The appropriate dose of antithymocyte globulin (ATG) to be utilized in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplant (alloHSCT) is as yet unknown. We retrospectively compared patients who received 7.5 mg/kg (R-ATG, 39 patients) and 6 mg/kg (r-ATG, 97 patients). The cumulative incidences of acute graft-versus-host disease (aGVHD) grade II-IV at 180 days were 46% and 41% and of aGVHD grade III-IV were 11% and 18% in r-ATG and R-ATG, respectively (p > 0.30). The respective estimated cumulative incidences at 24 months of cGVHD were 42% and 44% (p > 0.30). There was no significant difference in non-relapse mortality (p = 0.22), cumulative incidence of relapse (p = 0.53), progression-free survival (p = 0.69) or overall survival (p = 0.95). In conclusion, a decreased ATG dose of 6 mg/kg was associated with a similar proportion of GVHD to 7.5 mg/kg ATG. Given the increasing number of RIC HSCTs performed worldwide, the correct dose and preparation of ATG should be defined by prospective randomized trials.
Ibrutinib has single agent activity of 22-68% in relapsed B-cell non-Hodgkin's lymphoma (NHL). This study evaluated the safety and efficacy of ibrutinib combined with rituximab (R) and bendamustine. Patients received R 375 mg/m(2) day 1, bendamustine 90 mg/m(2) days 1 and 2, and ibrutinib (280 or 560 mg) days 1-28 every 28 days for 6 cycles followed by ibrutinib alone until progression. Forty-eight patients enrolled, including 12 patients with follicular lymphoma (FL), 16 with diffuse large cell lymphoma (DLCL), and 17 with mantle cell lymphoma (MCL). No dose limiting toxicities were observed. Patients received a median of 8 cycles, with 26 completing 6 cycles and continuing ibrutinib alone in cycles 7-34. The overall response rate (ORR) was 72%, with 52% complete responses (CR). By histology, the ORR was 94% (76% CR) in MCL, 37% (31% CR) in DLCL, and 90% (50% CR) in FL. Grade 3-4 toxicities included lymphopenia (77%), neutropenia (33%), thrombocytopenia (19%), and rash (25%). Median progression-free survival has not been reached (95% CI, 8.7 months - not reached). The recommended phase 2 dose of ibrutinib in combination with R-bendamustine in patients with NHL is 560 mg. The combination has promising efficacy, particularly in MCL and FL.
Only a minority of patients with high risk lymphoma will be cured with autologous transplant, so maintenance with vorinostat, an oral agent with activity in relapsed lymphoma, was studied starting day + 60 for 21 consecutive days followed by a week off for up to 11 cycles. Twenty-three patients with lymphoma were treated. Ten patients completed the full 11-cycle treatment plan per protocol, four patients were removed due to progressive disease and seven withdrew or were removed from the study due to toxicities. Despite Prevnar vaccine administration every 2 months for three injections, the mean antibody concentration never reached protective levels (> 0.35 ?g/mL). Fatigue and functional well-being measured by Brief Fatigue Inventory and Functional Assessment of Cancer Therapy-General improved significantly from cycle 1 to cycle 7, but depression scores from the Center for Epidemiologic Studies Depression scale did not change. Given the toxicities observed, this broad-spectrum deacetylase inhibitor at this schedule is not optimal for prolonged maintenance therapy.
Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance.
Although older patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) may experience higher morbidity, the impact of chronic graft-versus-host disease (GVHD) on quality of life (QOL) and survival outcomes for older compared with younger patients is currently unknown. We utilized data of patients with moderate or severe chronic GVHD (N = 522, 1661 follow-up visits, a total of 2183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. We examined the relationship between age group (adolescent and young adult, "AYA," 18 to 40 years; "middle-aged," 41 to 59 years; and "older," ? 60 years) and QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [FACT-BMT]), physical functioning (Human Activity Profile [HAP]), functional status (2-minute walk test [2MWT]), nonrelapse mortality, and overall survival. Because of multiple testing, P values < .01 were considered significant. This study included 115 (22%) AYA, 279 (53%) middle-aged, and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD. Despite more physical limitations in older patients as measured by worse functional status (shorter 2MWT [P < .001] and lower HAP scores [P < .001]) relative to AYA and middle-aged patients, older patients reported better QOL (FACT-BMT, P = .004) compared with middle-aged patients and similar to AYA patients (P = .99). Nonrelapse mortality and overall survival were similar between the age groups. Therefore, despite higher physical and functional limitations, older patients who are selected to undergo HSCT and survive long enough to develop moderate or severe chronic GVHD have preserved QOL and similar overall survival and nonrelapse mortality when compared with younger patients. Therefore, we did not find evidence that older age is associated with worse outcomes in patients with moderate or severe chronic GVHD.
Although allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for a number of hematologic malignancies, its use is limited by the development of acute and chronic graft-versus-host disease (GVHD). This potentially fatal complication occurs in approximately 50% of allo-SCT recipients.
Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.
Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
Chronic lymphocytic leukemia (CLL) exhibits a highly variable natural history, but the addition of genomic risk stratification to traditional clinical staging systems has begun to explain the heterogeneous clinical course. Overall response to treatment has significantly improved over the past three decades and for the first time, a survival benefit has been demonstrated with the use of monoclonal antibodies in combination with cytotoxic chemotherapy. Newer therapeutic strategies have abrogated the adverse prognosis associated with some higher risk features, but other genetic subgroups remain at high risk for rapid disease progression and early mortality. Patients at advanced age or with significant comorbidity constitute a large proportion of the CLL population and present unique clinical challenges. This article will discuss the evolution of contemporary therapeutic approaches to the initial treatment of CLL, and highlight the ways in which risk-adapted therapeutic strategies are improving clinical outcomes.
B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-?B. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-?), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.
Chronic lymphocytic leukemia (CLL) represents the most prevalent adult leukemia. Treatment with chemotherapy over the past 3 decades has been palliative. The introduction of therapeutic antibodies has increased the number of treatment options for this disease. Despite this increase, our true understanding of the mechanism of action of antibody therapy in CLL remains limited. Rituximab, a CD20 antibody, is currently widely used in combination-based strategies for both previously untreated symptomatic CLL and as salvage therapy. Recent data suggest that the addition of rituximab to fludarabine with or without cyclophosphamide prolongs survival in younger patients with CLL. Other improved CD20 antibodies with promising clinical activity, including ofatumumab and GA-101, are coming forward. Alemtuzumab, a CD52 antibody, likewise has demonstrated benefit in both symptomatic, previously untreated CLL and in patients with relapsed disease but has less selectivity. Development of other therapeutic antibodies targeting alternative B-cell-specific antigens in CLL has been less successful, although many promising candidate antibodies and/or small modular immune pharmaceuticals (SMIPs) are coming forward. In addition, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non-chemotherapy-based treatment approaches.
Rituximab is a class I chimeric anti-CD20 antibody that has shown efficacy in chronic lymphocytic leukemia (CLL), both as a single agent and in combination with traditional chemotherapies. The modest activity demonstrated in early studies evaluating rituximab in relapsed CLL was improved with higher doses or more dose-intensive regimens that overcame the unfavorable pharmacokinetic features commonly found in CLL. These studies led to a variety of combination trials of rituximab with chemotherapy, where both phase II and later phase III studies have shown great promise for the advancement of CLL therapy. Despite the therapeutic success of rituximab in CLL, studies demonstrating the definitive relative mechanism of tumor clearance are still lacking and this requires further investigation. In addition to being used as a therapy for CLL, rituximab is an effective treatment for autoimmune CLL complications such as hemolytic anemia and immune thrombocytopenia (ITP). Patients with CLL may experience early infusion-related side effects that can be diminished with corticosteroid pretreatment and stepped-up dosing. Risk factors for infusion-related toxicity may relate to atypical CLL expressing bright CD20 antigen expression, although several different studies have not clearly implicated elevated white blood cell count as a risk factor. Other adverse events, including delayed cytopenias, reactivation of hepatitis B, and development of progressive multifocal leukoencephalopathy, are rare. Future efforts focusing on novel combination-based strategies will be required to fully appreciate the benefit of this therapy in CLL.
Non-Hodgkin (NHL) and Hodgkin (HL) lymphomas are represented prominently in the adolescent and young adult (AYA) population. These diseases represent 11% of total cancer diagnoses in children, 4% in those 40 years of age and older, and 13% in AYA (aged 15-39 years). Although age-adjusted incidence rates of NHL increase with age, the more aggressive lymphomas are seen more commonly in the younger population with a transition to low-grade, indolent subtypes as the population ages. Burkitt lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and anaplastic large cell lymphoma make up the most common subtypes in the AYA population, although within the subgroup age 30-39 years, follicular lymphoma becomes more prominent. As a result, much of the armamentarium in the treatment of aggressive NHL and HL in adults is based on data from pediatric clinical trials. There are obvious limitations to this approach. It is vital that we gain a more thorough understanding of the biology and therapeutic responsiveness of NHL and HL in the AYA population. Thus, we must leverage the large prospective and retrospective trials that have been completed to date and redirect our approaches to cancer care in this unique population. We review the epidemiological data on NHL and HL from the Surveillance, Epidemiology and End Results registries as a cornerstone for a comparative analysis of therapeutic outcomes available in this population.
Complex karyotype (CK) on metaphase cytogenetics discriminates poor outcome in chronic lymphocytic leukaemia (CLL) patients undergoing salvage treatment; we hypothesized that it might provide prognostic information for patients undergoing allogeneic stem cell transplant. Fifty-one CLL patients were analysed following transplant; 18-month overall survival (OS), event-free survival (EFS) and cumulative incidence of progression estimates were 35%, 14% and 63%, respectively, in patients with CK (n = 19) versus 83%, 68% and 29% in patients without (n = 32) (P ? 0·0001, P ? 0·0001, and P = 0·02). In patients with high-risk interphase cytogenetics, CK remained predictive of worse OS (P = 0·02) and EFS (P = 0·009). These findings support further evaluation of metaphase karyotype in transplant risk assessment.
Over the past decade, numerous advances have been made in elucidating the biology of and improving treatment for chronic lymphocytic leukemia (CLL). These studies have led to identification of select CLL patient groups that generally have short survival dating from time of treatment or initial disease relapse who benefit from more aggressive therapeutic interventions. Allogeneic transplantation represents the only potentially curative option for CLL, but fully ablative regimens applied in the past have been associated with significant morbidity and mortality. Reduced-intensity preparative regimens has made application of allogeneic transplant to CLL patients much more feasible and increased the number of patients proceeding to this modality. Arising from this has been establishment of guidelines where allogeneic stem cell transplantation should be considered in CLL. Introduction of new targeted therapies with less morbidity, which can produce durable remissions has the potential to redefine where transplantation is initiated in CLL. This review briefly summarizes the field of allogeneic stem cell transplant in CLL and the interface of new therapeutics with this modality.
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