Ahmad Antar

Sorafenib Maintenance Appears Safe and Improves Clinical Outcomes in FLT3-ITD Acute Myeloid Leukemia After Allogeneic Hematopoietic Cell Transplantation

BACKGROUND The FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) gene is one of the most frequently observed genetic alterations in acute myeloid leukemia (AML), with an incidence of about 20% to 30%. FLT3-ITD is significantly associated with a poor outcome, and offering an allogeneic hematopoietic cell transplantation (allo-HCT) is recommended for patients harboring this mutation. Sorafenib is a tyrosine kinase inhibitor active against RAF, VEGF, and FLT3-ITD. It has been used in an off-label fashion in FLT3-ITD AML. PATIENTS AND METHODS We retrospectively assessed the successful use of sorafenib after allo-HCT in patients with FLT3-ITD AML. Six FLT3-ITD AML patients received sorafenib as posttransplantation maintenance therapy (n = 5) or as salvage therapy after a post-allo-HCT relapse (n = 1) and continued afterward. RESULTS One patient developed myocardial infarction 100 days after initiation of sorafenib. Interestingly, skin graft versus host disease (grade II) was observed in 5 of 6 patients and generally occurred within few days after initiation of sorafenib, but it responded promptly to corticosteroid therapy in all patients. All 6 patients were alive and in complete remission at a median follow-up of 16 months (range, 10-29 months) since first induction and at a median follow-up of 12 months (range, 4-20 months) since initiation of sorafenib. Remarkably, the disease of all patients was in molecular remission. CONCLUSION Sorafenib appears to be an effective maintenance therapy after allo-HCT in FLT3-ITD AML, with achievement of durable complete responses. This suggests an immunomodulatory effect of sorafenib in the posttransplantation setting and warrants a broader clinical evaluation of the use of maintenance sorafenib in FLT3-ITD AML.

Extracorporeal Photopheresis in Steroid-Refractory Acute or Chronic Graft-versus-Host Disease: Results of a Systematic Review of Prospective Studies

Acute and chronic graft-versus-host disease (GVHD) remain major obstacles for successful allogeneic hematopoietic cell transplantation. Extracorporeal photopheresis (ECP) modulates immune cells, such as alloreactive T cells and dendritic cells, and improves GVHD target organ function(s) in steroid-refractory GVHD patients. We performed a systematic review to evaluate the totality of evidence regarding the efficacy of ECP for treatment of acute and chronic steroid-refractory or steroid-dependent GVHD. Nine studies, including 1 randomized controlled trial, met inclusion criteria, with a total of 323 subjects. In pooled analyses, overall response rates (ORR) were .69 (95% confidence interval [CI], .34 to .95) and .64 (95% CI, .47 to .79) for acute and chronic GVHD, respectively. In acute GVHD organ-specific responses, ECP resulted in the highest ORR for cutaneous, with .84 (95% CI, .75 to .92), followed by gastrointestinal with .65 (95% CI, .52 to .78). Similar response rates were seen in chronic GVHD involving the skin and gastrointestinal tract. Conversely, ORR for chronic GVHD involving the lungs was only .15 (95% CI, 0 to .5). In chronic GVHD, grades 3 to 4 adverse events were reported at .38 (95% CI, .06 to .78). ECP-related mortality rates were extremely low. Rates of immunosuppression discontinuation were .55 (95% CI, .40 to .70) and .23 (95% CI, .07 to .44) for acute and chronic GVHD, respectively. In summary, albeit limited by numbers of available studies, pooled analyses of prospective studies demonstrate encouraging responses after ECP treatment in acute and chronic GVHD after failing corticosteroids. Further research efforts are needed to improve organ-specific responses.

Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia

Sorafenib has shown encouraging results in patients with Fms‐like tyrosine kinase 3 (FLT3)‐positive acute myeloid leukemia. Its role after allogeneic stem cell transplantation (HSCT) has been reported in a few cases with encouraging results.

Primary effusion lymphoma in an elderly patient effectively treated by lenalidomide: case report and review of literature.

Primary effusion lymphoma (PEL) is a rare aggressive subset of non-Hodgkin B-cell lymphoma. It is caused by Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8). It occurs mainly, but not exclusively, in HIV-positive patients. PEL predominantly develops in serous cavities and occasionally in extracavitary regions. PEL carries a very poor prognosis with a median survival time of <6 months. Indeed, currently used treatment modalities such as CHOP chemotherapy are far from achieving complete and sustainable remission. Therefore, there is no clear standard of care established in the treatment of PEL patients, stressing the need for novel-targeted approaches. Here, we have attempted a comprehensive assessment of the treatment of PEL, discussed avant-garde therapies and updated the state of preclinical research with promising clinical applications in the field. These include inhibitors of viral replication, modulators of cell signaling and inflammation, nuclear factor kappa B (NF-κB) and histone deacetylase inhibitors, and recently the combination of arsenic trioxide and interferon-alpha. Some of these targeted therapies have not yet reached clinical studies, although others were used in a few individual case reports with low numbers of patients. We also describe the first case of a 77-year-old, HIV-negative, HHV8-positive patient diagnosed with PEL limited to the pleural and peritoneal cavities. He received lenalidomide 25 mg/day for 21 days every 28 days. Treatment was well tolerated with no side effects. He rapidly improved after 1 month of treatment and progressively achieved complete remission persistent after 18 months of therapy. We believe that this review will bridge an important gap between classical chemotherapy and modern approaches of targeted therapy. Finally, our findings warrant further evaluation of lenalidomide in future prospective clinical studies.

Azacitidine in the treatment of extramedullary relapse of AML after allogeneic hematopoietic cell transplantation

Extramedullary relapse of AML after allogeneic hematopoietic SCT (HSCT) is rare and less well-defined than systemic disease relapse. In a European Group for Blood and Marrow Transplantation (EBMT) study, the incidence of extramedullary relapse after HSCT was as low as 0.65% in AML.1 However, other studies have reported an incidence of up to 20% among long-term survivors.1, 2, 3, 4, 5, 6 There are no established guidelines for clinical decision making pertaining to the treatment of extramedullary relapse after HSCT.7 Common practice entails a combination of localized radiation, systemic chemotherapy, immunotherapy with donor lymphocyte infusions (DLI), and repeated transplantation if possible. We present in this report our experience in treating two patients with extramedullary non-hematological disease in the setting of relapsed AML previously treated with HSCT, DLI, chemotherapy and radiotherapy.

G-CSF plus preemptive plerixafor vs hyperfractionated CY plus G-CSF for autologous stem cell mobilization in multiple myeloma: effectiveness, safety and cost analysis

The optimal stem cell mobilization regimen for patients with multiple myeloma (MM) remains undefined. We retrospectively compared our experience in hematopoietic cell mobilization in 83 MM patients using fractionated high-dose CY and G-CSF with G-CSF plus preemptive plerixafor. All patients in the CY group (n=56) received fractionated high-dose CY (5 g/m2 divided into five doses of 1 g/m2 every 3 h) with G-CSF. All patients in the plerixafor group (n=27) received G-CSF and plerixafor preemptively based on an established algorithm. Compared with plerixafor, CY use was associated with higher total CD34+ cell yield (7.5 × 106 vs 15.5 × 106 cells/kg, P=0.005). All patients in both groups yielded ⩾4 × 106 CD34+ cells/kg. Conversely, CY use was associated with high frequency of febrile neutropenia, blood and platelet transfusions need and hospitalizations. The average total cost of mobilization in Lebanon was slightly higher in the plerixafor group (

Inhibition of FLT3 in AML: a focus on sorafenib

7886 vs

KIR genotype distribution among patients with multiple myeloma: Higher prevalence of KIR 2DS4 and KIR 2DS5 genes.

7536; P=0.16). Our data indicate robust stem cell mobilization in MM patients with either fractionated high-dose CY and G-CSF or G-CSF alone with preemptive plerixafor. The chemo-mobilization approach was associated with twofold stem cell yield, slightly lower cost but significantly increased toxicity.

Successful treatment of hydroxyurea-associated chronic leg ulcers associated with squamous cell carcinoma.

FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma. Sorafenib monotherapy or in combination with conventional chemotherapy, has been evaluated in various settings in AML, including front-line, relapsed or refractory disease including post-allograft failures and, more recently, as post-transplant maintenance therapy. Encouraging data have emerged with several other agents like lestaurtinib, midostaurin, crenolanib, gilteritinib and quizartinib. Although transient responses to FLT3 inhibitors are often observed in case of disease relapse, the most promising approach is the use of FLT3 inhibitors either in combination with induction chemotherapy or as consolidation/maintenance therapy after allogeneic hematopoietic cell transplantation. In this review, we summarize the clinical data on sorafenib and other FLT3 inhibitors in AML.

Chronic active parietal osteomyelitis due to Salmonella typhi in a patient with Sickle Cell Anemia

Introduction Natural killer (NK) cells possess an antitumor activity against multiple myeloma cells proven by the susceptibility of plasmocytes to NK lysis. In the early stage of MM, the killing of MM cells is mediated by natural cytotoxicity receptors (NRC) and NKG2D-dependent pathway, while in the late stage, NK cells lose their killing potential against MM cells due to the high expression of HLA class I molecules on MM cells. Aim The aim of this paper is to study KIR expression of NK cells in MM patients and in healthy controls, to check for any association between KIR genotypes and MM. Methods KIR genotype was analyzed in 120 healthy Lebanese individuals and 34 MM patients using the KIR Genotyping SSP kit. Results KIR 2DS4*001/002 and KIR 2DS5 were found to be significantly more prevalent among MM patients as compared to controls. For MM patients, the AA, AB, and BB genotype frequencies were, respectively, 38.23%, 47.06% and 14.71% with an A:B ratio of 1.62:1. As for the healthy controls, the AA, AB, and BB genotype frequencies were, respectively, 39.17%, 50%, and 10.83% with an A:B ratio of 1.80:1. Conclusion The interesting observation of the significant presence of KIR2DS4 and KIR2DS5 genes more among multiple myeloma patients than controls is worth further clinical, translational as well as survival research studies in these cases.