Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms.

Outcomes with "7 + 3" are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. One hundred and twenty-one patients, median age 60 (range 21-81) years, were enrolled. In phase 1, cohorts of 6-12 patients were assigned to 12-18 mg/m2/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18 mg/m2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRDneg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRDneg) for a CR/CRi rate of 81/94 (86%). Four-week mortality was 2%. After adjustment, the MRDneg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7 + 3 at our center and 245 matched patients treated with 7 + 3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18 mg/m2/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial.

We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20+ lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL.

Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high-risk myelodysplastic syndrome.

Previous studies suggest that idarubicin/cytarabine(ara-C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly-diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment-related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1-8), cytarabine (1.5 g/m(2) /day; days 4-7), and idarubicin (12 mg/m(2) /day, days 4-6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were "good CR" rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true "good CR rate" was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty-four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved "good CR". 4 of 12 (33%) patients with "good CR" relapsed at median of 16 weeks (10.5-19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7-64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3-4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset.

A phase I study of pulse high-dose vorinostat (V) plus rituximab (R), ifosphamide, carboplatin, and etoposide (ICE) in patients with relapsed lymphoma.

Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 µmol/l concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients [median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants] were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 µmol/l (range 4·2-6·0 µmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.

Changing the treatment paradigm in myelodysplastic syndromes.

The treatment algorithm for the patient with myelodysplastic syndrome (MDS) is in the process of being revitalized based on recent results of clinical trials. Historically, the goal for lower-risk patients was hematologic improvement, and disease modification was reserved for patients in the higher-risk category. Recent data now favor shifting emphasis away from supportive care alone and toward altering the disease course and prolonging survival, particularly in patients with intermediate-2 and high-risk disease. In addition, there is a greater appreciation for the significant morbidity and mortality resulting from MDS and increased efforts to improve quality of life while pursuing treatment. Immunomodulation with lenalidomide has yielded durable cytogenetic and hematologic responses and also has shown potential to alter disease course. Similarly, immunosuppression with antithymocyte globulin has shown sustained hematologic responses in selected patient subgroups. The methyltransferase inhibitors have demonstrated the ability to alter the natural history of disease and thus prolong time to leukemic transformation. In addition, azacitidine has shown the capacity to extend survival compared with the previous gold standard of conventional care regimens. With these new data, evaluation of treatment options should no longer focus on response rates as the sole endpoint but rather on time to leukemic transformation and survival. Timing of available therapies, including stem cell transplantation, should be incorporated into the new treatment paradigm, with end goals of prolonging survival and optimizing patient outcomes.