Targeted Treatment of Follicular Lymphoma

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. Advanced stage disease is considered incurable and is characterized by a prolonged relapsing/remitting course. A significant minority have less favorable outcomes, particularly those with transformed or early progressive disease. Recent advances in our understanding of the unique genetic and immune biology of FL have led to increasingly potent and precise novel targeted agents, suggesting that a chemotherapy-future may one day be attainable. The current pipeline of new therapeutics is unprecedented. Particularly exciting is that many agents have non-overlapping modes of action, offering potential new combinatorial options and synergies. This review provides up-to-date clinical and mechanistic data on these new therapeutics. Ongoing dedicated attention to basic, translational and clinical research will provide further clarity as to when and how to best use these agents, to improve efficacy without eliciting unnecessary toxicity.

RTID-12. PHASE 2 TRIAL OF TUMOR TREATING FIELDS (TTFIELDS) PLUS RADIATION THERAPY (RT) PLUS TEMOZOLAMIDE (TMZ) COMPARED TO RT PLUS TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA (ndGBM)

OBJECTIVE In the EF-14 phase 3 trial, TTFields 9200 kHz) added to maintenance TMZ increased median OS to 20.9 months versus 16.0 months with maintenance TMZ (p< 0.001) in ndGBM. Preclinical investigations showed that TTFields/RT have a synergistic effect. A pilot study (N=10) in ndGBM demonstrated the feasibility and safety of TTFields combined with RT/TMZ (Grossman Front Onc 2020). The only TTFields-related adverse event was array-associated skin toxicity. Median PFS was 8.9 months. Based on these encouraging results, this prospective, randomized phase 2 study [NCT03869242] in 60 patients further investigates if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression. METHODS Following debulking surgery or biopsy, 60 patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy >3 months will be randomized 1:1 to: i) RT with concomitant TMZ/TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ combined with TTFields (experimental arm) up to 24 months; or ii) RT with concomitant TMZ alone followed by maintenance TMZ combined with TTFields (control arm). Patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or with implanted electronic devices will be excluded. The primary endpoint is the rate of progression free survival at 12 months (PFS12). Treatment with TTF will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. All adverse events will graded per CTCAE V5.0. The sample size of 60 patients provides 80% power with two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). Follow-up will continue for >12 months from recruitment of the last patient.

NIMG-55. TO ASSESS THE UTILITY OF ADVANCED QUANTITATIVE DIFFUSION MRI DERIVED FROM MULTI B VALUE ACQUISITIONS IN THE ASSESSMENT OF TREATMENT RESPONSE, USING A SPATIALLY-INDEPENDENT APPROACH

PURPOSE To assess the utility of advanced diffusion MRI derived from multi b value acquisitions in the assessment of treatment response, using a spatially-independent approach. METHOD AND MATERIALS 13 GBM patients were enrolled into our multicentre study. All patients completed RT with TMZ. Imaging was performed pre-RT and mid RT. The MRI protocol included a ‘low’ b value acquisition (b= 0s/mm, 50s/mm, 150s/mm, 200s/mm, 500s/mm, 1000s/mm) from which monoexponential diffusion indices ADC and biexponential indices, IVIM parameters D*, D and f were calculated. A ‘high b value’ acquisition (b=0 s/mm, 500s/mm, 1000s/mm, 1500s/mm, 2000s/mm, 2500s/mm, 3000s/mm, 3500s/mm, 4000s/mm) was acquired to allow stretched exponential diffusion indices, DDC and alpha to be derived. FLAIR sequences were used to define ROI and clinical assessment of mid-treatment and end-treatment response using RANO criteria. Histograms were generated from voxels located within manually segmented ROIs defined by increased signal on T2 FLAIR images. Changes in histogram percentile profiles were evaluated across the two timepoints and compared with RANO assessment at the mid treatment and end treatment timepoints. RESULTS Following completion of treatment, 5 patients had PD, 4 SD and 4 CR. Patients with PD showed a histogram shift to the left across all diffusion models, in keeping with increasing diffusion restriction and implying increased cellularity. Patients with SD or CR showed little or no shift in the histogram. DDC and f are the most predictive of progression against RANO assessment, and appear superior to routine ADC. Reduction in 75th centile (f) and 95th centile (DDC) are the most sensitive histogram metrics for predicting early progressive disease. CONCLUSION Results suggest association between early changes in specific diffusion components and subsequent treatment response. Spatially-independent diffusion parameter comparisons provide unbiased sampling of tumour heterogeneity and abrogate the confound of voxel-to-voxel misregistration due to tumour growth/shrinkage.

Circulating androgen receptor (AR) gene amplification and resistance to 177Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of a phase II clinical trial.

3020 Background: Plasma AR gain is associated with poor prognosis in mCRPC pts treated with abiraterone/enzalutamide, however these pts could benefit from docetaxel (Conteduca et al, Eur Urol 2019). In a phase 2 clinical trial with 177Lu-PSMA-617 in mCRPC pts who progressed after standard survival-prolonging treatments, we aimed to determine if plasma AR gene status enable early assessment of 177Lu-PSMA-617 activity for mCRPC. Methods: Between April 2017 and November 2018, 43 mCRPC pts were treated with 177Lu-PSMA-617 in a phase 2 study. Pts younger than 75 years and not heavily pretreated received 5.5 GBq of 177Lu-PSMA-617, while other pts received 4.2 GBq per cycle, for a total of 4-6 cycles, q8 weeks. We determined AR copy number by droplet digital polymerase chain reaction (ddPCR) on pretreatment plasma samples. We evaluated associations between plasma AR amplification and PSA response (≥50% PSA decline from baseline) and imaging response/progression (as measured by bone scan, CT, and PSMA PET/CT). Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95% CI) in order to evaluate the independent relevance of AR status and pts without PSA response and those with early progressive disease defined as treatment interruption occurring within 4 months of the start of 177Lu-PSMA-617. Results: Forty of 43 pts (median age: 72 years, range 54-86) were fully evaluable for this analysis. A PSA response was reported in 15 (37.5%) of the 40 pts, 3 of 15 (20%) with AR gene gain, and 12 of 25 (48%) with no gain (P = 0.080). Early progressive disease was observed in 17 (42.5%) of the 40 pts, 12 of 15 (80%) with AR gene gain and 5 of 25 (20%) with no gain (P = 0.0002). The OR for pts without PSA response (decline < 50%) having AR gain was 3.69, 95% CI 0.83-16.36, p = 0.085. The OR for pts with early PD having AR gain was 16.00, 95% CI 3.23-79.27, p = 0.0007. The evaluation of germline alterations in DNA damage repair (DDR) genes is ongoing (i.e., BRCA2, BRCA1, ATM). Conclusions: Plasma AR status assessment using ddPCR identifies mCRPC resistant to 177Lu-PSMA-617. These data suggest potential better activity of 177Lu-PSMA-617 in earlier phases of prostate cancer. Prospective evaluation of treatment decision making based on plasma AR status is warranted. Clinical trial information: NCT03454750.

Impact of the gut microbiota on immune checkpoint inhibitor-associated toxicities

Immune checkpoint inhibitors (ICIs) have transformed the treatment of patients with advanced cancers. However, the majority of patients do not respond or develop early progressive disease. A substantial number also develop immune-mediated toxicities that may lead to early treatment discontinuation. Gastrointestinal toxicities in the form of diarrhea and colitis are common and may resemble that observed in patients with inflammatory bowel disease (IBD). Alterations in the gut microbiota are thought to play an important role in mediating the intestinal inflammation that is associated with immune-mediated colitis. In this review, the authors’ objective is to provide an overview of the gastrointestinal and hepatic toxicities that can be seen with ICIs and discuss the interactions between gut microbiota and the immune response. The authors also highlight the potential role for fecal microbial transfer (FMT) as an approach to improve therapeutic efficacy and decrease toxicity.

A Rare Case of Glioblastoma Multiforme with Osseous Metastases

Glioblastoma multiforme is the most common malignant primary central nervous system neoplasm in adults. It has a very aggressive natural history with a median overall survival estimated at 14.6 months despite multimodality treatment. Extracranial metastases are very rare with few case reports published to date. We report the case of a 65-year-old male who underwent maximal safe resection for a newly diagnosed brain mass after presentation with new neurologic symptoms. He then received standard postsurgical adjuvant treatment for glioblastoma. Subsequently, he underwent another resection for early progressive disease. Several months later, he was hospitalized for new-onset musculoskeletal complaints. Additional investigation revealed new metastatic osseous lesions which were initially felt to be a new malignancy. The patient opted for supportive care and died 12 days later. Despite choosing no treatment, he elected to undergo a bone biopsy to understand the new underlying process. Results were that of metastatic GBM and were reported after the patient expired. Physicians caring for patients with GBM and new nonneurologic symptoms may contemplate body imaging.

Intensified Chemo-Immunotherapy Including up-Front Autologous or Allogeneic Stem Cell Transplantation (SCT) for Young Patients with Newly Diagnosed Peripheral T-Cell Lymphomas: Final Results of a Phase II Multicenter Prospective Clinical Trial

Abstract 1984 Background: Peripheral T-cell lymphomas (PTCL) are characterized by a poor prognosis, conventional chemotherapy provides a long-term survival of approximately 25%. Few prospective data suggest that autologous SCT (autoSCT) can improve prognosis when used up-front. Allogeneic SCT (alloSCT) can obtain a durable disease control at relapse in 40% of patients (pts). Based upon these premises, we designed a phase II trial for young pts (age 18 –60 yrs) in which intensified chemo-immunotherapy was used before auto or alloSCT. Transplant type was decided according to the donor availability. Primary endpoint was CR rate at one year after the end of treatment. This was the first prospective trial employing high-dose (hd) chemo-immunotherapy and alloSCT frontline in PTCLs. Methods: 64 pts with newly diagnosed PTCL (ALK-positive ALCL cases were excluded) were included (EudraCT N° 200600423433). Histology was centrally reviewed. The intensified pre-transplant phase consisted of 2 courses of CHOP-21 regimen preceded by alemtuzumab (30 mg total dose) followed by 2 courses of Hyper-C-Hidam (hd-methotrexate, hyper-fractionated cyclophosphamide and hd-ara-C). Autologous stem cells were collected after the second Hyper-C-Hidam or after a short course of intermediate dose Ara-C. Responding pts were transplanted according to a genetic stratification based on donor availability: pts with HLA-identical, one antigen mismatched sibling, or allele matched unrelated donors (MUD) received alloSCT. Conditioning regimen was thiotepa-fludara-cyclophosphamide [Corradini et al JCO 2004]; GVHD prophylaxis was cyclosporine, short course methotrexate and 7 mg/kg of Thymoglobuline for alternative donors only. Pts without a donor received BEAM followed by autoSCT. Results: A total of 64 pts were enrolled, but 61 fulfilled all the inclusion criteria and were thus evaluable. Diagnosis included PTCL-not otherwise specified (PTCL-NOS, n=38), ALK-negative ALCL (n=12), angioimmunoblastic lymphoma (AILT, n=9), enteropathy-type T-cell lymphoma (n=2). Median age was 48 years (range, 24–60 yrs). Fifty-seven pts (93%) had advanced disease; IPI was <2: 19 pts (31%), and ≥2: 42 pts (69%); PIT was 0–1 risk factors in 40 (66%), 2–4 risk factors in 21 (34%). Of 61 pts, 56 completed alemtuzumab-CHOP whereas 5 pts had early progressive disease (PD). After induction phase, 38 pts (62%) achieved a response [n=31 CR (51%), n= 7 PR (11%)] whereas 18 (30%) had PD and 5 (8%) died of toxicity in the Hyper-C-Hidam phase. All the 18 pts with early PD died of disease at median time of 180 days since the beginning of treatment. Transplantation-eligible pts were 38 (62%): 14 underwent autoSCT and 23 alloSCT whereas one patient, in continuous CR, did not receive autoSCT for previous viral infection. Overall, at a median follow-up of 33 months, 30 pts (49%) are alive in CR and 31 died (51%) (n=8 death for toxicity, n=23 for PD). Eleven of 14 pts who received autoSCT are alive in CR (3 relapsed). Sixteen of 23 pts who received alloSCT (n=10 matched siblings; n=13 MUD) are alive in CR, 4 (17%) died of disease, and 3 died for toxicity. In a intention-to-treat analysis, the estimated 3-years disease-free survival (DFS), PFS and overall survival (OS) values for entire cohort (61 pts) were 76%, 44%, 47%, respectively. The 3-year cumulative incidence of non-relapse mortality (NRM) and relapse were 13% and 42%, respectively. In univariate analysis, involvement of liver and/or gastrointestinal tract was associated to a poor outcome [PFS: 21% versus 53% (p=0.03); OS: 27% versus 55% (p=0.07)]. At multivariable analysis by Cox model (including as variables IPI, extranodal disease, response and SCT), pts not achieving a clinical response and not receiving SCT had a 5.8 (p=0.0003)- and 8-fold (p=0.0002) risk of death as compared to pts responding and transplanted. Pts not in response or in partial response had a 20-fold (p< 0.0001)- and 3-fold (p=0.07) risk of progression as compared to pts with CR maintained for at least 6 months. Conclusions: Our findings indicate: 1) the achievement of CR is an independent predictor of longer PFS and OS, regardless of IPI or gastric/liver disease; 2) although the trial was not sized for a formal comparison, up-front autoSCT appeared not inferior to alloSCT in responding pts; 3) the use of alemtuzumab and pre-transplant hd-chemotherapy did not reduce the amount of primary refractory or early progressive disease although SCT improves survival. Disclosures: No relevant conflicts of interest to declare.

Clinicopathologic and molecular factors associated with early progressive disease after front-line platinum-doublet chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC).

e18075 Background: The majority of cases of NSCLC are diagnosed at an advanced stage and treated with a platinum-doublet CT. However, some patients are resistant to this treatment and develop early progressive disease. We investigated the clinicopathologic and molecular characteristics of such patients. Methods: All consecutive patients with NSCLC IIIB−IV treated with a platinum-doublet CT between 2003 and 2006 were included. Platinum resistance was defined as early progressive disease at the first tumor assessment according to WHO criteria. The clinical, histologic and molecular characteristics (EGFR:exon 19, 20, 21 and KRAS:exon 2 by PCR sequencing; ALK by IHC, confirmed by FISH) and survival of patients with early progression (P) and controlled disease (C) were compared by univariate analysis. Factors differing between the two groups with a p-value <0.25 in univariate analysis were entered into multivariate analysis. Results: 178 patients were included (mean age 59.1 years, 66.3% male, 54.5% smokers). Platinum was associated with gemcitabine (52.2%), paclitaxel (32.6%) or docetaxel (11.8%). The first tumor assessment was carried out after a median of three cycles [range 1−4]. Forty-six (25.8%) patients had early progression. Overall survival of P-group was significantly shorter than that of C-group (median 5 months vs. 15.1 months, respectively; p <0.0001). Clinical presentation was similar in the two groups. The sarcomatoid histologic subtype was more common among P-group than C-group (10.9% vs. 1.5%, respectively; p=0.057). The proportion of EGFR (5.2% vs. 9.6%, respectively; p=0.224) and KRAS mutations (11.1% vs. 5.7%, respectively; p=0.357), and expression of ALK (6.3% vs. 2.5%, respectively; p=0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histologic subtype was the only factor associated with early progression [OR=7.50, 95%CI: 1.02−55.45; p=0.048]. Conclusions: Patients with early progression had a shorter survival than controlled patients. Sarcomatoid histologic subtype was the only independent factor associated with early progressive disease.