Second primary malignancies after chronic lymphocytic leukemia

Abstract With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17–1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12–1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5–1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41–1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003–2015 (SIR 1.36; 95% CI:1.3–1.42) as compared to 1973–1982 (SIR 1.19; 95% CI:1.12–1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31–1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13–1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.

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Neutropenia analysis of venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: Pooled data from VENICE-I and -II Phase IIIb trials.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e20011 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e20011-e20011

Author(s):

Mary Ann Anderson ◽

Matthew Steven Davids ◽

Arnon P. Kater ◽

Tara Cochrane ◽

Fatih Demirkan ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Median Number ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Post Hoc Analysis ◽

Pooled Data ◽

Concurrent Use ◽

Phase Iiib ◽

Second Primary Malignancies ◽

Post Hoc

e20011 Background: Neutropenia is a common hematologic Grade (Gr) 3+ adverse event (AE) recorded in patients with chronic lymphocytic leukemia (CLL) receiving venetoclax (VEN). In this analysis, we evaluated fixed duration VEN monotherapy given to patients with relapsed or refractory (R/R) CLL with and without pre-existing Gr3+ neutropenia. Methods: This post-hoc analysis pooled data from patients in the ongoing Phase 3b trials VENICE-I and VENICE-II with R/R CLL who had received ≥1 dose of VEN monotherapy (ramp-up to 400 mg QD). Gr4 hematologic AEs and Gr3+ neutropenia ( < 1000 cells/mm3) with infection or fever were managed using dose interruption/reduction. Granulocyte colony stimulating factor (G-CSF) was used in Gr3+ neutropenia. Results: At data cutoff (June 30, 2019), 44/468 (9%) patients had Gr3+ neutropenia at baseline (BL; Gr3+ neutropenia group), 80% of whom received G-CSF during the study vs 38% of those with < Gr3 neutropenia at BL ( < Gr3 neutropenia group). Median on-study duration for VEN was 20.2 months (range: 0.1–36.1). Median number of prior CLL therapies was 2 for both groups (range: 1–10). Serious infections were experienced by 10/44 (23%) and 69/424 (16%) of patients in the Gr3+ and < Gr3 neutropenia groups, respectively. The most common AEs leading to discontinuation overall were second primary malignancies (13/468; 3%). 5/468 (1%) patients in the total population discontinued due to neutropenia/febrile neutropenia. One case of Gr5 infection with concomitant Gr3 neutropenia was reported in the < Gr3 neutropenia group post-VEN discontinuation. See Table. Conclusions: In this large post-hoc analysis, discontinuation due to neutropenia was rare (1%) in the overall population and accounted for 3/11 AE discontinuations in the Gr3+ neutropenia group; 10 patients had a serious infection. Patients with pre-existing neutropenia can be managed on VEN, though concurrent use of G-CSF is likely to be required. Additional data to follow. Clinical trial information: NCT02756611; NCT02980731 . [Table: see text]

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Chronic lymphocytic leukemia and second primary malignancies: A relationship revisited

Indian Journal of Medical and Paediatric Oncology ◽

10.4103/ijmpo.ijmpo_282_20 ◽

2020 ◽

Vol 41 (5) ◽

pp. 787

Author(s):

Amarendra Amar

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Second Primary Malignancies

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Second primary malignancies in treated and untreated patients with chronic lymphocytic leukemia

American Journal of Hematology ◽

10.1002/ajh.26363 ◽

2021 ◽

Author(s):

Moritz Fürstenau ◽

Adam Giza ◽

Thomas Stumpf ◽

Sandra Robrecht ◽

Christian Maurer ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Second Primary Malignancies

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Primary Malignant Neoplasms Associated with Chronic Lymphocytic Leukemia

Tumori Journal ◽

10.1177/030089168006600404 ◽

1980 ◽

Vol 66 (4) ◽

pp. 431-438 ◽

Cited By ~ 17

Author(s):

Armando Santoro ◽

Franco Rilke ◽

Franca Franchi ◽

Silvio Monfardini

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Alkylating Agents ◽

Malignant Lesion ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Malignant Neoplasms ◽

Primary Malignancy ◽

Second Primary Neoplasms ◽

Primary Neoplasms ◽

Cellular And Humoral Immunity

Over the past 2 decades there has been an almost exponential increase in the frequency with which cases of leukemia associated with another primary malignant lesion have been reported. In this study we reported the occurrence of a second primary neoplasm in 82 consecutive cases of chronic lymphocytic leukemia (CLL) admitted to the Istituto Nazionale Tumori of Milan from September 1962 to December 1978. In 16 of these (19.5%), an associated neoplasm was diagnosed subsequently (8 cases) or concurrently (8 cases) to CLL. Head and neck carcinomas and breast cancer had the highest incidence (5 and 3 cases, respectively). The results of this study further support the hypothesis that patients with CLL are prone to develop subsequent cancer. The defective cellular and humoral immunity in CLL may have an etiological role in the development of an additional primary malignancy. Although alkylating agents are known carcinogens in experimental animals and man, our results support the lack of a correlation between treatment with alkylating agents and incidence of second primary neoplasms, as demonstrated by Greene et al. (10).

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Clinical Characteristics and Outcome of Young Chronic Lymphocytic Leukemia Patients: A Single Institution Study of 204 Cases

Blood ◽

10.1182/blood.v94.2.448 ◽

1999 ◽

Vol 94 (2) ◽

pp. 448-454 ◽

Cited By ~ 147

Author(s):

Francesca R. Mauro ◽

Robert Foa ◽

Diana Giannarelli ◽

Iole Cordone ◽

Sabrina Crescenzi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Clinical Features ◽

Median Survival ◽

Survival Probability ◽

Older Patients ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Age Group ◽

Single Institution ◽

Younger Patients

Abstract A retrospective analysis on chronic lymphocytic leukemia (CLL) patients ≤55 years observed at a single institution was performed with the purpose of characterizing the clinical features and outcome of young CLL and of identifying patients with different prognostic features. Over the period from 1984 to 1994, 1,011 CLL patients (204 [20%] ≤55 years of age and 807 [80%] >55 years of age) were observed. At diagnosis, younger and older patients displayed a similar distribution of clinical features, except for a significantly higher male/female ratio in younger patients (2.85 v 1.29;P < .0001). Both groups showed an elevated rate of second primary cancers (8.3% v 10.7%), whereas the occurrence of Richter’s syndrome was significantly higher in younger patients (5.9% v 1.2%; P < .00001). Younger and older patients showed a similar overall median survival probability (10 years) but were characterized by a different distribution of causes of deaths: CLL unrelated deaths and second primary malignancies predominated in the older age group, whereas the direct effects of leukemia were prevalent in the younger age group. Although younger and older patients displayed a similar survival, the evaluation of the relative survival rates showed that the disease had a greater adverse effect on the expected survival probability of the younger population. Multivariate analysis showed that for young CLL patients only dynamic parameters, such as lymphocyte doubling time and other signs of active disease, were the independent factors that significantly influenced survival probability (P = .00001). A prolonged clinico-hematologic follow-up allowed us to identify two subsets of young CLL patients with a different prognostic outcome: a group of patients (40%) with long-lasting stable disease without treatment and an actuarial survival probability of 94% at 12 years from diagnosis and another group (60%) with progressive disease and a median survival probability of 5 years after therapy. For the latter patients, the therapeutic effect of innovative therapies with curative intents needs to be investigated in prospective, comparative clinical trials.

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Long-term survival in chronic lymphocytic leukemia after first primary malignancy in the United States.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18090 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18090-e18090

Author(s):

Amir Bista ◽

Dipesh Uprety ◽

Subash Ghimire ◽

Megha Giri ◽

Binay Kumar Shah

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Relative Survival ◽

The United States ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Age Group ◽

Primary Cancer ◽

Primary Malignancy ◽

Term Survival ◽

Cancer Breast

e18090 Background: There has been significant improvement in survival among patients with primary Chronic Lymphocytic Leukemia (CLL) in recent years but, not much is known about survival among CLL developed after a first primary malignancy. Methods: SEER 18 database, 2015 submission, was used to calculate 5 and 10 year relative survival (RS) by period survival modeling method for 1993 to 2012, with division of the period into 4 cohorts of 5 years each. SEER*Stat software from National Cancer Institute was used to calculate relative survival (RS) for 4 different periods of 5 years duration. The trend in survival for cases with CLL as second primary cancer (CLLSPC) was evaluated using COX proportional hazard method using Cansurv software and also compared with that of primary CLL cases. Results: A total of 8731 patients with CLLSPC were included in the study, which represents 14.5% of all cases of CLL. The median age at diagnosis was 75 years. Median time to diagnosis of CLL was 50 months after diagnosis of first primary malignancy. Prostate cancer, breast cancer and colorectal cancer were 3most common primary cancers. 5-year and 10-year RS improved significantly in the year 2008-2012 compared to 1993-1997 (59.3% to 70.2%,P 0.044 and 40.1% to 50.6%, p 0.045). In subgroup analysis, significant improvement in 5-year and 10-year RS was seen in females and ≥ 80 years age group but no significant improvement was observed in males and age group 60-79 years. Survival among CLLSPC was significant worse compared to first primary CLL in all periods, even after adjusting for age and sex. Conclusions: CLLSPC represents about 14.5% of all CLL cases. Relative survival among patients with CLLSPC is gradually improving but still lags behind that of CLL as first primary cancer.

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Acalabrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.2020009617 ◽

2021 ◽

Author(s):

John C. Byrd ◽

Jennifer A. Woyach ◽

Richard R. Furman ◽

Peter Martin ◽

Susan O'Brien ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Phase 1 ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Efficacy And Safety ◽

Bleeding Events ◽

Second Primary Cancers ◽

Duration Of Response ◽

Treatment Naïve

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). The efficacy and safety of acalabrutinib monotherapy was evaluated in a treatment-naïve CLL cohort of a single-arm phase 1/2 clinical trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patient demographics included a median age of 64 years and 47% with Rai stage III/IV disease. Acalabrutinib was administered orally either 200 mg once daily (QD) or 100 mg twice daily (BID) until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene (IGHV), and 12 (18%) had TP53 aberrations. After a median follow-up of 53 months, 85 patients remain on treatment; 14 patients discontinued treatment, mostly due to adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Due to improved trough BTK occupancy with BID dosing, all patients were transitioned to 100 mg BID. The median duration of response (DOR) was not reached; the 48-month DOR rate was 97% (95% confidence interval [CI], 90%, 99%). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) due to second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). The durable efficacy and long-term safety of acalabrutinib in this trial provide support for its use in clinical management of symptomatic, untreated CLL patients.

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Clinical Characteristics and Outcome of Young Chronic Lymphocytic Leukemia Patients: A Single Institution Study of 204 Cases

Blood ◽

10.1182/blood.v94.2.448.414k13_448_454 ◽

1999 ◽

Vol 94 (2) ◽

pp. 448-454

Author(s):

Francesca R. Mauro ◽

Robert Foa ◽

Diana Giannarelli ◽

Iole Cordone ◽

Sabrina Crescenzi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Clinical Features ◽

Median Survival ◽

Survival Probability ◽

Older Patients ◽

Lymphocytic Leukemia ◽

Second Primary ◽

Age Group ◽

Single Institution ◽

Younger Patients

A retrospective analysis on chronic lymphocytic leukemia (CLL) patients ≤55 years observed at a single institution was performed with the purpose of characterizing the clinical features and outcome of young CLL and of identifying patients with different prognostic features. Over the period from 1984 to 1994, 1,011 CLL patients (204 [20%] ≤55 years of age and 807 [80%] >55 years of age) were observed. At diagnosis, younger and older patients displayed a similar distribution of clinical features, except for a significantly higher male/female ratio in younger patients (2.85 v 1.29;P < .0001). Both groups showed an elevated rate of second primary cancers (8.3% v 10.7%), whereas the occurrence of Richter’s syndrome was significantly higher in younger patients (5.9% v 1.2%; P < .00001). Younger and older patients showed a similar overall median survival probability (10 years) but were characterized by a different distribution of causes of deaths: CLL unrelated deaths and second primary malignancies predominated in the older age group, whereas the direct effects of leukemia were prevalent in the younger age group. Although younger and older patients displayed a similar survival, the evaluation of the relative survival rates showed that the disease had a greater adverse effect on the expected survival probability of the younger population. Multivariate analysis showed that for young CLL patients only dynamic parameters, such as lymphocyte doubling time and other signs of active disease, were the independent factors that significantly influenced survival probability (P = .00001). A prolonged clinico-hematologic follow-up allowed us to identify two subsets of young CLL patients with a different prognostic outcome: a group of patients (40%) with long-lasting stable disease without treatment and an actuarial survival probability of 94% at 12 years from diagnosis and another group (60%) with progressive disease and a median survival probability of 5 years after therapy. For the latter patients, the therapeutic effect of innovative therapies with curative intents needs to be investigated in prospective, comparative clinical trials.

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