Selective CD4<sup>+</sup> Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic Implications

Su, Yungpo Bernard; Sohn, SeJean; Krown, Susan E.; Livingston, Philip O.; Wolchok, Jedd D.; Quinn, Carolyn; Williams, Linda; Foster, Theresa; Sepkowitz, Kent A.; Chapman, Paul B.

doi:10.1200/jco.2004.07.060

Cited by 236 publications

(172 citation statements)

References 14 publications

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“…This may be related to the temozolomide-free intervals in the dosage regime for melanoma. Temozolomide is known to affect T-cell counts, but mostly if administered continuously (33)(34)(35)(36). The considerable immune response rate may, moreover, reflect a beneficial effect of temozolomide.…”

Section: Discussionmentioning

confidence: 99%

“…The considerable immune response rate may, moreover, reflect a beneficial effect of temozolomide. Several studies in mice have reported enhanced immunization after combining vaccination with temozolomide, or that temozolomide suppresses Treg function (4,(36)(37)(38)(39)(40). Chemotherapy may also suppress myeloid-derived suppressor cells (5).…”

Section: Discussionmentioning

confidence: 99%

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Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Kyte

Gaudernack

Dueland

et al. 2011

Clinical Cancer Research

101

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Purpose: The study is a proof-of-principle trial evaluating toxicity, immune response, and clinical response in melanoma patients after combined therapy with temozolomide and the telomerase peptide vaccine GV1001. Our previous GV1001 trials showed immune responses in approximately 60% of lung or pancreatic cancer patients. Experimental Design: Twenty-five subjects with advanced stage IV melanoma (M1B or M1C) received concomitant temozolomide and GV1001. Temozolomide was administered 200 mg/m2 orally for 5 days every fourth week, and GV1001 as eight injections over 11 weeks. Immune response was evaluated by delayed type hypersensitivity, T-cell proliferation, and cytokine assays. The immunologic responders continued monthly vaccination. Results: The treatment was well tolerated. A GV1001-specific immune response was shown in 18 of 23 evaluated subjects (78%). Patients developing long-term T-cell memory survived more than those rapidly losing their responses. The immune response exhibited several characteristics of possible clinical significance including high IFNγ/IL-10 ratios, polyfunctional cytokine profiles, and recognition of naturally processed antigens. Survival compared favorably with matched controls from a benchmark meta-analysis (1 year: 44% vs. 24%, 2 years: 16% vs. 6.6%). The clinical responses developed gradually over years, contrary to what is expected from chemotherapy. Five patients developed partial tumor regression and six more recorded stable disease. One patient has no remaining disease on fluorodeoxyglucose positron emission tomography scans after 5 years. Conclusions: The immunologic response rate is considerable compared with previous GV1001 trials without concomitant chemotherapy, although low toxicity is retained. The results warrant further studies of GV1001/temozolomide treatment and support the general concept of combining cancer vaccination with chemotherapy. Clin Cancer Res; 17(13); 4568–80. ©2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Kyte

Gaudernack

Dueland

et al. 2011

Clinical Cancer Research

101

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“…TMZ is associated with CD41 specific lymphopenia, and the degree of iatrogenic immunosuppression caused by TMZ requires careful monitoring of these patients, who are at risk for the complications of immune deficiency. 18 Although it is used in some centers, we did not routinely offer prophylaxis for infections such as Pneumocystis carinii pneumonia, as very few cases have occurred in patients from our population base.…”

Section: Discussionmentioning

confidence: 99%

Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule

Perry

Rizek

Cashman

et al. 2008

Cancer

122

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BACKGROUND. Despite advances in first‐line therapy, there are few data on treatment of glioblastoma multiforme (GBM) at recurrence. Temozolomide (TMZ) is well tolerated and may have activity despite prior TMZ exposure if novel dose schedules are used. METHODS. The authors reviewed their experience with a continuous TMZ schedule (50 mg/m2 daily), given at progression after conventional 5‐day TMZ. Patients were reported in 3 groups: 1) GBM after progression on conventional TMZ; 2) GBM at first recurrence after completion of standard concomitant and adjuvant TMZ; and 3) patients with other anaplastic gliomas at second relapse on conventional TMZ. RESULTS. In Group 1, 21 patients with a median age of 54 years (range, 33 years‐68 years) received a median of 3 cycles (range, 2‐12 cycles) of continuous TMZ at 50 mg/m2. Overall clinical benefit (complete response, partial response, and stable disease) was 47%, with 6‐month progression‐free survival (PFS) of 17%. In Group 2, 14 patients with GBM, median age 52 years (range, 38 years‐62 years) received continuous TMZ at progression after initial TMZ/radiotherapy (RT) and adjuvant TMZ. The median interval after adjuvant TMZ was 3 months (range, 2 months‐10 months). A median of 5 cycles of TMZ was given, and 6‐month PFS was 57%. In Group 3, 14 patients with a median age of 49 years (range, 34 years‐56 years) received continuous TMZ; 2 partial responses and 6 with stable disease were seen, with a 6‐month PFS of 42%. Toxicities were mild and well tolerated; lymphopenia was common but no serious opportunistic infections were identified. CONCLUSIONS. Although retrospective, our results demonstrate that continuous daily administration of TMZ is an active regimen despite prior TMZ therapy. The excellent tolerability of this regimen may allow future combination with other alkylating agents or with novel therapies. Cancer 2008. © 2008 American Cancer Society.

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“…Previous studies of several chemotherapeutic agents (eg, cyclophosphamide, temozolomide, or taxotere) have been shown to promote a desirable cytokine profile by inhibiting regulatory T-cells when administered at subtumoricidal levels. [34][35][36][37] Economic/Global Implications…”

Section: Immune Status In Acute Leukemiamentioning

confidence: 99%

Absolute lymphocyte count is a novel prognostic indicator in ALL and AML

Angulo¹,

Yuen²,

Palla³

et al. 2007

Cancer

113

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BACKGROUND.Leukemia is the leading cause of disease‐related death in children, despite significant improvement in survival and modern risk stratification. The prognostic significance of absolute lymphocyte counts (ALC) was evaluated in young patients with acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL).METHODS.In all, 171 consecutive de novo cases of AML and ALL, age ≤21 years, were analyzed. Age, initial white blood cell count, cytogenetics, and bone marrow response were compared with lymphocyte, neutrophil, and platelet counts at weekly intervals during induction chemotherapy.RESULTS.ALC is a significant independent predictor of relapse and survival. For example, in patients with AML an ALC on Day 28 of induction (ALC‐28) <350 cells/μL predicts very poor survival, with a 5‐year relapse‐free survival (RFS) of only 10% (hazard ratio [HR] 3.7, P = .003). In contrast, an ALC‐15 >350 cells/μL carries an excellent prognosis, with a 5‐year overall survival (OS) of 85% (HR 0.2, P = .012). Similarly in ALL, an ALC‐15 <350 cells/μL predicts poor survival, with a 6‐year RFS of 43% (HR 4.5, P = .002), whereas an ALC‐15 >350 cells/μL predicts excellent outcome, with a 6‐year OS of 87% (HR 0.2, P = .018). Importantly, ALC remains a strong predictor in multivariate analysis with known prognostic factors.CONCLUSIONS.ALC is a simple, statistically powerful measurement for patients with de novo AML and ALL. The results, when combined with previous studies, demonstrate that ALC is a powerful new prognostic factor for a range of malignancies. These findings suggest a need for further exploration of postchemotherapy immune status and immune‐modulating cancer therapies. Cancer 2008. © 2007 American Cancer Society.

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Selective CD4⁺ Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic Implications

Abstract: TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

Cited by 236 publications

References 14 publications

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule

Absolute lymphocyte count is a novel prognostic indicator in ALL and AML

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Selective CD4+ Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic Implications

Abstract: TMZ at this dose and schedule results in CD4(+) lymphopenia in a majority of patients that can result in OIs. Pneumocystis pneumonia prophylaxis should be considered for patients who develop sustained lymphopenia on TMZ.

Cited by 236 publications

References 14 publications

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule

Absolute lymphocyte count is a novel prognostic indicator in ALL and AML

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Product

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Selective CD4⁺ Lymphopenia in Melanoma Patients Treated With Temozolomide: A Toxicity With Therapeutic Implications