Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the ...efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee.
Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%).
Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.
RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with ...hematologic malignancies was conducted.
Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity.
RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response.
RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.
The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed ...to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.
Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m
on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine 1.4 mg/m
(maximum 2 mg) days 1, 8 for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue.
Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (
= 32), the RP2D was determined as 40 mg b.i.d. 1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).
The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.
Despite major scientific discoveries and novel therapies over the past four decades, the treatment outcomes of acute myeloid leukemia (AML), especially in the adult patient population remain dismal. ...In the past few years, an increasing number of targets such as CD33, CD123, CLL-1, CD47, CD70, and TIM3, have been developed for immunotherapy of AML. Among them, CLL-1 has attracted the researchers' attention due to its high expression in AML while being absent in normal hematopoietic stem cell. Accumulating evidence have demonstrated CLL-1 is an ideal target for AML. In this paper, we will review the expression of CLL-1 on normal cells and AML, the value of CLL-1 in diagnosis and follow-up, and targeting CLL-1 therapy-based antibody and chimeric antigen receptor T cell therapy as well as providing an overview of CLL-1 as a target for AML.
Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have profound immune defects and limited treatment options. Given the dramatic activity of lenalidomide in other B-cell ...malignancies and its pleotropic immunomodulatory effects, we conducted a phase II trial of this agent in CLL.
Patients with relapsed or refractory B-cell CLL (B-CLL) were eligible if they required treatment as per the National Cancer Institute Working Group 1996 guidelines. Lenalidomide was administered orally at 25 mg on days 1 through 21 of a 28-day cycle. Response was assessed after each cycle. Patients were to continue treatment until disease progression, unacceptable toxicity, or complete remission. Rituximab was added to lenalidomide on disease progression.
Forty-five patients were enrolled, with a median age of 64 years. Sixty-four percent of the patients had Rai stage III or IV disease, and 51% were refractory to fludarabine. The overall response rate was 47%, with 9% of the patients attaining a complete remission. Fatigue, thrombocytopenia, and neutropenia were the most common adverse effects noted in 83%, 78%, and 78% of the patients, respectively.
Lenalidomide is clinically active in patients with relapsed or refractory B-CLL. These findings are encouraging and warrant further investigation of this agent in the treatment of this disorder.
Obinutuzumab (GA101), a novel glycoengineered type II anti-CD20 monoclonal antibody, demonstrated responses in single-arm studies of patients with relapsed/refractory non-Hodgkin lymphoma. This is ...the first prospective, randomized study comparing safety and efficacy of obinutuzumab with rituximab in relapsed indolent lymphoma. The primary end point of this study was the overall response rate (ORR) in patients with follicular lymphoma after induction and safety in patients with indolent lymphoma.
A total of 175 patients with relapsed CD20(+) indolent lymphoma requiring therapy and with previous response to a rituximab-containing regimen were randomly assigned (1:1) to four once-per-week infusions of either obinutuzumab (1,000 mg) or rituximab (375 mg/m(2)). Patients without evidence of disease progression after induction therapy received obinutuzumab or rituximab maintenance therapy every 2 months for up to 2 years.
Among patients with follicular lymphoma (n = 149), ORR seemed higher for obinutuzumab than rituximab (44.6% v 33.3%; P = .08). This observation was also demonstrated by a blinded independent review panel that measured a higher ORR for obinutuzumab (44.6% v 26.7%; P = .01). However, this difference did not translate into an improvement in progression-free survival. No new safety signals were observed for obinutuzumab, and the incidence of adverse events was balanced between arms, with the exception of infusion-related reactions and cough, which were higher in the obinutuzumab arm.
Obinutuzumab demonstrated a higher ORR without appreciable differences in safety compared with rituximab. However, the clinical benefit of obinutuzumab in this setting remains unclear and should be evaluated within phase III trials.
This study aimed to determine activity and safety of weekly bortezomib and rituximab in patients with relapsed/refractory Waldenström macroglobulinemia (WM).
Patients who had at least one previous ...therapy were eligible. All patients received bortezomib intravenously weekly at 1.6 mg/m(2) on days 1, 8, and 15, every 28 days for six cycles and rituximab 375 mg/m(2) weekly on cycles 1 and 4. The primary end point was the percentage of patients with at least a minor response.
Thirty-seven patients were treated. The majority of patients (78%) completed treatment per protocol. At least minimal response (MR) or better was observed in 81% (95% CI, 65% to 92%), with two patients (5%) in complete remission (CR)/near CR, 17 patients (46%) in partial response, and 11 patients (30%) in MR. The median time to progression was 16.4 months (95% CI, 11.4 to 21.1 months). Death occurred in one patient due to viral pneumonia. The most common grade 3 and 4 therapy-related adverse events included reversible neutropenia in 16%, anemia in 11%, and thrombocytopenia in 14%. Grade 3 peripheral neuropathy occurred in only two patients (5%). The median progression-free (PFS) is 15.6 months (95% CI, 11 to 21 months), with estimated 12-month and 18-month PFS of 57% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%), respectively. The median overall survival has not been reached.
The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.
Purpose
Dinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute ...leukemia both in the clinic and in vitro.
Methods
Adults with relapsed/refractory acute myeloid leukemia (
n
= 14) and acute lymphoid leukemia (
n
= 6) were treated with dinaciclib 50 mg/m
2
given as a 2-h infusion every 21 days.
Results
Most patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients’ peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill.
Conclusions
While dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias.
Acute myeloid leukemia (AML) is the most common tumor in adult patients, most of the patients have a poor prognosis even after high-intensity chemotherapy, especially for relapsed, refractory or ...elderly patients. Therefore, new methods are needed to change the outcomes. In recent years, an increasing number of immune-therapies are emerging where adoptive cell therapy, a special immunotherapy, has become a promising strategy for AML. Here, we review the clinical application and advancement of donor lymphocyte infusion, chimeric-antigen receptor (CAR) T cell therapy, natural killer (NK) cell therapy and dendritic cell vaccination for AML, hopefully providing an overview of clinical aspects of advances in adoptive cell therapy for AML.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Romidepsin is a structurally unique, potent, bicyclic class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of patients with cutaneous ...T-cell lymphoma who have received ≥ 1 prior systemic therapy and patients with peripheral T-cell lymphoma (PTCL) who have received ≥ 1 prior therapy. Approval for PTCL was based on results (n = 130; median follow-up, 13.4 months) from the pivotal study of romidepsin for the treatment of relapsed/refractory PTCL. The objective is to present updated data (median follow-up, 22.3 months) and to characterize patients who achieved long-term responses (≥ 12 months) to romidepsin.
Patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; patients with response or stable disease could continue romidepsin beyond 6 cycles. The primary endpoint was rate of confirmed/unconfirmed complete response (CR/CRu) determined by an Independent Review Committee. Secondary endpoints included objective response rate (ORR) and duration of response (DOR). For patients who achieved CR/CRu, baseline characteristics by DOR (≥ 12 vs < 12 months) were examined.
The ORR to romidepsin was 25%, including 15% with CR/CRu. The median DOR for all responders was 28 months (range, < 1-48+) and was not reached for those who achieved CR/CRu. Patients with lack of response or transient response to prior therapy achieved durable responses with romidepsin. Of the 19 patients who achieved CR/CRu, 10 had long-term (≥ 12 months) responses; none of the baseline characteristics examined-including heavy pretreatment, response to prior therapy, or advanced disease-precluded long-term responses to romidepsin. With a median progression-free survival of 29 months, patients who achieved CR/CRu for ≥ 12 months had significantly longer survival vs those with CR/CRu for < 12 months or < CR/CRu. Extended treatment and longer follow-up did not affect the reported safety profile of romidepsin.
Treatment with romidepsin leads to highly durable responses in a subset of patients with relapsed/refractory PTCL, with responses ongoing as long as 48 months.
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