CLINICAL TOXICITIES OF GO

At 9 mg/m², GO commonly causes acute infusional reactions, with ~30% and 10% of patients experiencing grade 3/4 infusion-related events after the first and second dose, respectively. In the registration trials, such toxicities included chills (8%), fever (6%), hypotension (4%), nausea (3%), and hypertension (2%). Of note, hypotension – typically transient and fluid responsive – could occur several hours after completion of drug administration (130). Corticosteroids are effective in reducing these reactions (165). Subsequent other common grade 3/4 toxicities include invariable myelosuppression (neutropenia [98%], thrombocytopenia [99%]), transient and reversible liver enzyme abnormalities (hyperbilirubinemia [29%], elevation in asparate aminotransferase [18%] or alanine aminotransferase [9%]), sepsis (17%), fever (13%), chills (9%), nausea/emesis (10%), pneumonia (8%), dyspnea (8%), hypertension (8%), hypotension (8%), asthenia (6%), and neutropenic fever (6%) (130). As a curious rare side effect possibly related to effective elimination of CD163⁺ macrophages/monocytes, isolated cases with severe toxic symptoms during intravascular hemolysis secondary to impaired hemoglobin scavenging have been reported in children (166).

Read Also

• Apakah epilepsi pasca trauma berhubungan dengan risiko demensia jangka panjang?
• Penyakit Langka dan Kolaborasi Internasional: Berbagi Pengetahuan untuk Dampak Global
• Penelitian memberikan bukti bahwa penggunaan antidepresan pada kehamilan mempengaruhi perkembangan otak anak
• Pola makan kaya flavonol dikaitkan dengan penurunan angka kematian dan risiko penyakit, menurut penelitian
• Mengevaluasi kemanjuran iradiasi seluruh payudara ultrahipofraksionasi dalam uji coba acak FAST-Forward
• Merokok, minum minuman keras, dan kebiasaan makan dikaitkan dengan risiko kanker kepala dan leher, demikian temuan penelitian
• Keragaman bakteri usus terkait dengan berat badan, atlet menunjukkan profil yang lebih sehat
• Memerangi Bugs dan Blues: Interaksi antara Infeksi dan Emosi
• Imunoterapi sel T CAR pada kanker kolorektal
• Tanda Awal Kehamilan
• Perubahan Fungsi Kekebalan Tubuh Terkait Usia: Imunosenesensi dan Modulasi Kekebalan Tubuh

A characteristic adverse event that was noticed from the beginning of clinical drug testing is sinusoidal obstruction syndrome (SOS) or veno-occlusive disease (VOD) (129, 130, 167). GO-associated SOS presents as tender hepatomegaly, portal hypertension, fluid retention, weight gain as well as ascites and encephalopathy at later stages, with ascites being pathognomonic for the disease (168). Developing a median of 10-14 days following GO treatment, SOS is more likely when the drug is given at doses higher than 6 mg/m² or when it is combined with a hepatotoxic agent (e.g. thioguanin); in the initial clinical studies, SOS was observed most commonly when GO was used pre-transplant, in particular – in up to 65-90% in small patient series – when patients underwent allogeneic HCT within 3-4 months of receiving GO (169, 170). A small study suggested the possibility that the risk of SOS might be modified by a SNP within the glutathione-S-transferase genes, but this link is currently not firmly established (53). The identification of several GO-associated SOS cases shortly after drug approval led the FDA to request the establishment of an industry-sponsored prospective observational registry. Experience from this registry suggested a rate of SOS of around 10% (14.9% and 8.2% in patients undergoing or not undergoing HCT, respectively) (170). SOS proved highly fatal: among 99 cases captured in the FDA’s adverse drug event reporting system, 80% required hospitalization and 66% ultimately died (170). Treatment options for GO-associated SOS are poorly defined but limited data indicate that defibrotide may have a role in either prophylaxis or treatment of this condition (120, 171, 172). The etiology of SOS remains somewhat elusive although, based not only on clinical but also histological findings, toxic effects on cells in hepatic sinusoids are likely underlying this pathologic process. Proposed mechanisms include exposure to unconjugated calicheamicin- g₁^I in the circulation, nonspecific uptake of GO by CD33⁺ Kupffer cells, or CD33-mediated uptake of GO by one or more of the cell populations in the liver (173); indeed, some data suggest that perhaps, CD33 is also found on hepatocytes (174).

Not surprisingly, data from trials in which GO has been used at lower doses indicate that dose is the key element contributing to GO toxicity. In fact, in most of the recent phase 3 trials, there were no major differences with regard to non-hematologic toxicities between the GO-containing and the control arm when GO was added to conventional induction chemotherapy. Specifically, in the MRC/NCRI AML15 and AML16 trials, hematologic recovery was identical in both arms although patients treated with GO required more platelet transfusions and more days of intravenous antibiotics (146, 148). In contrast, in the ALFA trial, prolonged recovery of neutrophil and platelet counts were observed in the GO arm (145), possibly as a reflection of the more intense, fractionated dosing rather than single administration of GO. SOS was observed very infrequently but remained highly fatal, with 2 out of 3 affected patients dying as a consequence of this toxicity (145).