BIRC3 disruption and Copy Number Aberrations in Chronic Lymphocytic Leukemia (CLL) Patients with 11q Deletion

Abstract Introduction. Chronic lymphocytic leukemia (CLL) with 11q deletion has been associated to a poor prognosis, but the clinical course of patients carrying this lesion is variable. This aberration, most often monoallelic, is present in 10-17% of newly diagnosed CLL and in 20-30% of patients with progressive or chemorefractory disease. The minimal deleted region (MDR) (2-3 Mbp) is located on the 11q22.3-q23.1 region and includes ATM. Moreover, 30-40% of 11q- CLL have also an inactivating ATM mutation on the other allele. The deleted region on 11q can also include BIRC3, a gene that is often deleted or mutated in advanced/chemorefractory stages of the disease. Although BIRC3 disruption has been associated to a poor prognosis, its prognostic implications in addition to ATM deletion are not well defined. The aim of this study was to perform a copy number aberration (CNA) and gene sequencing analyses on a cohort of CLL patients with 11q- in order to identify subgroups with potential prognostic relevance based on: i) the inclusion of BIRC3 in the deleted region; ii) the presence of BIRC3 mutation; iii) the presence of other CNAs. Methods. The study has included 55 untreated CLL patients followed at our Institution or enrolled in GIMEMA clinical trials (2003-2013). Genomic DNA was extracted from peripheral blood samples. CNA analysis was performed by genomic hybridization on the CytoScan HD array (Affymetrix), which contains more than 2.6 x 106 markers for copy number analysis and 750.000 SNPs. Data were analyzed using both Partek Genomics Suite and ChAS (Chromosome Analysis Suite, Affymetrix) software. The resulting CNAs were verified by visual examination of the plotted copy number profiles. BIRC3 mutations (exons 6-9) were evaluated by Sanger sequencing. Time to first treatment (TFT) was calculated from the date of diagnosis to the date of first therapy or last follow-up; progression-free survival (PFS) from the date of first therapy to the date of progression, death or last follow-up. Results. Baseline characteristics of the 55 cases were as follows: median age at diagnosis 59 years (range 39-84), male gender in 81.8% of patients, progressive disease in 62%. All patients showed 11q- by FISH (median 80%, range 25-99% of nuclei); germline IGHV were present in 96.4% of cases; TP53 deletion in 1 case and TP53 mutation in none; NOTCH1 mutation in 4/40 cases; SF3B1 mutation in 5/40 (all mutually exclusive with only 1 case having both SF3B1 and BIRC3 mutations). By CytoScan HD array, the size of 11q- was very variable, ranging from 0.36 Mbp to 65.14 Mbp; the MDR was located on 11q22.3 region, encompassing 4 genes (ACAT1, ATM, CUL5, NPAT). BIRC3 was included in the deleted region in 45/55 cases (81.8%) and was mutated in 4/54 (7.5%), being always deleted on the other allele. Beside 11q-, 51 cases (92.7%) showed several additional CNAs (average 4.9, range 1-14 per patient), with 5 recurrent lesions: 2p gain in 11 cases, del4(p15.2) in 6, del19(p13.3) in 6, 8q gain in 5 and del4(q22.1) in 4. BIRC3 deletion was not associated to the number of additional CNAs nor to specific CNA. After a follow-up of 59.6 months (range 7.4-229.7), 40 of 47 evaluable patients have received treatment (median TFT 15.8 months, range 0-167). BIRC3 deleted cases (n=37) showed a TFT not significantly different from WT cases (n=10). Conversely, BIRC3 mutation was associated to a shorter TFT (p <0.0001), 0.5 vs 19.3 months of WT cases. Notably, 3/4 cases with the biallelic BIRC3 disruption had a marked hyperleukocytosis at diagnosis (212.4-302.8 x 109L). The presence of additional CNAs was associated to a shorter, though not significant, TFT considering either >3 CNAs larger than 5 Mb (n=14) or >10 CNAs (n=5), or the presence of 2p gain, del4(p15.2), del19(p13.3) or 8q gain. So far, 22 patients have been evaluated for PFS after first-line therapy (median 28.7 months). BIRC3 deleted cases (n=17) were not associated to a shorter PFS compared to WT cases (n=5), in line with the results from Rose-Zerilli et al (Haematologica 2014). Conclusions. Among CLL with 11q-: 1) BIRC3 deletion involves more than 80% of cases, whilst the mutation is rare (7.5%); 2) BIRC3 deletion is not associated to a higher genomic complexity; 3) BIRC3 deletion does not seem to influence TFT or PFS of 11q- CLL; 4) BIRC3 mutation is strongly associated to a short TFT; 5) BIRC3 biallelic lesions can be associated to a marked hyperleucocytosis at diagnosis and immediate need of treatment. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2019-124489 ◽

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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Rituximab and High-Dose Dexamethasone (R-dex) Is Effective In The Treatment Of Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v122.21.4184.4184 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4184-4184

Author(s):

Martin Simkovic ◽

David Belada ◽

Monika Motyckova ◽

Lukas Smolej ◽

Pavel Zak

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Antimicrobial Prophylaxis ◽

Univariate Analysis ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Published Data ◽

High Dose ◽

High Dose Dexamethasone ◽

Tertiary Center

Abstract Introduction High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but serious infections are frequent. Recently published data suggest that high-dose dexamethasone might be equally effective to HDMP despite lower cumulative dose. Aims To assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in relapsed/refractory CLL. Patients and Methods A total of 60 pts (pts) with relapsed/refractory CLL treated at a single tertiary center between September 2008 and October 2012 were included in this retrospective analysis. Basic characteristics are summarized in Table 1. The schedule of R-dex consisted of rituximab 500 mg/m2 i.v. day 1 (375 mg/m2 in cycle 1) and dexamethasone 40 mg orally on days 1-4 and 10-13. Treatment was repeated every 3 weeks for a maximum of 8 cycles. All pts received antimicrobial prophylaxis with sulfamethoxazole/trimethoprim and aciclovir. Results Median number of administered R-dex cycles was 6 (range, 1-8). The overall response (ORR)/complete remissions (CR) were achieved in 75/3%. At the median follow-up of 9 months, median progression-free survival was 8 months and median overall survival 24 months. Significant predictors of short PFS in univariate analysis were bulky lymphadenopathy (p=0.023) and refractoriness to fludarabine (p=0.02). Interestingly, activity of R-dex in bulky fludarabine-refractory CLL was similar to ofatumumab (ORR 62 %, median PFS, 4 months, median OS, 12 months) (Wierda et al., 2010). R-dex was successfully used as a debulking regimen before allogeneic stem cell transplantation in 8 patients. Serious (CTCAE grade III/IV) infections occurred in 29% of patients; 19% pts developed steroid diabetes requiring temporary short-acting insulin. Conclusions Our data show that R-Dex is an active and feasible treatment for patients with relapsed/refractory CLL; however, major infections remain relatively frequent despite combined antimicrobial prophylaxis. In addition, durable responses are infrequent. Therefore, further optimization of this therapeutic approach is warranted. Updated results will be presented. Disclosures: No relevant conflicts of interest to declare.

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Other Cancers in Long-Term Survivors of Chronic Lymphocytic Leukemia: Incidence and Prognostic Relevance

Blood ◽

10.1182/blood.v124.21.3323.3323 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3323-3323 ◽

Cited By ~ 2

Author(s):

Lorenzo Falchi ◽

Michael Keating ◽

Susan Lerner ◽

Xuemei Wang ◽

Kplola Y Elhor Gbito ◽

...

Keyword(s):

Bladder Cancer ◽

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Observation Time ◽

Lymphocytic Leukemia ◽

P Value ◽

Prognostic Impact ◽

Long Term Survivors

Abstract Introduction. The clinical course of chronic lymphocytic leukemia (CLL) is mostly indolent. About one third of the patients are managed with lifelong watch-and-wait (WW) and those who receive therapy often achieve a durable remission. As a result, the majority of patients with CLL will live with their disease for long periods of time, and be exposed to several complications, including the occurrence of other cancers (OC). Patients with CLL may have an increased incidence in OC. Published reports indicate an incidence of 3-27%, mostly in treated patients, however, very little is known on OC in patients with CLL not requiring therapy. Furthermore, observation time in published studies is limited to <5 years, and the incidence of OC in patients followed for longer than 10 years is unknown. We, therefore, studied the incidence and prognostic impact of OC in treatment-naïve patients with CLL followed for ≥10 years. Methods. We reviewed our database and identified all patients with CLL untreated at the time of referral. We selected long-term survivors (LTS), defined as patients with a follow-up ≥10 years, and analyzed the incidence and prognostic impact of OC in this population. Non-melanoma skin cancers were excluded since these were diagnosed and treated promptly in virtually all cases and felt not to have prognostic impact. Standardized incidence ratios (SIR) were calculated for OC occurring after the diagnosis of CLL that were reportable to the Surveillance, Epidemiology and End Results program.The estimated overall survival (OS) according to the presence of OC was plotted considering OC as a time-dependent covariate. Results. We identified 797 LTS of CLL seen at our institution between 1957 and 2003. Median age was 56 years (24-88). 57% of patients were males. Median follow-up for the entire population is 154 months (120-485). We recorded 383 OC in 286 (36%) patients. 76/286 (26%) patients had >1 OC (62 had 2 OC, 10 had 3, 2 had 4, 1 had 5 and 1 had 6).The firstOC preceded or was diagnosed concomitantly with CLL in 100 patients (35%), while in the remaining 186 (65%) it occurred later during the course of the disease. 570 patients (71%) required treatment for CLL. Median time to treatment was 18 months (0-454). In treated patients, the cumulative frequency of OC was 205/570 (36%) and in WW patients 81/227 (36%). The SIR for all OC was 1.2 (p = .034). Males and patients younger than 60 years had a significantly higher incidence of OC (SIR 1.31 and 1.27, respectively). Among OC types, secondary leukemia, melanoma and head and neck cancers had the highest observed-to-expected ratio. Surprisingly, lung, digestive tract, and bladder cancer had a lower-than-expected incidence (table). 474 patients (59%) are alive. 222/570 (39%) treated patients and 101/227 (44%) WW patients have died. The median OS was longer in patients without OC (279 months) vs. those with OC (189 months). Independent predictors of shorter survival in multivariate analysis included higher creatinine, the presence of OC, and older age. Discussion. This is the first study to address the incidence of OC in LTS of CLL, including WW patients. In our population, the frequency of OC is similar in treated and WW patients. Although the incidence of OC in LTS of CLL is higher compared to matched general population, the incidence of lung, digestive and bladder cancer is lower than expected. Reasons of this finding remain to be identified.The occurrence of OC is an independent predictor of shorter survival, thus constituting a relevant competing risk of mortality in LTS of CLL. Variable Observed Expected Person-years SIR (O/E) 95% CI for O/E P -value Overall 148 123.34 10956 1.20 1.01 – 1.40 0.034 Male 96 73.4 5885 1.31 1.06 – 1.58 0.013 Female 52 49.93 5071 1.04 0.78 – 1.36 0.67 Age ≥60 years 60 54.33 3416 1.10 0.84 – 1.42 0.44 Age <60 years 88 69.02 7540 1.27 1.02 – 1.57 0.027 OC type Prostate 28 25.92 11809 1.08 0.72 – 1.56 0.64 Lung 20 29.08 11942 0.69 0.42 – 1.06 0.04 Breast 19 18.60 11855 1.02 0.62 – 1.59 0.96 Melanoma 16 4.23 11926 3.78 2.16 – 6.14 0.00 Leukemia 15 4.27 12009 3.51 1.96 – 5.79 0.00 Non-Hodgkin lymphoma 6 6.38 11996 0.94 0.34 – 2.05 1.00 Digestive 16 40.4 11937 0.40 0.23 – 0.64 0.00 Colon 8 19.42 11972 0.41 0.18 – 0.81 0.006 Pancreas 2 4.83 12024 0.41 0.05 – 1.49 0.18 Rectal 3 8.69 12011 0.34 0.07 – 1.00 0.05 Bladder 3 11.18 11993 0.27 0.05 – 0.78 0.009 Multiple Myeloma 2 1.98 12012 1.01 0.12 – 3.64 1.00 Lip 3 0.02 12015 150 31.00 – 438.5 0.00 Salivary gland 2 0.03 12026 66.66 8.00 – 240.06 0.00 Disclosures No relevant conflicts of interest to declare.

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MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score.

Blood ◽

10.1182/blood.v112.11.1066.1066 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1066-1066

Author(s):

Basile Stamatopoulos ◽

Nathalie Meuleman ◽

Dominique Bron ◽

Benjamin Haibe-Kains ◽

Pascale Saussoy ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Noncoding Rna ◽

Poor Prognosis ◽

Lymphocytic Leukemia ◽

Early Therapy ◽

Mutational Status ◽

Igvh Mutational Status ◽

Binet Stage

Abstract Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest. Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR). Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P<0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of >312, 129, 80, 36 and 19 months, respectively (HR=17.00, P<0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of >312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P<0.0001 and HR=12.5, P=0.0068, respectively). Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.

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FCR for Advanced Chronic Lymphocytic Leukemia: Real Life Results from a Series of 50 Patients Treated at a Single Institution

Blood ◽

10.1182/blood.v126.23.5300.5300 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5300-5300

Author(s):

Angela Gravetti ◽

Giuseppe Monaco ◽

Carolina Copia ◽

Salvatore Palmieri ◽

Fioravante Ronconi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Real Life ◽

Staging System ◽

Daily Practice ◽

Lymphocytic Leukemia ◽

Virus Reactivation ◽

Single Institution ◽

Current Standard

Abstract Introduction: The combination of fludarabine, cyclophoshamide and rituximab (FCR) represents the current standard of treatment of fit patients with chronic lymphocytic leukemia (CLL). However, despite the success of the FCR regimen, a number of questions exist on its optimal administration as well as on its short and long term toxicity. As a consequence, in the daily practice (Knauf et al, Hematological Oncology, 2015) less intensive regimens such as bendamustine plus rituximab (BR) are often adopted also in fit patients. Most data on the FCR regimen derive from clinical trials, while data from real life are poor. Methods: Here we report our experience on a series of 50 previously untreated patients with CLL, managed with FCR at a single institution in Italy. Patients were programmed to receive 6 courses plus 2 additional rituximab infusions. The median age of the whole patient population was 60 years (range 41-75), there were 29 males (58%) and 21 females (42%). 44 patients (88 %) received the classical schedule (Fludarabine 25 mg/sqm and Cyclophosphamide 250 mg/sqm, on days 1-3) , while 6 patients (12%), all aged over 70 years, were given FCR-lite (Fludarabine 15 mg/sqm and Cyclophosphamide 200 mg/sqm). In all patients Rituximab was given at 375 mg/sqm on course 1, and 500 mg/sqm infusions 2 to 6. According to Binet staging system, 20 patients were in stage B and 30 in stage C. Patients were carefully selected according to the absence of hepatic, cardiac, renal and respiratory comorbidity and medical judgment (go patients). 40 patients were evaluable for cytogenetic examination (FISH) and none of them had 17 p abnormality. Results: Overall, 46 patients (92%) received the 6 programmed FCR courses, while in four patients therapy was stopped after 1, 2, 4 and 5 courses due to unexplained cytopenia, while CLL cells were undetectable in the bone marrow. Overall response rate was 90 % (74 % CR, 16 % PR) The median duration of response was 30 months, after a median follow up of 38 months. 8 patients have relapsed from CR achievement and 2 of them achieved sustained response with BR, one is on treatment with ibrutinib, while 5 were refractory to salvage therapy. 5 patients died in the setting of refractory disease, 44 are alive and one has been lost to follow-up. Major toxicities (grade 3-4) included: neutropenia registered in 25 patients (50 %), needing G-CSF administration in all cases and producing delay in the administration in 35 % of patients; anemia requiring blood transfusions was registered in 10% of the cases, while no patient required platelet units. Hepatitis B and Herpes Zoster virus reactivation occurred in 1 (2%) and 2 patients (4%), respectively. Overall, 5 patients were hospitalized, all because of febrile neutropenia successfully managed with antibiotic therapy and G-CSF. Conclusions: We conclude that FCR in the "real life" is effective and well tolerated in patients with advanced CLL, provided that a careful evaluation of is made as to eligibility to therapy, mainly in terms of absence of comorbidities. This work was supported by AIL Napoli, "Sezione Bruno Rotoli". Disclosures No relevant conflicts of interest to declare.

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Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia: Long-Term Follow-Up of CALGB Study 9712

Journal of Clinical Oncology ◽

10.1200/jco.2010.31.1811 ◽

2011 ◽

Vol 29 (10) ◽

pp. 1349-1355 ◽

Cited By ~ 93

Author(s):

Jennifer A. Woyach ◽

Amy S. Ruppert ◽

Nyla A. Heerema ◽

Bercedis L. Peterson ◽

John G. Gribben ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Variable Region ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Free Survival ◽

Mutational Status ◽

Long Term Follow Up

Purpose The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited. Methods We report the long-term follow-up of the chemoimmunotherapy trial CALGB 9712 from the Cancer and Leukemia Group B, for which treatment regimen was previously reported, to examine end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN). Results A total of 104 patients were enrolled on this study and now have a median follow-up of 117 months (range, 66 to 131 months). The median OS was 85 months, and 71% of patients were alive at 5 years. The median PFS was 42 months, and 27% were progression free at 5 years. An estimated 13% remained free of progression at almost 10 years of follow-up. Multivariable models of PFS and OS showed that immunoglobulin heavy chain variable region mutational status was significant for both, whereas cytogenetic abnormalities were significant only for OS. No patient developed t-MN before relapse. Conclusion Long-term follow-up of CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab. Patients treated with fludarabine plus rituximab administered concurrently or sequentially have a low risk of t-MN. These long-term data support fludarabine plus rituximab as one acceptable first-line treatment for symptomatic patients with CLL.

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Isochromosome 17q in Chronic Lymphocytic Leukemia

Leukemia Research and Treatment ◽

10.1155/2015/489592 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Eyad Alhourani ◽

Martina Rincic ◽

Joana B. Melo ◽

Isabel M. Carreira ◽

Anita Glaser ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Prognostic Marker ◽

Chromosomal Aberrations ◽

Poor Prognosis ◽

Lymphocytic Leukemia ◽

Response To Treatment ◽

Cytogenetic Abnormalities ◽

Follow Up Studies

In chronic lymphocytic leukemia (CLL), presence of acquired cytogenetic abnormalities may help to estimate prognosis. However, deletion of TP53 gene, which is associated with an aggressive course of the disease and poor prognosis along with a lack of response to treatment, is one of the alterations which may escape cytogenetic diagnoses in CLL. Thus, other techniques have emerged such as interphase fluorescence in situ hybridization (iFISH). Deletion of TP53 may but must not go together with the formation of an isochromosome i(17q); surprisingly this subgroup of patients was not in the focus of CLL studies yet. This study was about if presence of i(17q) could be indicative for a new subgroup in CLL with more adverse prognosis. As a result, TP53 deletion was detected in 18 out of 150 (12%) here studied CLL cases. Six of those cases (~33%) had the TP53 deletion accompanied by an i(17q). Interestingly, the cases with i(17q) showed a tendency towards more associated chromosomal aberrations. These findings may be the bases for follow-up studies in CLL patients with TP53 deletion with and without i(17q); it may be suggested that the i(17q) presents an even more adverse prognostic marker than TP53 deletion alone.

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Increased SERUM VON Willebrand Levels in Chronic Lymphocytic Leukemia (CLL) Patients Are Related to a Shorter Time to Treatment

Blood ◽

10.1182/blood-2018-99-119520 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5547-5547

Author(s):

Thommais Tryfou ◽

Paraskevi Papaioannou ◽

Panagiotis Repousis ◽

Annita Ioanna Gkioka ◽

Sotirios Sachanas ◽

...

Keyword(s):

Endothelial Cell ◽

Chronic Lymphocytic Leukemia ◽

Von Willebrand Factor ◽

Conflicts Of Interest ◽

Umbilical Vein ◽

Lymphocytic Leukemia ◽

Endothelial Cell Proliferation ◽

Von Willebrand ◽

Willebrand Factor

Abstract CLL is a frequent and usually indolent disease that require only follow-up in about 2/3 of patients while the rest 1/3 of patients are symptomatic, have a worse outcome and need to be treated. The role of angiogenesis in CLL prognosis remains unclear. It has been shown that CLL plasma promotes von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs) [1]. Therefore, we investigated whether serum vWF levels in CLL patients at diagnosis could provide prognostic information. Patients and methods: 33 CLL patients were studied of whom 55%, 32% and 13% were Binet staged A, B and C respectively. 45% never required treatment while 55% required treatment either at the time of diagnosis or during their follow-up. The time to first treatment (TFT) was 34 months. Serum vWF was measured by ELISA (R&D Quantiquine, duo Set) in frozen sera drawn at patients' diagnosis and in 10 healthy individuals (HI). Measurements were performed in duplicate according to the manufacturer's instructions. Statistical analysis was performed by conventional methods, using the SPSS v.22 software. P values below 0,05 were considered statistically significant. Results: Serum vWF levels ranged from 178,5 to 14353,5 pg/ml (median 1028,5) in patients and from 374,6 to 1141,3 pg/ml (median 528,5) in HI, the difference being statistically significant (p< 0,05). Patients with Serum vWF levels above 528,5 pg/ml (median normal value) had a significantly shorter TFT than the others (p=0,01) as shown in figure. Otherwise, serum vWF levels correlated only with hypogammaglobulinemia (p=0,04). Conclusion: Serum vWF levels were increased in CLL patients. Importantly, we showed for the first time, to our knowledge, that higher vWF levels correlated with a shorter TFT, suggesting that increased vWF levels reflect active neoangiogenesis that in turn, contributes to a more aggressive disease behavior. [1] Shahidi M et al, Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-κB. Blood Coagul Fibrinolysis. 2016 Sep;27(6):711-6. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Safe Start of Ibrutinib in Patients with Chronic Lymphocytic Leukemia and Uncontrolled Autoimmune Hemolytic Anemia

Blood ◽

10.1182/blood-2018-99-120129 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5560-5560 ◽

Cited By ~ 1

Author(s):

Alejandro Garcia-Horton ◽

Rosanne St. Bernard ◽

Alejandro Lazo-Langner ◽

Anargyros Xenocostas ◽

Joy Mangel ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Hemolytic Anemia ◽

Autoimmune Hemolytic Anemia ◽

Conflicts Of Interest ◽

Case Reports ◽

Laboratory Data ◽

Case Series ◽

Lymphocytic Leukemia ◽

Positive Direct

Abstract It is estimated that 4-10% of patients with chronic lymphocytic leukemia (CLL) will develop autoimmune hemolytic anemia (AIHA) over the course of their disease. Ibrutinib has proven to be effective in treatment of relapsed, refractory, 17p deleted, and treatment naïve CLL. The effect of ibrutinib on AIHA in the context of CLL has not been established since patients with active hemolysis were excluded from major trials. In this abstract, we present a case series of patients that were actively hemolyzing at the start of ibrutinib therapy and in which their AIHA achieved prolonged response. Patient characteristics and laboratory data are shown in Table. Five patients (3 women, 2 men), median age 61 years (range 57 to 78), with CLL and active, uncontrolled AIHA at the time of ibrutinib initiation were identified. Uncontrolled AIHA was defined as anemia with evidence of hemolysis (at least two of the following: increased reticulocyte count, elevated lactate dehydrogenase, elevated indirect bilirubin, and reduced haptoglobin and a positive direct antiglobulin test (DAT)). Patients had a median hemoglobin of 70 g/L (range 69-96) prior to start of ibrutinib and 3 of them required transfusion support for symptomatic anemia. All patients were receiving prednisone for management of AIHA at the time of ibrutinib initiation and had been on it for a median of 10 days (range 9 - 25) without AIHA resolution. 1 patient received intravenous immunoglobulin concurrently. All patients had received at least one line of therapy for CLL in the past and 3 had experienced previous AIHA responsive to steroids. AIHA in 2 patients was related to previous fludarabine exposure but had responded to a prednisone tapering schedule and were off steroids by the time of the new AIHA flare. Median hemoglobin of 130 g/L (range 113-149) was reached at time of AIHA response. All 5 patients tolerated 420mg oral daily of ibrutinib therapy and AIHA was controlled in a median of 6.5 weeks (range 6-10). Discontinuation of steroids was achieved in all patients at a median of 10 weeks (range 6-17) without evidence of further hemolysis. All patients except one are receiving ongoing follow up and have been followed up for a median of 130 weeks (range 15-150) since ibrutinib start. Patients have not shown evidence of AIHA relapse and continue off AIHA treatment (prednisone). One patient required discontinuation of ibrutinib 6 months after starting due to neutropenia but there was no evidence of AIHA relapse in follow up. The patient has passed away from unrelated GI bleed 2 years after the initial AIHA event. This is the largest case series to our knowledge on the safe start of ibrutinib in CLL complicated by active AIHA. Hemolysis in all patients responded to a short prednisone taper with ibrutinib concurrently and obtained a sustained response at follow up without any flare ups or further AIHA treatment use. These cases suggest that it is safe to start ibrutinib during uncontrolled, active hemolysis in contrast to 2 previous case reports that suggested causal relationship between ibrutinib and onset of severe CLL-associated AIHA (Rider et al, 2015; Hodskins et al, 2014). As previously reported, AIHA occurrence or relapse once ibrutinib has been started is rare (Rogers et al, 2016). Disclosures No relevant conflicts of interest to declare.

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Incidence and Implications of Skin Cancers in Cancercare Manitoba Chronic Lymphocytic Leukemia (CLL) Clinic Patients

Blood ◽

10.1182/blood.v128.22.4359.4359 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4359-4359

Author(s):

Sara Beiggi ◽

Mohammad Pannu ◽

Versha Banerji ◽

Dhali H.S. Dhaliwal ◽

Spencer B. Gibson ◽

...

Keyword(s):

Skin Cancer ◽

Chronic Lymphocytic Leukemia ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

P Value ◽

Close Monitoring ◽

Mutational Status ◽

Skin Cancers ◽

Increased Risk

Abstract Background:We previously conducted a population-based study on chronic lymphocytic leukemia (CLL) in Manitoba, which showed that second cancers are twice as common and skin cancers eight times as common in this disease, as compared to an age- and sex-matched control population and patients with follicular lymphoma. It is postulated that this is related to immunosuppression, secondary to the disease and chemo-immunotherapy. Here we set out to investigate rates and types of skin cancers in CLL patients and how these influence the outcome of CLL patients. Methods: Newly diagnosed CLL patients attending the CancerCare Manitoba CLL Clinic from the January 1st, 2002 until December 31st, 2012 were selected for this study. Patients were followed until December 31, 2014. Cox Proportional Hazard models were constructed to predict hazard's ratios (HR) and 95% confidence intervals (95% CI) for survival as well as risk of non-cutaneous malignancies. Association between skin cancer and CLL prognostic markers were investigated by Fisher's Exact test, Student's t-test and logistic regression analysis. P-value <0.05 was considered statistically significant. Statistical analysis was performed using SAS Studio 3.5. Results: There were 582 CLL patients in this study. The median age was 67 years (range 36-99 years) with a M:F ratio of 1.6:1. This compares with a median age of 71.5 years and a M:F ratio of 1.3:1 in the Manitoba CLL population. The median follow-up for the study was 5.8 years (range 0.1-13.0 years). There were 131 (23%) CLL patients with at least one skin cancer; 73 (56%) had their first skin cancer before the diagnosis of CLL and 58 (44%) after. Rates of first skin cancer diagnoses were constant before CLL diagnosis (5.2 per 1000 CLL cases), but began to increase three years prior to the CLL diagnosis (10.2 per 1000 CLL cases) and continued to increase after the CLL diagnosis (22.7 per 1000 CLL cases). There were a total of 368 skin cancers; 208 (57%) were basal cell carcinomas (BCC), 92 (25%) were squamous cell carcinomas (SCC), 47 (13%) were Bowen's disease, 18 (5%) were melanomas, and three (1%) were Merkel cell carcinomas. Interestingly, multiple skin cancers with varying histologies occurred in almost half the patients. When the total number of skin cancers/year was assessed, the number started to increase seven years before the CLL diagnosis and continued to increase yearly after the CLL diagnosis. Within the follow-up period, 154 (27%) patients died, with the major causes of death being CLL and second malignancies. However, the presence of skin cancers did not appear to influence survival. There were a total of three deaths due to skin cancers; two patients died of melanoma and one from BCC. However, the presence of a skin cancer, in CLL cases without a history of a solid tumor, increased the risk of a non-cutaneous malignancy by seven-fold (HR 7.55, 05% CI 3.92 - 14.53, p<0.0001). The presence of a skin cancer prior to the diagnosis of CLL did not predict CLL aggressiveness at diagnosis, as evaluated by Rai stage, Zap-70 or CD38 status, immunoglobulin levels or IGHV mutational status. However, for those patients developing their first skin cancer after the CLL diagnosis, the risk of developing a skin cancer correlated with the unmutated IGHV status (HR 1.54, 95% CI 1.01 - 2.34, p=0.0462) and baseline CD38 positivity (HR 1.58, 95% CI 1.02 - 2.44, p=0.0405). Interestingly, the risk of developing skin cancer was not increased by chemotherapy. Discussion: In summary, with a median follow-up of 5.8 years, 23% of patients had a skin cancer, half before the diagnosis of CLL and half after the CLL diagnosis. The incidence of skin cancers increased prior to the diagnosis of CLL, indicating that immunosuppression possibly preceded the diagnosis of CLL by years. The increased risk of developing skin cancers in patients with unmutated IGHV and CD38 positivity indicates that CLL patients with a more aggressive disease are more likely to develop skin cancer, probably due to a more pronounced immune deficiency. The diagnosis of skin cancer in CLL patients was associated with a seven-fold increased risk of developing a solid tumour. These results underscore the need for close monitoring and active surveillance of CLL patients for skin and other cancers throughout their disease course, by clinicians experienced in skin and other malignancies. Disclosures No relevant conflicts of interest to declare.

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