White blood cell count nadir to zero following intensive chemotherapy as a predictive factor for patients with acute myeloid leukemia.

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.

Multi-gene measurable residual disease assessed by digital polymerase chain reaction has clinical and biological utility in acute myeloid leukemia patients receiving venetoclax/azacitidine.

Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies.

Monoclonal antibodies targeting CD38 are important for treatment of both newly diagnosed and relapsed multiple myeloma (MM). Daratumumab and isatuximab are anti-CD38 antibodies with the US Food and Drugs Administration approval in multiple different combinations. Despite good initial efficacy, patients inevitably develop drug resistance. Whether patients can be effectively re-treated with these antibodies in subsequent lines of therapy is unclear. Thus far, studies have mostly been limited to clinical retrospectives with short washout periods. To answer whether patients regain sensitivity after longer washouts, we used ex vivo sensitivity testing to isolate the anti-CD38 antibody-specific cytotoxicity in samples obtained from patients who had been exposed to and then off daratumumab for up to 53 months. MM cells from patients who had been off daratumumab for >1 year showed greater sensitivity than those with <1 year, although they still were less sensitive than those who were daratumumab naïve. CD38 expression on MM cells gradually recovered, although, again, not to the level of anti-CD38 antibody-naïve patients. Interestingly, low MM CD38 explained only 45% of cases identified to have daratumumab resistance. With clinical follow-up, we found ex vivo sensitivity predicted subsequent clinical response but CD38 overexpression did not. Patients clinically re-treated with anti-CD38 antibodies had <6 months of clinical benefit, but 1 patient who was daratumumab exposed but not refractory achieved complete response lasting 13 months. We conclude that transient efficacy can be achieved by waiting 1 year before CD38 antibody rechallenge, but this approach may be best used as a bridge to, or after, chimeric antigen receptor T-cell therapy.

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia.

Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: i) higher doses of venetoclax are tolerable and more effective, and ii) azacitidine can be discontinued after deep remissions. Forty-two newly diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine+Venetoclax (HiDDAV) Study (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital polymerase chain recation. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400 mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.

Clinical and Radiographic Predictors of Progression and Survival in Relapsed/Refractory Lymphoma Patients Receiving Anti-CD19 CAR T-cell Therapy.

INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas, though certain patients do not respond to treatment or relapse afterwards. The purpose of this study is to determine patient variables that are predictive of response to CAR-T therapy. METHODS: We conducted a retrospective review of 59 R/R B-cell non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy. Risk factors for progression free survival (PFS) and overall survival (OS) were identified and multivariate logistic regression models for PFS and OS at 1 year were created using stepwise selection. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). RESULTS: At median follow up of 25.6 months, median overall survival was not reached, and median progression free survival was 5.7 months. Stage IV disease (odds ratio (OR) 9.335, P = .025) was identified as a predictive variable for progression at day 365 with an AUC of 0.7922 (P < .001). IPI (OR 2.828, P = .014), ALC ≥ 0.50 at collection (OR 0.183, P = .043), CRP ≥ 11 (OR 6.177, P = .019), and tocilizumab administration (OR 0.062, P = .005) as predictors for death at day 365 with an AUC 0.8626 (P < .001). CONCLUSION: Clinical variables identify R/R lymphoma patients who are at risk for progression and poor overall survival after CAR T-cell therapy. IPI, CRP, ALC, and tocilizumab administration may be predictors of survival.

Incidence of Invasive Fungal Infections in Patients With Previously Untreated Acute Myeloid Leukemia Receiving Venetoclax and Azacitidine.

Background: Acute myeloid leukemia (AML) is associated with poor prognosis, particularly in elderly patients with comorbidities. Combining azacitidine (AZA) with BCL-2 inhibitor venetoclax (VEN) demonstrated significant improvement in outcomes for newly-diagnosed AML patients compared to AZA alone. However, this regimen is myelosuppressive, and the incidence of invasive fungal infections (IFIs) and impact of antifungal prophylaxis are not well defined. Methods: This retrospective cohort study evaluated newly-diagnosed AML patients treated with VEN/AZA at the University of Colorado Hospital from January 2014 to August 2020. Patients with history of prior IFI were excluded. Primary outcome was IFI incidence during VEN/AZA therapy. χ2 and Fisher exact tests assessed the impact of patient demographics, AML-specific risk factors, and receipt of antifungal prophylaxis on IFI incidence. Results: 144 VEN/AZA-treated AML patients were included in the study. 25 (17%) patients developed IFI: 8% (n = 2) "proven," 24% (n = 6) "probable," and 68% (n = 17) "possible" per European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium criteria. There was no statistically significant association between IFI incidence with age, sex, or European LeukemiaNet classification. 10 patients received antifungal prophylaxis; none developed IFI. IFI incidence rate per 1000 patient-days was greatest 0-9 days after starting VEN/AZA, at 8.39. Conclusions: Incidence of "proven" and "probable" IFI in our VEN/AZA-treated AML cohort was 5.6%, in-line with incidence rates reported by recent similar studies. Furthermore, IFI incidence decreased as days from starting VEN/AZA therapy increased.

Outcomes Are Similar After Allogeneic Hematopoietic Stem Cell Transplant for Newly Diagnosed Acute Myeloid Leukemia Patients who Received Venetoclax + Azacitidine Versus Intensive Chemotherapy.

Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age.

ABO Blood Groups Are Not Associated With COVID-19 Disease Incidence and Severity When Correcting for Ethnicity Differences in Blood Type.

OBJECTIVES: To determine if blood type is a risk factor for coronavirus disease 2019 (COVID-19) disease incidence and severity after correcting for ethnicity differences between novel infections and known ABO blood type frequency differences. METHODS: We performed a retrospective analysis on all severe acute respiratory system coronavirus 2 (SARS-CoV-2) infections and disease severity across two major testing sites in Colorado. We evaluated all individuals with a SARS-CoV-2 nucleic acid test (NAT) and a known blood type between March 1, 2020, and June 1, 2020. We then created a prediction algorithm based on the corrected blood types by ethnicity using data from the Colorado Department of Health and established blood types by ethnicity. We applied this prediction algorithm to all patients in our sample. RESULTS: Of 8,676 patients, 485 (5.6%) had a positive SARS-CoV-2 NAT test and 8,191 (94.4%) had a negative test. All patients had ABO blood types that mirrored the expected blood type distribution within the state of Colorado (P = .15, χ 2 statistic = 5.31). No differences in expected blood groups were present between ethnicity-adjusted SARS-CoV-2-negative and SARS-CoV-2-positive patients (χ 2 = 3.416313, P = .332). CONCLUSIONS: Blood type is not associated with COVID-19 disease incidence or severity after correcting for ethnicity differences in expected blood type frequencies.

Venetoclax and azacitidine followed by allogeneic transplant results in excellent outcomes and may improve outcomes versus maintenance therapy among newly diagnosed AML patients older than 60.

The combination of venetoclax (ven) and azacitidine (aza) has resulted in high response rates in the upfront treatment of AML in patients age > 75 and patients unfit for intensive chemotherapy. Given the poor historical outcomes in patients age ≥ 60 treated with induction chemotherapy, ven/aza has become our institutional preference for the initial treatment of non-core binding factor (CBF) AML patients age ≥ 60. The benefit of allogeneic stem cell transplant (SCT) in patients who achieve response to ven/aza is uncertain. We report outcomes of SCT-eligible patients treated at our center. Between 1/2015 and 1/2020, 119 newly diagnosed non-CBF AML patients age ≥ 60 received ven/aza as initial therapy. 21 patients underwent SCT; 31 additional patients were potentially SCT eligible but deferred SCT. Overall survival (OS) was significantly greater among SCT patients (median survival not reached) versus potentially SCT eligible patients not undergoing SCT (median 518 days) (p = 0.01). Our data suggest that ven/aza followed by SCT in newly diagnosed AML patients older than ≥ 60 results in excellent outcomes and likely improves outcomes over maintenance therapy. Ongoing investigation will further refine the optimal timing of and selection of patients for SCT based on prognostic disease features and response assessments.

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia.

BACKGROUND: The time-limited combination of venetoclax and obinutuzumab (VenG) was established by the German CLL Study Group in the CLL14 trial for the upfront management of newly diagnosed chronic lymphocytic leukemia (CLL), showing a superior progression free survival benefit. The incidence of grade 3-4 neutropenia was reported in the range of 52.8%-57.7%. However, patients who develop neutropenia with this combination have yet to be formally characterized in the literature as it has impact on the clinical practice setting. AIM: To determine the incidence of grade 3 and 4 neutropenia and identify risk factors for neutropenia among CLL patients treated with the VenG regimen. METHODS: We conducted a retrospective, single-center study of all adult patients with a diagnosis of CLL treated with VenG at the University of Colorado Hospital. Demographic information, laboratory data, clinical data, and medication prescriptions were collected from the patients' electronic medical record. RESULTS: A total of 14 patients (73%) developed neutropenia during the course of therapy. The mean time to neutropenia from the start of treatment was 42 days (range 1-131). Our cohort harbored more high risk disease features and more comorbidities (CIRS score of 12). Four patients (28.6%) in the neutropenic group developed infectious complications during therapy and 6 (31%) patients were unable to be dose escalated to the final FDA approved dose of 400 mg. CONCLUSION: Our study cohort had higher incidence of grade 3 and 4 neutropenia occurring in 73% of patients. This could be attributed to a higher rate of comorbidities, high risk features, concomitant interacting medications, and prior chemotherapy. Further studies are warranted to determine if growth factor support is efficacious to achieve dose escalation with this therapy.

Venetoclax and azacitidine compared with induction chemotherapy for newly diagnosed patients with acute myeloid leukemia.

Venetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.

The propriety of upgrading responses to venetoclax + azacitidine in newly diagnosed patients with acute myeloid leukemia.

Widely-used response criteria, conditional upon count recovery, were developed for acute myeloid leukemia (AML) in the context of intensive chemotherapy (IC). Extending these definitions to continuously-administered venetoclax-based therapies might underestimate responses. Best practices for venetoclax-based therapies mandate interruption after an end-of-cycle 1 bone marrow biopsy shows morphologic remission with cytopenias. We analyzed 435 patients with newly-diagnosed AML and follow-up response assessments. Of the 101 who responded to venetoclax + azacitidine, overall survival for patients whose response was upgraded due to count recovery during a 14-day post-disease assessment period, from complete remission (CR) with incomplete recovery of blood counts to CR, was not different compared to patients who did not need the 14-day period for count recovery. These results were distinct from 138 IC patients. Although sample sizes for the comparison groups were small, and conclusions are exploratory and must be verified, these findings support consideration of new response criteria for venetoclax-based regimens.

Thirty-Day Outcomes From Standalone Minimally Invasive Surgery-Transforaminal Lumbar Interbody Fusion Patients in an Ambulatory Surgery Center vs. Hospital Setting.

Objectives We sought to evaluate differences in perioperative baseline characteristics, operative efficiency, and 30-day safety events for patients undergoing standalone minimally invasive surgery-transforaminal lumbar interbody fusion (MIS-TLIF) in a hospital versus an ambulatory surgery center (ASC). Methods Patients were retrospectively identified and sequentially enrolled from the office records of a single, community neurosurgeon. Records for the first 50 qualifying patients in the hospital and ASC cohorts were retrieved. Variables collected included: baseline demographic and health status, operative safety (intra-op complications) and efficiency (operative time, fluoroscopy time, etc.), and 30-day post-operative safety (emergency room visits, re-admission, and re-operation). Results At baseline, hospital and ASC patients were equivalent in gender distribution, BMI, and pre-operative narcotic use. Statistically significant differences were found in age and comorbidity burden (ASA status and Charleson Comorbidity Index); p < 0.0001, p = 0.0039, and p < 0.001 respectively. The only significant difference in construct type between hospital and ASC patients was the proportion of one- versus two-level fusions; all two-level fusions were performed in the hospital group. There were no differences in operative time, need for transfusions, or iatrogenic complications. There were also no differences between the groups in 30-day events of ER visits, re-admission, re-operation, or post-operative narcotic refill use. The length of stay was significantly different between the ASC and hospital settings (p < 0.0001). Conclusions As expected, ASC patients were younger and relatively healthier compared to their hospital counterparts. Thirty-day safety events of ER visits, re-admission, re-operation, and narcotic refill utilization were representative of population norms. Patients with standalone, expandable MIS-TLIF underwent efficient operative procedures and experienced minimal 30-day complications independent of their operative status. ASC patients had the added benefit of significantly reduced length of stay over their hospital counterparts. Given the equivalency of the 30-day post-operative course for both patient cohorts, a substantial reduction in economic burden is likely for the ASC patients.

Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells.

We previously demonstrated that leukemia stem cells (LSCs) in de novo acute myeloid leukemia (AML) patients are selectively reliant on amino acid metabolism and that treatment with the combination of venetoclax and azacitidine (ven/aza) inhibits amino acid metabolism, leading to cell death. In contrast, ven/aza fails to eradicate LSCs in relapsed/refractory (R/R) patients, suggesting altered metabolic properties. Detailed metabolomic analysis revealed elevated nicotinamide metabolism in relapsed LSCs, which activates both amino acid metabolism and fatty acid oxidation to drive OXPHOS, thereby providing a means for LSCs to circumvent the cytotoxic effects of ven/aza therapy. Genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide metabolism, demonstrated selective eradication of R/R LSCs while sparing normal hematopoietic stem/progenitor cells. Altogether, these findings demonstrate that elevated nicotinamide metabolism is both the mechanistic basis for ven/aza resistance and a metabolic vulnerability of R/R LSCs.

Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression.

The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. Many different MM drugs have emerged, however, that attack various phenotypic aspects of malignant plasma cells. These drugs are administered in numerous, seemingly interchangeable combinations. Although the availability of many treatment options is useful, no clinical test capable of optimizing and sequencing the treatment regimens for an individual patient is currently available. To overcome this problem, we developed a functional ex vivo approach to measure patients' inherent and acquired drug resistance. This method, which we termed myeloma drug sensitivity testing (My-DST), uses unselected bone marrow mononuclear cells with a panel of drugs in clinical use, followed by flow cytometry to measure myeloma-specific cytotoxicity. We found that using whole bone marrow cultures helped preserve primary MM cell viability. My-DST was used to profile 55 primary samples at diagnosis or at relapse. Sensitivity or resistance to each drug was determined from the change in MM viability relative to untreated control samples. My-DST identified progressive loss of sensitivity to immunomodulatory drugs, proteasome inhibitors, and daratumumab through the disease course, mirroring the clinical development of resistance. Prospectively, patients' ex vivo drug sensitivity to the drugs subsequently received was sensitive and specific for clinical response. In addition, treatment with <2 drugs identified as sensitive by My-DST led to inferior depth and duration of clinical response. In summary, ex vivo drug sensitivity is prognostically impactful and, with further validation, may facilitate more personalized and effective therapeutic regimens.

Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia.

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.

Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells.

Venetoclax with azacitidine (ven/aza) has emerged as a promising regimen for acute myeloid leukemia (AML), with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed and the majority of relapsed patients do not achieve remission with ven/aza. We previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. Herein we demonstrate that resistance to ven/aza occurs via up-regulation of fatty acid oxidation (FAO), which occurs due to RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism, thereby rendering ven/aza ineffective. Pharmacological inhibition of FAO restores sensitivity to ven/aza in drug resistant AML cells. We propose inhibition of FAO as a therapeutic strategy to address ven/aza resistance.

Evaluating Novel PET-CT Functional Parameters TLG and TMTV in Differentiating Low-grade Versus Grade 3A Follicular Lymphoma.

BACKGROUND: Follicular lymphoma (FL) grading, low-grade 1-2 (LG) versus grade 3A (3A), informs management. However, accurate grading is challenging owing to disease heterogeneity and inter-reader variability. The [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) parameter maximum standardized uptake value (SUVmax) has utility in differentiating LG from 3A FL, but the utility of novel parameters total lesion glycolysis (TLG) and total metabolic tumor volume (TMTV) is unknown. PATIENTS AND METHODS: Retrospective review of diagnostic pre-treatment PET-CTs of patients aged > 18 years with FL grades 1-3A from 2009-2017 was performed. PET-CT parameters SUVmax, TLG, and TMTV values were generated using manual (MW) and semi-automated workflows (SW). Poisson regression and receiver operating characteristic curves were used to compare PET-CT parameters between LG and 3A. RESULTS: A total of 49 patients with FL were identified: 38 LG and 11 3A. PET-CT parameters were significantly higher in 3A as compared with LG in both workflows. The cutoff values, sensitivities, and specificities were as follows: SUVmax: 10.4, 64%, and 74% in MW and 11.9, 73%, and 76% in SW; TLG: 543, 82%, and 74% in MW and 371, 73%, and 74% in SW; and TMTV: 141, 73%, and 76% in MW and 93, 64%, and 76% in SW. SUVmax had identical cutoff, sensitivity, and specificity across all 3 SWs, whereas TLG and TMTV had considerable variance across all 3 SWs. CONCLUSIONS: TLG and TMTV are comparable to SUVmax in differentiating LG versus 3A FL. Cutoffs, sensitivities, and specificities varied in MW versus SW. Novel PET-CT parameters serve as reproducible adjuncts but not replacements for biopsy in differentiating grades of FL.