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The search for effective therapeutic interventions for sickle cell disease (SCD) has been an ongoing endeavor for over 50 years. During this period, only hydroxyurea (HU), which received US FDA approval in February 1998, was identified as an effective therapeutic agent in preventing or ameliorating the frequency of vaso-occlusive crises, acute chest syndrome and the need for blood transfusion. Approximately 25% of patients with sickle cell anemia (SCA), however, do not respond to HU and some patients experiencing serious side effects of this chemotherapeutic agent. Nevertheless, the success of HU opened the sluice gates to identify other effective drug therapies. The objective of this review is to describe the emerging drug therapies for SCA.In this review, we describe the pathophysiology of SCD and provide an in-depth analysis of the current and new pharmacologic therapies in the field. Literature searches involved multiple databases including Medline In-ProcessOther Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Scopus.SCA is a heterogeneous disease that has caused tremendous global morbidity and early mortality. More effective, individualized and inexpensive therapies are needed. New therapies targeting multiple pathways in its complex pathophysiology are under investigation.

Although bone metastasis to the acetabulum can cause significant disability from pain and immobility, little has been written about the diagnosis and management of a pathologic acetabular fracture. We present three patients with metastatic acetabular fractures and discuss an approach to evaluation and management. When a high index of suspicion of fracture exists, further radiographic workup is warranted. Management requires a multidisciplinary approach. Factors such as age, associated comorbidities, natural history of the underlying primary cancer, general health status, prognosis, acetabular fracture characteristics, and quality of bone should be considered. We briefly discuss the options available to nonoperative candidates.

Hydroxyurea was approved by the Food and Drug Administration for the treatment of adults with moderate to severe sickle cell anemia and sickle-β0-thalassemia. Its major side effect is myelotoxicity, which is reversible upon discontinuation of the drug. Other side effects that have been described in animal studies but unconfirmed in humans include its teratogenic and carcinogenic potential. Additionally, hydroxyurea has idiosyncratic side effects that occur in some individuals and this may be a genetic or epigenetic phenomenon. We report three idiosyncratic side effects of hydroxyurea in four patients with sickle cell anemia (SS). Desquamating rash, decreased libido and partial complex seizures have not been previously described in patients who are hydroxyurea responders. Although these reactions are rare, they can be serious in some patients.

Treating Acquired von Willebrand’s Syndrome (AVWS) is a challenge requiring multiple therapeutic modalities to achieve success in controlling and preventing bleeding episodes. From review of the literature, clinical use of rituximab, an anti-CD20 monoclonal antibody, in AVWS has not been reported. We present our experience with four patients treated with rituximab for steroid or intravenous immunoglobulin (IVIG) refractory and/or dependent AVWS associated with IgG monoclonal gammopathy of undetermined significance. Rituximab at a dose of 375mg/m2 was administered intravenously weekly for 4 consecutive weeks in the first patient. After 3 cycles of rituximab, we observed a correction of her bleeding time to normal, improvement of her prolonged aPTT, a decrease in her monoclonal IgG and cessation of her bleeding episodes for 29 months. She relapsed and was retreated with rituximab at the same dose for 3 cycles with no improvement in aPTT and bleeding time. She has had no further bleeding episodes after compliance with epsilon aminocaproic acid for one year. The second patient received rituximab intravenously at a dose of 375 mg/m2 weekly for 4 weeks. Prolonged aPTT was unchanged after treatment. He was asymptomatic for 8 months and then received prophylactic IVIG and von Willebrand Factor concentrate (Humate-P) for elective hand surgery. The third patient had a concomitant worsening idiopathic neuropathy and received rituximab 375mg/m2 intravenously daily for 2 consecutive days two weeks apart for his neuropathy. His neuropathy and prolonged aPTT did not improve and he developed gastrointestinal bleeding 1.5 months later. The fourth patient received rituximab 150mg/m2 intravenously weekly for 4 consecutive weeks. Prolonged aPTT was unchanged after treatment. He experienced no bleeding symptoms for 38 months. Factor VIII, Ristocetin Cofactor, von Willebrand Antigen and IgG levels were not significantly affected by rituximab use in cases 2–4. Rituximab seemed to be most effective in the first and fourth cases. The dosing and number of cycles is unclear. Success in the first case with multiple cycles of therapy may be needed for response and warrants further evaluation. Additionally, it appears therapy needs to be reinforced with other agents to prevent or stop bleeding. It was well tolerated with no infectious complications in our patients. Only one patient had an infusion related reaction, which did not require stopping therapy. Further prospective studies are needed to evaluate the efficacy of rituximab and establish the dosing and treatment duration in AVWS.

Autologous transplant has emerged as the standard of care for the treatment of relapsed B-cell non-Hodgkin’s lymphomas (NHL). However, for the treatment of T-cell NHL, the role is not as clear. We report our experience with 24 patients with T-cell NHL who underwent autologous transplantation at time of first relapse. Lymphoma types were varied (peripheral T-cell = 8, lymphoblastic = 6, anaplastic large cell = 5, not otherwise specified = 5). All patients received CHOP as primary therapy, except one patient who received ProMACE/CytaBOM, one who received Stanford V, and two who received HyperCVAD. Patients had either relapsed disease (14 patients) or primary refractory disease (9 patients). One patient underwent autologous transplant as consolidation therapy. Mobilization regimens varied, consisting of dexamethasone, ifosphamide, etoposide, and cisplatin (DICE, 12 patients), dose intensive cyclophosphamide, etoposide, cisplatin (DICEP, 5 patients), cyclophosphamide/etoposide (3 patients), cyclophosphamide (2 patients), or other regimens (2 patients). Adequate collection of stem cells was seen in all but one case, which required bone marrow collection. The conditioning regimen used was BVAC (BCNU 600 mg/m2, etoposide 1600 mg/m2, cytarabine 24 g/m2, and cyclophosphamide 90 mg/kg) in 23 patients. One patient received melphalan conditioning. For the entire group, the overall survival at 3 years was 50%. This compares favorably with 336 relapsed B-cell NHL patients who underwent autologous transplant with the identical conditioning regimen (BVAC) in the same period of time (OS = 52%). At 5 years, the overall survival of the B-cell lymphoma group was stable at 49%. However, the overall survival for the T-cell NHL group declined to 30%. The primary cause of death post transplant was disease relapse. When divided among specific lymphoma subtypes, 3 of 8 patients with peripheral T-cell lymphoma, 4 of 5 patients with anaplastic large cell lymphoma, 3 of 6 patients with lymphoblastic lymphoma and 3 of 5 patients with other T-cell lymphoma subtypes remain alive. Although there are too few patients to draw any definite conclusions, it appears that autologous stem cell transplant for relapsed or refractory T-cell NHL results in similar 3-year overall survivals when compared to B-cell NHL using the same conditioning regimen. However, T-cell NHL appear to be associated with a higher late relapse rate which is reflected in the lower overall survivals at 5 years. Although there may be a benefit to autologous transplant in relapsed anaplastic large cell lymphomas, relapsed/refractory T-cell NHL had inferior long term overall survival compared to their B-cell counterpart transplanted with the same regimen. Novel approaches should be considered in the treatment of relapsed or refractory T-cell NHL.