ALBERT

Beschreibung: Introduction: FL is generally responsive to conventional-dose chemotherapy but long term disease-free survival (DFS) is uncommon. High-dose chemo-radiotherapy followed by ASCT has the potential to induce remission in this disease but the long-term benefit of this modality remains to be determined. Methods: Between 1990 and 2003, we transplanted 52 pts originally diagnosed with low-grade FL (31 grade 1, 21 grade 2). Twenty-five (48%) had biopsy-proven large cell transformation (FL grade 3 or diffuse large cell lymphoma) before ASCT. The median number of prior therapies was 2 (range: 1 to 7). Prior to ASCT, 45 pts (87%) were responsive to salvage therapy with 20 pts (38%) in CR. Five pts (10%) had chemo-resistant disease at the time of ASCT. High-dose regimens included BCNU-cyclophosphamide-etoposide (31%), melphalan/TBI (27%), and cyclophosphamide/TBI (25%). Thirty-eight pts (73%) received peripheral stem cells (PSCT) and 14 pts (27%) received autologous bone marrow (BM) with 4-hydroxyperoxycyclophosphamide (4-hc) purging in 9 cases (17%). The median age was 49 yrs (range: 29–65). Results: There was 1 treatment-related death during the first 100 days. After ASCT, 36 pts (69%) achieved a CR, 2 (4%) had a PR, and 7 (13%) had stable disease. Among those in CR, 20 (56%) had a CR pre-ASCT, 14 (41%) had a lesser response, and 1 (3%) was chemo-resistant. Median follow-up (f/u) of survivors was 5.3 yrs (range: 1.7 months to 12.4 yrs). The median overall survival (OS) has not yet been reached. The median event-free survival (EFS) is 3.4 yrs (range: 1.7 months to 12.4 yrs). Among complete responders, more than 50% are disease free at last follow-up (range 1.7 months to 12.1 yrs). Variables favorably affecting EFS and OS are age 〈 60 yrs (p = 0.007, 0.015 respectively), achievement of a CR after ASCT (p = 0.002, 0.001), absence of transformation (p = 0.038, 0.017), BM vs. PSCT (p = 0.042, 0.086), and 4-hc BM purging (p = 0.044, 0.059). Number of prior regimens, response prior to ASCT, type of preparative regimen, and addition of TBI, were not significantly associated with EFS, DFS, or OS. In multivariable analysis, achievement of CR after ASCT and age 〈 60 yrs are the only significant predictors of EFS and OS. Adjusted for age, 53% of pts with a CR after ASCT are alive and event-free at last f/u (range: 2.4 months to 12.4 yrs) (Figure 1). In contrast, the median EFS among pts without a CR is 0.5 yrs (range: 1.7 months to 5.3 yrs). Conclusion: ASCT is a reasonable therapeutic approach to FL, resulting in long term EFS for some pts, even with relapsed, refractory and/or transformed disease. In our experience, significant predictors of EFS and OS after ASCT are complete response and age

Beschreibung: BACKGROUND: Conventional treatment options for patients with relapsed hematologic malignancies are both limited and highly toxic driving the pursuit of more tumor specific and less toxic therapies. RNA targeted oligonucleotides are potentially powerful drugs with the ability to silence genes required for malignant hematopoietic cell growth at the post transcriptional level. Studies from our laboratory have validated the c-myb proto-oncogene, which regulates important hematopoietic cell functions and is overexpressed in many hematologic malignancies, as a target for this technology. A prior Phase I trial using a 24 nucleotide phosphorothioated antisense oligodeoxynucleotide targeted to c-Myb mRNA (C-MYB AS ODN) did not identify a maximum tolerated dose (MTD) of the drug. Here we report initial results of a follow up Phase I dose escalation trial using C-MYB AS ODN at higher dose levels than previously studied in subjects with refractory hematologic malignancies. METHODS: C-MYB AS ODN is administered as a 7 day continuous infusion. 5 dose levels ranging from 3mg/kg/day to 12mg/kg/day are planned. Subjects are enrolled using an accelerated dose escalation scheme in which one subject is enrolled on each dose level (DL) with plans to revert to the standard 3+3 design in the event of significant attributable toxcity. C-MYB AS ODN concentrations are measured in peripheral blood (PB) and in mononuclear cells (MNC) by slot blotting at baseline, days 3 and 7 of infusion and two weeks after cessation of infusion. C-myb expression is assessed at these timepoints though QRT-PCR for c-myb RNA. Disease specific assessments of response are measured at predefined timepoints after therapy. RESULTS: 6 subjects, all with refractory acute myelogenous leukemia (AML) have enrolled to date. Escalation through the first 3 DLs occurred without any toxicities. At DL4 (10mg/kg/day) abnormalities have been noted in coagulation assays. The first subject enrolled on DL 4 developed a grade 3 prolongation of the activated partial thromboplastin time (PTT) attributable to drug which returned to normal within 48 hours of drug cessation. Factor levels, DIC parameters and reptilase time were normal. The PTT abnormality was consistent with a “lupus like” inhibitor effect (DRVVT was abnormal and the PTT corrected with the addition of phospholipid in two independent tests.) The 2nd subject treated at DL 4 developed a milder but similar PTT prolongation. The 3rd subject enrolled on DL 4 had a normal PTT throughout therapy. No subjects developed bleeding complications. Plasma and intracellular drug concentrations were dose related (320–640pg/l and 2–80 ng/5×10e6 cells respectively). Peak drug concentrations were found on Days 3–7. By 14 days after infusion, most ODN was cleared from plasma, but remained measurable in MNC at concentrations 30–50% of the maximum value detected. QRT-PCR for c-myb mRNA was performed in 3 subjects. Subject 1’s (DL 1) c-myb mRNA levels gradually decreased from baseline during infusion and nadired two weeks after cessation of infusion. Subjects 3 (DL 3) & 5 (DL 4) had a decrease in c-myb mRNA levels midway through infusion but c-myb RNA levels increased back to baseline by cessation of infusion. To date no subject has had a clinically important response to therapy. Accrual continues for DL 5. CONCLUSIONS: C-MYB AS ODN is detectable in plasma and MNCs of subjects during continuous drug infusion with a steady state reached by day 3 of infusion. Plasma drug levels were markedly reduced 14 days after cessation of infusion but MNC drug levels remained elevated. C-MYB AS ODN at DL 4 (10mg/kg/day) is associated with a PTT prolongation consistent with a “lupus inhibitor” like effect. While encouraging biological activity was identified optimal dose and delivery remain to be established before clinically significant effects can be reasonably expected.

Beschreibung: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. Our previous phase I study in non-M3 AML showed evidence of leukemic response as manifested by reduction in bone marrow blast counts (15% response rate), improved platelet counts (41%) and improved neutrophil counts (26%). Based on these results, a phase II trial in non-M3 AML was initiated at the phase I MTD. In the current phase II trial, bexarotene (300mg/m2) was administered daily as monotherapy until disease progression or unacceptable side effects occurred. Fourteen patients have been enrolled: 8M/6F, median age 74 (range 20–83), 9 secondary AML (MDS or prior chemotherapy), 9 primary refractory or relapsed 〈 1 year after induction, 5 no prior induction chemotherapy, 5 requiring hydroxyurea at the time of enrollment for leukemic blast control, 4 prior allogeneic stem cell transplant, 12 blood transfusion dependent, 11 platelet transfusion dependent, and 8 neutropenic. Overall, no significant adverse events were noted. All patients received prophylactic antihyperlipidemic agents and achieved good lipid control. Two patients developed mild hypothyroidism related to bexarotene. Five patients were evaluable with bone marrow biopsy at 2 months: 1 50% reduction in absolute blasts, 1 SD and 3 PD. Similar to data from our prior phase I study, evidence of clinical activity was manifested as platelet count response in 1 patient and neutrophil increases attributable to bexarotene in 2 patients. When combining the results of our phase I experience (27 patients) with our phase II data (14 patients), there is a suggestion of increased activity in patients with 5q minus abnormalities with 4/7 (57%) benefiting (2 BM response, 4 neutrophil improvements and 1 platelet response). Conversely rates of clinical benefit were lower in patients with multiple (〉3) cytogenetic abnormalities (2/13), relapse after stem cell transplant (1/9) or requiring hydroxyurea for peripheral blast control at the time of study enrollment (0/10). Bexarotene is very well tolerated at the dose level studied. Early evidence for clinical activity has been seen as exemplified by improvement in platelet count, increased neutrophil counts and decreased bone marrow blasts. In summary, we conclude that bexarotene is an active agent in a subgroup of patients with AML. Study enrollment continues with amended inclusion criteria to focus on patients more likely to benefit from treatment.

Beschreibung: High-dose melphalan followed by ASCT is a common component of the early treatment for patients with multiple myeloma. Daily subcutaneous injections of filgrastim (Neupogen) at 5 ug/kg/day until ANC 〉 500/ul are routinely administered at our center from day +4 following ASCT, in order to accelerate hematopoietic recovery and lessen neutropenic complications. Pegfilgrastim (Neulasta) as a single 6 mg fixed dose subcutaneous injection has been shown to have similar efficacy and ease of use when compared to filgrastim in the non-transplant setting, but little data is available in the transplant setting. We began using pegfilgrastim day +1 following ASCT for patients with multiple myeloma and performed a retrospective cohort study comparing those who received filgrastim (n=6) with those who received pegfilgrastim (n=11). Transplants occurred between July 2002 and January 2004 and included all patients transplanted for myeloma in that time period for whom sufficient data was available. All patients had at least 2 x 106 CD34+ cells/kg peripheral stem cells harvested after cytoxan and filgrastim mobilization. Main outcome measures were: days from stem cell infusion to WBC nadir, days to ANC〉500/ul, and days to ANC〉1000/ul. Subjects were excluded if CBCs were drawn less frequently than every four days. There were no significant differences between the filgrastim and pegfilgrastim groups with respect to the following demographic variables: age, gender, hemoglobin, creatinine, calcium, albumin and beta-2 microglobulin at diagnosis. The groups were also balanced with respect to SPEP, UPEP, presence of lytic lesions and number of prior lines of therapy. The median number of CD34+ cells infused was similar: 5.7 x 106 in the filgrastim group vs 4.8 x 106 in the pegfilgrastim group (p=0.28). After transplant, median number of days to WBC nadir in the filgrastim group (FG) was 7 (range 5–9) vs 6 (range 5–8) in the pegfilgrastim group (PG) (p=0.31). However, median number of days to ANC〉500/ul in the FG was 11.5 (range 11–17) vs 10 (range 9–12) for PG (p=0.02). Similarly, median number of days to ANC〉1000/ul was 12 (range 11–17) for FG vs 11 (range 10–13) for PG (p=0.03). Five of six patients in the FG had neutropenic fever after transplant, compared to five of eleven patients in the PG (p=0.30). Currently, no significant differences in infection or relapse rates between groups have been noted and there were no deaths in either group. In this retrospective cohort study, pegfilgrastim was safe and at least equivalent to filgrastim for accelerating hematopoiesis after ASCT for multiple myeloma. Furthermore, there was no significant difference in the incidence of neutropenic fever, infection and survival, suggesting a similar clinical utility.

Beschreibung: On behalf of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) GVHD remains a major limitation of allogeneic hematopoietic cell transplantation (HCT). Steroids are the standard initial therapy yet prior data suggested only 35% complete response (CR) at day 28. We report the results of a randomized, four-arm, phase II trial designed to identify the most promising agent(s) for combination with steroids as initial therapy for aGVHD. Between August, 2005 and March, 2008, 180 pts with newly diagnosed aGVHD were randomized to receive steroids (2 mg/kg/day methylprednisolone) plus either: Etanercept, MMF, Denileukin Diftitox or Pentostatin. Pts who received MMF as GVHD prophylaxis in the preceding 7 days were randomized between the 3 non-MMF arms. The primary objective was to estimate the CR rate at day 28 for each of the four agents and evaluate secondary outcomes pertinent to the best agent for testing in a planned followup phase III trial vs steroids alone. PATIENTS AND RESULTS: Median age was 50 yrs (range, 7.5–69.9) with 96% 〉18 yrs; 39% had AML and 63% were male. The graft was peripheral blood (PB) in 61%, bone marrow (BM) in 25% and cord blood (CB) in 14% of pts. HCT was performed with myeloablative conditioning and/or unrelated donor grafts in 66% and 53%, respectively. Forty-four pts (24%) received MMF as aGVHD prophylaxis and were randomized to a non-MMF arm. At enrollment, 68% of patients had grade I-II aGVHD; 32% had grade III/IV. 53% of pts had visceral organ involvement at the time of enrollment. The treatment arms were balanced except CB grafts were more common in the Denileukin Diftitox arm (26%, p=0.006); PB were more common in the Etanercept arm (78%, p=0.006); and the MMF arm had more myeloablative HCT (82%, p=0.04). The proportion of CR at day 28 were: Etanercept (26%), MMF (60%), Denileukin Diftitox (53%) and Pentostatin (38%), and day 56 CR+PR rates were 59%, 78%, 68%, and 71%, respectively. 6 month chronic GVHD (cGVHD) incidence was: Etanercept (21%), MMF (25%), Denileukin Diftititox (29%), and Pentostatin (24%). Overall survival (OS) at 6 months was Etanercept (59%), MMF (71%), Denileukin Diftitox (63%), and Pentostatin (55%), respectively. After excluding pts who received MMF prophylaxis, the MMF arm still had the highest day 28 CR rate and OS. Overall toxicities and post-randomization infections were less frequent in pts randomized to MMF and Etanercept. CONCLUSIONS: These efficacy and toxicity data, particularly response, survival, cGVHD, and infections, suggest MMF + steroids to be the most promising regimen to compare against steroids alone in a randomized Phase III trial. Treatment Arm Outcome Etanercept (N=46) MMF (N=45) Denileukin Diftitox (N=47) Pentostatin (N=42) Day 28 CR 12 (26%) Skin: 12/36 (33%) 27 (60%) Skin: 21/35 (60%) 25 (53%) Skin: 17/35 (49%) 16 (38%) Skin: 14/34 (41%) L.G.I.: 4/12 (33%) L.G.I.: 12/18 (67%) L.G.I.: 5/14 (36%) L.G.I.: 7/17 (41%) U.G.I.: 5/10 (50%) U.G.I.: 11/12 (92%) U.G.I.:10/14 (71%) U.G.I.: 8/13 (62%) Liver: 2/6 (33%) Liver: 5/7 (71%) Liver: 3/7 (43%) Liver: 2/5 (40%) Day 28 CR (excl. prior MMF ) 9 (28%) 27 (60%) 15 (48%) 11 (39%) Day 28 CR/PR 22 (48%) 35 (78%) 28 (60%) 26 (62%) Day 56 CR/PR 27 (59%) 35 (78%) 32 (68%) 30 (71%) Day 56Treatment Failures 12 (26%) 4 (9%) 12 (26%) 13 (31%) OS Post-Randomization at 6 months 59% (95% CI: 43%–72%) 71% (95% CI: 54%–82%) 63% (95% CI: 47%–76%) 55% (95% CI: 38%–69%) OS Post-Randomization at 6 months (excl. prior MMF) 70% (95% CI: 51%–83%) 71% (95% CI: 54%–82%) 61% (95% CI: 40%–76%) 54% (95% CI: 33%–71%) Cum Incidence of Initial D/C of steroids at 9 months 34% (95 % CI: 20%–48%) 31% (95% CI: 17%–45%) 20% (95% CI: 8%–32%) 20% (95% CI: 8%–33%) Cum Incidence Day 56 Grade 3–5 Toxicity (%) 76% (95% CI: 63%–88%) 80% (95% CI: 67%–92%) 76% 95% CI: 64%–89%) 67% (95% CI: 52%–81%) Cum Incidence Severe/ Life Threatening/Fatal Infections at Day 270 47% (95% CI: 32%–62%) 44% (95% CI: 29%–59%) 58% (95% CI: 43%–72%) 56% (95% CI: 40%–71%) Cum Incidence of acute GVHD Flare after CR at Day 90 36% (95% CI: 21%–50%) 28% (95% CI: 14%–41%) 35% (95% CI: 21%–49%) 36% (95% CI: 21%–51%) Cum Incidence of cGVHD at Day 180 21% (95% CI: 9%–33%) 25% (95% CI: 11%–39%) 29% (95% CI: 15%–43%) 24% (95% CI: 10%–38%) Cum Incidence of Relapse at Day 180 14% (95% CI: 3%–24%) 10% (95% CI: 1%–19%) 9% (95% CI: 1%–19%) 13% (95% CI: 2%–24%)

Beschreibung: Abstract 3962 Introduction: Lenalidomide is an immunomodulatory drug with effects on the innate immune system that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods: Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continues during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab. Results: As of May 16, 2010, 27 pts have started therapy; diagnoses include: follicular (n = 18), mantle cell (n = 5), small lymphocytic (n = 3), and marginal zone (n = 1) lymphomas; median age is 60 years (range: 35–85); male: female ratio is 4:5; median number of prior therapies is 3 (range: 1 – 7); LDH is increased in 22% of pts. There were 2 deaths during protocol therapy: 1 death due to myocarditis during Part I treatment and 1 death due to lymphoma in a patient removed from study due to grade 3 rash, which subsequently resolved. One patient was removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. One patient has not completed Part II response assessment. For 23 pts completing Parts I and II, median follow-up is 12 months (range: 3.1 – 25.3) with a progression-free survival of 78% (95% CI: 50 – 91) [Figure below]. Overall response rate (ORR) after Part I is 22% (3 CR; 2 PR; 16 SD; 2 PD); ORR after Part II is 57% (7 CR; 6 PR; 8 SD; 2 PD). After Part II, the ORRs by histology were follicular lymphoma 60% (9/15 pts), mantle cell lymphoma 50% (2/4 pts), small lymphocytic lymphoma 67% (2/3 pts), and marginal zone lymphoma 0% (0/1 pt). Grade 3 or 4 non-hematologic adverse events possibly related to lenalidomide include hypokalemia (4 pts), hypophosphatemia (3 pts), pneumonia (3 pts), fatigue (1 pt), elevated ALT (1 pt), elevated AST (1 pt), tumor flare (1 pt), pulmonary embolism (1 pt), and hyperuricemia (1 pt). Conclusions: These data indicate that the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with durable responses in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas. Disclosures: Off Label Use: Phase II Trial of Lenalidomide - Dexamethasone - Rituximab in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab. Schuster:Celgene: Research Funding.

Beschreibung: Abstract 3570 Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. The best initial treatment regimen remains unclear. Although it is generally acknowledged that aggressive approaches using combination chemotherapy and/or high dose chemotherapy can prolong survival, consensus on upfront treatment strategies for advanced MCL is currently lacking without randomized controlled data to guide treatment decisions. We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-HCVAD (N=43) with or without autologous stem cell transplant (ASCT) or Rituximab maintenance. The primary study endpoints were PFS and OS as assessed by chart review and confirmed by SSDI database. Median follow up for all pts was 3 years. The median age was 53.7, and 76.7 % (n=33) were stage IV at diagnosis. 15 patients underwent consolidative ASCT. 11 pts received Rituximab maintenance. Comparing patients treated with R-HCVAD vs R-HCVAD + R maintenance vs. R-HCVAD + ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. Median PFS for all patients was 3.9 years: R-HCVAD alone 2.1 years vs. R-HCVAD+R 3.9 years (P=0.02, HR 3.51, 95%CI: 1.2–10.2) vs R-HCVAD + SCT not reached (p=0.017, HR 3.7, 95%CI: 1.26–10.63). PFS survival rates at 2 years were 50%, 88% and 70%; 33%, 71/% and 63% respectively at 3 years, and 0%, 33% and 33 % at 5 years. 3 year OS for all patients was 84% (95% CI: 65–94) with no significant differences among the three approaches. Notably, only 1/8 patients treated with R-HCVAD + SCT relapsed after 2 years, with a median follow up of 4.8 years for these patients. Our data suggest a further improved PFS when R-HCVAD is consolidated with either Rituximab maintenance or ASCT. While neither of the two consolidative approaches appears superior in our limited data set, both show significant PFS prolongation when compared to R-HCVAD alone. Further prospective investigation of consolidative approaches after RHCVAD in a randomized fashion is warranted. Figure 1: Figure 1:. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Abstract 4574 Background CTCLs are generally incurable with conventional therapies. In particular, advanced mycosis fungoides (MF), Sézary syndrome (SS) and gamma delta varieties of CTCL have poor survival rates and are often refractory to traditional chemotherapy. Allogeneic SCT may provide a GVL effect and improve outcomes for these patients. Methods A retrospective analysis was performed at the University of Pennsylvania to identify all patients with CTCL who underwent allogeneic transplantation. 12 patients were identified who were transplanted between 2004 to 2010. A chart review was performed to obtain data about demographics, diagnosis, staging, treatment, transplantation and outcomes. Results Median age at diagnosis was 49 yrs and M:F ratio was 5:7. Prior to transplantation, 4 had MF (stages IIB, IIIB, IVA1, IVB; 2 with nodal transformation), 4 had SS (one stage IVA1, three IVA2; 1 with nodal transformation), and 3 had gamma delta T-cell lymphoma (all T3b). Median time from diagnosis to transplantation was 3.3 yrs (range 0.5@02b97 yrs). Patients had received a median of 8 non-chemotherapy, and 2 chemotherapy-based treatment modalities before being transplanted. Only 3 patients were in complete remission (CR) at the time of conditioning and 9 had evidence of active disease. Reduced intensity conditioning (RIC) was used in 10 cases (Flu/Bu, Flu/Cy or Flu/Mel), and conventional myeloablative conditioning (Cy/TBI) was used in 2. GVHD prophylaxis consisted of calcineurin inhibitor and methotrexate in all patients. The median follow up for all pts is 6.6 months (range 1.4 to 37.1 months) and 11.2 months for surviving patients. All patients engrafted with an ANC 〉500 a median 13 days after SCT. Median donor chimerism at day 100 after SCT in 10 evaluable pts was 97%. 7 of 12 patients developed acute GVHD, 4 of whom had grade 3 GVHD. Two patients died within the first 100 days, from sepsis with active disease. At day 100, 7 of 10 evaluable patients were in CR, with an additional patient achieving CR shortly after; therefore transplant induced and maintained CR in 6 pts with active disease. 3 patients relapsed after achieving CR a median of 11.4 months (range 5.3–13.0 months) after SCT. 2 patients never achieved CR, and progressed within a month of transplantation. The median PFS for all pts was 31 wks, and 1 yr and 2 yr PFS were 48% and 32% without an obvious plateau. 2 year OS was 53% (Figure 1). Median OS is not reached. 6 patients have died from progression (5) and GVHD (1), 5 remain in CR and 1 is alive with active disease. Conclusion RIC SCT can provide long-term disease control in patients with advanced CTCL otherwise refractory to immunotherapy and chemotherapy. Given the limited TRM, consideration for earlier transplant should be given. Larger retrospective and ideally prospective studies will further define the role of allogeneic SCT in this disease. Disclosures: Rook: Therakos: Speakers Bureau; HY Biopharma: Consultancy. Kim:TenX: Research Funding; Biocryst: Research Funding; Genmab: Research Funding; Glouchester: Research Funding; Celgene: Research Funding; Eisai: Consultancy.

Beschreibung: In vitro, bexarotene has been shown to inhibit the proliferation of non-M3 AML cell lines and induce differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with non-M3 AML. Bexarotene was administered orally daily until disease progression occurred. Prophylactic antihyperlipidemic agents were used in all patients. Six dose levels ranging from 100 to 400mg/m2 are planned. Dose escalation occurred in cohorts of 3–6 patients based on dose-limiting toxicity. Twenty patients have been enrolled in 5 dose cohorts (100–300mg/m2) with enrollment demographics: 13M/7F, median age 69 (range 51–82), 11 prior MDS, 8 primary refractory, median number of induction attempts 2, no prior induction chemotherapy 2, prior autologous stem cell transplant 4, 19 blood transfusion dependent, 13 platelet transfusion dependent, and 16 neutropenic. Consistent with reported toxicity, 2 patients developed hypothyroidism, 7 patients developed grade 2–4 hypertriglyceridemia and 1 patient developed grade 2 pancreatitis. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea/hypoxia, pleural/pericardial effusions, weight gain/edema and dry cough in the setting of a rapidly rising neutrophil count. This syndrome resolved within 48 hours of stopping bexarotene and initiating steroids. No CR’s were noted, however significant evidence of drug activity were seen. Six patients showed evidence of neutrophil response (pretreatment median ANC 286/μL, range 28–1,037/μL, posttreatment ANC 3,150/μL, range 1,100–27,207/μL). Flow sorted peripheral blood neutrophils were collected from three of these patients and examined by FISH. Between 92–100% of purified neutrophils contained the patient’s leukemic cytogenetic abnormality suggesting differentiation of the leukemic blasts. Bone marrow blasts decreased to

Beschreibung: High-dose therapy and autologous stem cell transplant (SCT) is an option for patients with AML most commonly performed in first complete remission (CR1) or CR2. Stem cell (SC) collection in CR1 typically follows consolidation. SC collection in CR2 is limited by the need to achieve a second remission prior to harvest, and the use of additional induction therapy that may result in marrow toxicity and SC depletion. In addition, a SC product collected in CR2 might be more likely to have leukemia cell contamination that could contribute to subsequent relapse. Prophylactic collection of SC from patients in CR1 who are not imminently going on to SCT may therefore be reasonable and theoretically could improve outcome of SCT in CR2. However, many patients never relapse, and for those who do, alternative options, and the need to achieve a 2nd CR, further limit the chance that these cells will be used. The morbidity and cost of SC collection, and the need for prolonged storage, call into question the practice of routine prophylactic SC harvest. To determine the utility of SC collection in CR1, we identified 67 patients with AML who had autologous SCs collected between 1995 and 2002. Charts were reviewed to assess whether the collection was prophylactic or for immediate use and we reviewed the timing and outcomes of transplant. 61/67 patients had SCs collected in CR1, 5 in CR2, 1 in CR3. 22 had collection for imminent therapeutic use and 45 for potential future use. Among the 22 patients whose cells were collected for planned SCT, cells were collected in CR1 in 17 cases and CR2 in 5 cases. 11 (50%) remain in CR a median of 58 mo (range 4–103) after SCT, and 11 died a median of 11 mo (4 – 28) after SCT. Causes of death were relapse (n=8), transplant related mortality (TRM) (n=1), TRM after allogeneic SCT (n=1), and unrelated causes (n=1). Of 17 patients transplanted in CR1, 8 (47%) remain in CR. Of the patients whose cells were both collected and used in CR2, 3/5 remain in remission 8, 53, and 103 mo after SCT and 2 died of relapse 10 and 24 mo after SCT. 5/45 patients whose stem cells were collected prophylactically in CR1 used these cells for SCT in CR2 a median of 16 months (15 – 28) after collection. 2/5 of these patients remain in CR 21 mo and 51 mo and 3 had died of relapsed disease 9–12 mo after SCT. Stem cells remain unused in 40 of these patients and 21 (53%) remain in CR a median of 39 mo (7–98 ) after collection. 15/21 remain in CR without further therapy. 3 patients are currently alive receiving therapy for relapse and therefore may use cells in the future. 6 patients are in CR after allogeneic SCT in CR1 (2), CR2 (3) or untreated relapse (1). 16/40 will never use stored cells. 12 died of disease a median of 10 mo (4–22) after prophylactic SC collection and 4 died from complications of allogeneic SCT in CR1 (3) or CR2 (1). In summary, of the 45 patients with SCs harvested prophylactically in AML CR1, 5/21 (23%) who required further therapy went on to use these cells with 2/5 long-term survivors. Another 24 have done well with initial therapy but remain at risk for relapse and may use SCs in the future. In our experience, prophylactic autologous SC harvest and storage from patients with AML in CR1 remains a reasonable option. Additionally, SCT for AML in CR has resulted in frequent long-term remission at our institution.