COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency

Molecular analysis of immunoglobulin genes in multiple myeloma

The study of immunoglobulin genes in multiple myeloma over the last five years has provided important information regarding biology, ontogenetic location, disease evolution, pathogenic consequences and tumor-specific therapeutic intervention with idiotypic vaccination, Detailed analysis of V-H genes has revealed clonal relationship between switch variants expressed by the bone marrow plasma cell and myeloma progenitors in the marrow and peripheral blood. V-H gene usage is biased against V4-34 (encoding antibodies with cold agglutinin specificity; anti-l/i) explaining the absence of autoimmune phenomena in myeloma compared to other B-cell lymphoproliferative disorders. V-H genes accumulate somatic hypermutations following a distribution compatible with antigen selection, but with no intraclonal heterogeneity. V-L genes indicate a bias in usage of V kappa I family members and somatic hyper mutation, in line with antigen selection, of the expressed V kappa genes is higher than any other B-cell lymphoid disorder. A complementary imprint of antigen selection as evidenced by somatic hypermutation of either the V-H or V-L clonogenic genes has been observed. The absence of ongoing somatic mutations in either V-H or V-L genes gives rise to the notion that the cell of origin in myeloma is a post-germinal center memory B-cell. Clinical application of sensitive PCR methods in order to detect clonal immunoglobulin gene rearrangements has made relevant the monitoring and follow-up of minimal residual disease in stem cell autografts and after myeloablative therapy. The fact that surface immunoglobulin V-H and V-L sequences consitute unique tumor-specific antigenic determinants has stimulated investigators to devise strategies aiming to generate active specific immunity against the idiotype of malignant B-cells in myeloma by constructing vaccines based on expressed single-chain Fv fragments, DNA plasmids carrying V-H+V-L clonogenic genes for naked DNA vaccination, or dendritic cell-based vaccination armed with the tumor-specific idiotype

Acute promyelocytic leukemia relapsing into FAB-M2 acute myeloid leukemia with trisomy 8

Acute promyelocytic leukemia was diagnosed in a 48-year-old man; the karyotype was normal, whereas reverse transcriptase polymerase chain reaction (RT-PCR) analysis identified PML/RAR alpha chimeric transcripts of the bcr3 type. Rather unexpectedly, the patient did not respond to all-trans retinoic acid administration; he attained complete remission with conventional chemotherapy and became PML/RAR alpha negative. Two years later while PML/RAR alpha negative nn RT-PCR he presented with thrombocytopenia. Bone marrow examination was compatible with myelodysplasia of the RAEB type; the karyotype was normal. Then, after 10 months, he developed overt acute myeloid leukemia with PML/RAR alpha negative, French-American-British MZ blasts; karyotypic analysis revealed mosaicism for trisomy 8. (C) Elsevier Science Inc., 2000. All rights reserved

Selection of immunoglobulin diversity gene reading frames in B cell lymphoproliferative disorders

Assembly of immunoglobulin (Ig) heavy (H) variable (V), diversity (D) and joining (J) gene segments constitutes an important determinant of commitment to the B cell lineage. The randomly selected D gene segment of a given VDJ complex can potentially be found in all three possible reading frames (RFs). In the present study, we examined the distribution of D gene RF in ‘immature’ and ‘mature’ B cell lymphoproliferative disorders (BCLD). We analyzed the clonotypic VDJ junctional sequences of our previously reported cases of follicular lymphoma (FL), as well as bcl-2/IgH junctions with recognized D elements, A marked under-representation of RF1 was observed, with almost equal usage of RF2 and RF3. A literature search for VDJ published sequences in various BCLD identified a similar pattern of D gene RF usage in multiple myeloma (MM), with marked predilection for RFs 2 and 3, In B cell chronic lymphocytic leukemia (B-CLL), the pattern of D-RF was 25% for RF1, 46% for RF2 and 29% for RF3, while in B cell precursor acute lymphoblastic leukemia (precursor-B-ALL) all three RFs were used with similar frequencies. The marked under-representation of RF1 in FL and MM clonogenic rearranged D genes suggests selection on the basis of antigenic properties, possibly due to constraints in forming a flexible loop within CDR3. In contrast, the more even distribution of D-RF usage in B-CLL and precursor-B-ALL suggests that, for these disorders, transformation of a immature type B cell repertoire has occurred

Phase I-II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer

Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I-II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel-ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70-100 mg m(-2) over 1 h on day 1 followed by ifosfamide 5-6 g m(-2) divided over days I and 2 (2.5-3.0 g m(-2) day(-1) over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32-72) years and performance status (WHO) of I (range, 0-2) were treated at five DLs as follows: 21 in phase I DLs (DL I : 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3-68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3-24 months), median time to progression 6.5 month (0.1-26 month), and median overall survival 13 months (0.1-33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients-with 63% developing grade 4 neutropenia (less than or equal to7 days) and in 12% of these FN, while no grade 3/4 thrombocytopenia was observed. Other toxicities included peripheral neuropathy grade 2 only in 12%, grade 1/2 reversible CNS toxicity in 17%, no renal toxicity, grade 2 myalgias in 10%, grade 3 diarrhoea in 10%, skin/nail toxicity in 17%, and grade 2 fluid retention in 2% of patients. One patient in the study treated at phase II died as a result of acute liver failure after the first cycle. In conclusion, the present phase I-II study determined the feasibility of the docetaxel-ifosfamide combination, defined the MTD and demonstrated the encouraging activity of the regimen in phase II, thus warranting further randomised phase III comparisons to single-agent docetaxel or combinations of the latter with other active agents. (C) 2003 Cancer Research UK

Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma

In this study, we analyzed the targeting of the somatic hypermutation (SHM) mechanism at specific hotspot sequence motifs in the V-H and V kappa genes of 10 follicular lymphoma (FL) cases and the V kappa and V lambda genes of 11 kappa- and six lambda -light chain expressing multiple myeloma (MM) cases. These sequences were analyzed for targeting of specific motifs, ie certain highly mutable trinucleotides (3-NTPs), the tetranucleotide (4-NTP) RGYW and its complementary, WRCY (where R = purine, Y = pyrimidine and W = A or T). Comparisons were carried out between mutation frequencies in RGYW vs WRCY and the incidence of mutations in complementarity determining region (CDR)-1 vs CDR2 vs CDR3. Statistically significant differences were obtained when comparing: (1) the ratio of mutations in 4-NTPs (RGYW, WRCY, RGYW+WRCY)/mutations in the whole V sequence in MM-V kappa vs MM-V lambda; (2) the total number of mutated 4-NTPs in MM-V kappa vs FL-V kappa; (3) the number of mutated RGYW 4-NTPs in MM-V kappa vs FL-V kappa and FL-V-H vs FL-V kappa; (4) the number of mutated WRCY 4-NTPs in MM-V kappa vs FL-V kappa (P = 0.006) and FL-V-H vs FL-V kappa; (5) the targeting of RGYW vs WRCY in the CDRs of FL-V-H genes. Similar results (regarding statistical significance) were obtained when undertaking intergroup comparisons for 3-NTPs. These findings conform well with relevant data derived from normal peripheral B cells. The differences observed in favor of 4-NTP (RGYW and WRCY) targeting in FL-V-H vs FL-V kappa and MM-V kappa vs FL-V kappa may implicate differences in the evolution of SHM coupled with selection in different stages of B cell ontogeny. Several explanations can be offered for the fact that hotspot sequences were not always targeted by SHM in FIL and MM: (1) other unrecognized motifs may be targets of SHM; (2) ‘inappropriately’ introduced mutations were fixed and propagated by the neoplastic process; (3) certain FL and MM cases might have lost their ability to correct mutations introduced in classic hotspots due to deficient mismatch-repair (MMR) mechanisms; conversely, in other cases with intact MMR function, the hotspot to non-hotspot targeting of somatic hypermutation is balanced