W. Christopher Ehmann

Phase III Randomized Multicenter Study of a Humanized Anti-CD33 Monoclonal Antibody, Lintuzumab, in Combination With Chemotherapy, Versus Chemotherapy Alone in Patients With Refractory or First-Relapsed Acute Myeloid Leukemia

PURPOSE Lintuzumab (HuM195) is an unconjugated humanized murine monoclonal antibody directed against the cell surface myelomonocytic differentiation antigen CD33. In this study, the efficacy of lintuzumab in combination with induction chemotherapy was compared with chemotherapy alone in adults with first relapsed or primary refractory acute myeloid leukemia (AML). PATIENTS AND METHODS Patients with relapsed or primary resistant AML (duration of first response, zero to 12 months) were randomly assigned to receive either mitoxantrone 8 mg/m(2), etoposide 80 mg/m(2), and cytarabine 1 g/m(2) daily for 6 days (MEC) in combination with lintuzumab 12 mg/m(2), or MEC alone. Overall response, defined as the rate of complete remission (CR) and CR with incomplete platelet recovery (CRp), was the primary end point of the study, with additional analyses of survival time and toxicity. RESULTS A total of 191 patients were randomly assigned from November 1999 to April 2001. The percent CR plus CRp with MEC plus lintuzumab was 36% v 28% in patients treated with MEC alone (P = .28). The overall median survival was 156 days and was not different in the two arms of the study. Apart from mild antibody infusion-related toxicities (fever, chills, and hypotension), no differences in chemotherapy-related adverse effects, including hepatic and cardiac dysfunction, were observed with the addition of lintuzumab to induction chemotherapy. CONCLUSION The addition of lintuzumab to salvage induction chemotherapy was safe, but did not result in a statistically significant improvement in response rate or survival in patients with refractory/relapsed AML.

Rituximab Extended Schedule or Re-Treatment Trial for Low–Tumor Burden Follicular Lymphoma: Eastern Cooperative Oncology Group Protocol E4402

PURPOSE In low-tumor burden follicular lymphoma (FL), maintenance rituximab (MR) has been shown to improve progression-free survival when compared with observation. It is not known whether MR provides superior long-term disease control compared with re-treatment rituximab (RR) administered on an as-needed basis. E4402 (RESORT) was a randomized clinical trial designed to compare MR against RR. PATIENTS AND METHODS Eligible patients with previously untreated low-tumor burden FL received four doses of rituximab, and responding patients were randomly assigned to either RR or MR. Patients receiving RR were eligible for re-treatment at each disease progression until treatment failure. Patients assigned to MR received a single dose of rituximab every 3 months until treatment failure. The primary end point was time to treatment failure. Secondary end points included time to first cytotoxic therapy, toxicity, and health-related quality of life (HRQOL). RESULTS A total of 289 patients were randomly assigned to RR or MR. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years for patients receiving RR and 4.3 years for those receiving MR (P = .54). Three-year freedom from cytotoxic therapy was 84% for those receiving RR and 95% for those receiving MR (P = .03). The median number of rituximab doses was four patients receiving RR and 18 for those receiving MR. There was no difference in HRQOL. Grade 3 to 4 toxicities were infrequent in both arms. CONCLUSION In low-tumor burden FL, a re-treatment strategy uses less rituximab while providing disease control comparable to that achieved with a maintenance strategy.

Congenital afibrinogenemia and splenic rupture.

<0.05). These data show that there was improvement in all measured variables following reduction in PCV to 0.5, and that this continued as the red cell mass was further decreased. Thus, we conclude that in this group of patients with normal cardiorespiratory function, a reduction of PCV to 0.40 L-L-r results in optimal function. The situation in patients with hypoxic lung or cyanotic congenital heart disease may well be different because oxygen transport could be deleteriously impaired when the hemoglobin concentration is reduced. Perloff et al

Cutaneous B-cell lymphoma with loss of CD20 immunoreactivity after rituximab therapy

Background:  Antibodies to the B‐cell‐specific antigen CD20 are widely used for immunohistochemical identification of B‐cell lymphomas, approximately 95% of which are strongly CD20‐positive.

A phase 2 study of inotuzumab ozogamicin and rituximab, followed by autologous stem cell transplant in patients with relapsed/refractory diffuse large B-cell lymphoma

This study evaluated the safety and efficacy of inotuzumab ozogamicin (INO), a targeted humanized anti-CD22 antibody conjugated to calicheamicin, plus rituximab (R-INO) every 3 weeks, up to six cycles, followed by high dose therapy and autologous stem cell transplant (HDT-aSCT) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9–41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL.

A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy.

This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti‐CD20 radioimmunotherapy. Patients received InO 1·8 mg/m2 intravenously on a 28‐d cycle for a planned 4–8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty‐one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression‐free survival was 12·7 (8·9–26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity.

Lacunar and Reed-Sternberg–Like Cells in Follicular Lymphomas Are Clonally Related to the Centrocytic and Centroblastic Cells as Demonstrated by Laser Capture Microdissection

Two cases of follicular lymphoma (FL) with numerous large cells resembling the lacunar and Hodgkin and Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma were studied to determine clonal relationships between the HRS-like cells and centrocytic and centroblastic (CCCB) cells. In both cases, CCCB cells were typical of FL; CD45RB, CD20, CD10 and BCL-2 positive. In case 1, the HRS-like cells were positive for CD45RB, CD20, CD10, CD30, OCT2, and BOB.1 and negative for CD15 and bcl-2. In case 2, the HRS-like cells were positive for CD30, fascin, CD20, OCT2, and BOB.1 and negative for CD45RB, CD10, CD15, and bcl-2. CCCB and single HRS-like cells were isolated by laser capture microdissection followed by polymerase chain reaction amplification and sequencing of immunoglobulin heavy chain gene rearrangements. In both cases, identical sequences were obtained from CCCB and HRS-like cells. These findings confirm that although the HRS cells and CCCB cells in these cases demonstrate morphologic and immunophenotypic divergence, they share a common cell of origin. These cases further highlight the potential diagnostic pitfall presented by FL with HRS-like cells.

Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402.

The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub‐study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B‐cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31–49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.

Ocular findings in HIV-infected haemophiliacs

Ocular complications of HTV infection are common. Up to 40% of patients with AIDS [1-4] develop CMV retinitis, and about one-third of HIV-infected subjects develop cotton-wool spots [3]. Most of these data are from HIV-seropositive subjects who acquired HIV by sexual transmission. Little is known about the risk of ocular complications in HIV-infected haemophiliacs We evaluated 28 HIV-infected haemophiliacs with CD4 lymphocyte counts < 200 cells/mm3. Ophthalmologic examinations and CD4 counts were performed at least every 6 months, beginning in 1989. CMV seropositivity was determined as part of the Multicenter Hemophilia Cohort Study [5]. All subjects were males who by 1989 had been HIV seropositive for a mean of 6.5 (SD 2) years. Six of the 28 entered the study with a CD4 count of <50 cells/mm3, and the CD4 count decreased to this level in eight other subjects during the 6 years of the study. Eleven of the 28 subjects (39%) died during the study. Two patients developed CMV retinitis, and another developed an idiopathic unilateral vitritis which resolved. The two with CMV retinitis had CD4 counts <50 cells/ mm3, and had been infected with HIV infection for 8 and 15 years, respectively, when their retinitis was diagnosed, N o other ocular lesions developed. T w o patients developed non-ocular CMV infections; one had colitis, and another had oesophagitis. The patient with oesophagitis was one of two patients with CMV retinitis. To our knowledge, this is the first prospective study to specifically examine ocular complications in a group of HIV-infected haemophiliacs. The overall risk of CMV or non-infectious retinitis appears lower than in persons who acquire AIDS from homosexual activity or intravenous drug use [1-4]. Only 7% of the haemophilic patients developed CMV retinitis after 6 years of observation, compared to 19% of homosexual men after 27 months of observation [2]. None of the six haemophilic patients with CD4 lymphocyte counts <50 cells/mm3 had CMV retinitis within 27 months, compared to 42% of homosexuals followed for the same length of time [2]. In addition, none of the 28 haemophilic patients were found to have cotton-wool spots or retinal haemorrhages, compared to 35% of persons infected sexually [3]. The absence of any cotton-wool spots in haemophiliacs leads us to question whether a coagulation disorder might protect against these infarcts. The lower rate of CMV seropositivity (56%) in these haemophiliacs compared to homosexuals or i.v. drug users (9&100°/o) is likely to be an important factor in the lower risk of CMV disease. The rate of CMV seropositivity is directly associated with age at HIV seroconversion IS], but the apparently lower risk of CMV disease is not agerelated. The mean age of these haemophiliacs is similar to that of other cohorts of CMV retinitis patients. We have demonstrated an apparently low incidence of both CMV retinitis and non-infectious retinopathy in this cohort of haemophilic patients with profoundly low CD4 counts who were followed for long periods of time. We await confirmation of these findings in other haemophilic groups.

Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia

BackgroundT cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML.MethodsPeripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response.ResultsBlimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression.ConclusionsOur study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics.