Here, we present a novel case of a patient with chronic lymphocytic leukemia (CLL) who received CTLA-4 and then PD-1 immune-checkpoint blockade (ICB) as treatment for concomitant metastatic melanoma. Whereas the metastatic melanoma was responsive to ICB, the CLL rapidly progressed (but responded to ICB cessation and ibrutinib). There were no new genetic mutational drivers to explain the altered clinical course. PD-1/PD-L1/PD-L2 and CTLA-4/CD80/CD86 expression was not increased in CLL B cells, CD8+ or CD4+ T-cell subsets, or monocytes. The patient’s CLL B cells demonstrated strikingly prolonged in vitro survival during PD-1 blockade, which was not observed in samples taken before or after ICB, or with other patients. To our knowledge, a discordant clinical course to ICB coupled with these biological features has not been reported in a patient with dual malignancies.

Keywords:
CLL, Metastatic melanoma, Immune-checkpoint blockade

Immune-checkpoint blockade (ICB) with anti-programmed death-1 (PD-1) and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies is active in cancers such as metastatic melanoma and Hodgkin lymphoma but is less efficacious in others [1‒4]. Mechanisms of ICB resistance are an area of active research.

Here, we report a novel case in a patient with the B-cell lymphoproliferative disorder chronic lymphocytic leukemia (CLL), who sequentially received CTLA-4 and then PD-1 ICB as treatment for concomitant metastatic melanoma. Whereas the metastatic melanoma went into metabolic remission with PD-1 blockade, the CLL rapidly accelerated. The discordant clinical course between the two malignancies was not explained by new genetic drivers of CLL. In vitro investigations were consistent with a reversible cell-autonomous rather than cell-extrinsic driven process that resolved when the patient ceased pembrolizumab and commenced ibrutinib therapy.

Written informed consent was obtained from the patient for this case report, as part of a broader observational correlative science study approved by an appropriate Ethics Committee. The study was performed in accordance with the Declaration of Helsinki.

A 67-year-old male presented with melanoma (T1bNxM0) [5] over his left scapula, treated with wide local excision. One month later, there was an incidental finding of lymphocytes 4.24 × 109/L in the peripheral blood count (Fig. 1a; day −498), with 72% CD19/CD20/CD5/CD23/κ+ (weak) clonal B cells. Bone marrow aspirate/trephine (BMAT) showed 38% CLL with low-volume adenopathy but no enlarged liver or spleen on computerized tomography (CT). Although lymphocytosis was <5 × 109/L, on the basis of the BMAT and CT findings, a diagnosis of CLL, Rai stage 1, was made [6]. Fluorescent in situ hybridization indicated 17p (29%) and 13q deletion (20%) and immunoglobulin heavy chain variable region (IGVH) analysis showed unmutated IGVH. CLL-directed therapy was not commenced as the patient was asymptomatic.

Fig. 1.
Clinical findings in the patient with concomitant CLL and melanoma. a Timeline of treatment regimens and laboratory parameters in a patient with concomitant CLL and melanoma. b Heatmap demonstrating the variant allele frequency of the 20 mutations (once germline mutations removed) detected in serial samples using whole exome capture DNA sequencing. Dx, CLL diagnosis; CP, cyclophosphamide; Pem, pembrolizumab; Ipi, ipilimumab; Hb, hemoglobin; ICB, immune-checkpoint blockade; VAF, variant allele frequency.
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Clinical findings in the patient with concomitant CLL and melanoma. a Timeline of treatment regimens and laboratory parameters in a patient with concomitant CLL and melanoma. b Heatmap demonstrating the variant allele frequency of the 20 mutations (once germline mutations removed) detected in serial samples using whole exome capture DNA sequencing. Dx, CLL diagnosis; CP, cyclophosphamide; Pem, pembrolizumab; Ipi, ipilimumab; Hb, hemoglobin; ICB, immune-checkpoint blockade; VAF, variant allele frequency.

Fig. 1.
Clinical findings in the patient with concomitant CLL and melanoma. a Timeline of treatment regimens and laboratory parameters in a patient with concomitant CLL and melanoma. b Heatmap demonstrating the variant allele frequency of the 20 mutations (once germline mutations removed) detected in serial samples using whole exome capture DNA sequencing. Dx, CLL diagnosis; CP, cyclophosphamide; Pem, pembrolizumab; Ipi, ipilimumab; Hb, hemoglobin; ICB, immune-checkpoint blockade; VAF, variant allele frequency.
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Clinical findings in the patient with concomitant CLL and melanoma. a Timeline of treatment regimens and laboratory parameters in a patient with concomitant CLL and melanoma. b Heatmap demonstrating the variant allele frequency of the 20 mutations (once germline mutations removed) detected in serial samples using whole exome capture DNA sequencing. Dx, CLL diagnosis; CP, cyclophosphamide; Pem, pembrolizumab; Ipi, ipilimumab; Hb, hemoglobin; ICB, immune-checkpoint blockade; VAF, variant allele frequency.

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One year after excision, relapse of melanoma occurred at the original site. Positron emission tomography (PET) confirmed a fluorodeoxyglucose-avid subcutaneous nodule under the scar with no evidence of systemic melanoma and low-avidity lymphadenopathy comparable in size and distribution to the imaging performed at CLL diagnosis. Lymphocytes were 11.79 × 109/L (day −200). In the same month, wide local excision of the recurrence and a left axillary dissection were performed. Two nodes showed evidence of melanoma; all others were effaced by CLL. In the absence of distant metastases, no systemic therapy was offered as per the standard of care at that time. Five months later, he developed a new mass over the thorax and PET demonstrated intensely avid subcutaneous lesions with muscular extension and multiple lung nodules, and he was diagnosed with metastatic melanoma. He commenced ipilimumab (3 mg/kg IV 3 weekly; day 0). Lymphocytes were 35.57 × 109/L. He received 4 cycles with complete resolution of the axillary mass and partial response in the lung by CT scan. His CLL nodal burden remained stable, but lymphocytes increased to 124.4 × 109/L (day +166). Given lack of complete response, the patient commenced pembrolizumab 2 mg/kg IV 3 weekly. After 6 cycles, PET confirmed metabolic remission of all melanoma deposits. Conversely, mildly avid hilar and infra-diaphragmatic nodal lesions, presumed to reflect CLL, had modestly increased in size and there was new splenomegaly. Lymphocytes had increased to 434 × 109/L, with reduced hemoglobin (100 g/L) and platelets (127 × 109/L) (day +409). BMAT indicated 89% lymphocytosis (fluorescent in situ hybridization: 100% and 90% 17p and 13q deletion, respectively). The patient commenced cyclophosphamide (300 mg PO for 6 weeks) while access to compassionate use targeted therapy was sought. During this time, the CLL progressed. On day +417, compassionately accessed ibrutinib (420 mg PO daily) began. This therapy was characterized by an early increase in ALC, peaking at 675 × 109/L on day 3 of ibrutinib therapy, but with almost immediate improvement in palpable nodal disease. PET at 5 weeks post-commencement of ibrutinib demonstrated partial response with regard to CLL nodal disease and ongoing metabolic response of previous melanoma deposits. At 8 weeks, lymphocytes were 268.0 × 109/L (day +493). Ibrutinib continued, lymphocytes continued to fall, and there was resolution of the cytopenias. The patient presented with new neck/back pain 16 months later. PET showed multiple new bilateral pulmonary and adrenal lesions as well as innumerable intensely FDG-avid focal bony lesions throughout the axial and appendicular skeleton (although reduction in abdomino-pelvic lymphadenopathy was noted). Bone biopsy confirmed metastatic melanoma. Due to deteriorating performance status, the patient was admitted to hospital for palliative care, developed a hospital-acquired pneumonia, and died 8 days later.

CLL progression is associated with a larger number of CLL drivers and acquisition of additional genetic hits including TP53 [7]. The index patient had high-risk genetic features at diagnosis. To establish whether the patient’s CLL course was associated with an altered mutational profile, whole exome sequencing was retrospectively performed on sequential samples. This detected 20 somatic mutations (Fig. 1b) including TP53. The variant allele frequency of TP53 increased over time (samples A 0.7; C 0.87; E 0.94). The remaining mutations were present at low variant allele frequency, with none shown to be recurrently mutated in CLL (online suppl. Table S1; see www.karger.com/doi/10.1159/000527631 for all online suppl. material). As their allele frequency was stable, it is unlikely that they were responsible for the accelerated clinical course observed.

A rare but devastating type of ICB resistance is hyperprogressive disease, in which tumor cells undergo rapid expansion in numbers [8‒10]. Hyperprogressive disease typically arises in patients receiving anti-PD-1 ICB; however, cases have occurred with concurrent/preceding CTLA-4 blockade. Postulated mechanisms include cell-extrinsic drivers involving the tumor immune microenvironment [4, 11‒13] and tumor cell-intrinsic (i.e., cell-autonomous) mechanisms including mutations in EGFR, KRAS, or TSC2 [14‒16] (not detected by whole exome sequencing) and PD-1 acting as a tumor suppressor [17]. To investigate the biological basis for the CLL rapid disease progression, cell-extrinsic and cell-autonomous tests were undertaken (see online suppl. methods).

Samples before and during ICB were tested in immune subsets for PD-1/PD-L1/PD-L2 and CTLA-4/CD80/CD86 (Fig. 2a–c). Results were compared with 5 CLL patients who did not receive ICB or have accelerated disease. Regulatory T cells were similar across index and patient controls (mean 10.88%, vs. 9.11%). CTLA-4 expression was negligible in regulatory T cells whereas PD-1/PD-L1/PD-L2 were detectable in the index and controls across CD4+ T-cell subsets and CD8+ T cells. PD-1 expression prior to ICB was similar to controls but was subsequently reduced, consistent with surface-bound pembrolizumab. In all samples, monocytes overwhelmingly displayed a “classical” (CD16−veCD14+) phenotype which expressed high level of PD-L1/PD-L2 and CD86 (>80%) across all samples. In CLL B cells, PD-1 on index samples was lower relative to controls, with levels of PD-L1/PD-L2/CTLA-4/CD80/CD86 minimal.

Fig. 2.
Flow cytometry and cell culture assays in the patient with concomitant CLL and melanoma. a Percentage of PD-1+ and CTLA-4+ cells within CD8, TREG, TH17, TH1, TH2, T-cell subsets, at time-points A (pre-ipilimumab) and E (pembrolizumab) in the index patient, compared to patients with CLL alone (n= 5) and without disease acceleration. b Percentage of PD-L1+, PD-L2+, CD80+, and CD86+ cells within classical (CD16−veCD14+) monocytes. c Percentage of PD-1+, CTLA-4+, PD-L1+, PD-L2+, CD80+ and CD86+, and CTLA-4+ cells within CD19+/CD5+ malignant B cells. Data presented for CLL alone patients in mean ± standard deviation (SD). d CLL PBMCs were cultured at high density (10–20 × 106 cells/mL) and cell viability examined by trypan blue exclusion and expressed as the number of viable cells relative to initial seeding number. Survival of CLL PBMCs from patient with concomitant CLL and melanoma, post-pembrolizumab and -CP compared to CLL PBMC cell survival of 58 patients with CLL alone. Cell survival was examined over a 6-week period and survival curves generated using one phase exponential decay with least squared fit. Survival of PBMC cultures from the CLL patient with melanoma in samples F and G and 4 patients with CLL alone are highlighted, with cytogenetics and IGVH mutational status shown. e CLL PBMCs on samples A–I were cultured at high density from serial samples collected from the patient with CLL and melanoma. Each PBMC culture was cultured in triplicate and data are presented as mean ± SD. pvalues are relative to sample A. f Absolute lymphocyte counts on three patients with CLL and concomitant melanoma were followed for 6 months from ICB initiation. The patients were not receiving anti-CLL therapy while on ICB. Each had isolated 13q cytogenetic abnormalities without 17p deletion and were categorized as low-risk CLL. No other molecular profiling was available. Patient 1 was male, 63 years old at time of ICB; patient 2 was female, 84 years old at time of ICB; and patient 3 was male, 79 years old at time of ICB. The % change in absolute lymphocyte count from initiation of ICB is shown. Over the 6-month period, patients 1–3 received ×13 2-weekly cycles of nivolumab (patient 1); ×4 cycles of 3-weekly ipilimumab followed by ×7 cycles of 2-weekly nivolumab (patient 2); and ×8 cycles of 2-weekly nivolumab (patient 3, discontinued early due to toxicity), respectively. *p< 0.5; **p< 0.01; ***p< 0.001; ****p< 0.0001.
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Flow cytometry and cell culture assays in the patient with concomitant CLL and melanoma. a Percentage of PD-1+ and CTLA-4+ cells within CD8, TREG, TH17, TH1, TH2, T-cell subsets, at time-points A (pre-ipilimumab) and E (pembrolizumab) in the index patient, compared to patients with CLL alone (n= 5) and without disease acceleration. b Percentage of PD-L1+, PD-L2+, CD80+, and CD86+ cells within classical (CD16−veCD14+) monocytes. c Percentage of PD-1+, CTLA-4+, PD-L1+, PD-L2+, CD80+ and CD86+, and CTLA-4+ cells within CD19+/CD5+ malignant B cells. Data presented for CLL alone patients in mean ± standard deviation (SD). d CLL PBMCs were cultured at high density (10–20 × 106 cells/mL) and cell viability examined by trypan blue exclusion and expressed as the number of viable cells relative to initial seeding number. Survival of CLL PBMCs from patient with concomitant CLL and melanoma, post-pembrolizumab and -CP compared to CLL PBMC cell survival of 58 patients with CLL alone. Cell survival was examined over a 6-week period and survival curves generated using one phase exponential decay with least squared fit. Survival of PBMC cultures from the CLL patient with melanoma in samples F and G and 4 patients with CLL alone are highlighted, with cytogenetics and IGVH mutational status shown. e CLL PBMCs on samples A–I were cultured at high density from serial samples collected from the patient with CLL and melanoma. Each PBMC culture was cultured in triplicate and data are presented as mean ± SD. pvalues are relative to sample A. f Absolute lymphocyte counts on three patients with CLL and concomitant melanoma were followed for 6 months from ICB initiation. The patients were not receiving anti-CLL therapy while on ICB. Each had isolated 13q cytogenetic abnormalities without 17p deletion and were categorized as low-risk CLL. No other molecular profiling was available. Patient 1 was male, 63 years old at time of ICB; patient 2 was female, 84 years old at time of ICB; and patient 3 was male, 79 years old at time of ICB. The % change in absolute lymphocyte count from initiation of ICB is shown. Over the 6-month period, patients 1–3 received ×13 2-weekly cycles of nivolumab (patient 1); ×4 cycles of 3-weekly ipilimumab followed by ×7 cycles of 2-weekly nivolumab (patient 2); and ×8 cycles of 2-weekly nivolumab (patient 3, discontinued early due to toxicity), respectively. *p< 0.5; **p< 0.01; ***p< 0.001; ****p< 0.0001.

Fig. 2.
Flow cytometry and cell culture assays in the patient with concomitant CLL and melanoma. a Percentage of PD-1+ and CTLA-4+ cells within CD8, TREG, TH17, TH1, TH2, T-cell subsets, at time-points A (pre-ipilimumab) and E (pembrolizumab) in the index patient, compared to patients with CLL alone (n= 5) and without disease acceleration. b Percentage of PD-L1+, PD-L2+, CD80+, and CD86+ cells within classical (CD16−veCD14+) monocytes. c Percentage of PD-1+, CTLA-4+, PD-L1+, PD-L2+, CD80+ and CD86+, and CTLA-4+ cells within CD19+/CD5+ malignant B cells. Data presented for CLL alone patients in mean ± standard deviation (SD). d CLL PBMCs were cultured at high density (10–20 × 106 cells/mL) and cell viability examined by trypan blue exclusion and expressed as the number of viable cells relative to initial seeding number. Survival of CLL PBMCs from patient with concomitant CLL and melanoma, post-pembrolizumab and -CP compared to CLL PBMC cell survival of 58 patients with CLL alone. Cell survival was examined over a 6-week period and survival curves generated using one phase exponential decay with least squared fit. Survival of PBMC cultures from the CLL patient with melanoma in samples F and G and 4 patients with CLL alone are highlighted, with cytogenetics and IGVH mutational status shown. e CLL PBMCs on samples A–I were cultured at high density from serial samples collected from the patient with CLL and melanoma. Each PBMC culture was cultured in triplicate and data are presented as mean ± SD. pvalues are relative to sample A. f Absolute lymphocyte counts on three patients with CLL and concomitant melanoma were followed for 6 months from ICB initiation. The patients were not receiving anti-CLL therapy while on ICB. Each had isolated 13q cytogenetic abnormalities without 17p deletion and were categorized as low-risk CLL. No other molecular profiling was available. Patient 1 was male, 63 years old at time of ICB; patient 2 was female, 84 years old at time of ICB; and patient 3 was male, 79 years old at time of ICB. The % change in absolute lymphocyte count from initiation of ICB is shown. Over the 6-month period, patients 1–3 received ×13 2-weekly cycles of nivolumab (patient 1); ×4 cycles of 3-weekly ipilimumab followed by ×7 cycles of 2-weekly nivolumab (patient 2); and ×8 cycles of 2-weekly nivolumab (patient 3, discontinued early due to toxicity), respectively. *p< 0.5; **p< 0.01; ***p< 0.001; ****p< 0.0001.
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Flow cytometry and cell culture assays in the patient with concomitant CLL and melanoma. a Percentage of PD-1+ and CTLA-4+ cells within CD8, TREG, TH17, TH1, TH2, T-cell subsets, at time-points A (pre-ipilimumab) and E (pembrolizumab) in the index patient, compared to patients with CLL alone (n= 5) and without disease acceleration. b Percentage of PD-L1+, PD-L2+, CD80+, and CD86+ cells within classical (CD16−veCD14+) monocytes. c Percentage of PD-1+, CTLA-4+, PD-L1+, PD-L2+, CD80+ and CD86+, and CTLA-4+ cells within CD19+/CD5+ malignant B cells. Data presented for CLL alone patients in mean ± standard deviation (SD). d CLL PBMCs were cultured at high density (10–20 × 106 cells/mL) and cell viability examined by trypan blue exclusion and expressed as the number of viable cells relative to initial seeding number. Survival of CLL PBMCs from patient with concomitant CLL and melanoma, post-pembrolizumab and -CP compared to CLL PBMC cell survival of 58 patients with CLL alone. Cell survival was examined over a 6-week period and survival curves generated using one phase exponential decay with least squared fit. Survival of PBMC cultures from the CLL patient with melanoma in samples F and G and 4 patients with CLL alone are highlighted, with cytogenetics and IGVH mutational status shown. e CLL PBMCs on samples A–I were cultured at high density from serial samples collected from the patient with CLL and melanoma. Each PBMC culture was cultured in triplicate and data are presented as mean ± SD. pvalues are relative to sample A. f Absolute lymphocyte counts on three patients with CLL and concomitant melanoma were followed for 6 months from ICB initiation. The patients were not receiving anti-CLL therapy while on ICB. Each had isolated 13q cytogenetic abnormalities without 17p deletion and were categorized as low-risk CLL. No other molecular profiling was available. Patient 1 was male, 63 years old at time of ICB; patient 2 was female, 84 years old at time of ICB; and patient 3 was male, 79 years old at time of ICB. The % change in absolute lymphocyte count from initiation of ICB is shown. Over the 6-month period, patients 1–3 received ×13 2-weekly cycles of nivolumab (patient 1); ×4 cycles of 3-weekly ipilimumab followed by ×7 cycles of 2-weekly nivolumab (patient 2); and ×8 cycles of 2-weekly nivolumab (patient 3, discontinued early due to toxicity), respectively. *p< 0.5; **p< 0.01; ***p< 0.001; ****p< 0.0001.

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To test whether the survival of CLL B cells was altered during the patient’s disease, we utilized a culture system in which nurse-like cells support CLL B-cell survival [18‒20]. Typically, CLL B-cell survival reduces in weeks 1-2, then decline further with <30% cells surviving at 4 weeks. This is illustrated in 58 CLL patients without prior ICB (Fig. 2d). By contrast, in cultures from the index patient taken while on pembrolizumab, >80% of CLL B cells survived out to 6 weeks. To determine whether these findings varied according to the index patient’s treatment course, assays were repeated in 9 sequential blood samples (A–I) (Fig. 2e). Strikingly, at 4 weeks the patient samples taken during or following pembrolizumab treatment (D–G) all showed highly significantly prolonged cell survival (>85%) compared to pre-therapy sample (A) (4.2%; p < 0.0001). The two samples taken after ipilimumab (before pembrolizumab; B, C) also showed significantly improved survival (>30%; p = 0.03). Data indicate that prolonged in vitro B-cell survival is higher than at pre-therapy in the samples taken when on ipilimumab and is markedly higher when on pembrolizumab but is reversed on ibrutinib. Preclinical data indicate that combining ibrutinib with PD-1 blockade improves CD8+ T-cell function and control of CLL [21]. However, as the patient did not receive ibrutinib and pembrolizumab in combination, the impact on CD8+ T-cell function from the two agents combined could not be tested.

ICB has revolutionized the management of patients with metastatic melanoma [22]. However, data have been largely restricted to patients on clinical trials with specific exclusion criteria. There have been five case series with a dual diagnosis of CLL and metastatic melanoma, encompassing 23 patients, with no clinical responses in CLL to ICB [23‒27]. No cases of CLL acceleration were described. We identified three additional patients with CLL that received ICB for concomitant melanoma who were not receiving anti-CLL therapy. Each had isolated 13q cytogenetic abnormalities without 17p deletion and were categorized as low-risk CLL [28]. Unlike the index case, the lymphocyte kinetics of patients 1–3 following ICB did not show rapid escalation (Fig. 2f). It remains unknown whether it the dual (13q and 17p) deletions drove the response to ICB observed in the index patient. Although it cannot be ruled out that melanoma itself has an immunomodulatory interaction with CLL that helps suppress CLL progression, the absence of CLL acceleration in these 26 patients once melanoma treatment was initiated makes this less likely. However, there are insufficient data to draw definitive conclusions on this, or regarding the frequency of the phenomenon observed in the index patient. Furthermore, because ICB in B-cell malignancies are modulating a CLL B-cell/host T-cell relationship distinct from that found in solid tumors [4], it is inappropriate to extrapolate the findings to other cancers.

We report a unique case of rapid disease progression associated with ICB in a patient with CLL. Over the same period, the patient’s melanoma went into remission. A causal relationship between pembrolizumab administration and CLL progression in this patient with high-risk genetic features is not proven. Furthermore, it is likely that ibrutinib rather than discontinuation of pembrolizumab resulted in control of CLL. However, in detailed laboratory assays there was prolonged CLL B-cell survival which were not observed in samples taken before ICB or when PD-1 blockade had ceased and ibrutinib commenced. Findings indicate that disease progression in the malignant B cells was driven by an as yet undetermined reversible cell-autonomous process.

The work utilized the flow cytometry core facility at the Translational Research Institute, Brisbane, Queensland, Australia.

This study protocol was reviewed and approved by Metro South Health Human Research Ethics Committee (2006/077). Written informed consent was obtained from the patient for publication of the details of their medical case.

The authors declare no competing nonfinancial interests but the following competing financial interests: Maher K. Gandhi receives research funding from Janssen and has received honoraria from Novartis.

This work was supported by the Mater Foundation (Maher K. Gandhi) and a Medical Research Future Fund Early Career Fellowship (Colm Keane).

Melinda Burgess, Colm Keane, Josh WD Tobin, Nicholas A. Saunders, Devinder Gill, and Maher K. Gandhi conceived and designed the study; Peter Mollee, Colm Keane, Josh WD Tobin, Nicholas A. Saunders, Devinder Gill, Victoria Atkinson, and Maher K. Gandhi provided study materials and/or patients; Melinda Burgess, Josh WD Tobin, Soi C. Law, and Muhammed B. Sabdia collected and assembled data; Melinda Burgess, Adam D. Ewing, Colm Keane, Josh WD Tobin, Nicholas A. Saunders, Devinder Gill, Alison Griffin, and Maher K. Gandhi provided data analysis and interpretation; and all authors undertook manuscript writing, final approval, and are accountable for all aspects of the work.

The PET images, sequencing, culture assay, and flow cytometry individual patient data are not publicly available for the following reason: data contain information that could compromise research participant privacy. However, the data can be made available upon reasonable request to the corresponding author.

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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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