Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270-360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90-18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

Efficacy and safety of bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia in the Asian subpopulation of the phase 3 BFORE trial.

Bosutinib is approved in the United States, Europe, Japan, and other countries for treatment of newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML), and CML resistant/intolerant to prior therapy. In the phase 3 BFORE trial (Clinicaltrials.gov, NCT02130557), patients were randomized 1:1 to first-line bosutinib or imatinib 400 mg once daily. We examined efficacy, safety, and patient-reported outcomes of bosutinib vs imatinib and pharmacokinetics of bosutinib in the Asian (n = 33 vs 34) and non-Asian (n = 235 vs 234) subpopulations of BFORE followed for at least 24 months. At the data cutoff date, 72.7 vs 66.7% of Asian and 70.6 vs 66.4% of non-Asian patients remained on treatment. The major molecular response rate at 24 months favored bosutinib vs imatinib among Asian (63.6 vs 38.2%) and non-Asian (60.9 vs 52.6%) patients, as did the complete cytogenetic response rate by 24 months (86.7 vs 76.7%, 81.5 vs 76.3%). Treatment-emergent adverse events in both subpopulations were consistent with the primary BFORE results. Trough bosutinib concentration levels tended to be higher in Asian patients. Health-related quality of life was maintained after 12 months of bosutinib in both subpopulations. These results support bosutinib as a first-line treatment option in Asian patients with CP CML.

Event-free survival at 12 months is a strong surrogate endpoint for stage 1 diffuse large B cell lymphoma: a report from Nation Wide Registry Thai Lymphoma Study Group.

Event-free survival at 12 months (EFS12) is a surrogate endpoint for long-term outcomes in many histologic lymphoma subtypes. However, most reports have primarily investigated the implication of EFS12 in advanced-stage non-Hodgkin lymphoma (NHL). There are limited data regarding the significance of EFS12 in early-stage NHL. Herein, we evaluated the prognostic significance of EFS12 in patients with stage 1 diffuse large B-cell lymphoma (DLBCL). Out of 282 patients with stage 1 DLBCL who received intensive therapy, 227 (80.5%) achieved EFS12. The 4-year overall survival (OS) was 91.4% and 4.0% for patients who achieved and failed to achieve EFS12, respectively. Multivariable analyses demonstrated response to treatment and achievement of EFS12 as independent predictors for OS. In conclusion, our study demonstrated EFS12 as a powerful prognostic factor for stage 1 DLBCL. Further validation in more extensive prospective studies is warranted.

Characteristics, treatment patterns, prognostic determinants and outcome of peripheral T cell lymphoma and natural killer/T cell non-Hodgkin Lymphoma in older patients: The result of the nationwide multi-institutional registry Thai Lymphoma Study Group.

INTRODUCTION: Peripheral T cell NHL (PTCL) and natural killer/T cell NHL (NKTCL) are relatively rare disorders. Data on clinical presentation, treatment and outcome are limited especially in older age groups. METHODS: We identified 127 patients with PTCL and NKTCL, excluding cutaneous T/NK cell lymphoma, aged over 60 years old from Thailand nationwide multicenter registry. RESULTS: Of 127 patients, median age of diagnosis was 67 years old. Patients aged older than 75 years old had similar characteristics to younger (60-74 years old) but higher comorbidity index. Seventy-nine patients (62.2%) received intensive/definite multi-agent chemotherapy, however, the proportion was significant lower in older patients (70.4% vs 34.5%, p < .001). After a median follow up duration of 17.3 months, 2-year progression free survival and overall survival were 38.1% and 48.5%. Univariate and multivariable analysis demonstrated older age, poor performance status and absence of definite multi-agent chemotherapy were associated with inferior survival. Definite multi-agent lymphoma specific chemotherapy was an independent factor for overall survival after adjustment for age, comorbidity index, performance status and prognostic index for T cell lymphoma. CONCLUSION: Despite overall poor prognosis of PTCL and NKTCL in older adults, chemotherapy could result in objective response and long-term survival in selected patients of this vulnerable age group thus emphasizing the importance of comprehensive geriatric evaluation.

Event free survival at 24 months is a strong surrogate prognostic endpoint of peripheral T cell lymphoma.

Event free survival at 24 months (EFS24) has been described as a powerful predictor for outcome in several subtypes of B cell lymphoma. However, it was limitedly described in T cell lymphoma. We explored the implication of EFS24 as a predictor marker for peripheral T cell lymphoma (PTCL). We reviewed 293 systemic PTCL patients at 13 nationwide major university hospitals in Thailand from 2007 to 2014. The median event free survival (EFS) and overall survival (OS) of PTCL patients in our cohort was 16.3 and 27.7 months with corresponding 2-year EFS and 2-year OS of 45.8% and 51.9%, respectively. A total of 118 patients achieved EFS24 (no events during the first 24 mo). Patients who achieved EFS24 had better OS than patients who did not (2-y OS 92% vs 18.8%; HR, 0.1; P < .001). The standardized mortality ratio of patients achieving EFS24 was 18.7 (95% CI, 14.6-22.8). Multivariable analysis demonstrated performance status, histologic subtype, remission status, and EFS24 achievement as independent predictors for OS. Our study affirmed the value of EFS24 as a powerful prognostic factor for PTCL. Further validation in prospective study setting is warranted.

Non-Hodgkin lymphoma in South East Asia: An analysis of the histopathology, clinical features, and survival from Thailand.

Systemic reports on the descriptive epidemiology of non-Hodgkin lymphoma (NHL) from Southeast Asia are scarce. A nationwide multi-institutional registry was conducted to compare the histopathology, clinical features, and survival of Thai adult patients with NHL using large registries, especially those from Far East Asia (FEA). Using a web-based registry system, 13 major medical centers from the 4 geographic regions of Thailand prospectively collected, from 2007 to 2014, the diagnostic pathology, according to the World Health Organization classification, 2008, clinical features and survival of 4056 patients who were newly diagnosed with NHL. The median age of the patients was 56 years (range, 16-99 years). The male-to-female ratio was 1.3:1. From the total of 4056 patients, T/NK-cell lymphoma (TNKCL) accounted for 12.6% of cases, and 5.1% had human immunodeficiency virus-associated lymphoma. The four leading histological subtypes were diffuse large B-cell lymphoma, not otherwise specified (58.1%); follicular lymphoma (5.6%); extranodal mucosa-associated lymphoid tissue lymphoma (5.2%); and peripheral T-cell lymphoma, not otherwise specified (4.0%). With a median follow-up duration of 46.1 months, the median overall survival of B-cell NHL was significantly longer than that of patients with TNKCL (76.5 vs 28.8 months, P = .0001). Compared to FEA, the Thai registry had an approximately one-half lower relative frequency of TNKCL; the prevalence of extranodal mucosa-associated lymphoid tissue lymphoma was much lower than in Korea, and the frequency of extranodal TNKCL, nasal type, was strikingly low compared to China. It is concluded that while the median age of Thai patients with NHL was approximately a decade younger than for Caucasians, the long-term survival rates for most histological subtypes were comparable. While the histological distribution generally complied with the characteristic Asian features, some differences from FEA were observed.

Secondary central nervous system relapse in diffuse large B cell lymphoma in a resource limited country: result from the Thailand nationwide multi-institutional registry.

Secondary central nervous system (CNS) relapse is a serious and fatal complication of diffuse large B cell lymphoma (DLBCL). Data on secondary CNS (SCNS) relapse were mostly obtained from western countries with limited data from developing countries. We analyzed the data of 2034 newly diagnosed DLBCL patients enrolled into the multi-center registry under Thai Lymphoma Study Group from setting. The incidence, September 2006 to December 2013 to represent outcome from a resource limited pattern, management, and outcome of SCNS relapse were described. The 2-year cumulative incidence (CI) of SCNS relapse was 2.7 %. A total of 729, 1024, and 281 patients were classified as low-, intermediate-, and high-risk CNS international prognostic index (CNS-IPI) with corresponding 2-year CI of SCNS relapse of 1.5, 3.1, and 4.6 %, respectively (p < 0.001). Univariate analysis demonstrated advance stage disease, poor performance status, elevated lactate dehydrogenase, presence of B symptoms, more than one extranodal organ involvement, high IPI, and high CNS-IPI group as predictive factors for SCNS relapse. Rituximab exposure and intrathecal chemoprophylaxis offered no protective effect against SCNS relapse. At the time of analysis, six patients were alive. Median OS in SCNS relapsed patients was significantly shorter than relapsed patients without CNS involvement (13.2 vs 22.6 months) (p < 0.001). Primary causes of death were progressive disease (n = 35, 63.6 %) and infection (n = 9, 16.7 %). In conclusion, although the incidence of SCNS relapse in our cohort was low, the prognosis was dismal. Prophylaxis for SCNS involvement was underused even in high-risk patients. Novel approaches for SCNS relapse prophylaxis and managements are warranted.

Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial.

BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. METHODS: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. FINDINGS: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). INTERPRETATION: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. FUNDING: Novartis Pharmaceuticals.

Inferior progression-free survival for Thai patients with diffuse large B-cell lymphoma treated under Universal Coverage Scheme: the impact of rituximab inaccessability.

The impact of health insurance with inequitable rituximab coverage on the survival of patients with diffuse large B-cell lymphoma (DLBCL) has never been reported. We conducted a nationwide multicenter analysis on the outcome of 553 adult patients consecutively diagnosed with DLBCL between July 2003 and June 2006, in whom treatment cost was reimbursed under the Civil Servant Medical Benefit Scheme (CSMBS) (n =201) or the Universal Coverage Scheme (UCS) (n =352). The international prognostic index was comparable between the two payment groups. Rituximab-based therapy was administered in 45.3% and 3.1% of CSMBS and UCS patients, respectively (p <0.001). With a median follow-up of 24.6 months, the 6-year progression-free survival (PFS) was superior for CSMBS patients (34.2 vs. 23.2%, p =0.005). "Not treated with rituximab-based therapy" was the strongest adverse prognostic feature indicating a short PFS (hazard ratio 2.1, p <0.001). It is concluded that lack of access to rituximab is the principal factor accounting for the inferior PFS observed in Thai patients with DLBCL who are treated under the UCS.

Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models.

PURPOSE: Camptothecin (CPT) has potent broad-spectrum antitumor activity by inhibiting type I DNA topoisomerase (DNA topo I). It has not been used clinically because it is water-insoluble and highly toxic. As a result, irinotecan (CPT-11), a water-soluble analogue of CPT, has been developed and used as salvage chemotherapy in patients with relapsed/refractory lymphoma, but with only modest activity. Recently, we have developed a cyclodextrin-based polymer conjugate of 20-(S)-CPT (IT-101). In this study, we evaluated the preclinical antilymphoma efficacy of IT-101 as compared with CPT-11. EXPERIMENTAL DESIGN: We determined an in vitro cytotoxicity of IT-101, CPT-11, and their metabolites against multiple human lymphoma cell lines. In human lymphoma xenografts, the pharmacokinetics, inhibitions of tumor DNA topo I catalytic activity, and antilymphoma activities of these compounds were evaluated. RESULTS: IT-101 and CPT had very high in vitro cytotoxicity against all lymphoma cell lines tested. As compared with CPT-11 and SN-38, IT-101 and CPT had longer release kinetics and significantly inhibit higher tumor DNA topo I catalytic activities. Furthermore, IT-101 showed significantly prolonged the survival of animals bearing s.c. and disseminated human xenografts when compared with CPT-11 at its maximum tolerated dose in mice. CONCLUSIONS: The promising present results provide the basis for a phase I clinical trial in patients with relapsed/refractory lymphoma.

Hematopoietic stem cell transplantation for patients with advanced-stage follicular lymphoma.

Patients with advanced-stage follicular lymphoma (FL) are considered to be incurable and eventually relapse after conventional chemotherapy. High-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (AHSCT) can unequivocally prolong the disease-free survival (DFS) but not overall survival (OS) in the first complete remission and in a salvage setting. Recently, the incorporation of rituximab and radioimmunoconjugates in HDT with AHSCT seems to be promising and widely accepted. Although allogeneic hematopoietic stem cell transplantation (alloHSCT) consistently demonstrates longer DFS compared with historical controls of HDT followed by AHSCT, this approach cannot be considered as a standard of care due to its unacceptably high treatment-related mortality (TRM) and the lack of improving OS. With highly encouraging results and less TRM, the role of nonmyeloablative hematopoietic stem cell transplantation (NMHSCT), especially after AHSCT needs to be validated in randomized controlled trials with a long-term follow-up.

Antigen-independent and antigen-dependent methods to numerically expand CD19-specific CD8+ T cells.

OBJECTIVE: Preclinical and clinical trials are investigating the potential of T cells genetically modified to express a first-generation CD19-specific chimeric antigen receptor (CAR), designated CD19R, for adoptive immunotherapy of B-lineage leukemias and lymphomas. Currently, our genetically modified CD19-specific CD8+ (CD19R+CD8+) T cells are expanded ex vivo using a rapid expansion protocol (REP) to clinically meaningful numbers after antigen-independent activation with anti-CD3epsilon and recombinant human interleukin-2 on a double-cell feeder-layer of gamma-irradiated allogeneic peripheral blood mononuclear cells and a lymphoblastoid cell line. We now compare the ability of the REP with CD19-dependent numerical expansion using CD19+ artificial antigen-presenting cells to propagate CD19R+CD8+ T cells. MATERIALS AND METHODS: We evaluated long-term (28 days) propagation, CD19R CAR expression, and cytolytic activity of CD19R+CD8+ T cells expanded by either a REP or an antigen expansion protocol (AEP) using K562-derived artificial antigen-presenting cells coexpressing CD19 antigen and two T-cell costimulatory molecules (4-1BB ligand and major histocompatibility class I-related chains A) in the presence of exogenous recombinant human interleukin-2 and recombinant human interleukin-15. RESULTS: Populations of CD19R+CD8+ T cells could be numerically expanded on AEP to meet anticipated clinical need. The AEP was superior to REP, as this method selected for an outgrowth of T cells with increased CD19R CAR expression and improved redirected cytolytic activity. CONCLUSION: Robust propagation of CD19R+CD8+ T cells achieved by AEP supports qualifying this cell line for use in current good manufacturing practices for CAR+ T cells as an alternative to REP for adoptive immunotherapy clinical trials.

Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy.

Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)-derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.

Comparative study of low-dose oral granisetron plus dexamethasone and high-dose metoclopramide plus dexamethasone in prevention of nausea and vomiting induced by CHOP-therapy in young patients with non-Hodgkin's lymphoma.

Standard-dose (2 mg/day) oral granisetron seems to have more antiemetic efficacy than that of high-dose (0.5-1 mg/kg/dose) metoclopramide in moderately emetogenic chemotherapy. However, the cost of oral granisetron is much higher than that of metoclopramide so the authors tried to overcome this disadvantage by dose reduction and adding dexamethasone to enhance the antiemetic effect of oral granisetron. Twenty four young patients (aged < 50 years), with non-Hodgkin's lymphoma receiving CHOP-therapy were enrolled and evaluated in a randomized, double-blind, crossover study comparing the antiemetic efficacy, toxicity and patients' preference of a combination of low-dose oral granisetron plus intravenous dexamethasone (gran/dex) with a combination of high-dose metoclopramide plus intravenous dexamethasone (met/dex) on days 1-5 after chemotherapy. The acute, delayed (day 2-5) and 5-day total control of nausea and vomiting in the gran/dex group were significantly higher than those of the met/dex group (75.0% vs 25.0%; p-value = 0.004, 79.2% vs 33.3%; p-value = 0.007 and 75.0% vs 25.0%; p-value = 0.004, respectively). Except for extrapyramidal reactions in the met/dex group, the side effects in both groups were comparable. The mean total score of antiemetic preference in the gran/dex group was also significantly higher than that of the met/dex group (9.0 vs 7.5; p-value = 0.004). In conclusion, low-dose oral granisetron combined with intravenous dexamethasone had significantly higher protective effects against both acute and delayed nausea and vomiting induced by CHOP-therapy. Thus, this regimen may be considered as an alternative outpatient antiemetic treatment for young patients with non-Hodgkin's lymphoma.