Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses.

Patients and methods: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone.

Results: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS.

Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Keywords: anti-CTLA-4; anti-PD-1; chronic lymphoid leukemia; immune checkpoint inhibitors; melanoma.

Figure 1.. AM response rates and survival following ICI, in the absence or presence of concomitant CLL.

(A) CONSORT diagram describing the comparison of ICI-dependent outcomes between Australian patients with concomitant CLL and AM (N = 19) versus AM alone (N = 148). (B) Pie charts describing radiographic response by RECIST v1.1 assessment in Australian cohorts of patients treated with ICI for AM in the presence of concomitant CLL (top, AUS-CLL, N = 19) or absence of concomitant CLL (bottom, AUS-CTRL, N = 147, *response data available for 147 patients). Objective responses (CR or PR) resulted in 53% of patients with CLL and AM versus 48% in patients with AM alone (P = 0.81). (C) Kaplan–Meier plot comparing OS between patients with concomitant CLL and AM (AUS-CLL, P = 19) and AM alone (AUS-CTRL) (P = 167, P = 0.46 by log-rank test). (D) Kaplan–Meier plot comparing PFS between patients with concomitant CLL and AM (AUS-CLL, N = 19) and AM alone (AUS-CTRL) (N = 167, P = 0.32 by log-rank test). AM, advanced melanoma; CLL, chronic lymphocytic leukemia; CR, complete response; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; OS, overall survival; PD, progressive disease; PD-1, programmed cell death protein 1; PFS, progression-free survival; PR, partial response; SD, stable disease.

Figure 2.. Sub-analysis of ICI-dependent outcomes (ORR, OS, and PFS) among patients with concomitant CLL and AM by ICI subtype and patient history of prior CLL therapy.

(A) CONSORT diagram describing the comparison of ICI-dependent outcomes among all patients with concomitant CLL and AM, stratified by whether patients had prior treatment for their CLL. (B) Waterfall plot describing response to first-line ICI as percentage change in SLD of metastatic melanoma by RECIST v1.1, stratified by type of ICI subtype. These plots display evaluable radiographic responses (N = 34) from ICI treatments from the US cohorts (N = 39). Pie charts, below, further describe radiographic response in this cohort. (C) Waterfall plots describing radiographic response to first-line ICI as percentage change SLD of metastatic melanoma, stratified by whether patients had received prior CLL treatment. These plots include evaluable radiographic responses (N = 34) from ICI treatments from the US cohorts (N = 39). Pie charts, below, further describe response in this cohort. Kaplan–Meier plots comparing OS (D) and PFS (E) between patients with no prior CLL treatment (CLL observation), prior treatment with targeted therapies, or prior treatment with chemoimmunotherapy. AM, advanced melanoma; CLL, chronic lymphocytic leukemia; CR, complete response; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; OS, overall survival; PD, progressive disease; PD-1, programmed cell death protein 1; PFS, progression-free survival; PR, partial response; SD, stable disease; SLD, sum of longest diameter.

Figure 3.. Clinical vignettes of patients treated with ICI for AM in the context of concomitant CLL.

Clinical vignette #1 describes a 76-year-old male who was diagnosed with low-risk CLL and was managed on observation. A year later, he developed a cutaneous melanoma with clinically palpable nodal disease and was managed with wide local excision, lymph node dissection, and adjuvant taxane therapy. Months later, new metastatic disease was identified on surveillance imaging in bilateral adrenal glands. Following treatment with anti-CTLA-4 monotherapy, 3-month post-ICI imaging revealed a near-complete radiographic response. His response has been durable, with no relapse up to the date of this publication. Clinical vignette #2 describes a 67-year-old male who was diagnosed with Rai stage IV CLL with a high-risk 17p deletion by FISH, who was treated, first with combination fludarabine, cyclophosphamide, rituximab, then after CLL progression, with ibrutinib and rituximab. A year later, he developed a cutaneous melanoma treated with wide excision, sentinel lymph node biopsy, and subsequent lymph node dissection due to occult nodal disease. A year later, he developed a large hepatic metastasis and was treated with anti-PD-1 monotherapy. Unfortunately, follow-up imaging demonstrated rapid disease progression. AM, advanced melanoma; CLL, chronic lymphocytic leukemia; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; PD-1, programmed cell death protein 1.