Progress in Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical hematopoietic cell transplantation (HaploHCT), with cells from HLA-half-matched first degree related donors (siblings, children and parents), could revolutionize hematopoietic transplantation as it expands this form of treatment to approximately 40% of patients who do not have an HLA-matched donor in USA. This need is particularly acute in developing countries, which usually do not have an unrelated donor registry and/or cost is a major issue in acquiring unrelated donor stem cells. Accordingly, the number of haploSCTs done in USA, Europe, China, and developing countries is on the rise. Advantages to HaploHCT include almost universal (more than 95% of patients will have a half-matched related donor) and immediate availability of donor progenitor cells, the opportunity to select the best donor among family members to minimize treatment-related mortality, decrease relapse rate and improve outcomes [2], and the possibility to collect donor cells for cellular therapy post-transplantation, with the goal to enhance the anti-tumor effects of the graft. Despite its potential advantages, until recently, high donor-recipient HLA-histoincompatibility has proven very difficult to overcome

Treatment of iron deficiency anemia associated with gastrointestinal tract diseases

The gastrointestinal (GI) tract is a common site of bleeding that may lead to iron deficiency anemia (IDA). Treatment of IDA depends on severity and acuity of patients’ signs and symptoms. While red blood cell transfusions may be required in hemodynamically unstable patients, transfusions should be avoided in chronically anemic patients due to their potential side effects and cost. Iron studies need to be performed after episodes of GI bleeding and stores need to be replenished before anemia develops. Oral iron preparations are efficacious but poorly tolerated due to non-absorbed iron-mediated GI side effects. However, oral iron dose may be reduced with no effect on its efficacy while decreasing side effects and patient discontinuation rates. Parenteral iron therapy replenishes iron stores quicker and is better tolerated than oral therapy. Serious hypersensitive reactions are very rare with new intravenous preparations. While data on worsening of inflammatory bowel disease (IBD) activity by oral iron therapy are not conclusive, parenteral iron therapy still seems to be advantageous in the treatment of IDA in patients with IBD, because oral iron may not be sufficient to overcome the chronic blood loss and GI side effects of oral iron which may mimic IBD exacerbation. Finally, we believe the choice of oral vs parenteral iron therapy in patients with IBD should primarily depend on acuity and severity of patients’ signs and symptoms

Molecular basis and management of gastrointestinal stromal tumors

Molecularly targeted agents have dramatically impacted the management of several cancers. Targeting KIT has led to a new treatment paradigm in gastrointestinal stromal tumors (GISTs). KIT is a cell surface receptor with tyrosine kinases that, upon binding of its ligand, stem cell factor, activates various signaling pathways. Imatinib and sunitinib, both tyrosine kinase inhibitors directed to KIT, were approved for first- and second-line treatment of metastatic and unresectable GISTs. In this article, we will review the molecular pathogenesis of GISTs followed by a discussion of imatinib and sunitinib’s role in the treatment of GISTs. Finally, we will introduce novel therapeutic options for imatinib- and sunitinib-resistant GISTs

Primary ocular adnexal mucosa-associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients

Extranodal marginal zone B-cell lymphoma is the most common orbital tumour. We conducted a retrospective analysis to examine: (i) the impact of initial presentation and staging on outcome and (ii) response to various treatment modalities and the effect of the latter on recurrence. Ninety patients with primary ocular adnexal marginal zone lymphoma (POAML) diagnosed at our institution between 1984 and 2009 were studied. POAML was associated with monoclonal gammopathy (13%) at presentation. Most POAML patients (86%) presented with Ann-Arbor stage I disease. Radiotherapy led to excellent local control, but relapses occurred in 18% of Ann-Arbor stage I patients during a median follow-up of 5 years. Local relapses, including secondary central nervous system (CNS) involvement, were observed in patients receiving radiation doses <30·6 Gy. No differences in relapse rate and survival were observed between patients who did or did not undergo staging bone marrow biopsy. Ann-Arbor stage II-IV disease and high lactate dehydrogenase levels were associated with shorter freedom from progression. In conclusion, POAML is an indolent lymphoma with continuous risk for relapse. Radiation doses of at least 30·6 Gy should be given in Ann-Arbor stage I disease, since lower doses may be more frequently associated with relapses, including CNS relapses

High-Dose Methotrexate and Azidothymidine in Combination with Alternating DA-EPOCH Is An Effective Regimen for the Treatment of EBV-Related Plasmablastic Lymphoma

Abstract Abstract 4753 Introduction Plasmablastic lymphoma (PBL) is an aggressive and generally fatal, rare type of B-cell non-Hodgkin's lymphoma (NHL) with predilection to sino-oral mucosa. PBL is usually associated with human immunodeficiency virus (HIV) and displays an unusual phenotype lacking the expression of B-cell surface antigens. PBLs are infected by Epstein Barr virus (EBV) in approximately 80% of cases and exhibit a restricted pattern of EBV gene expression as they do not typically express latent membrane proteins (LMPs), which enforce viral latency. Azidothymidine (AZT), a thymidine analogue, is an excellent substrate for EBV thymidine kinase, and is capable of inducing EBV lytic gene expression and apoptosis in primary Type I latency EBV+ Burkitt lymphoma (BL) cell lines. AZT was initially developed as an antineoplastic agent but was found to have low efficacy due to poor affinity to human DNA polymerase and low incorporation into DNA. The chemotherapy drug methotrexate (MTX), which also induces gamma-herpes virus lytic induction, inhibits thymidylate synthase thus blocking de novo synthesis of dTMP increasing the likelihood of AZT incorporation into DNA. Indeed, the combination of high-dose MTX and AZT was found to be clinically efficacious in HIV-infected patients with aggressive relapsed NHL. Similarly, at the University of Miami, we have found this drug combination to be highly effective when used in patients with aggressive gamma-herpes virus lymphomas including EBV+ BL and human herpes virus 8 (HHV-8) related primary effusion lymphoma (solid PEL). We report here the role of high dose MTX plus intravenous AZT with alternating infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin) in the treatment of HIV associated EBV+ plasmablastic lymphoma. Methods Three HIV+ patients with biopsy proven, EBV-encoded RNA (EBER)+ PBL in sino-oral mucosa were treated with high dose methotrexate (4.5 g/m2 IV on day 1) and AZT 1.5 g IV infusion q12 hours (days 1-3) alternating with dose-adjusted (DA) EPOCH chemotherapy for 6-8 cycles as first line therapy. Patients were started/kept on HAART and were administered prophylactic intrathecal MTX±cytarabine. Responses were evaluated by oral exam and CT scans. Results Selected characteristics of patients are demonstrated in Table. Only Patient 2 was on HAART at the time of diagnosis. Patient 1 had intracranial extension of the large left maxillary lesion through sphenoid sinus with negative CSF cytology. All patients treated with HD-MTX/AZT and alternating EPOCH as above achieved a complete remission (CR). Patient 1 achieved CR after the 3rd cycle. However, 19 days after the 4th cycle he was found to have local recurrence, which was thought to be secondary to poor chemotherapy penetration to necrotic oral palate tissue, and was administered a total of 4620 cGy intensity-modulated radiotherapy to head and neck region followed by consolidation with the same chemotherapy regimen for 4 more cycles. He remains alive and free of disease after 14 months. Patient 2 and 3 received a total of 6 cycles of chemotherapy and remain disease-free after 12 and 13 months, respectively. No grade ≥3 toxicities were encountered during the treatment. Conclusion The combination of high dose MTX and AZT plus alternating DA-EPOCH chemotherapy is a tolerable and effective treatment for HIV related EBV+ plasmablastic lymphomas. The combination of MTX and AZT is a highly active, EBV lytic inducing and targeted regimen which deserves further investigation in the treatment of gamma-herpes virus associated malignancies. Disclosures: No relevant conflicts of interest to declare

Primary CNS lymphoma in HIV-positive and -negative patients: Comparison of clinical characteristics, outcome, and prognostic factors.

Primary central nervous system lymphoma (PCNSL) accounts for approximately 4% of all primary brain tumors and has a poor prognosis in both immunocompetent as well as in immunocompromised patients. We conducted a retrospective analysis to examine the clinical characteristics and prognostic factors in HIV-negative and HIV-positive patients with PCNSL and to assess the effect of highly active antiretroviral therapy (HAART) therapy on the outcome of HIV-positive patients. Patients diagnosed with PCNSL between 1999 and 2008 at our institution were divided into two groups based on their HIV status. Their demographic and clinical characteristics were compared using the chi-square test. Kaplan–Meier survival curves were constructed employing the univariate log-rank test. Multivariate analyses of survival were performed by Cox proportional hazards models incorporating the prognostic factors identified in the univariate log rank test. Forty-one HIV-positive patients and 45 HIV-negative patients were identified. HIV-positive patients were younger, more likely to present with seizures and elevated serum LDH levels. There were significant differences in complete remission (CR) rates (P = 0.010) and overall survival (OS) (P = 0.034) in favor of the HIV-negative group. In the HIV-positive group, OS was better in patients with KPS > 70 and patients who received HAART, but remained inferior to that in the HIV-negative patients. HIV-positive patients had a worse prognosis compared to HIV-negative patients despite similar clinical characteristics. Better performance status (KPS > 70) and treatment with HAART conferred better OS in HIV-positive patients

Vitamin D receptor upregulation in alloreactive human T cells

Vitamin D deficiency is adversely associated with diseases characterized by inflammation. The combination of the high incidence of vitamin D deficiency in patients undergoing allogeneic stem cell transplants (SCT) and the potential role of vitamin D deficiency in influencing graft-versus-host disease led us to further characterize the expression of VDR on alloreactive T cells. We hypothesized that vitamin D receptor expression may directly regulate alloreactive T cell responses. To overcome existing limitations in measuring VDR in bulk cellular populations, we developed a flow cytometric assay to measure cytoplasmic VDR in human T cells. Upon stimulation, VDR was expressed extremely early and exhibited sustained upregulation with chronic stimulation. VDR expression was also coupled to cytokine production, proliferation, and ERK1/2 phosphorylation. In addition, VDR exhibited a maturation stage-specific pattern of expression, with greatest expression on cells known to mediate GVHD, naïve and early memory T cells. Alloreactive T cells upregulated VDR, whereas the nonreactive T cells did not. Finally, repletion of vitamin D in vitro was sufficient to significantly reduce alloreactive T cell responses. These data suggest that vitamin D effects on T cells may be important in reducing graft versus host disease (GVHD) in the allogeneic stem cell transplant setting

Zidovudine-based lytic-inducing chemotherapy for Epstein–Barr virus-related lymphomas

Treatment of Epstein–Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDSPCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT–methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT–hydroxyurea treatment resulted in dramatic responses in patients with AIDSPCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas