Oxaliplatin desensitization for ovarian cancer in pregnancy: A case report.

•Incidence of cancer in pregnancy is rising and successful treatment of these patients requires expert multidisciplinary care.•Platinum hypersensitivity reactions in ovarian cancer are commonly treated with desensitization protocols.•To our knowledge, chemotherapy desensitization in pregnant patients has not been previously reported.•Oxaliplatin desensitization during pregnancy may be safe and feasible.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

Utility of Risk Stratification for Paclitaxel Hypersensitivity Reactions.

BACKGROUND: Hypersensitivity reactions (HSRs) are a common impediment to paclitaxel therapy. Management strategies to guide care after a paclitaxel-induced HSR are needed. OBJECTIVE: The objective was to evaluate the utility and safety of risk stratification on the basis of severity of the initial HSR. METHODS: A risk stratification pathway was developed on the basis of a retrospective review of the management and outcome of 130 patients with paclitaxel-induced HSRs at Massachusetts General Hospital. This pathway was then studied prospectively in patients referred to Allergy/Immunology with paclitaxel-induced HSRs. RESULTS: The study population (n = 35) had a mean age of 56.1 ± 12 years and most were women (n = 33 [94%]). All 5 patients (15%) with grade 1 initial HSRs were successfully reexposed to paclitaxel, 1 patient at the standard infusion rate and 4 patients at 50% of the standard infusion rate. Thirty patients (85%) with grade 2 to 4 initial HSRs underwent initial paclitaxel desensitization based on the risk stratification pathway. No patients developed severe HSRs using the pathway. Eleven (31%) patients had HSRs that were mild to moderate in nature (grade 1, n = 4 [11%]; grade 2, n = 6 [17%]; grade 3, n = 1 [3%]) during their first desensitization. Sixteen (46%) of the 35 patients safely returned to the outpatient infusion setting for paclitaxel treatment at 50% of the standard infusion rate. Seven (20%) discontinued paclitaxel before the completion of the risk stratification pathway because of disease progression, completion of therapy, or death. CONCLUSIONS: A management strategy using the initial HSR severity for risk stratification allowed patients to receive paclitaxel safely.

Reactions to Rituximab in an Outpatient Infusion Center: A 5-Year Review.

BACKGROUND: Reactions to rituximab occur frequently, with up to 77% of patients developing a reaction during initial exposure. The safety of rechallenging patients after a reaction is not clear and standard guidelines are lacking. OBJECTIVE: To better understand clinical decision making surrounding rituximab reactions and subsequent rechallenge. METHODS: We performed a 5-year retrospective review of all rituximab reactions at a large academic outpatient infusion center. Patients' demographic characteristics, clinical symptoms, and management of reactions were reviewed. Reaction severity was classified using standard criteria. RESULTS: Between June 2006 and January 2011, 67 patients (mean age, 58 ± 13 years, 54% men) with at least 1 rituximab reaction were identified. Most reactions occurred during the first exposure to rituximab (63%). Most reactions (n = 59 [88%]) were grade 1 or 2. Fifty-one patients (n = 51 [88%]) were rechallenged with rituximab on the same day as the initial reaction. Most patients with a grade 1 reaction tolerated rechallenge. Conversely, all 4 patients with a grade 3 reaction had a reaction during rechallenge. The outcome of same-day rechallenge after an initial grade 2 reaction was varied; most patients (26 of 31 [84%]) tolerated same-day challenge, but 5 patients had a reaction (all grade 1-2 severity). CONCLUSIONS: Consistent with previous data, our observations suggest that patients who experience grade 1 reactions to rituximab can be safely rechallenged the same day. A grade 3 or 4 reaction should prompt referral to an allergy specialist for risk assessment before additional rituximab administration. Further research is needed to understand the optimal management of patients with grade 2 reactions.

Skin Testing in the Evaluation and Management of Carboplatin-Related Hypersensitivity Reactions.

Carboplatin-induced hypersensitivity reactions (HSRs) are a frequent occurrence in patients being retreated for malignancy. The most common and severe reactions are thought to be IgE mediated. Currently, skin testing is the only method used clinically to identify individuals sensitized to carboplatin. Despite almost 20 years of clinical use, a standardized approach to skin testing and its use in the management of carboplatin HSRs has not been well established. We review the utility of carboplatin skin testing and discuss factors that influence the interpretation of skin testing results. A risk stratification strategy using skin testing and desensitization to manage patients with carboplatin HSRs is proposed.

Successful desensitization of two patients with ALK-positive lung cancer and hypersensitivity to crizotinib.

The tyrosine kinase inhibitor crizotinib is an effective therapy for patients with cancers harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene. Here, we describe two patients with advanced ALK-positive lung cancer who developed hypersensitivity to crizotinib, requiring temporary discontinuation of the drug. Both patients were treated with a rapid oral desensitization protocol allowing them to resume crizotinib without further signs or symptoms of hypersensitivity.

Management of hypersensitivity reactions to Carboplatin and Paclitaxel in an outpatient oncology infusion center: a 5-year review.

BACKGROUND: A high incidence of hypersensitivity reactions (HSR) to carboplatin and Taxol is limiting the use of carboplatin and Taxol. OBJECTIVE: We conducted a 5-year study of all patients with HSR to carboplatin or Taxol to better understand the nature of infusion HSR and success or failure of management plans after the initial HSR. METHODS: We performed a retrospective chart review of all safety reports from the Massachusetts General Hospital outpatient chemotherapy infusion center between January 2006 and February 2011. All the patients with HSRs to carboplatin or Taxol were identified and included in the final analysis. We reviewed patient characteristics, clinical symptoms, timing, and treatment of the initial HSR, and determined if the patient was rechallenged despite an initial HSR. RESULTS: We identified 152 patients with HSR to carboplatin (n = 45) or Taxol (n = 107). Carboplatin HSR was less severe than Taxol HSR. When comparing the 2 groups, the patients with carboplatin HSRs more commonly described itchy palms and feet, generalized itch, and general urticaria and/or erythema, whereas patients with Taxol HSR more commonly described facial flushing, back pain, and chest or throat tightness (all P < .05). Among 40 patients with mild-to-moderate carboplatin HSRs, only 7 were rechallenged, and 100% tolerated rechallenge without desensitization. None of the patients with severe carboplatin HSRs (n = 5) were rechallenged. Most patients (75%) with Taxol HSRs were rechallenged, and 91% tolerated rechallenge without desensitization; the patients with a severe HSR to Taxol were less likely to be rechallenged. CONCLUSION: The clinical symptoms and timing of carboplatin HSR are distinct from Taxol HSR. Most patients with carboplatin HSR were not rechallenged, whereas most patients with Taxol HSR were successfully rechallenged.

Cavernous sinus/orbital apex syndrome associated with indwelling orbital catheter use.

A 46-year-old man with a history of right orbital fractures and blindness underwent simultaneous fracture repair and enucleation with orbital implantation. During surgery, an orbital catheter was placed for administering local anesthesia to control postoperative pain. After administration of local anesthesia through the catheter on postoperative day 1, the patient had development of a complete ptosis, total ophthalmoplegia, mydriasis, vision loss from 20/20 to NLP, and hypesthesia of the V1 and V2 trigeminal nerve distribution. Intraocular pressures and dilated funduscopic examination were normal. There was no evidence of central nervous system effects or respiratory depression. After 4 hours of observation, the vision, sensation, motility, ptosis, and pupil response all returned to normal. Although rare, contralateral cavernous sinus/orbital apex syndrome may occur with indwelling orbital catheter administration of local anesthetic in an orbit with fractures.

Gene therapy of Fanconi anemia: preclinical efficacy using lentiviral vectors.

Fanconi anemia (FA) is an inherited cancer susceptibility syndrome caused by mutations in a DNA repair pathway including at least 6 genes (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG). The clinical course of the disease is dominated by progressive, life-threatening bone marrow failure and high incidence of acute myelogenous leukemia and solid tumors. Allogeneic bone marrow transplantation (BMT) is a therapeutic option but requires HLA-matched donors. Gene therapy holds great promise for FA, but previous attempts to use retroviral vectors in humans have proven ineffective given the impaired proliferation potential of human FA hematopoietic progenitors (HPCs). In this work, we show that using lentiviral vectors efficient genetic correction can be achieved in quiescent hematopoietic progenitors from Fanca(-/-) and Fancc(-/-) mice. Long-term repopulating HPCs were transduced by a single exposure of unfractionated bone marrow mononuclear cells to lentivectors carrying the normal gene. Notably, no cell purification or cytokine prestimulation was necessary. Resistance to DNA- damaging agents was fully restored by lentiviral transduction, allowing for in vivo selection of the corrected cells with nonablative doses of cyclophosphamide. This study strongly supports the use of lentiviral vectors for FA gene therapy in humans.

Fanconi anemia group A and C double-mutant mice: functional evidence for a multi-protein Fanconi anemia complex.

OBJECTIVE: Fanconi anemia (FA) is a genetically heterogeneous disorder associated with defects in at least eight genes. The biochemical function(s) of the FA proteins are unknown, but together they define the FA pathway, which is involved in cellular responses to DNA damage and in other cellular processes. It is currently unknown whether all FA proteins are involved in controlling a single function or whether some of the FA proteins have additional roles. The aim of this study was 1) to determine whether the FA group A and group C genes have identical or partially distinct functions, and 2) to have a better model for human FA. MATERIALS AND METHODS: We generated mice with a targeted mutation in fanca and crossed them with fancc disrupted animals. Several phenotypes including sensitivity to DNA cross linkers and ionizing radiation, hematopoietic colony growth, and germ cell loss were analyzed in fanca-/-, fancc-/-, fanca/fancc double -/-, and controls. RESULTS: Fibroblast cells and hematopoietic precursors from fanca/fancc double-mutant mice were not more sensitive to MMC than those of either single mutant. fanca/fancc double mutants had no evidence for an additive phenotype at the cellular or organismal level. CONCLUSIONS: These results support a model where both FANCA and FANCC are part of a multi-protein nuclear FA complex with identical function in cellular responses to DNA damage and germ cell survival.