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Supplementary Figure from Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma

Supplementary Data from Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma

Supplementary Table from Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma

Purpose:Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model.Experimental Design:We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment.Results:Patients with >0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P 20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2 g/dL M-protein, and >0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk score based on the percentages of SLAN+ and SLAN− nonclassical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient’ stratification into low, intermediate-low, intermediate-high, and high-risk disease with 0%, 20%, 39%, and 73% rates of progression at 2 years.Conclusions:This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.

Return to work (RTW) is a marker of functional recovery in cancer patients, with quality of life, financial and social implications. We investigated frequency and factors associated with RTW in a cohort of patients younger than 66 years, with newly diagnosed multiple myeloma (MM), uniformly treated with a bortezomib-based induction followed by autologous stem cell transplantation (ASCT). Socio-economic and working status data were collected by a self-administered questionnaire. One hundred and eighty-six patients entered the study. Of whom, 145 (78%) where employed at diagnosis, which was more frequent in younger (median 55 vs. 60 years, p < 0.001), men (59.3% vs. 34.2%, p = 0.004), and with college studies (44.8% vs. 24.4%, p = 0.008). Forty-three (30%) of the 145 patients who had a job at diagnosis, RTW after ASCT in a median of 5 (range 1-27) months. Factors independently associated with RTW were having three or more children (HR 2.87, 95% CI 1.33-6.18), college studies (HR 2.78, 95% CI 1.21-6.41), and a family income >40 × 10(3)€/year (HR 2.31, 95% CI 1.12-4.78). In conclusion, the frequency of RTW herein reported in MM patients seems lower than reported in other malignancies. The risk factors observed may guide the design RTW programs.

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry)

Background and objective SARS-CoV-2 infection has bimodal distribution in Europe with a first wave in March to June 2020 and a second in September 2020 to February 2021. We compared the frequency, clinical characteristics and outcomes of adults with acute lymphoblastic leukemia (ALL) and infection in the first vs. second pandemic waves in Spain. Patients and Methods In this prospective study the characteristics of ALL and COVID-19 infection, comorbidities, treatment and outcome in the two periods were compared. The study ended when vaccination against SARS-CoV-2 was implemented in Spain. Results Twenty eight patients were collected in the first wave and 24 in the second. The median age was 46.5 years (range 20–83). Patients from the first wave had a trend to more severe ALL (higher frequency of patients under induction or submitted to transplantation or under immunosuppressive therapy). No significant differences were observed in need for oxygen support, intensive care unit (ICU) requirement, days in ICU and time to COVID-19 infection recovery. Seventeen patients (33%) died, with death attributed to COVID infection in 15 (29%), without significant differences in the 100 day overall survival (OS) probabilities in the two waves (68% ± 17% vs. 56% ± 30%). The only prognostic factor for OS identified by was the presence of comorbidities at COVID-19 infection (HR: 5.358 [95% CI: 1.875- 15.313]). Conclusion The frequency and mortality of COVID-19 infection were high in adults with ALL, without changes over time, providing evidence in favor of vaccination priority for these patients., Microabstract The characteristics and outcome of ALL in adults with COVID-19 infection in the first two waves of the pandemic in Spain were compared. The frequency and mortality of COVID-19 infection were high in adults with ALL, without changes over time. Comorbidities at COVID-19 infection was the only prognostic factor for survival.

[Background]: The treatment of acute lymphoblastic leukemia (ALL) in older adults and elderly patients is a challenge, and modern protocols include targeted therapy and immunotherapy in combination with attenuated or minimal chemotherapy. However, frail patients are excluded from these trials, and reports on the outcome of this subgroup of patients are scarce. Our objective was to analyze the outcome of unfit older adults and elderly patients with Philadelphia chromosome-negative ALL included in a prospective trial (ALL-07FRAIL)., [Patients and Methods]: Older adults and elderly patients with Charlson Comorbidity Index (CCI) ≥ 4 were included. Induction therapy consisted of vincristine and dexamethasone, and maintenance therapy with mercaptopurine and methotrexate for 2 years., [Results]: Seventy-two patients with a median age of 67 years (range, 57-89 years) and a median CCI of 5 (range, 4-12) were included. The rates of early withdrawal, early death, resistance, and complete response (CR) were 5%, 10%, 31%, and 54%, respectively. Six patients with CR abandoned the study, 5 died in CR, and 23 relapsed (cumulative relapse incidence 75%). The medians of disease-free and overall survival (OS) were 6.9 months (95% confidence interval [CI], 0.3-13.5 months) and 7.6 months (95% CI, 6.3-8.9 months), respectively. The most frequent toxic events were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases). Eastern Cooperative Oncology Group score but not the CCI had significant impact on OS., [Conclusion]: Complete remission with very attenuated chemotherapy can be attained in one-half of older or elderly infirm patients with ALL. These results suggest that some of these patients could benefit from the concomitant or subsequent use of immunotherapy and/or targeted therapy., This study was supported in part by the CERCA Program/Generalitat de Catalunya, Spain and the Josep Carreras Leukemia Research Institute, Badalona, Spain.

Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients. We found that VEGFC expression was higher in AML patients with myelodysplasia-related changes (AML-MRC) than in patients with non-AML-MRC. We also found an association between VEGFC expression and the patient cytogenetic risk group, with those with a worse prognosis having higher VEGFC expression levels. No correlation was observed between VEGFC expression and survival or complete remission. VEGFC expression strongly correlated with expression of the VEGF receptors FLT1, KDR, and NRP1. Thus, in this series, VEGFC expression was increased in AML-MRC and in subgroups with a poorer prognosis, but has no impact on survival.

We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time., This work was supported by the Fundación CRIS and Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (Ref.: RD12/0036/0061 to JML).

Introduction and objective. Despite a high complete remission (CR) rate obtained with frontline therapy most adults with T-ALL eventually relapse. Although promising therapies are emerging, salvage options for T-ALL are currently limited. Little is known about outcome of patients (pts) with relapsed T-ALL (R T-ALL) treated with contemporary MRD-oriented trials. Our goal was to analyze the outcome of pts with R T-ALL included in two successive MRD-oriented trials (ALL-AR-03 and ALL-HR-11) from the Spanish PETHEMA Group. Methods. Retrospective study of R T-ALL adults diagnosed between 2003 and 2019 and included in the protocols ALL-AR-03 (NCT00853008) and ALL-HR-11 (NCT01540812). The clinical characteristics at baseline and at relapse, salvage therapies and outcomes (CR and OS) were analyzed and a study of prognostic factors for OS was performed. Results Forty-nine patients were identified (ALL-AR-03 [n=27], ALL-HR-11 [n=22]). Median age (range) at diagnosis was 29 (16-58) yrs, 38 males (78%), CNS involvement 6 (12%), mediastinal mass 30 (61%), WBC count 40.8 x109/L (0.6-351.0), early T-cell precursor 11 (23%), pre-T 8 (16%), cortical 16 (33%), mature 9 (18%), T unspecified 5 (10%). Post-induction-1 MRD level ≥0.1%: 14/42 (33%), ≥0.01%: 17/39 (44%). Nine pts (18%) required 2nd induction therapy (resistant disease after induction-1 [n=5], MRD≥0.1% after induction-1 [n=4]). Allogeneic HSCT in CR1: 8 pts. Interval CR1-relapse: 11.2 [0.1-36.7] months. Relapse was located in BM (n=20, 41%), BM+extramedullary (n=16, 33%) and extramedullary (n=13, 26%). CNS at relapse was involved in 18 pts (37%, isolated in 8 cases). Median number of rescue lineages was 2 (range 1-5). The most frequent first salvage schedules were FLAG-Ida (n=24, 49%), HyperCVAD (n=8, 16%) and nelarabine (n=4, 8%) (other schedules in 13 pts). Second CR was attained in 21/48 pts (44%). The patients with poor morphologic and/or poor MRD response after Induction-1 in first line therapy (n=9) did not respond to first salvage therapy (0/9 vs. 21/39, p=0.003). AlloHSCT was performed in 19 pts (15 in CR2) (HLA-identical sibling: 9, URD: 9, haploidentical: 1, myeloablative conditioning: 16). Thirty-nine pts died (progression: 27, toxicity of rescue regimens: 7, TRM: 5) and 9/10 alive patients were submitted to HSCT (the remaining is on rescue therapy). Median OS (95%CI) was 6.1 (4.9-7.2) months, 5yr OS probability 21% (9%-33%) (Figure 1). By multivariable analysis, only the CR after first salvage regimen emerged as favorable prognostic factor for OS (HR 3.110, 95%CI: 1.579-6.124) (Figure 2). Conclusion. This study shows poor outcome of adults with R T-ALL, with CR to first salvage therapy of 44% and a median OS of 6 months. Poor early response to first line therapy correlated with poor response to salvage-1. The only independent predictor for better survival was CR to first salvage regimen. This study highlights the unmet need for novel effective therapies for T-ALL. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation; ISCIII (PI19/01828), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future". Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Barba:Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire: Consultancy; Amgen, Celgene, Novartis, Pfizer: Speakers Bureau. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Giménez Conca:AbbVie: Honoraria, Speakers Bureau.

Objective The presence of plasmacytomas (Ps) in patients with multiple myeloma (MM) is associated with a poor outcome, both in patients treated conventionally and in patients treated with novel agents. Two types of plasmacytomas have being recognized: paraskeletal plasmacytomas (PPs) and extramedullary plasmacytomas (EMPs), being the incidence of EMPs lower but with worse prognosis. Our aim has been to analyze the efficacy of the pomalidomide-dexamethasone combination in this patient profile. Method In the present study, the efficacy of pomalidomide and dexamethasone in 21 patients from nine hospitals of Catalonia (Spain), with relapsed or refractory MM and Ps, was analyzed. For this purpose, we describe the evolution of paraprotein in serum and urine and the size of plasmacytomas during treatment with pomalidomide-dexamethasone. Results While 34% of the patients achieved a paraprotein response, only two patients with PPs (9%) responded (RC and PR). There were no responses among patients with EMPs. The median progression-free survival from the start of treatment with pomalidomide/dexamethasone was only 1.7 months and the median overall survival of 4.5 months. Conclusion In conclusion, pomalidomide and dexamethasone has limited efficacy in patients with advanced MM and soft-tissue plasmacytomas.

Background and objective: The prognosis of acute lymphoblastic leukemia (ALL) is poor in older adults and elderly patients, and subtype-oriented prospective trials are scarce in these patients. We present the results of three prospective parallel subtype-oriented protocols in fit patients older than 55 years. Patients and methods: In 2008, three prospective phase II trials in patients older than 55 years were activated: ALLOLD07 for Philadephia (Ph) chromosome-negative ALL, ALLOPHO7 for Ph-positive ALL, and BURKIMABO8 for mature B-ALL. Early death (ED), complete remission (CR), disease-free survival (DFS), overall survival (OS) and toxicity were analyzed. Results: 56, 53 and 21 patients from the ALLOLD07, ALLOPHO7 and BURKIMABO8 trials, respectively, were evaluable. CR was 74%, 87% and 70%, with an ED rate of 13%, 11% and 15%, respectively. The medians of DFS were 8 and 38 months for ALLOLD07 and ALLOPHO7 protocols, not being achieved in the BURKIMABO8 trial (p = 0.001), and the median OS was 12, 37 and 25 months, respectively (p = 0.030). Neutropenia, thrombocytopenia and infections were less frequent in the ALLOPHO7 trial vs. ALLOLD07 and BURKIMAB trials, and renal toxicity and mucositis were more frequent in the BURKIMABO8 trial vs. the ALLOLD07 and ALLOPHO7 trials. ECOG score and WBC count had prognostic significance for OS in ALLOPHO7 and BURKIMABO8 trials, whereas no prognostic factors were identified in ALLOLD07 protocol. Conclusion: Subtype-oriented treatment had an impact in the outcome of older adults with ALL. The poorest outcome was observed in Ph-negative non-Mature B-cell ALL patients, for whom improvements in therapy are clearly needed. (C) 2015 Elsevier Ltd. All rights reserved.

Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio ( We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

Background Cytogenetics at diagnosis is the most important prognostic factor in acute myeloid leukemia (AML). Of note, intermediate cytogenetic risk group (IR-AML) is a very heterogeneous subset including normal karyotypes and all the cytogenetic abnormalities not included in the favorable or the adverse groups. Molecular alterations affecting NPM1, FLT3 and CEBPA show a prognostic impact in IR-AML. MLL partial tandem duplications (MLL-PTD) have also been described in this group of AML, but their prognostic impact have not been well established. Aim To analyze the prognostic relevance of MLL-PTD in the subset of patients diagnosed with IR-AML since 2003, and included in the CETLAM protocols LMA-2003 and LMA-2012. Methods Between 2003 and 2004 MLL-PTD were analyzed by Southern Blot (enzymes employed BglII, EcoRI, BamHI). Since 2004, a long PCR strategy was used to identify this abnormality. Results NPM1 mutations (NPM1mut), FLT3 internal tandem duplications (FLT3-ITD) and MLL-PTD were available for 893 patients. No MLL-PTD was found among 111 and 161 patients of the good and poor cytogenetic risk groups, respectively. The IR-AML group included 621 patients, and 37 carried a MLL-PTD (6%), thus only this cytogenetic group of patients was analyzed. NPM1mut were found in a 41% of patients and none of them had a concomitant MLL-PTD (p Conclusions MLL-PTD is a genetic alteration found in a 6% of IR-AML. Patients with this abnormality have a worse LFS and OS than the rest of patients of the IR-AML group. Based on these results, patients with MLL-PTD should be considered as patients with poor cytogenetic risk AML for treatment allocation. Disclosures No relevant conflicts of interest to declare.