C. Gasparetto

Phase II Feasibility and Pharmacokinetic Study of Concurrent Administration of Trastuzumab and High-Dose Chemotherapy in Advanced HER2+ Breast Cancer

Purpose: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer. Experimental Design: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as ≥4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day −5), HDC (days −5 to −2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65. Results: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day −4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13–58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively. Conclusions: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

Analysis of Common Eligibility Criteria of Randomized Controlled Trials in Newly Diagnosed Multiple Myeloma Patients and Extrapolating Outcomes

&NA; The strict exclusion criteria of clinical trials in multiple myeloma (MM) limit the enrollment of patients reflective of a general patient population. Using the Connect MM Registry data representative of an unselected newly diagnosed MM population, 563 of 1406 patients (40.0%) were identified as ineligible for clinical trials. This study provides insight into potential modifications of standard eligibility criteria that can lead to improved trial design. Background: The performance of multiple myeloma (MM) therapies in a general patient population and specific eligibility criteria that might limit enrollment into randomized controlled trials (RCTs) have not been evaluated in depth. This study aimed to determine if improvements seen with MM therapies in RCTs are reflected in the general patient population and to identify eligibility criteria that can be modified to increase enrollment. Patients and Methods: The Connect MM Registry is a prospective observational cohort study of patients with newly diagnosed MM (NDMM) in the United States. Using common RCT exclusion criteria collected from 16 published studies, patients in the registry were categorized according to their eligibility for inclusion in RCTs. Results: On the basis of common criteria, 563 of 1406 of registry patients (40.0%) are ineligible for RCTs. Criteria leading to exclusion included M‐protein ≤ 1.0 g/dL (25.2%), creatinine > 2.5 mg/dL (13.9%), low absolute neutrophil count (10.0%), and low hemoglobin (9.6%). Significantly more RCT‐ineligible versus RCT‐eligible patients had hypercalcemia (11.0% vs. 5.5%), elevated creatinine levels (38.9% vs. 6.2%), low hemoglobin levels (59.5% vs. 39.5%), or International Staging System stage III disease (40.1% vs. 22.1%; P < .001 for all comparisons). RCT‐ineligible patients had a lower 3‐year survival rate than RCT‐eligible patients (63% vs. 70%). The incidence of serious adverse events was similar between groups. Conclusion: Of patients with NDMM enrolled in the Connect MM Registry, 40% are ineligible for RCTs. This study provides insight into potential modifications of standard eligibility criteria that can lead to improved RCT design and accelerated enrollment.

4-Hydroperoxycyclophosphamide–purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia

We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 microg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach.

Autologous/Allogeneic Hematopoietic Cell Transplantation versus Tandem Autologous Transplantation for Multiple Myeloma: Comparison of Long-Term Postrelapse Survival

We compared postrelapse overall survival (OS) after autologous/allogeneic (auto/allo) versus tandem autologous (auto/auto) hematopoietic cell transplantation (HCT) in patients with multiple myeloma (MM). Postrelapse survival of patients receiving an auto/auto or auto/allo HCT for MM and prospectively reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2010 were analyzed. Relapse occurred in 404 patients (72.4%) in the auto/auto group and in 178 patients (67.4%) in the auto/allo group after a median follow-up of 8.5 years. Relapse occurred before 6 months after a second HCT in 46% of the auto/allo patients, compared with 26% of the auto/auto patients. The 6-year postrelapse survival was better in the auto/allo group compared with the auto/auto group (44% versus 35%; P = .05). Mortality due to MM was 69% (n = 101) in the auto/allo group and 83% (n = 229) deaths in auto/auto group. In multivariate analysis, both cohorts had a similar risk of death in the first year after relapse (hazard ratio [HR], .72; P = .12); however, for time points beyond 12 months after relapse, overall survival was superior in the auto/allo cohort (HR for death in auto/auto =1.55; P = .005). Other factors associated with superior survival were enrollment in a clinical trial for HCT, male sex, and use of novel agents at induction before HCT. Our findings shown superior survival afterrelapse in auto/allo HCT recipients compared with auto/auto HCT recipients. This likely reflects a better response to salvage therapy, such as immunomodulatory drugs, potentiated by a donor-derived immunologic milieu. Further augmentation of the post-allo-HCT immune system with new immunotherapies, such as monoclonal antibodies, checkpoint inhibitors, and others, merit investigation.

Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy.

ABSTRACT We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.