Eµ-TCL1mTerc -/- Mouse Model for Telomere Dysfunction in Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1724-1724
Author(s):  
Annika Scheffold ◽  
Billy Michael Chelliah Jebaraj ◽  
André Lechel ◽  
Sarah-Fee Katz ◽  
Daniela Steinbrecher ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Lymphocytic Leukemia ◽  
Mouse Model ◽  
Disease Burden ◽  
Disease Onset ◽  
Lymphocytic Leukemia ◽  
Telomere Dysfunction ◽  
Significant Difference ◽  
Tumor Load

Abstract Telomeres are nucleo-protein complexes at the ends of the chromosomes that play a key role in protection of the ends from being recognized as DNA damage and to prevent fusion of the chromosomes. The telomeric DNA shortens with each cell division in the absence of telomerase, due to end replication problem. In chronic lymphocytic leukemia (CLL), short telomeres were found to be associated with poor prognostic factors and poor survival in various univariable and multivariable analyses. Short telomeres in CLL are known to be frequently associated with increased DNA damage response and to undergo fusion events, conferring genomic instability. But the contribution of telomere dysfunction to CLL pathogenesis and disease progression has never been studied in vivo using mouse models. Here, we hypothesized that genomic instability resulting from telomere dysfunction could drive acquisition of genetic lesions, contributing to CLL pathogenesis, progression and disease evolution. Thus, the CLL mouse model with telomere dysfunction was generated by crossing the Eµ-TCL1 (TCL1+) mouse with mTerc-/- mouse. The first generation TCL1+ mTerc-/- (G1) mice were inter-crossed to obtain generations G2 and G3, as telomeres are known to shorten with subsequent generations. The TCL1+ mTerc-/- mice from the generations G1 (N=14), G2 (N=33) and G3 (N=26), including TCL1+ (N=34), wildtype (WT, N=18) and mTerc-/- G1 (N=4), G2 (N=5) and G3 (N=13) as controls were initially analyzed for disease burden in peripheral blood (PB) by bleeding at an interval of 4 weeks, starting from 12 weeks and the percentage of CD19+ CD5+ cells was estimated by FACS. No difference in disease onset or progression was observed between the TCL1+ mTerc-/- G1, G2 and G3 in comparison toTCL1+ mice (Fig. 1a). Similarly, analysis of survival showed no significant difference between the TCL1+ mTerc-/- G1 (N=14), G2 (N=33) and G3 (N=26) mice, compared to TCL1+ (N=34) (median: 53, 55, 52 weeks vs. 50.5 weeks, Fig. 1b). Spleen and liver weights in the TCL1+ mTerc-/- G1 (N=12), G2 (N=33) and G3 (N=26) mice were highly variable (spleen: 0.1g to 3.5g, liver: 0.1g to 8.0g) as in the TCL1+ (N=27, spleen: 0.3g to 5.0g, liver: 1.7g to 7.4g) mice but no significant difference in spleen (Fig. 1d) and liver weights was observed between the subgroups. Interestingly, spleen weights were associated with survival only in the TCL1+ mice, with larger spleens associated with worse survival (48.5 vs. 57.5 weeks, P=0.091). Since no difference in disease characteristics was observed, it was verified using Q-PCR, if telomere lengths vary in the tumors from the different subgroups. Telomere lengths of CLL cells from the spleen were significantly shorter (Fig. 1c) in the G1 (median: 20.5kb, P=0.0002), G2 (median: 18.5kb, P=0.0016) and G3 (median: 13.2kb, P<0.0001) compared to TCL1+ (median: 28.7kb). The absence of correlation of telomere length with survival in the murine CLL models with telomere dysfunction may indicate that a critical telomere length in the tumor is yet to be reached to elicit genetic alterations and clonal selection. Additionally, the G3 mTerc-/- microenvironment is known to restrict B and T lymphopoiesis and thus might influence CLL cell proliferation, masking disease aggressiveness in the TCL1+ mTerc-/- G3 mice. To overcome the influence of mTerc-/- microenvironment, CLL cells obtained from spleens of TCL1+ and TCL1+ mTerc-/- G3 mice were transferred into syngeneic C57Bl6 mice. Briefly, 20 million cells were intravenously injected into the tail vein and disease was monitored by analysis of CD19+ CD5+ cells in PB, once every 4 weeks. Early follow up of 8 weeks clearly show a trend towards increase in CLL cells in PB of mice transferred with TCL1+ mTerc-/- G3 tumors compared to those with TCL1+ tumors (median tumor load: 15.75% vs. 6.1%, P=0.0553). Longer follow up of the experiment is ongoing. In summary, the TCL1+ mTerc-/- mice across the generations G1, G2 and G3 showed no difference in disease onset, progression, disease burden and survival in comparison to TCL1+ mice. The absence of increased disease manifestation in the TCL1+ mTerc-/- may be attributed to the microenvironmental influence on lymphopoiesis, as syngeneic transfer of CLL from TCL1+ mTerc-/- G3 mice showed an increase in tumor load compared to that of TCL1+ tumors, indicating a contribution of telomere shortening to disease aggressiveness in CLL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Fludarabine, Cyclophosphamide and Rituximab (FCR) Related Prolonged Cytopenia Is Frequent and Adverse Factor Affecting Survival of Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1790-1790
Author(s):  
Petra Obrtlikova ◽  
Anna Jonasova ◽  
Magda Siskova ◽  
Eduard Cmunt ◽  
Adela Berkova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Significant Difference

Abstract Abstract 1790 Background: The immunochemotherapy regimen composed of fludarabine, cyclophosphamide and rituximab (FCR) has emerged as highly effective frontline or second line therapy for chronic lymphocytic leukemia (CLL). This regimen may be however associated with prolonged cytopenia and the risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Aims and methods: In our retrospective single center analysis, we evaluated the efficacy and the toxicity of FC or FCR regimen in unselected population of CLL patients with treatment indication. The overall survival (OS) and progression free survival (PFS) was calculated for all patients as intent to treat analysis. The prolonged cytopenia was defined as cytopenia (grade 2–4 according to CTCAE v.4 ) developing during of after the last cycle of FC/FCR and persisting two or more months. Cytopenia was evaluated in patients with follow-up at least 6 months after this treatment. Patients were excluded from analysis of cytopenia if they underwent immediate other treatment (antibody maintenance, high dose therapy with autologous stem cell transplantation (ASCT) consolidation, or they received other therapy due to unsatisfactory response to FCR). Patients with missing laboratory data after FC(R) were also excluded. Kaplan Maier curves for PFS and OS were calculated and log rank test was used for survival comparison. Results: Altogether, 252 patients started the treatment with FC or FCR in the years 2000–2012 at our institution. There were 86 (34%) women and 166 (66%) men with a median age of 62 years (31–87) at the time of FC(R) therapy. 52 (21%) pts received FC regimen, including 40 pts treated in first line therapy and 12 pts in second line therapy. FCR therapy was administered in 200 pts (79%): 153 pts received FCR as first line therapy, 38 pts as second line therapy and 8 pts as third or fouth line therapy. The median number of FC cycles was 5 (1–8) with or without R. The estimated OS for the first line therapy was 87,5% in FCR group vs 80% at 3y in FC group (p ns) (Hallek,CLL8: 87% vs 83%) and PFS was 70% in FCR group vs 50% in FC group (p=0,004) with the median of follow-up 45 months. Altogether 184 pts fulfill the criteria for cytopenia analysis. The most frequent immediate subsequent therapy considered as exclusion for this analysis was ASCT consolidation (n 20). Out of 184 pts, 146 recieved FC(R) as 1st line treatment and 38 subsequent therapy. The prolonged cytopenia was observed in 54 pts (29%), 42 (29%) in 1st line group and 12 (32%) in subsequent line group. Median duration of cytopenia was 8 m (2–65), 29 out of 54 patients have had persistent cytopenia at the time of last follow up. The cumulative probability to develop cytopenia was 30.3% at 2y among all pts and 29.7% among first line FCR treated pts. There was no significant difference between FC and FCR treated pts. Eleven pts developed MDS/AML, 7 cases were observed in the followed group of 184 pts (with probability 6.1% at 6y), in all cases the cytopenia preceded the MDS onset, 6y probability to develop MDS was 25.2% for patients who develop prolonged cytopenia after FC(R). Moreover 2 MDS and 1 AML were observed among 20 pts treated with ASCT (6y probability 5.6%, 8y probability 22.5%). The OS probability from 1stcycle of FC(R) was significantly better for pts without cytopenia (75.5% vs 57.5% at 5y, p<0.005), nonsigificant trend was observed if only first line FCR pts were analyzed (88% vs 85%). The median survival for the MDS pts from the time of MDS dg was 6 months only. Conclusions: Although the FCR is the best available standard treatment option for CLL pts, it is associated with prolonged cytopenia in 30% of cases. These patients with prolonged cytopenia afte FC(R) have considerably high probability (25.2%) to develop MDS and they have worse OS compared to pts without cytopenia. Disclosures: No relevant conflicts of interest to declare.

Vertebral Compression Fractures in Patients with Chronic Lymphocytic Leukemia: Incidence and Risk Factors

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4586-4586
Author(s):  
Amrita Desai ◽  
Benjamin Kuritzky ◽  
Jorge J Castillo ◽  
Adam J. Olszewski
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Bone Density ◽  
Watchful Waiting ◽  
Compression Fracture ◽  
Lymphocytic Leukemia ◽  
Vertebral Compression Fractures ◽  
Radiographic Findings ◽  
Compression Fractures ◽  
Significant Difference

Abstract Abstract 4586 Introduction: Patients with chronic lymphocytic leukemia (CLL) have infiltrative bone marrow changes in vertebral bodies on radiographic studies. Whether CLL is associated with an increased risk of compression fracture and/or osteoporosis in correlation with the burden or duration of the disease has not been studied. For this purpose, we performed a retrospective case-control study. Methods: After obtaining Institutional Review Board approval, we reviewed the records of CLL patients managed in our centers with watchful waiting from diagnosis until treatment. Data on demographic, clinical and laboratory variables, radiographic findings and treatment were collected. Presence of osteoporosis and compression fractures was ascertained from physician evaluation notes, bone densitometry studies and/or computed tomography (CT) scan results prior to initiation of chemotherapy. CLL cases were matched by age, sex and body mass index (BMI) at 1:2 ratio to healthy controls derived from a local Family Practice database. Cox regression models were used for the evaluation of hazard ratios (HR) and 95% confidence intervals (CI) for factors associated with compression fractures in patients with CLL undergoing a watchful waiting approach. Results: Among 96 CLL cases included in the analysis there were 48% women, 10% current and 34% former smokers. The median age was 71 years (range, 44–99), median BMI 26 (18–50) and median follow up time 2.9 years (0–22, with the last follow up between 2003 and 2012). The median absolute lymphocyte count (ALC) was 40,850/mm3 (5,700–969,000/mm3), mean hemoglobin 12.4 g/dL (+/− 2.2 g/dL), lactate dehydrogenase 202 IU/L (+/− 95 IU/L), 25-OH-vitamin D 30.7 ng/mL (+/− 12.3 ng/mL). Staging CT scans were available in 68% of cases, but bone density scans only in 13% (2% men, 24% women). Chemotherapy was started in 41% of patients after a median time of 2.4 years from diagnosis. Osteoporosis and osteopenia were each recorded in 12% of patients while a vertebral compression fracture was present in 7%. With marked differences in the availability of evaluation tests (e.g. bone density, p<0.001) and length of period of observation between CLL cases and matched controls, there was no significant difference in the odds of compression fracture (odds ratio 1.0, 95%CI 0.32–2.84, p=1.0). In the time-to-event analysis, the rate of compression fracture occurrence was 1.7% per year (95%CI 0.8–3.6%). Compression fractures in CLL patients were associated with underlying osteoporosis or osteopenia (HR 12.8, 95%CI 1.5–109, p=0.004), ALC over 100,000/mm3 (HR 5.1, 95%CI 1.1–23.7, p=0.04) and anemia, defined as hemoglobin less than 12 g/dL (HR 8.9, 95%CI 1.1–74, P=0.01, Fig.1). Conclusions: CLL patients managed with watchful waiting may be at risk of vertebral compression fractures proportional to the burden of disease. Further prospective research may delineate potential role for screening for osteoporosis and prevention of osteoporosis and vertebral fractures in this population. Disclosures: No relevant conflicts of interest to declare.

Qualitative and Quantitative PCR Monitoring of MRD: Practical Implications of a Surrogate Marker for GVL Effect after RIC Allogeneic Transplantation in Relapsed Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1659-1659
Author(s):  
Lucia Farina ◽  
Cristiana Carniti ◽  
Anna Dodero ◽  
Antonio Vendramin ◽  
Anna Raganato ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Real Time ◽  
Real Time Pcr ◽  
Lymphocytic Leukemia ◽  
Molecular Monitoring ◽  
Molecular Remission ◽  
Relapse Risk ◽  
Post Transplant ◽  
Tumor Load

Abstract Reduced intensity allogeneic stem cell transplantation (RIC alloSCT) is a therapeutic option for poor risk relapsed chronic lymphocytic leukemia (CLL) and can lead to 50% of progression-free survivors. The aims of this study were: to assess the “molecular quality” of clinical remission after RIC alloSCT in CLL patients; to investigate whether molecular remission (MR) can correlate with a lower relapse risk; to understand the clinical role of molecular monitoring in post-transplant immunotherapy. Twenty-nine patients with a molecular marker (heavy chain gene immunoglobulin rearrangement, IgH) were monitored for minimal residual disease (MRD). All patients had a relapsed disease; 75% had an unmutated IgH; cytogenetic analysis was available in 13 patients at first relapse, and 5 of them (38%) showed a 17p deletion. Median age at transplant was 60 years (range, 44–69). Median number of previous chemotherapy was 3 (range, 1–6) and 29% of patients failed autologous transplant. Eleven patients (38%) were chemorefractory before transplant. The conditioning regimen included thiotepa-cyclophosphamide-fludarabine in HLA identical sibling transplants (n=21), and an in vivo T cell depletion in haploidentical and unrelated alloSCT (n=8). Molecular monitoring was performed by nested-PCR on bone marrow using CDR-2 and CDR-3-derived patient-specific primers. For real-time PCR a FR3-derived probe was used. Post-transplant samples were amplified including the pre-transplant sample as positive control, and ΔCT was calculated after normalization for GAPDH gene. Eight patients (28%) were PCR-negative: 4 of them (14%) have been always PCR-negative while 4 patients (14%) experienced a delayed clearance of MRD during the first year after transplant. All these patients are alive and in CR at the median follow-up of 24 months (range, 3–71). Seven patients (24%) showed a mixed pattern of PCR positivity and negativity: one patient died of secondary acute leukemia, another patient had a nodal relapse, the others are in CR at a median follow-up of 30 months (range, 6–60). Fourteen patients (48%) were always PCR-positive: 7 of them relapsed after a median time of 9 months (range, 3–12); 2 patients died of TRM in MR; 5 patients are alive and in CR after a median follow-up of 15 months (range, 3–24). Relapse risk was higher for PCR-positive patients compared to PCR-mixed/negative patients (p=0.014). Eighty percent of PCR-mixed/negative patients experienced GVHD compared to 43% of PCR-positive patients (p=0.06). In 5 PCR-positive patients real-time PCR was carried out. In 3 patients that did not relapse a decreasing tumor load was detected; these patients were affected by extensive chronic GVHD. In the other 2 patients after an initial reduction, the tumor load increased on day +300 and +270: both patients relapsed on days +420. In conclusion, in poor risk relapsed CLL clinical and molecular remission can be achieved in a sizeable fraction of patients after RIC alloSCT. Persistent PCR positivity correlates with a high incidence of relapse and requires novel treatments, while a mixed-PCR pattern can be observed without clinical relapse.

Clinical Outcome of Chronic Lymphocytic Leukemia Patients with Sole 13q FISH Detectable Defects: One Versus Two 13q Deletions.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1068-1068
Author(s):  
Daniel L. Van Dyke ◽  
Tait D. Shanafelt ◽  
Timothy G. Call ◽  
Clive S. Zent ◽  
Stephanie A. Smoley ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcome ◽  
Median Time ◽  
Risk Model ◽  
Lymphocytic Leukemia ◽  
Risk Category ◽  
Time To Treatment ◽  
Significant Difference ◽  
13Q Deletion

Abstract Figure Figure Background: An isolated 13q deletion in patients with chronic lymphocytic leukemia (CLL) is the single most common cytogenetic abnormality and is a favorable prognostic parameter (Dohner et al., NEJM3432:1910, 2000). Although 13q- can occur as either a heterozygous (13q-x1) or homozygous (13q-x2) deletion, it is unknown whether these two genetic types differ in their impact on clinical outcome. We previously postulated that 13q-x2 may be a more aggressive anomaly than 13q-x1 (Dewald et al., BJH121:287, 2003) and have undertaken a long-term clinical follow-up of patients with an isolated FISH detectable 13q- to test this hypothesis. Methods: We identified patients diagnosed with CLL between October 1992 to May 2008 and who had 13q deletion as their sole FISH abnormality. FISH was performed within 2 years of diagnosis and prior to treatment in all patients. Patients were sorted into three groups: 13q-x1 only, 13q-x2 only, or mosaic with both 13q-x1 and 13q-x2 cells. We assessed differences in percentage of abnormal cells, demographic characteristics, and clinical outcome among the three groups. Results: We identified 259 patients with isolated 13q deletion. Age ranged from 38 to 90 years (median=61) and included 99 women and 160 men. With respect to Rai stage, 142 patients (60%) had low risk [Rai 0], 81 (34%) intermediate risk [Rai I-II], and 13 (6%) high risk [Rai III-IV] disease. After a median follow-up of 1.9 years, 40 patients (15%) have been treated and 17 (7%) have died. Median TFS and OS for all patients were 6.9 and 9.3 years, respectively. The mean percentage of abnormal nuclei in the three groups was 44%, 53%, and 47% for 13q-x1 only, mosaic 13q-x1/13q-x2, or 13q-x2 only, respectively (p=0.22). No significant difference in age or gender was observed based on whether 13q- occurred as a heterozygous or homozygous deletion, or was mosaic. Likewise, no significant difference in survival (p=0.313, see Table) or time to treatment (p=0.53) was found among the three groups. Five year OS rates for the 13q- x1 only, 13q- x2 only, and mosaic 13q- x1/13q- x2 are 85%, 95%, and 83%, respectively Median time to treatment for 13q-x1 was not reached, and for the mosaic13q-x1/13q-x2 and 13q-x2 groups median time to treatment was 6.9 and 4.9 years, respectively. Conclusions: The presence of deletion in one versus two 13q- chromosomes in CLL patients appears to have no significant impact on treatment free or overall survival. This observation supports the grouping of CLL patients with isolated 13q- of one or both alleles into a single risk category as originally proposed in the risk categorization by Dohner et al. Taking the present findings together with those of Dohner et al and Dewald et al, we propose a hierarchical risk model of FISH abnormalities in CLL as 17p- à 11q- à 6q- à +12 à normal à 13q-, from most to least aggressive. The 13q- group would now include 13q-x1, 13q-x2, and the mosaic subgroups.

Chemoimmunotherapy Improves Survival of Patients with Chronic Lymphocytic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3908-3908
Author(s):  
Gabriela Ghita ◽  
Julio Delgado ◽  
Tycho Baumann ◽  
Ivan Dlouhy ◽  
Marta Aymerich ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Lymphocytic Leukemia ◽  
Disease Evolution ◽  
Prognostic Features ◽  
Purine Analogs ◽  
Significant Difference ◽  
Binet Stage

Abstract Abstract 3908 INTRODUCTION Chemoimmunotherapy, namely the combination of fludarabine, cyclophosphamide and rituximab (FCR), results in a higher response rate and a longer progression-free survival in patients with chronic lymphocytic leukemia (CLL). There is also evidence coming from several historical comparisons, observational, and epidemiological studies and, above all, a large randomized clinical trial (German CLL Study Group – Hallek M et al, Lancet 2010) that FCR prolongs survival. Since additional randomized studies to validate the superiority of FCR over older therapies in CLL are difficult to envisage, other approaches to confirm this observation are worth to be considered. AIM The aim of this study was to ascertain whether chemoimmunotherapy given at any time over the course of the disease, independently of the treatment phase, prolonged survival in a group of unselected patients with CLL from the Hospital Clínic of Barcelona. MATERIALS AND METHODS Out of 1042 consecutive patients diagnosed and followed-up from 1980 to December 2010, we selected 484 patients who received at some point of their disease evolution: (1) alkylating agents and no purine analogs (PA) nor rituximab (R) (no PA no R) (n=211; of which 67 < 65 years). (2) purine analogs but no R (PA) (n=159). (3) PA plus rituximab (PA+R) (n=114). Clinical information (age, sex, Binet stage) and laboratory characteristics (β2-microglobulin, CD38, ZAP-70, genomic alterations, IGHV mutational status) at disease presentation, treatment, and follow-up was obtained from a database prospectively managed at our institution from the 1970s onwards. All treated patients were included in the analysis regardless of the number of cycles of therapy given and independently of whether they had participated in clinical trials or not. RESULTS The median age (range) of the whole series (n=340, 222M/118F) was 56 (24–84) years. The three groups were well balanced for key clinical characteristics such as age, sex, and Binet stage at treatment. It should be noted that patients older than 65 years were initially excluded from the analysis to avoid a bias in the results due to the general worse prognosis of older patients. On the other hand, patients from the PA and PA+R groups presented poorer risk prognosis factors such as a higher expression of CD38 (p=0.006), ZAP-70 (p=0.052), and adverse cytogenetic abnormalities (p=0.026) or unmutated IGHV genes (p=0.005) than those in the no PA no R group. After a median follow up of 9.4 years (range, 0.3–21), 148 (44%) patients remain alive. At 10 years, the overall survival of the PA+R group was 65% (95% CI, 53–77%) compared with 43% (35–51%) and 43% (31–54%) for the no PA no R and PA groups, respectively (p<0.001) (Figure 1). When all patients who did not receive PA or R were included in the study (n=211), the statistically significant difference was, not surprisingly, maintained (data not shown). In addition, patients from both the PA group and the PA+R group had poorer prognostic features. These data are in keeping with a conservative therapeutic approach in patients with low-risk disease and a poorer risk of patients treated with PA with or without R. This is also an additional argument in favor of the effectiveness of chemoimmunotherapy in high-risk patients. Interestingly, when survival of patients treated with PA+R was analyzed according to the time at which treatment was administered (first line, n=55 vs. ≥ second line, n=59), no differences were observed (p= 0.8) (Figure 2) CONCLUSION Chemoimmunotherapy prolongs survival of patients with CLL. Moreover, this effect could be independent of the phase of the disease at which chemoimmunotherapy is given. Disclosures: No relevant conflicts of interest to declare.

Survival for melanoma patients with pre-existing chronic lymphocytic leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19057-e19057
Author(s):  
Eric D. Whitman ◽  
Rami Bustami
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Proportional Hazards ◽  
Cox Model ◽  
Cox Proportional Hazards ◽  
Lymphocytic Leukemia ◽  
Chi Square ◽  
Risk Of Death ◽  
Increased Risk ◽  
Significant Difference

e19057 Background: Recent successes in melanoma drug development have rekindled interest in immunotherapy for melanoma (MM). Patients (pts) with chronic lymphocytic leukemia (CLL), a malignant expansion of B-lymphocytes, have an impaired immune system and not uncommonly develop secondary MM. We hypothesized that MM pts with pre-existing CLL are more likely to die than MM pts without a second malignancy. Methods: Pts were identified in the updated Surveillance Epidemiology and End Results (SEER) (1973-2008) database with MM only (MEL) or with primary CLL and secondary MM (MELpCLL). Time between diagnosis and death or last follow up and other demographic SEER data were recorded. The Chi-Square Test was used to make unadjusted comparisons between group death rates. A Cox proportional hazards regression model, adjusted for patient characteristics, predicted the risk of death by group. Results: 8,294 SEER pts were included (8,115 in MEL, 179 in MELpCLL). With a median follow-up time of 7 years, 2,454 pts (30%) died. There was a significant difference in mortality rates between the groups: MEL 29% / MELpCLL 71%; p<0.001 by Chi-Square. In the multivariate Cox model (Table), MELpCLL pts were significantly more likely to die than MEL pts (HR = 1.22, 95% CI = 1.02-1.46, p = 0.034). Higher risk of death was also significantly associated with older age and male gender (p<0.001) but not MM location (data not shown). MM data like thickness and ulceration were only available in more recent SEER records, precluding survival analysis. Conclusions: MELpCLL pts had a 22% increased risk of death compared to MEL pts in multivariate analysis, consistent with the hypothesis. [Table: see text]

scholarly journals Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort

Haematologica ◽  
2018 ◽  
Vol 104 (5) ◽  
pp. e208-e210 ◽  
Author(s):  
Maria Winqvist ◽  
Per-Ola Andersson ◽  
Anna Asklid ◽  
Karin Karlsson ◽  
Claes Karlsson ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Real World ◽  
Lymphocytic Leukemia ◽  
Compassionate Use

scholarly journals Lenalidomide and Rituximab Maintenance Therapy after Front-Line Induction Chemoimmunotherapy in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5470-5470
Author(s):  
Julie E Chang ◽  
Vaishalee P. Kenkre ◽  
Christopher D. Fletcher ◽  
Aric C. Hall ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Second Malignancies ◽  
Front Line ◽  
First Line ◽  
11Q Deletion ◽  
Line Chemotherapy

Introduction: Chronic lymphocytic leukemia (CLL) is incurable with standard therapy. With first-line chemotherapy, some patients (pts) may achieve durable remissions of many months/years. Lenalidomide (LEN) has improved progression-free survival (PFS) when given as maintenance (MNT) therapy after front-line chemotherapy (CALGB10404, CLLM1). The combination of LEN + rituximab (LR) has activity in relapsed CLL, hypothesizing benefit as MNT therapy after first-line chemotherapy. Methods: Adult pts ≥18 years with previously untreated CLL received induction bendamustine (B) 90 mg/m2 IV days 1 & 2 and rituximab (R) IV day 1 (375 mg/m2 cycle 1, then 500 mg/m2 cycles 2-6) for 6 treatment cycles (as few as 4 cycles allowed). MNT therapy with LR was initiated within 12 weeks after cycle 6, day 1 of BR. Criteria to start LR MNT included: neutrophils ≥1000/microliter (uL), platelets ≥75 K/uL, and creatinine clearance ≥40 mL/min. LEN was administered in 28-day cycles for 24 cycles, initially 5-10 mg daily continuous dosing, later modified to 5-10 mg on days 1-21 of each 28-day cycle in 6/2018 due to neutropenia and second malignancy risk. LEN was reduced to 5 mg every other day for toxicities at 5 mg/day. R 375 mg/m2 IV was given every odd cycle (total of 12 doses). Patients discontinuing LEN for any reason were allowed to continue R MNT per protocol. The primary endpoint is PFS with LR MNT therapy, calculated from the first day of MNT therapy until progressive disease (PD), death, or start of a new therapy. Secondary endpoints are response rate and overall survival. Results: Thirty-four pts have enrolled beginning 11/2013, with follow-up through 6/2019. Median age is 64 years, with 8 pts ≥70 years; 8 women and 26 men. CLL FISH panel is available on all pts: 14 with 13q (as sole abnormality), 9 with 11q deletion, 6 with trisomy 12, 4 with normal FISH panel and 1 with 17p deletion. Heavy chain mutation analysis is available on 11 pts: 8 unmutated, 2 mutated, 1 indeterminate. Thirty-one pts completed 4 (n=2) or 6 cycles of induction BR; 3 pts are receiving induction BR. Twenty-four pts have received MNT LR; 7 did not receive LR for reasons of PD during induction (n=2), infection (n=1), pt preference (n=2), renal insufficiency (n=1), and new carcinoma (n=1). MNT LR was completed in 7 pts; 9 pts are still receiving LR. Fourteen subjects have discontinued protocol therapy, 3 during induction due to PD (n=2) and infection (n=1), and 8 during MNT. Toxicities that led to discontinuation of LR were recurrent infections in 7 pts, including 2 events of PJP pneumonia; 4 pts had recurrent neutropenia with infections; 1 pt had neutropenia without infections. Response is assessable in 31 patients using the International Working Group Consensus Criteria. Best responses to treatment were: partial response 65% (22/34), complete response (CR)/unconfirmed CR 24% (8/34). The median number of MNT cycles received is 16. The dose intensity of LEN across total cycles received (n=278): 5 mg every other day (52.5%), 5 mg/day (43.9%), and 10 mg/day (3.6%). The most common reason for dose reduction or dose holding was neutropenia. Most common Gr 3/4 toxicities (reported as events Gr3/Gr4) during MNT therapy were: neutropenia (20/20), leukopenia (19/4), febrile neutropenia (3/1), and infections (11/-). The majority of Gr3 infections were pneumonia/respiratory (n=5). One event of disseminated herpes zoster occurred. Second malignancies during MNT included: basal cell CA (n=1), squamous cell carcinoma (n=5), and colon cancer (n=1). No unexpected second malignancies were observed in pts receiving LR. Two-year PFS (defined from day 1 of MNT therapy) is 90% (95% confidence interval [CI] 0.78-1), and the median follow-up for 24 patient who started maintenance therapy is 1.79 years (95% CI 1.53-2.7). There have been no deaths. Conclusion: The combination of LR is effective in sustaining remissions after a BR induction in previously untreated CLL, but with frequent neutropenia and infections even at low doses of LEN. Most patients discontinuing MNT did so due to neutropenia and/or infections. A shorter planned interval of MNT LR (i.e., 6-12 months) may confer similar benefit to extended dosing that is more tolerable. Pts at high risk for short remissions after front-line chemotherapy (e.g., unmutated heavy chain status, 11q deletion and/or failure to achieve minimal residual disease after induction) may be the populations for which LR MNT therapy is most appropriate. Disclosures Chang: Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Lenalidomide administered as maintenance therapy for first treatment of CLL/SLL.

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