The majority of patients with acute myeloid leukemia (AML) who achieve complete remission (CR) relapse with conventional postremission chemotherapy. Allogeneic stem-cell transplantation (alloSCT) ...might improve survival at the expense of increased toxicity. It remains unknown for which patients alloSCT is preferable.
We compared the outcome of 185 matched pairs of a large multicenter clinical trial (AMLCG99). Patients younger than 60 years who underwent alloSCT in first remission (CR1) were matched to patients who received conventional postremission therapy. The main matching criteria were AML type, cytogenetic risk group, patient age, and time in first CR.
In the overall pairwise compared AML population, the projected 7-year overall survival (OS) rate was 58% for the alloSCT and 46% for the conventional postremission treatment group (P = .037; log-rank test). Relapse-free survival (RFS) was 52% in the alloSCT group compared with 33% in the control group (P < .001). OS was significantly better for alloSCT in patient subgroups with nonfavorable chromosomal aberrations, patients older than 45 years, and patients with secondary AML or high-risk myelodysplastic syndrome. For the entire patient cohort, postremission therapy was an independent factor for OS (hazard ratio, 0.66; 95% CI, 0.49 to 0.89 for alloSCT v conventional chemotherapy), among age, cytogenetics, and bone marrow blasts after the first induction cycle.
AlloSCT is the most potent postremission therapy for AML and is particularly active for patients 45 to 59 years of age and/or those with high-risk cytogenetics.
Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor ...vascular thrombosis with infarction. Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. Results: MTD was 3 mg/m2 tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t1/2(terminal) of 8 to 9 h without accumulation in daily administrations. Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.
Background Allogeneic hematopoietic cell transplantation is considered the preferred post-remission therapy in patients with acute myeloid leukemia cytogenetically defined as being at high risk. To ...substantiate evidence for allogeneic hematopoietic cell transplantation in first complete remission in these high-risk patients we performed a landmark analysis within a single prospective multicenter treatment trial.
By the time of analysis, 2,347 patients had been accrued into the AMLCG 99 trial between 1999 - 2007. Out of this population, 243 patients under 60 years old fulfilled the criteria for high-risk cytogenetics. Landmark analyses were performed with a control cohort, who remained in first complete remission at least the median time from complete remission to transplantation in the intervention group.
After standardized induction therapy, 111 patients under 60 years old achieved complete remission. A matched allogeneic donor was identified for 59 patients (30 sibling donors, 29 unrelated donors). Fifty-five patients received an allogeneic hematopoietic cell transplant after a median time of 88 days in first complete remission. Of the remaining 56 patients, 21 relapsed within 90 days after achieving first complete remission and for 7 patients with relevant comorbidities no donors search was initiated, leaving 28 patients given conventional post-remission therapy as the control cohort. The median follow-up of surviving patients was 60.4 months. Patients with an allogeneic donor had substantially better 5-year overall and relapse-free survival rates than the control group (48% versus 18%, P=0.004 and 39% versus 10%, P<0.001, respectively). A survival benefit from transplantation was evident regardless of donor type, age and monosomal karyotype. Conclusions Beyond evidence available for subgroups of high-risk patients, the findings of this study establish in a broader manner that allogeneic hematopoietic cell transplantation is a preferable consolidation treatment for patients with acute myeloid leukemia and high-risk cytogenetics. The study was registered at Clinicaltrials.gov as NCT00266136.
Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a ...phase 2 study on reduced-intensity myeloablative conditioning with fractionated 8-Gy total body irradiation (TBI) and fludarabine (120 mg/m2). Patients received mobilized peripheral blood stem cells (n = 68) or bone marrow (n = 3) from siblings (n = 39) or unrelated donors (n = 32). Thirty-six patients received a transplant in complete remission (CR) and 35 had untreated or refractory disease (non-CR). Median patient age was 51 years (range, 20-66 years). Sustained engraftment was attained in all evaluable patients. With a median follow-up of 25.9 months (range, 3.7-61.2 months) in surviving patients, probabilities of overall survival for patients who received a transplant in CR and non-CR were 81% and 21% at 2 years, respectively. Relapse-free survival rates were 78% and 16%. The cumulative incidence of nonrelapse mortality (NRM) in CR patients was 8% at 2 years and beyond but amounted to 37% at 2 years in non-CR patients. Outcome data in this poor-risk population indicate that allogeneic HSCT from related or unrelated donors with 8-Gy TBI/fludarabine conditioning is feasible with low NRM and preserved antileukemic activity in AML patients in first or later CR.
Allogeneic hematopoietic stem cell transplantation (allo-SCT) from an HLA-identical sibling donor (SIB) is considered the preferred postremission therapy for younger patients with HiRi AML in CR1. ...The role of allo-SCT from volunteer unrelated donors (VUDs) is less clear and randomized controlled trials addressing this issue do not exist. We performed an observational landmark analysis on parallel cohorts of patients aged <60 years with AML in CR1 and HiRi cytogenetics who had been enrolled into the AML Cooperative Group (AMLCG) 1999 trial. 2347 patients were evaluable for the present update. 243/2347 patients were <60 years of age and had unfavorable cytogenetics complex karyotype, -5/5q-, -7/7q, abnormal 3q21/3q26, or abnormal 11q23. 111 of the 243 patients (45.7%) achieved CR1 after double induction with either TAD-HAM (123) or HAM-HAM (120). Of those 111 patients, 21 received an allo-SCT from a SIB while in first or higher CR (16 in CR1) and 34 were transplanted from a matched VUD in first CR (25; ≥6/10 HLA match: n=8, ≥8/10 HLA match: n=17) or higher CR (9). Of the 56 CR1 patients receiving conventional postremission therapy, 37 with relapse-free survival (RFS) ≥90 days were eligible for the control cohort. The 90-day landmark was set in order to account for the median time from entry into CR1 to transplant in the two allo-SCT groups. Median age in the SIB allo-SCT group was 46 years (range: 25–58), in the VUD cohort 45 (21–58), and in the control cohort 49 (22–59). Overall survival (OS) at 2 years for the SIB cohort was 68% (95% CI: 43–92%), for the VUD cohort 59% (95% CI: 38–81%), and for the control group 28% (95% CI: 13–44%). Projected RFS and OS at 4 years for the SIB allo-SCT cohort were 23% and 45%, for the VUD allo-SCT cohort 39% and 44%, and for the control group 14% and 25%, respectively (RFS: p=0.02; OS: p=0.03; log-rank test for differences between groups). The 4 year OS after any allo-SCT (SIB or VUD) is 48% versus 25% in the control group (p=.009). In a Cox regression model, survival end points in HiRi AML patients in CR1 were influenced by patient age and type of postremission therapy only. Hazard ratios (HRs) for RFS were 0.6 (95% CI: 0.3–1.3: p=.19) for SIB allo-SCT and 0.4 (0.2–0.8; p<.01) for VUD allo-SCT, respectively, versus the control group in a model including patient age. HRs in OS were 0.6 (0.2–1.3; p=.16) for SIB allo-SCT and 0.4 (0.2–0.9; p=.03) for VUD allo-SCT. Despite the limitations inherent to this type of analysis and the limited numbers of patients, we consider the data as best available controlled evidence that patients <60 years of age with HiRi AML in CR1 benefit from allo-SCT as postremission consolidation with the results of VUD allo-SCT in this setting being at least comparable, if not superior to those achieved with SIB allo-SCT.
Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that elevates plasma 2′-deoxyguanosine (dGuo) and intracellular deoxyguanosine triphosphate ...(dGTP) levels, leading to T-cell apoptosis. It has shown promising clinical activity in patients with T-cell malignancies. Here we describe our experience with three patients with refractory or relapsed T-cell acute lymphocytic leukemia (T-ALL) who received IV forodesine before or after allogeneic transplant (pts. treated within an ongoing study from BioCryst Pharmaceuticals, Inc, Birmingham, Alabama, USA; ClinicalTrials.gov Identifier: NCT00095381).
Methods: Forodesine was given at 40 mg/m2 for 5 days per week (1 cycle) for ≥6 cycles. Patients 1 and 2 received forodesine at 443 and 161 days after allogeneic hematopoietic stem cell transplantation (HSCT), respectively. Patient 3 received forodesine until 4 days before conditioning therapy prior to allogeneic HSCT.
Results: Patient 1 with T-ALL was transplanted in the 2nd CR (10/10 HLA-identical sibling donor), after conditioning therapy and developed extensive wide-spread nodal relapse. After 2 weeks of forodesine, he had a very good partial response. The patient developed new-onset chronic graft-versus-host disease (GVHD) of the oral mucosa and lung during treatment. After 6 cycles, treatment was stopped and corticosteroids were given for the GVHD. This patient has been in CR3 (minimal residual disease MRD-negative by molecular analysis and complete donor cell chimerism) for >6 months and is no longer receiving immunosuppressives. Patient 2 is a 3-year-old girl with T-ALL who, following two induction failures, proceeded to uncomplicated 6/6 unrelated marrow transplantation in CR1. She had a bone marrow relapse 5 months after transplantation and was started on forodesine on study. After 2 weeks of treatment she achieved a CR, was MRD-negative by flow cytometry, and had 100% donor chimerism. By the middle of week 3 of treatment, she developed GVHD of the liver and was treated with cyclosporine and prednisone. Twice-weekly forodesine was restarted, and all laboratory parameters returned to normal and repeat bone marrow showed continuous CR2. This patient received forodesine twice weekly for 9 additional months and remains in CR with 100% donor chimerism for >12 months (she is no longer receiving forodesine). Patient 3, who had refractory T-ALL and disease progression shortly after relapse therapy with cladribine, cytarabine, and V16, achieved stable remission after 2 weeks of forodesine and completed 6 weeks of treatment. He then received conditioning therapy followed by an HSCT from a 10/10 HLA-identical sibling donor, and remains in CR2. No drug-specific adverse events of grade 2 or higher were seen in these patients.
Conclusions: These encouraging experiences in patients with relapsed and refractory T-ALL suggest that forodesine monotherapy can be effective before and after allogeneic HSCT with minimal toxicity and without affecting potential graft-versus-leukemia effects.
Forodesine Treatment in Patients before and after Allogeneic HSCTPatient No.Age/GenderDiagnosisHSCT (prior/post forodesine Tx)ResponseDisease Status128/MT-ALL, relapsePriorPRCR ongoing 215+ days23/FT-ALL, relapsePriorCRCR ongoing 398 + days327/MT-ALL, refractoryPostCRCR ongoing 180+ days
Seventy-one patients with acute myeloid leukemia (AML), most of them (63/71) considered ineligible for conventional allogeneic hematopoietic stem cell transplantation (HSCT), were enrolled into a ...phase II study on reduced intensity myeloablative conditioning with fractionated 8 Gy total body irradiation (TBI) and fludarabine (120 mg/m2) (Blood. 2005 Nov 1;106(9):3314–21). Patients received mobilized peripheral blood stem cells (n=68) or bone marrow (n=3) from siblings (n=39) or unrelated donors (n=32). HLA-typing was performed for HLA-A, -B, -Cw (serological matching or intermediate resolution DNA typing), DRB1 and DQB1 (high resolution DNA typing). Three patients had unrelated donors with an allele mismatch in HLA DRB1 (2 with an additional mismatch in HLA Cw) and 7 patients were transplanted from unrelated donors with an antigen mismatch in HLA Cw. Thirty-six patients were transplanted in complete remission (CR) and 35 with untreated or refractory disease (non-CR). Median patient age was 51 years (range, 20–66). Sustained engraftment was attained in all evaluable patients. With a median follow-up of now 41.3 months (range, 20.4–70.4) in surviving patients, probabilities of overall survival for patients transplanted in CR and non-CR were 80% (95% CI, 66 to 94%) and 17% (95% CI, 5 – 29%) at 4 years, respectively. Relapse-free survival rates were 57% (95% CI, 39 – 75%) and 14% (95% CI, 2 – 26%). Of the 35 evaluable patients transplanted in CR, 10 patients suffered a relapse between days 68 and 868 after transplantation (cumulative incidence 29%). Five patients with late relapse (>1 year after transplantation) achieved a subsequent CR after conventional chemotherapy, blood stem cell boost and treatment with granulocyte-macrophage colony-stimulating factor, lasting 2000+, 1841+, 909+, 847+ and 480 days, respectively. Depending on donor type, relapse-free survival was similar in patients transplanted from unrelated or sibling donors. Overall survival in patients transplanted in complete remission from unrelated vs. sibling donors was 84% (95% CI, 73 – 95%) vs. 77% (95% CI, 68 – 86%). The cumulative incidence of non-relapse mortality (NRM) in CR patients was 11% at 4 years and beyond (3 patients deceased before day 100 and 1 patient 25 months after transplantation), but amounted to 37% at 4 years in non-CR patients. Nine of the 33 surviving patients (27%) have actually active chronic GvHD (5 limited and 4 extensive disease). This update confirms that allogeneic HSCT from related or unrelated donors with 8 Gy TBI/fludarabine conditioning is feasible with low NRM and preserved long-term antileukemic activity in AML patients in first or later CR.
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