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Alloreactivity forms the basis of allogeneic hematopoietic cell transplantation (HCT), with donor derived T cell response to recipient antigens mediating clinical responses either in-part or entirely. These encompass the different manifestations of graft vs. host disease (GVHD), infection risk as well as disease response. Whilst the latter is contingent upon disease biology and thus may be less predictable, the former two are more likely to be directly proportional to the magnitude of donor derived T cell recovery. Herein we explore the quantitative aspects of immune cell recovery following allogeneic HCT and clinical outcomes in two cohorts of HLA matched allograft recipients who received rabbit anti-thymocyte globulin (ATG) on different schedules (days -9 to -7 vs. -3 to -1). Monocyte as well as donor derived T cell (ddCD3) recovery was superior in those given ATG early in their course (days -9/-7). This difference was related to a more rapid rate of ddCD3 recovery, largely driven by CD3+/8+ cells in the first month following transplantation. Early monocyte recovery was associated with later T cell recovery and improved survival. In contrast rapid and early ddCD3 expansion out of proportion to monocyte recovery was associated with a high likelihood of acute GVHD and poor survival. This analytic methodology demonstrates that modelling ‘early-term immune reconstitution' following HCT yields insights that may be useful in management of post-transplant immunosuppression and adaptive cellular therapy to optimize clinical outcomes.

Important advances in the treatment landscape of multiple myeloma (MM) had been seen over the past two decades leading to improved overall survival but despite the progress multiple myeloma is still considered incurable and the prognosis of the pentarefractory patients have been poor. The development of immunotherapy and in particular adoptive cell therapy with chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of heavily pretreated relapsed/refractory MM patients. The bulk of CAR T-cell constructs currently in clinical development target the B-cell maturation antigen (BCMA) and to date only idecabtagene vicleucel (ide-cel) is approved by the Food and Drug Administration (FDA) for commercial use in adult patients with relapsed or refractory MM based on the promising clinical responses and positive safety record shown in the pivotal KarMMa study. This review focus on the development of CAR T-cell therapy for multiple myeloma as well as a brief review of the mechanisms of resistance, toxicity and new approaches under development.

Azacitidine (Aza) may promote cytotoxic effects against hematologic tumor cells when combined with donor lymphocyte infusions (DLIs). This study sought to verify Aza-DLI's efficacy and tolerability in patients with relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic stem cell transplantation (SCT) and identify cohorts benefitting most from therapy. Twenty-eight patients with recurrent AML or MDS following SCT received Aza-DLI. One-year overall survival (OS) after therapy initiation was 44%; two-year OS was 35%. Molecular/cytogenetic-only relapse, the development of cGVHD after therapy initiation, and a greater number of Aza and DLI were associated with remission. There was a trend toward higher absolute CD4+ cell count in those achieving remission. This study demonstrates Aza-DLI to be effective and highlights the importance of minimal residual disease testing and alloreactivity in managing post allograft relapsed hematological malignancy.

Anti-thymocyte globulin (ATG) mitigates graft vs host disease (GVHD) risk in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Due to T cell depletion there remains a concern that ATG administration may be associated with an increased risk of malignancy, relapse, and infection in recipients of reduced intensity conditioning (RIC). It was hypothesized that ATG infusion early in the course of conditioning will promote rapid immune reconstitution because of lower levels at the time of graft infusion and will thus help to improve clinical outcomes in RIC. Rabbit ATG (Thymoglobulin, Sanofi Aventis) was administered from day (d) -9 to -7 to HLA matched-unrelated (MUD; 5 mg/kg in divided doses) and -related (MRD; 3.5 mg/kg) donor transplant recipients conditioned with Fludarabine and Melphalan (ATG -9 cohort; N=36). Immune reconstitution and clinical outcomes were compared with a historical control group of patients who received the same doses of ATG from d-3 to -1 (ATG -3 cohort; N=28). Standard GVHD prophylaxis with calcineurin inhibitor and antimetabolite was administered, with CMV and EBV monitoring. ATG -9 cohort had more, MUD recipients 80% vs. 64%; myeloid malignancy (AML, MDS, MPD) 83% vs. 35%. Age (56 vs. 57), graft type (97 vs. 92% PBSC) and CD34+cell dose infused (4.8 vs 4.7 E6/KG) were similar. Immune reconstitution was uniformly superior in ATG -9 cohort, with significantly higher absolute monocyte counts (AMC) at d30, 60 and 90 (P Given the relatively low number of patients in each cohort, the effect of immune reconstitution on clinical outcomes was evaluated in the pooled population. Survival was improved in those with AMC and ddCD3+ cell counts >200/µL at d60 (P=0.004 & 0.016 respectively), and in patients with T cell - monocyte vector magnitude > median (577.48/µL) at that time (P= 0.008), as well as in those with a calculated dT/dt > median (1.96 cells/µL/day) at d45 (P=0.047). The latter was also associated with a reduction in relapse rate (P=0.04), as was ddCD8+ cell count >145/µL at d60 (P=0.04). Acute GVHD risk was increased when dT/dt was >median (7.60 cells/µL/day) at d15 (P=0.0095), and correspondingly with T cell - monocyte vector magnitude > median (1033.3/µL) at d30 (P=0.017). In conclusion, this retrospective study demonstrates that equal doses of ATG administered earlier (d -9 to -7 as opposed to d-1 to -3) during conditioning yield more rapid and robust immune reconstitution. Monocyte and ddCD3+ cell recovery kinetics have a favorable impact on survival and relapse risk following HLA matched HCT. Patients at risk for acute GVHD may be identified as early as d15 post HCT by analyzing ddCD3+ cell reconstitution kinetics. Different ATG administration schedules should be studied prospectively with a focus on immune reconstitution kinetics as a determinant of clinical outcomes. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Rabbit anti-thymocyte globulin for GVHD prophylaxis.

Intravenous (IV) ascorbic acid (AA) improves organ function and reduces inflammation in sepsis, an inflammatory state similar to the post-hematopoietic cell transplant (HCT) milieu. This salutary effect is mediated by antioxidant activity as well transcriptional modulation by AA. HCT recipients are deficient in AA, therefore we evaluated the safety and efficacy of patients receiving parenteral AA after myeloablative conditioning for allogeneic HCT compared to similarly treated historical controls who did not receive AA. Methods: Patients with hematologic malignancies, AML (48% of patients), ALL (28%), and CML+MDS (25%) were enrolled in an IRB approved prospective phase 2 clinical trial (NCT03613727). IV AA 50 mg/kg/d divided in 3 doses was given on days 1-14 after HCT, followed by oral AA 500 mg bid from day 15 until 6 months post HCT (FDA-IND 138924). Conditioning regimens utilized included; fludarabine & melphalan (45%), cyclophosphamide with either busulfan (30%) or total body irradiation (25%). GVHD prophylaxis included calcineurin inhibitors and methotrexate or cellcept along with anti-thymocyte globulin (ATG). Primary endpoint was reduction in TRM at 1 year. Propensity score matching was used for matching study patients with similarly treated historical controls, matching for diagnosis, conditioning regimen, and CIBMTR disease risk category for comparison of clinical outcomes. Cox-proportional hazard models were used to estimate adjusted hazard ratios (AHR) between the time-to-event outcomes and study group, adjusted for patient age, donor type, stem cell source, diagnosis, conditioning regimen, and CIBMTR disease risk. Results of an interim analysis following a period of COVID 19 mandated suspension of study accrual are reported. Results: As of March 2020, 40 patients have received IV AA: these include HLA-matched related donor (MRD; n=11), and either 10/10 or 9/10 HLA- matched unrelated donor (MUD; n=22 & 7 respectively) recipients. Graft source was either peripheral blood (n=38) or bone marrow (n=2); 88% patients had CIBMTR high risk disease. Median age was 55 years; males (19). All patients enrolled were deficient in AA at day 0, median AA level 0.3 mg/dL (range: 0.1-0.5); post AA infusion level was normal at 1.6 (1.2-5.7) on day 14. Median neutrophil and platelet recovery was by 12 days (range: 9-15 & 8-21 days respectively) with sustained donor engraftment. Median absolute CD3+ cell count at day 30 was 330 cells/microL. With a median follow up of 220 days in AA recipients, no statistically significant difference was observed in transplant related mortality between propensity matched historical controls and study patients (AHR 0.6, 95% CI: 0.2-1.5; p-value = 0.27); univariate survival analysis is depicted in Figure 1. Relapse was also similar (AHR 1.2, 95% CI: 0.3-4.5; p-value = 0.82), and despite a larger number of HLA mismatched unrelated donor recipients, acute GVHD (Grade II-IV) rates were similar in the two groups for both grade II-IV (AHR 0.8, 95% CI: 0.7-1.7; p-value = 0.65) and grade III-IV disease (AHR 0.6, 95% CI: 0.2-1.6; p-value = 0.32). Chronic GVHD rates were also similar (AHR 0.4, 95% CI: 0.1-2.7; p-value = 0.74). There are no attributable grade 3 - 4 toxicities from AA; CMV and EBV reactivation rates were not different in the two groups. Conclusions: In patients undergoing myeloablative allogeneic HCT the administration of IV ascorbic acid is safe and does not negatively impact myeloid engraftment or immune reconstitution. In this interim analysis, transplant related mortality, relapse and GVHD are not increased in IV AA recipients compared to historical controls. Thus, given its safety and tolerability, and possible salutary impact on survival and relapse in these high-risk patients, we posit the feasibility of a randomized phase 3 trial with IV AA in the post-transplant setting to determine its effect on relapse and TRM. Disclosures No relevant conflicts of interest to declare.

Intravenous (IV) ascorbic acid (AA) improves organ function and reduces inflammation in sepsis, an inflammatory state similar to post-hematopoietic cell transplant (HCT) milieu. This salutary effect is mediated by antioxidant activity as well transcriptional modulation by AA. We evaluated the safety and efficacy of IV AA in ameliorating the inflammatory milieu following myeloablative conditioning and allogeneic HCT. Methods: Patients with advanced hematologic malignancies (CML, AML, ALL, MDS) were enrolled in an IRB approved prospective phase 2 clinical trial (NCT03613727). IV AA 50mg/kg/d divided in 3 doses was given on days 1-14 after HCT followed by oral AA 500mg bid from day 15 until 6 months post HCT (IND 138924). The treatment regimens included myeloablative fludarabine & melphalan, or cyclophosphamide with either busulfan or total body irradiation. GVHD prophylaxis included ATG. FDA mandated safety lead-in cohort enrollment for the trial is complete with ongoing accrual to target primary end point of reducing 1-year non-relapse mortality. Cytokines were measured at various time points following HCT. Results: As of October 2019 21 patients have received IV AA: these include HLA-MRD (n=5), and 10/10 or 9/10 HLA-MUD (12 & 4 respectively) recipients. Graft source was either peripheral blood (19) or bone marrow (2). Median age was 56 years; males (11). All patients enrolled were deficient in AA at day 0, median 0.3 mg/dL (range: 0.1-0.5), day 14, post AA infusion level was normal at 1.6 (1.2-5.7). Neutrophil recovery was by 11 days (9-15 days) and platelets by 12 (9-19) with sustained donor engraftment. Median absolute CD3+ cell count at day 30 was 390/mL (55-2288) with 100% donor chimerism. Pro-inflammatory cytokines IL-1b, IL-2, IL-6, IL-12, TNF-α, IFN-γ, as well as soluble thrombomodulin remained unchanged between day 0 and day 14 & day 30 after HCT (P=NS for all comparisons Figure 1). At a median follow up of 201 days (13-335) there is a 95% survival observed (Figure 2). There was no VOD and no attributable grade 3 and 4 toxicities to AA. Mucositis was mild and TPN was required in only 43% of patients. The cumulative incidences of grades II–IV and grades III–IV acute GVHD were 33% and 9% respectively, and moderate chronic GVHD 21%. No severe cGVHD has been observed, only one relapse has occurred. Conclusions: In patients undergoing myeloablative allogeneic HCT the administration of IV ascorbic acid is safe and does not negatively impact myeloid engraftment or immune reconstitution. Pro-inflammatory cytokines and endothelial injury markers remain around baseline levels, with no VOD and low rates of GVHD observed. IV AA requires further investigation in HCT given its safety, and low cost (∼$450 for 14 day infusion in a 80 KG recipient) and potential for worldwide use.

Hematopoietic cell transplantation (HCT) conditioned using myeloablative conditioning (MAC) is complicated by end organ injury due to endothelial dysfunction and graft versus host disease. Mucositis and oxidant injury results in micronutrient deficiency. Ascorbic acid (AA) levels were measured in 15 patients undergoing HCT conditioned with MAC (11 allogeneic and four autologous HCT). Ascorbate levels declined postconditioning to 27.3 μMol/L (±14.1) by day 0 (P = .03 compared with pretransplant baseline), reaching a nadir level of 21.5 (±13.8) on day 14 (P = .003) post-transplant. Patients undergoing allogeneic HCT continued to have low AA levels to day 60 post-transplant. The role of AA in maintaining endothelial function and hematopoietic as well as T-cell recovery is provided, developing the rationale for repletion of vitamin C following HCT.

Hematopoietic cell transplantation (HCT) conditioned using myeloablative conditioning (MAC) is complicated by end organ injury due to endothelial dysfunction and graft versus host disease. Mucositis and oxidant injury results in micronutrient deficiency. Ascorbic acid (AA) levels were measured in 15 patients undergoing HCT conditioned with MAC (11 allogeneic and 4 autologous HCT). Ascorbate levels declined post conditioning to 27.3 (±14.1) by day 0 (p

Treatment of acute fibrinous organizing pneumonia following hematopoietic cell transplantation with etanercept

Clinical outcomes following hematopoietic cell transplant (HCT) are considered stochastic with different outcomes despite uniformity in characteristics between patients. However, immune reconstitution following SCT has features of a dynamical system, making it likely that clinical outcomes are partially deterministic. We hypothesized that early cessation of mycophenolate mofetil (MMF) in reduced intensity conditioning (RIC) transplants will hasten T cell reconstitution without adversely impacting clinical outcomes. This idea is being tested in a randomized phase 2 clinical trial comparing GVHD prophylaxis using a regimen of tacrolimus & MMF 15 mg/kg q 12 h for 30 days in the control (MMF30) vs. 15 days in the study cohort (MMF15). The MMF15 patients received GM-CSF to promote early monocyte recovery; MMF 30 got G-CSF. All patients underwent reduced intensity conditioning with ATG 1.7 mg/kg/d given on days -9 thru -7 & 450 cGy total body irradiation on d-1 & 0. Patients were stratified based on diagnosis and donor type (8/8 or 7/8 HLA MRD or MUD). A response-adaptive randomization scheme was used to increase the probability that patients were allocated to the treatment regimen which yields superior donor-derived CD3+ (ddCD3) cell count by 8 weeks; primary endpoint is relapse free, DLI free survival. Preliminary results from the first 21 evaluable patients are presented. Patients baseline characteristics are summarized in table 1. Mean ddCD3 count at 8 weeks post HCT favored the MMF group (461 vs. 329), which led to more patients allocated to MMF15 cohort. Median myeloid engraftment at day 60 was 100% in both cohorts. Mean absolute lymphocyte count, CD3+ and CD4+ T-cell counts were higher in the MMF15 cohort on day 30 (500 vs 200/mL−1, P=0.005; 254 vs. 71/mL−1, P=0.0188; 107 vs. 25/mL−1, P=0.0036 respectively). There was a trend for higher ddCD3 cell count in the MMF15 cohort (Fig. 1). Despite this there were no significant differences noted on in lymphoid recovery at later time points. Despite a shorter course of MMF there was no significant difference in the rates of acute and chronic GVHD, relapse and patient survival between the two cohorts (Fig 2). In conclusion these early data demonstrate that a shorter 15-day course of MMF plus GM-CSF led to rapid, early T cell reconstitution post HCT without a significant increase in the risk of acute or chronic GVHD, or disease relapse. This effect is consistent with immune reconstitution post HCT being a dynamical rather than a stochastic process, which may be modified in real-time by adjustments in the intensity of GVHD prophylaxis.

Introduction Melphalan 200 mg/m2 on day -2 (Mel 200) is the standard conditioning regimen in autologous stem cell transplant (ASCT) for multiple myeloma (MM). This regimen is associated with significant gastrointestinal (GI) toxicity, including diarrhea, vomiting, and mucositis; therefore the dose may be reduced to 100-140 mg/m2 based on performance status or age. As the true difference in GI toxicity in older vs. younger patients is unknown, dose reductions may unnecessarily compromise efficacy outcomes. The objective of this study was to define the incidence of GI toxicity in patients age ≥ 60 vs. patients age Objectives Review dose adjustments for melphalan conditioning prior to ASCT in MM. Identify toxicities associated with melphalan conditioning for ASCT in MM. Compare melphalan toxicity between patients age ≥ 60 vs. patients age Methods A retrospective cohort study was conducted via medical record review of adult patients treated with Mel 200 followed by first ASCT for MM from September 2012 to September 2017. The primary endpoint was incidence of GI toxicity, defined by Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher diarrhea or grade 3 or higher mucositis during transplant admission. Secondary endpoints included subdivided primary endpoints, complete response rates, and measurements of recovery. Subgroup analyses were performed for patients age ≥ 65, and patients with renal impairment. Results A total of 167 patients were included, with 116 patients in the age Conclusion This single-center, retrospective medical record review demonstrated that patients older than age 60, particularly those 60 to 65 years of age, may receive Mel 200 with no difference in the incidence of GI toxicity compared to younger patients. Further study in a larger population of patients age 65 or older is needed to establish conclusions in this patient population.

BH3 mimetic drugs induce cell death by antagonizing the activity of antiapoptotic Bcl-2 family proteins. Cyclin-dependent kinase (CDK) inhibitors that function as transcriptional repressors downregulate the Bcl-2 family member Mcl-1 and increase the activity of selective BH3 mimetics that fail to target this protein. In this study, we determined whether CDK inhibitors potentiate the activity of pan-BH3 mimetics directly neutralizing Mcl-1. Specifically, we evaluated interactions between the prototypical pan-CDK inhibitor flavopiridol and the pan-BH3 mimetic obatoclax in multiple myeloma (MM) cells in which Mcl-1 is critical for survival. Coadministration of flavopiridol and obatoclax synergistically triggered apoptosis in both drug-naïve and drug-resistant MM cells. Mechanistic investigations revealed that flavopiridol inhibited Mcl-1 transcription but increased transcription of Bim and its binding to Bcl-2/Bcl-xL. Obatoclax prevented Mcl-1 recovery and caused release of Bim from Bcl-2/Bcl-xL and Mcl-1, accompanied by activation of Bax/Bak. Whether administered singly or in combination with obatoclax, flavopiridol also induced upregulation of multiple BH3-only proteins, including BimEL, BimL, Noxa, and Bik/NBK. Notably, short hairpin RNA knockdown of Bim or Noxa abrogated lethality triggered by the flavopiridol/obatoclax combination in vitro and in vivo. Together, our findings show that CDK inhibition potentiates pan-BH3 mimetic activity through a cooperative mechanism involving upregulation of BH3-only proteins with coordinate downregulation of their antiapoptotic counterparts. These findings have immediate implications for the clinical trial design of BH3 mimetic-based therapies that are presently being studied intensively for the treatment of diverse hematopoietic malignancies, including lethal multiple myeloma. Cancer Res; 72(16); 4225–37. ©2012 AACR.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anticancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction.A number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down-regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising.In general, the antitumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad-spectrum CDK inhibition will likely be required for most cancers.

Developing the optimal models for pretransplant assessment as more reduced intensity conditioning regimens are implemented and the higher median age of transplant. The pre-transplant assessment of mortality (PAM) assesses all cause mortality at 2 years and the Hematopoietic Stem cell Transplantation specific comorbidity index (HCT-CI) which previously used Charlson comorbidity index (CCI) to assessed NRM based on history and organ function. Previous studies have shown that certain biomarkers such as ferritin and albumin may help optimize risk assessment before transplant. We tested the validity of PAM, HCT-CI, serum ferritin and albumin to predict GVHD, relapse and overall survival (OS) in our older patient population. IRB approval was obtained to retrospectively review clinical outcomes in patients undergoing allogeneic stem cell transplantation at our institution between, 2010 - 2013. We examined a total of 94 patients with myeloid malignancies (see Table 1 for patient characteristics). Risk variables assessed included calculated PAM, HCT-CI and KPS scores and pre HCT serum ferritin and albumin levels. We examined the predictive value of these biomarkers with respect to GVHD, relapse, and overall survival. Of the 94 patients 46% are alive and in remission, 20% have relapse and GVHD developed in 56% of patients. To determine the optimal cutoff for classifying into high and low groups for each risk measure, first the association between the measure and clinical outcomes was determined to obtain the logistic regression. Then area under the curve (AUC) of the receiver operating characteristic (ROC) curve for each clinical outcome against the risk measure was calculated. The cutoff that maximized the sum of the ROC-AUC across all measured was selected. Patients with HCT-CI > 4, (cut off 4), had a less likelihood of survival than those with HCT < 4 OR 4.3 (95% CI: 1.6-11.2) (p=.0033). Similarly, patients with low albumin, (cutoff 4.1), were less likely to than those with high albumin survive OR 0.4 (95% CI: 0.2-0.9) (p=0.02). Patients in the high ferritin group, (cut off 2425) were less likely to survive than those with low ferritin OR 4.0 (95% CI:1.3-2.3) (p=0.016). The high HCT-CI group, (cut off 4) was more likely to relapse than lower HCT-CI OR 2.9, (95% CI: 1.1-8.1) (p=0.04) and patients with a high KPS, (cutoff 81), were less likely to relapse than lower KPS OR 0.3 (95% CI: 0.1-0.8) (p=0.22). In the high ferritin group, (cutoff 2020) patients were more likely to have GVHD than low ferritin group OR 0.2 (95% CI: 0.1-0.7) (p=0.005). (Table 2) We conclude that HCT-CI was more predictive of mortality than the PAM score in our cohort or patients with median age 65 years old. Our results are concordant with previously reported data showing serum ferritin and albumin is useful biomarkers to predict GVHD, relapse and survival. We are now incorporating objective markers such as ferritin, albumin, and other functional assessments to objectively quantify risk in our current patients presenting for allogeneic HSCT. | | All Patients (N = 94) | | ---------------------------------------------------------------------------------- | --------------------- | | | N (%) | | Patient Age | | | < 50 | 33 (35) | | 50-59 | 35 (37) | | 60-70 | 26 (28) | | Race | | | Caucasian | 76 (81) | | African American | 14 (15) | | Other | 4 (4) | | Donor | | | Related | 40 (43) | | Unrelated | 54 (57) | | HLA Mismatch | | | No | 71 (76) | | Yes | 10 (11) | | Missing | 13 | | Stem Cell Source | | | BM | 5 (5) | | PBSC | 89 (95) | | Conditioning | | | Myeloablative | 47 (50) | | Reduced Intensity | 47 (50) | | ATG | | | No | 13 (14) | | Yes | 81 (86) | | Patient CMV Sero status | | | Negative | 41 (44) | | Positive | 48 (51) | | Missing | 5 | | KPS | | | < 90 | 17 (18) | | 90-100 | 77 (82) | | BM indicates bone marrow; PBSC, peripheral blood stem cells; CMV, cytomegalovirus. | Table 1. Patient Characteristics | Biomarkers | GVHD | Relapse | Survival | | ---------- | ------- | ------- | -------- | ------- | | Cut-off | p-value | Cut-off | p-value | Cut-off | p-value | | PAM | 24 | 0.1222 | 24 | 0.4911 | 21 | 0.2077 | | HCT-CCI | 2 | 03308 | 4 | 0.0495 | 4 | 0.0033 | | Ferritin | 2020 | 0.0054 | 1070 | 0.3818 | 2425 | 0.0164 | | KPS | 81 | 0.1679 | 81 | 0.0226 | 91 | 0.1289 | | Albumin | 4.2 | 0.1103 | 4.2 | 0.2750 | 4.1 | 0.0220 | Table 2. Biomarkers and Clinical Outcomes Disclosures No relevant conflicts of interest to declare.