Miguel A. Pavlovsky

Oligoclonal bands and immunoglobulin isotype switch during monitoring of patients with multiple myeloma and autologous hematopoietic cell transplantation: a 16-year experience.

Abstract Background: Over the last 20 years, high dose therapy followed by hemopoietic stem cell transplantation has been employed in patients with multiple myeloma (MM). During 16 years of follow-up, the degree of tumor response and survival in 238 patients with autologous stem cell transplantation (ASCT) and changes in the serum protein electrophoretic pattern were analyzed. Methods: Agarose gel electrophoresis with densitometric analysis and immunofixation were performed to evaluate serum monoclonal protein. IgM, IgA, IgG and β2-microglobulin (β2M) were quantitated. Urine protein electrophoresis with IF was performed on cellulose acetate gel using colloidal silver staining without concentrating. Results: After 34 months of follow-up (range 1–160 months), eight patients (3.4%) showed a distinct monoclonal protein band that was different from their original isotype switch. This was observed to be a transient phenomenon (22.2 months). Thirty-seven patients (15.5%) developed oligoclonal bands (OB) between the first and the twentieth month after ASCT (mean 4.4 months), which persisted for 7.9 months (1–36 months). The mean overall survival time was statistically different (p<0.05) between the group with OB and the group without them. Mean values of serum albumin, β2M, and non-involved immunoglobulins did not show statistical differences. Conclusions: The occurrence of OB could be a potential favorable prognostic marker after transplantation due to the prolonged survival observed. Close follow-up of anomalous protein bands, either in serum or urine, is essential due to the additional difficulty in interpretation when the therapeutic response and evolution are evaluated. Clin Chem Lab Med 2010;48:727–31.

Increased immature hematopoietic progenitor cells CD34+/CD38dim in myelodysplasia

Myelodysplastic syndromes (MDS) are clonal disorders affecting hematopoietic progenitor cells (HPC). Despite the relevance of clonal CD34+ cells in developing MDS, only few studies analyze the phenotype of this cell population. The aim of this study was to evaluate phenotypic changes on HPC in MDS that could reflect abnormalities in the differentiation process of stem cells.

SOXC and MiR17-92 gene expression profiling defines two subgroups with different clinical outcome in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a heterogeneous B‐cell lymphoid malignancy where most patients follow an aggressive clinical course whereas others are associated with an indolent performance. SOX4, SOX11, and SOX12 belong to SOXC family of transcription factors involved in embryonic neurogenesis and tissue remodeling. Among them, SOX11 has been found aberrantly expressed in most aggressive MCL patients, being considered a reliable biomarker in the pathology. Several studies have revealed that microRNAs (miRs) from the miR‐17‐92 cluster are among the most deregulated miRNAs in human cancers, still little is known about this cluster in MCL. In this study we screened the transcriptional profiles of 70 MCL patients for SOXC cluster and miR17, miR18a, miR19b and miR92a, from the miR‐17‐92 cluster. Gene expression analysis showed higher SOX11 and SOX12 levels compared to SOX4 (P ≤ 0.0026). Moreover we found a negative correlation between the expression of SOX11 and SOX4 (P < 0.0001). miR17‐92 cluster analysis showed that miR19b and miR92a exhibited higher levels than miR17 and miR18a (P < 0.0001). Unsupervised hierarchical clustering revealed two subgroups with significant differences in relation to aggressive MCL features, such as blastoid morphological variant (P = 0.0412), nodal presentation (P = 0.0492), CD5+ (P = 0.0004) and shorter overall survival (P < 0.0001). Together, our findings show for the first time an association between the differential expression profiles of SOXC and miR17‐92 clusters in MCL and also relate them to different clinical subtypes of the disease adding new biological information that may contribute to a better understanding of this pathology.

Molecular Monitoring of Imatinib in Chronic Myeloid Leukemia Patients in Complete Cytogenetic Remission: Does Achievement of a Stable Major Molecular Response at any Time Point Identify a Privileged Group of Patients? A Multicenter Experience in Argentina and Uruguay

BACKGROUND Monitoring minimal residual disease (MRD) by real-time quantitative polymerase chain reaction (RT-PCR) in chronic myeloid leukemia (CML) patients is mandatory in the era of tyrosine kinase inhibitors. Achieving a major molecular response (MMR) at 12 and 18 months predicts a better progression and event-free survival. PATIENTS AND METHODS The objective of this prospective, multicentric study was to evaluate MRD by standardized RT-PCR in 178 patients with chronic-phase CML who were treated with imatinib at different institutions in Argentina and Uruguay and to determine if achievement of a stable MMR (BCR-ABL transcript levels < 0.1%) identifies a low-risk cytogenetic relapse group. The median age of the patients was 50 years, and 55% of them had received imatinib as first-line therapy. BCR-ABL transcript levels were measured after achievement of complete cytogenetic remission (CCyR) and at 6-month intervals. RESULTS MMR was detected in 44% patients at the start of the study. This value increased to 79% at month 36 of evaluation. Complete molecular response (CMR) also increased from 24% to 52% of patients. Not achieving a stable MMR determined a higher risk of cytogenetic relapse (9% of MMR patients not achieving an MMR vs. 1% of patients who achieved MMR). Patients with sustained MMR had a significantly better cytogenetic relapse-free survival at 48 months (97% vs. 87%; P = .008) but showed no differences in overall survival. Patients who did not remain in CCyR changed treatment. CONCLUSIONS A stable MMR is a strong predictor for a durable CCyR. Standardized molecular monitoring could replace cytogenetic analysis once CCyR is obtained. These results emphasize the validity and feasibility of molecular monitoring in all standardized medical centers of the world.

Serum free light chains and oligoclonal bands in patients with multiple myeloma and autologous stem cell transplantation.

Abstract Background: To establish stringent complete remission (SCR) in patients with multiple myeloma (MM), it is currently recommended to obtain a normal serum free light chains (sFLC) ratio. The appearance of serum oligoclonal bands (OB) after autologous stem cell transplantation (ASCT) is considered a favorable prognostic factor. The objective of this study was to examine sFLC for assessing SCR in patients with MM, and ASCT with OB. We also examined how capillary electrophoresis (CE) compares with agarose gel electrophoresis (Aga) in identifying oligoclonal bands. Methods: Out of 238 patients studied in our institution between April 1992 and December 2008 a serum protein electrophoresis (SPE) was performed by means of CE and sFLC determination on 37 patients with MM in complete remission (CR), ASCT and OB presence were assigned by conventional Aga electrophoresis and IF. Results: Statistically significant differences (SSD) were found when comparing CE vs. Aga, regarding BO visualization in SPE, favoring the latter. In connection with sFLC, the group of patients with an abnormal ratio presented elevated values in the γ-globulin zone of the SPE, whereas the group of patients with a normal ratio of sFLC presented with normal values resulting in SSD between the groups. Conclusions: It is essential to perform immunofixation to certify the presence of OB, especially if CE is used as it is difficult to distinguish them using this method. A normal sFLC was observed in most of the patients with OB and normal values of the SPE γ-globulin zone. The above-mentioned information might demonstrate a limitation of sFLC test in SCR evaluation for patients with MM, ASCT and CR if OB has been detected.

Prognostic factors in monoclonal gammopathy of undetermined significance

A retrospective evaluation of 285 patients with monoclonal gammopathy of undetermined significance was performed to identify variables associated with progression, actuarial progression free survival (PFS) and overall survival (OS). Three variables, level of uninvolved immunoglobulins (HR 4.98, CI95% 2 –12.4, p=0.0006), monoclonal protein concentration (HR 4.04, CI95% 1.6–10.34, p=0.004), and erythrosedimentation rate (HR 3.94, CI95% 1.33–11.6, p=0.01), showed independent prognostic significance. With a median follow-up of 66 months (range 6–378), PFS and OS at 10 years were 89% and 91% respectively.

Risk-Adapted Therapy With Three or Six Cycles of Doxorubicin/Bleomycin/Vinblastine/Dacarbazine Plus Involved-Field Radiation Therapy in Hodgkin Lymphoma, Based on Prognosis at Diagnosis and Early Response: Results From the GATLA Study

BACKGROUND Doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) plus involved-field radiation therapy (IFRT) is the gold-standard treatment for early and advanced stages of Hodgkin lymphoma (HL). We evaluated the outcomes of patients according to prognosis at diagnosis and over time to determine who achieved complete remission (CR). PATIENTS AND METHODS Treatment-naive patients under the age of 75 years at all stages of HL were eligible. The favorable group (FG) contained patients with stage IA-IIIA disease without bulky areas who achieved CR after the third cycle of ABVD. They received only IFRT at 25 Gy. Patients in the unfavorable group (UG) exhibited stages IIIB and IV HL. The UG also included all patients with bulky disease and the subset of the FG without CR after 3 cycles of ABVD, ie, slow responders (FGSR). The UG received 6 cycles of ABVD plus IFRT at 30 Gy to bulky areas at diagnosis or to those areas remaining positive after the third cycle of ABVD. RESULTS In total, 584 patients were evaluable: 285 of them belonged to the FG, and 299 to the UG. Rates of CR were 98% and 85% for the FG and the UG, respectively (P < .001). Sixty patients in the FG received 6 cycles of ABVD because they had not achieved CR after 3 cycles (ie, the FGSR subgroup). The 5-year event-free survival rate was 89% for the FG, 66% for the FGSR, and 72% for the UG (P < .001). The overall survival at 5 years was significantly better for the FG (98%) than for the FGSR (87%) and the UG (88%; P < .001). CONCLUSION Patients from the FG demonstrated excellent outcomes compared with those from the FGSR and UG, despite receiving less chemotherapy and fewer doses of IFRT.

Impact of Ibrutinib in Quality of Life (QoL) in Patients with Chronic Lymphocytic Leukemia (CLL): Preliminary Results of Real-World Experience

S218 association of several mutations is common. VAF is very variable, whether patients appear in clinical response or progressive. These results raise the question of the clinical significance of these mutations and a follow-up is required to determine if all these mutations are actually predictive of disease progression.