A 40-year-old female patient was admitted to the Department of Oral Medicine due to oral ulcerations. Oral ulcerations were present on vestibular mucosa above teeth 21, 22, 25 and 26 and were 1 cm in ...diameter, and also around teeth 45 and 46. The patient had prolonged neutropenia due to therapy-related myelodysplastic syndrome that progressed to therapy-related acute myeloid leukemia. Initially, the patient was successfully treated with polychemotherapy for non-Hodgkin lymphoma. Unfortunately, many toxic complications ensued, such as peripheral neuropathy, dilated cardiomyopathy and therapy-related myelodysplastic syndrome/therapy-related acute myeloid leukemia. The onset of therapy-related myelodysplastic syndrome was less than six months after initiation of chemotherapy treatment, which was rather early, but cytogenetic changes (monosomy 5 and 7) were consistent with the diagnosis. Upon admission to our Department, microbiological swabs were obtained and were all negative, while x-ray finding showed that ulcerations did not have dental cause. Biopsy was not obtained as the patient had severe neutropenia and thrombocytopenia. While viral and fungal swabs were negative,
was cultured from the oral cavity. Thus, differential diagnoses are listed in this report. Neutropenic ulcerations did not heal albeit extensive medicamentous oral and systemic treatments were applied and the patient died.
(1) Background: This study aimed to examine the difference in efficacy and toxicity of involved-field (IFRT) and involved-site radiotherapy (ISRT) fields in infradiaphragmal aggressive non-Hodgkin ...lymphoma patients. (2) Methods: In total, 140 patients with infradiaphragmal lymphoma treated between 2003 and 2020 were retrospectively evaluated. There were 69 patients (49%) treated with IFRT, and 71 (51%) patients treated with ISRT. The median dose in the IFRT group was 36 Gy, (range 4-50.4 Gy), and in the ISRT group, it was 30 Gy (range 4-48 Gy). (3) Results: The median follow-up in the IFRT group was 133 months (95% CI 109-158), and in the ISRT group, it was 48 months (95% CI 39-57). In the IFRT group, locoregional control was 67%, and in the ISRT group, 73%. The 2- and 5-year overall survival (OS) in the IFRT and ISRT groups were 79% and 69% vs. 80% and 70%, respectively (
= 0.711). The 2- and 5-year event-free survival (EFS) in the IFRT and ISRT groups were 73% and 68% vs. 77% and 70%, respectively (
= 0.575). Acute side effects occurred in 43 (31%) patients, which is more frequent in the IFRT group, 34 (39%) patients, than in the ISRT group, 9 (13%) patients,
> 0.01. Late toxicities occurred more often in the IFRT group of patients, (10/53) 19%, than in the ISRT group of patients, (2/37) 5%, (
= 0.026). (4) Conclusions: By reducing the radiotherapy volume and the doses in the treatment of infradiaphragmatic fields, treatment with significantly fewer acute and long-term side effects is possible. At the same time, efficiency and local disease control are not compromised.
Composite mature B-cell lymphoproliferative neoplasms are rare entities characterized by the simultaneous presence of two or more distinctive B-cell derived monoclonal malignancies. This ...retrospective study used multiparametric flow cytometric analysis aimed at immunophenotypic profiling of composite mature B-cell lymphoproliferative neoplasms in a cohort of 413 subsequent patients with de novo leukemic B-cell chronic lymphoproliferative disorders diagnosed in our institution during a 30-month period. Biclonality was found in 16 (3.9 %) patients. The vast majority (88 %) of the cases had one of the clones phenotypically corresponding to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Only when composite cases were categorized by phenotype of the non-CLL/SLL malignant population did we find a statistically significant (
P
= 0.001) higher frequency of biclonality among cases with hairy cell leukemia (22 %). Biclonal cases had the overall B-cell membrane
κ
to
λ
ratio within the normal range (median, 1.9; reference interval 0.5–4.0), making recognition of malignancy somewhat challenging. Our analysis strategy was therefore based on the detection of aberrant B-cell phenotypes, with subsequent confirmation of the monoclonal nature of neoplastic clones with regards to light chain restriction analysis. Discrimination of the coexisting clones in biclonal cases was possible on the basis of the expression of other antigen(s) (63 %), light scatter properties (44 %), different surface light chain restriction (69 %) and/or pattern of expression (44 %). The most informative cell surface antigens proved to be CD22, CD20, surface IgM, and CD23. In conclusion, historic
κ
/
λ
ratio is not a reliable approach and is a poor measurement for the detection of composite lymphomas. More creative analysis techniques should be utilized for this purpose.
Recent developments in the diagnosis and treatment of chronic lymphocytic leukemia (B-CLL) have led to change of approach in clinical practice. New treatments have been approved based on the results ...of randomized multicenter trials for first line and for salvage therapy, and the results of numerous ongoing clinical trials are permanently providing new answers and further refining of therapeutic strategies. This is paralleled by substantial increase in understanding the disease genetics due to major advances in the next generation sequencing (NGS) technology. We define current position of the Croatian Cooperative Group for Hematologic Disease on diagnosis and treatment of CLL in the transition from chemo-immunotherapy paradigm into a new one that is based on new diagnostic stratification and unprecedented therapeutic results of B-cell receptor inhibitors (BRI) and Bcl-2 antagonists. This is a rapidly evolving field as a great number of ongoing clinical trials con-stantly accumulate and provide new knowledge. We believe that novel therapy research including genomic diagnosis is likely to offer new options that will eventually lead to time limited therapies without chemotherapy and more effective clinical care for B-CLL based on individualized precision medicine.
Relapsed/refractory Hodgkin’s lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes ...of 58 patients treated with 2 cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5 g/m
2
/day and MESNA 5 g/m
2
/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5 g/m
2
over 12 h (day 3), and mitoxantrone 20 mg/m
2
(day 1) administered every 2 weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96 % of patients. Overall response rate was 74 % (89 % in relapsing and 45 % in refractory patients) with 31 % complete remissions. After a median follow-up of 54 months, 5-year event-free survival was 56 % (69 % for relapsing and 35 % for refractory patients), and 5-year overall survival was 67 % (73 % for relapsing and 55 % for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options.
The influence of the germinal-center B-cell (GCB) and the non-GCB phenotypes of diffuse large B-cell lymphoma (DLBCL) on the outcome of 92 patients treated with cyclophosphamide, doxorubicin, ...vincristine, and prednisone (CHOP) or CHOP-like chemotherapy, with or without rituximab was determined in this study. The differentiation between the GCB and non-GCB types was arrived at by immunohistochemistry using previously published criteria. Thirty-nine patients had the GCB and 53 had the non-GCB type of DLBCL. Forty-nine patients were treated with rituximab and chemotherapy; 43 were treated with chemotherapy alone. The GCB and non-GCB group did not differ in their international prognostic index factors and score, presence of bulky disease, or frequency of rituximab treatment. Median follow-up of the surviving patients was carried out for 37 months. There was no difference between the GCB and non-GCB groups in both overall response rates (67 vs. 70%, respectively) and estimated rates of 3-year event-free (46 vs. 49%, respectively) and overall (54 vs. 56%, respectively) survival. In addition, no differences of the outcomes were observed between the subgroups treated with or without rituximab. The patients of this study with immunohistochemically determined GCB-type DLBCL did not have an improved prognosis, irrespective of whether they had received rituximab or not.
A proportion of patients with multiple myeloma (MM) who have already undergone autologous stem cell transplantation (autoSCT) might benefit from a further transplantation. For this, they might need ...to undergo another round of stem cell mobilization. We analyzed retrospectively the outcomes of stem cell mobilization with plerixafor and granulocyte colony‐stimulating factor (G‐CSF) in a group of 30 patients who had undergone autoSCT previously, and in 46 other patients. The previously transplanted patients were significantly different from the remaining patients with respect to the intensity and number of previous therapies. We observed that the median peripheral blood concentration of CD34+ cells after the first administration of plerixafor was lower in previously transplanted (19 cells/μL) than in other patients (30 cells/μL, P < 0.05). Despite a comparable number of apheresis sessions being performed, the median total yield of CD34+ cells was significantly lower in the previously transplanted than in the remaining patients (2.8 × 106 cells/kg vs. 4.2 × 106 cells/kg, P < 0.05). However, successful collection of at least 2.0 × 106 CD34+ cells/kg was achieved finally in a similar proportion of previously transplanted and other patients (70% vs. 82.6%). Our data suggest that stem cell mobilization with plerixafor and G‐CSF might overcome the negative effect of prognostic factors for poor stem cell mobilization in patients with MM who have undergone autoSCT previously.
To evaluate the clinical utility of incorporating a novel heavy/light chain immunoassay (HLC) into the existing methods for the assessment of multiple myeloma (MM) patients.
Convenience sera samples ...from 90 previously treated IgG and IgA MM patients in different disease stages were analyzed. The study was conducted in Clinical Hospital Center Zagreb between 2011 and 2013. The collected sera were analyzed by standard laboratory techniques (serum protein electrophoresis, quantification of total immunoglobulins, serum immunofixation, serum free light chain FLC assay) and HLC assay.
HLC ratios outside the normal range were found in 58 of 90 patients, including 28 out of 61 patients with total immunoglobulin measurements within the normal range and 5 out of 23 patients in complete response. Both elevated HLC isotype level and abnormal HLC ratio correlated with the parameters of tumor burden, including percentage of plasma cells in the bone marrow (P<0.001 and P=0.002, respectively) and an abnormal serum FLC ratio (for both P<0.001). In addition, abnormal HLC isotype level correlated with serum beta-2-microglobulin level (P=0.038). In terms of prognosis, abnormal HLC isotype level and abnormal HLC ratio were significantly associated with shorter overall survival (P<0.001 and P=0.002, respectively). Interestingly, suppression of the uninvolved (polyclonal) isotype pair, but not other non-myeloma immunoglobulin isotypes, was also associated with a shorter overall survival (P=0.021). In a multivariate analysis, an abnormal HLC ratio and β2-microglobulin level >3.5mg/L were independent risk factors for survival.
The new HLC assay has greater sensitivity in detecting monoclonal protein, correlates with tumor burden markers, and affects patients' outcome.
The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the ...interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-κB) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells’ interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.
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