with new therapies was significant in both younger and older patients with relapsed and refractory multiple myeloma with a cut-off age of 65–75 years.

Legal entity responsible for the study

APHP

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Copanlisib, a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms, has recently been shown to achieve a 59% objective tumor response rate (ORR) in a phase II study in patients with relapsed or refractory (r/r) indolent B-cell lymphoma. We report here the results of subgroup analyses conducted based on demographic and baseline disease characteristics.

Methods

Patients with indolent B-cell non-Hodgkin lymphoma (4 subtypes: follicular [FL], marginal zone [MZL], small lymphocytic [SLL] and lymphoplasmacytoid/Waldenström macroglobulinemia [LPL-WM]) and r/r to ≥ 2 prior lines of treatment were eligible. Previous treatment had to include rituximab and an alkylating agent. Copanlisib (60 mg, I.V.) was administered intermittently on days 1, 8 and 15 of a 28-day cycle. The primary efficacy endpoint was ORR as assessed per independent radiologic review (Cheson et al. 2007).

Results

The full analysis set comprised 142 patients, of which 141 patients had indolent lymphoma (FL/MZL/SLL/LPL-WM: 104/23/8/6). ORR per histological subgroup was 58.7%/69.6%/75.0%/16.7%, respectively. ORR based on demographics were generally consistent across categories. Likewise, there were no major differences in ORR between any of the baseline disease characteristics and prior therapy subgroups with regards to ECOG PS (0 [58.8%] vs. ≥ 1 [59.7%]), longest diameter of baseline lesion (< 7cm [59.8%] vs. ≥ 7cm [59.1%]), received prior bendamustine (yes [62.7%] vs. no [56.6%]), number of prior therapies (< 4 [59.8%] vs. ≥ 4 [57.5%]), or refractoriness to last regimen (yes [60.5%] vs. no [57.1%]). Median duration of response (DOR) by tumor histology for the subgroups with ≥ 10 responders was 370 days (range 33-687) for FL patients and had not yet been reached for MZL patients (2 of 16 responders having progressed).

Conclusions

Objective response rates were consistently high in patients with r/r indolent B-cell lymphoma treated with copanlisib with the exception of LPL-WM patients. There were no major differences in the ORR between any of the baseline disease characteristics and prior therapy subgroups, confirming the robustness of the primary efficacy endpoint.

Clinical trial identification

NCT01660451

Legal entity responsible for the study

Bayer AG

Funding

Bayer AG

Disclosure

T. Ishida: Employment: Bayer SA. L. Huang, J. Garcia-Vargas, B.H. Childs: Employment: Bayer HealthCare Pharmaceuticals Inc. M. Dreyling: Advisory boards: Bayer, Gilead Honoraria: Bayer, Gilead. All other authors have declared no conflicts of interest.

Background

Copanlisib, a novel class I PI3K inhibitor with predominant activity against α and δ isoforms, has shown robust single agent anti-tumor activity in a phase 2 study in heavily pretreated patients with indolent NHL (iNHL) and follicular lymphoma (FL) (NCT01660451; Part B), with response rates of 59.6% and 58.7%, respectively. Baseline tumor gene expression profiling (GEP) was performed to confirm if gene signatures identified in patients with indolent or aggressive NHL (NCT01660451; Part A) are molecular determinants for copanlisib antitumor activity in Part B.

Methods

Signaling pathway gene sets (n = 33) were ranked by enrichment analysis (GSEA) for association with objective response based on normalized enrichment score (NES) and false discovery rate (FDR) q values. The association of weighted gene-expression score (WGS, reflecting the overall expression level for each gene set) with response was analyzed by logistic regression.

Results

Seventy-one patients with iNHL, including 54 FL, had both response data and evaluable gene expression data. All 5 gene sets reflecting upregulated PI3K/BCR signaling were top-ranked for association with higher response rates in iNHL (GSEA NES ≥ 1.93, FDR q < 0.01; WGS AUC ≥0.65, nominal p ≤ 0.04) and FL (GSEA NES ≥1.50, FDR q ≤ 0.01; WGS AUC ≥0.60, nominal p ≤ 0.23). Among patients with objective responses, 66% (33/47) of iNHLs and 71% (24/36) of FLs had high PI3K/BCR gene signature expression levels; for patients with CR, 86% (6/7) iNHL and 83% (5/6) FL had high levels. Further, 4 gene sets enriched with T-cell signatures were associated positively with copanlisib response (NES ≥1.48, FDR q ≤ 0.08). In contrast, up-regulation of macrophage/stromal gene sets was potentially associated with a lower likelihood of response to copanlisib treatment in FL (NES ≤ -1.21, q ≤ 0.21).

Conclusions

Tumor gene expression profiling demonstrates that up-regulation of the BCR/PI3K pathway is frequent and dominant in iNHL and FL, and is associated with the high and durable copanlisib responses. These findings are consistent with copanlisib’s mode of action and strongly support the rationale for treatment of iNHL and FL patients with copanlisib.

Clinical trial identification

NCT01660451; Part B

Legal entity responsible for the study

Bayer AG

Funding

Bayer AG

Disclosure

L. Liu: Employee: Bayer HealthCare Pharmaceuticals. K. Köchert, H. Seidel: Employee: Bayer AG. J. Garcia-Vargas, B.H. Childs, C. Peña: Employment: Bayer HealthCare Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

There are few studies that analyze follicular lymphoma (FL) mortality compared to the general population of the same -sex and age group. Given the recent clinical relevance of the predictive event-free survival (EFS) indexes EFS12 and EFS24, we obtained them in our study cohort in order to estimate their association with overall survival (OS).

Methods

Patients diagnosed with FL were prospectively enrolled from 1980 to 2013. Standardized mortality ratios (SMR) were obtained using yearly sex and age specific mortality rates in Spain, and OS was compared with age- and sex-matched general population data. EFS were defined as the time from diagnosis until relapse or progression, unplanned retreatment of lymphoma after initial management, or death due to any cause. EFS12 and 24 were defined as EFS status at 12 or 24 months from diagnosis, respectively. The crude probability of death was estimated by using the Kaplan–Meier method, and differences between patient groups were assessed by the log-rank test. In order to investigate the specific contribution of age, sex, period of diagnosis, treatment and FLIPI score, a multivariable Cox proportional hazards model was adjusted, all statistical tests were two-sided, and a p-value <0.05 was considered statistically significant.

Results

A total of 1074 patients with newly diagnosed FL were enrolled. The median OS was 231 months (CI 95% 195-267). EFS at 12 and 24 months was associated with increased probability of early death, with an SMR of 10.27 (95% CI: 8.26-12.77). The prognostic value of traditional scales such as FLIPI is maintained in our study, with a hazard ratio of 2.7 (95% CI: 1.9- 4.0) for a score of 2-5. Of note, no significant difference in mortality was observed between FL patients at 10 years since diagnosis compared to the general population (SMR of 1.02; 95% CI 0.57, 1.85).

Conclusions

EFS12 and 24 predicted an early increase in mortality. The long-term SMR, over 10 years of follow-up, shows that patients with FL have a similar risk of dying than the general population of the same sex and age.

Legal entity responsible for the study

GOTEL (Spanish Lymphoma Oncology Group)

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Single-drug maintenance after salvage therapy could prolong survival of pts with rDLBCL not eligible to ASCT. LEN could be an excellent candidate as it is an oral agent, active against DLBCL, with excellent safety profile. Herein, we report results of a multicentre phase II trial addressing LEN maintenance (mLEN) in pts with chemosensitive rDLBCL.

Methods

HIV-negative pts with DLBCL relapsed after R-CHOP or similar and responsive to salvage therapy were registered and treated with LEN 25 mg/day for 21 days out of 28 until lymphoma failure or unacceptable toxicity. Primary endpoint was the 1-year PFS. Estimated sample size (Simon's two-stage optimal design; type I error 5%, power 80%, P0 30%, P1 50%) was 47 pts; mLEN would be considered effective if ≥ 19 pts will be progression-free survivors at 1 year. The prognostic role of cell of origin, assessed by NanoString and Hans algorithm, was investigated.

Results

46 of 48 enrolled pts were assessable (median age 72 years; 34-86); 26 pts started mLEN in CR and 20 in PR after salvage therapy. 639 LEN courses were delivered, with an average of 14 courses/pt (3-53). LEN was well tolerated: with the exception of neutropenia, grade 3-4 toxicities were uncommon (≤3% of courses). LEN dose reduction was indicated in 25 pts. Three pts died of toxicity: intestinal infarction, meningitis, unknown cause; 2 pts developed a second cancer. The pre-determined efficacy threshold (n ≥ 19) was largely achieved: 32 pts were progression free at 1 year from registration. At a median follow-up of 38 (14-95) months, 23 events occurred: PD in 19 pts, death of toxicity in 3, death while off therapy in 1, with a 1-yr PFS of 70% (95%CI=59-81). The benefit of mLEN was observed both in pts with de novo or transformed DLBCL, and both in GCB- or nonGCB-DLBCL. 29 (63%) pts are alive, with a 3-yr OS of 64%.

Conclusions

With the limitations of a non-randomized design, this trial soundly promotes the use of mLEN in pts with chemosensitive rDLBCL not eligible for ASCT or experiencing relapse after ASCT. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts.

Clinical trial identification

NCT00799513

Legal entity responsible for the study

IRCCS San Raffaele

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL). Histological transformation (HT) refers to the evolution of a clinically indolent NHL to an aggressive one. The rates of HT in published series range from 10% to 60%. There are no specific clinical characteristics that can predict transformation. Some molecular parameters associated with transformation are: p53 expression, expression of c-MYC, BCL-6 mutations. This suggests that multiple alternative mechanisms are likely to be involved in the pathogenesis of HT.

Methods

We report a prospective, multicenter (39 Spanish member institutions of Grupo Oncológico para Tratamiento de Linfomas-GOTEL-), observational study designed to collect data on disease presentation, treatment and clinical outcomes of HT. Inclusion criteria for this analysis were initial diagnosis of grade 1-3a FL and enrolment from 1990 to 2016. HT was defined as refractory/recurrent disease with clinical or pathologic diagnosis. Whole exome sequencing of the HT samples has been performed and compared with samples from patients with LF without transformation.

Results

Of the 975 evaluable patients, 64 had HT. Characteristics associated with an increased risk of HT were: the presence of B symptoms (p = 0.001), increased LDH (p = 0.02), high Follicular Lymphoma International Prognostic Index (FLIPI) (p = 0.01) and poor perfomance status (p = 0.01). In this group of patients, the cumulative incidence rate of HT at 5 years was 7.3%; the rate of HT remained constant, reaching a plateau after 14 years. Expectant management also predicted for a higher risk of HT (p = 0.0001). The median survival from transformation was 5 years. Regarding molecular characteristics, we found that all patients with HT had more than 4 mutations at diagnosis of FL in a group of 14 genes that are frequently mutated in patients with HT: CSMD3, DTX1, FOXO1, LRP1B, NOTCH2, PIM1, POU2F2, ATM, BCL7A, HIST1H1E, IRF8, PCLO, EZH2 and TNFAIP3.

Conclusions

There are clinical (increased LDH, B symptoms, high FLIPI, poor performance status) and molecular factors (more than 4 mutations in specific genes) at diagnosis correlate with an increased risk of HT. These predictors of HT could help to develop targeted therapies to prevent HT in high risk patients or improve current salvage approaches.

Clinical trial identification

GOTEL trial of histological transformation

Legal entity responsible for the study

GOTEL (Grupo Oncológico para el Tratamiento y Estudio de Linfomas)

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

The purpose of this study was to develop a newly accepted prognostic nomogram to estimate overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) and assess its incremental value to the traditional International Prognostic Index (IPI) and NCCN-IPI for individual OS estimation.

Methods

The clinical data from 1,118 patients with DLBCL treated at Cancer Hospital Chinese Academy of Medical Sciences between 2006 and 2012 were reviewed. A nomogram was developed that predicted OS based on the Cox proportional hazards model. To contrast the utility of the nomogram against the widely used IPI and NCCN-IPI, we used the concordance index (C-index) and a calibration curve to determine its predictive and discriminatory capacity.

Results

The 5-year OS rate was 64.1% for the entire group. The entire group were divided into the primary (n = 783) and validation (n = 335) cohorts. The nomogram included eight important variables based on a multivariate analysis of the primary cohort: Ann Arbor stage; age; ECOG PS; LDH; β2-MG; CD5; Bcl-6 and Ki-67 index. The calibration curve showed that the nomogram was able to predict 5-year OS accurately. The C-index of the nomogram for OS prediction was 0.77 in the primary cohort and 0.76 in the validation, which was superior to the predictive power (range, 0.71-0.74) of the IPI and NCCN-IPI in the primary and validation cohorts. To detect the accuracy of the nomogram for rituximab plus CHOP (R-CHOP) like regimen, we took subgroup analysis. The C-index of the nomogram for OS prediction was 0.78 in the R-CHOP like regimen subgroup, and 0.76 in the CHOP like regimen subgroup.Table:

1005PD Multivariate analysis of 783 patients in the primary cohort

Conclusions

The proposed nomogram provides an individualized risk estimate of OS in patients with DLBCL, especially for the patient who received R-CHOP like regimen.

Clinical trial identification

This project was approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences.

Legal entity responsible for the study

National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

The current standard treatment for diffuse large B-cell lymphoma (DLBCL) is Rituximab-CHOP (cyclophosphamide (CPM), doxorubicin(DXR), vincristine(VCR), prednisolone). It is well known that VCR causes peripheral neuropathy and is often dose-reduced or omitted from the treatment. Whether the omission of VCR from 1 or more cycles of therapy could jeopardize the survival of patients with DLBCL has not yet been adequately addressed. Our study aimed to investigate any differences in progression free (PFS) and overall (OS) survival in R-CHOP treated patients with DLBCL between those with omission of VCR or not.

Methods

In this Swedish multi-institutional, retrospective, cohort study we included all adult patients diagnosed with and primarily treated for DLBCL or subgroups of high-grade malignant B-cell lymphoma with either R-CHOP/CHOEP (CHOP plus Etoposide) or mini-CHOP (dose-reduced), between 2000-2013. All information on patients’ characteristics, treatment outcome, and survival was extracted from the in-hospital computer based systems. Any clinical variables significantly associated with PFS or OS in univariate analysis by the log-rank test were considered for entry into a multivariate Cox proportional hazard regression model. Omission of VCR was included in all models as an independent variable of interest. All statistical analyses were performed with IBM SPSS statistics version 22.

Results

In total 541 patients were included in the study cohort. In 95 (17.6%) patients, VCR was omitted due to toxicity. The omission was more often decided during the last 3 cycles of chemotherapy (86 patients, 90.5%). Univariate analysis revealed 9 potential prognostic factors associated with PFS and 10 with OS. Omission of VCR was not associated with either PFS or OS in both univariate and multivariate analyses (HR for PFS: 1.21, 95% Confidence Interval (CI) 0.76-1.95; HR for OS; 1.12, 95% CI 0.75-1.69). For PFS only advanced stage at diagnosis was found to be significantly associated with worse outcome (p = 0.047). In respect of OS kidney/adrenal involvement (p = 0.014), Doxorubicin –RelativeDoseIntensity<70% (p = 0.014), age ≥60 years (p = 0.025) and bulky disease (p = 0.037) were significant predictors of survival.Table:

1006PD

Conclusions

Omission of VCR does not affect either PFS or OS in patients with DLBCL treated with R-CHOP/CHOEP. As a result, clinicians can safely decide to omit VCR in case of severe neurotoxicity due to VCR. Considering the association of bulky disease and kidney/adrenal manifestation of lymphoma on survival, further studies should focus on whether the treatment options for these subgroups need to be individualized. Finally, clinicians should be aware of the importance of giving adequate dose of DXR during treatment given the growing body of evidence on the role of dose intensity on survival.

Legal entity responsible for the study

Charlott Mörth

Funding

Centre for Clinical research Sörmland, Uppsala university

Disclosure

All authors have declared no conflicts of interest.

Background

Outcomes for adult pts with R/R ALL are poor. Promising results were observed with axi-cel (KTE-C19), an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in B cell malignancies (Locke et al. AACR 2017, #9986). Severe cytokine release syndrome (CRS) and neurologic events (NE) have been observed in pts with R/R ALL who received anti-CD19 CAR T cell therapy.

Methods

Eligible pts were aged ≥18 years with R/R ALL (Ph+ pts eligible), >5% bone marrow (BM) lymphoblasts, ECOG status 0-1, and adequate organ function. Pts received 1 or 2 × 106 CAR T cells/kg after conditioning (cyclophosphamide + fludarabine). Phase 1 primary endpoint was incidence of dose-limiting toxicity (DLT). Secondary endpoints were efficacy outcomes.

Results

As of 12/31/2016, 12 pts were enrolled; 11 received KTE-C19. One pt was excluded due to a serious adverse event (SAE) prior to dosing. Pts were 64% men, had 56-100% BM lymphoblasts before conditioning and 64% vs 36% had relapsed vs primary refractory disease. No DLTs were observed in the DLT-evaluation period of this trial. Of the first 6 pts enrolled at the 2 × 106 dose, 1 experienced Gr5 CRS. No KTE-C19-related Gr5 AEs were observed at 1 × 106 dose in 5 subsequent pts. Overall, the most common Gr ≥ 3 AEs were cytopenias (64% thrombocytopenia, 55% neutropenia). Gr ≥ 3 CRS and NE were reported in 27% and 55% of pts. Tocilizumab (toci) or steroids was given for AE management in 10 and 7 pts, respectively. All CRS (except 1 Gr 5) and NE resolved. Of the 10 efficacy-evaluable pts, 9 (90%) achieved minimal residual disease-negative remission (8 CR or CR with partial/incomplete hematopoietic recovery; 1 blast-free hypoplastic/aplastic BM). Median follow-up was 3.8 mos; 3 pts relapsed: 2 CD19- and 1 CD19+ disease. Efficacy was similar across KTE-C19 doses. To refine dosing and AE management, additional pts were treated with lower CAR T cell doses and received prophylactic toci. Clinical outcomes and translational data from these pts will be presented.

Conclusions

KTE-C19 demonstrates promising efficacy with a manageable safety profile for adult R/R ALL pts. Novel approaches to reducing toxicity, namely CRS and NE, may improve the overall risk: benefit profile for this class of therapies.

Clinical trial identification

NCT02614066

Legal entity responsible for the study

Kite Pharma

Funding

Kite Pharma

Disclosure

B. Shah: Celgene: Advisory Board, Speaker Fees, Honorarium Bayer: Honorarium Spectrum: Speaker Fees Pharmacyclics: Speaker Fees Plexus Communications: Honorarium Rosetta Genomics: Grant Support Acetilon: Advisory Board Pfizer: Advisory Board Baxalta: Honorarium. W. Stock: Honoraria: Amgen, Pfizer, Seattle Genetics. W. Wierda: Research Funding: Kite, Juno; Travel/Accomodations/Expenses: Kite, Juno. M. Topp: Honoraria: Amgen Consulting or Advisory: Amgen, Regeneron, Roche Travel, Accomodation, Expenses: Amgen, Roche Speakers Bureau: Amgen Research Funding: Amgen, Regeneron, Roche Expert Testimony: Amgen, Regeneron. G.J. Schiller: Research Funding: Novartis, Karyopharm, Amgen, Sunesis, Astellas, Spectrum, Bluebird, Celgene, Array Pharmaceutical Honorarium: Amgen, Sunesis, Celgene Speakers Bureau: Amgen, Celgene. A. Mardiros: Patents: Mustang Bio. J. Rossi, Y. Jiang, T. Shen, J. Aycock, S. Stout: Employment: Kite Pharma. J. Wiezorek: Leadership: Kite. R. Jain: Patent: Kite Pharma. All other authors have declared no conflicts of interest.

Background

ALL is the most common childhood malignancy; up to 20% of pts relapse after initial therapy, and have poor clinical outcomes (Hoffman and Gore. Front Oncol 2014). Promising results were observed with KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in B cell malignancies (Locke at al. AACR 2017, #9986). We present preliminary ZUMA-4 phase 1 results.

Methods

Pts aged 2-21 y with R/R ALL and adequate organ function received the planned dose of 1 or 2 × 10⁶ CAR T cells/kg after low-dose conditioning chemotherapy (cyclophosphamide/fludarabine, CyFlu). Pts enrolled after the study’s dose-limiting toxicities (DLTs) portion receive tocilizumab ≤36 h after CAR T cell infusion. Phase 1 primary endpoint is the incidence of DLTs. Secondary endpoints include efficacy and biomarker assessments.

Results

As of Dec 31, 2016, 4 of 5 enrolled pts have been treated; median follow-up, 5.3 mo (1.9-8.6). All pts had ≥2 prior lines of therapy and 1 pt had prior stem cell transplant (SCT). All pts received bridging chemotherapy due to high disease burden (baseline blasts, 41-99%) prior to KTE-C19. KTE-C19 was successfully manufactured in a centralized 6-7 d process across a range of baseline absolute lymphocyte counts (0.5–17.1 × 10⁹/L) and CD4:CD8 ratios (0.1-0.7). KTE-C19 could not be manufactured for 1 pt who progressed with WBC >150,000/µL at apheresis and <0.2% T cells in the apheresis collection. There were no DLTs. One pt had a gr 5 AE due to intracranial hemorrhage from disseminated mucormycosis. All pts had cytokine release syndrome (all ≤gr 3; all resolved with supportive care) and 1 pt had gr 3 neurologic events. All pts achieved MRD- remission (1 ongoing). One pt received SCT post-remission. Peak CAR T cell expansion was 1-2 weeks post-KTE-C19 infusion. Data from additional pts and implemented safety measures (eg, mandatory tocilizumab) will be presented.

Conclusions

KTE-C19 after low-dose CyFlu was tolerable and appears safe for further analysis in pediatric and adolescent pts with R/R ALL. KTE-C19 can induce deep remissions in heavily pre-treated pts with high disease burden. Based on these results, ZUMA-4 continues to enroll (NCT02625480).

Clinical trial identification

NCT02625480

Legal entity responsible for the study

Kite Pharma

Funding

Kite Pharma

Disclosure

D.W. Lee: Honoraria from Juno. A.S. Wayne: Pfizer: Consultancy, Honoraria, advisory board; Kite Pharma: Research Funding, Honoraria, Advisory Board; NIH: Patents; MedImmune: Research Funding; Spectrum Pharmaceuticals: Research Funding; Spectrum: Honoraria, advisory board. R. Handgretinger: Patents and Royalties: Milteny Biotech. J. Rossi, Y. Jiang, L. Navale, S. Stout, J. Aycock: Employment/Stock Ownership: Kite Pharma. A. Mardiros: Employment/Stock Ownership: Kite Pharma; Patents: Mustang Bio. J. Wiezorek: Leadership/Employment/Stock Ownership: Kite Pharma. R. Jain: Patent/Employment/Stock Ownership: Kite Pharma. All other authors have declared no conflicts of interest.

Background

AML is a cluster of hematopoietic syndromes characterized by proliferation of immature myeloid cells in the bone marrow resulting in cytopenias. While prognostic indices may predict therapy response, no consensus exists regarding optimal therapy for elderly AML pts.

Methods

Newly diagnosed AML pts aged ≥60 years were retrospectively identified from a large US electronic medical record from 1/1/2008-7/31/2015. AML diagnosis included ≥1 inpatient or ≥ 2 outpatient claims with an AML ICD-9/10 code (the first record was the index date). First-line therapy (1LT) was defined as an AML-specific treatment initiated on/after the index date; a switch in agent triggered second-line therapy (2LT). Pts were followed until death, end of follow-up, or end of study (9/31/2015).

Results

Of 704 eligible AML pts, 398 received 1LT. Mean age was 70.6 years, 55.5% were male, and 19.1% had a Charlson comorbidity index score of ≥ 2. 1LT regimens included cytarabine-based induction 1LT (C-IC) in 54.3% (n = 216, combined with an anthracycline [ie, 7 + 3 or 7 + 3-like] in 87.5% of these), hypomethylating agents (HMAs) (azacitidine and decitabine) in 30.2% (n = 110), other cytotoxic IC (other-IC) in 8.5% (n = 34), and sorafenib in 1.0% (n = 4). 44 pts (11.1%) had record of stem cell transplant during 1LT for AML. A higher proportion of pts who received HMAs (67.3%) were ≥75 years of age compared to those receiving C-IC or other-IC (18.5%; 23.5%). Overall, 84 pts (23%) received 2LT, with C-IC still predominating (n = 37; 44.0%), followed by HMAs (n = 31; 36.9%) and other-IC (n = 15; 17.9%). At a median follow-up of 8.5 months (interquartile range: 3.2, 20.1) for all pts with 1LT, 59.6% (n = 237) had died. During follow-up for all treated pts, 78.6% (n = 313) received erythrocyte or platelet transfusion support with a mean number of unique transfusion service dates per patient of 12.3 (standard deviation: 15.9), and 38.9% (n = 155) received colony-stimulating factors.

Conclusions

Overall, the majority of AML pts who are ≥60 years of age are treated with C-IC. Age ≥75 years may influence choice of 1LT between HMAs vs IC. More research is needed to evaluate other factors in therapy selection and prognosis for the elderly AML population.

Clinical trial identification

N/A

Legal entity responsible for the study

Takeda Pharmaceuticals

Funding

Takeda Pharmaceuticals

Disclosure

J.A. Bell, A. Galaznik, D.V. Faller: Employment by and stock ownership in Takeda Pharmaceuticals. E. Farrelly, M. Pollack, A. Raju, A. Ogbonnaya, M. Eaddy: Employee at Xcenda, a healthcare consulting firm that received funding from Takeda Pharmaceuticals to conduct this study. R. Fram: Consultant for Takeda Pharmaceuticals.