ALBERT

Description: Although treatment outcomes for adult ALL remain stagnant at 35–40% 5 yr event free survival (EFS), allogeneic transplant particularly from unrelated donors has frequently been reserved for patient beyond first complete remission (CR1) with the exception of patients with a t(9;22) or Philadelphia (Ph+) cytogenetic abnormality. Between 4/1/2001 and 11/14/2007, 67 patients with ALL received URD-HCT; disease status at HCT was (CR1) in 27 pts (40%), CR2 in 20 pts (30%) and advanced disease (AD) which included induction failure, relapse or CR3 in 20 pts (30%). Age ranged from 2–58 yrs with median age of 29.5 yr. One third of the patients were Ph+. An additional 18 pts had high or very high risk cytogenetics abnormalities. The majority (≥75%) of Ph+ patients had received Gleevec prior to HCT. The conditioning regimen was FTBI 1320 Gy given as 11 fractions over four days followed by VP-16 60 mg/kg. Graft vs. host disease (GVHD) prophylaxis was tacrolimus (FK) and methotrexate (MTX) in 20 pts; sirolimus (Siro) was added to this regimen in 15 pts. Other GVHD regimens used were FK, MTX and Cellcept (12 pts) FK and siro (4 pts) and anti thymocyte globulin was added in 11 pts. Graft source was marrow in 12 pts and peripheral blood stem cells in 55 pts. Median time to ANC 〉 500 was 17 days (range 11–36d) and for platelets was 24 days (range 15–218d). Three patients died prior to day 18 of infectious complications and were considered unevaluable for engraftment. The incidence of acute GVHD Grade II-IV was 57% with Grade III-IV in 18%. Chronic GVHD occurred in 52% of 56 patients at risk. Treatment related mortality was 16% at 100 days and 28% at 1yr. At two years the event free survival (EFS) was 58% for CR1 pts vs 23% for CR2 and 17% for AD. Relapse rates were 18%, 24% and 40% respectively EFS was 62% at 2 yrs for Ph- pts and 50% for Ph+ in CR1 vs 19% for pt 〉 CR1 who were Ph-and 40% for Ph+ (p=0.31). Remission status (CR1 vs 〉 CR1) was a significant predictor of survival (p=0.01) and EFS (p=0.03) in multivariate analysis while age and Ph+ status had no impact on survival end points. Conclusion: The preparative regimen of FTBI and VP16 offers 2 yr EFS rates of 50–60% in patients receiving URD-HCT in CR1, including patients with Ph+ and other high risk cytogenetic risk groups. These results are comparable to those reported with sibling donor transplants and provide a curative option for patients in CR1 lacking a family donor. Figure Figure

Description: Current CGVHD prognostic and staging systems are still undergoing development and have identified plt count; CGVHD types progressive(P), quiescent(Q), de novo(DN); KPS, and GI involvement as significant risk factors affecting outcome. A simple reproducible staging system such as used for AGVHD to apply in clinical trials is still lacking. We evaluated whether the PSE dose required to control CGVHD at 3 months from diagnosis would have a prognostic effect on survival and in and of itself serve as a criteria for secondary intervention or investigational therapy. We hypothesized that by 3 months from start of treatment patients would be on the lowest dose dictated by medical necessity rather than by physician driven dose preference. A retrospective analysis of charts from 109 patients diagnosed with CGVHD between 6/2000 and 6/2003 was done. Data collected included age, donor type(mud/sib), plt count, CGVHD type(P/Q/DN), KPS, GI involvement. Outcome analysis included survival and cause of death. PSE dose was calculated in mg/kg at 3 months from first diagnosis of CGVHD. With a median follow up of 47.2 months(range 6.6–67.2) relapse censored survival of patients on a 3 month PSE dose of more than .3 mg/kg was 53% compared to all lower doses 86%(P.03). In a univariate analysis only PSE dose (P .05) and KPS (P

Description: Introduction: More than half of patients diagnosed with AML are over 60 years old and have few effective treatment options due to both patient-related factors such as co-morbidities and poor performance status, and high-risk disease features such as complex cytogenetics and preceding myelodysplastic syndrome (MDS). Decitabine, a potent DNA hypomethylating agent, has been approved for the treatment of patients with all FAB subtypes of MDS, including those with secondary MDS and those who have received prior therapy for MDS. In AML, decitabine may target the frequent aberrant DNA methylation patterns and is a lower intensity therapy that may be better tolerated in this challenging patient population. Study: The primary objective of this multicenter, open label Phase II trial was establishing the morphologic complete response (CR) rate in patients 60 years and older with newly diagnosed, untreated AML, who were not candidates for standard induction chemotherapy. Decitabine was administered at a dose of 20 mg/m2 intravenously over 1-hour for 5 consecutive days every 4 weeks. Results: Fifty-five patients were enrolled in the trial [27 men, 28 women; median age: 74 years (range, 61–87); ECOG Score: 0 (47%), 1 (35%), or 2 (18%)]. Most patients had intermediate (53%) or poor (42%) risk cytogenetics. Fifty-six percent had de novo AML, 35% were transformed from MDS, 7% had AML secondary to prior therapy, and 2% had other. According to the AML response criteria (Cheson, JCO 2003), the expert-reviewed overall response rate in the intent-to-treat (ITT) population was 26%, with 13 (24%) morphologic complete responses (CR) and 1 (2%) CR with incomplete blood count recovery (CRi) (Table). The median time to response was 3 months (range, 51–164 days). Responses were seen in all subgroups of patients, including 5 of 19 patients with a prior history of MDS (CR or CRi, 26%) and 5 of 23 patients with poor-risk cytogenetics (22%). A median of 3 cycles (range, 1–25) was administered to the ITT population. Sixty-four percent of patients received 3 or more cycles of therapy. Twenty-four patients (44%) maintained stable disease during a median 5 cycles of therapy. With 1-year duration of follow-up, the overall median survival was 9.6 months. Besides myelosuppression, the most commonly reported adverse events considered possibly related to decitabine treatment were febrile neutropenia (24%), fatigue (24%), pneumonia (11%), sepsis (9%), dyspnea (9%), and bacteraemia (7%). Three deaths occurred on study and were attributed to sepsis. The 30-day mortality rate on this trial was 4%, which compares favorably to the ~20% mortality rate typically seen in this population treated with standard induction therapy (Stone RM. CA Cancer J Clin.2002;52(6):363). Conclusion: These preliminary results suggest that decitabine given daily for 5 days demonstrates efficacy in patients with newly diagnosed AML, with a toxicity profile that was manageable in this elderly patient population. This study supports the investigation of decitabine in an ongoing Phase III survival trial (n=480) of the 5-day regimen in elderly patients with AML. Table N CR CRi Overall Response Rate % All Patients 55 13 1 26% AML Diagnosis De novo 31 7 0 23% Transformation from MDS 19 4 1 26% Secondary to Prior Therapy 4 2 0 50% Other 1 0 0 0% Cytogenetic Risk Poor 23 5 0 22% Intermediate 29 6 1 24%

Description: Tandem cycle high-dose melphalan (Mel) followed by Mel +/− total body radiation therapy improves progression-free (PFS) and overall survival (OS) in comparison to single cycle Mel, but is associated with 3% treatment-related mortality (TRM). We tested a new tandem regimen (THDCT) followed by maintenance therapy in order to lower TRM, while enhancing efficacy. Between 5/94 and 8/04, 114 patients (pts) were enrolled on 2 sequential studies. First, pts received Mel 150 mg/m2 [cycle 1 (C1)], oral busulfan (bu 16 mg/kg; 46 pts), and cyclophosphamide 120 mg/kg (Cy; C2); the next cohort received the same THDCT but bu was given intravenously (i.v. 12.8 mg/kg; 68 pts). All pts were to receive maintenance IF 3 million units/m2 given subcutaneously, 3 times/week. Pts participating on the 2nd study were to receive thal together with IF provided that they were not in CR at 6 months post-THDCT. Peripheral blood progenitor cell mobilization consisted of G-CSF 10 microgram/kg to procure 4 x 106 CD34+ cells/kg without (first 46 pts) or with Cy 1.5 g/m2 (last 68 pts). Pts ≤65 years, with responsive or stable MM, with

Description: Reduced intensity allogeneic stem cell transplantation is increasingly used for patients who are at high risk for mortality following conventional full-intensity regimens. Defining the risk of CMV-related events in this growing modality has a significant implication in future immunologic interventions to improve their transplant outcomes. Therefore, we analyzed 160 patients at risk for CMV (R+ and/or D+) who received a reduced intensity transplant (RIT) between May 2000 and February 2004 from either a matched-related (n=91) or unrelaed donor (n=69) under the City of Hope IRB protocol #02047. The median age of the cohort was 51 (range: 15–71) and recipient/donor CMV serostatus was; R+D+=87, R+D-=44, R-D+=29. Conditioning regimens were reduced but myeloablative (fludarabine + melphalan or busulfan) in 124 or truly non-myeloablative (TBI 200cGy +/− fludarabine) in 36 patients. Fourteen received a bone marrow graft and the remaining 146 received PBSC graft. GVHD prophylaxis consisted of cyclosporine and mycophenolate +/− short course of methotrexate. CMV reactivation was monitored by shell vial blood culture (BC) twice a week from d21 until d100 or longer if clinically indicated. Additional monitoring with quantitative PCR was available in 57 patients. Preemptive therapy with ganciclovir was started at the first positive BC at 5mg/kg twice a day for a week, followed by maintenance therapy for 5 weeks. Of 160 patients, at the time of analysis 94 patients are alive with a median follow up of 12.2 months. The actuarial probabilities of overall survival, disease-free survival, and relapse for the entire cohort at 1 year were 55.9 %, (95%CI: 51.1–60.5), 40.4% (95% CI: 37.1–43.7), and 40.1% (95%CI: 34.8–46.2), respectively. Grade 2–4 acute GVHD occurred in 91 (56%) patients. Eighty-one patients developed CMV reactivation (actuarial probability of 52+/−4%) at the median of 44 days post-transplant (range: d20-d216, 8 after d100). Of these, 42 (52%) had either persistent or recurrent reactivation. Nineteen patients (12%) developed CMV disease (8 with pneumonitis, 11 with GI tract) at the median onset of 56 days (range d28-d591: 5 after d100). Seven of these 19 patients had both BC and PCR data, which were consistent each other in all but one. CMV viremia itself did not predict poorer survival (p=NS), but CMV disease was associated with lower overall survival (37% vs. 65%, p=0.02). The univariate analysis revealed two major findings: 1) CMV seropositive patients were at seven times the ‘hazard’ (HR: 7.2, 95%CI: 2.3–22.9) for CMV reactivation compared to those who were CMV seronegative (p

Description: Tipifarnib (R115777, Zarnestra) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 37 patients were accrued, with 32 evaluable for toxicity. Median age at treatment is 62 (range 33–77), with 15 F, 22 M. RESULTS: The MTD on this schedule was 1200 mg B.I.D., with the major dose limiting toxicity determined by course one being creatinine elevation. At the 6 pts treated at the MTD there was one DLT (grade 3 creatinine), one grade 3 nausea (not a DLT), and grade 2 toxicities including liver enzyme abnormalities, nausea/vomiting, and rash. At dose level 1, metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy was observed. Two patients treated at the MTD had a complete remission: a 69-yr old male who relapsed after 231 days, and a 66-yr old male who relapsed after 258 days, but who responded to re-treatment with tipifarnib and is disease-free 548 days (18 months) since enrolling in the study. At 1000mg BID dose, a 69-yr old woman with relapsed AML after autologous transplant had a CR after 2 cycles and went on receive a successful allogeneic transplant and is in remission 2yrs from her first cycle of tipifarnib. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. Higher doses resulted in a higher incidence of dose limiting renal toxicity, fewer courses, and no complete remissions. Additional patients are accruing at the MTD to further understand the toxicities on this schedule. In AML patients, a two-fold increase in tipifarnib dosing can be tolerated on this dosing schedule with responses seen at the higher doses. A monotherapy phase 2 or tipifarnib combination study in AML using this schedule appears warranted.

Description: The current paradigm of cytarabine-based induction chemotherapy followed by repetitive cycles of similar consolidation has yielded 2-year disease-free survival (DFS) of no more than 20% in older pts (≥60 yrs) who achieve remission. Induction failure (IF) is also high in this population (20–35%), depending on cytogenetic risk. Regimen-related toxicities have been a barrier to allogeneic HCT in older pts. RI conditioning provides a means to harness graft vs. leukemia in this group. Between 2/2000 and 3/1/2007, 46 pts ≥ 60 yrs (median 63 yr, range 60–71) received RI HCT from either related (26) or unrelated (20) HLA matched donors. In 23 pts, RI HCT was used as consolidation of remission (CR1 [19 pts] + CR2 [4 pts]) while 23 had active disease, including 10 IF. Karyotype was favorable in 9%, intermediate in 48% and poor in 41%. The median % marrow blasts for non-remission pts was 31% (6–80%) and peripheral blood blast was 5% (0–78%). The majority (41 pts) received fludarabine (FLU)/melphalan (MEL) for conditioning. Four pts received FLU with either 200G total body irradiation (TBI) (3 pts) or busulfan (1 pt) and one received TBI alone. Graft vs. host disease (GVHD) prophylaxis was based on either cyclosporine/mycophenolate mofetil alone or with methotrexate (MTX) (20/10) or tacrolimus/sirolimus +/− MTX (2/14 pts). The graft source was peripheral blood in 43 pts and marrow in 3 pts. Engraftment occurred at a median of 15 days (0–27 days) in 98% of recipients; graft failure occurred in one sibling HCT. Donor engraftment based on DNA analysis ranged from 30–100% at 4–6 wks post-HCT (median 100%) in the 33 analyzed pts. Mortality at day 100 was 10.8%. Acute GVHD (Grade 2–4) occurred in 61% of recipients and chronic GVHD has occurred in 23/33 evaluable pts. With a median follow-up of 24.5 months (m) for surviving pts (4–83 m), 25/46 (64.5%) pts are alive. For remission pts, the 2 yr DFS is 65% (CI 51–76%). For pts who received RI HCT as “salvage”, 34% are DF at 2 yrs. (CI 27–41%). Relapse rates were 11% for remission pts and 60% for non-remission pts. Deaths post HCT were attributed to relapse in 12 pts and treatment related mortality due to GVHD (6 pts) or infection (3 pts). Conclusion: DFS can be improved for older patients with the use of RI HCT as remission consolidation. RIC also provides a meaningful salvage option for pts with IF or early relapse. Evaluation of donor options including both siblings and unrelated donors should be considered during induction for patients with good performance status.

Description: Vascular endothelial growth factor (VEGF) plays a seminal role in neo-angiogenesis. VEGF is present on myeloma cells, and its receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR) are detectable on the surface of neighboring myeloid and monocytic elements. Hence, VEGF is implicated in the pathogenesis of multiple myeloma (MM). Thalidomide, an important agent in the treatment of MM, among its many postulated mechanisms of actions also inhibits VEGF-mediated neo-angiogenesis. We set out to test the feasibility and explore the efficacy of combining an anti-VEGF agent with thalidomide. With the availability of the anti-VEGF antibody rhuMAB bevacizumab, a trial of bevacizumab 10 mg/kg given intravenously every 2 weeks alone (in thalidomide-exposed patients) versus a randomized comparison of bevacizumab +/− thalidomide 50–400 mg/day (in thalidomide naive patients) was initiated by the California Cancer Consortium. Twelve patients (median age:58 years; range:50–75) with initial stages of I (n:2), II (n:2) and III (n: 8), all with refractory MM have been enrolled. Patients received a median of 1 prior regimen (range:0–5). Six patients had failed an autologous stem cell transplant prior to enrollment. In patients who have received bevacizumab alone, grade 3 toxicities included fatigue and neutropenia (1), hypertension (1), and hyponatremia (1). In the group receiving bevacizumab and thalidomide, grade 3 lymphopenia was observed in 1 patient during cycle 3, and one patient was taken off study due to exacerbation of pre-exisiting (diet pill induced) pulmonary hypertension and was considered inevaluable. Median time to progression for the 6 patients treated with bevacizumab alone was 2 (range 1–4) months. Progression-free survival for the 5 evaluable patients treated with bevacizumab and thalidomide is 6 +, 7, 8 +, 10, and 30 + months, with 2 patients still on study and in response. Two of these patients did not progress but were taken off study (one for patient’s choice, and one due to the physician’s choice to pursue a stem cell transplant at 7.5 months, this patient is listed above as in response at 30 + months). Immunohistochemical staining (IHC) revealed 2 + to 4 + expression of VEGF on myeloma cells in 7 cases of the available 8 pre-treatment bone marrow samples. Weak staining (1+) of VEGFR1 was observed on the surface of myeloma cells in 5 cases. VEGFR2 expression was also observed on plasma cells by IHC (1+ to 2+) in 5 cases. Myeloma cells from a patient treated with bevacizumab alone for a duration of 4 months, and from a patient receiving bevacizumab and thalidomide for 7.5 months before going on to transplant, demonstrated the strongest staining intensity for VEGF. Due to slow accrual the study had been closed to accrual, although 2 patients continue on the bevacizumab and thalidomide arm. However, in light of our findings further testing of bevacizumab, preferably in combination with other active agents is warranted. Supported by NO1 CM 17101.

Description: Tipifarnib (R115777, Zarnestra®) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 30 patients have been accrued. with 27 patients evaluable for toxicity. Median age is 64.5 (range 33–75). Grade 3 toxicities were seen at dose levels 1 (400 mg bid)- metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy, and level 5 (1200 mg bid)- grade 3 creatinine elevation. Other grade 1 and 2 toxicities included fatigue, nausea, anorexia, elevated liver enzymes, increased bilirubin, and renal insufficiency. The maximum target treatment dose, 1600 mg PO bid was attained. There were 3 complete responses (CR) out of 9 patients treated at the 1000–1200 mg bid dose level- after cycle 1 in a 47 year old woman with relapsed AML after autologous transplant, with a 10 month continuing remission as of 8/06 (she underwent successful allogeneic transplant); after 2 cycles in a 69 year old man with relapsed AML, who relapsed after 5 months, (with response after retreatment with tipifarnib), and in a 67 year old man with relapsed AML who achieved PR after one cycle and CR after five cycles. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. In AML patients, greater than two fold increase in tipifarnib dosing can be tolerated on this dosing schedule with efficacy perhaps enhanced. Based on these promising results a monotherapy phase 2 or tipifarnib combination study in AML appears warranted.

Description: Biphenotypic acute leukemia is a rare disease accounting for approximately 10% of acute leukemias using the new scoring system. No standard therapeutic approach exists for this entity. In addition, the prognosis for these patients (pts) is poor and thought to be worse than for acute myelogenous leukemia (AML). ASCT may provide improved disease free survival for patients with high risk AML, but its role in BAL is unknown. We undertook a retrospective study of pts with BAL to determine if outcome was similar following ASCT to pts with AML in first remission. Between 7/93 and 2/04, nine patients with BAL who underwent ASCT were identified. Criteria for the diagnosis of BAL was based on the scoring system adapted from the European Group of Immunological Classification of Leukemia. Pts with Philadelphia positive acute lymphoblastic leukemia (ALL) were excluded. Cytogenetics at presentation included 1 pt with deletion7 and trisomy 8, 1 with 11q23, 2 with complex karytoype, 4 with normal cytogenetics ,1 unknown. Six pts were treated with an AML induction of Idarubicin/Cytarabine, two with an ALL regimen Daunorubicin/Vincristine/Prednisone and one with an Idarubicin- AML based first induction, and then a combination of an ALL/AML reinduction at first relapse. Eight pts were in first complete remission (CR) and one pt in second CR at ASCT. Median age at ASCT was 34 years (range 11–60). Median time from diagnosis to ASCT was 3.4 mos (range 1.5–5.2). Seven pts received sibling donor (SIB) and two received unrelated donor (URD) stem cells. Two pts received marrow and seven received peripheral stem cells. The conditioning regimen consisted of 1320cGy total body irradiation (TBI)+VP16 60mg/kg in 6 pts, 1320cGy TBI+Cyclophosphamide 120mg/kg in 1 pt, Fludarabine125mg/m2+Melphalan 140mg/m2 in 2 pts. Seven received a Cyclosporin- based graft versus host disease prophylaxis regimen (GVHD) and two a Tacrolimus- based regimen. Six pts developed grade III GVHD. Two patients died of pulmonary toxicity, one of GVHD, one from infection and one from disease relapse. One year overall survival (OS) is 39%( 95% CI 13–73). The relapse rate at one year was 20%. In conclusion, despite unfavorable cytogenetics in many patients, relapse rates are low following ASCT for BAL and comparable to pts undergoing ASCT for AML. Future approaches include methods to reduce transplant related mortality which was the major cause of reduced survival in this series.