Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare, cutaneous lymphoma involving subcutaneous adipose tissue. SPTL is associated in less than 20% with hemophagocytic syndrome (HPS). A ...5-year overall survival rate is inferior in patients with SPTL and HPS (46%) as compared with 91% in patients without HPS. No standardized therapy for SPTCL has yet been established. This is a case of 35-year-old Caucasian man with a one-month history of B symptoms with the suspicion of Still’s disease, at admission with leucopenia, high LDH, ferritin, sIl-R2, and triglycerides levels, hepatosplenomegaly, small right supraclavicular nodule, and irregular thickening of trunk subcutaneous tissue. The abdomen MRI showed generalized thickening of mesentery and colonic mucosa. In the patient, diagnosis of SPTCL was established with secondary HPS. CHOEP chemotherapy and modified HLH 2014 protocol were applied with subsequent high dose chemotherapy (BEAM) supported by autologous stem cells transplantation. Treatment was complicated by pancytopenia and pneumonia. The outcome of the disease treated by intensive protocol seems to be good.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute ...to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10
for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10
for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.
Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). ...However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60‐65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.
We evaluated the association between germline genetic variants located within the 3′‐untranlsated region (polymorphic 3′UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We ...performed a case‐control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10‐rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3′‐UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A‐allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10‐rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.
What's new?
The polymorphic 3′‐untranslated region (p3UTR) has been shown to affect gene expression and lead to differential predisposition or prolonged survival in a variety of cancer types. Here, the authors evaluate the association between germline genetic variants within the p3UTR of candidate genes involved in multiple myeloma. The results show that IL10‐rs3024496 might affect immune homeostasis through the modulation of IL10 mRNA expression. Overall, the findings suggest that the inclusion of personal genetic background information into the clinical evaluation criteria could help to improve the stratification of patients with multiple myeloma in terms of risk progression and prognosis.
Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of ...low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission CR, 32%; CR with incomplete hematologic recovery CRi, 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.
We present the results of a prospective, non-randomized phase 2 trial in which 253 AML patients (pts) under 60 years old received DAC (Daunorubicin + AraC + Cladribine) as first induction followed by ...CLAM (Cladribine + AraC + Mitoxantrone) as early second induction on day 16 based on bone marrow (BM) blasts on day 14 (D14). The CR/CRi rate after a single course of DAC was 83% for pts with D14 BM blasts less than 10%. Forty-six pts had >10% BM blasts on D14, of whom 35 received CLAM with rates of CR/CRi 60% and early death (ED) 23%. The remaining 11 pts were not fit to receive CLAM, with rates of CR/CRi 28%, PR 18%, and ED 18%. Median OS was 7.2 versus 7.5 months, respectively. The overall CR/CRi rate was 77% after the first induction, with final CR/CRi rate 80% after DAC reinduction for pts who achieved PR with initial DAC course. CLAM used as early second induction might improve CR/CRi rates for younger AML pts with poor early response to DAC induction, but may be associated with higher mortality.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a ...major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18–1·95, P = 0·00087, and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44–3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2‐rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2‐rs4148388 and MM outcome that is supported by a plausible biological explanation.
Systemic mastocytosis (SM) is a rare clonal disorder with multi-organ involvements and shortened life expectancy. To date, no curative treatment for SM exists. Cladribine (2-CdA) is a purine analogue ...showing activity against neoplastic mast cells and its use was found to be effective in some patients with SM. Nine patients (six males and three females) with advanced SM at median age of 63 years (range 33–67) who received at least one course of 2-CdA were included in a retrospective analysis. Study patients were classified as having aggressive SM (ASM;
n
= 7) and SM with an associated hematological neoplasm (SM-AHN;
n
= 2). The “C” findings were as follows: (1) absolute neutrophil count (ANC) < 1 × 10
9
/l (
n
= 1) and/or hemoglobin level < 10 g/dl (
n
= 4) and/or platelet count < 100 × 10
9
/l (
n
= 4); (2) hepatomegaly with ascites (
n
= 4); (3) skeletal involvement (
n
= 2); (4) palpable splenomegaly with hypersplenism (
n
= 3) and (5) malabsorption with weight loss (
n
= 5). Treatment consisted of 2-CdA at dose 0.14 mg/kg/day intravenously over a 2-h infusion for 5 consecutive days. Median dose per cycle was 45 mg (range 35–60). Median number of cycles was 6 (range 1–7). Overall response rate (ORR) was 66% (6/9 pts) including three partial responses and three clinical improvements. ORR was 100% and 66% for SM-AHN and ASM, respectively. Median duration of response was 1.98 years (range 0.2–11.2). At the last contact, five patients died, four have little disease activity, but remain treatment- free. 2-CdA seems to be beneficial in some patients with SM, however the response is incomplete.
Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms ...(SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p = .0055, Bonferroni corrected p = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p = .0063, Bonferroni corrected p = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p = .0054, Bonferroni corrected p = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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