Prognostic Value of Flowcytometric Minimal Residual Disease Combined with PET/CT at Multiple Time Points before and after Autologous Stem Cell Transplantation in Multiple Myeloma

Background: Multiple myeloma is a plasma cell malignancy. With the emerging novel therapy and deepening response to therapy, minimal residual disease (MRD) now has been widely accepted as the response assessment beyond complete response. New generation flow (NGF) and new generation sequencing (NGS) assess the MRD status of the bone marrow, which might result in false-negative MRD because of the well-known spatially heterogeneous and extramedullary involvement in MM. To overcome this limitations, whole body functional imaging technique such as positron emission tomography/computed tomography (PET/CT) is required. To our knowledge, there is limited data examining the prognostic value of flow MRD and FDG-PET/CT at multiple time points before and after ASCT in MM. In this study, we aimed to elucidate the prognostic valued of MRD by flow combined with PET/CT at different time points in the long-term outcomes for transplant-eligible NDMM patients. Methods: This observational cohort study was approved by the ethnic committee of Sun Yat-sen University. The inclusion criteria were 1) patients with transplant eligible NDMM; 2) received uniform induction regimen of PAD and proceeded to the following ASCT; 3) received PET/CT scan in our hospital before receiving any anti-myeloma therapy. Whole-body 18F-FDG PET/CT was carried out in all patients at baseline and was then repeated post-induction (median 38days after the completion of induction), and at 6th, 12th and 24th month post-transplant. Flow MRD status were analyzed by 8-color multiparameter flow cytometry with the sensitivity of 10 -5. Results: From July 2012 to Apr 2017, 94 consecutive patients with transplant eligible NDMM were included in the final analysis. To standardize the PET/CT interpretation, 5-points scale of Deauville score (DS) was applied to evaluate the FDG uptake of bone marrow and focal lesions together. "Flow MRD" and "PET Deauville score" were highly discordant. No matter choosing DS 1, 2 or 3 as the cutoff for PET/CT positivity, there was no significant agreement between PET/CT and flow MRD assessment after induction. At 6th and 12th month post-transplant, neither existed the significant agreement between these 2 assessments if DS 1 or 2 as the cutoff; even if DS 3 as the cutoff, the agreement degree was very poor at these early time points post-transplant. At the 24th month post-transplant, adopting DS3 as the cutoff for PET/CT positivity, the agreement degree between flow MRD and PET/CT was significantly improved to moderate level with the kappa score of 0.579. In the univariate analysis, no matter the flow MRD status was positive or negative, patients with PET DS1-2 at each time points had similar favorable TTP (table 2) whereas patients with PET DS4-5 at each time points had similar poor TTP. In the subgroup of PET DS3, as early as after the induction, patients with flow MRD-negative already show the trend of better TTP (p = .083); while at the 6th, 12th, 24th month post-transplant, patients with flow MRD - negative had significantly better TTP than those with flow MRD - positive. In the multivariate analysis (table3), the lesion DS≤4 at baseline and standard risk FISH were Independent predictive factors for TTP and the lesion DS ≤4 was the only independent predictive factor for OS. After induction and 6th month after transplant, the baseline DS were excluded from the Cox model. The post-therapy PET DS 3 might be a good cutoff value for PET/CT MRD positivity because it significantly predicted both the TTP and OS. However, since 12th month after transplant, compared to patients with DS3, those with DS 1-2 had favorably TTP. The cutoff value shifted to DS2. Conclusion: PET/CT and flow MRD are highly discordant until 2 years after transplant for patients with NDMM. Patients with low Deauville score (1-2) had good prognosis at different time points no matter the MRD status, reflecting the importance of PET/CT in evaluation the aggressive degree of MRD clone. Patients with high Deauville score (4-5) had poor prognosis at different time points no matter the MRD status, reflecting the importance of PET/CT in overcoming the uneven and extramedullary disease in MM. The Deauville score of PET/CT remained as the independent prognosis factor at post-induction, 6 th -, 12 th -, and 24 th month post-transplant. However, the cut-off value of PET/CT Deauville score shift from score 3 before 1-year post-transplant to score 2 at and beyond 1-year post-transplant. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Classical Hodgkin Lymphoma; Real-World Observations from Physicians, Patients, and Caregivers on the Disease and Its Treatment (CONNECT): Observations of Physicians on Treatment and Interim PET-Adapted Regimens

Background Current NCCN guidelines recommend 1 of 3 first-line (1L) regimens for stage III or IV classical Hodgkin lymphoma (cHL): ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), A+AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine), or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone); preferred regimens vary by region (e.g., North America vs Europe). The NCCN recommends positron emission tomography/computerized tomography (PET/CT) imaging after cycle 2 (interim PET2) to guide ABVD escalation or de-escalation. We surveyed physicians on their cHL treatment decision-making process and how PET/CT scan access, reimbursement, and comprehension influence their choices as part of CONNECT, the first real-world survey of physicians, patients, and caregivers in cHL. Methods Medical oncologists, hematologist/oncologists, or hematologists who treat cHL were invited to participate in an Institutional Review Board-approved, 30-minute online anonymous survey. Eligible participants had ≥2 years of practice experience in the United States (US) and treated ≥1 adult (aged ≥18 years) with stage III or IV cHL and ≥1 adult with cHL in the 1L setting within the prior 12 months. Surveys were completed from October 19, 2020-November 16, 2020. Results Of 301 participating physicians, 80% were hematologist/oncologists with a median practice duration of 15 years; 62% practiced in community and 38% in academic settings. Participants were located in the US (South, 34%; Northeast, 26%; West, 21%; Midwest, 20%) and spent 90% of their professional time in direct patient care. In the preceding 12 months, participants treated a median (interquartile range) of 16 (7-40) patients with active cHL (stage III [median], 4; stage IV, 5) and 15 (8-40) cHL survivors. When treating cHL, 88% of participants reported giving NCCN guidelines somewhat/significant consideration. Overall, 94% of participants (n=284) reported using a PET/CT combined scan to diagnose/stage cHL, in line with current guideline recommendations. Of these participants, 97% reported typically getting an interim PET/CT scan for stage III or IV cHL with 65% typically getting the scan after cycle 2 (Figure A). Participants reported both escalating and de-escalating treatment based on interim PET/CT results (Figure B) with 61% making decisions after cycle 2. Of participants using a PET/CT scan, 42% reported receiving both a Deauville score and a standardized uptake value (SUV; Figure C) with 62% of participants noting that the Deauville score was the primary system used for reviewing PET/CT results (Figure D). However, 19% of participants reported challenges interpreting PET/CT results. Among participants using a Deauville score (n=209), consensus was limited on what defined a positive scan (≥3, 44%; ≥4, 37%). Challenges obtaining PET/CT scans were reported by 16% of participants using PET/CT scans. However, despite not reporting challenges 55% of participants on average were unable to obtain a PET/CT scan 20% of the time. Of participants using PET/CT scans, 86% reported typically receiving results within 2 business days and 14% within 3-5 business days. Twenty-one percent of participants reported that delays in PET/CT results affected their ability to use a PET-adaptive approach. Forty-nine percent of those using PET/CT scans reported increased difficulty in PET/CT access for stage III or IV cHL due to lack of insurance coverage. In absence of a PET/CT scan, 36% of participants reported using an interim biopsy and 63% an interim CT scan to inform treatment choices. Among all participants, 36% reported increased difficulty in getting patients with cHL access to PET/CT scans due to COVID-19. Conclusions Although participants consider NCCN guidelines when treating cHL, interim PET scans are not universally obtained after cycle 2 for stage III or IV cHL, with 65% of participants who use PET/CT scans obtaining an interim PET scan after cycle 2 for stage III or IV cHL. When PET/CT scans are obtained, Deauville scores are commonly provided; however, there is variability in what is termed a positive or negative Deauville score. Challenges in obtaining PET/CT scans, with increased difficulty during COVID-19, were reported. Also, there are other barriers, such as lack of insurance, that may prohibit the optimal adherence to guidelines on interim PET/CT utilization. Figure 1 Figure 1. Disclosures Parsons: SeaGen: Consultancy. Yu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Liu: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Kumar: Seagen, Inc: Consultancy. Fanale: Seagen, Inc: Current Employment, Current equity holder in publicly-traded company. Flora: Seagen, Inc: Research Funding.

Prognostic Parameters on Baseline and Interim F-18-FDG-PET/CT in Diffuse Large B-cell Lymphoma Patients

Purpose FDG-PET/CT is a widely used imaging method in the management of diffuse large B-cell lymphomas (DLBCL). Our aim was to investigate the prognostic performance of different PET-biomarkers in a multicentre setting. Methods We investigated baseline volumetric values (MTV and TLG, also normalized for body weight) segmented with three different methods (>SUV4 [glob4]; 41% isocontour [41pc], and a gradiant-based lesion growing algorithm [grad]) and interim parameters (Deauville-score, ΔSUVmax, modified qPET, and rPET) alongside clinical parameters (stage, R-IPI), using 24-month progression-free survival as the clinical endpoint. Receiver operating characteristics analyses were performed to define optimal cut-off points for the continous PET-parameters.Results 107 DLBCL patients were included (54 women; mean age: 53.7 years). MTV and TLG calculations showed good correlation among glob4, 41pc and grad methods, however, optimal cut-off points were markedly different. Significantly different PFS was observed between low- and high-risk groups according to baseline MTV, bwaMTV, TLG, bwaTLG, as well as interim parameters Deauville-score, ΔSUVmax, mqPET, and rPET. Univariate Cox-regression analyses showed hazard ratios lowest for bwaMTVglob4 (HR=2.3) and highest for rPET (HR=9.09). In a multivariate Cox-regression model, rPET was shown to be an independent predictor of PFS (p=0.041; HR=9.15). A combined analysis showed that ΔSUVmax positive patients with high MTV formed a group with distinctly poor PFS (35.3%).Conclusion Baseline MTV and TLG values and optimal cut-off points achieved with different segmentation methods varied markedly and showed limited prognostic impact. Interim PET/CT parameters provided more accurate prognostic information with semiquantitative „Deauville-like” parameters performing best in the present study.

[18F]FDG PET-CT in Patients With DLBCL Treated With CAR-T Cell Therapy: A Practical Approach of Reporting Pre- and Post-treatment Studies

Purpose: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes depend, however, on selection of patients and on accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), one month (M1) and three months (M3) post therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy.Methods: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, TLG were calculated in all scans. Response was assessed using Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4-16.0) months from CAR-T infusion.Results: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv<0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv<0.01), LDH > 450 U/l (HR 7.7; Pv<0.01) and ECOG score > 1 (HR 5.5; Pv=0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv<0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when comparison of M1-SUVmax was made to TD-SUVmax (Pv=0.02) and not to TT-SUVmax (Pv=0.38).Conclusion: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report.

Role of 18F-FDG PET/CT in the Management of Patients Affected by HHV-8-Associated Multicentric Castleman’s Disease

Our aim was to investigate the usefulness of 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the diagnosis, treatment response evaluation, and follow-up of human herpesvirus-8 (HHV-8)-associated multicentric Castleman’s disease (MCD). Fifteen patients with histologically diagnosis of HHV-8-associated MCD were retrospectively included. For all patients, a 18F-FDG PET/CT scan was performed before any treatment for diagnosis and PET/CT scans after Rituximab (4 cycles) for the evaluation of treatment response; moreover, 22 PET/CT were performed during the follow-up to check disease status. To evaluate treatment response, we applied Deauville criteria. PET/CT findings were compared with other conventional imaging (CI) findings. At diagnosis, 18F-FDG PET/CT showed an increased FDG-uptake in all cases corresponding to lymph nodes and confirming the MCD. The average SUVmax of the FDG avid lesions were 8.75, average lesion-to-liver SUVmax ratio was 3.6, and average lesion-to-blood pool SUVmax ratio was 3.9. After first-line therapy, 18F-FDG PET/CT resulted negative (Deauville score < 4) in seven patients and positive in the remaining eight (Deauville score 4–5). A negative restaging PET/CT was associated with a lower risk of relapse. During follow-up, PET/CT detected the presence of relapse or progression in 5 (23%) cases with an accuracy higher than CI. 18F-FDG PET/CT seems to be an useful tool in studying HHV-8-associated MCD both at diagnosis and during follow-up.

Biomodulatory Treatment Regimen, MEPED, Rescues Relapsed and Refractory Classic Hodgkin’s Disease

Introduction: Current combined intensive chemotherapy and radiation regimens yield excellent survival rates in advanced classic Hodgkin’s lymphoma (cHL). However, acute toxicity in elderly, comorbid patients can be challenging and long-term survival in refractory patients remains poor.Patients and Methods: We report on six patients with r/r HL, three patients with long-term follow-up, three newly treated, after biomodulatory therapy. All patients received MEPED (treosulfan 250 mg p.o. daily, everolimus 15 mg p.o. daily to achieve serum trough levels of 15 ng/ml, pioglitazone 45 mg p.o. daily, etoricoxib 60 mg p.o. daily and dexamethasone 0.5 mg p.o. daily). Patients had either received every at that time approved systemic treatment or were ineligible for standard treatment, including immune checkpoint inhibition (ICPi) due to prior demyelinating autoimmune polyneuropathy, myasthenia gravis and previous allogeneic hematopoietic-stem-cell transplant (alloHSCT). Medication was administered continuously from day 1. One patient with relapse after alloHSCT received trofosfamide 50 mg daily instead of treosulfan to avoid risk of increased myelotoxicity. The patients were treated in individual healing attempts outside a clinical trial after institutional review board approval. 18F-fluoro-2-deoxy-d-glucose positron emission tomography combined with computed tomography scan (FDG-PET/CT) was performed to monitor treatment and follow-up.Results: In the three newly treated patients, CT scans showed partial remissions after 2–5 months on MEPED treatment. Two patients had achieved PET Deauville score 2 and 3, while the third remained positive at Deauville score 5. One patient achieving PR became eligible for alloHSCT, while the other two patients continued treatment with MEPED. All patients eventually achieved continuous complete remission (cCR), one after consecutive alloHSCT, one after discontinuing MEPED consolidation for &gt;1 year and one on on-going MEPED consolidation, respectively. Only one patient experienced Grade 3 toxicity (bacterial pneumonia) requiring temporary discontinuation of MEPED for 10 days. All three previously published patients received allo HSCT for consolidation and have achieved cCR.Conclusions: MEPED is well tolerated with low toxicity and highly efficacious in relapsed/refractory cHL, including severely comorbid patients. Due to its immunomodulatory components, MEPED might also have a synergistic potential when combined with ICPi but requires further evaluation within a clinical trial.

The effect of reduced scan time on response assessment FDG-PET/CT imaging using Deauville score in patients with lymphoma

Purpose [18F]Fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) is used for response assessment during therapy in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Clinicians report the scans visually using Deauville criteria. Improved performance in modern PET/CT scanners could allow for a reduction in scan time without compromising diagnostic image quality. Additionally, patient throughput can be increased with increasing cost-effectiveness. We investigated the effects of reducing scan time of response assessment FDG-PET/CT in HL and NHL patients on Deauville score (DS) and image quality. Methods Twenty patients diagnosed with HL/NHL referred to a response assessment FDG-PET/CT were included. PET scans were performed in list-mode with an acquisition time of 120 s per bed position(s/bp). From PET list-mode data images with full acquisition time of 120 s/bp and shorter acquisition times (90, 60, 45, and 30 s/bp) were reconstructed. All images were assessed by two specialists and assigned a DS. We estimated the possible savings when reducing scan time using a simplified model based on assumed values/costs for our hospital. Results There were no significant changes in the visually assessed DS when reducing scan time to 90 s/bp, 60 s/bp, 45 s/bp, and 30 s/bp. Image quality of 90 s/bp images were rated equal to 120 s/bp images. Coefficient of variance values for 120 s/bp and 90 s/bp images was significantly < 15%. The estimated annual savings to the hospital when reducing scan time was 8000-16,000 €/scanner. Conclusion Acquisition time can be reduced to 90 s/bp in response assessment FDG-PET/CT without compromising Deauville score or image quality. Reducing acquisition time can reduce costs to the clinic.