ALBERT

Beschreibung: Eradication of minimal residual disease (MRD) during the first months of treatment for patients (pts) with ALL is associated with improved disease-free survival (DFS). We hypothesized that Alemtuzumab, a humanized monoclonal antibody directed against CD52, might be an effective, novel agent for eradication of MRD in ALL based on data demonstrating strong CD52 expression in other lymphoid malignancies and in several ALL cell lines, and from case reports of clinical activity in advanced ALL. In CALGB 10102, to define the percentage of CD52+ cases and to demonstrate feasibility, we tested dose escalation of Alemtuzumab in sequential cohorts to a target dose of 30 mg administered sc 3X/week for 4 weeks (12 doses) during post-remission therapy. Pts are eligible to receive Alemtuzumab if lymphoblast CD52 expression at diagnosis is ≥ 10% as determined in a CALGB reference laboratory. The 10102 therapy is composed of monthly treatment modules outlined below: Treatment module sequence is: A,B,C, D, A, B, C followed by maintenance therapy for a total of 2 years. Antimicrobial prophylaxis for cytomegalovirus (CMV) (e.g. acyclovir 800 mg qid) and pneumocystis carinii is mandated. Weekly quantitative monitoring for CMV viremia is performed. 150 pts with untreated ALL have enrolled: Median age is 48 yrs. 124 (83%) pts have precursor-B; 19(13%) have precursor T-ALL and 7 (4%) have biphenotypic or bilineal ALL. Of 139 evaluable pts, 95 (68%) had CD52 ≥ 10%. By immunophenotype, 72% of precursor B and 61% of precursor T pts were eligible to receive Alemtuzumab. Phase I dose escalation was recently completed. Dose limiting toxicity (DLT) for Phase I was defined as the inability to proceed with protocol treatment within 6 weeks of the last dose of Alemtuzumab. Non-heme toxicities have been mild and sc Alemtuzumab administration was well tolerated. Hematologic and infectious toxicities are summarized below: Myelosuppression was transient and use of G-CSF was permitted during Module D. 2 pts were treated for CMV viremia due to rising CMV titers in 2 sequential assays. 6 other pts had transient CMV elevations during or immediately following completion of Alemtuzumab that did not require treatment. 22/24 phase I pts received all 12 doses of Alemtuzumab. There were 2 DLTs reported: 1 pt in cohort 2 due to CMV viremia requiring gancyclovir following completion of Alemtuzumab; and 1 pt in cohort 3 due to ANC 〈 1500 six weeks after Alemtuzumab (pt was not given G-CSF). Based on these Phase I data, the targeted dose of 30 mg Alemtuzumab was recommended for further study in the ongoing Phase II study. In summary, we report for the first time that CD52 is expressed in the majority of ALL cases and demonstrate the feasibility of employing Alemtuzumab in front-line therapy. Ongoing accrual to the phase II study will evaluate the efficacy of Alemtuzumab in eradication of MRD in adult ALL. Module A Module B Module C Module D (Alemtuzumab) Maintenance Cytoxan Cytoxan Methotrexate (IV, PO, IT) 10 mg* cohort 1 Vincristine Daunorubicin Cytarabine Vincristine 20 mg* cohort 2 Dexamethasone Vincristine Vincrisitne 6-MP 30 mg* cohort 3 6-MP Dexamethasone L-asparaginase *Phase I dose escalation Methotrexate L-asparaginase IT-Methotrexate Alemtuzumab cohorts N Myelosuppression (grades 3 or 4) Lymphopenia CMV viremia 10 mg 6 2 1 2 20 mg 10 1 1 4 30 mg 8 1 0 2

Beschreibung: Twenty-nine of 172 patients (17%) who received an allogeneic bone marrow transplant (BMT) from histocompatible sibling donors for hematologic malignancies were mixed hematopoietic chimeras; ie, they had a mixture of donor and host hematopoietic or lymphohematopoietic cells at greater than or equal to 14 days after transplantation. Twenty- four of the 29 mixed chimeras (83%) have remained in continuous complete remission for up to 116 months (greater than 9 years) following BMT. Four of the 29 patients (14%) have had recurrent leukemia, and 7 of the 29 (24%) have had moderate or severe graft-v- host disease (GVHD). Twelve of these 29 patients have persisted as stable mixed chimeras for greater than or equal to 2 years after BMT, whereas other patients converted to all donor-type hematopoiesis. The incidence of mixed chimerism was independent of the pretransplant regimen, the donor or recipient age (less than 20 v greater than 20 years), remission status (first complete remission of acute leukemia and first chronic phase of chronic myelocytic leukemia v later stages of disease), and type of leukemia. Our data indicate that mixed hematopoietic chimerism is not rare after BMT for hematologic malignancies and that its presence is compatible with long-term disease- free survival. Prospective studies of mixed chimerism after BMT are warranted to achieve better understanding of its biologic importance.

Beschreibung: Two tools have recently been developed to predict allogeneic HCT tolerance: the HCT-comorbidity index (HCT-CI) (Sorror, Blood 2005) and “risk group” (Artz BBMT, 2006). The HCT-CI focuses on a comprehensive list of comorbidities whereas the “risk group” combines a simple comorbidity tool and performance status to identify patients at high risk for transplant-related mortality (TRM) and inferior survival. However, clinical parameters have limitations of reproducibility and accuracy. Biomarkers represent another promising method of risk stratification. Thus, we analyzed whether biomarkers independently predicted HCT tolerance. Among 112 consecutive transplants on a single protocol, 81 patients with pre-HCT cryopreserved sera underwent analysis of C-reactive protein (CRP) and 79 of interleukin-6 (IL-6) levels. AML and MDS represented the most common diagnosis (57%). All patients underwent HCT using fludarabine (125 mg/m2 IV total), melphalan (140 mg/m2 IV total) and alemtuzumab (100 mg IV total). The median age was 52 yrs and 46% had active disease at HCT. The median follow-up was 42 months. To determine tolerance, we evaluated initial hospital duration, aGVHD, and TRM. Median duration of initial hospitalization for HCT was 23 days and Grade II–IV aGVHD developed in 30 pts. Day 100 and day 180 TRM were 17% and 23% respectively. The median pre-HCT CRP level was 18.5 mg/L (mean, 40.5 mg/L; range, 0.17 to 180). The median IL-6 was 78.3 mg/L (range, 10 to 2258). CRP and IL-6 above the median were tested as adverse risk factors. High CRP was strongly associated with prolonged hospitalization (P=0.007) whereas increased IL-6 was not (P=0.30). HCT-comorbidity index (HCT-CI) ≥ 3(P=0.126) and “risk-group” (P=0.091) did not confer an increased risk of prolonged hospitalization. In univariate analysis, CRP above the median also predicted for grade II–IV aGVHD (P= 0.003). TRM was predicted by CRP (P=0.013) but not IL-6 (P=0.22). Multivariate analysis showed CRP retained independent predictive value for TRM when considering adverse risk factors of age ≥50, HCT-CI ≥ 3, active disease, or “risk group”. The impact of these biomarkers was limited to HCT tolerance as CRP and IL-6 did not predict for increased relapse (P=0.42 for both). Finally, inferior overall survival was associated with pre-HCT CRP (P= 0.029) but not IL-6 (P= 0.48). CRP holds promise as a reproducible biomarker to predict HCT related morbidity and mortality independent of standard measures. IL-6 may be less useful. These findings require validation, but because of the ready availability and reproducibility of CRP, this biomarker could be rapidly integrated into other HCT risk-assessment tools. P value for Transplant-Related Mortality Predictive Factor Univariate Multivariate HCT- CI-hematopoietic cell transplant comorbidity index Age 0.27 0.79 Disease 0.16 0.26 HCT-CI 0.79 0.98 Risk Group 0.11 0.061 C-reactive protein 0.013 0.047 Interleukin-6 0.22 -

Beschreibung: Increased drug delivery through enhanced formulations of standard acute lymphoblastic leukemia (ALL) therapies may improve outcomes while producing less toxicity. Preclinical and Phase 1 and Phase 2 clinical studies of vincristine sulfate encapsulated in liposomes (VSLI, Marqibo®) have shown enhanced efficacy and acceptable tolerability in a variety of solid and hematologic malignancies. A maximum tolerated dose (MTD) of 2.25 mg/m2 with no dose cap has been established for VSLI, which contrasts with the 2 mg dose cap for conventional vincristine (VCR). Pharmacokinetic studies have shown that altered distribution and elimination phases may lead to increased exposure versus traditional VCR and may account for the increased efficacy observed in nonclinical models. The current Phase 2 trial is evaluating VSLI in adult (Ph-) subjects with ALL in second relapse or after progression following two prior ALL therapies. Subjects are receiving intravenous (IV) 2.25 mg/m2 VSLI weekly with no dose cap for up to 12 months. The study will enroll approximately 56 subjects with response rate as the primary endpoint. To date, 23 subjects have received at least one dose of IV VSLI. Preliminary reports indicate that five of these subjects achieved responses (CR/CRi/CRp). While data review is not complete, preliminary signs of efficacy in this underserved patient population warrant discussion: Two subjects had fewer than 5% lymphoblasts; one on Day 28 and the other on Days 28 and 56 after initial VSLI treatment and subsequently underwent stem cell transplant. The latter subject achieved a CR to a single agent (VSLI) in her first relapse (systemic and extramedullary) after a prior allogeneic transplant. One subject achieved a CR with no residual blasts (normocellular bone marrow) and resolution of extramedullary disease including resolution of bilateral pleural effusions without thoracentesis and marked decrease of an anterior mediastinal mass by Day 28. Her chest pain resolved after the first dose of VSLI. This subject subsequently went on to receive a second stem cell transplant. One subject with extramedullary disease of the kidney achieved a CR with no residual blasts detected in the kidney or bone marrow. This subject achieved a true CR (2 confirmed kidney biopsies one month apart) after 11 doses VSLI. One subject with bone marrow disease achieved a CR that was durable for approximately 5 months. Although these data are preliminary in this patient population, these findings are encouraging given that this is a single agent chemotherapy being given to a heavily pretreated leukemic population. The drug appears well tolerated to date with no reports of subjects experiencing Grade 4 toxicity. VSLI appears to have a safety profile similar to conventional VCR. Common AEs include neutropenia, fatigue, constipation, peripheral neuropathy, and nausea. In the previous VSLI (Marqibo) Study VSLI-06, VSLI appeared to be highly effective in second relapsed subjects achieving a CR rate of 29% with a limited sample size (2 out of 7 subjects). The preliminary CR (CR/CRi/CRp) rate from this study further corroborates this result: the CR rate is 28% among patients who completed study treatment and is at least 22% (≥5/23 subjects) among all subjects including those who just started receiving VSLI. The projected rate of activity in this ongoing trial supports these previous Phase 1 study results and confirms the importance of VSLI (Marqibo) in this patient population. These preliminary results are extremely encouraging, as VSLI was given as a single agent to a patient population that typically has a very low response rate to anti-leukemia therapies. Phase 3 combination studies are planned.

Beschreibung: Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing. Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status 1.5 mg/m2 n = 5 1.825 mg/m2 n = 3 2 mg/m2 n = 3 2.25 mg/m2 n = 18 2.4 mg/m2 n = 7 Total n = 36 1st salvage 1/1 0/1 -- 2/7 1/4 4/13 (31) 2nd or later salvage 1/4 1/2 0/3 1/11 0/3 3/23 (13)

Beschreibung: ABT-869 is an orally bioavailable, potent and specific inhibitor of multiple receptor tyrosine kinases (RTKs) including vascular endothelial and platelet growth factor, FLT3, STAT5, and ERK receptors. Since multiple RTKs, particularly FLT3, are commonly expressed and activated in AML/MDS, ABT-869 may prove to be an attractive therapeutic option. The current multi-center, two arm, dose-escalation study was designed to assess the safety, pharmacodynamics, pharmacokinetics (PK) and preliminary anti-tumor activity of ABT-869 as monotherapy in arm A, and to determine the PK, safety profile and potential of a PK or PD mediated drug interaction in patients with AML or MDS treated with ABT-869 plus Cytosine arabinoside (Ara-C) in arm B. No dose was administered on D7 (arm A) and D12 (arm B). In single-agent Arm A enrollment is complete (N=29) with 9, 4, 12 and 4 patients enrolled in each of the 10, 12.5, 15, and 20 mg cohorts, respectively. Dosing began with the 10 mg/day cohort and escalated to the 20 mg/day cohort to define a recommended phase 2 dose (RP2D) of 15 mg. During dose escalation, in the 10 mg cohort, 2 patients experienced DLTs of fatigue while in the 20 mg cohort, 3 patients experienced DLTs of fatigue and 1 patient experienced a DLT of proteinuria. In currently enrolling arm B (N=17), ABT-869 was administered in combination with Ara-C. ABT-869 was initiated on day 6 following administration of Ara-C at 1.5 mg/m2 on days 1–3 (patients ≥64 years old) or days 1–4 (patients

Beschreibung: Introduction: In patients (pts) with relapsed/refractory CLL, responses achieved with conventional salvage chemotherapy may have limited durability, likely due to the presence of residual disease remaining in the bone marrow (BM) or peripheral blood (PB). The anti-CD52 monoclonal antibody alemtuzumab (Campath®) demonstrates single-agent efficacy in relapsed/refractory CLL and has been shown to induce MRD-negative (-) responses in 20% of pts (Moreton et al J Clin Oncol2005;23:2971–2979). A recent phase 2 study reported that treatment with SC alemtuzumab with or without the addition of oral fludarabine in pts with relapsed/refractory CLL resulted in a 49% overall response (OR) rate and 16% complete response (CR) rate; MRD(-) CR was achieved in 10% of pts (Sayala et al Blood2006;108: abstract 34). We evaluated the safety and efficacy of SC alemtuzumab combined with intravenous (IV) fludarabine in pts with previously treated CLL and report the responses and results from MRD analysis. Methods: Eligible pts had active CLL requiring therapy and had relapsed after at least 1 prior therapy. SC alemtuzumab 30 mg days 1–5 and IV fludarabine 25 mg/m2 days 1–5 were administered on a 28-day cycle for 4 cycles. Pts with