Provenge plus Cyclophosphamide (see side effect below) plus Pidilizumab (made by TEVA).
Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting,[17] bone marrow suppression,[18] stomach ache, hemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, and lethargy. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow-healing existing wounds, unusual decrease in the amount of urine, or unusual tiredness or weakness.[citation needed]
Cyclophosphamide is itself carcinogenic and may increase the risk of developing lymphomas, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies.[19] Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma, and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients without a history of cyclophosphamide use.[20] Secondary acute myeloid leukemia (therapy-related AML, or "t-AML") is thought to occur either by cyclophosphamide inducing mutations or selecting for a high-risk myeloid clone.[21] This risk may be dependent on dose and a number of other factors, including the condition being treated, other agents or treatment modalities used (including radiotherapy), treatment intensity and length of treatment. For some regimens, it is a very rare occurrence. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) seems to carry an AML risk of less than 1/2000th, with some studies even finding no increased risk compared to the background population. Other treatment regimens involving higher doses may carry risks of 1-2% or higher, depending on regimen. Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk has fallen to the level of the regular population. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML.[citation needed]
Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria.[22] Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage, and mesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein.[23][24] Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein, and has equal efficacy to daily treatment in the management of lupus nephritis.[25]
Cyclophosphamide has also been found to significantly increase the risk of premature menopause in females and of infertility in males and females alike, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary but can rarely be permanent.[26] The use of leuprolide in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.[27]
Cyclophosphamide is a Pregnancy Category D drug and has been shown to cause birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus has shown a pattern of anomalies labeled "cyclophosphamide embryopathy," including growth restriction, ear and facial abnormalities, absence of digits, and hypoplastic limbs.[28][29] Women previously treated with alkylating agents are often able to conceive and deliver health children.[30][31]
Neutropenia or lymphoma arising secondary to cyclophosphamide usage can predispose patients to a variety of bacterial, fungal and opportunistic infections.[32] There are no published guidelines for PCP prophylaxis for patients with rheumatological diseases receiving immunosuppressive drugs, but some advocate its use when receiving high-dose medication.[33][34]
Pulmonary injury appears rare,[35] but can present with two distinct clinical patterns: an early, acute pneumonitis and a chronic, progressive fibrosis.[36] Cardiotoxicity is a major problem with oncology patients treated with higher dose regimens.[37]
High-dose intravenous cyclophosphamide can also cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by the intravenous fluids administered to prevent drug-induced cystitis.[38] While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with the lower doses used in the management of inflammatory disorders.[39]
