Anti-PD-1 therapy in advanced sarcomas: is cutaneous primary site a stronger predictor of response than histologic subtype?

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown modest antitumor activity in unselected advanced sarcomas. Histology driven approach to patient selection is the current standard for off-label anti-programmed cell death 1 (PD1) immunotherapy use. METHODS: We retrospectively reviewed the clinical characteristics and outcomes of patients with advanced sarcoma who were treated with off label anti-PD1 immunotherapy at our center. RESULTS: A total of 84 patients with 25 histological subtypes were included. Nineteen patients (23%) had a cutaneous primary tumor site. Eighteen patients (21%) were classified as having clinical benefit, including 1 patient with complete response, 14 with partial response, and 3 with stable disease lasting over 6 months with previously progressive disease. Cutaneous primary site location was associated with higher clinical benefit rate (58% vs. 11%, p < 0.001), longer median PFS (8.6 vs. 2.5 months, p = 0.003) and OS (19.0 vs. 9.2 months, p = 0.011), compared to non-cutaneous primary. Patients with histological subtypes that pembrolizumab is indicated per current National Comprehensive Cancer Network guidelines had modestly higher rate of clinical benefit versus other histologies, however, the difference was statistically insignificant (29% vs. 15%, p = 0.182) and no statistically significant difference in PFS or OS was observed between these groups. Immune-related adverse events were more frequently seen among patients with clinical benefit (72% vs. 35%, p = 0.007). CONCLUSIONS: Anti-PD1-based immunotherapy is highly efficacious in advanced sarcomas of cutaneous primary site. Cutaneous primary site location is a stronger predictor of ICI response than histologic subtype and should be accounted for in treatment guidelines and clinical trial design.

Disseminated Toxoplasmosis in an Allogeneic Hematopoietic Stem Cell Transplant Recipient: A Case Report and Review of the Current Literature.

Reactivation infections in hematopoietic stem cell transplants are mitigated by prophylactic regimens. Despite high rates of exposure, morbidity and mortality secondary to toxoplasmosis are limited to subsets of patients such as immunocompromised persons. We describe the first case of disseminated toxoplasmosis in a double umbilical cord blood transplant recipient.

Serotonin Syndrome Complicating Treatment of Ifosfamide Neurotoxicity With Methylene Blue.

Methylene blue is a widely used treatment for ifosfamide neurotoxicity. We present a case of severe encephalopathy complicating ifosfamide-based therapy for recurrent retroperitoneal leiomyosarcoma. After treatment with methylene blue, the patient experienced clinical decompensation and was diagnosed with serotonin syndrome based on a constellation of clinical findings. Withdrawal of methylene blue and other serotonergic medications led to clinical stabilization and ultimately neurological recovery. Our case highlights the challenge of diagnosing serotonin syndrome in the face of preexisting ifosfamide neurotoxicity, as there is significant clinical overlap between these 2 syndromes. Practitioners must remain vigilant of this potential life-threatening complication in this vulnerable population.

Fever in Patients With Cancer.

BACKGROUND: The definition of fever is flexible and depends on the clinical context. Fever is frequently observed in patients with cancer. METHODS: Infectious and noninfectious causes of fever in patients with various oncological and hematological malignancies and the usefulness of biomarkers are discussed. RESULTS: To treat patients in a timely manner and to minimize morbidity and mortality, it is paramount that health care professionals determine the cause of fever. The usefulness of biomarkers in febrile patients with cancer continues to be controversial. CONCLUSIONS: Fever is frequently seen in patients with cancer and can be associated with a variety of infectious and noninfectious causes. The utility of acute-phase reactants, such as erythrocyte sedimentation rate, C-reactive protein, and procalcitonin, along with a nonsteroidal anti-inflammatory drug challenge should be further evaluated as adjunct tools for the workup of fever in patients with cancer.

Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome.

Drug reaction with eosinophilia and systemic symptom syndrome is a potentially fatal drug reaction that must be recognized quickly. Ipilimumab and nivolumab are both important agents in the treatment of melanoma and continue to be studied in other malignancies. We believe the mainstay of therapy for immunotherapy-induced drug reaction with eosinophilia and systemic symptom syndrome is early recognition, discontinuation of the inciting agent, supportive care, and treatment with high dose corticosteroids with appropriate tapers that may reduce the length of internal organ injury in cases with liver or kidney involvement.

New-onset toxicity with programmed death-1 inhibitor rechallenge.

Immunotherapy has become a mainstay in the treatment of metastatic melanoma. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and programmed death-1 (PD-1) inhibitors, which have been added more recently, represent two of the main classes of immunomodulating agents. PD-1 inhibitors are well tolerated and are known to have a decreased rate of occurrence of adverse effects compared with CTLA-4 inhibitors. However, the risk remains for serious immune-mediated adverse reactions. Given their long half and extended efficacy, treatment with a CTLA-4 inhibitor before use of a PD-1 inhibitor may increase the risk of adverse effects. In addition, caution should be exercised when rechallenging grade 3 or 4 adverse effects with the same agent or a different agent of the same class. The re-emergence of a previous toxicity may occur or, as found in this case, a new severe effect may arise. This article will present a case of fatal immune-related hepatoxicity in a patient treated with a CTLA-4 inhibitor, followed by treatment with a PD-1 inhibitor. The mechanisms of action and safety profiles for both classes of drugs will also be reviewed.

Docetaxel/Cyclophosphamide-Induced Phototherapy Recall.

Phototherapy recall can occur unexpectedly as a result of treatment with commonly used medications and chemotherapy. These reactions are rare. The recall reaction is an inflammatory response that is triggered by many medications. Cyclophosphamide and docetaxel are widely used chemotherapeutic agents that are useful in the management of many different malignancies. The pathophysiology of phototherapy recall is not clearly understood. This case highlights the need for practitioners to be aware of this potential reaction, even though UV exposure may have occurred in the distant past. We present, to the best of our knowledge, the first phototherapy recall dermatitis that occurred years after UV exposure induced by cyclophosphamide and docetaxel. The frequency of administration of this drug and the profound implications of this adverse effect make this case an important contribution to the medical literature.

Delayed dermatologic hypersensitivity reaction secondary to ipilimumab.

The treatment of melanoma has long favored the use of immunologic agents. Ipilimumab is a monoclonal antibody used to enhance the immune response. This therapy is associated with a variety of adverse reactions including skin reactions. Although dermatologic toxicities associated with the use of ipilimumab are common, delayed hypersensitivity reactions related to the drug have yet to be identified. This report is believed to be the first case of a delayed, severe dermatologic drug-related reaction secondary to ipilimumab. This case highlights the potential for severe toxicity for long periods after administration of ipilimumab.

Fluconazole associated agranulocytosis and thrombocytopenia.

CASE: We describe a second case of fluconazole associated agranulocytosis with thrombocytopenia and recovery upon discontinuation of therapy. The patient began to have changes in white blood cells and platelets within 48 h of administration of fluconazole and began to recover with 48 h of discontinuation. This case highlights that drug-induced blood dyscrasias can occur unexpectedly as a result of treatment with a commonly used drug thought to be "safe". CONCLUSION: According to Naranjo's algorithm the likelihood that our patient's agranulocytosis and thrombocytopenia occurred as a result of therapy with fluconazole is probable, with a total of six points. We feel that the weight of the overall evidence of this evidence is strong. In particular the temporal relationship of bone marrow suppression to the initiation of fluconazole and the abatement of symptoms that rapidly reversed immediately following discontinuation.

Cumulative dermatologic toxicity with ipilimumab and vemurafenib responsive to corticosteroids.

Dermatologic toxicity is a known reaction of ipilimumab and vemurafenib. Because of the lack of effective treatments and aggressive nature of melanoma, treatments are often discontinued and new treatments are initiated in rapid succession. We report what we believe to be the first case of cumulative dermatologic toxicity secondary to rapid-sequential treatment with ipilimumab and vemurafenib for metastatic melanoma that responded to high-dose steroids. This case highlights the combined toxicity of these two drugs that can occur as a result of overlapping toxicity. It also illustrates the need for a substantial wash out period between rapid cycling of these two drugs secondary to ipilimumab's long half-life.