Experiences of and preferences for self-management among low grade non-Hodgkin's lymphoma survivors: A qualitative interview study.

PURPOSE: Supporting self-management is one strategy to help cancer survivors optimise their quality of life. Low grade non-Hodgkin's lymphoma is often incurable with a chronic disease trajectory requiring lifelong self-management. This study explored the views on self-management and preferences for self-management support among survivors of low grade non-Hodgkin's lymphoma and their informal caregivers more than 6 months after completion of systemic anti-cancer therapy. METHOD: In-depth semi-structured telephone interviews were conducted. Key themes and subthemes were determined using inductive and deductive thematic analysis. RESULTS: The sample included eight survivors of low grade non-Hodgkin's lymphoma and two family caregivers. There were four themes. 1) The chronic nature of low grade non-Hodgkin's lymphoma shapes perceptions of self-management; participants described their cancer as a chronic condition and self-management strategies reflected this. 2) Social networks enable self-management; participants emphasised the importance of making low grade non-Hodgkin's lymphoma survivors aware of social networks. 3) Support and monitoring are needed immediately after the initial treatment phase ends. 4) Preferred components of self-management support; this included regular review with monitoring, advice on diet, and strategies to manage the psychosocial consequences of low grade non-Hodgkin's lymphoma. CONCLUSIONS: Providing self-management support to those diagnosed with low grade non-Hodgkin's lymphoma is relevant given the chronic trajectory of the disease. Findings suggest that necessary components of a self-management support programme for those with low grade non-Hodgkin's lymphoma should include regular review with monitoring and practical support around facilitating engagement with social networks.

TP53 Mutations Identified Using NGS Comprise the Overwhelming Majority of TP53 Disruptions in CLL: Results From a Multicentre Study.

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations.

Regions of acquired uniparental disomy at diagnosis of follicular lymphoma are associated with both overall survival and risk of transformation.

Acquired homozygosity in the form of segmental acquired uniparental disomy (aUPD) has been described in follicular lymphoma (FL) and is usually due to mitotic recombination. SNP array analysis was performed with the use of the Affymetrix 10K 2.0 Gene-chip array on DNA from 185 diagnostic FL patients to assess the prognostic relevance of aUPD. Genetic abnormalities were detected in 118 (65%) of 182 patients. Number of abnormalities was predictive of outcome; more than 3 abnormalities was associated with inferior overall survival (OS; P < .03). Sites of recurrent aUPD were detected on 6p (n = 25), 16p (n = 22), 12q (n = 17), 1p36 (n = 14), 10q (n = 8), and 6q (n = 8). On multivariate analysis aUPD on 1p36 correlated with shorter OS (P = .05). aUPD on 16p was predictive of transformation (P = .03) and correlated with poorer progression-free survival (P = .02). aUPD is frequent at diagnosis of FL and affects probability of disease transformation and clinical outcome.

Posttransplant Lymphoproliferative Disorder After Solid Organ Transplant: A Heterogeneous, Aggressive Disorder.

Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplant. We identified 40 patients diagnosed with PTLD between 2009 and 2020 and analyzed their presentation, treatment strategies, and outcomes. Median age at diagnosis was 52.5 years (range 21.3 to 79). Median duration of immunosuppression was 95 months (range 4 to 292). Diffuse large B cell lymphoma (n = 16, 40%) and Burkitt lymphoma (n = 6, 15%) were the most common histological subtypes. First-line therapy varied. The median number of treatment lines was 1 (range 0 to 4). Sixteen patients (40%) achieved complete response after first-line therapy. Nineteen patients (47.5%) relapsed or progressed and received salvage therapy; 45% were alive at the end of the study period (median survival 52 months; range 1 to 266; 95% confidence interval 0 to 104). Causes of death included lymphoma-related (45.5%), therapy-related (27.3%), and other (27.3%). Five (22.7%) died within 3 months of diagnosis. Pearson's r test identified disease stage (P = .045) and proliferation index (P = .005) as negative predictors of response to frontline therapy. Bone marrow involvement (P = .033) and increased age (P = .018) were significant predictors of survival. Early mortality and poor response to frontline therapy are common, outlining the need for improved treatment strategies.

The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival.

The International Prognostic Index and the Follicular Lymphoma International Prognostic Index are widely used for the risk assessment of follicular lymphoma (FL). Although molecular studies have provided insight into the biology of FL, no molecular marker has impacted on treatment stratification. Because TP53 mutations are associated with poor prognosis in hematologic malignancies, we investigated the prognostic value of TP53 mutation at diagnosis in FL. Heterozygous TP53 mutation was detected in 12 of 185 (6%) analyzed cases. Mutation was associated with older age (P = .02) and higher International Prognostic Index score (P = .04). On multivariate analysis, TP53 mutation correlated with shorter progression-free survival (P < .001) and overall survival (P = .009). TP53 mutation was associated with low expression of the immune-response 1 gene expression signature (P = .016) and with an unfavorable gene expression-based survival predictor score (P < .001), demonstrating for the first time that molecular features of the malignant cell may correlate with the nature of the immune response in FL.

Molecular Monitoring in Adult Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with the Variant e13a3 BCR-ABL1 Fusion.

Monitoring BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a widely adopted method to assess response to therapy. However, a small minority of Ph+ ALL patients express variant BCR-ABL1 transcript types, usually due to splicing of alternative BCR or ABL1 exons. Whether patients expressing these rare, variant BCR-ABL1 transcripts have a distinct phenotype or response to therapy is not known due to the limited number of reported cases. Here, we report the presenting features of Ph+ ALL in a young adult with a variant e13a3 BCR-ABL1 fusion. Molecular monitoring reflected the disease response from diagnosis through allogeneic stem cell transplantation which resulted in undetectable e13a3 BCR-ABL1 transcripts. This case highlights the value of molecular monitoring in Ph+ ALL patients with variant BCR-ABL1 transcripts and the requirement for standardization of such assays.

Impact of HLA class I and class II DNA high-resolution HLA typing on clinical outcome in adult unrelated stem cell transplantation after in vivo T-cell depletion with alemtuzumab.

Survival after volunteer unrelated donor (VUD) stem cell transplantation (SCT) is influenced by matching for human leucocyte antigens (HLA). We analysed the effects of serological and molecular typing at HLA-A, -B, -C and -DRB1 in 100 patient/VUD pairs from a single transplant centre. Patients received SCT for good risk [chronic myeloid leukaemia in first chronic phase (CML-CP1), n=55] or poor risk (n=45) diseases after myeloablative conditioning and T-cell depletion with alemtuzumab. By serological typing, 70 pairs were fully matched, whereas molecular typing revealed 10 pairs with additional mismatches. The day 100 transplant related mortality was 15%. Acute graft versus host disease (GvHD) grades III-IV occurred in 11%, whilst extensive chronic GvHD in 13% of evaluable patients. There was no statistical difference in GvHD rates between patients who received grafts from fully matched or from mismatched donors. In univariate analysis the disease risk group and CMV seronegativity of recipient and donor were the only significant predictors for survival, with 3-year survival probabilities of 71.2% for CML-CP1 and 28% for poor risk diseases. In the poor risk group, HLA mismatches had a negative impact on survival (p=0.003) and progression free survival (p=0.009) contrary to CML-CP1 patients, in whom HLA mismatches at molecular or serological level did not have any impact.

Chronic Myeloid Leukemia with an e6a2 BCR-ABL1 Fusion Transcript: Cooperating Mutations at Blast Crisis and Molecular Monitoring.

A minority of chronic myeloid leukemia patients (CML) express a variety of atypical BCR-ABL1 fusion variants and, of these, the e6a2 BCR-ABL1 fusion is generally associated with an aggressive disease course. Progression of CML to blast crisis is associated with acquisition of additional somatic mutations yet these events have not been elucidated in patients with the e6a2 BCR-ABL1 genotype. Moreover, molecular monitoring is only sporadically performed in CML patients with atypical BCR-ABL1 fusion transcripts due to lack of consensus approaches or standardization. A case of CML is described in which comprehensive molecular analysis, including targeted next-generation sequencing, revealed a single ASXL1 mutation cooperating with an e6a2 BCR-ABL1 fusion transcript at blast crisis. A quantitative molecular monitoring approach was devised and adopted that reflected the disease response from initial treatment through allogeneic stem cell transplantation which resulted in undetectable e6a2 BCR-ABL1 transcripts. This case emphasizes the requirement for molecular monitoring in CML patients with atypical BCR-ABL1 fusion transcripts and emphasizes that comprehensive sequencing has the potential to identify targets for novel therapies in CML patients with advanced disease.

CALR mutation profile in Irish patients with myeloproliferative neoplasms.

Insertion and/or deletion mutations of the CALR gene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALR mutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALR mutations. CALR mutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n=40) followed by Type 2 and Type 2-like insertion mutations (n=17). The CALR mutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management.

Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.

Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia.

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.

Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy.

We identified 243 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) who had BCR-ABL transcripts monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) after allogeneic stem cell transplantation for a median of 84.3 months. Individual patients were regarded as having achieved molecular relapse (MR) if the BCR-ABL/ABL ratio exceeded 0.02% on 3 occasions or reached 0.05% on 2 occasions. Patients were allocated to 1 of 4 categories: (1) 36 patients were "persistently negative" or had a single low-level positive result; (2) 51 patients, "fluctuating positive, low level," had more than 1 positive result but never more than 2 consecutive positive results; (3) 27 patients, "persistently positive, low level," had persisting low levels of BCR-ABL transcripts but never more than 3 consecutive positive results; and (4) 129 patients relapsed. In 107 of these, relapse was based initially only on molecular criteria; in 72 (67.3%) patients the leukemia progressed to cytogenetic or hematologic relapse either prior to or during treatment with donor lymphocyte infusions. We conclude that the pattern of BCR-ABL transcript levels after allograft is variable; only a minority of patients with fluctuating or persistent low levels of BCR-ABL transcripts satisfied our definitions of MR, whereas the majority of patients who did so were likely to progress further.