IntroductionCMX001, an oral Lipid-Antiviral-Conjugate, generates high intracellular levels of cidofovir-diphosphate. CMX001 has potent in vitro activity against dsDNA viruses including herpesviruses, adenoviruses, polyomaviruses, and orthopoxviruses. Patients treated for these infections under individual EIND protocols experienced reductions in virus loads following CMX001 treatment; however, controlled human safety and efficacy data were previously not available.MethodsThis randomized, placebo-controlled, dose-escalation study (CMX001-201) enrolled adult allogeneic CMV-seropositive stem-cell transplant (SCT) recipients from 27 centers in USA. Patients, stratified post-engraftment by acute GVHD requiring systemic glucocorticoid therapy or CMV viremia, were randomized (3:1) to receive CMX001 or placebo into 5 sequential dose-escalating cohorts. Subjects were treated either once weekly (QW) or twice weekly (BIW) for 9 to 11 weeks until Week 13 post-transplant with a 4 to 8 week safety follow-up period. Virology and safety assessments were conducted weekly throughout the treatment period. A DSMB reviewed safety data and directed CMX001 doses for each cohort. Efficacy was measured by a composite endpoint of CMV disease or the appearance/progression of CMV viremia. Patients with these endpoints discontinued study drug and received anti-CMV treatment. This study was registered with ClinicalTrials.gov, NCT00942305.ResultsTableCMX001-201 Study. Selected Baseline Characteristics and Efficacy/Safety Summary Data (blinded data, as of 30 September 2011)Cohort40mg/placebo QW100mg/placebo QW200mg/placebo (QW)200mg/placebo BIW100mg/placebo BIWPatients enrolled, N4039534067Evaluable patients, N3337534067Baseline characteristicsPercent of Evaluable PatientsPeripheral Stem-Cell recipients85%89%72%75%87%Bone Marrow Recipients6%3%19%20%10%Umbilical Cord-Blood Recipients9%8%9%5%3%ATG Administration during Conditioning15%14%8%15%18%Acute GVHD at baseline18%16%11%17%9%CMV PCR negative before dosing70%84%76%78%84%Completed treatment36%49%43%28%57%Efficacy ResultsCMV Events to End of Treatment42%32%19%20%18%CMV DNAemia >1000 copies/mL45%27%21%18%12%Serious Adverse Events (SAE)Patients with SAEs Leading to Discontinuation21%12%9%25%6% Open table in a new tab ConclusionsIn this first Phase 2 trial of CMX001 ever conducted, a reduction in new or progressive CMV infection occurred in allogeneic SCT patient cohorts receiving higher doses of CMX001 (≥200mg weekly). An increased incidence of diarrhea occurred in patients receiving the highest dose of CMX001 (200mg BIW). CMX001 has potential as a prophylactic antiviral agent in this population. IntroductionCMX001, an oral Lipid-Antiviral-Conjugate, generates high intracellular levels of cidofovir-diphosphate. CMX001 has potent in vitro activity against dsDNA viruses including herpesviruses, adenoviruses, polyomaviruses, and orthopoxviruses. Patients treated for these infections under individual EIND protocols experienced reductions in virus loads following CMX001 treatment; however, controlled human safety and efficacy data were previously not available.

cGVHD is the most serious and common long-term complication of this allogeneic transplantation, occurring in 30-70% of patients surviving more than 100 days. cGVHD is associated with a high degree of morbidity and mortality and remains a major cause of late death. Initial therapy involves systemic corticosteroids which can contribute to further complications. In cases where steroids are ineffective or poorly tolerated, effective therapeutic options are limited. Anecdotal reports of myeloma patients treated with bortezomib after transplantation have shown improvement in cGVHD. We have begun a trial of bortezomib in patients with steroid-refractory cGVHD. Patients receive 1.6 mg/m2 q wk x 4 followed by one week of rest, for up to six cycles. To date 9 patients have been entered on trial and 5 have completed between 2 and 4 cycles. The treatment has been well tolerated with no grade 3 or higher adverse events (AE). AE have been grade 1-2 nausea (3), grade 1-2 diarrhea (6) grade 1-2 fatigue (4), one grade 2 transient neuropathy has been reported. There have been 3 treatment delays (1 patient) and dose reduction due to decreased hemoglobin and one due to transient neuropathy. Subjective improvement has reported in 6 of the first 8 patients, Improvement in general well-being has been noted as early as the first treatment. Two patients have had improvement in severe long standing sclerotic changes, including the ability to extend fingers that had long been contracted. Average Rodnan scores on 5 patients with sclerosis completing 2 or more cycles of therapy decreased from (31±9.6 to 13.8±7.5) One patient with non-healing suppurating lesions of his lower extremities has shown marked healing, another has significant decrease in chronic diarrhea. Weekly bortezomib for cGVHD appears to be well tolerated and results in early improvement in long standing refractory disease. Our plan is to enroll twenty-five patients to determine if these encouraging findings are sustainable.

All prospective autologous and allogeneic progenitor cell recipients and allogeneic donors must undergo pre-HSCT evaluation. Collection of defined elements of the evaluation process in real time with frequent updates requiring daily communication between physicians and HSCT staff is challenging, especially in a large HSCT program. Efficient data collection and management of pre-HSCT evaluation data allows inpatient and outpatient personnel the ease of accessing useful information on a patient in a quick and efficient manner, and should result in high quality of data for patient registration to CIBMTR. The customized PDI application developed at Baylor University Medical Center (BUMC) provides a user-friendly web-enabled database containing pre-HSCT patient and donor information, able to detect and flag deviations to standard of care. The PDI is available and accessible through the BUMC Intranet, in a password protected environment. Authorized users are granted different levels of access. The PDI also has a user tracking capability with user tracking being recorded each time it is accessed. The pre-HSCT evaluation process, data management and patient pre-registration with the CIBMTR have been supported by data collected, stored and accessed through the PDI. Physicians and authorized HSCT staff have access to pre-HSCT evaluation information regarding patients and donors undergoing blood and marrow transplantation. Examples of available information include: demographic information, diagnosis, disease markers, staging studies, prior treatments, comorbidities, organ function studies, infectious disease testing , HLA typing, and psychosocial summary. As physicians and designated HSCT staff enter pre-transplant evaluation data at specific time points, it goes through a logical algorithm that detects and generates deviations to standard of care and flags them. The PDI produces a comment box next to the flagged deviation for the physicians to enter a justification for the deviation so that the patient can proceed with a HSCT. Use of the PDI results in a better coordination of the pre-transplant evaluation process. It allows the data management staff access to accurate pre-HSCT information useful to register patients with the CIBMTR. Most of all it helps us ensure better quality and completeness of pre-HSCT evaluation data useful for statistical outcome analysis.

7064 Purpose: To evaluate the efficacy/safety of a novel AML regimen in elderly patients with heart disease or in patients with a contraindication to ‘standard‘ anthracycline-containing regimens. Patients and Methods: Phase II, open-label design. Eligible pts had elderly de-novo or relapsed AML or would not benefit from 7+3 or simlar therapy. Treatment was CLOF 40 mg/m 2 , Ara-C 1,000 mg/m 2 . (d1–5). Results: Patients were accrued and treated from April 2005 through Oct 2006. All pts signed IRB-approved consents. The median age was 67 years (range 38–82 years). Twenty (67%) subjects had received at least one prior cytoxic regimen (excluding 5-AZA). Significant cardiovascular (history of MI, bypass grafting, cardiomyopathy) was present in 43% (13/30) prior to therapy. Thirty pts were enrolled and all recieved at least one day of therapy. 1 pt died within 24 hours of starting treatment due to disease progression. Of the remaining, 29/30 received at least one complete cycle of therapy and 5 received 2 cycles. None received more than 2 cycles. Toxicities were greater in those receiving a second cycle. Grade 4 neutropenia developed in all patients. There were no cases of regimen-related cardiac toxicity. Most patients had some degree of edema and third-spacing syndrome. Several developed a significant but reversible acral rash. 25 patients survived >28 days and are evaluable for hematologic response. The histologic response rate (RR) is 68% (17/25) consisting of 14 (56%) complete remissions (marrow blasts <5%) and 3 (12%) partial responses (PR). There were 13 subjects with known cytogenetic abnormalities, 1 favorable and 12 unfavorable. Complete cytogenetic remissions (CytoCR) occurred in 4 of those patients, by chromosome analysis and/or FISH. Durable remissions and low toxicity allowed some patients to proceed to nonablative allogeneic stem cell transplantation. Conclusion: Clofarabine and Ara-C is an active and well tolerated regimen in myeloid malignancies including “elderly AML” a distinct entity usually associated with poor response rate and high treatment-related toxicities. Other drug combinations with clofarabine are ongoing in hematopoietic transplant and other high risk subgroups. No significant financial relationships to disclose.

PURPOSE: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in adult patients with refractory or relapsed acute myeloid leukemia and in selected elderly patients with untreated AML and heart disease.

Poster Presentations -Session II transplantation (SCT) for lymphomas and the engraftment of donor immnnocompetent cells is essential.The height of host "immunological barrier" belongs to the major factors influencing engraftment.Some patients transplanted after non myeloablative regimens finally reconstituted their own immunocompetent cells because of insufficient immunosuppression and there has been no room for GvL effect.On the other hand, many pretrcated immunocompromised recipients developed severe complications due to unnecessary toxicity.11 patients with non-hodgkin lym pbomas (NHL -8x) and chronic lymphatic leukemia (CLL -3x) underwent non-myeloablative allogeneie SCT fronl sibling donor.No one of them was in complete remision (CR) before SCT.The recipients with the pretransplant level of CD3+ cells below than 0, 5x10 9/L were grafted after conditioning combined flndarabin (125rag/m2) and cyclophosphamide (120mg/kg).Those ones with CD3+ cells above 0, 5x10 9/L underwent SCT after fludarabin and melphalan (140rag/m2), fludarabin, melphalan and ATG (40mg/kg)or fludarabin, cyclophosphamide and ATG.The "graft versus host disease" (GvHD) prophyla~s consisted of cyclosporine A (CsA) only or CsA combined with the short-course of methotrexate (MTX).Donor chilnerism was evaluated in T-cell population at day +30, +60, +100 after SCT.CsA tapering depended on the grade of donor chimerism in T-cells. 10 patients (90, 0%) achieved complete donor chimerism in T-cells and sustained CR of their disease at the posttransplant follow-up period (median 134 days).6 recipient (54, 5%) developed GvHD.3 patients (27, 3%) died of transplant-related complications.The combination of fludarabin and cyclophosphamide (+/-ATG) was associated with significantly lower to, city and allowed sufficient engraftment of donor cells with effective immunological mmour control in severe immunocompromised hosts.The reduction of conditioningorelated to,city without the decrease of CR rate fully advocate the pretransplant evaluation of T-cell populations in recipients.

Antibody concentrations to vaccine-preventable diseases decline following BMT and an optimal schedule for vaccination after transplant has not been established. We examined antibody responses to tetanus toxoid (TT) and Haemophilus influenzae type b-conjugate (HIB) vaccines of BMT patients immunized at 6, 12 and 24 months (6 month group, n = 21) and compared them to those previously reported for patients immunized at 3, 6, 12 and 24 months (3 month group, n = 74) or at 12 and 24 months (12 month group, n = 17) following transplantation. Geometric mean total anti-HIB and IgG anti-TT concentrations were significantly higher after the 12 month dose in the 3 and 6 month immunization groups compared to the group who received their first dose at 12 months. Although HIB antibody concentrations were higher in the 3 month and 6 month groups 12 to 24 months after BMT, the proportion of patients with protective levels was not significantly different from the proportion protected in the 12 month group. Following the 24 month immunizations, geometric mean antibody concentrations to HIB and TT were similar for all three immunization groups. The proportion of patients in each group with protective levels of HIB antibody after the 24 month dose was ⩾80%. A two dose schedule of HIB and TT vaccines at 12 and 24 months after BMT should afford protection.

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1997.15.2.860 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9053514 Sweet's syndrome. E VancexE VanceSearch for articles by this author , S GranterxS GranterSearch for articles by this author , A SkarinxA SkarinSearch for articles by this author Show More Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA. https://doi.org/10.1200/JCO.1997.15.2.860 PDF "Sweet's syndrome.." Journal of Clinical Oncology, 15(2), pp. 860–861© 1997 by American Society of Clinical Oncology