Lazaros J. Lekakis

Fatal Rhizopus Pneumonia in Allogeneic Stem Cell Transplant Patients Despite Posaconazole Prophylaxis: Two Cases and Review of the Literature

Posaconazole is a triazole with broad spectrum of activity against multiple fungi including members of the fungal order Mucorales. This activity has been shown both in clinical and in vitro studies, which are critically reviewed here. It has become very popular in prophylaxis in acute myelogenous leukemia (AML) induction and in the graft-versus-host disease (GVHD) settings after 2 recent prospective trials that showed advantage of posaconazole prophylaxis compared to fluconazole or itraconazole. In this report, 2 patients are presented, in whom, despite posaconazole prophylaxis, invasive and ultimately fatal Rhizopus pulmonary infections developed. These cases are similar to a previously reported case of Rhizopus infection in a stem cell transplant recipient who also received posaconazole, indicating a potential newly recognized pattern of breakthrough infections in patients receiving posaconazole prophylaxis.

BK virus nephropathy after allogeneic stem cell transplantation: A case report and literature review†

Polyomaviruses are increasingly recognized as important human pathogens. Among those, BK virus has been identified as the main cause of polyomavirus‐associated nephropathy (PVAN), a major cause of renal allograft failure. PVAN has also been well described in the setting of non‐renal solid organ transplantation. The reports of PVAN after hematopoietic stem cell transplantation (HCT) are surprisingly very few. Here, we describe a patient with treatment‐related myelodysplastic syndrome who received an unrelated donor HCT after ablative conditioning and in vivo T cell depletion with alemtuzumab. He developed a biopsy‐proven BK nephropathy, which contributed to his renal failure. Leflunomide as well as cidofovir were given at different times, both in combination with intravenous immunoglobulin. Both treatments were effective in reducing the BK viral load, the cystitis symptoms and both stabilized but did not really improved the renal function. The patient was still dialysis‐dependent when he died from Pseudomonas sepsis 13 months after HCT. A critical review of the literature and the treatment modalities for post‐HCT PVAN are provided. Am. J. Hematol. 2009.

Anomalous constitutive Src kinase activity promotes B lymphoma survival and growth

BackgroundPreviously we have shown that B cell receptor (BCR) expression and B cell receptor signaling pathways are important for the basal growth of B lymphoma cells. In particular we have shown that the activation of Syk, a non-src family protein tyrosine kinase and the mitogen activated protein kinases (MAPK), ERK and JNK that mediate BCR signals are required for the constitutive growth of B lymphoma cells. Since src family protein tyrosine kinases (SFKs) like Lyn are known to be needed for the phosphorylation of BCR co-receptors, Ig-α and Ig-β, we hypothesized that one or more SFKs will be constitutively activated in B lymphoma cells and may be necessary for B lymphoma growth.ResultsSrc kinase activity was found to be constitutively high in many murine and human B lymphoma cell lines and primary lymphoma samples. The specific pharmacological inhibitors of SFKs, PP1 and PP2 inhibited the proliferation of a number of both murine and human B lymphomas in a dose-dependent manner. Importantly, dasatinib (BMS-354825), an oral dual BCR-ABL and SFK specific inhibitor inhibited the growth of B lymphomas in the nanomolar range in vitro and strongly inhibited a mouse lymphoma growth in vivo. Among the SFKs, Lyn is predominantly phosphorylated and Lyn-specific small interfering RNA inhibited the growth of B lymphomas, supporting an important role for Lyn in B lymphoma growth. Suppression of SFK activity blocks BCR mediated signaling pathways. PMA or CpG can partially reverse the growth inhibition induced by SFK inhibition. Although blocking SFK activity inhibited the growth of a number of B lymphomas, some lymphomas such as SudHL-4, SudHL-6, OCI-Ly3 and OCI-Ly10 are more resistant due to an increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL.ConclusionsThese studies further support our concept that BCR signaling pathways are important for the continued growth of established B lymphoma cells. Some of the intermediates in this BCR pathway are potential immunotherapeutic targets. In particular, inhibition of SFK activity alone or in synergy with inhibition of the prosurvival Bcl-2 proteins holds promise in developing more effective treatments for B lymphoma patients.

Long-term complete regression of nodal marginal zone lymphoma transformed into diffuse large B-cell lymphoma with highly active antiretroviral therapy alone in human immunodeficiency virus infection.

Since the introduction of combination antiretroviral therapy (cART), there has been a decrease in the incidence of non-Hodgkin lymphoma among the HIV-infected population and also significantly improved survival rates. We describe a remarkable case of a HIV-infected patient whose large B-cell lymphoma, most likely arising by transformation of a nodal marginal zone lymphoma, completely regressed with the use of cART alone. He remained disease-free for almost 3 years and he finally died from presumed flare up of his lymphoma. There are very few cases of spontaneous regression of lymphomas with cART alone in the HIV population. This is an extreme example of the significance of cART in improving survival in HIV-non-Hodgkin lymphoma and changing the face of the HIV epidemic in general.

Novel Preparative Regimens in Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation is an established treatment modality for malignant and non-malignant diseases. Prior to the infusion of allogeneic or autologous cells, patients usually receive radiation or chemotherapy. This preparative or conditioning regimen provides treatment for the underlying disease and is expected to impair the recipients immune system and allow engraftment. The last decade witnessed a significant reduction in treatment-related mortality, in great part a result of less toxic preparative regimens and improvements in supportive care. Another important trend has been the incorporation of newer drugs to classic conditioning regimens, as illustrated by the addition of rituximab to BEAM and other combinations. It is expected that this trend will continue leading to increased cure rates by incorporation of targeted therapies to hematopoietic transplant. The next decade will likely witness further integration of new preparative regimens with graft engineering, and pharmacologic, cellular and immunologic post transplant interventions. The design of creative clinical trials that will allow the critical evaluation of the role of these new approaches in transplantation will also be a major challenge to the transplant community in the years to come. In this article, we review newer transplant conditioning regimens and discuss their indications and future directions in this rapidly changing landscape.

Reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy with a peak incidence over the age of 55 years. AML of older patients is less curable with conventional chemotherapy, and, when it relapses, is almost uniformly fatal. Novel treatments hold the promise of improving the results of therapy, but have failed so far to show dramatic change in the prognosis. Allogeneic stem cell transplantation using traditional myeloablative preparative regimens is not easily tolerated by the elderly and/or frailer patient, and may lead to prohibitive treatment-related mortality rates. Most patients treated in the past were younger and devoid of comorbid clinical conditions. Novel reduced-intensity regimens made allogeneic transplants applicable to the elderly, providing the benefit of the graft-versus-leukemia effect to a larger number of patients in need. Here we review the indications for allogeneic transplants in AML and discuss reduced-intensity conditioning regimens.

First-time use of bevacizumab for aggressive, metastatic hepatocellular carcinoma in an HIV/hepatitis B virus coinfected patient: a case report.

We present a case of an HIV-1 infected patient with history of chronic hepatitis B and chronic alcohol use without cirrhosis, who presented with aggressive hepatocellular carcinoma with multiple metastases. Systemic chemotherapy combined with use of bevacizumab (anti-vascular endothelium growth factor monoclonal antibody) was without effect and the patient succumbed to his disease within few weeks. To our knowledge, this is the first report in the English literature of bevacizumab use for metastatic hepatocellular carcinoma in HIV-infected patients.

Increased polyclonal CD5+ B1a lymphocytes in a haploidentical stem cell transplant recipient†

Atypical lymphocyte populations may be seen in the peritransplant setting. In this case report, we describe an unusually high number of CD5+ B‐cells (B1a cells) following transplant.