ALBERT

Description: Background: Assessing MRD has become a standard procedure in clinical trials to evaluate treatment efficacy. In accordance with its consistent prognostic value, the International Myeloma Working Group added MRD-negative criteria into response guidelines for its standardized use in clinical trials. That notwithstanding, the expectations for MRD as biomarker are to use it in routine clinical practice to help in treatment decisions, since in most clinical trials the therapeutic approach is defined upfront and does not vary according to patients' depth of response. However, the use of MRD in clinical practice is controversial and it remains unknown if tailoring treatment to achieve MRD-negativity is safe and improves patients' survival. Aim: Compare in clinical practice, outcome and tolerability of a treatment strategy tailored to achieve sustained undetectable MRD by NGF and imaging, as compared to conventional treatment approaches that are not modified according to patients' depth of response. Methods: This study was conducted in a single Hospital and included a total of 66 patients with newly-diagnosed MM from July 2014 to May 2019. All patients younger than 76 were prospectively included, whereas patients with high frailty score, severe senile dementia, other neoplasms, or with significant comorbidities in whom the therapeutic objective was only palliative care were excluded. In accordance to the local ethical committee and the Helsinki Declaration, all patients gave informed consent prior entering the study and were given the choice between the MRD and image driven (MRD-driven) and the conventional treatment (CT) approach. In the former, persistent MRD after the first-line of therapy was considered as treatment failure and patients received subsequent lines until achieving undetectable MRD by NGF and imaging (treatment endpoint). In the CT approach, subsequent lines of therapy were given upon progressive disease. The most commonly used first, second, and third line therapies in the MRD-driven approach were VBMCP/VBAD, VCD, and lenalidomide combinations, whereas in the CT cohort these were VCD for first-line, and lenalidomide combinations in second and third lines. Maintenance therapy (Interferon α2b + Prednisone for a year) was administered in 61% of patients treated according to the MRD-driven approach, and in 12% (bortezomib until progression) in the CT cohort. MRD was assessed in patients achieving complete remission using EuroFlow NGF, with a limit of detection of 2x10-6. Undetectable MRD by imaging was defined by negative PET/CT and by negative MRI of the spine and pelvis. Results: Of the 66 patients enrolled thus far, 49 were treated with the MRD-driven and 17 with the CT approach. There were no significant differences between groups regarding patients' age (median, 62 years), the Revised-ISS (37.5%, 53% and 37.5% with R-ISS-I, -II and -III) or the usage of HDT/ASCT (85% vs 76%; P〉.05). Approximately 80% of patients treated with the MRD-driven approach achieved undetectable MRD at 30 months. The median time from start of treatment to undetectable MRD was 24 months, after a average of 2.2 lines of therapy. By contrast, only 1 (6%) patient treated with CT showed undetectable MRD after first line of therapy. With a median follow-up of 29 months, progression-free survival (PFS) rates at 30 months were 92% for patients treated with the MRD-driven vs 28% for the CT approach (hazard ratio 0.10 [0.04-0.30]; p

Description: BACKGROUND Current treatment choices are based on generalized outcome data from clinical trials, but not all MM patients respond the same and a considerable percentage of them do not achieve a desirable treatment endpoint. Contradictory results based on the rate of descent of the monoclonal component (M-component) to predict long-term outcome have been published, but no to identify patients with insufficient response to a therapeutic regimen. The ability to identify treatment early on resistance could accelerate the introduction of another (and more effective) line of therapy. AIM Develop and validate a rule based on the rate of descent of the M-component, to predict the probability of disease resistance to reach a complete remission (CR) in MM patients. METHODS Three studies were conducted: exploratory, confirmatory, and clinical validation. A total of 87 patients treated between July 2014 and September 2018, were included for the first two. Patients who were unable to complete the planned treatment due to toxicity or comorbidities, and those treated for palliative purposes only, were excluded. A therapeutic regimen was considered to be effective if CR was achieved with it. Conversely, a therapeutic regimen was considered to be ineffective if disease progression was observed during treatment, or if CR was not achieved with it. The percentage of the daily decrease in the M-component achieved by each treatment cycle is calculated dividing the percentage of the decrease during the cycle by the number of days elapsed (n.nn% /day). Timing between measurement of the M-component do not differed more than 15% from the scheduled cycle time. In the exploratory study using the receiver operating characteristic (ROC) curve through SPSS v24, the ability to discriminate between effective and ineffective therapeutic regimen was investigated in 99 cycles, to identify the optimal cutoff, and to desing a rule; followed by a confirmatory study of the rule in 52 cycles different from those of the first study. A third clinical validation study was carried out with 62 patients, 31 with treatment guided by response speed rule (RSR-guided) and 31 not (unguided). RESULTS In the exploratory study it was observed that the area under the ROC curve was 0.971 (CI 95%: 0.93 - 1.00) (p 1.40% /day in a first cycle it does not indicate efficacy. In the confirmatory study it was observed for the RSR a sensitivity 100% (CI 95%: 92 - 100), specificity 100% (CI 95%: 66 - 100), reliability 100% (CI 95%: 93 - 100). In the clinical validation study the most common treatments in 1st, 2nd, and 3rd line were VBCMP/VBAD, VCD, and KRd for candidates, and VCD, Rd, DRd or KRd in non-candidates respectively. No significant differences were observed in the type of treatment used between RSR-guided and unguided patients. The median (months) to reach the CR in the RSR-guided patients was lower (8.5 vs 12.1 months; p = 0.003). RS-guided patients need fewer cycles to achieve CR (5.29 vs. 10.84; p = 0.002). The CR rate at 18 months was 94.3% (CI 95%: 84.1 - 100) and 74.2% (CI 95%: 58.4 - 90.0) for RSR-guided and unguided patients respectively, although in unguided patients the rate rose to 96.8% (CI 95%: 90.4 - 100.0) continuing treatment until 30 months. No significant differences were found in the number of lines for CR (1.96 vs 2.42; p = 0.054). CONCLUSIONS The Response Speed Rule (RSR), defined as a speed of M-component descent of ≤ 1.40% /day in two successive cycles, predicted with great accuracy the current ineffectiveness of a therapeutic regimen to deliver CR. During the clinical validation of this cutoff, it was shown that CR is achieved in less time and with fewer cycles using RSR. This is a simple metric that can be used broadly and accelerate the introduction of another (and more effective) line of therapy. Figure Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Up to 20% of patients (pts) with essential thrombocythemia (ET) and up to 10-15% of pts with polycythemia vera (PV) are diagnosed before the age of 40 years and the percentage is even lower in pts with primary myelofibrosis (PMF). Pregnancy (Pcy) in MPN is associated with an increased incidence of thrombotic and bleeding events and obstetric complications with live birth rates of 50% to 70%. There are no evidence-based guidelines for the management of these pts and most of the data come from case series of few pts. There are no validated variables that can predict outcomes in pregnant women with MPN. Objetives: Primary: To learn the incidence of thromboembolic, hemorrhagic and OC in pregnant women with MPN in Argentina. Secondary: To evaluate parameters such as mutational status, platelet count, history of complications in previous Pcy, use of aspirin (ASA), low molecular weight heparin (LMWH) or interferon (IFN) and their relationship with obstetric outcomes. Materials and methods: Retrospective evaluation of medical records of pts with diagnosis of MPN and Pcy. Quantitative variables were expressed as median and interquartile range (IQR) and qualitative variables as total number and percentage (%). Fisher's exact test was used to analyze variables and their association with events and Wilcoxon test for platelet counts. Results: A total of 30 Pcy in 23 women with a diagnosis of MPN were recorded, 20 Pcy in pts with ET, 4 Pcy in pts with PV and 6 MF pregnancies. Pcy was planned in 56.6% of cases. There were OC in 15/19 previous Pcy. The median age was 32.9 years (IC25-75% 30-36 years). Mutational status was assessed in 22 pts: 9/22 JAK2 +, 7/22 CALR +, 1/22 triple-negative, 1/22 JAK2-CALR- and MPL not performed, 6/22 JAK2- CALR and MPL without data. The overall number of live births and first trimester spontaneous abortions (SA) were 26(86%) and 4(13.3%) respectively, without cases of second (2T) and third trimester (3T) fetal loss or stillbirths. There was a case of neonatal death in a patient with MF. We detected 13 obstetric events (ET: 9/20, PV: 2/4, and MF 2/6): 4 SA, 5 cases of fetal growth retardation, 1 partial placental abruption and 3 placental hematomas. There was no significant association between JAK2 mutational state, history of complications in previous Pcy, platelet count, use of ASA, LMWH or IFN and obstetric outcomes. Two of the pts who had SA presented smoking as a cardiovascular risk factor. There was heterogeneity among hematologist regarding therapeutic management: ASA was indicated in 24 Pcy and LMWH in prophylactic doses during Pcy in 15. In 21/25 cases LMWH was indicated as postpartum prophylaxis, only in 3/21 it was extended for 6 weeks(wks). Before Pcy 17 cases received cytoreductive treatment: 2 with HU and 1 with anagrelide that were discontinued at the time Pcy was confirmed, 5 with peg IFN, and 9 conventional IFN. During Pcy 8 continued with cytoreductive treatment (6/9 conventional IFN, 2/9, pegIFN, including 1 patient previously receiving HU) and 5 initiated IFN (1/5 conventional, 4/5 pegIFN). Platelet counts in pts who did not require cytoreduction dropped from 600 x 109/L (290-1596 x 109/L) at the beginning of Pcy to 470 (240-1548) x 109/L, p=0.0068, and 423 (240-843) x 109/L, p=0.0005, in the 2T and 3T, respectively, with non-significant increase after delivery to 494 x 109/L (122-1600 x 109/L). No cases of maternal thrombosis and 2 episodes of major postpartum bleeding who required surgical intervention one of them with hysterectomy were found.The median time of delivery was at 38 wks of gestation (IC25-75% 36.5-38.5). Vaginal delivery was performed in 6 Pcy, caesarean section (CS) was required due to emergency in 2, because of lack of fetal progression in 2, and 16 were scheduled CS. The median birth weight was 2900g (IC25-75% 2500-3300g). No congenital malformations in live births were detected. Conclusions: Pcy is a rare but high-risk event in MPN pts with 11/30 OC in this cohort. The live birth rate was high compared to the literature. The risk of MC was low, without thrombotic complications and 2/30 episodes of major postpartum bleeding. There was no correlation between mutational status, platelet count or treatments received and obstetric outcomes. There was a significant reduction in the number of platelets in pts with thrombocytosis without requiring cytoreduction. The high percentage of pts who finished their pregnancy with scheduled CS is highlighted. Disclosures No relevant conflicts of interest to declare.

Description: Leukemia relapse occurring in donor cells, so called donor cell leukemia (DCL) after allogeneic hematopoietic stem cell transplantation has been previously reported in the literature. Some authors have suggested that the development of DCL is perhaps a more common occurrence than traditionally thought. Donor cell myeloma (DCM) seems to be less frequent than DCL. This 46-year old male when first seen in 2000 was diagnosed with stage IIIa multiple myeloma. A monoclonal IgA kappa spike was recorded at diagnosis. Treatment with melphalan and prednisone was delivered every four to six weeks for a total of 22 courses. Fourty months after the initial diagnosis, an M2 acute myelogenous leukemia was identified. Treatment with chemotherapy resulted in complete remission. Matched UCB cells were localized at the London Cord Blood Bank. The UCB belonged to a male product of a white western European mother and a black Nigerian father who was a carrier of hemoglobin S. Hemoglobins A, F and S were detected in the UCB, consonant with sickle cell trait. The patient was allografted employing the "Mexican" NST conditioning regimen, granulocyte count recovered to more than 0.5 x 109/L on day 14, with the platelet count never dropping below 20 x 109/L. On day +40, the polymorphic microsatellite markers revealed mixed chimerism. The hemoglobin S gene was identified on day +20 and on day +60, full chimerism was shown. Cyclosporine A was stopped on day +350. The patient returned 170 months after the transplant with low back pain and the bone marrow aspiration disclosed 80% abnormal plasma cells, an IgA kappa monoclonal spike of 3.1 gr/dl, and complete chimerism. Malignant plasma cells were sorted by means of flow cytometry before genetic fingerprinting; cells were stained with an admixture of fluorescent monoclonal antibodies and cells co-expressing dim CD45, bright CD38 and CD56 were sorted out to ≥99% purity. Sorted cells were shown to have donor origin (Figure 1). The patient was treated with thalidomide, dexamethasone and bortezomib and the monoclonal spike disappeared; an autologous stem cell transplant is planned. Most people consider that the development of a malignancy in the cells of the donor is a rare event and very few prospective studies have analyzed the real prevalence of this phenomenon. Prospectively, we have found that 7% (95% CI 2.9 to 13.6%) of patients with leukemic activity after an allogeneic graft do have a donor cell-derived leukemia; this figure contrasts with those described elsewhere in non-prospective studies. A major problem in the analysis of donor cell derived malignancies is that demonstration of the donor cell origin of malignant activity. In this case, the demonstration of DNA of the donor in the fluorescence-activated sorted malignant plasma cells is indicative of the origin of the myeloma cells. Interestingly, the immunoglobulin type produced by the initial myeloma cells is the same as that of the donor-cell myeloma; Despite being two myelomas producing the same immunoglobulin subtype, both should be considered as de novomalignancies and as such, treated; we have previously shown that donor cell leukemias do have a response when treated as de novo, non-secondary leukemias. To our best knowledge, this is the second report of DCM following allogeneic HSCT. Prior to this case, Kim et al reported a DCM after an allogeneic transplant in a patient with refractory anemia with ringed sideroblasts. Previously, two cases have been reported of donor-origin MM, but they occurred in patients who underwent solid organ transplantation of the kidney and heart-lung. Kumar et alreported a case of DCM developing after unrelated allogeneic HSCT in the both donor and recipient but they did not conducted a comprehensive molecular cytogenetic study. In the case published by Maestas et al, an abnormal proliferation of plasma cells was identified in the donor, thus making possible that a malignant plasma cell clone was already present in the donor stem cells. In summary, we have clearly shown that this patient has had three different malignancies: 1) De novomultiple myeloma, 2) Secondary acute myelogenous leukemia and 3) De novodonor cell-derived multiple myeloma. The mechanisms involved in these episodes could be useful to better understand tumorigenesis. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: CC analysis of the CSF is considered as the reference method to diagnose meningeal disease in patients with B-NHL. However, recent studies suggest that in patients with B-NHL who are at high risk of CNS relapse, FCM could be more sensitive than CC for detecting meningeal disease in CSF. Objective: To evaluate the sensitivity and specificity of a standardized FCM immunophenotypic approach vs CC for detecting the presence of neoplastic cells in CSF, in patients with aggressive B-NHL who are at high risk of CNS relapse. Patients and methods: A total of 29 CSF samples were analysed (total volume: 0.8 to 4ml; median: 2.4) in newly diagnosed patients with aggressive B-NHL, from a total of 14 different hospitals (diffuse large B cell lymphoma-DLBCL: 17; Burkitt’s lymphoma-BL: 9; follicular lymphoma transformed to DLBCL -tFL: 2; and T-cell-rich B-NHL: 1). Of the 29 patients studied, 15 were men (52%) and 14 women (48%) with a mean age of 55 ± 19 years (range: 16–86). In all cases, the CSF samples were analysed simultaneously by CC at the institution of origin and FCM, centrally one institution. For the FCM analysis of the CSF, stabilised samples (Transfix, CYTOMARK) were systematically stained with the following combination of monoclonal antibodies: CD8-sIgl/CD56-sIgk/CD4-CD19/CD3/CD20/CD45 (FITC/PE/PERCPCY5.5/PECY7/APC/APCCY7). If the FCM test showed infiltration, an additional 6-color antibody panel was used for full phenotypic characterisation of the disease. Results: Haematopoietic cells were detected in all cases (mean: 2.2 ± 4 cells/μl; range: 0.2–14). Systematically, these cells included T cells (mean: 0.6±0.8/μl; range: 0.1–4) and monocytes (mean: 1±2/μl; range: 0.1–9). Furthermore, in 31%, 3%, 3% and 14% of cases the following cell populations were also detected: polyclonal B-lymphocytes (mean: 0.06±0.07/μl; range: 0.01–0,2), plasma cells (0.09/μl), natural killer cells (0.03/μl) and neutrophils (mean: 0.6±1/μl; range: 0.03–2), respectively. Of the 29 cases studied, 5 (17%) showed infiltration by neoplastic B-cells by FCM, while CC only showed infiltration in two of these patients (7%). Cases with CNS infiltration by both methods included one tFL (82%; 14 neoplastic cells/μl by FCM) and one BL (68%; 8 neoplastic cells/μl using FCM). The three patients with FCM+/CC- presented a lower percentage of pathological B-cells (2% in one DLBCL and 1% and 0.1% in two BL, respectively). One of these three patients presented neurological symptoms (meningism). Conclusion: Although preliminary, these results suggest that FCM is more sensitive that CC in detecting CSF infiltration by neoplastic B-cells in aggressive B-NHL, especially when these cells are present in a relatively low numbers.

Description: Introduction Graft versus host disease (GvHD) is the main cause of morbimortality after allogeneic stem cell transplantation (allo-SCT). Several single-nucleotide polymorphisms (SNPs) in in the promoter region of cytokine genes have shown to alter their expression and are therefore associated with donor-recipient alloreactivity and, ultimately, with SCT outcome. Interleukin 17 (IL-17) is secreted by CD4+ T-cells and has been implicated in the pathogenesis of various autoimmune diseases but its importance in SCT is not well-known. Objective To analyse the influence of IL-17A SNP genotypes on the risk and severity of GvHD and other complications after HLA-identical allo-SCT. Patients and Methods Genomic DNA obtained from peripheral blood samples belonging to 546 patients and their HLA-identical sibling donors (Table 1) included in the DNA Bank of the Spanish Group for Hematopoietic Stem Cell Transplantation (GETH). Genotyping of the polymorphisms of interest, rs8193036 (-737C〉T), rs2275913 (-197G〉A), rs3819024 (-444A〉G), rs4711998 (-877A〉G), were performed by multiplex primer extension followed by mass spectrometry (MALDI-TOF; Sequenom MassArray). Results Genotype frequencies are shown in Table 2 and the association between IL-17A genotypes and complications after allo-SCT are shown in Table 3. Patients transplanted from donors harboring genotype CC for the SNP rs8193036 show increased risk of grade III-IV acute GvHD (7/26 vs 47/397, p=0.035) and of grade II-IV acute GvHD (13/26 vs 133/409, p=0.048). Patients transplanted from donors harboring allele A in the SNP rs4711998 show increased risk of extensive chronic GvHD (53/161 vs 43/177, p=0.045). Relapse rate was not related with IL-17A SNP genotypes. Finally a higher risk of toxicity-related mortality (TRM) was observed in patients transplanted from donors harboring allele A for SNP rs2275913 (78/293 vs 46/227, p=0.048), donors harboring allele G for SNP rs3819024 (78/279 vs 46/242, p=0.011) and donors harboring allele A for SNP rs4711998 (68/250 vs 55/229, p=0.044). Conclusions IL-17A SNP genotyping might be useful to anticipate complications after sibling HLA-identical allo-SCT and, therefore, to improve the clinical management of transplanted patients. This results further support the idea of a genetic predisposition to certain complications after allo-SCT. Paper presented on behalf of the GvHD/Immunotherapy committee of the Spanish Group for Hematopoietic Transplantation (GETH). Disclosures: No relevant conflicts of interest to declare.

Description: Background and Objectives: Following cord blood transplants (CBT) there is a period of severe and often prolonged immune deficiency that results in long term susceptibility to infections. Immune reconstitution is an important factor for long term survival. We analyzed the immune reconstitution of adult recipients of a single unit CBTs supported by a low number of third party donor highly purified mobilized hematopoietic stem cells (dual CB/TPD transplants), as previously described (Magro et al. Haematologica2006;91:640–8). This strategy results in transient double chimerism of CB and TPD cells and early granulocyte recovery, initially of TPD predominance. Complete CB chimerism is regularly achieved within 100 days.The objective of this study is to evaluate immune reconstitution in this CBT. Patients and Methods: Data were obtained from 19 patients between July 2004 and July 2006. Data collection was initiated at different intervals (from day −7 to +720, quartiles Q1=35, Q2=90 and Q3=210). Samples were obtained on days +15, +35, +55, +90 and monthly thereafter up to two years. By four-color flow cytometric immunophenotyping we analyzed the subsets of peripheral blood lymphocytes: CD3+/CD4+ (T helper/inducer), CD3+/CD8+ (T suppressor/cytotoxic), NK cells (CD3−/CD56+/CD16+) and B cells, as well as cells with naïve, memory and effector T-cell immunophenotypes. TREC bearing cells were analyzed by quantitative PCR in sorted CD4+ and CD8+ T cells collected from 3 months post-transplant onwards. Results: CD56+ cells recovered early after transplantation, with median absolute number counts (ANC) of 69 (range 18–307), 170 (0–366) and 159 (32–531) cells/uL in days +15, +35 and +55 samples [normal controls 153 (71–438)], representing the largest subset within the first two months (decreasing proportions of 60%, 50% and 40%, respectively). ANC of CD4 and CD8 T cells remained low for several months, progressively increasing to reach normal ranges at different intervals. Naïve CD4 and CD8 cells (CD45RO−/CD27+) start to be detected by immunophenotyping after three months post-transplantation with median ANC of 17 (12–79) and 12 (5–103) cells/uL respectively and increasing thereafter [normal controls 860 (552–1072) and 331 (227–521)]. By the end of the first year values of T cell subsets were: CD4+, 823 (16–1123) cells/uL [normal controls 872 (470–1093)]; CD8 934 (56–1174) [normal controls 371 (208–808)], with persisting predominance of the naive phenotypes and proportions of memory phenotypes slowly increasing. B cells became detectable around day +90 with median ANC of 249 (0–1934) cells/uL, rapidly reaching values within the normal range [275 (133–684)]. Transient acute GVHD was developed by six of the 19 patients. All showed a transient drop in absolute numbers of NK, T and B cells. Chimerism analysis showed initial transient double chimerism of CB and TPD cells. Complete CB chimerism was achieved between days +15 and +94 (median, +35). Results of chimerism of lymphocyte subsets and TREC are not yet available. Conclusions: Following dual CB/TPD transplants we have observed early recovery of NK and B-cells and slow development of T cells subsets and of non-naive immunophenotypes.

Description: Background: Patients with high-risk FL intensified with HDT/ASCT may achieve prolonged remissions. The best timing for the procedure remains controversial. Patients who are transplanted in first response show a major Progression Free Survival (PFS) and Event Free Survival (EFS) advantage compared to those treated with conventional chemotherapy. Nevertheless, no randomized studies have yet shown an overall survival (OS) benefit. Populational-based and very long-term retrospective analysis are indispensable tools to assess the actual impact on outcome of therapeutic interventions in FL. With this assumption we performed a retrospective analysis in FL patients undergoing HDT/ASCT intensification included in the GELTAMO Spanish Group Registry. Objectives: The overall outcome as well as the clinical evolution according to the disease status at transplant, to the Follicular Lymphoma International Prognostic Index (FLIPI and FLIPI II) and to the previous exposure to Rituximab. Series characteristics: Six hundred and sixty six patients with FL (mean age 47 years, male 49%) undergoing HDT/ASCT between 1989 and 2007 were reported to the GELTAMO registry. Patients with histological transformation at the time of HDT/ASCT, those undergoing a 2nd transplant and those with a follow-up of less than 7 years were excluded. Thus, 640 patients were included in the analysis. Median follow-up was 12.2 years from HDT/ASCT and 14.2 years from diagnosis. Follow-up from HDT/ASCT was over 16 years for 153 patients (3rd quartile). The median time from diagnosis to HDT/ASCT was 1.8 years. Two hundred and forty-seven patients (38%) never achieved a complete remission (CR) before HDT/ASCT. Two hundred patients (31%) received HDT/ASCT after achievement of first CR (CR1), 43% of them requiring more than one chemotherapy line to achieve CR1; 26% in 2nd CR, 5% in 3rd CR, 21% in 1st partial response (PR), 12% in chemosensitive recurrence, and 5% with active disease. Of the 321 patients assessable for the FLIPI, 33% had a low-risk (LR), 36% an intermediate-risk (IR), and 45% a high-risk (HR) score; and of the 305 patients assessable for the FLIPI II, 22% had a LR, 38% an IR and 40% a HR. Of the 127 patients in CR1 assessable for the FLIPI, 28% had a LR, 40% an IR, and 32% a HR; of the 115 patient assessable for FLIPI II, 14% had a LR, 46% an IR, and 40 % a HR. One third of patients received Rituximab prior to transplant. Results: Median PFS and OS were 9.4 and 21.3 years, respectively. Patients transplanted in CR1 achieved significantly better final PFS (68%) and OS (73%), than those transplanted in 2nd CR (median PFS 110 months (mo.) and final OS 58%; P

Description: FLC is a recognized biomarker used for monitoring response and outcome of patients with amyloidosis and oligosecretory and non-secretory MM. Nevertheless, the role of FLC in the early prediction of response to the treatment in patients with gammopathies has not been fully ascertained. Against this background, we have evaluated the relationship between early FLC detection and the achievement of a deep and prolonged response after the end of the treatment in a series of patients diagnosed with MM and homogeneously treated in a single institution. Eighty-six newly diagnosed patients with MM between 2011 and January 2018 at the University Hospital Vall d'Hebron treated front-line with a bortezomib-based scheme were retrospectively analyzed. All patients had FLC levels measured by the Freelite® nephelometric assay at diagnosis, after the 2nd cycle of therapy, and at the end of treatment. Different parameters related to the FLC measurement were evaluated: normalization of the involved FLC (iFLC), ratio of involved/uninvolved FLCs (R_FLC)95% compared to the baseline, and normalization of the ratio Kappa/lambda FLC (R_K/L). The predictive value of these parameters on the response after chemotherapy treatment was evaluated by using the Pearson´s exact test, and their impact on outcomes was analyzed by Kaplan Meier method using the long rank test for comparisons. The median age of the series at diagnosis was 69 years old (45-89). Forty-seven patients (55%) were considered candidate for autologous hematopoietic stem cell transplantation, therefore receiving induction treatment with the VTD combination (bortezomib-talidomide-dexametasone). In contrast, 39 patients (45%) were not candidate for autologous transplantation and were treated with MPV (melfalan-prednisone-bortezomib). The involved Ig was IgG in 54.7% of cases, IgA in 18.6%, IgD in 1.2% and IgM in 1.2%. Twenty-four percent of patients were diagnosed with MM of light chains (12% kappa and 12% lambda), whereas only 3 patients were diagnosed as having a oligosecretory MM. Twenty-nine percent of the cases were ISS III, 33% had increased serum LDH levels, and 79% showed immunoparesis. The kappa FLC mean at diagnosis was 1603.61 mg/dL (0.06 -36100 mg/dL) and lambda FLC was 1104 mg/dL (0.05-26500 mg/dL). Kappa FLC mean after 2nd cicle was of 192.14 mg/dL (1,61-6430 mg/dL) and lambda FLC was 61.41 mg/dL (0.05-1434 mg/dL). Thrirty-seven percent of patients obtained a profound response (≥VGPR) after the 2nd cycle of therapy, being this percentage increased to 63% of patients at the end of the chemotherapy treatment. Alongside this, the normalization of the iFLC was observed after the 2nd cycle of treatment in 44% of patients, the normalization of the R_K/L in 42%, R_FLC95% was observed in 57% of patients. The great majority (80-87%) of patients attaining the normalization of any of these parameters after the 2nd cycle experienced a response ≥VGPR at the end of the treatment (table 1). With a median follow-up of 28.2 months (7-84 months), the overall PFS of the series was of 26.7 months. Of note, median PFS was of 40.3 months for patients who achieved the normalization of the iFLC after the 2nd cycle vs. 24.6 months for those who did not (p=0.047) (figure 1). Moreover, PFS was 27.3 months for those who had R_FLC95% exhibited a trend for a longer PFS (40.3 vs. 23.5 months) (p=0.09), as those patients with normalization of R_K/L who presented a PFS of 40.3 vs. 26.5 months (p=0.099). In conclusion, patients with normalization of different parameters related to FLC at 2 months of the onset of treatment exhibit a deeper and prolonged response to bortezomib-based chemotherapies, suggesting that this assessment could be of paramount interest in the early prediction of outcomes in patients with MM receiving treatment. Therefore, early FLC determinations should be incorporated into prospective clinical trials to validate these observations. Disclosures No relevant conflicts of interest to declare.

Description: Marrow cells of myeloid lineage from 115 patients with myelodysplastic syndrome (MDS) were characterized by multidimensional flow cytometry and compared with findings in 104 patients with various disorders and 25 healthy donors. Based on phenotypic and scatter characteristics, a flow cytometric scoring system (FCSS) was developed that allowed for a simple numerical display of results. The flow cytometric scores were categorized as normal/mild (0-1), moderate (2-3), or severe (≥ 4). Most flow cytometric abnormalities were significantly (P 〈 .05) more frequent in patients with MDS than in the control cohort. Flow cytometric scores in MDS patients were then retrospectively compared with marrow blast counts assessed by morphology, cytogenetics, hematologic parameters, and International Prognostic Scoring System (IPSS) risk categorization. The flow cytometric scores correlated inversely with leukocyte and absolute neutrophil counts (P 〈 .01) and correlated directly with IPSS scores (P 〈 .01) and with IPSS cytogenetic risk categories (P 〈 .01). In 111 MDS patients who underwent allogeneic hematopoietic stem cell transplantation, flow scores correlated with posttransplantation outcome. The probabilities of posttransplantation relapse were 3%, 15%, and 33% for patients with mild, moderate, and severe FCSS scores, respectively (P 〈 .01), and overall survival was 74%, 40%, and 36%, respectively, for the 3 groups (P 〈 .01). In multivariate analyses, there was a significant contribution of the flow score independent of the IPSS in predicting survival and relapse (P 〈 .01, P = .02, and P = .03, respectively). These data suggest that FCSS is useful in assessing marrows for diagnosis of MDS and in determining the prognostic outcome in patients with this disorder. (Blood. 2003;102:394-403)