Abstract
Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the anti-melanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for treatment of their melanoma at Memorial Sloan Kettering Cancer Center between January 1, 2010 and January 1, 2017 were retrospectively identified. Clinical characteristics including absolute lymphocyte counts during therapy were recorded along with response to treatment (objective radiographic response, progression-free survival, and adverse events) for each patient. Of 9 response-evaluable patients treated with ipilimumab, 3 (33%) had a partial response, 1 (11%) had stable disease, and 5 (56%) developed progressive disease. Objective tumor responses were also observed with single-agent therapy pembrolizumab and with combination therapy of nivolumab and ipilimumab. Grade 3 or 4 toxicity was observed in 6 of 15 patients (40%), including diarrhea, transaminitis, rash, and hemolytic anemia. Although our retrospective assessment was limited, there was no evidence that CLL responded to checkpoint blockade. This case series demonstrates that ipilimumab, pembrolizumab, and combined ipilimumab and nivolumab therapies show clinical activity in patients with melanoma and concomitant CLL, at rates consistent with those previously reported. This population may warrant closer surveillance for hematologic immune-related toxicities such as autoimmune hemolytic anemia.
Keywords: Melanoma, CLL, Checkpoint Blockade, PD-1, CTLA-4
Introduction
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States, with >20,000 cases diagnosed annually.1 Patients with CLL are at increased risk for developing solid tumors, including melanoma.2, 3 CLL patients develop melanoma at 3 times the rate of age-matched normal controls. Patients with CLL who develop melanoma also have inferior survival than those with melanoma without CLL.4, 5 Although the mechanism underlying this increased risk remains unclear, it has been suggested that concomitant immune dysfunction in CLL may impair host tumor immunosurveillance, facilitating immune escape of nascent solid tumors.
In addition to well-characterized hypogammaglobulinemia in CLL, this cancer is also associated with T-cell abnormalities such as impaired CD4+ signaling downstream of the T-cell receptor,6 a reversed CD4+/CD8+ ratio,7 and impaired immunological synapse formation. Furthermore, some of the immunologic changes associated with CLL impact checkpoint molecules that regulate T-cell function. Patients with CLL have higher levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4) expressed on circulating T cells, including regulatory T cells, when compared with healthy controls.8,9, 10 Additionally, programmed death ligand 1 (PD-L1) is upregulated by CLL cells, leading to induction of T-cell exhaustion and immune dysfunction.11 Although T cells from CLL patients exhibit features of T-cell exhaustion, they do retain the capacity for cytokine production. In addition, when co-cultured with CLL cells in the context of CTLA-4 blockade, T cells demonstrate higher levels of proliferation.9 It is not known whether use of immune checkpoint inhibition can reinvigorate exhausted cytotoxic T cells in CLL patients, leading to antitumor response against melanoma or CLL, or if the T cells’ proliferative potential might lead to over-exuberant T-cell responses and excess immune-related toxicity.12, 13
While immune checkpoint blockade has recently revolutionized the treatment of metastatic melanoma, the clinical trials that led to the FDA approvals of ipilimumab and pembrolizumab generally excluded patients with other active malignancies, including CLL.14, 15 Antibodies targeting CTLA-4 or programmed death 1 (PD-1) rely on an intact immune system to exert antitumor effects, which might be dysregulated or compromised in patients with CLL. In addition, in the absence of exogenous immune stimulation, CLL can be associated with autoimmune phenomena including autoimmune hemolytic anemia (AIHA). This association prompted us to ask if CLL would either alter the anti-melanoma activity or exacerbate immune-related toxicities seen in patients with locally advanced or metastatic melanoma treated with checkpoint blockade. Furthermore, we wondered if checkpoint blockade could directly impact the biology of CLL and either reverse or hasten progression of CLL in this population, which remains unknown as studies of PD-1 blockade as a treatment strategy for CLL in combination with ibrutinib are ongoing.16
Here we describe our experience at Memorial Sloan Kettering Cancer Center (MSK) treating 15 patients with both melanoma and CLL using anti-CTLA-4, anti-PD-1, or combination immunotherapy. While a case report of a clinical response to pembrolizumab in one patient with melanoma and concomitant CLL has been previously described,17 this is the largest reported series of outcomes of checkpoint blockade therapy in this patient population.
Methods
This retrospective study was reviewed and approved by the MSK Institutional Review Board. Electronic medical records at MSK were queried for melanoma patients who carried a second cancer diagnosis and were treated with ipilimumab, nivolumab, or pembrolizumab between January 1, 2010 and January 1, 2017. Of 4215 patients with melanoma who received checkpoint blocking antibodies during this period, 150 patients with a second malignancy were identified; among them, 18 had a diagnosis of CLL. Fifteen patients with an established CLL diagnosis at the time of initiation of immunotherapy were included for the analysis of response to checkpoint blockade. Three of the 18 patients with melanoma and CLL were excluded: 2 were enrolled in a clinical trial for the treatment of melanoma with an investigational agent at the time of data collection. The third patient developed and was diagnosed with CLL while in complete remission for melanoma and after discontinuation of immunotherapy. While this patient was excluded from analysis of response to checkpoint blockade, the patient’s experience with toxicity is described.
Clinical data were abstracted from available medical records. An estimated Rai stage was generated using radiographic hepatomegaly and splenomegaly, platelet count, and hemoglobin levels for each patient. Rai stages 0 and 1 were combined to account for possible confounding lymphadenopathy by nodal melanoma metastases. Objective radiographic response to checkpoint blockade was determined using modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines, and progression-free survival (PFS) was calculated from clinical data.18 Enlarged lymph nodes were only selected as target lesions for radiographic response assessment if they had been biopsy-proven to contain metastatic melanoma. Adverse events (AEs) were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Results
Patients Under Study
Fifteen patients with metastatic melanoma and CLL at the time of immunotherapy treatment were further analyzed. Cohort characteristics are described in Table 1. Ten patients received single agent ipilimumab as first-line immunotherapy, 2 received single-agent pembrolizumab, and 3 received combination ipilimumab and nivolumab. Among the patients who received first-line ipilimumab, 3 subsequently received pembrolizumab monotherapy. Most patients were treatment-naive prior to starting immunotherapy, but 2 patients treated with ipilimumab received prior temozolomide, and 1 patient treated with combination ipilimumab and nivolumab received prior paclitaxel.
Table 1. Cohort characteristics.
Includes all patients with known diagnosis of CLL at the time of immunotherapy for melanoma.
| N | 15 | |
|---|---|---|
| Median age (Range) | 74 years (52–83) | |
| Sex | M | 12 (80%) |
| Race | White | 15 (100%) |
| Other oncologic history (Number of patients) | Prostate cancer | 2 |
| Hematologic characteristics | ||
| Estimated Rai stage | 0/I | 8 (53%) |
| Median ALC (Range) | 8.1 × 103
(0.4 – 72 × 103) |
|
| Hepatomegaly | 0 (0%) | |
| Splenomegaly | 7 (47%) | |
| Anemia (Hb <11 mg/dL) | 4 (27%) | |
|
Thrombocytopenia
(Plt < 100 × 103/μL) |
2 (13%) | |
| Melanoma characteristics | ||
| Mutational status | BRAF | 4 (27%) |
| Elevated LDH | 8*(62%) | |
| 0 | 1 | |
| Prior systemic melanoma therapy | Temozolomide | 1 (7%) |
LDH values unavailable for 2 patients. ALC: absolute lymphocyte count; Hb: hemoglobin; LDH: lactate dehydrogenase; Plt: platelet.
The exact or approximate date of CLL diagnosis was known for 14 patients; the median time from CLL diagnosis to start of immunotherapy was 8 years (range, 0 to 21 years). Thirteen patients had not received prior therapy for CLL; 1 patient received 3 cycles of fludarabine, cyclophosphamide, and rituximab 3 years prior to treatment with ipilimumab, and 1 patient received ibrutinib, which was stopped several weeks before initiation of treatment with pembrolizumab. At the start of immunotherapy, the median absolute lymphocyte count (ALC) was 8.1 × 103 cells/μL (range, 0.4 × 103 to 72 × 103 cells/μL). The normal ALC range was initially 0.5 to 5.3 × 103 cells/μL, though this range was independently adjusted to 0.9 to 3.2 cells/μL by the MSK lab department during the period of data collection.
Clinical Activity
Of 10 patients treated with first-line ipilimumab, 9 had imaging for evaluation of best radiographic response (Table 2). Three patients (33%) had a partial response (PR), 1 patient (11%) had stable disease (SD), and 5 patients (56%) developed progressive disease (PD). One patient who did not have imaging developed grade 4 toxicity after a single dose of ipilimumab and was initiated on another therapy prior to response assessment. The median PFS was 3 months (range, 1–11 months) and the median overall survival was 16 months (range, 2–54 months). Three patients were re-treated with ipilimumab; all had PD. Three patients who were treated with second-line pembrolizumab after upfront ipilimumab had available follow-up information; 1 additional patient received 1 dose of pembrolizumab after progression on dabrafenib plus trametinib and did not have subsequent imaging. This patient died 2 months after this dose. The 3 evaluable responses to pembrolizumab in this setting included 1 patient with PD, 1 with SD for 4 months, and 1 with PR for 19 months.
Table 2.
Safety and efficacy of ipilimumab, pembrolizumab, and ipilimumab plus pembrolizumab in 15 melanoma patients with underlying CLL. Chemotherapy regimens are IPI: ipilimumab 3 mg/kg induction; PEMBRO: pembrolizumab 2 mg/kg; NIVO: nivolumab 1 mg/kg. ALC: absolute lymphocyte count; NA: not available; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response; SD: stable disease.
| Patient ID | Melanoma M stage at presentation | Estimated Rai stage | ALC at start of immunotherapy (cells × 103/uL) | Immunotherapy courses | Best radiographic response | Adverse events by grade | PFS (Months) | OS (Months) |
|---|---|---|---|---|---|---|---|---|
| 1 | M1b | II | 8.1 | IPI | PR | Gr 1 diarrhea | 11 | 27 |
| 2 | M1c | II | 47.2 | IPI | PD | Gr 4+ hepatotoxicity; Gr 2 nausea & vomiting; Gr 2 fatigue | 1 | 2 |
| 3 | M1c | II | 11 | IPI | PD | Gr 3 diarrhea | 3 | 8 |
| 4 | M1c | IV | 2.2 | IPI | PD | - | 1 | 11 |
| 5 | M1c | II | 72 | IPI | NA | Gr 4 hepatotoxicity | NA | 4 |
| 6 | M1c | III | 0.4 | IPI | PR | - | 11 | 22 |
| 7 | M1b | 0/I | 8.4 | IPI | PR | Gr 1 diarrhea | 7 | 33 |
| 8 | M1b | IV | 0.5 | IPI | PD | Gr 3 rash | 3 | 18 |
| 9 | M1b | III | 23.6 | IPI | PD | Gr 4 Hemolytic anemia | 1 | 13 |
| 10 | M1c | 0/I | 3.2 | IPI | SD | - | 6 | 54* |
| 11 | M1c | I | 1.6 | PEMBRO | PD | Gr 3 hepatotoxicity | 3 | 9 |
| 12 | M1a | III | 12.1 | PEMBRO | PD | Gr 2 pneumonitis | 3 | 5 |
| 13 | M1a | I | 4.1 | IPI + NIVO | PR | Gr 4 neurotoxicity; Gr 2 hypothyroidism; Gr 2 hepatotoxicity | 7 | 19* |
| 14 | 0 | I | 2.0 | IPI + NIVO | CR | Gr 2 pneumonitis; Gr 2 hypophysitis; Gr 1 rash | 33* | 33* |
| 15 | M1c | 0 | 8.5 | IPI + NIVO | PD | Gr 1 diarrhea | 2 | 3 |
Censored survival data.
Of 3 patients treated with combination nivolumab and ipilimumab as first-line immunotherapy, 1 had a complete response (CR), 1 had a PR, and 1 had PD. The patient with a CR had ongoing CR of 33 months at the time of data collection. Two patients were treated with first-line single-agent pembrolizumab and had PD as their best response.
Immune-Related Toxicity
Among 10 patients treated with ipilimumab monotherapy, 5 patients (50%) experienced grade 3 or 4 AEs during treatment. Two patients (Patients 2 and 5) had grade 4 elevations in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT); liver biopsies for these patients were not performed. One patient (Patient 2) presented 3 weeks after the second dose of ipilimumab with progressive transaminitis; their liver function tests did not improve with IV steroids and reimaging suggested rapid progression of disease in the liver. This patient died 7 days after admission from fulminant liver failure. The other patient (Patient 2) developed transaminitis 4 days after the first dose of ipilimumab and responded to intravenous (IV) dexamethasone with normalization of AST and ALT. This toxicity was attributed to ipilimumab.
One patient initially treated with ipilimumab (Patient 9) developed a grade 4 Coombs-positive warm autoimmune hemolytic anemia approximately 3 weeks after the first ipilimumab dose. The anemia resolved with 8 doses of weekly rituximab and a concomitant prednisone taper. Other grade 3 events included 1 rash (Patient 8) managed with prednisone, cyclosporine, and acitretin, and 1 case of grade 3 diarrhea (Patient 3) from presumed immune-related enterocolitis managed with methylprednisolone and infliximab. Additional low-grade toxicities are described in Table 2.
Among the 3 patients who received pembrolizumab after ipilimumab, 1 patient (Patient 9) was admitted to an outside hospital for suspected respiratory infection and was treated for sepsis. Shortly after admission, the patient was intubated for respiratory failure. The patient did not improve with antibiotics and supportive care. Thus, a decision was made to withdraw support, and the patient died 5 days after admission. The possibility that a drug-related toxicity, such as pneumonitis, contributed to this event cannot be excluded. No other toxicities were identified.
Of the 2 patients who received pembrolizumab as first-line immunotherapy, 1 patient (Patient 11) developed grade 3 autoimmune hepatitis. Of the 3 patients who received combination nivolumab and ipilimumab, 1 patient (Patient 13) developed grade 4 autoimmune demyelinating polyneuropathy within 1 week of the fourth dose of ipilimumab—this was confirmed with lumbar puncture. At this point, immunotherapy was discontinued.
The single patient later diagnosed with CLL after completing treatment with nivolumab and ipilimumab for melanoma (not included in the primary analysis) developed hypothyroidism, pernicious anemia (confirmed with positive antibody against intrinsic factor), and Coombs-positive hemolytic anemia at various time points while on treatment.
CLL Course on Treatment
No patients experienced sustained improvement in ALC with ipilimumab, pembrolizumab, or combined ipilimumab and nivolumab therapy (Figure 1). Five of the 6 patients who had elevated ALC (>20 × 103 cells/μL) after receiving ipilimumab were treated with steroids for AEs that coincided with rising ALCs; 3 of the 5 had rising ALC levels recorded prior to the first dose of steroids, 1 had an elevated ALC on the day of the first steroid dose, and 1 had only one follow-up ALC level recorded after the initiation of steroids. For 3 patients, ALC levels returned to baseline.
Figure 1.
Change in ALC from start of checkpoint inhibitor therapy (ipilimumab). Green traces indicate patients with PR; gray traces indicate patients with SD or PD. Triangles: recorded immunotherapy doses. Grey boxes: recorded treatment with oral or IV steroids. ALC: absolute lymphocyte count.
One patient (Patient 9) with an elevated ALC prior to first treatment with ipilimumab (mean range, 19.4–23.6 × 103 cells/μL) developed a precipitous rise in ALC accompanying an immune-related AE and developed a new Coombs-positive hemolytic anemia (4+ immunoglobulin G, C3 negative), which responded to 8 doses of weekly rituximab and concomitant corticosteroid taper. A bone marrow biopsy and aspirate performed during the AIHA prior to rituximab treatment demonstrated 82% monotypic kappa-restricted B-cell population with immunophenotype CD5+, CD10−, CD20+, CD23+, FMC7−. Peripheral blood flow cytometry was not available but the episode was accompanied by a peripheral blood leukocytosis (white blood cell count 99.2 × 103 cells/ μL, 94.1% lymphocytes, ALC 93.3 × 103 cells/μL). Of note, following treatment of AIHA with rituximab and steroids, this patient’s ALC returned to normal limits. Later in the clinical course, the patient developed a skin rash and elevated ALC level to 5.4 × 103 cells/μL following treatment with pembrolizumab for progressive melanoma. The rash was treated with a prednisone taper with normalization of ALC, but on completion of steroid taper the patient’s ALC increased to 5.5 × 103 cells/μL and the patient developed rapid-onset respiratory failure and died of unclear causes. Sepsis or possible pneumonitis were suspected causes of death. A computerized tomography angiogram performed just prior to rapid clinical deterioration showed progressive metastases, prominent ground-glass opacities, and nonspecific interstitial markings in the left upper lobe, and new splenomegaly compared with imaging performed 1 month prior to death.
Two patients (Patients 2 and 5) who had autoimmune hepatitis and were treated with ipilimumab monotherapy had progressive increases in ALC that did not resolve prior to their deaths. We noted a trend in patients treated with ipilimumab, for whom all immune-related AEs were accompanied by increases in ALC, which resolved with immunosuppressive therapies used to manage those AEs. This association was not observed with patients treated with pembrolizumab or combined nivolumab and ipilimumab combination therapy, for whom ALC trends remained relatively stable.
Discussion
As melanoma patients with underlying CLL were largely excluded from initial studies of checkpoint blocking antibodies, it has remained unclear whether patients with CLL could benefit from these agents. Specifically, questions remained about whether anti-melanoma immune responses could be mounted in the setting of CLL-associated immune dysfunction, or if patients may be susceptible to a different profile of immune-related AEs or at risk for CLL progression. In this retrospective series of 15 patients with concomitant CLL and melanoma, we evaluate the clinical experience with checkpoint blockade. Among 10 patients treated with ipilimumab, we observed 3 patients whose melanoma responded to therapy. While small sample size in this dataset precludes a formal comparison of clinical activity, response rates previously described for ipilimumab are in the range of 10% to 15%.14,19Additionally, responses were observed with pembrolizumab and with combined ipilimumab and nivolumab. In this small experience, there does not appear to be evidence that the clinical activity of checkpoint blockade is compromised in patients with CLL.
Grade 3 or 4 toxicity related to treatment occurred in 5 of 10 patients treated with ipilimumab (50%). While it is difficult to compare AE rates in a cohort of this size, grade 3 or 4 toxicities were observed in only 15% and 28% of patients without concomitant malignancies in larger phase 3 studies of ipilimumab, respectively.14, 20 However, all the toxicities identified in this case series have been previously reported. Of note, 2 patients developed AIHA, a toxicity that is rarely seen in patients treated with checkpoint blockade— it remains unclear whether AIHA was caused by CLL, ipilimumab, or the combination of both. Given the small sample size in this study, it is difficult to compare the observed rate of AIHA to the baseline lifetime risk for AIHA in all CLL patients (7–10%).21 While a potentiation of CLL-driven hemolysis by checkpoint blockade is biologically plausible, the higher rate of AIHA in this case series could also be explained by chance or by confounding factors such as the overrepresentation of male patients,1 as male gender is a risk factor for development of AIHA as well as poor prognosis in CLL.22, 23 Larger studies would be needed to more definitively link AIHA to checkpoint blockade therapy exposure in study populations with CLL.
We also attempted to track the effects of ipilimumab on CLL among these patients by following trends in ALC and reviewing available laboratory and physician assessments. By these rough metrics, no patient developed definitive evidence of CLL progression including Richter’s transformation. Several patients had significant increases in ALC during treatment with ipilimumab, although most elevations proved to be transiently associated with immune-related AEs and resolved either spontaneously or with corticosteroid treatment. ALC has been described as a pharmacodynamic marker associated with clinical outcomes in patients with melanoma receiving ipilimumab.24
While the use of corticosteroids to treat immune-related AEs could potentially confound the observed increases in ALC, in our study 3 of 5 patients treated with corticosteroids had increases in ALC prior to administration of steroids, which represents a different phenomenon. It is likely that more frequent hematologic sampling from the other 2 patients would have revealed similar evidence of rising ALC levels prior to steroid therapy. Furthermore, 1 patient developed elevated ALC without the use of any steroids. These observations align with the biological understanding that steroids are generally lymphotoxic to both CLL and nonmalignant lymphocytes.25 However, as repeat flow cytometry data were generally unavailable, it is unknown whether the observed lymphocytic expansions represented as rising ALC during therapy represented reactive polyclonal expansions of lymphocytes or clonal proliferations of CLL.
Although most is known about CTLA-4 expression on T cells, B cells also express CTLA-4, and CTLA-4 expression is heterogeneous in CLL patients.26–28 CTLA-4 expression on CLL cells is predictive of survival and response to therapy in CLL. Patients whose CLL cells express high levels of CTLA-4 have improved outcomes, longer times to therapy, and improved survival.28 Recent studies highlight that CTLA-4 is relevant to the biology and proliferative potential of CLL cells. Expression of CTLA-4 on CLL cells is associated with a higher proportion of cells in the G0-G1 phase of the cell cycle. This association suggests that CTLA-4 may play a role in delaying progression of the cell cycle, and limiting proliferation of CLL via B-cell proliferation and survival pathways at multiple levels downstream of the interferon and B-cell receptor. These pathways include Janus kinase/signal transducers and activators of transcription signaling, activity of anti-apoptotic protein Bcl-2, and transcription factor c-Myc.27, 29 Ex vivo CTLA-4 blockade of CLL cells that have high CTLA-4 expression induced pro-survival signaling pathways, and it is an open question whether CTLA-4 blockade might be counterproductive in patients with high CTLA-4 expression on CLL. It is not known why anti-melanoma responses can be induced without corresponding responses engendered against CLL cells when both malignancies co-exist, but perhaps the expression of immune checkpoints by CLL cells play a protective role in this scenario.
While initial studies of checkpoint blockade in CLL have mostly focused on Richter’s transformation and advanced stage disease,16, 30, 31 this analysis includes patients who had earlier stages of disease. Further prospective analyses of toxicity and response to immune checkpoint blockade in patients with CLL and melanoma would be needed to further elucidate the intersecting relationships between melanoma, checkpoint blockade, and CLL. Correlative evaluation of CTLA-4 or PD-L1 expression levels on CLL cells with response and toxicity could influence the sequence or components of immune checkpoint therapy (e.g., CTLA-4 vs. PD-1 monotherapy or combination therapy) or help risk-stratify toxicity in patients with metastatic melanoma and concomitant CLL who require immune checkpoint blockade.
Conclusions
We observed that patients with melanoma and underlying CLL can have anti-melanoma responses to checkpoint inhibitor therapy and experience immune-related AEs, indicating that anti-melanoma T-cell responses are preserved despite the presence of CLL. There were no CLL responses, and future studies may shed light on the discordance in anti-tumor effect between cancers in this unique population with two concomitant cancer diagnoses.
Supplementary Material
Suppl. Fig 1. Change in ALC from start of checkpoint inhibitor therapy (Top: pembrolizumab; Bottom: combined nivolumab + ipilimumab). Traces are censored at time of next systemic therapy or death. Green traces indicate patients with PR; gray traces indicate patients with SD or PD. Triangles: recorded immunotherapy doses. Grey boxes: recorded treatment with oral or IV steroids. ALC: absolute lymphocyte count.
Acknowledgements.
We would like to thank our patients and their families. Editorial support in the preparation of this article was provided by Myra Partridge, MA, and Hannah Rice, ELS.
Sources of Funding. This work was supported in part by the Memorial Sloan Kettering Cancer Center (MSK) NCI Core Grant P30 CA008748 (J.H.P, M.A.P, A.N.S., P.B.C., J.D.W., M.K.C). This work was supported in part by the Memorial Sloan Kettering Cancer Center (MSK) Mortimer J. Lacher Fellowship established by The Lymphoma Foundation (M.J.P), who is also supported in part by a grant from the National Institutes of Health/National Center for Advancing Translational Sciences (UL1TR00457), administered by the Clinical and Translational Science Center at Weill Cornell Medical Center and MSK. M.K.C., A.N.S. and J.D.W. are members of the Parker Institute for Cancer Immunotherapy at MSK. Additionally, J.D.W receives funding as the head of the Ludwig Collaborative and Swim Across America Laboratory.
Footnotes
Competing interests. Smithy: Owns shares of Johnson & Johnson. Pianko: None. Maher: None. Postow: Consulting fees from 2015-Present: BMS, Merck, Array BioPharma, Novartis, Incyte, NewLink Genetics, Aduro; Honoraria: BMS and Merck; Institutional Support: RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis, AstraZeneca. Shoushtari: Consultant for: BMS, Immunocore, Castle Biosciences. Institutional research support: BMS, AstraZeneca, Immunocore, Xcovery. Momtaz: None. Chapman: Consulting, advisory, or speaking compensation for: Immunocore, Merck, Cell Medica, Takeda Millennium, and Astra Zeneca, Research support from Pfizer, and Stock Ownership in Rgenix. Park: Consulting fees from Novartis, Amgen, Incyte, AstraZeneca, Kite Pharma, Juno Therapeutics, Adaptive Biotechnologies, GSK, Takeda, Pfizer, and Bayer; Institutional support: Genentech, Shire. Wolchok: Consultant for: Adaptive Biotech; Advaxis; Amgen; Apricity; Array BioPharma; Ascentage Pharma; Astellas; Bayer; Beigene; Bristol Myers Squibb; Celgene; Chugai; Elucida; Eli Lilly; F Star; Genentech; Imvaq; Janssen; Kleo Pharma; Linneaus; MedImmune; Merck; Neon Therapeutics; Ono; Polaris Pharma; Polynoma; Psioxus; Puretech; Recepta; Trieza; Sellas Life Sciences; Serametrix; Surface Oncology; Syndax. Research support: Bristol Myers Squibb; Medimmune; Merck Pharmaceuticals; Genentech. Equity in: Potenza Therapeutics; Tizona Pharmaceuticals; Adaptive Biotechnologies; Elucida; Imvaq; Beigene; Trieza; Linneaus. Callahan: Institutional research support and employment of a family member by Bristol-Myers Squibb; Consulting, advisory, or speaking compensation for: AstraZeneca/MedImmune, Incyte, Moderna and Merck.
Ethics approval and consent to participate. This retrospective study was reviewed and approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board.
Consent for publication. Not applicable.
Availability of data and material. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
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Supplementary Materials
Suppl. Fig 1. Change in ALC from start of checkpoint inhibitor therapy (Top: pembrolizumab; Bottom: combined nivolumab + ipilimumab). Traces are censored at time of next systemic therapy or death. Green traces indicate patients with PR; gray traces indicate patients with SD or PD. Triangles: recorded immunotherapy doses. Grey boxes: recorded treatment with oral or IV steroids. ALC: absolute lymphocyte count.