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Azacitidine (AZA) is effective in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia type 2 (CMML-2) and low blast count acute myeloid leukemia (AML) patients not suitable ...for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified.
We evaluated clinical predictors of OS and overall response rate (ORR; complete/partial response CR/PR; stable/progressive disease SD/PD) to AZA in a real life cohort. We studied 94 consecutive patients, treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. OS was measured from the starting of AZA treatment. Table 1 shows the clinical characteristics pre- and post-AZA: most patients (68%) were AREB1 or AREB2, 13% RCUD/RCMD or MDS NOS according to WHO 2008 classification, 17% AML, 2% CMML. At the onset of AZA therapy the majority of MDS cases (68%) showed an intermediate-2 risk, according to the International Prognostic Scoring System (IPSS) and high/very high risk (78%) according to IPSS-revised. Secondary and de novo cases, as well as cytogenetics risk groups, were equally represented; 50% of patients were transfusion dependant and moderate to severe neutropenia or thrombocytopenia were present in roughly 50/70% of cases respectively. As expected, bone marrow biopsies pre-AZA showed hypercellularity in most patients (65%). Remarkably, 47,5% of cases showed bone marrow fibrosis of ≥1 grade before AZA initiation. These findings were mostly unchanged at post-AZA evaluation. On the whole, 93 patients receiving > 4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-44), ORR was 41.9% (CR 18.3%, PR 11.8%, SD with hematologic improvement HI 11.8%), SD was 21.5%, PD 10.7% and 25.8% failed to achieve a response. Thirteen percent of patients reached at least partial cytogenetic response and 50% a HI. ORR was not influenced by monocytosis, neutropenia or IPSS cytogenetic risk category. Interestingly, pre-AZA marrow blast percentage, cytogenetic risk, time from diagnosis to AZA and the interval from 1st to 6th cycle had no impact on response. As regards marrow characteristics, patients with MF-0 pre-AZA displayed significantly lower PD rate and higher ORR, SD and HI than those with any grade of fibrosis (21.4% vs 51.4% and 78.6% vs 48,6%, respectively p=0.006, Fig1). This observation was also confirmed at marrow evaluation after AZA (22% versus 48% for PD and 78% versus 52% for ORR/SD/HI, p=0.05, Fig1). Regarding cellularity pre- and post-AZA, higher ORR,SD and HI and lower PD were observed for patients with normo/hypo compared to those with hyper-cellularity (Fig1) although not significantly. Forty-one percent of cases presented a hematologic toxicity (33% neutropenia and 18% thrombocytopenia of any grade) occurring after a median of 2 (1-18) AZA cycles. Moreover 28.6% of patients had an infection during AZA treatment, not related to neutropenia degree. Of note, toxicities did not affect median time from the 1st to the 6th AZA cycle (170,115-240 days), nor ORR. Median OS from the beginning of therapy was 18.5 months (12.7-24.4, 95% CI). IPSS high category HR 2.24 (1.19-4.20) p=0.01, poor cytogenetics 2.19 (1.27-3.78) p=0.005, and lower ORR 0.46 (0.26-0.80) p=0.006 significantly affected OS. Unexpectedly, a response obtained after less than 4 cycles negatively impact OS HR 0.86 (0.80-0.92) p<0.0001. Notably, cases with pre-AZA fibrosis ≥MF-1 showed lower OS 2.26 (1.28-3.99) p=0.005. In conclusion we provide evidence of no relationship between neutropenia and infections and of no impact of toxicities on dose-density and ORR to AZA treatment. Moreover, high marrow fibrosis and hypercellularity may affect response to AZA therapy. Further studies are needed to disclose the clinical/biological significance of marrow fibrosis/cellularity in the era of hypomethylating agents.
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Reda:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.
Background:
CAR T therapy is FDA approved for specific relapsed/ refractory (R/R) B cell lymphomas and acute lymphoblastic leukemia (ALL), and clinical trials are ongoing for R/R multiple myeloma ...(MM). Cytopenias have been observed post-CAR T, yet there is minimal data delineating the pathobiology and trends. We report the largest series to our knowledge thus far, of hematological recovery and factors affecting count recovery after CAR T.
Methods:
We retrospectively reviewed adult patients who received CAR T for R/R B cell lymphomas after FDA approval and those treated for R/R B cell ALL (NCT01044069) and MM (NCT03070327) at our center. Blood counts were collected for up to 12 months or until censored for relapse, progression or initiation of chemotherapy/ conditioning for autologous or allogeneic stem cell transplantation (HCT)/ subsequent treatment with CAR T. Only patients with follow-up > 30 days were included. “Recovery” for the respective blood count was defined as hemoglobin > 8g/dL and platelets > 50,000/µL without transfusion support in 2 weeks and 1 week, respectively; absolute neutrophil count (ANC) > 1,000/µL and white cell count (WBC) > 3,000/µL without growth factor support in 2 weeks. “Normalization” was defined as normal range for the laboratory; hemoglobin > 11.2g/dL in women and 12.5g/dL in men, platelets > 160,000/µL, ANC > 1,500/µL and WBC > 3,000/µL without transfusion support as above. “Complete count recovery” refers to recovery per above criteria in all 4 counts. Categorical variables were compared using Fisher's exact test and continuous variables using the Wilcoxon rank-sum test.
Results:
Eighty three patients were included (Table 1). Using the noted nadir values, grade 1-2 and 3-4 anemia was seen in 22% and 78%, thrombocytopenia in 29% and 66%, neutropenia in 3% and 96% while leucopenia in 0% and 100%, respectively. During the follow-up, 66% patients received packed red cell transfusion, 52% received platelet transfusion and 62% received growth factor support.
By 1 month (n=83), recovery of hemoglobin, platelets, ANC and WBC was noted in 61%, 51%, 33% and 28%, respectively. At 3 months (n=41), these respective percentages were 93%, 90%, 81% and 59%. All patients had recovered hemoglobin and platelet count by 4 months (n=17), and ANC by 9 months (n=14). By 3 months, normalization of hemoglobin, platelets, ANC and WBC was noted in 39%, 34%, 71%, and 39%, respectively.
Upon examination of potential variables in a univariate model, lack of recovery of hemoglobin, platelets, ANC and complete counts recovery at 1 month was statistically significantly associated with type of CAR construct, higher grade (grade 3-4 vs grade 1-2 vs none) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as well as a higher peak CRP and ferritin (data for complete count recovery in Table 2). Additionally, lack of hemoglobin recovery at 1 month was associated with lymphodepletion using high dose cyclophosphamide (recovered vs no recovery in 58% vs 42%, p=0.01) and diagnosis of ALL (65% vs 35%, p = <0.001). Similarly, inability to recover platelets at 1 month was significantly associated with prior HCT (63% vs 36%, p =0.04); while ANC was associated with prior HCT (87% vs 13%, p = 0.004) and > 3 prior lines of therapy (78% vs 22%, p = 0.04). At 3 months, absence of complete count recovery was associated only with the CAR T construct utilized. A multivariate logistic regression model resulted in wide confidence intervals due to small size of subgroups, hence leading to unreliable point estimates (data not shown).
Conclusions:
Our study shows that blood counts recover in most patients who have not progressed or received additional therapy by 3 months post-CAR T. The association of count recovery with severity of CRS, ICANS as well as inflammatory marker levels indicates that inflammatory response post-CAR T influences hematological recovery in these patients. The association of count recovery and CAR construct can be influenced by underlying diagnosis as specific CAR constructs were used for specific diagnosis. Since patients with no disease response were excluded and were censored at progression, these effects are less likely to be affected by disease response; however the association of depth of response could not be evaluated in this study. These results warrant future studies to understand underlying mechanisms of inadequate recovery.
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Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy. Sauter:Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Celgene: Consultancy; GSK: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy. Santomasso:Novartis: Consultancy; Kite/Gilead: Consultancy; Juno/Celgene: Consultancy. Palomba:Noble Insights: Consultancy; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen: Research Funding; Janssen: Research Funding. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Brentjens:Celgene: Consultancy; JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding. Park:Takeda: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Incyte: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy. Perales:Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mailankody:Celgene: Research Funding; Juno: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria.
Introduction
Chimeric Antigen Receptor (CAR) T cells are associated with unique toxicities, including cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome ...(ICANS). Patients (pts) with severe CRS and ICANS exhibit hemodynamic instability and coagulopathy with evidence of endothelial activation and increased blood brain barrier permeability. Increases in inflammatory cytokines and biomarkers of endothelial activation in serum and CSF have been associated with severe CRS and ICANS. The EASIX (Endothelial Activation and Stress Index) score lactate dehydrogenase (LDH) (U/L) × creatinine (mg/dl) / platelets (PLT) (109 cells/L) correlates with severe fluid overload and survival in allogeneic transplant pts. Elevated LDH and low PLT levels have been associated with severe ICANS development, and high IL-6 levels are seen in severe CRS and ICANS. We hypothesized that the EASIX and a newly proposed version of it, the modified-EASIX (mEASIX), in which creatinine is replaced by CRP (mg/dL) as an easily available surrogate for IL6, would be associated with CRS and ICANS in CAR T cells pts.
Methods
We analyzed 2 different populations of adult CAR T cells pts treated at our institution: 1) B-cell acute lymphoblastic leukemia (B-ALL) pts treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) aggressive diffuse large B-cell lymphoma (DLBCL) pts treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval starting from 2018. EASIX and mEASIX scores were calculated for each patient daily from start of lymphodepletion conditioning to day +14. A log transformation using base 2 (log2) was applied to all EASIX/mEASIX variables to reduce skew. CRS and ICANS were graded according to the ASTCT grading system.
Results
87 pts, B-ALL (n=53) and DLBCL (n=34), were analyzed. According to ASTCT grading, 83% (72/87) experienced CRS and 54% (47/87) developed ICANS, grade ≥3 in 23% (20/87) and 40% (35/87) of pts, respectively. When analyzed by disease, CRS and ICANS rates were 87% (46/53) and 55% (29/53) for B-ALL and 76% (26/34) and 53% (18/34) for DLBCL, respectively. CRS and ICANS were grade ≥3 in 28% (15/53) and 45% (24/53) of B-ALL pts and in 15% (5/34) and 32% (11/34) of DLBCL pts, respectively. Median time of onset of CRS after CAR T cell infusion was day +2 and median onset of ICANS was day +6 for the overall population and the subgroups. High EASIX and mEASIX scores at start of conditioning were both associated with development of any grade CRS OR=1.81 (95% CI 1.09-3.36) p=0.038 and OR=1.94 (95% CI 1.32-3.38) p=0.005 and grade ≥3 CRS OR=1.47 (95% CI 1.05-2.29) p=0.049 and OR=1.34 (95% CI 1.07-1.80) p=0.024, respectively (Table). Following CAR T cell infusion, high scores of both EASIX OR=1.60 (95% CI 1.12-2.43) p=0.017 and mEASIX OR=1.32 (95% CI 1.07-1.69) p=0.014 on day +1 were associated with development of grade ≥3 CRS. Moreover, both high EASIX OR=1.43 (95% CI 1.08-1.96) p=0.018 and mEASIX OR=1.29 (95% CI 1.07-1.60) p=0.010 scores on day +3 were associated with grade ≥3 ICANS. When analyzed by disease, results were confirmed for severe CRS and ICANS in B-ALL patients, while in the DLBCL group only mEASIX at start of conditioning and at day +1 was associated with development of any grade CRS. EASIX and mEASIX scores were not associated with response rates to CAR T cells therapy.
Conclusions
EASIX and mEASIX scores calculated at baseline (before lymphodepletion) are associated with development of CRS and severe CRS. Moreover, both high EASIX and mEASIX scores on day +1 and day +3 are associated with occurrence of grade ≥3 CRS and grade ≥3 ICANS, respectively. We conclude that EASIX and mEASIX, as markers of endothelial damage and inflammation, could be useful as early predictors in guiding treatment decisions before the onset of severe symptoms.
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Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brentjens:JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy. Giralt:Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Kite: Consultancy. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Evelo: Equity Ownership; MSK (IP for Juno and Seres): Patents & Royalties; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy. Santomasso:Kite/Gilead: Consultancy; Juno/Celgene: Consultancy; Novartis: Consultancy. Sauter:GSK: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Perales:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees.
Introduction
Cytokine release syndrome (CRS) and immune effector cells-associated neurotoxicity syndrome (ICANS) are commonly associated with Chimeric Antigen Receptor (CAR) T cells therapy. To ...assess CAR T cell safety, various grading systems were developed and used in clinical trials: Lee, Penn, Memorial Sloan Kettering Cancer Center (MSKCC), CARTOX and CTCAEv5.0 for CRS; and CTCAEv4.03 and CARTOX for ICANS. While these grading systems evaluate mostly uniform symptoms, their intensity gradings differ. The American Society for Transplantation and Cellular Therapy (ASTCT) recently developed a simplified consensus grading system for CRS and ICANS. To validate the ASTCT grading, we compared it to the aforementioned gradings.
Methods
We included 2 populations of adult patients (pts) treated at our center: 1) B-cell acute lymphoblastic leukemia (B-ALL) treated with CD1928z CAR T cells from 2010 to 2016 (NCT01044069), and 2) diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) after FDA approval from 2018. Upon chart review, one expert clinician re-graded all CRS and ICANS. For validation, another expert independently graded a randomly selected sample (20%). A neurologist and an intensivist supervised the review process. CRS/ICANS rates and concordance rates were assessed for all grading systems. In pts with DLBCL (treated with axi-cel or tisa-cel), we used ASTCT grades to predict treatment according to currently available guidelines (axi-cel and tisa-cel FDA insert packages, CARTOX and NCCN guidelines) and compare it to the actual treatment received at our institution.
Results
We analyzed 102 pts: 53 B-ALL and 49 DLBCL (axi-cel: 36, tisa-cel: 13). According to ASTCT grading, 82% pts had CRS, 87% in B-ALL and 77% in DLBCL pts (axi-cel: 86%, tisa-cel: 54%). The concordance rate on diagnosis of CRS (yes vs no) across all scores was 99%. Concordance rate grade by grade, instead, was 27%, with major discordance in grades 1 to 3 (figure a-b). The Penn score upgraded 91% pts from gr 1 to 2 (neutropenic fever requiring inpatient antibiotics), and 93% from gr 2 to 3 (fluid responsive hypotension or low-dose oxygen). Grading concordance increased to 78% when Penn was excluded, with other differences due to: 1) CARTOX downgraded 15% of gr 2 pts with hypotension, for systolic blood pressure >90; and 2) CARTOX and Lee upgraded 8% pts for organ damage.
By ASTCT, 50% pts experienced ICANS, 55% in B-ALL and 45% in DLBCL pts (axi-cel: 55%, tisa-cel: 15%). By CTCAEv4.03, ICANS incidence was 55% because 5 pts with headache and slurred speech with trouble word finding didn't meet criteria for ICANS by ASTCT (due to normal ICE score), leading to a 91% global concordance rate. Concordance grade by grade was 57%, mainly due to gr 1 and gr 3-4 ICANS (figure c). CARTOX upgraded 42% of gr 3 pts to gr 4 because of brief generalized seizures which, notably, where mostly seen in B-ALL pts compared to DLBCL (30% vs 6%). Another pt was upgraded from gr 2 to 4 for asymptomatic intracranial pressure >20 mmHg without cerebral edema.
We then looked at implications on management in the DLBCL group (Table 1). For CRS, only 4 pts with gr 3-4 CRS would receive tocilizumab according to tisa-cel's label (doesn't include tocilizumab for gr 2 CRS) compared to 24, 19, 25 pts according to axi-cel's label, CARTOX and NCCN, respectively. In our practice, 22 patients received tocilizumab. For ICANS, steroids use was consistent across all guidelines (16 pts, 5 with gr 2 ICANS and 11 with gr ≥3 ICANS) and almost comparable to our practice (19 pts treated). Conversely, only a few pts at our institution received tocilizumab for ICANS with concurrent CRS (2 pts vs 7, 11, 11 for axi-cel, CARTOX and NCCN, respectively).
Conclusions
Over or under attribution of symptoms due to CAR T cells results in inconsistent scores across different grading systems. Current guidelines for CRS and ICANS management are based on the experience derived from single products and various grading systems, which may result in either overtreating or delaying treatment. As such, they cannot be universally applied. To avoid discrepancies in assessing safety and in managing different product toxicities, we conclude that a unified grading system should be utilized across clinical trials and in clinical practice, and that similar consensus management guidelines be developed and adopted.
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Santomasso:Juno/Celgene: Consultancy; Kite/Gilead: Consultancy; Novartis: Consultancy. Batlevi:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brentjens:Celgene: Consultancy; JUNO Therapeutics: Consultancy, Patents & Royalties, Research Funding. Giralt:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Novartis: Consultancy; Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy. Palomba:MSK (IP for Juno and Seres): Patents & Royalties; Evelo: Equity Ownership; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Hemedicus: Speakers Bureau; Merck & Co Inc.: Consultancy; Seres Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Membership on an entity's Board of Directors or advisory committees. Sauter:Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; GSK: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Celgene: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Incyte: Consultancy. Perales:Miltenyi: Research Funding; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees.
The development of chimeric antigen receptor T cell (CAR T) therapy has revolutionized the treatment of relapsed refractory diffuse large b-cell lymphoma (DLBCL). However, its impact in vulnerable ...older patients, especially those with multi-morbidity and functional limitations, has not been explored. Moreover, the Centers for Medicare & Medicaid Services (CMS) has recently proposed Coverage with Evidence Development for CAR T, emphasizing the need for evidence in older patients.
We retrospectively examined outcomes of older patients referred for commercial CAR T products, axicabtagene ciloleucel and tisagenlecleucel, at our institution from January 2018 to March 2019. Forty-two consecutive older patients (≥65yo) were included in the analysis of post-relapse (last documented relapse or refractory state) overall survival (PR-OS) accounting for time of CAR T entry. Geriatric assessment, including comorbidity, basic and instrumental activities of daily living, prior falls, and weight loss, was performed either by a geriatrician prior to admission, or by interdisciplinary clinical staff on the day of admission. In parallel, we compared the safety and toxicities of CAR T between older (≥65yo, n=24) and younger (<65yo, n=25) patients.
Among the 42 patients ≥65yo, 18 did not receive CAR T due to clinical ineligibility and/or death during the pre-requisite clinical evaluation. Their gender distribution, comorbidity burden, measured by Deyo/Charlson Comorbidity Index (DCI/CCI), and Karnofsky Performance Status (KPS) were comparable to the 24 older patients who received a CAR T product. With a median follow-up of 291 days (range 162 - 572) for survivors, the PR-OS favored the group of older patients who had received CAR T with estimated 1-year PR-OS of 0.67 (95% CI: 0.43, 0.99) versus 0.44 (95% CI: 0.27, 0.75) for patients who did not receive CAR T (p=0.04) (Figure).
We next compared the safety and toxicity profiles among older (≥65yo, n=24) versus younger patients (<65yo, n=25) who received a CAR T. Baseline characteristics were similar among the two groups including: KPS, the prevalence of functional impairment, prior fall, and weight loss, and pre-treatment tumor burden measured by LDH (Table). The older group had more females (p<0.001) and higher comorbidity burden measured by DCI/CCI (p=0.04) (Table). Numerically more younger patients (84%) received axicabtagene ciloleucel compared to tisagenlecleucel versus older patients (63%; p=0.11). Importantly, the two groups had similar incidences of cytokine release syndrome (CRS) and neurotoxicity (NT) of all grades (Table). We also examined the incidence of grade 3-4 hematologic and non-hematologic toxicities by CTCAE v5.0 and found that numerically, older patients appeared to have less infection and cytopenia, and more metabolic and other toxicities (Table). In addition, the rate of Intensive Care Unit admission was similar. At the time of last follow-up, we observed only 1 treatment-related death, a 69-year-old female with a history of prior allogeneic hematopoietic cell transplantation who died of influenza pneumonia 129 days after CAR T infusion.
Although limited by small sample size, retrospective design, and possible patient selection bias regarding disease biology, our results highlight potential benefits of CAR T in selected older patients even with functional limitation, multi-morbidity, and significant tumor burden; and the lack of excessive CRS, NT, and other high-grade toxicities. These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and support that, with meticulous management of CAR T toxicities, older patients should not be excluded from CAR T based on chronologic age alone. Detailed geriatric assessment and correlation with toxicities should allow better selection of older adults who could benefit from this curative treatment. In addition, the biology of CAR T response in older adults may warrant additional investigation in the context of aging-associated changes in the immune system.
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•NRD is not inferior to traditional PD during neutropenia after HSCT.•Multiple myeloma diagnosis, antibiotic prophylaxis, and absence of mucositis reduce the risk of grade ≥2 infections.
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Infections are a major cause of morbidity and mortality during neutropenia after hematopoietic stem cell transplantation (HSCT). The use of a low-microbial protective diet (PD) in the peritransplantation period is a standard of care, although its efficacy has never been tested prospectively. We conducted a multicenter, randomized, noninferiority trial, enrolling all consecutive adult patients undergoing high-dose induction chemotherapy or HSCT with the objective to compare nonrestrictive diet (NRD) vs PD. Overall, 222 patients were enrolled, randomly assigned, and analyzed. One hundred seventy-five subjects (79%) received autologous HSCT (auto-HSCT), 41 (18%) received allogeneic HSCT (allo-HSCT), and 6 (3%) patients received high-dose induction chemotherapy. There was no significant difference in terms of incidence of grade ≥2 infections and death during neutropenia in the 2 arms. In multivariable analysis, only multiple myeloma diagnosis, fluoroquinolone prophylaxis, and the absence of mucositis were associated with a lower incidence of grade ≥2 infections. We did not report any significant variation in terms of hospitalization length, incidence of mucositis and gastrointestinal infections, body weight, and serum albumin variations in the 2 arms. In allo-HSCT recipients, the incidence of acute graft-versus-host disease grade ≥3 was similar. NRD was associated with higher patient-reported satisfaction. In conclusion, NRD is not inferior to a traditional PD during neutropenia after HSCT, and our results demonstrated that implementing a restrictive diet unnecessary burdens patients' quality of life. The clinical trial was registered prospectively in the clinical trial registry of the Istituto Nazionale dei Tumori of Milan as INT54/16.
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