High LDH Levels Research Articles

OAB-056: A machine learning model based on tumor and immune biomarkers to predict undetectable measurable residual disease (MRD) in transplant-eligible multiple myeloma (MM)

<h3>Background</h3> There is expectation of using biomarkers to personalize treatment. Yet, a successful treatment selection cannot be confirmed before 5 or 10 years of progression-free survival (PFS). Treatment individualization based on the probability of an individual patient to achieve undetectable MRD with a singular regimen, could represent a new model towards personalized treatment with fast assessment of its success. This idea has not been investigated previously. <h3>Methods</h3> We sought to define a machine learning model to predict undetectable MRD in newly-diagnosed transplant-eligible MM patients (n=278). The training (n=152) and internal validation cohort (n=60) consisted of 212 active MM patients enrolled in the GEM2012MENOS65 clinical trial. The external validation cohort was defined by 66 high-risk smoldering MM patients enrolled in the GEM-CESAR clinical trial, which treatment differed only by the substitution of bortezomib by carfilzomib during induction and consolidation. Patients were included in the study based on data availability of 17 parameters (p≤.05) associated with MRD outcomes. <h3>Results</h3> We started by investigating patients' MRD status after VRD induction, HDT/ASCT and VRD consolidation (GEM2012MENOS65) according to their ISS and Revised-ISS, LDH levels, and cytogenetic alterations. High LDH levels and del(17p13), two features relatively infrequent at diagnosis, were the only parameters associated with lower rates of undetectable MRD. The ISS and R-ISS were not predictive. Therefore, we aimed to evaluate other disease features associated with MRD outcomes and develop more effective models based on machine learning logistic regression. The most effective one resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (plasma cell clonality in bone marrow and circulating tumor cells in peripheral blood) and immune related (myeloid precursors, mature B cells, intermediate neutrophils, eosinophils, CD27negCD38pos T cells and CD56brightCD27neg NK cells) biomarkers. Data obtained for an individual patient can be substituted into our formula, which results in a numerical probability of achieving undetectable (>0.5) vs persistent (0.685 or <0.365 (observed in 102/212 patients), MRD outcomes are respectively predicted with higher confidence. Standard-confidence, high-confidence, and external validation predictions were accurate in 152/212 (71.7%), 85/102 (83.3%), and 48/66 (72.7%) patients respectively. Patients predicted to achieve undetectable MRD using standard and high-confidence values showed longer PFS and OS than those with probability of persistent MRD. <h3>Conclusions</h3> We demonstrated that selecting a regimen based on probable MRD outcomes, and confirming soon after if that probability was accurate, is a possible new approach towards individualized treatment in MM. The model is available at www.MRDpredictor.com to facilitate its use in clinical practice.

MM-301: Plasma Cell Leukemia, PCL

Context PCL is a rare entity and a very aggressive disease. The diagnosis is based on the presence of more than 20% of PCL in peripheral blood or an absolute plasma cell count of more than 20×109. It is classified as primary PCL when it occurs in a patient with no previous history of MM and as a secondary PCL when it is observed as the leukemic transformation of relapsed or refractory recognized MM. Objective Diagnostic challenges and treatment of PCL. Case Report A 34-year-old female was accepted in clinic in 2019. She has spleen: 161 mm; liver: 148 mm. High levels of beta-2M and LDH. More than 30% of plasma cells in peripheral blood. Severe anemia, leukocytosis, and thrombocytopenia. Flow cytometry showed clonality for plasma cells. Results We treated our patient with VTD-PACE regimen (a combination of bortezomib 1 mg/m2, s.c, D1, D5, D8, and D11; dexamethasone 40 mg D1–D4 i.v.; thalidomide 200 mg/d, D7–D28, p.o.; cisplatin 10 mg/m2 D1–D4, i.v.; adriamycin 10 mg/m2 D1–D4,i.v.; cyclophosphamide 400 mg/m2 D1–D4, and etoposide 40 mg/m2 D1–D4, i.v.). We recommended HSCT, and she went abroad because this procedure cannot be performed in our country yet. Conclusions PCL is a rare entity, very aggressive, with a poor prognosis. Early diagnosis and early treatment are very important prognostic factors. Treatment with immunomodulatory drugs such as bortezomib-based regimens, followed by stem cell transplant, is recommended. References Harousseau JL, Atal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in phase II clinical trial. Leukemia. 2009;23:1337-1341. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma; changes in early mortality and outcomes in older patients. Leukemia. 2013;28(5):1122-1128.

UBE2D3 contributes to myocardial ischemia-reperfusion injury by regulating autophagy in dependence of p62/SQSTM1

The impairment of autophagic flux has been widely recognized in myocardial ischemia-reperfusion (I/R) injury, but its underlying mechanism contributing to impaired autophagic flux is poorly understood. As celluar major degradation systems, autophagy and ubiquitin proteasome system (UPS) participate in the multitudinous progression of disease by interactive relationship. Especially UBE2D3, one of the ubiquitin-binding enzyme E2 family, is closely related to the regulation impairment of autophagic flux under I/R in our study. Therefore, this study aims to further explore the regulatory mechanism of UBE2D3 in I/R induced autophagy. We determined interference with UBE2D3 alleviated injury of myocardial cells both in vivo and in vitro. Conversely, when inhibiting proteasome function by injecting MG-132, myocardial infarct size of rats became increasingly enhanced, along with the high expression levels of LDH and CK-MB in serum, compared with myocardial I/R injury without treatment of MG-132. This had been caused by UBE2D3 promoting p62/SQSTM1(p62) ubiquitination(Ub), which lead to worsen the impairment of autophagic flux induced by myocardial I/R injury. In addition, UBE2D3 could also participate in the regulation of autophagy by negatively regulating mTOR. But more surprisingly, this mechanism was independent of the known mTOR-beclin1 pathway. These results suggested that in myocardial I/R injury, UBE2D3 promoted p62 ubiquitination to aggravate the impairment of autophagic flux. Moreover, mTOR was also involved in its regulation of autophagic flux in a way escaped from beclin1.

Role of 23.4Gy upfront whole-brain radiation therapy following high-dose methotrexate for primary central nervous system lymphoma: a comparative analysis of whole-brain radiation therapy versus no radiation therapy.

We aimed to investigate the role of upfront whole-brain radiation therapy (RT), with a reduced dose of 23.4Gy, following high-dose methotrexate (HD-MTX) in patients with primary central nervous system lymphoma (PCNSL). We retrospectively reviewed 185 patients with PCNSL treated with HD-MTX between January 2013 and January 2020; 145 patients underwent no RT and 40 patients underwent upfront RT. Using propensity score matching (PSM) to adjust for clinical factors, 40 patients were selected from each treatment group. Event-free survival (EFS) and overall survival (OS) were compared between treatment groups. At baseline, patients in the upfront RT group were younger, had higher LDH levels, received less frequent rituximab and stem cell transplantation than those in the no-RT group. Patients in the upfront RT group also showed a lower response rate after initial HD-MTX than those in the no-RT group (73% vs. 88%, p = 0.038). The median follow-up was 25.1 (interquartile range 13.7-43.0) months. Comparable 2-year EFS and OS rates were observed between the upfront RT and no-RT groups (56.6% vs. 53.8%, p = 0.170; and 81.7% vs. 75.3%, p = 0.097, respectively). Upfront RT was related to improved EFS and OS in patients with stable disease or progressive disease after HD-MTX, but not in patients with complete or partial response after HD-MTX. Upfront RT was also an independent predictor of EFS and OS in the PSM cohort. The cumulative incidences of treatment-related neurotoxicity at 3years were 20.2% and 21.2% in the upfront RT and no-RT groups, respectively (p = 0.630). Upfront RT with a reduced dose of 23.4Gy, showed favorable outcomes in patients with stable disease or progressive disease after initial HD-MTX. In addition, upfront RT appears to be an effective treatment for PCNSL when rituximab or stem cell transplantation is not feasible.

Transferability Of Results From Randomized Trials To Clinical Practice: The Case Of Diffuse Large B Cell Lymphoma Patients Treated With R-CHOP When Comorbidities Are Present

BackgroundImmuno-chemotherapy with Rituximab and CHOP (R-CHOP) represents the standard of care for Diffuse Large B Cell Lymphoma DLBCL patients of any age. The clinical outcome of patients treated by this program has been reproducibly confirmed by many independent randomized clinical trials that recruited patients on the basis of restrictive inclusion/exclusion criteria. Few information is available about the short and long term outcome of patients who, in the daily clinical practice, are treated by R-CHOP despite the presence of one or more co-morbidities that should have been considered as exclusion criteria for the aforementioned clinical trials. AimTo evaluate the response rate, the early death as well as overall survival of DLBCL patients who received a front-line R-CHOP or R-CHOP/like programs despite the presence at diagnosis of one or more severe comorbidities. PatientsFrom April 2000 to March 2013 we evaluated 473 consecutive and unselected DLBCL homogeneously treated at our institution with R-CHOP or R-CHOP/like as first line treatment. These patients were males in 53%, had a median age of 64 years (range 18 -89), clinical stage III-IV in 54%, B symptoms in 31%, bone marrow involvement in 14%, Bulky disease (> 7 cm) in 34%, Extranodal presentation (>1 site) in 30%, ECOG (>2) in 25%, a high LDH level in 48% and high IPI (>2) in 42%. For the present analysis, patients were divided in group A (n=257) and B (n=216) according to whether they met or not clinical trial enrollment criteria respectively (as reported by Cunningham et al, Lancet 2013). Reasons for not meeting these criteria were the following organ dysfunctions: cardiovascular (75%), liver (35%), lung (14 %) and renal (5%) or the presence of a positive serology for HCV, HBV and HIV that were detected in 73%, 38% of and 10% of these patients, respectively. Of note, 41 patients (8%) had a previous solid tumor. Overall 63% of patients had only one comorbidity, 30% more than two and 6% more than three. ResultsGender and patients with bulky disease were equally distributed between group A and B. However, patients belonging to group A were younger (58 vs 70, p=0.0001), had a less advanced stage disease (stage III and IV 46% vs 54, p= 0,001), fewer B symptoms (45% vs 55%, p= 0,024), less BM infiltration (34% vs 65%, p= 0,002), less extranodal involvement (42% vs 57%, p= 0,004) and showed a better performance status (ECOG >2 41% vs 59%, p= 0,005), a lower proportion of cases with high LDH level (46% vs 54%, p= 0,002) and a better IPI (IPI >2, 40% vs 60%, p= 0,000). After 6 chemotherapy cycles, the response rate was slightly lower in group B (82% vs 89%, p=ns). The proportion of early deaths (events registered within 6 months from start of chemotherapy), was lower in group A (7/257, 2.7%) as compared to group B (22/216, 10.2%, p=0.001), independently of age (> or<60 year). Of note, the early death rate in group A reproduced that seen in several randomized clinical trials. Main reasons of early death were: bacterial infections, acute liver failure, myocardial infarction and progressive disease. The median time to early death was 1.8 months in group A as compared to 2.35 in group B (p= ns), respectively. By multivariate logistic regression analysis, corrected by age, IPI and bone marrow positivity, the presence of B symptoms (OR 3.32, 95% CI 1.23-9.01, p= 0.018) and the presence of any comorbidity (OR 3.13, 95% CI 1.07-9.14, p= 0.037) proved as strongly independent predictors of early deaths. The 2 year probability of overall survival was 87% and 72% (p= 0.0001) in group A and B, respectively (Figure 1). B symptoms, and the presence of any comorbidity and IPI >2 were also significantly affecting the long term overall survival (B symptoms, HR 1.59, 95% CI 1.04-2.43; any comorbidity, HR 1.71, 95% CI 1.12-2.61; IPI >2, HR 2.38, 95% CI 1.48-3.82). Based on this analysis, we finally identified three risk categories: low (no B symptoms, no comorbidity and no high IPI), intermediate (presence of either B symptoms or any comorbidity or high IPI) and high (co-presence of B symptoms, any comorbidity and High IPI) that were associated to a significantly different 2 year survival of 93%, 81% and 48% (p= 0.0000), respectively. ConclusionsThe clinical outcome of a large proportion of DLBCL patients treated in the daily clinical practice is negatively affected by comorbidities. This should be considered when analyzing transferability of results from randomized clinical trials into clinical practice. [Display omitted] Disclosures:Rambaldi:Roche, SpA, Italy: Consultancy, Honoraria.

High lactate dehydrogenase at time of admission for allogeneic hematopoietic transplantation associates to poor survival in acute myeloid leukemia and non-Hodgkin lymphoma.

Risk stratification is important for balancing potential risks and benefits of allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. We retrospectively studied 1119 patients undergoing allogenic-HSCT in a single center for five hematological indications assessing the prognostic role of LDH at admission for survival (OS), progression-free survival (PFS), relapse incidence (RI), and nonrelapse mortality (NRM). In non-Hodgkin lymphoma (NHL) and acute myeloid leukemia (AML), higher than median LDH had an adverse effect on survival. The prognostic significance was strongest in AML, with higher LDH levels having lower 1-and 3-year survival 69.2% vs. 50.8%, P < 0.001 and 51.9% vs. 39.2%, P < 0.001, respectively, reduced 1-and 3-year PFS 62.4% vs. 42.1%, P < 0.001 48% vs. 35.2%, P < 0.001, respectively, higher cumulative incidence of 1-and 3-year NRM 11% vs. 17.3%, p = 0.01 and 15.7% vs. 19.6%, P = 0.04, and higher 1-and 3-year relapse incidence (RI) 26.7% vs. 40.7%, p < .0001 36.2% vs. 40.7%, respectively, P < 0.0001). In multivariate analysis LDH maintained significant prognostic capacity in OS, PFS and RI. These findings in AML, validated in an independent cohort, suggest that LDH is a readily available tool that could be integrated into transplant risk assessments to aid decision-making and identify high-risk patients who may benefit from post-transplant pharmacological or cellular strategies.

Diffuse peritoneal lymphomatosis or abdominal tuberculosis: a clinico-radiological conundrum

Primary extra nodal lymphoma occurs in approximately 25% to 40% of patients and is more common in patients with NHL. Diffuse large B-cell lymphoma (DLBCL) is the dominant histological subtype. A 60-year-old gentleman presented to our hospital with pain abdomen associated with abdominal distension since a month, few constitutional symptoms with bilateral axillary and inguinal lymphadenopathy. Blood investigations showed high total count with significantly high LDH levels. Provisional diagnosis of tubercular Abdomen/Malignant Ascites with Unknown primary was made. CT Abdomen showed large bowel wall thickening with parietal peritoneal lesions with omental cake. Excision biopsy of inguinal lymph node showed lymphoid follicles with poorly defined attenuated mantle zones having centrocytes and centroblasts. Immunohistochemistry was positive for markers, which confirmed the diagnosis of Stage 4B DLBCL, germinal center B-cell type. Sepsis and acute kidney injury occurred and the patient expired, 6 days after diagnosis. To conclude, Peritoneal lymphomatosis is an extremely rare condition. This case highlights the need to have a high index of suspicion for malignancy, when a given case is clinically diagnosed with tuberculosis as and when new findings appear during investigation.

Efficacy and safety of anti-PD-1 inhibitor combined with nab-paclitaxel in Chinese patients with refractory melanoma.

This retrospective study aimed to evaluate the combined effect of anti-PD-1 inhibitor and nanoparticle albumin-bound (nab)-paclitaxel for refractory melanoma among Chinese patients. Data from January 2018 to March 2021 were retrospectively collected and analyzed. Sixty-four patients were eligible for analysis from a single Chinese cancer center. The median follow-up was 16.0months at data cutoff. The objective response rate (ORR) was 29.7%, and the disease control rate (DCR) was 67.2% in all patients. Treatment-naïve patients had significantly higher ORR than pretreated patients (42.9% vs 13.8%, p = 0.011). Cutaneous melanoma patients with NRAS gene mutation benefited more than non-mutated patients (DCR of 100% vs. 54.5%) (p = 0.030). The median progression-free survival (mPFS) of all patients was 5.2months and the duration of response was 10.8months. Median duration of disease control was 7.7months. Prior treatment-naïve patients had significantly longer PFS than those who accepted prior treatments (7.2 vs. 5.1months, p = 0.024). Patients with abnormally high LDH level had shorter mPFS (3.6months vs. 6.6months, p = 0.020). Median overall survival was not reached in this study. Most patients experienced adverse events (AEs), but only 17.2% of patients experienced grade 3 severe AEs. The most common AEs were alopecia (89.1%), neutropenia (18.8%), pruritus (15.6%), and arthralgia (14.1%). Some patients had immune related AEs (irAEs). No grade 4 or 5 AEs were observed. Patients with ≥ 3 AEs or with irAEs had longer mPFS (p < 0.05). Nab-paclitaxel combined with PD-1 antibody is a well-tolerated and effective regimen for Chinese patients with refractory melanoma.

A Prospective Registry Study of Peg-G-CSF Prophylaxis for Patients with Diffuse Large B-Cell Lymphoma (CISL 1403)

BackgroundFebrile neutropenia (FN) is the most important side effect of chemotherapy in diffuse large B cell lymphoma (DLBCL) causing not only treatment-related morbidity but also suboptimal chemotherapy delivery. Prophylactic use of granulocyte colony stimulating factor (G-CSF) or pegylated G-CSF (PEG-G-CSF) is known to reduce the incidence of both neutropenia and FN. We conducted a prospective registry study to evaluate prophylactic effect of PEG-G-CSF in DLBCL patients treated with R-CHOP regimen (ClinicalTrials.gov Identifier: NCT02474550).Patients and MethodSince January 1st 2015, after written informed consent, patients receiving R-CHOP therapy with curative intent were registered and prospectively monitored. All patients were pathologically confirmed with DLBCL according to World Health Organization Classification 2008. Prophylactic Peg-G-CSF was given 24 hours after R-CHOP chemotherapy subcutaneously. The incidence of neutropenia and neutropenic fever were studied. Febrile neutropenia (FN) is defined as an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2h and an absolute neutrophil count <0.5 × 109/l, or expected to fall below 0.5 × 109/l. This interim-analysis was performed as of 1st June 2017.ResultsA total of 2957 cycles in 694 patients were included in the analysis. Base-line characteristics are summarized in Table 1. Median age at diagnosis was 62 (10-86) with a predominance of males (67%). Most patients had extranodal involvement (90.7%) and 257 patients (37%) had two or more extra-nodal involvements. The most common extranodal involvement sites were stomach (16.6%), bone (11.7%), intestine (11.4%) and lung (8.8%). Bone marrow involvement was observed in 281 patients (40.5%). At the time of analysis 407 (58.6%) patients completed 6 cycles of R-CHOP therapy. Forty-three patients (6%) experienced primary failure with R-CHOP treatment. Treatment related mortality occurred in 41 patients (5.9%). Grade III/IV neutropenia was developed with the incidence of 13.6% (402/2957 cycles) in the patients. FN developed in 74 (10.7%) patients with the overall incidence of 4.2% (124/2957) in the cycles (Table 2.). Twenty-five patients (33.7%) had multiple episodes of FN. Most patients (78.9%) experienced the first episode of FN within three cycles. Among pretreatment clinical factors analyzed, age, ECOG performance status and LDH level were related with the development of FN (Table 3.). Vitamin D deficiency at diagnosis was observed in 74.6% (347/501) of the patients but not associated with the development of FN. Deranged Light chain level is detected in 23.3% (112/479) of the patients, but not associated with the development of FN as well.ConclusionThis interim analysis showed clinical feature of FN with PEG-G-CSF prophylaxis in DLBCL patients. Peg-G-CSF prophylaxis was effective in reducing the incidence of neutropenia and FN. However, the patients who were elderly, with poor performance status or high LDH level still had high incidence of FN. We will further study whether this result could be translated into better treatment outcomes in the patients. [Display omitted] DisclosuresKim:Celltrion, Inc: Consultancy, Honoraria; Takeda: Research Funding; Kyowa-Kirin: Research Funding; J&J: Research Funding; Novartis: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Roche: Research Funding.

Prognostic Factors and Survival Outcomes in Blast Transformed Chronic Myelomonocytic Leukemia: A Mayo Clinic-MD Anderson Cancer Center Study of 171 Cases

Background:Blast transformed (BT) chronic myelomonocytic leukemia (CMML); defined by ≥20% blood or bone marrow (BM) blasts, occurs in 15-30% of patients and is a major cause of mortality. Reported risk factors include high risk karyotype, circulating blast count, circulating immature myeloid cells (IMC), CMML morphological subtype, and the presence of ASXL1 mutations. In the current study, we reviewed consecutive cases of BT CMML from the Mayo Clinic, MN, and the MD Anderson Cancer Center, Texas, USA, with the intent to examine i) prognostic factors, ii) survival trends, and iii) treatment outcomes.Methods:Diagnoses of CMML and BT-CMML were according to the 2016 WHO criteria. Treatment response in BT-CMML patients was assessed according to standard AML response criteria. Statistical analyses considered clinical and laboratory data collected at the time of BT. Survival was calculated from the date of BT to the date of death or last contact.Results:171 cases of BT CMML were identified from the Mayo Clinic (n=84) and MDACC (n=87). The median age at BT was 69 years and 64% were male. Eight one (49%) had received prior hypomethylating agent (HMA) therapy (Decitabine 50, 5-azacitidine 31), with 30% having achieved a complete remission (CR) prior to BT. CMML patients that received prior HMA therapy were more likely to have thrombocytopenia (p=0.03), higher LDH levels (p=0.007), lower frequency of TET2 mutations (p=0.04) and higher risk stratification by the Mayo prognostic model (p=0.009). The two institutional cohorts were comparable with regards to variables, both at CMML diagnosis and BT.Patient characteristics at time of BT: The median time from CMML diagnosis to BT was 12 months (range, 1-36). At BT, 16 (10%) presented with extramedullary disease, 81 (63%) with an abnormal karyotype, 41 (34%) with cytogenetic clonal evolution, with the following mutational distribution; TET2 50%, ASXL1 39%, NRAS 39%, FLT3 ITD 20%, NPM1 6%, RUNX1 6%, and 5% each for IDH1/2, EZH2 and JAK2 . Molecular clonal evolution was seen in 4 (22%) of 18 evaluable cases.Survival trends: After a median follow-up of 4.4 months (range 0-122), 141 (82%) deaths were recorded. Median overall survival (OS) was 6 months with 1- and 3-year survival rates of 25% and 9%, respectively; survival trends were similar (p=0.4) for patients diagnosed prior to and after the year 2006 (figure 1A).Treatment and response rates: Specific treatment for BT-CMML was documented in 157 cases and included induction chemotherapy (n=61), induction chemotherapy followed by stem cell transplant (HCT, n=18), HCT alone (n=3), HMA (n=18), novel therapeutic agents (n=18), and best supportive care (BSC, n=39). Treatment response was assessable in 113, including 76 treated with induction chemotherapy, 18 with HMA and 16 with novel therapeutics; with respective CR rates of 24%, 0% and 41%; with an additional 24%, 16% and 16% of patients achieving CR with incomplete blood count recovery (CRi), with a survival similar to those with CR (figure 1B). HCT was reported in 25 patients, 17 myeloablative and 8 reduced intensity, with a median OS of 7 months.Predictors of survival in BT-CMML: In univariate analysis of variables recorded at time of BT, risk factors adversely impacting survival included older age, lower hemoglobin, PB blast %, adverse cytogenetics at BT, prior exposure to HMA, not receiving induction chemotherapy, not achieving CR or CRi and not receiving HCT; all of these risk factors remained significant when analysis was adjusted for age. In multivariable analysis, lack of prior HMA exposure (p=0.001, HR 5.1; 95% CI 1.9-14.1) and the achievement of CR/CRi (p=0.02, HR 1.4; 95% CI 1.2-3.4) remained significant while HCT lost its significance (p=0.09). Gene mutations, including FLT3 ITD, cytogenetic and molecular clonal evolution at the time of BT did not impact survival. The 3-year survival rates for BT patients receiving induction chemotherapy, induction chemotherapy followed by HCT, HMA, novel agents and BSC were 8%, 20%, 12%, 3% and 0% respectively (figure 1C).Conclusions: Survival in patients with BT- CMML is dismal (≈6 months) and is adversely impacted by prior exposure to HMA and by the failure to achieve CR/CRi. After BT, the use of HMA therapy is largely ineffective (0% CR), with intensive therapies such as induction chemotherapy with or without HCT, failing to achieve durable remissions. [Display omitted] DisclosuresJabbour:Amgen: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Takeda Oncology: Research Funding. Kantarjian:Amgen: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding.

Mycobacterium Tuberculosis infection in Patients with Hematologic Malignancies in an Endemic Setting: An Initial Analysis

Introduction: Patients with hematologic malignancies (HM) are at high risk for developing concomitant infections given their immunosuppression. Tuberculosis (TB) is a worldwide public health issue which affects developing countries most severely, and within them, patients with decreased immunity are most vulnerable. There are few studies examining the clinical factors associated with development of TB and survival, this is especially true in high-endemic developing countries where previous analysis have considered both microbiologically confirmed and suspected TB.Objective: Our primary objective was to examining clinical and pathologic factors associated with development of clinically active TB in a cohort of patients with HM and microbiologically confirmed TB. A secondary objective was to analyze factors associated with survivalMethods: This single-center retrospective cohort study included 46 adult patients with HM (Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia) and subsequent development of clinically active TB with microbiological confirmation (either through Acid Fast Bacilli stain or culture) at Instituto Nacional de Enfermedades Neoplasicas (INEN) a tertiary cancer center in Peru between January 2006 and September 2015. Patients were divided into two groups based on their HM diagnosis: Lymphomatous (n=32, 69.6%) and Leukemic/myeloma (n=14, 30.4%). Medical records were reviewed, including demographic data, pertinent laboratory data, Charlson Comorbidity Index (CCI), history of previous TB or contact with TB patients, ECOG, viral co-infections, treatment modality and response. Data was analyzed using T-Test and chi-square test, survival curves were estimated by Kaplan-Meier and comparison was done by log-rank test. Multivariate analysis for survival was performed with Cox proportional hazard regression.Results: Over the 10-year period we identified 46 adult patients with HM who subsequently developed culture confirmed TB during the observation period. Lymphomatous (L) and Leukemic/Myeloma (LM) subjects had a mean age of 57.03 and 40.93 respectively (p=0.009). LM patients had lower Hemoglobin (8.75 vs 11.18, p=0.003) and higher LDH levels (3134 vs 936, p=0.027). LM diagnosis was also associated with CCI scores less or equal to 4 (OR: 8.76, 95% CI [1.67, 45.88], p=0.005), negative HIV status (OR: 1.33, 95% CI [1.092, 1.629], p=0.004) and lower presence of constitutional symptoms (OR: 0.139, 95% CI [0.033, 0.578], p=0.004). Median times to development of Tuberculosis (dTB) were 4.9 months overall, 3.76 in the LM and 5.26 in the L group, the difference was not statistically significant (p=0.272). Mean overall survival (OS) were 67.94 for LM and 68.73 for L, difference was not statistically significant (p=0.56). In multivariate analysis for the entire cohort, age greater than 65, CCI of 5 or more, Absolute lymphocyte count <1000, LDH>1500, previous TB, presence of HIV and HTLV infection were associated with earlier dTB (see Table). Malnutrition and having an ECOG score of 3 or more were also associated but without statistical significance. HTLV infection and Absolute Lymphocyte Count <1000 were associated with mortality. TB related variables, including: Site of TB, Acid Fast Stain Status and Tuberculosis Treatment Regimen were not associated with mortality.Conclusions: We have analyzed the first cohort of HM patients with microbiologically confirmed TB in a high prevalence setting and have identified risk factors for development of TB including age, CCI, lymphopenia, high LDH, HIV and HTLV. This study will facilitate the identification of patients with HM at risk of developing TB. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nutritional parameters associated with prognosis in non-critically ill hospitalized COVID-19 patients: The NUTRI-COVID19 study

Background & aimsTo investigate the association between the parameters used in nutritional screening assessment (body mass index [BMI], unintentional weight loss [WL] and reduced food intake) and clinical outcomes in non-critically ill, hospitalized coronavirus disease 2019 (COVID-19) patients.MethodsThis was a prospective multicenter real-life study carried out during the first pandemic wave in 11 Italian Hospitals. In total, 1391 patients were included. The primary end-point was a composite of in-hospital mortality or admission to ICU, whichever came first. The key secondary end-point was in-hospital mortality.ResultsMultivariable models were based on 1183 patients with complete data. Reduced self-reported food intake before hospitalization and/or expected by physicians in the next days since admission was found to have a negative prognostic impact for both the primary and secondary end-point (P < .001 for both). No association with BMI and WL was observed. Other predictors of outcomes were age and presence of multiple comorbidities. A significant interaction between obesity and multi-morbidity (≥2) was detected. Obesity was found to be a risk factor for composite end-point (HR = 1.36 [95%CI, 1.03–1.80]; P = .031) and a protective factor against in-hospital mortality (HR = 0.32 [95%CI, 0.20–0.51]; P < .001) in patients with and without multiple comorbidities, respectively. Secondary analysis (patients, N = 829), further adjusted for high C-reactive protein (>21 mg/dL) and LDH (>430 mU/mL) levels yielded consistent findings.ConclusionsReduced self-reported food intake before hospitalization and/or expected by physicians in the next days since admission was associated with negative clinical outcomes in non-critically ill, hospitalized COVID-19 patients. This simple and easily obtainable parameter may be useful to identify patients at highest risk of poor prognosis, who may benefit from prompt nutritional support. The presence of comorbidities could be the key factor, which may determine the protective or harmful role of a high body mass index in COVID-19.

Poor Prognosis of CD5 Positive with Non Germinal Center Type of Diffuse Large B Cell Lymphoma Especially Having the Aberration of 19q13

Introduction ; One of biological molecule markers, CD5 positive (CD5+) DLBCL has been recognized as one of the poor prognostic factors. Almost all CD5+DLBCL cases have higher age, aggressive clinical features, poor performance status (PS), and high LDH level compared to CD5 negative (CD5-) DLBCL. These clinical features are close to ABC type DLBCL and also some gene expression profiling detected the similar point of CD5+ DLBCL with ABC type of DLBCL, such as down-regulation of ECUM genes. Various chromosomal aberrations and polyploidy also have been detected in CD5+ DLBCL, although, specific features of karyotype or markers of gene expression have not been identified. In previous data, we presented the poor prognosis of CD5+non germinal center (NGC) type of DLBCL compared to CD5+ germinal center (GC) type DLBCL and CD5-DLBCL, furthermore additional 19q13 were frequently exhibited in CD5+NGC DLBCL (ASH 2015, poster). In this time we added the more analysis of G-band analysis of DLBCL and CGH array of CD5+NGC with additional 19q13 and analyzed the prognostic factor of CD5+NGC DLBCL.Methods and Results ; We analyzed our treated 373 DLBCL patients by R-CHOP during 2005-2015 in our institute retrospectively. This protocol was approved by our Institutional Review Board and Genomic review Board. All cases were classified depend on CD5+ or CD5- expression by immuno-staining and/or flowcytometry from tumor-biopsy specimen and furthermore sub-divided to GCB or NGC by immuno-staining, as CD10, bcl-6, and MUM-1. 350 cases were encluded, then CD5+ were 41 (41/350; 11.7%) CD5+NGC type were 30 (30/41; 73.2%). 3.5 year-PFS was as follows, CD5-GCB; 84.0% (95%CI 77.4-88.8%), CD5+GCB; 65.9% (95%CI 56.2-74.0%), CD5-NGC; 81.8% (95%CI 44.7-95.1%), and CD5+NGC; 40.6% (95%CI 22.5-58.0%), respectively. The 3.5 year-OS was as follows, CD5-GCB; 85.0% (95%CI 78.4-89.8%), CD5+GCB; 79.7% (95%CI 70.9-86.1%), CD5-NGC; 90.9% (95%CI 50.8-98.7%), and CD5+NGC; 44.5% (95%CI 25.2-62.1%), respectively. CD5+NGC type of DLBCL were demonstrated the worst prognosis in both PFS (P=0.00104) and OS (P <0.001), respectively. By the multivariate analysis of prognostic factors, CD5+ (HR; 2.180, 95%CI; 1.263-3.764, P=0.0051) and IPI (HR; 1.678, 95%CI; 1.151-2.449, P=0.0071) were estimated as individual factors for OS. CD5+NGC type of DLCBL frequently showed the chromosomal aberration of additional 19q13 (7/13 cases; 53.8%). additional 19q13 was also showed only one case of CD5-NGC type of DLBCL. Six cases (6/7; 85.7%) in CD5+NGC had disease progression (two cases relapsed after CR and four had progression during R-CHOP therapy) and followed by death. CGH analysis was performed with the five cases having additional 19q13 in CD5+NGC type. All cases exhibited the aberration of 19q13.41-42 lesions. Three cases showed wide gene amplification in 19q13.32-q13.42. Three cases showed gene loss at the 19q13.41 or 19q13.42. Regarding other chromosomes, all five cases showed gene loss at 1p31.3 and gain at 1q25.1, 2p22.1, 2p22.3, 4p16.1, 4p15.1, 7q33, 12p13.2, 14q32.33.Discussion and Conclusion ;Our study showed significant poor prognosis CD5+NGC type of DLBCL. The gene aberration of 19q13 was frequently expressed in CD5+NGC type of DLBCL and it suggested the relationships between aberration of 19q13 and the poor prognosis. Several study also demonstrated the relationships between aberration of 19q13 and the poor prognosis of the DLBCL. Our CGH analysis demonstrated the aberration of 19q13.41-42 lesions. Already known representative CNVs in this area include CYP2A, SIGLEC14, and LILRA. Those candidate genes have reported to have the relationships with stimulation of leukocyte or lymphoid cell signaling. The further investigation of gene aberration regarding to additional 19q13 might be one of the procedure to overcome the tolerability for the treatment of CD5+NGC DLBCL. From our data we could consider that it is important to identify the CD5+NGC type of DLBCL as poor prognostic factor in DLBCL, and R-CHOP therapy could not improved their prognosis. The new treatment strategy should be planned as soon as possible, such as intensive chemotherapy or immunotherapy. DisclosuresMishima:Chugai Pharmaceutical, Inc: Other: consignment job. Terui:Novartis Pharma K.K.: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Celgene Corporation: Speakers Bureau; Bristol-Myers Squibb company: Speakers Bureau. Yokoyama:Chugai Pharmaceutical, Inc: Other: consignment job. Nishimura:Chugai Pharmaceutical, Inc: Other: consignment job. Hatake:AbbVie, Gilead, Celgene, Solasia, Pfizer, Bristol-Myers Squibb, Janssen, Ghugai: Research Funding; Mundipharma K.K.: Honoraria.

Frontline High-Dose Therapy (HDT) for Adults with Disseminated Aggressive Lymphoma (NHL): Analysis of 327 Patients Included in 3 Prospective Trials (GOELAMS 071, 072, 074) over 12 Years.

We have demonstrated in a randomised prospective trial (GOELAMS 072) that front line HDT including an autologous stem cell transplantation improved significantly the EFS and OS as compared to standard CHOP regimen in adults with aggressive NHL and a high-intermediate age-adjusted-IPI (NEJM 2004). In order to further precise the benefit and risks as well as the prognostic factors with that type of treatment we decided to analyse the patients who entered the high-dose arm of successive prospective GOELAMS' trials designed for patients 15 to 60 y.o. with non previously treated aggressive NHL (excluding mantle cell, Burkitt, Lymphoblastic and transformation of known low grade) Ann.Arbor. stage II with abdominal bulk (> 7cm), III and IV, HIV neg and having given an informed consent (GOELAMS 071 BJH 2000; GOELAMS 072; GOELAMS 074 Blood 2004- ASH). Over a 12 years period 327 pts entered the high-dose arm of these trials. The median age was 44 yo, 60% male, 91% stage III/IV, 65% LDH>N, 33% PS≥2, 30% aa-IPI interm-low, 50% aa-IPI interm-high, 20% aa-IPI high. Histology was Diffuse large cell in 237, anaplastic in 29 and peripheral T cell in 16. Overall 75% of the pts received the planned treatment with autologous transplant. The median FU for surviving patients is 57 m (2 to 148m). The KM 5y and 10y survival is 63% and 55% respectively. Overall 114 pts died a median of 13 m after inclusion (1–130m). The main cause of death was lymphoma relapse or progression (86 pts-75% of the deaths); 12 pts died from TRM; 4 from second cancer (3 solid, 1 MDS). In UV analysis prognostic factors for OS were: PS=4, LDH>4xN, Peripheral T cell LNH. The median, KM 5y and 10y EFS are 77m, 51% and 49% respectively. In UV analysis prognostic factors for EFS were LDN>4xN and Peripheral T cell LNH.Survival and EFS according to aa-IPISurvivalEFSMedian (m)5 y10 ymedian (m)5 y10 yaa-IPI interm-lowNR65%53%12454%53%aa-IPI interm-highNR67%63%12853%53%aa_IPI high8556%44%1743%39%NR: not reachedThese results confirm that intensive short term treatment is able to produce long term survival for a high number of patients with intermediate or poor prognosis without long term toxicity at least in term of second cancer. For T cells LNH and very high LDH levels other treatments are needed.

Impact of High-Dose Methotrexate on the Outcome of Patients with Diffuse Large B-Cell Lymphoma and Skeletal Involvement

Simple SummaryIn this retrospective study, we analyzed the impact of adding high-dose methotrexate to standard chemotherapy on the outcome of patients with diffuse large B-cell lymphoma and skeletal involvement. Our results suggest improved outcome in those who received high-dose methotrexate which should be confirmed in prospective controlled studies. Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1–0.3, p < 0.001 and HR: 0.1, 95% CI: 0.04–0.3, p < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, p <0.001 and 83 vs. 58%, p < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, p = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, p = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.

The Pan-Immune-Inflammation Value in Patients with Metastatic Melanoma Receiving First-Line Therapy.

Since a non-negligible fraction of patients with metastatic melanoma does not experience long-term disease control, even with immunotherapy and targeted therapy, new biomarkers for patient stratification and treatment tailoring are needed in this setting. We investigated the association of a novel immune-inflammatory blood-based biomarker, the Pan-Immune-Inflammation Value (PIV), with clinical outcomes of patients with metastatic melanoma receiving first-line therapy. We retrospectively included patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan and having an available baseline complete blood cell count (CBC). PIV was calculated as: [neutrophil count (103/mm3) × platelet count (103/mm3) × monocyte count (103/mm3)]/lymphocyte count (103/mm3). A total of 228 patients were included: 119 (52%) had been treated with immunotherapy and 109 (48%) with targeted therapy. PIV was significantly higher in patients with ECOG PS ≥ 1, high disease burden, synchronous metastases, and elevated baseline LDH level. High baseline PIV was independently associated with poor overall survival (adjusted hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.30-3.29; adjusted P=0.002) and progression-free survival (adjusted HR 1.56; 95% CI 1.01-2.41; adjusted P=0.044). High PIV was also associated with primary resistance to both immunotherapy (odds ratio [OR]: 3.98; 95% CI 1.45-12.32; P=0.005) and targeted therapy (OR: 8.42; 95% CI 2.50-34.5; P < 0.001). PIV showed a promising discrimination ability in terms of AIC and c-index when compared with other CBC-based biomarkers. PIV may guide the treatment decision process and the development of novel first-line treatment strategies in melanoma, but warrants further study and validation.

MO172HYPONATREMIA IN PATIENTS WITH COVID19

BackgroundAmong laboratory abnormalities described in the context of SARS-COV-2 infection, hyponatremia seem to be the most common. The mechanism of this sodium disbalance is not well known.AimsCharacterize the incidence, etiology and prognostic value of sodium disbalance in patients with COVID19.MethodObservational pilot study with 37 patients admitted to Hospital Ramon y Cajal in Madrid, Spain, between March and April 2020, with a confirmed diagnosis of COVID19. Patients were followed until discharge or death. Clinical and laboratory data were collected at admission and before the clinical outcome. Variables were analyzed comparing hyponatremic vs eunatremic patients.ResultsDistribution of patients according to their serum sodium was as follows: 16 patients with hyponatremia (44%), 19 with normal serum sodium (51%) and 2 with hypernatremia (5%). The average sodium level in hyponatremic patients was 130 ±3.2 mmol/l, median urine sodium was 36 ±3.2 mmol/l (only 6 urine sample available). Hyponatremia was associated with dyspnea at admission and with higher levels of LDH, neutrophil cells account and C reactive protein. However, no worse prognostic was associated with lower serum sodium. All patients recover sodium levels at discharge treated with salt supplementation and free water intake.Conclusionmild hyponatremia is a common electrolyte disorder associated with COVID19. Sing as low urine sodium and recover with water and salt ingestion, point toward hydrosaline dehydration instead of SIADH as most common origin of hyponatremia.

MO819RISK FACTORS FOR COVID-19 MORTALITY IN HEMODIALYSIS PATIENTS

Background and AimsThe global pandemic with SARS-CoV-2 virus and Covid-19 threatened hemodialysis patients as vulnerable category with high risk for fatal outcome. The aim of the study was to determine the prevalence and risk factors for mortality in hemodialysis (HD) patients with confirmed Covid-19.MethodThis study was retrospective, multicentric, and included all HD patients with positive PCR test for SARS-CoV-2 during the period of 10 months from March 1 – December 31/2020. The outcome of patients with positive PCR test for SARS CoV-2 was evaluated. The following clinical parameters were compared in two groups of patients (the deceased and alive): age, sex, hemodialysis vintage, type of vascular access, BMI, Hemoglobin, WBC, Platelets, CRP, LDH, D-dimer, s-albumin, radiological findings, smoking abuse, therapy with ACE and ARBs, presence of symptoms and comorbidities: hypertension (HTA), diabetes mellitus (DM), coronary artery disease (CAD), chronic pulmonary disease (CPD), dyslipidemia, atrial fibrillation (AFF), malignancy, treatment in hospital and intensive care unit (ICU) with oxygen support and mechanical ventilation, and anticoagulant therapy. Statistical analysis was performed by SPSS, continued variables with ANOVA and categorical variables with Pearson Chi- square test and logistic regression.ResultsOf total 631 hemodialysis patients during the period of 10 months 162 patients (113 M and 49 F) or 25,67% were with positive PCR test for SARS-CoV-2, they have had mean age 62,47±13,14 years and HD vintage 71,93±68,01 months. During the observed period 38 patients with Covid-19 (25 M and 13 F) deceased, that represents mortality of 23,45%, 8 patients deceased at home and 30 patients in hospital. The mortality in patients with age range 18-49 years was 8%, with 50-59 years 18,9%, with 60-69 years 22,2%, with 70-79 years 31,2% and in patients with ≥ 80 years was 50%. Clinical parameters showed that the deceased patients compared with alive patients have had statistically significant higher age (67,7±10,57 vs 60,85±13,46 years; p=0.004), biochemical findings WBC (9,13±4,07 vs 6,45±3,0; p<0.001), LDH (394±4,07 vs 294±143; p=0.032), D-dimer (3699±4,07 vs 2025±2628; p=0.041), lower s-albumin (25,03±4,0 vs 34,57±6,89; p<0.001), and less hospital days (9,87±12,15 vs 16,24±14,31; p=0.04). Regarding comorbidities the mortality in the deceased patients was significantly higher in patients with chronic pulmonary disease (CPD) in comparison to patients without CPD (56,3% vs 19,9%; p=0.001), and in patients with malignancy in comparison to patients without malignancy (57,1% vs 21,9%; p=0.032). The mortality in hospitalized patients was significantly higher in comparison to treated patients at home (25,8% vs 10,5%; p<0.001) and was significantly higher in patients treated in ICU in comparison to patients treated at hospital (40,7% vs 25%; p<0.001). By logistic regression model it was determined that presence of chronic pulmonary disease (HR=6,178; p=0.008), ICU treatment (HR=5,311; p=0.01) and malignancy (HR=16,766; p=0.01) were the most predictive risk factors for mortality.ConclusionOur study showed that mortality is high in HD patients with Covid-19 and amounts 23,45%, which is in accordance with other larger studies of ERACODA and ERA-EDTA registry regarding mortality of hemodialysis patients with Covid-19 (25% vs 20%). The mortality in HD patients with Covid-19 was associated with advanced age, high level of WBC, LDH and D-dimer, and low level of s-albumin. In contrast to general population, no association with gender, diabetes and cardiovascular disease, but significant association of mortality with presence of chronic pulmonary disease, malignancy, hospital and ICU treatment was found.

Apatinib in combination with camrelizumab, a humanized immunoglobulin G4 monoclonal antibody against programmed cell death-1, in patients with metastatic acral melanoma.

9539 Background: Patients(pts) with metastatic acral melanoma respond poorly to anti–PD-1 monotherapy. Apatinib, a vascular endothelial growth factor (VEGF) inhibitor, is a kind of anti-angiogenic drugs which have shown synergistic therapeutic effects in combination with PD-1 blockade. We conducted this single-center, open label phase trial to evaluate the safety and efficacy of camrelizumab in combination with apatinib in advanced treatment-naïve acral melanoma pts. Methods: Eligible participants were adult pts (aged 18 to 75) with histologically confirmed unresectable stage or distant metastatic acral melanoma. Exclusion criterion included unknown primary melanoma, brain metastatic disease or previous use of anti PD-1 ab. Pts received camrelizumab at 200mg intravenous infusion every 2 weeks, in combination with apatinib 250 mg orally once a day. The primary endpoint was ORR according to RECIST 1.1 criteria, and the secondary endpoints were safety and RFS. Results: Thirty pts were enrolled from April 2019 to January 2021. Basic characteristics: the mean age was 56.7 years, 22 pts were at stage, 33.3% had an elevated LDH level. Median tumor burden was 45mm (10-187). Gene mutation: Nras 4, cKit 3, Braf 2. Up to January 2021, 27 pts could be evaluated, in which 2 pts got CR, 4 pts achieved PR, and 63% experienced tumor shrinkage. The ORR and DCR were 22.2% and 77.8%, respectively. With a median follow up time of 8.3 months, the median PFS was 8.0 months (95% CI, 3.68, 10.19), the one-year durable response rate was 83.3% and the duration of response time was still not reached. Univariate analysis showed high LDH level was negatively associated with PFS. Whole exome data of baseline tumor biopsies revealed a positive correlation between high copy number variation (CNV) plus high mutational load (TMB) and efficacy，and all of the 4pts with MDC1 gene mutation got tumor shrink and 2 got PR. 96.7% pts experienced treatment-related AEs (TRAEs), including hand foot syndrome in 40%, proteinuria in 40%, liver dysfunction in 36.7%, and hypothyroidism in 30%. The grade 3-4 TRAEs were 33.3%. AE-related permanent discontinuation occurred in only 13.3% pts. 6 pts had delays of treatment due to the COVID-19 epidemic. No dose-limiting toxicities and suspected unexpected AEs were observed in the combination. Conclusions: The combination of apatinib plus camrelizumab was tolerable and showed promising antitumor activities and PFS improvement in pts with treatment-naïve metastatic acral melanoma. The survival is still in follow up. Clinical trial information: NCT03955354.

Treatment Following Progression in Metastatic Melanoma: the State of the Art from Scientific Literature to Clinical Need.

In the last few years, the advent of targeted therapy and immunotherapy has improved the management and the prognosis of metastatic melanoma, but the spread of resistance mechanisms can lead to disease progression. The clinical management in this setting can be challenging because the oncologist has to decide what is the best treatment strategy among therapy beyond progression (TBP), therapy change, and the rechallenge approach. This review of the relevant scientific literature is intended to clarify which patients with progressing metastatic melanoma will benefit from continuation of ongoing therapy and which ones will not. The data are based on a total of about 4300 patients coming from the main retrospective studies in the chosen field. The article body is divided into four sections which analyze respectively the targeted therapy beyond progression, the immunotherapy beyond progression, the possible treatment sequences, and finally the rechallenge strategy. Despite the possible approaches of TBP or rechallenge, the patient may not have an optimal response and may need new therapy, which is currently missing. To broaden the pharmacological offer in the fight against melanoma, cancer research is studying new disease targets, like the NRAS, PI3K, and cKIT pathways or combination treatment of targeted therapy plus immunotherapy. Despite the limitations of this work, mainly due to the limited number of studies, their retrospective nature and the lack of comparative studies, the analysis performed allows us to draw some important conclusions: therapy beyond progression, both targeted therapy and immunotherapy, represents a valid treatment option with positive effects on disease control and survival outcomes for patients with low clinical risk, expressed as low disease burden, normal LDH levels, and good performance status; moreover, the prognosis and quality of life of these patients improve when TBP is associated with locoregional treatments. In patients with progressive metastatic melanoma and high clinical risk (high disease burden, high LDH levels, and poor performance status), it is recommended to change therapy, without ever forgetting the possibility of enrolling the patient in a clinical trial. Finally, an efficacious treatment alternative is the rechallenge strategy; this approach consists in a re-treatment with the same drug after a variable interval of discontinuation. Preliminary studies seem to have demonstrated that patients retreated with targeted therapy achieved a greater benefit if they had a low clinical risk and if the drug doublet (BRAF + MEK inhibitors) was used. On the side of immunotherapy, the rechallenge strategy produced a major benefit in patients who prior experienced a severe toxic episode.