Term Disease Free Survival Research Articles

Factors Predicting Long Term Survival after Reduced Intensity Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia.

Allogeneic stem cell transplantation (SCT) performed using a reduced intensity conditioning (RIC) regimen represents an important new treatment modality in older patients with high risk acute myeloid leukaemia (AML) whose outlook with conventional chemotherapy would be poor. However assessment of its role has been hampered by the absence of long term follow-up data. Furthermore factors determining survival after RIC SCT have not been rigorously defined. In order to examine the anti-leukemic activity of RIC allografts in more detail we have examined the outcome of 170 patients with AML transplanted using a uniform conditioning regimen over a ten year period. Long term follow-up data (maximum 119 months) was collected on patients transplanted using a conditioning regimen consisting of fludarabine (30 mg/m2 x 5 days), melphalan 140 mg/m2 x 1 day and alemtuzemab (10 mg x 5 days). The median age of transplanted patients was 54 years (range 18–71). 88 patients were in CR1 at the time of transplant, 63 CR2/3 and 19 had relapsed or refractory disease. Cytogenetic information was available on 149 patients and of these 33 patients had adverse risk and 116 intermediate risk cytogenetics by MRC criteria. 83 transplants were performed using an HLA identical sibling donor and 87 using a volunteer unrelated donor. The 100 day transplant related mortality was 9%. 29% of patients developed Grade II-IV acute GVHD and 22% chronic GVHD. The 3 year overall survival (OS) for the whole group was 48% and 3 year disease free survival (DFS) 45%. 20 patients remain in remission more than five years post-transplant. Survival was significantly influenced by status at transplant (p=0.01), patient age (p= 0.01) and presentation cytogenetics (p=0.05) as determined by multivariate Cox proportional hazards regression. The 3 yr OS for patients transplanted in CR1 or CR2 was 51% and 52% respectively compared to 13% for patients with relapsed/refractory disease. Three year OS for patients with intermediate risk cytogenetics was 52% compared with 34% for adverse risk patients. Three year OS for patients under 60 years was 51% compared with 36% for older patients. This study demonstrates the ability of RIC allografts to deliver encouraging long term disease free survival rates in high risk AML. Pre-transplant characteristics can be used to predict outcome after a RIC allograft and older patients with active disease at the time of transplant or adverse cytogenetics require novel strategies in order to improve long term survival.

Expression of the Cancer-Testis Antigens, SEMG 1 and Protamine 1, in Early CLL: Their Relationship to Disease Stage and Zap 70 Expression.

Despite advances in modern chemotherapy, CLL remains incurable. CLL is an indolent disease. It expresses a panel of Cancer-Testis (CT) antigens. CLL leukemia cells are susceptible to the cytotoxicity of T cells. CLL is, therefore, an ideal disease for immunotherapeutic approaches. Immunotherapy, in addition to being less toxic and more specific than chemotherapy, provides a different mode of cytotoxicity that may synergize with that induced by chemotherapeutic agents. Immunotherapy also offers the prospect of inducing immune memory that may be important for long term disease-free survival of patients with CLL. However, there are obstacles that may prevent successful immunotherapy. CLL patients are generally immunosuppressed even before any therapy is given and the immunosuppression increases as the disease progresses. Therefore, any immunotherapeutic approaches for CLL should be aplied in early disease when immunosuppression is least encountered. We previously demonstrated the expression of a CT antigen, SEMG 1, in 3/9 patients with CLL. Furthermore, we also demonstrated that the presence of high titer IgG in the serum of patients expressing SEMG 1, suggesting the in vivo immunogenicity of SEMG 1 in the cancer-bearing autologous host. We have also recently used SEMG 1 as the bait in a yeast two-hybrid system of testicular cDNA library and identified that Protamine 1 is the interacting ligand of SEMG 1 and that Protamine 1 is also a novel CT antigen, suggesting that both SEMG 1 and Protamine 1 may be suitable antigens for tumor vaccine development. However, the expression of SEMG 1 and Protamine 1 in early CLL is unknown. We have in this study set out to determine whether or not SEMG 1 and/or Protamine 1 could be used for the design of tumor vaccine for the targeting of patients with early CLL, in particular, those with poor risk disease, as predicted by Zap 70 expression. Using pairs of sequence-specific primers in RT-PCR on a cohort of CLL (41 Stage 0/I and 6 Stage II/III), we found that SEMG 1 gene is expressed in 24/47 (51%) and Protamine 1 in 16/47 (34%) of CLL patients. Gene expression in most cases was associated with the detection by immunocytochemistry of SEMG 1 and/or Protamine 1 in the CLL cells. The expression frequency of SEMG1 and Protamine 1 in CLL did not appear to differ between early and late stage disease. 19/41 of patients with early stage disease and 5/6 of patients with late disease expressed SEMG 1; 12/41 of patients with early stage disease and 4/6 patients with late disease expressed Protamine 1. Furthermore, the expression of these antigens was equally distributed between Zap 70+ and Zap 70− CLL. SEMG 1 was expressed in 4/6 of Zap 70+ CLL (all 6 had early disease) and 2/9 of Zap 70− CLL (1/8 early disease and 1/1 late disease). Interestingly, although Protamine 1 expression in CLL predicted for SEMG 1 co-expression, only 67% of SEMG 1+ CLL expressed Protamine 1. Our results, therefore, suggest that both SEMG 1 and Protamine 1 are suitable targets for tumor vaccine development for some patients with early CLL, especially those with high risk disease, as predicted by Zap 70 expression.

Brachytherapy Monotherapy for Older Men with Prostate Cancer

Men with low-risk localized prostate cancer are presented with several definitive treatment choices: radical prostatectomy, external-beam radiotherapy or brachytherapy. Although these three treatment choices confer a statistically equivalent likelihood of long- term disease-free survival, these therapies differ in their acute and long-term side-effect profiles. Brachytherapy is a minimally invasive radiotherapy procedure, and is an excellent treatment in men who do not want, or are unable to tolerate, a prostatectomy. The following article will present an overview of the epidemiology of prostate cancer, brachytherapy eligibility and a description of the techniques, side effects and efficacy, with a special emphasis on applicability to older men.

End Points for Colon Cancer Adjuvant Trials: Observations and Recommendations Based on Individual Patient Data From 20,898 Patients Enrolled Onto 18 Randomized Trials From the ACCENT Group

The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.

Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2

BackgroundThe HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses.MethodsSubjects with stage II (≥ 6 +LN), III, or stage IV breast cancerwith > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact.ResultsAll seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6–6.7 years of follow-up.ConclusionAlthough this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population.Trial RegistrationClinicalTrials.gov NCT00005956

Therapy of Relapsed Hodgkin Lymphoma

The majority of patients who are diagnosed with Hodgkin lymphoma (HL) will be cured with primary chemotherapy. For those who relapse, autologous stem cell transplantation (ASCT) has become the standard of care. Randomized clinical trials have demonstrated that approximately 50% of patients with chemosensitive relapsed HL can achieve long term disease free survival with ASCT. However, optimal therapy of those who have chemorefractory disease or who relapse after an ASCT has not been established. Reduced intensity allogeneic stem cell transplantation may benefit these patients, although a definite graft versus HL effect has not been demonstrated and treatment-related mortality remains relatively high. New salvage regimens that incorporate gemcitabine, vinorelbine, rituximab, and/or monoclonal antibodies against CD30 are being investigated.

Long term disease-free survival in acute leukemia patients recovering with increased γδ T cells after partially mismatched related donor bone marrow transplantation

Allogeneic stem cell transplantation (ASCT) has improved leukemia-free survival (LFS) in many but not all patients with acute leukemia. This is an eight-year follow-up to our previous study showing a survival advantage to patients with an increased gammadelta T cells following ASCT. gammadelta T cell levels were collected prospectively in 153 patients (acute lymphoblastic leukemia (ALL) n = 77; acute myelogenous leukemia (AML) n = 76) undergoing partially mismatched related donor ASCT. Median age was 22 years (1-59), and 62% of the patients were in relapse at transplant. Patient-donor human leukocyte antigen (HLA) disparity of three antigens was 37% in the graft-versus-host disease (GvHD) and 29% in the rejection directions. All patients received a partially T cell-depleted graft using T10B9 (n = 46) or OKT3 (n = 107). Five years LFS and overall survival (OS) of patients with increased gammadelta compared to those with normal/decreased numbers were 54.4 vs 19.1%; P < 0.0003, and 70.8 vs 19.6% P < 0.0001, respectively, with no difference in GvHD (P = 0.96). In a Cox multivariate analysis, normal/decreased gammadelta (hazard ratio (HR) 4.26, P = 0.0002) and sex mismatch (HR 1.45 P=0.049) were associated with inferior LFS. In conclusion, gammadelta T cells may facilitate a graft-versus-leukemia (GvL) effect, without causing GvHD. Further evaluations of this effect may lead to specific immunotherapy for patients with refractory leukemia.

370: Fludarabine-busulphan reduced intensity conditioning (RIC) identical sibling allogeneic stem cell transplantation (allo-SCT) in high risk acute myeloid leukemia and myelodisplastic syndrome

Background-purpose: The use of reduced intensity conditioning regimen (RIC) may reduce non-relapse mortality (NRM) and allow long term disease free survival (DFS) and overall survival (OS) through graft versus leukemia (GVL) effect in patients considered not eligible for convenitonal allogeneic stem cell transplantation (Allo-SCT). In this multicenter, prospective study we report our experience wit RIC regimen based on fludarabine and busulfan. Patients and methods: We included all 93 consecutive patients with AML and MDS who underwent fludarabine-busulphan RIC-Allo-SCT from an HLA identical sibling, in 6 Spanish centers since 1998 to 2005.

Allogeneic Stem Cell Transplantation (ASCT) in CML with Partial T-Cell Depletion, No Prophylaxis for Graft-Versus-Host Disease (GvHD) and Preemptive DLI for Patients with Post-Transplant Minimal Residual Disease (MRD): An Alternative Approach in CML Transplantation with Low Morbidity and Long Term Disease Free Survival.

The introduction of imatinib mesylate has revolutionized the treatment of CML, but despite significant cytogenetic responses primary therapy failure and emergence of resistance pose a major obstacle to successful treatment. ASCT still has a pivotal role in the treatment of CML and reduction of morbidity and mortality remains an important focus of ongoing studies in CML. We conducted a prospective study with ablative conditioning and partial T cell depleted ASCT from a matched sibling donor with no post-transplant GvHD prophylaxis. This was followed by an escalated donor lymphocyte infusion (DLI) administered if there was evidence for the presence of MRD, as determined by FISH and PCR/RQ-PCR for bcr-abl. Patients and methods: 40 consecutive patients underwent ASCT for CML between 1999–2005. The transplant regimen contained busulfan (12mg/kg), cyclophosphamide (120 mg/kg), anti-thymocyte globulin (ATG-Fresenius) (25mg/kg) and fludarabine (200mg/kg) followed by an infusion of ≥5×106/kg of G-CSF-mobilized and positively selected CD34 cells and 1×105/kg T cells. No post-transplant GvHD prophylaxis was given. The presence of MRD was determined every 3 months. DLI was administered in escalated doses starting with 3×106/kg and escalating in increments up to 1×108/kg. Results: 40 patients, median age 38 (19–63), 35 transplanted in first chronic phase (CP), 1 in second CP and 4 in accelerated phase. Patients were transplanted at a median of 4 months from diagnosis (1–66). The median of positively selected CD34+ cells was 9×106 cells/kg (5–24). 39 patients engrafted neutrophils at a median of 11 days (9–25) and platelets at a median of 15 days (9–134). Primary non-engraftment occurred in one patient and late graft failure in two, all salvageable by back-up marrow in two patients or donor stem cell boost in a single patient. The median follow-up of the entire cohort is 44 months (6–84).Overall Survival80%Transplant Related Mortality (TRM)day 1005%day > 10010%Acute GvHDPost transplant (n = 38)Post DLI (n= 24)grade I-II21%21%grade II-III08%grade IV00Chronic GvHDPost transplant (n = 38)Post DLI (n= 24)limited2.6%16%extensive00Need for DLIOne dose63%Two doses31%≥ Three doses16%Disease-Free SurvivalMajor cytogenetic response6%Major molecular response6%Complete cytogenetic and molecular response88%Disease Progression10%None of the patients developed significant VOD. Post transplant acute GvHD developed in only 21% of patients and was confined to grade I–II, all responding to a short course of immunosuppression. Additional 7 out of the 24 patients receiving DLI developed acute GvHD. There was no grade IV or mortality from GvHD. At the time of this analysis all apart from 1 patient were able to stop immunosuppressive treatment for GvHD. There were no significant infectious complications in this group. All late TRM were secondary to autoimmune complications, unrelated to GvHD, and occurred in 5 patients (13% of all) at 6–14 months post transplant. These complications included: ITP, AIHA, autoimmune pneumonitis, nephritic syndrome, TTP and Kaposi sarcoma. The mortality from these complications was 80% (4 out of 5 patients). 4 patients developed blast crisis post transplant; 2 patients have died; and the others are currently in CR post salvage treatment, DLI and imatinib. Twenty five percent of patients attained complete molecular remission without ever needing DLI, while 75 % responded after DLI, mostly following a single dose. Two patients are in major cytogenetic response, one of whom received back-up marrow and for the other a DLI donor is not available. The two patients in major molecular response are awaiting DLI. Conclusions: Matched ASCT for CML can be performed with significantly reduced TRM and morbidity using partial T cell depletion, no GvHD prophylaxis and preemptive DLI. This regimen offers > 80% long-term curative potential. Programmed DLI is safe and associated with a low risk of GvHD. The late immunological complications pose a major risk. This appears to be related to an imbalance between B and T cell reconstitution and the precise mechanisms of this need to be elucidated. In the imatinib era ASCT using this approach may be reserved for patients not responding or resistant to the imatinib mesylate.

Long Term Follow-Up of the Gimema GSI 103 AMLE Randomized Trial: Daunoxome Seems To Improve Disease-Free Survival (DFS) of Elderly Patients with Acute Myelogenous Leukemia (AML).

The GSI 103 AMLE was a randomized phase III clinical trial to explore the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) standard treatment in AML elderly patients. From 10/2001 to 2/2004, 301 patients aged 61 to 75 years with a diagnosis of AML according to WHO classification and eligible for intensive chemotherapy were enrolled in this trial by 39 GIMEMA Centers. Patients were randomized to receive induction treatment with DNR (45 mg/sqm day 1 to 3) or DNX (80 mg/sqm day 1 to 3) plus AraC (100 mg/sqm day 1 to 7 by continuous infusion): as consolidation therapy, patients in CR received a further course of the assigned induction treatment. After the consolidation course, patients in CR underwent a 2nd randomization independently from the 1st random, to receive as maintenance therapy either AraC (20 mg twice daily day 1 to 10) plus all-trans retinoic acid (ATRA) (45 mg/sqm day 1 to 10) every 28 days for a maximum of 12 cycles (Arm A) or no further treatment (Arm B). 153 patients were enrolled in the DNR arm and 148 in the DNX arm: the two arms were comparable as to relevant patient characteristics, including karyotype. In the DNR arm, 77 patients (50.3%) achieved CR, 56 (36.6%) were resistant and 20 (13.1%) died during induction (ID). In the DNX arm, 73 patients (49.3%) achieved CR, 47 (31.8%) were resistant and 28 (18.9%) died during induction. Differences between the two arms at univariate analysis were not statistically significant either considering the 3 different types of response or considering ID versus other (Chi-square 0.34 and 0.17 respectively). After CR, the effect of DNX seems to be time-related, due to higher incidence of early deaths in CR (11% vs 3%, p=0.053) and lower incidence of relapse beyond 6 months (at 24 months 60% vs 80%, p=0.064). This translates in a cross of the OS and DFS curves between the two arms, with initial advantage for the DNR arm followed by an advantage for DNX arm after 12 months from diagnosis. A time-dependent covariate Cox model and a landmark analysis on patients in CR after 6 months revealed a better outcome of DNX patients (p= 0.029 and p=0.092, respectively) in the long term DFS follow-up. No difference has been observed in the DFS curves according to maintenance randomization. In conclusion, DNX is as effective as DNR in the induction phase of AML elderly patients, with a trend of increased early toxicity (ID + deaths in CR): however, DNX seems to improve the OS and DFS in the long-term follow-up of these patients, due to a reduction of late relapses. Further trials in more selected elderly patients or in younger patients will be helpful to define the exact role of DNX in AML.

Long term disease-free survival resulting from combined modality management of patients presenting with oligometastatic, non-small cell lung carcinoma (NSCLC)

We report outcomes on 23 patients with oligometastastic (1 or 2 sites) NSCLC treated with aggressive local, regional, and systemic treatment. The results suggest that this is a favorable subset of patients who may benefit from such an approach, with a 22% rate of long-term survival. This treatment strategy is a departure from the usual practice of palliative-only therapy for all NSCLC patients presenting with metastatic disease.

Mantle cell lymphoma (MCL): Induction therapy with HyperCVAD/High-dose methotrexate and cytarabine (M-C) (±rituximab) improves results of autologous stem cell transplant in first remission

7511 Background: Although patients (pts) with MCL have a high response rate to standard chemotherapy, they continue to relapse with no plateau in long term disease-free survival. The use of dose intense induction therapy such as HyperCVAD (M-C) ±Rituximab(R) and high-dose therapy and stem cell may improve these results. In this analysis the outcomes of pts receiving a standard anthracycline induction therapy or HyperCVAD(M-C)(±R) then followed by a stem cell transplant in first complete (CR1) or partial remission (PR1) were compared. Methods: Between 6/91 and 11/05, 124 pts with MCL received high-dose chemotherapy and a stem cell transplant. Of these pts, 80 received an autologous stem cell transplant in CR1 (N = 47) or PR1 (N = 33). A standard anthracycline based CHOP-like (±R) induction therapy was given to 48 pts compared with 32 pts who received HyperCVAD(M-C)(±R) prior to transplant. Results: The median age of pts was 56 years (range 33–70). The male:female ratio was 33:57. Bone marrow involvement prior to conditioning was present in 52% of pts. An elevated lactic dehydrogenase (LDH) was present in 58% of pts. 65% of patients received one prior chemotherapy before coming to stem cell transplant. The median follow up of pts is 38 months (range 3–143). Progression-free survival (PFS) and overall survival (OS) are outlined in table 1 . Characteristics associated with an improved OS by multivariate analysis included receiving HyperCVAD induction (p = 0.04), transplant in CR1 (p = 0.009), ≤ 3 prior chemotherapy regimens (p = 0.02) and no B symptoms at transplant (p = 0.05). Conclusions: To improve the long term disease free survival for pts with MCL, Hyper-CVAD(M-C)(±R) induction should be given to eligible patients with autolgous stem cell transplantation in CR1. [Table: see text] No significant financial relationships to disclose.

Haploidentical stem cell transplantation for children with acute leukaemia

Some children with relapsed or high-risk acute leukaemia have an improved outcome if they have an allogeneic stem cell transplant, preferably from a sibling or well-matched unrelated donor. However, some children do not have these options or there is an urgent need to proceed to transplant because of disease status. We have investigated the role of haploidentical family members as donors in 34 patients with acute leukaemia (median age 11 years, range 1-16 years). Patients were conditioned with cyclophosphamide and total body irradiation (14.4 Gy in eight fractions) and received T-cell depleted peripheral blood stem cell grafts with a median CD34 cell dose of 13.8 x 10(6)/kg (range 4.2-35.1) and 0.7 x 10(4) CD3-positive cells/kg. The actuarial survival at 2 years was 26% (13-41%, 95% CI). Eight patients have survived disease-free with a median follow up of 62 months. They have good performance status and a median lymphocyte count of 1.8 x 10(9)/l. Relapse (14 patients) and adenoviral (six patients) or fungal infections (four patients) were the major causes of death. Haploidentical stem cell transplantation can produce medium term disease-free survival in a proportion of children with high-risk or relapsed acute leukaemia. None of the nine patients with acute myeloid leukaemia not in remission have survived.

2-CdA in the treatment of hairy cell leukemia: a review of long-term follow-up

Hairy cell leukemia is a rare, indolent, chronic lymphoproliferative disorder characterized by the proliferation of a malignant B-cell clone with irregular cytoplasmic projections. Treatment with purine analogs such as 2-chlorodeoxyadenosine (2-CdA) is associated with excellent remission rates and long-term survival. Although the majority of patients achieve a complete remission (CR), most have minimal residual disease detected by sensitive methods. Despite the long term disease-free survival, approximately 36% of patients relapse and many require further therapy. Repeat administration of 2-CdA is very effective in achieving a second CR. Recently, new agents such rituximab and BL22 were shown to be effective in the treatment of relapsed and refractory disease.

Long-Term Follow-Up Results of Adults with T-Cell Acute Lymphoblastic Leukemia (T-ALL)-The Vancouver Experience.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease accounting for approximately 20–25% of adult cases of ALL. The outcome of adult T-ALL has improved in the past decades, but relapse remains the major cause of treatment failure. Few studies have reported on the long-term outcome of adults with T-ALL. We retrospectively reviewed the charts of 39 adult patients (pts) diagnosed with T-ALL and treated at our center between August 1986 and April 2004.Characteristics: Male/female ratio was 3.3/1. Median age was 28.4 years (16.8–73.2). ECOG PS: 0/1(n=27), ≥ 2 (n=12). Median WBC at diagnosis was 12.2 (0.9–445), Platelets 60.7 (6–270), LDH <2 x normal (n= 14), ≥ 2 x normal (n=23), unknown (n=2). CSF was involved in 7/39 pts, splenomegaly found in 13/39, mediastinal mass in 16/39 and lymphadenopathy in 16/39 pts. 36/39 pts received a consistent induction chemotherapy regimen consisting of prednisone, vincristine and daunorubicin ± L-asparaginase. A second phase of induction comprised of cyclophosphamide, cytarabine, methotrexate and mercaptopurine. Intensification was with dexamethasone, vincristine, daunorubicin, cyclophosphamide, cytarabine and thioguanine. Four cycles of consolidation with cytarabine and tenoposide were given. 30/39 pts (77%) achieved complete remission with induction chemotherapy. 1 patients died during induction chemotherapy secondary to disseminated aspergillosis, 2 patient during consolidation secondary to cerebral edema and aspergillosis. 8/30 pts proceeded to allogeneic BMT in CR1(4/8 due to high WBC>150, 3/8 MRD availability,1/8 in CR1 after salvage chemotherapy) of whom two pts died due to aGVHD and infection after transplantation. 8 pts had refractory disease; Only 1/8 achieved CR on salvage chemotherapy. 16/30 (53%) relapsed of whom 12/16 (75%) died of disease progression, 1 died of sepsis in CR2 and 3 pts alive in CR2. Median follow up of the 15 surviving patients is 59 months (1.5–183.4).Results: Overall survival (OS) and event-free survival (EFS) at 3 years for all patients were 33.7% (95% CI 19–49%) and 28% (95% CI 13–43%) respectively. Using univariate analysis, significant factors for poor survival were CSF involvement: [3-year EFS was 14% vs 34% (p = 0.05)], LDH levels higher than 2 times normal [3-year EFS was 7% vs 43.5% (p = 0.005)] and ECOG PS ≥2: [3-year EFS was 16.6% vs 37% (p = 0.05)]. Non-significant factors included sex, age < 30 vs 30–55, presence of mediastinal mass, lymphadenopathy, splenomegaly, WBC > 50.Conclusions: Adult T-ALL presents more commonly in young males with a third having a mediastinal mass. The outcome of treatment results in a 30% long term disease free survival. Patients refractory to induction as well as those who relapse have poor prognosis. As expected poor PS, high LDH and CSF involvement dictates worse outcome. Neither age, nor high WBC count contributed to worse prognosis.

Long Term Survival of Patients with Chronic Myelocytic Leukemia after Allogeneic Stem Cell Transplant Using a Reduced Intensity Regimen of Melphanlan, Lomustine and Cyclophosphamide.

Introduction: Non-ablative regimens have been shown to be effective and less toxic than traditional ablative regimens, but they usually need close monitoring and skillful manipulates e.g. donor lymphocyte infusions. In the present study, we used a novel reduced intensity regimen with melphanlan, lomustine and cyclophosphamide to treat patients with chronic myelocytic leukemia and made a long term follow-up.Methods: 14 patients with median age of 35(23~52) were treated with MCC regimen(Melphanlan 170 mg/m2/d×1, Lomustine 400 mg/m2/d×1, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 6 years; another 16 patients with median age of 33(16~44) were treated with BuCy regimen(Busulfan 4 mg/kg/d×4, Cyclophosphamide 60 mg/kg/d×2) and the median follow-up time is 4 years.Results: All the patients were engrafted successfully and the platelet recovery to 20×109/L was earlier at median 3 days in patients with MCC regimen. 4 of 10 patients examined in MCC group showed mixed chimerism at day 100 post transplant, whereas only 1 of 12 patients examined in BuCy group showed mixed chimerism. All the patients became complete donor sources later without any DLI. The regimen related toxicity was relatively lower in MCC group, especially the incidence and severity of mucositis and liver dysfunction were decreased significantly. The median duration of hospitalization was 39 days (25~55)for patients with MCC regimen, and 55 days (39~90) for BuCy regimen. The 5 year disease-free survival was 71.4% for MCC group and 62.5% for BuCy group, respectively. The transplant related mortality and relapse rate were 21% and 7% for MCC regimen, whereas 25% and 12% for BuCy regimen.Conclusions: MCC regimen is an effective and less toxic conditioning regimen and the long term disease-free survival is as the same as that of BuCy regimen. Considering the cost-effect efficacy, MCC regimen may have some prominent advantages over BuCy regimen. [Display omitted]

Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning (RIC) Regimen Has the Capacity To Produce Durable Remissions and Long Term Disease-Free Survival in Patients with High Risk Acute Myeloid Leukemia (AML).

The toxicity of allogeneic stem cell transplantation (SCT) can be substantially reduced by the use of a reduced intensity conditioning (RIC) regimen and this has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with AML and MDS has not yet been defined and consequently their role in the management of these diseases remains conjectural. Seventy-six patients with high risk AML or MDS were allografted using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range 18–71 years). There were 46 males and 30 females; 41 patients received an allograft from an unrelated donor and 35 from a matched sibling donor. The 100 day transplant related mortality was 9% and no patient developed greater than Grade 2 graft-versus-host disease (GVHD). With a median follow-up of 36 months (range 13–70 months) 27 patients were alive and in remission with a 3y actuarial overall survival (OS) and disease-free survival (DFS) rate of 41% and 37% respectively. The 3y OS and DFS of patients with AML in complete remission (CR) at the time of transplantation was 48% and 42% respectively. In a multivariate setting, Cox regression analysis demonstrated prognostic significance of disease stage at the time of transplant with improved DFS in patients with AML in CR at the time of transplantation (HR=2.03, 95% CI=1.02–4.07). Disease relapse was the commonest cause of treatment failure occurring at a median time of 6 months post-transplant. Fourteen out of 27 (52%) patients relapsed within 6 months and 23/27 (85%) within twelve months defining a relatively narrow window for therapeutic intervention to prevent disease recurrence. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts are capable of producing sustained disease free survival in a significant number of patients with AML who would be ineligible for allogeneic transplantation using a myeloablative conditioning regimen.

A phase II study of cisplatin plus epirubicin salvage chemotherapy in refractory germ cell tumors

4526 Background: Initial cisplatin combination chemotherapy will cure 70% of patients with disseminated testicular cancer. Approximately 1/3 will be cured with subsequent salvage therapy. This phase II clinical trial evaluated the combination of cisplatin plus epirubicin in patients with refractory germ cell tumors (GCT) not amenable to cure with standard salvage therapy. Methods: Between march 2001 and October of 2004, 24 patients with refractory GCT were enrolled, of which 1 was too early to evaluate. Patients who had progressed within 4 weeks of prior platinum based chemotherapy were ineligible. All pts were male, with median age 36 (range 24–45). Median number of previous regimens was 2 (range 1–3). Five pts had extragonadal non-seminomatous germ cell tumor(NSGCT). Fifteen pts (68%) were late relapses (>2 years). Patients received epirubicin 90mg/m2 day 1 and cisplatin 20 mg/m2 on days 1–5 every 3 weeks for a maximum of four cycles. Support with granulocyte colony stimulating factor (GCSF) or pegfilgrastim was given to all pts. Results: Eighteen of 23 pts (78%) received all four cycles. Toxicity was primarily hematologic: grade 3/4 neutropenia, 3 pts (1 neutropenic fever); 2 pts had grade 3 thrombocytopenia, and 3 pts had grade 3/4 anemia. Non-hematologic toxicity was: grade 3 electrolyte wasting, 2 pts; grade 3 nausea/vomiting, 6 patients; grade 3 diarrhea, 1 patient. There were no cases of severe mucositis or cardiotoxicity, and no treatment related deaths. Twelve of 23 pts (52%) had objective response to therapy. Seven pts achieved a no evidence of disease status (NED), 2 of these after resection of persistent carcinoma, and 1 after resection of persistent teratoma. Five of these 7 pts remained NED at 3+, 3+, 19+, 32+, and 36+ months. Two additional pts remain alive with persistent radiological abnormalities but normal serum markers at +10 and +31 months. Conclusions: Cisplatin plus epirubicin is an active regimen in refractory GCT, with an acceptable toxicity profile. this regimen offers palliation but also a potential for long term disease-free survival in this refractory population. This trial was partially supported by Pharmacia. No significant financial relationships to disclose.

Endpoints for Colon Adjuvant Clinical Trials (CACT): Recommendations based on individual patient data (IPD) from 20898 patients (pts) and 18 randomized trials

3512 Background: The traditional endpoint for CACT is OS, with 5 years (yr) used to demonstrate adequate follow-up (f-u). We have shown previously that disease free survival (DFS) outcomes after 3 yr minimum (min) f-u are excellent predictors of OS results. Here we explore shorter term DFS and OS endpoints, and the stage (stg) dependency of the concordance. Methods: IPD from 18 phase III CACT involving 25 treatment comparison conducted from 1978–96 were pooled. Trials included 43 arms: 9 no chemotherapy (CT) arms and 34 5-FU based CT arms; the pooled sample size was 20898 pts. Concordance measures included correlation (corr) of rates within arms, corr of hazard ratios (HR) from within study comparisons (comp), trial level significance (sig) comp (via log-rank testing), and trial level association from a formal surrogacy model. Results: The table presents primary results for DFS and OS at different time points. DFS with 3yr median (med) (opposed to min) f-u remained an excellent predictor of 5 yr OS. DFS at earlier time points was less accurate in predicting OS, but 2 YR DFS remained a strong predictor. No within trial comp without a sig difference in 1 yr min DFS was sig for 5 yr OS. OS with 3 yr min f-u was the most accurate predictor for 5 yr OS; OS with < 3 yr min f-u suffered from poorer prediction. Association between 3 yr DFS and 5 yr OS was greater for stg III pts; corr of HR within trials was 0.92 for stg III pts, 0.65 for stg II, likely due to a larger proportion of deaths without recurrence for stg II pts (17% stg III, 32% stg II, p < 0.001). Conclusions: DFS outcomes after 2 or 3 yr med f-u are excellent predictors of 5 yr OS outcomes. OS with 3 yr min f-u is the strongest predictor of 5 yr OS, but OS concordance degrades quickly with less f-u. 1 yr DFS comp detected all sig differences in 5 yr OS. DFS results are maximally relevant for trials where the majority of pts are stg III. DFS after 2 or 3 yr med f-u should be considered in designing future CACT. No significant financial relationships to disclose.

Long-term outcomes of autologous stem cell transplantation for follicular non-Hodgkin’s lymphoma: Effect of histologic grade

6567 Background: The potential for long term disease-free survival for patients with recurrent follicular lymphoma receiving high-dose chemotherapy and an autologous hematopoietic stem cell transplant is unknown. Few large studies with extensive follow-up are available for analysis. Methods: Between 7/87 and 6/03, 248 patients (pts) with recurrent follicular non-Hodgkin’s lymphoma (NHL) were treated with high-dose chemotherapy and an autologous stem cell transplant. The median age of the patients was 47 (range 20–67). Sixty-four pts had follicular grade I NHL (FL1), 98 (40%) had follicular grade II (FL2) and 86 (35%) had follicular grade III (FL3). The majority of the patients, 189 (76%) were undergoing transplant > 12 months from the time of their original diagnosis. Pts had received a median of 2 prior chemotherapies and 82% of the patients were chemosensitive to their last chemotherapy regimen. Sixty-seven (27%) of the patients had an elevated lactic dehydrogenase (LDH) at the time of transplant and 81 (35%) of the pts had bone marrow involvement with NHL at the time of transplant. One hundred and ten patients received a chemotherapy only high-dose regimen, 99 received a chemotherapy/total body irradiation regimen, and 39 received a chemotherapy/monoclonal antibody based transplant regimen. Results: The median follow-up of surviving pts is 6.0 years (range 1.0 to 16.0 years). One hundred seventeen patients (47%) have progressed; 80 of whom have subsequently died and 37 remain alive after progression. Thirty-three (13%) have died without NHL progression due to other causes. The overall 5 year event-free survival (EFS) is 44% and the 5 year overall survival (OS) is 63%. The 5 year EFS by histologic grade is FL1 (47%), FL2 (48%), FL3 (36%) (p=0.21). The 5 year OS by histologic type is FL1 (61%), FL2 (70%), FL3 (57%) (p=0.35). Conclusions: Long-term EFS is possible following high-dose chemotherapy and autologous stem cell transplantation for follicular lymphoma. Histologic grade of the follicular lymphoma does not effect the results of the transplant. However, the timing of the transplant does effect outcome with the best results seen in patients in first or second relapse. No significant financial relationships to disclose.