Melphalan 140mg/m2 or 200mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party

Melphalan at a dose of 200mg/m2 is standard conditioning prior to autologous haematopoietic stem cell transplantation for multiple myeloma, but a dose of 140mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine if melphalan 200 and melphalan 140 are equally effective and tolerable in clinically relevant patient subgroups we analysed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, haematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 (n=245) and melphalan 200 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 versus melphalan 140: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favoured melphalan 140 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 and melphalan 140 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favour melphalan 200 or melphalan 140 for key transplant outcomes (NCT01362972)

High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes have been shown to account for the majority of hereditary breast and ovarian cancers. The purpose of our study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1/2 genes in high-risk Czech families. METHODS: A total of 96 Czech families with recurrent breast and/or ovarian cancer and 55 patients considered to be at high-risk but with no reported family history of cancer were screened for mutations in the BRCA1/2 genes. The entire coding sequence of each gene was analyzed using a combination of the protein truncation test and direct DNA sequencing. RESULTS: A total of 35 mutations in the BRCA1/2 genes were identified in high-risk families (36.5%). Pathogenic mutations were found in 23.3% of breast cancer families and in 59.4% of families with the occurrence of both breast and ovarian cancer. In addition, four mutations were detected in 31 (12.9%) women with early onset breast cancer. One mutation was detected in seven (14.3%) patients affected with both a primary breast and ovarian cancer and another in three (33.3%) patients with a bilateral breast cancer. A total of 3 mutations in BRCA1 were identified among 14 (21.4%) women with a medullary breast carcinoma. Of 151 analyzed individuals, 35 (23.2%) carried a BRCA1 mutation and 9 (6.0%) a BRCA2 mutation. One novel truncating mutation was found in BRCA1 (c.1747A>T) and two in BRCA2 (c.3939delC and c.5763dupT). The 35 identified BRCA1 mutations comprised 13 different alterations. Three recurrent mutations accounted for 71.4% of unrelated individuals with detected gene alterations. The BRCA1 c.5266dupC (5382insC) was detected in 51.4% of mutation positive women. The mutations c.3700_3704del5 and c.181T>G (300T>G) contributed to 11.4% and 8.6% of pathogenic mutations, respectively. A total of eight different mutations were identified in BRCA2. The novel c.5763dupT mutation, which appeared in two unrelated families, was the only recurrent alteration of the BRCA2 gene identified in this study. CONCLUSION: Mutational analysis of BRCA1/2 genes in 151 high-risk patients characterized the spectrum of gene alterations and demonstrated the dominant role of the BRCA1 c.5266dupC allele in hereditary breast and ovarian cancer

Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor

Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups

Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

<p>Abstract</p> <p>Background</p> <p>Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations.</p> <p>The current study was aimed at establishing the mutation spectrum of <it>BRCA1/2 </it>in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families.</p> <p>Methods</p> <p>The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the <it>BRCA1/2 </it>screening were: (i) probands with at least two first degree relatives with breast and ovarian cancer; (ii) probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii) individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family.</p> <p>Results</p> <p>Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A <it>BRCA1/2 </it>mutation was found in 56 (39%). Two novel large deletions covering consecutive exons of <it>BRCA1 </it>were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the <it>BRCA1 </it>gene and IVS16-2A>G in the <it>BRCA2 </it>gene). The IVS16-2A>G in the <it>BRCA2 </it>gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the <it>BRCA1/2 </it>positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of the cryptic cysteine residues of the <it>BRCA1 </it>Ring Finger domain.</p> <p>Conclusion</p> <p>A high mutation detection rate and the frequent occurrence of a limited array of recurring mutations facilitate <it>BRCA1/2 </it>mutation screening in Slovenian families.</p

Presymptomatic breast cancer in Egypt: role of BRCA1 and BRCA2 tumor suppressor genes mutations detection

<p>Abstract</p> <p>Background</p> <p>Breast cancer is one of the most common diseases affecting women. Inherited susceptibility genes, <it>BRCA1 </it>and <it>BRCA2</it>, are considered in breast, ovarian and other common cancers etiology. <it>BRCA1 </it>and <it>BRCA2 </it>genes have been identified that confer a high degree of breast cancer risk.</p> <p>Objective</p> <p>Our study was performed to identify germline mutations in some exons of <it>BRCA1 </it>and <it>BRCA2 </it>genes for the early detection of presymptomatic breast cancer in females.</p> <p>Methods</p> <p>This study was applied on Egyptian healthy females who first degree relatives to those, with or without a family history, infected with breast cancer. Sixty breast cancer patients, derived from 60 families, were selected for molecular genetic testing of <it>BRCA1 </it>and <it>BRCA2 </it>genes. The study also included 120 healthy first degree female relatives of the patients, either sisters and/or daughters, for early detection of presymptomatic breast cancer mutation carriers. Genomic DNA was extracted from peripheral blood lymphocytes of all the studied subjects. Universal primers were used to amplify four regions of the <it>BRCA1 </it>gene (exons 2,8,13 and 22) and one region (exon 9) of <it>BRCA2 </it>gene using specific PCR. The polymerase chain reaction was carried out. Single strand conformation polymorphism assay and heteroduplex analysis were used to screen for mutations in the studied exons. In addition, DNA sequencing of the normal and mutated exons were performed.</p> <p>Results</p> <p>Mutations in both <it>BRCA1 </it>and <it>BRCA2 </it>genes were detected in 86.7% of the families. Current study indicates that 60% of these families were attributable to <it>BRCA1 </it>mutations, while 26.7% of them were attributable to <it>BRCA2 </it>mutations. Results showed that four mutations were detected in the <it>BRCA1 </it>gene, while one mutation was detected in the <it>BRCA2 </it>gene. Asymptomatic relatives, 80(67%) out of total 120, were mutation carriers.</p> <p>Conclusions</p> <p><it>BRCA1 </it>and <it>BRCA2 </it>genes mutations are responsible for a significant proportion of breast cancer. <it>BRCA </it>mutations were found in individuals with and without family history.</p

Prospective noninterventional study on peripheral blood stem cell mobilization in patients with relapsed lymphomas

Item does not contain fulltextHigh-dose chemotherapy followed by autologous stem cell transplantation (ASCT) to rescue hematopoiesis is considered standard care for patients with a relapsed chemosensitive lymphoma, but diagnosis of lymphoma has been a risk factor for poor mobilization in several studies. The aim of this prospective noninterventional clinical audit was to review the mobilization strategies used by EBMT centers in relapsed lymphoma and to evaluate their efficacy. Between 2010 and 2014, 275 patients with relapsed lymphoma from 30 EBMT centers were prospectively registered. Almost all patients were mobilized with chemotherapy plus G-CSF (96%), but there was a large variation in chemotherapy schedules. Thirty (11%) of them were poor mobilizers (<2 x 106 CD 34+ cells/kg body weight) at the first mobilization. Poor mobilization was not associated with gender, age, bone marrow involvement at diagnosis, primary diagnosis, number of previous chemotherapy lines, previous radiotherapy or mobilization with G-CSF alone. The use of high dose cyclophosphamide alone was associated with mobilization failure (P = 0.0006), whereas the use of a platinum-containing regimen was associated with a good mobilization outcome (P = 0.013). Because failure rate is low, we can conclude from this study that PBSC mobilization failure in relapsed lymphomas is not an important problem in the EBMT centers