64 research outputs found
No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(Immuno)therapy
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
Simultaneous PML/RAR alpha and AML 1/ETO gene rearrangements in a patient with acute myeloid leukemia
Autoimmune hemolytic anemia during alpha-interferon treatment in a patient with chronic myelogenous lenkemia
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
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