Sunita Nathan

Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation

For diffuse large B‐cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3‐year probabilities of non‐relapse mortality, progression/relapse, progression‐free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1‐year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1‐year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low‐risk (0 points), intermediate‐risk (2‐5 points), high‐risk (6‐9 points) or very high‐risk (11 points), predicting 3‐year PFS of 40, 32, 11 and 6%, respectively, with 3‐year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long‐term survival with alloHCT after a failed prior autoHCT.

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

Clinical and Safety Profile of High-Dose Interleukin-2 Treatment in Elderly Patients with Metastatic Melanoma and Renal Cell Carcinoma

Objective: High-dose interleukin-2 (IL-2) is effective immunotherapy for the treatment of metastatic melanoma and renal cell carcinoma (RCC) but has been contraindicated in elderly patients. This study assessed the safety and therapeutic efficacy of high-dose IL-2 in patients ≥65 years of age with metastatic melanoma and RCC. Methods: A prospectively collected clinical database of 104 consecutive melanoma or RCC patients treated with high-dose IL-2 between 2009 and 2012 was used to compare clinical outcomes and adverse events in patients ≥65 years of age with those of younger patients. Results: There were 22 (21%) patients ≥65 years and 82 (79%) patients <65 years of age. The mean number of IL-2 doses was lower in older patients during cycle 1 of treatment (7.2 vs. 8.6, p = 0.012). There were no other differences in dosing pattern by age group. There was a higher rate of selected cardiac, constitutional, hematologic, metabolic and renal toxicities in younger patients (p < 0.05). Overall, objective responses and survival were not affected by age, though older patients had a higher partial response rate (p = 0.04). Conclusions: IL-2 is safe and has comparable therapeutic effectiveness in patients ≥65 years. Age should not be considered a contraindication to treatment with IL-2 in otherwise eligible patients.

Role of allogeneic transplantation in patients with chronic lymphocytic leukemia in the era of novel therapies: a review

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia and is characterized by a highly variable clinical course. In the past decade, several prognostic risk factors have been identified facilitating the classification of CLL into various risk groups. Patients with poor risk disease, such as poor cytogenetics or relapsing after purine-based analogues, had limited therapeutic options, with allogeneic hematopoietic cell transplantation (allo-SCT) the only known therapy with curative potential. More recently, the introduction of novel agents inhibiting the B-cell receptor pathway, and the early success with chimeric antigen receptor T cells offers an effective and relatively safe option for this poor prognostic group which holds promise in the future. Alternatively, the use of reduced intensity conditioning regimens in the allo-SCT setting has led to a significant decrease in nonrelapse mortality to 16–23%, making it an attractive therapeutic option. No recent guidelines have been developed since these novel therapies became available regarding the optimal time to allo-SCT in this patient population. The advent of these novel and highly active therapeutic agents, therefore, warrants a reappraisal of the role and timing of allo-SCT in patients with CLL. In this article, we summarize the literature regarding the novel therapeutic agents available today as well as focus on the efficacy and safety of allo-SCT.

Polymorphic lymphoid proliferation presenting as ileocecal intussusception.

Dear Editor, Polymorphic lymphoid proliferation is a rare type of lymphoproliferative disorder (LPD) in immunodeficiency associated with human immunodeficiency virus (HIV) infection [1]. Here, we report a case of polymorphic lymphoid proliferation in a 30-year-old HIV+ African American female presenting as ileocecal intussusception. The patient presented to the emergency room with complaints of diarrhea, abdominal distention and pain for a week. CT scan revealed ileocecal intussusception. Laparotomy confirmed the ileocecal intussusception. Right hemicolectomy and ileostomy were performed, followed by ileostomy stump takedown procedure 3 months later. All bowel segments showed multiple small sessile polypoid lesions with unremarkable overlying mucosa. Histologically, the lesions consisted of sub-mucosal lymphoid aggregates with polymorphous populations of plasma cells, polyclonal lymphocytes with full range of maturation, and histiocytes. No cellular atypia and clonality or lymphoepithelial lesions were seen. Frequent lymphocytes were detected positive for Epstein–Barr virus (EBV) (Fig. 1). The cause of intussusception was due to EBV+ polymorphic lymphoid proliferation, which is HIV related. Meanwhile, the patient developed high-grade large (CD20+) B cell lymphoma involving the adenoid gland (Fig. 2) with extensive involvement of the bone marrow. She died shortly after, in less than 4 months of initial clinical presentation. LPD in immunodeficiency associated with HIV infection is of predominantly B cell origin. It consists of a heterogeneous spectrum of lesions ranging from polymorphic lymphoid proliferation, polymorphic B cell hyperplasia, to polymorphic and monomorphic B cell lymphomas. Most lesions are positive for EBV infection suggesting crucial pathogenetic roles. Among all lesions, polymorphic lymphoid proliferation is least common with less than 5% in ratio [1]. This is in drastic contrast to its counterpart, which occurs commonly in post-transplant lymphoproliferative disorder (PTLD) due to immunosuppression [1]. Intussusception caused by polymorphic lymphoid proliferation in this case is unusual due to the rarity of both entities. Unlike that in the pediatric scenario, the intussusception in adults is often associated with a pathological process, notably malignancy, as the lead point. It has been reported in association with enteric infection [2], reactive lymphoid hyperplasia [3], intestinal Kaposi’s sarcoma [4] and lymphomatous polyposis due to the T cell immunoblastic large cell lymphoma [5] in adults with HIV infection. Diagnosis of polymorphic lymphoid proliferation in LPD associated with HIV infection is often overlooked due to its seemingly benign histology [1]. According to the scant literatures on polymorphic lymphoid proliferation in HIV infection, morphologic presentation appears closely associated with molecular and genetic alterations [6, 7]. The attempt to define the lesion requires the consideration of Ann Hematol (2007) 86:453–454 DOI 10.1007/s00277-006-0241-y

Efficacy of High-Dose Therapy and Autologous Hematopoietic Cell Transplantation in Gray Zone Lymphoma: A US Multicenter Collaborative Study

High-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) has been anecdotally prescribed in gray zone lymphoma (GZL), showing encouraging efficacy. We conducted a multicenter retrospective study aimed at assessing outcomes after auto-HCT in 32 patients with GZL treated at 9 transplantation centers in the United States. The median age of patients at transplantation was 38 years (range, 18 to 70 years), and the majority were male (n = 21; 66%). The median number of lines of therapy before transplantation was 2 (range, 1 to 4). BEAM was the most commonly prescribed regimen (n = 23; 72%). The median duration of follow-up for surviving patients was 34 months (range, 1 to 106 months). Median overall survival (OS) was not reached. The 3-year progression-free survival (PFS) and OS for all patients were 69% and 78%, respectively. Three-year PFS and OS were 100% for patients who received only 1 line of therapy before auto-HCT versus 65% (PFS, P = .25) and 75% (OS, P = .39) for those receiving >1 line. The cumulative incidence of relapse/progression was 4% at 1 year post-transplantation and 31% at 3 years post-transplantation. The 3-year nonrelapse mortality was 0%. These findings suggest that HDT and auto-HCT is an effective treatment in patients with GZL. Our findings ideally require confirmation in a larger cohort of patients, preferably in the setting of large prospective multicenter randomized controlled trials. However, we acknowledge that such studies could be difficult to conduct in patients with GZL owing to the diseases rarity. Alternatively, a multicenter prospective study that includes tissue banking and a data registry is warranted to help better understand the biology and natural history of the disease.

Potential role of enzastaurin in the treatment of patients with relapsed or refractory advanced cutaneous T-cell lymphomas: a review

Correspondence: Lydia Usha Rush University Medical Center, 1725 West Harrison Street – Suite 809, Chicago, IL 60612, USA Tel +1 312 563 2200 Fax +1 312 942 3192 Email lydia_usha@rush.edu Abstract: Cutaneous T-cell lymphomas (CTCLs) are rare extranodal non-Hodgkin lymphomas characterized by neoplastic T-lymphocyte accumulation in the skin. The two most common types of CTCLs are mycosis fungoides and the leukemic variant, Sezary syndrome. Prognosis of CTCLs depends on the stage, with a poor prognosis in advanced-stage disease. A number of agents have recently been developed for the treatment of CTCLs: chemotherapeutic agents such as pralatrexate, interferon-alpha, retinoids such as bexarotene, monoclonal antibodies such as alemtuzumab, and histone deacetylase inhibitors such as vorinostat and romidepsin. Nevertheless, there is no cure for CTCLs except for allogeneic stem cell transplant. A promising new drug is enzastaurin. Enzastaurin is a novel serine/threonine kinase inhibitor that binds to protein kinase C-β (PKC-β) and inhibits the phosphoinositide-3 kinase (PI3K)/AKT/phosphatase and tensin homolog (PTEN) signaling pathway. Enzastaurin induces apoptosis and inhibits angiogenesis; it was also shown to suppress growth of CTCL cell lines in vitro. Given its low toxicity, enzastaurin has been tested against both solid tumors and hematologic malignancies. This article is focused on the potential role of enzastaurin in the treatment of CTCLs. A phase II multicenter trial evaluated enzastaurin monotherapy in patients with CTCLs. However, the results from this study were disappointing, demonstrating that enzastaurin had only modest clinical activity. Hence, enzastaurin is not currently developed for treating CTCLs. Potential strategies to improve enzastaurin efficacy against CTCLs are discussed: validation of enzastaurin targets such as PKC-β expression in CTCL lesions and or/blood; measurement of serum vascular endothelial growth factor levels; dose optimization; combining enzastaurin with other antiangiogenic agents, or glycogen synthase kinase inhibitors, or mammalian target of rapamycin (mTOR) inhibitors. Ultimately, developing more potent inhibitors of PKC-β and PI3K/AKT/PTEN/mTOR signaling pathways may be necessary to improve clinical outcomes in CTCLs.

Induction chemotherapy before autologous stem cell transplantation for symptomatic plasma cell myeloma – does it matter?

Autologous stem cell transplantation is the preferred treatment option for younger patients with symptomatic plasma cell myeloma. Most patients with newly diagnosed plasma cell myeloma receive 3–4 cycles of induction chemotherapy to achieve a level of disease control before proceeding to stem cell transplant. The ideal induction regimen for transplant-eligible patients shall allow more patients to proceed with transplant, rapidly and effectively control the disease, reverse disease-related complications, avoid early death, and is associated with minimal acute and long-term toxicities. Because of the concerns of potential damages to hematopoietic stem cells, alkylating agent regimens, specifically melphalan, are usually avoided for induction in transplant-eligible patients. Before the advance of immunomodulatory agents (IMiD) and proteasome inhibitors, the combination of vincristine, adriamycin, and dexamethasone (VAD) and variants were the most commonly used induction regimens. Recent reports as discussed in this review suggests that VAD is no longer the induction chemotherapy of choice for transplant eligible patients. Newer regimens incorporating IMiD and/or proteasome inhibitor into the induction regimen improve response rates and progression-free survival before and after the transplant and are evolving as the treatment of choice. Here, we review the available data on these newer induction regimens and to evaluate the potential impacts on the patient outcomes.