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The treatment landscape of chronic lymphocytic leukemia (CLL) has been challenged by the advent of novel classes of drugs, such as B-cell receptor (BCR)-inhibitors and BCL-2 antagonists. In selected high-risk patients, the choice to start allogeneic hematopoietic stem cell transplantation (alloHCT) or continue these agents is a matter of debate. Furthermore, published data about the impact on the feasibility of alloHCT and the optimal timing of administration are limited. Here we present a case of relapsed TP53 mutated CLL treated with ibrutinib as a bridge to alloHCT, discussing risks and benefits of different treatment options in a “real life” situation.

We evaluated 58 patients with relapsed or refractory (r/r) acute B-lymphoblastic leukemia (B-ALL; median age 42.5 years; range, 16-69 years), treated with inotuzumab ozogamicin (INO) between 2016-2022 and who received an allogeneic hematopoietic stem cell transplantation (allo-HCT) consecutively. Forty-seven (81%) of the 58 patients were heavily pretreated receiving intensive chemotherapy +/- tyrosine kinase inhibitor, blinatumomab in 24 (41%) and allo-HCT at first-line in 11 (19%) patients. Complete remission rate prior to allo-HCT was 84%. Median follow-up was 30.5 months and median overall survival (OS) measured from start of INO was 11.2 months. One- and 2-year OS rates were 50% (95% confidence interval [CI]: 38.4-56.1) and 36.7% (95% CI: 25.5-52.9), respectively. Sinusoidal obstruction syndrome/venous occlusive disease (SOS/ VOD) after allo-HCT occurred in 17 (29%) patients. Of those, nine (53%) patients died due to SOS/VOD and multi-organ failure. Two had received >2 INO cycles (3 cycles, 5 cycles, N=1, each), all others ≤2 INO cycles prior to allo-HCT. Logistic regression analysis revealed conditioning with double alkylators (P=0.038) and allo-HCT during first-line therapy (P=0.050) as significant risk factors for SOS/VOD and in trend allo-HCT ≤60 days from last INO application (P=0.07), whereas number of INO cycles before allo-HCT and time between last INO application and allo-HCT were not significant. Relapse/progressive disease occurred in 20 (34%) patients. Of those, five (25%) patients are still alive, whereas 15 succumbed of their disease. Treatment with INO seems to be an effective approach with successful bridge-to-transplant. However, risk of SOS/VOD is high, necessitating continuous monitoring and recognition of SOS/VOD risk factors.

There is much evidence demonstrating that psychosocial interventions in caregivers and oncological staff produce an improvement in their patients' quality of life. The aim of this explorative study was to evaluate the effect of a new approach in promoting more functional ways to face stressful situations in the constellation of people around patients: caregivers, physicians and nurses. Thirty-four subjects were divided into three groups: 10 caregivers, 11 physicians, and 13 nurses. A "Balint Group" method modified according to a mindfulness technique was used as the intervention. Three assessment tools were administered to the participants at baseline, during, and after completion of the study: the Response Evaluation Measure (REM-71), the Satisfaction Profile (SAT-P), and the Group Climate Questionnaire (GCQ). Mean values of defense mechanisms determined by the REM-71 were compared with those of the standard population. At baseline, we observed a prevalence of immature defenses in the three groups, with mean values above those in the standard population. After the psychological intervention, a tendency to normalization of the mean values was observed, indicating the development of more adaptive ways of using defense mechanisms and the effectiveness of the intervention. Group climate, assessed through the GCQ, showed an increase in the "Engagement" factor and a decline in the "Conflict" factor in all groups. This study suggests that group treatment focused on changing personal responses to stressful situations can induce more adaptive strategies enabling caregivers, hematologists, and nurses to help patients better and thereby improve their quality of life., (© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We characterized immunoglobulin heavy chain (IGH) gene rearrangements and searched for clusters of stereotyped B-cell receptors in 123 patients with Waldenström macroglobulinemia (WM; n = 59) or immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) (n = 64). A productive monoclonal IGHV-D-J rearrangement was obtained in 99/123 patients (80%). Immunoglobulin heavy chain variable (IGHV) genes were mutated in 94/99 patients (95%) with a median somatic hypermutation rate of 6.7% (2.1-14.5). Compared with the normal B-cell repertoire, patients with WM/IgM-MGUS showed an over-representation of the IGHV3 subgroup (83% vs. 55%, p < 0.0001) and an under-representation of IGHV1 (7% vs. 14%, p = 0.04) and IGHV4 (7% vs. 23%, p = 0.0001) subgroups. At the gene level, in WM/IgM-MGUS there was an over-representation of IGHV3-23 (24% vs. 12%, p = 0.0003), IGHV3-64 (3% vs. < 1%, p = 0.003), IGHV3-7 (12% vs. 4%, p = 0.0001) and IGHV3-74 (9% vs. 2%, p < 0.0001), while IGHV4-39 was never used (0 vs. 5%, p = 0.03). Intra-WM/IgM-MGUS search for HCDR3 similarity showed no association fulfilling criteria for stereotyped receptors. WM/IgM-MGUS sequences were unrelated to known chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL) or mantle cell lymphoma (MCL) subsets. In conclusion, the IGHV gene usage in WM and IgM-MGUS is remarkably biased as compared to the normal B-cell repertoire. WM and IgM-MGUS-specific HCDR3 clusters do not occur with a frequency detectable with currently available databases, not supporting a B-cell receptor-driven pathogenesis in WM and IgM-MGUS.

Objective: Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS) require quantification of bone marrow plasma cells (BMPCs) and skeletal survey to discriminate between MGUS and multiple myeloma (MM). By contrast, recent published guidelines suggest that these procedures could be avoided in the presence of serum monoclonal spike (M-spike) of small amount (≤1.5 g/dL). Aim of this study is to better quantify the risk of missing a diagnosis of MM, not performing bone marrow aspirate and skeletal survey in patients with M-spike ≤ 1.5 g/dL asymptomatic for bone pain., Methods: We reviewed data of 2282 patients consecutively observed from January 1974 to December 2010 in our single hematology department. We considered eligible for this study 1271 patients with grade <2 NCI bone pain, confirmed to have an MGUS or an MM after extensive standardized diagnostic workup including bone marrow biopsy, skeletal bone survey and laboratory tests., Results: The risk of finding a BMPC infiltration ≥10% in patients with an M-spike ≤ 1.5 g/dL was very low (7.3%), although significantly different according to IgH isotype (4.7% for IgG vs. 20.5% for IgA). The risk of finding bone lesions with M-spike ≤ 1.5 g/dL was negligible (2.5%), regardless of IgH isotype., Conclusion: In asymptomatic patients with M-spike of small amount (≤1.5 g/dL): (i) BMPC evaluation may be reasonably avoided in patients with IgG M-spike, while should always be part of diagnostic workup in the presence of IgA M-spike and (ii) skeletal survey, less predictive for MM, should not be routinely indicated irrespective of IgH isotype., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: High-dose therapy with autologous peripheral stem cell transplantation represents today the standard approach for younger multiple myeloma patients. This study aimed to evaluate the long term economic impact of autologous transplantation with respect to conventional therapy., Methods: We retrospectively reviewed the charts of multiple myeloma patients diagnosed at our department between 1986 and 2003 and treated according to the therapy considered standard at the time of diagnosis. Analysis of costs was done by assessing resource utilization and direct costs were measured and monetized before proceeding with the analysis, based on public health service tariffs., Results: Group A including 78 patients treated with Melphalan and Prednisone was compared with Group B including 74 patients who received an autologous transplant. The median overall survival was 3.2 and 5.4 years respectively (p = 0.0002). Mean cost per patient was significantly higher in group B with respect to group A (102373€ vs 23825€; p<0.001). The final quality-adjusted-life-year gain in group B patients as compared to group A was 1.73 QALY, with an incremental cost-effectiveness ratio of 45460€. With a threshold of 75000€ per QALY gained, the cost effectiveness acceptability curve indicated that the probability that autologous transplantation in multiple myeloma is a cost-effective intervention is 90%., Conclusions: The cost of autologous transplantation remains high. The calculated incremental cost-effectiveness ratio, however, given the significant prolongation of overall survival obtained with autologous transplantation, is within an acceptable threshold. Notwithstanding, its high cost should be taken into account when considering the whole cost of multiple myeloma.

Since multiple myeloma (MM) is still not-curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B-MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80-100 mg/m² i.v.) on day 1. The original 21-day schedule was early amended for extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty-four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression-free survival (PFS) was 19.1 months. B-MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib-naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B-MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase., (Copyright © 2012 Wiley Periodicals, Inc.)

In this study, IGHV1-69 gene usage was detected in 46 out of 379 cases (12%) of chronic lymphocytic leukemia (CLL). In comparison with patients using alternative immunoglobulin heavy-chain variable (IGHV) genes, patients with IgHV1-69 CLLs more often presented at advanced stage, lacked somatic hypermutation (unmutated cases, 87% vs. 35%; P = .00001), and expressed unfavorable biologic characteristics. In 12 patients (26%), common amino acid motifs within the heavy-chain third complementarity-determining region were identified, allowing assignment to previously reported stereotyped subsets. In our study, treatment-free survival of patients with unmutated IGVH1-69 did not differ significantly from that of patients expressing unmutated alternative IGHV genes. As such, IGHV1-69 gene usage per se did not seem to be predictive of progressive disease, progression being primarily related to the unmutated IGHV profile.