Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM)

Abstract Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented. Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months. Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials. Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis

Incidence and outcome of chronic graft-versus-host disease using National Institutes of Health consensus criteria

Chronic graft-versus-host disease (cGVHD), a common complication after stem cell transplant (SCT), has an impact on morbidity and survival. Previous classification of cGVHD has not been reproducible or prognostic for nonrelapse mortality (NRM). Recently the National Institutes of Health (NIH) consensus criteria were proposed, but the ability of this classification to predict outcome of various subtypes of cGVHD is unknown. Patients (N = 110) undergoing an SCT for a hematologic malignancy and surviving until day 100 posttransplant from 2001 to 2003 were studied. The overall survival (OS) using a landmark analysis at day 100 was 44% versus 66% (no GVHD vs. GVHD, P = .026). The OS of patients with various types of GVHD as proposed by the NIH criteria were significantly different (P < .0001). In a univariate analyses, this was more apparent when patients with any acute features of GVHD were compared to classic cGVHD (3-year OS 46% vs. 68%, P = .033). The 3-year NRM for the entire cohort was 21%, and was not affected by presence or absence of GVHD or subtypes of GVHD. In a multivariable analysis, extensive cGVHD (hazard ratio [HR] 0.35, P = .015) and having any acute feature of GVHD after day 100 (HR 3.36, P = .0144) were significant independent predictors of survival. The OS with different NIH subtypes of GVHD after day 100 from SCT varies, and is superior for patients with classic cGVHD

High-dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin lymphoma: prognostic features and outcomes

Between January 1990 and April 2001, 115 patients received high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL). With a median follow-up of 58 months (range, 1 - 175 months), 5-year progression-free survival (PFS) and overall survival (OS) were 46% and 58%, respectively. Twelve patients with primary refractory disease had a 5-year PFS of 41% and OS of 58%, not significantly different from those of the remaining cohort. Early and overall regimen related mortality were 7% and 16%, respectively. Male gender (P = 0.04) and a time to relapse (TTR) < 12 months (P = 0.03) were associated with decreased OS by univariate analysis. In multivariate analysis, TTR < 12 months remained statistically significant (P = 0.04). We have confirmed that HDT and ASCT result in long-term survival for a proportion of patients with relapsed or refractory HL. All patients, including those with primary refractory disease, benefited from HDT and ASCT

Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study

Background ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195. Findings Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60.8%, 95% CI 52.3-68.9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7.9 weeks (range 2.1-39.6) and median duration of response was 49.1 weeks (95% CI 39.3-75.4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9.7 months (95% CI 7.7-12.8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87.9% (95% CI 81.3-92.3) and 74.8% (66.4-81.5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). Interpretation Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.