Extramedullary Toxicity Research Articles

Treosulfan-Versus Melphalan-Based Reduced Intensity Conditioning in HLA-Haploidentical Transplantation for Patients ≥ 50 Years with Advanced MDS/AML.

Relapse and regimen-related toxicities remain major challenges in achieving long-term survival, particularly among older patients with high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have demonstrated the feasibility of treosulfan-based conditioning, noting stable engraftment and low non-relapse mortality (NRM) in patients undergoing HLA-matched allo-HSCT. However, data on treosulfan-based conditioning in the HLA-haploidentical transplantation (HaploT) setting are limited. We retrospectively compared conditioning with fludarabine-cyclophosphamide (FC)-melphalan (110 mg/m2) and FC-treosulfan (30 g/m2) prior to HaploT using post-transplantation cyclophosphamide (PTCy) in patients with high-risk MDS/AML patients ≥ 50 years, transplanted from 2009-2021 at our institution (n = 80). After balancing patient characteristics by a matched-pair analysis, we identified twenty-one matched pairs. Two-year OS and LFS were similar among the groups (OS 66% and LFS 66%, p = 0.8 and p = 0.57). However, FC-melphalan was associated with a significantly lower probability of relapse compared to FC-treosulfan (0% vs. 24%, p = 0.006), counterbalanced by a higher NRM (33% vs. 10%, p = 0.05). Time to engraftment and incidences of acute and chronic graft-versus-host disease (GvHD) did not differ significantly. In conclusion, HaploT using FC-treosulfan in combination with PTCy in patients aged ≥50 years with MDS/AML appears safe and effective, particularly in advanced disease stages. We confirm the favorable extramedullary toxicity profile, allowing for potential dose intensification to enhance antileukemic activity.

Gemtuzumab Ozogamicin in Acute Myeloid Leukemia: Efficacy, Toxicity, and Resistance Mechanisms-A Systematic Review.

Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on developing targeted therapies that may allow for improved antileukemic effects while reducing toxicity significantly. Gemtuzumab ozogamicin (GO) is one of the most thoroughly studied molecularly targeted therapies in adults. GO is a monoclonal antibody against CD33 IgG4 linked to the cytotoxic drug calicheamicin DMH. The use of GO as a chemotherapeutic agent is not generalized for all patients who suffer from AML, particularly for those whose health prevents them from using intensive conventional chemotherapy, in which case it can be used on its own, and those who have suffered a first relapse, where its combination with other chemotherapeutic agents is possible. This systematic review aimed to comprehensively evaluate GO, focusing on its molecular structure, mode of action, pharmacokinetics, recommended dosage, resistance mechanisms, and associated toxicities to provide valuable information on the potential benefits and risks associated with its clinical use. A systematic review of eight scientific articles from 2018 to 2023 was conducted using PRISMA analysis. The results showed that GO treatment activates proapoptotic pathways and induces double-strand breaks, initiating DNA repair mechanisms. Cells defective in DNA repair pathways are susceptible to GO cytotoxicity. GO has recommended doses for newly diagnosed CD33+ AML in combination or as a single agent. Depending on the treatment regimen and patient status, GO doses vary for induction, consolidation, and continuation cycles. Multidrug resistance (MDR) involving P-glycoprotein (P-gp) is associated with GO resistance. The overexpression of P-gp reduces GO cytotoxicity; inhibitors of P-gp can restore sensitivity. Mitochondrial pathway activation and survival signaling pathways are linked to GO resistance. Other resistance mechanisms include altered pharmacokinetics, reduced binding ability, and anti-apoptotic mechanisms. GO has limited extramedullary toxicity compared to other AML treatments and may cause hepatic veno-occlusive disease (HVOD). The incidence of hepatic HVOD after GO therapy is higher in patients with high tumor burden. Hematological side effects and hepatotoxicity are prominent, with thrombocytopenia and neutropenia observed. In conclusion, GO's reintroduction in 2017 followed a thorough FDA review considering its altered dose, dosing schedule, and target population. The drug's mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity.

Busulfan versus treosulfan conditioning for acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis.

e19032 Background: Busulfan containing myeloablative conditioning regimens are widely used before allogeneic hematological stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Treosulfan-based conditioning regimens are a potential alternative with potent myelotoxic immunosuppressive characteristics and favorable extramedullary toxicity profile compared to busulfan. In order to determine the optimal conditioning regimen, we conducted a systematic review and meta-analysis to compare the efficacy and safety outcomes of busulfan and treosulfan based conditioning regimens in patients with AML/MDS. Methods: A retrospective systematic literature search was undertaken on PubMed, Cochrane, Embase and Clinicaltrials.gov, using MeSH terms and relevant keywords for AML, MDS, busulfan and treosulfan, to retrieve studies published prior to February 5, 2023. Efficacy outcomes were overall survival (OS), disease-free survival (DFS), and relapse. Safety outcomes included non-relapse mortality (NRM), acute (a) and chronic (c) graft-versus-host disease (GvHD). The random-effects model with the Mantel-Haenszel method was used to pool risk ratios (RR) for dichotomous variables in Revman version 5.4. Results: The initial search retrieved 1094 articles. After removal of duplicates, reviews and non-relevant articles, data was extracted from seven different studies. Busulfan and treosulfan were employed in 4706 and 1979 patients, respectively. The median age ranged from 55 to 61 years, and the median follow-up ranged from 14 to 58 months. The treosulfan and busulfan doses administered ranged from 10-42 g/m2 and 0.8-12.8 mg/kg, respectively. Treosulfan was superior to busulfan in terms of OS (RR 1.39, 95% CI 1.15-1.68, p-value 0.0007, I2 58%), DFS (RR 1.39, 95% CI 1.10-1.75, p-value 0.006, I2 60%) and NRM (RR 0.95, 95% CI 0.90-1.00, p-value 0.05, I2 67%). The two regimens were comparable in terms of relapse (RR 0.96, 95% CI 0.89-1.04, p-value 0.33, I2 76%), aGvHD (RR 1.00, 95% CI 0.65-1.54, p-value 1.00, I2 94%) and cGvHD (RR 1.00, 95% CI 0.95-1.05, p-value 0.92, I2 0%). Conclusions: Treosulfan was superior in terms of OS, EFS and NRM, whereas both regimens were comparable in terms of relapse, aGvHD and cGvHD. Treosulfan may be more favorable compared to busulfan as conditioning in AML/MDS. Large scale prospective studies are needed to confirm the most suitable option.

WITHDRAWN: Azacitidine plus low-dose CLAG regimen for relapsed/refractory acute myeloid leukemia: A case report

The prognosis of patients with relapsed/refractory acute myeloid leukemia (AML) is poor, with a 3-year overall survival rate ranging between 10% and 29%. Moreover, the optimal treatment for these patients remains unclear. We designed a new salvage regimen consisting of azacitidine combined with cladribine, cytarabine, and granulocyte-stimulating factor (CLAG) for AML treatment. Here, we describe the case of a 21-year-old female patient who relapsed with AML [karyotype t(8,21)(q22,q22)]. The patient did not respond to standard induction chemotherapy but achieved complete remission without severe hematological or extramedullary toxicity following the azacitidine plus low-dose CLAG treatment. The results indicate that this latter regimen is a promising reinduction therapy option for patients with relapsed/refractory AML. Nevertheless, further research is required as this report describes only a single case treated using the new regimen.

Gene Therapy for Beta Thalassemia: Preliminary Results from the PHASE I/II Tiget-Bthal Trial of Autologous Hematopoietic Stem Cells Genetically Modified with GLOBE Lentiviral Vector

Gene Therapy for Beta Thalassemia: Preliminary Results from the PHASE I/II Tiget-Bthal Trial of Autologous Hematopoietic Stem Cells Genetically Modified with GLOBE Lentiviral Vector

Alpha-Particle Therapy for Acute Myeloid Leukemia

Early studies using the humanized anti-CD33 monoclonal antibody lintuzumab labeled with β-emitters showed significant activity against acute myeloid leukemia (AML) but produced prolonged myelosuppression necessitating hematopoietic cell transplantation (HCT). Targeted α-particle therapy may produce more efficient tumor killing while sparing normal cells. An initial phase I trial of bismuth-213 (213Bi)-lintuzumab in relapsed and refractory (R/R) AML provided proof-of-principle for systemically administered α-particle therapy (Jurcic, Blood 2002). 213Bi-lintuzumab demonstrated rapid targeting of disease sites without significant extramedullary toxicity. Target-to-whole body dose ratios were greatly enhanced compared to β-emitting immunoconjugates. Anti-leukemic effects were seen across all dose levels with a decrease in marrow blasts in 78% of patients. In a subsequent phase I/II trial, 213Bilintuzumab was administered following partial cytoreduction with cytarabine (Rosenblat, Clin Cancer Res 2010). Among patients receiving the maximum tolerated dose of 37 MBq/kg or higher, responses were seen in 24% of patients. The 46-minute half-life of 213Bi, however, remained an obstacle to its widespread use. Therefore, a more potent second-generation construct containing actinium-225 (225Ac) (t½ = 10 days), which generates four α-particle emissions, was developed. A phase I study demonstrated that a single dose of 225Aclintuzuamb was safe at doses of 111 kBq/kg or less and produced marrow blast reductions in 67% of evaluable patients with R/R AML (Jurcic, ASH 2011). Dose-limiting toxicity was prolonged myelosuppression, and no evidence of radiation-induced nephrotoxicity was seen. Based on these findings, 225Ac-lintuzumab was investigated in a multicenter phase I/II trial in combination with low-dose cytarabine for older patients with untreated AML (Jurcic, SNMMI 2017). During the first cycle of therapy, two fractions of 225Ac-lintuzumab (18.5-74 kBq/kg/fraction) were administered one week apart after completion of chemotherapy. Five of 18 patients (28%) had objective responses. All responses occurred after the first cycle. The baseline peripheral blood blast count was a strong predictor of outcome, as responses were seen only in patients with peripheral blast counts < 200/μL. This is most likely explained by preferential antibody binding to peripheral sites in patients with higher circulating blast counts, leading to decreased marrow targeting. Because of this observation, a multicenter phase II trial of 225Ac-lintuzumab monotherapy using hydroxyurea to lower peripheral blast counts if needed was undertaken in older AML patients (Finn, ASH 2017). Objective responses were seen in nine of 13 patients (69%) after two doses of 225Ac-lintuzumab (74 kBq/kg) administered one week apart. Myelosuppression, however, was considered to be longer than acceptable in this population, and additional patients were treated with two fractions of 55.5 kBq/kg each. 225Ac-lintuzumab has shown significant activity in AML both alone and in combination with chemotherapy. Future development of 225Ac-lintuzumab includes combinations with standard chemotherapy and novel targeted agents for R/R AML, treatment for measurable residual disease in AML, and conditioning before HCT in patients with high-risk myelodysplastic syndromes.

Decitabine plus CLAG chemotherapy as a bridge to haploidentical transplantation in the setting of acute myeloid leukemia relapse after HLA-matched sibling transplantation: a case report

BackgroundPatients with relapsed/refractory acute myeloid leukemia after hematopoietic stem cell transplantation (HSCT) have a poor prognosis, with a 2-year survival rate of 14%. The optimal treatment for these patients remains unclear. To treat these patients, we designed a new salvage regimen consisting of decitabine, cladribine, cytarabine, and granulocyte-stimulating factor (D-CLAG).Case presentationHere, we describe a case of acute monocytic leukemia with a complex karyotype in a 38-year-old female patient who relapsed after her first HSCT, which was performed using a matched sibling donor. The patient did not respond to standard induction chemotherapy and subsequently achieved complete remission with the D-CLAG regimen. No severe hematological or extramedullary toxicity was observed. Subsequently, the patient received a second D-CLAG regimen as a bridge therapy and directly underwent haploidentical related HSCT. Following HSCT, the marrow showed complete hematologic and cytogenetic remission. Currently, 1 year after transplantation, the patient’s general condition remains good.ConclusionsThis case suggests that the D-CLAG regimen can be an option for reinduction in relapsed refractory AML patients as a bridge to transplantation. Nevertheless, further research will be required in the future as this report describes only a single case.

Alpha-Particle Therapy for Acute Myeloid Leukemia

Early studies using the humanized anti-CD33 monoclonal antibody lintuzumab labeled with β-emitters showed significant activity against acute myeloid leukemia (AML) but produced prolonged myelosuppression necessitating hematopoietic cell transplantation (HCT). Targeted α-particle therapy may produce more efficient tumor killing while sparing normal cells. An initial phase I trial of bismuth-213 (213Bi)-lintuzumab in relapsed and refractory (R/R) AML provided proof-of-principle for systemically administered α-particle therapy (Jurcic, Blood 2002). 213Bi-lintuzumab demonstrated rapid targeting of disease sites without significant extramedullary toxicity. Target-to-whole body dose ratios were greatly enhanced compared to β-emitting immunoconjugates. Anti-leukemic effects were seen across all dose levels with a decrease in marrow blasts in 78% of patients. In a subsequent phase I/II trial, 213Bilintuzumab was administered following partial cytoreduction with cytarabine (Rosenblat, Clin Cancer Res 2010). Among patients receiving the maximum tolerated dose of 37 MBq/kg or higher, responses were seen in 24% of patients. The 46-minute half-life of 213Bi, however, remained an obstacle to its widespread use. Therefore, a more potent second-generation construct containing actinium-225 (225Ac) (t½ = 10 days), which generates four α-particle emissions, was developed. A phase I study demonstrated that a single dose of 225Aclintuzuamb was safe at doses of 111 kBq/kg or less and produced marrow blast reductions in 67% of evaluable patients with R/R AML (Jurcic, ASH 2011). Dose-limiting toxicity was prolonged myelosuppression, and no evidence of radiation-induced nephrotoxicity was seen. Based on these findings, 225Ac-lintuzumab was investigated in a multicenter phase I/II trial in combination with low-dose cytarabine for older patients with untreated AML (Jurcic, SNMMI 2017). During the first cycle of therapy, two fractions of 225Ac-lintuzumab (18.5-74 kBq/kg/fraction) were administered one week apart after completion of chemotherapy. Five of 18 patients (28%) had objective responses. All responses occurred after the first cycle. The baseline peripheral blood blast count was a strong predictor of outcome, as responses were seen only in patients with peripheral blast counts < 200/μL. This is most likely explained by preferential antibody binding to peripheral sites in patients with higher circulating blast counts, leading to decreased marrow targeting. Because of this observation, a multicenter phase II trial of 225Ac-lintuzumab monotherapy using hydroxyurea to lower peripheral blast counts if needed was undertaken in older AML patients (Finn, ASH 2017). Objective responses were seen in nine of 13 patients (69%) after two doses of 225Ac-lintuzumab (74 kBq/kg) administered one week apart. Myelosuppression, however, was considered to be longer than acceptable in this population, and additional patients were treated with two fractions of 55.5 kBq/kg each. 225Ac-lintuzumab has shown significant activity in AML both alone and in combination with chemotherapy. Future development of 225Ac-lintuzumab includes combinations with standard chemotherapy and novel targeted agents for R/R AML, treatment for measurable residual disease in AML, and conditioning before HCT in patients with high-risk myelodysplastic syndromes.

Preclinical IV busulfan dose-finding study to induce reversible myeloablation in a non-human primate model.

In this study we utilized a large animal model to identify a dose of intravenous busulfan that can cause reversible myelosuppression. Nine baboons (Papio anubis) were treated with IV busulfan at 6.4 (Group A), 8 (Group B), or 9.6 mg/kg (Group C). Peripheral blood counts were measured up to 90 days after treatment and serial bone marrow samples were obtained to analyze CD34+ cell content and colony forming units. Overall, the highest grade of peripheral blood cytopenia was observed 15 days after treatment in all three groups (n = 3/group). In particular, we observed a notable reduction of neutrophil and platelet counts in the blood and the number of marrow CD34+ cells and colony forming units. In contrast, the effect of busulfan on hemoglobin levels was mild. Baboons who received the highest dose of busulfan showed only a 25–35% recovery of marrow CD34+ cells and colony forming units after 90 days of busulfan administration. However, all three groups of animals showed a full recovery of peripheral blood counts and normal marrow cellularity and tri-lineage hematopoiesis after treatment. Notably, all three doses of busulfan were tolerated well without significant extra-medullary toxicity. These results validate the hierarchy of blood cells likely targeted by busulfan, and based on these findings, clinical trials using myelotoxic but not myeloablative doses of intravenous busulfan will be designed for patients with myeloid malignancies.

Bone Marrow Transplantation after Nonmyeloablative Treosulfan Conditioning Is Curative in a Murine Model of Sickle Cell Disease

Allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for patients with sickle cell disease (SCD). However, morbidity associated with myeloablative conditioning and graft-versus-host disease has limited its utility. To this end, autologous HSCT for SCD using lentiviral gene-modified bone marrow (BM) or peripheral blood stem cells has been undertaken, although toxicities of fully ablative conditioning with busulfan and incomplete engraftment have been encountered. Treosulfan, a busulfan analog with a low extramedullary toxicity profile, has been used successfully as part of a myeloablative conditioning regimen in the allogeneic setting in SCD. To further minimize toxicity of conditioning, noncytotoxic monoclonal antibodies that clear stem cells from the marrow niche, such as anti-c-Kit (ACK2), have been considered. Using a murine model of SCD, we sought to determine whether nonmyeloablative conditioning followed by transplantation with syngeneic BM cells could ameliorate the disease phenotype. Treosulfan and ACK2, in a dose-dependent manner, decreased BM cellularity and induced cytopenia in SCD mice. Conditioning with treosulfan alone at nonmyeloablative dosing (3.6 g/kg), followed by transplantation with syngeneic BM donor cells, permitted long-term mixed-donor chimerism. Level of chimerism correlated with improvement in hematologic parameters, normalization of urine osmolality, and improvement in liver and spleen pathology. Addition of ACK2 to treosulfan conditioning did not enhance engraftment. Our data suggests that pretransplant conditioning with treosulfan alone may allow sufficient erythroid engraftment to reverse manifestations of SCD, with clinical application as a preparative regimen in SCD patients undergoing gene-modified autologous HSCT.

Preliminary Results from a Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Subjects with Newly Diagnosed Acute Myeloid Leukemia (AML)

Preliminary Results from a Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Subjects with Newly Diagnosed Acute Myeloid Leukemia (AML)

Astarabine, a Novel Leukemia-Targeted Cytarabine Composition Allows, for the First Time, the Delivery of High Cytarabine Doses for Older or Unfit Patients with Acute Leukemia. Results of an Ongoing Phase I/IIa Study

Introduction: Therapy of acute myeloid leukemia (AML) has not changed significantly during several decades. High-dose cytarabine, although used as the first-line treatment for AML since 1970s and as a second-line treatment for acute lymphoblastic leukemia (ALL), is associated with severe side effects, such as cerebellar toxicity and bone marrow suppression. Hence, while the incidence of AML increases with age, doses of cytarabine are significantly attenuated or the drug is entirely excluded from the regimen used in older adults due to its potential toxicities, particularly in individuals with hepatic or renal dysfunction.Astarabine is a new composition of cytarabine covalently bound to asparagine. It is designed to target cytarabine to leukemic blasts, thus avoiding extramedullary toxicity. Leukemic cells, which are dependent on an external source of amino acids in general and asparagine in particular, due to their high metabolic rate, have a relatively increased uptake of Astarabine. Inside the blasts, Astarabine is cleaved to cytarabine, enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults who otherwise can be given supportive therapy only. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia.Methods: This Phase I/IIa prospective open label study enrolled patients aged ≥18 years with relapsed/refractory or newly-diagnosed acute leukemia unfit for intensive therapy, as judged by the treating physician. The study was approved by the Rambam IRB (approval #0384-11). Patients were enrolled into 6 Astarabine escalating-dose cohorts, each composed of 3-6 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. For cohorts 1-4, Astarabine doses for each infusion were 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. The doses were reduced by 50% for patients >50 years. Since dose limiting toxicity (DLT) was not reached in cohorts 1-4, the study was extended to include cohorts 5 and 6 with daily Astarabine doses of 4.5g/m2 and 6g/m2, respectively, with no dose reduction for patients >50 years old.Results: The outcome of 15 patients is reported herein. Six patients with a median age of 64 years (range 27-81) had refractory/relapsed AML, 9 patients with a median age of 80 years (range 70-90) were newly diagnosed (secondary AML - 6, de-novo AML - 2, de-novo ALL - 1) and unfit for intensive therapy. Astarabine treatment was well-tolerated. Two patients died (one from pneumonia and one from sudden death 2 weeks from end of treatment) before completing 30 days post-treatment and hence were excluded from the outcome analysis. Response to the treatment was observed in the bone marrow of 6 of the 7 newly-diagnosed patients for whom bone marrow analysis was available, 3 of whom had a continuous complete remission (CR) for 4 (ongoing), 8, and 10 months post-treatment, and 3 had a continuous partial remission (PR) for 3,7, and 7 (ongoing) months. The median overall survival (OS) of the patients with CR/PR is 7 months to date (table 1). No significant response was observed in the relapsed/refractory patients, with a median OS of 2.5 months. Twelve patients died from disease progression.Conclusions: Astarabine, a new composition of leukemia-targeted cytarabine, is safe and very well tolerated, even in patients over 80 years of age, resulting in response in 6 of 7 newly diagnosed patients with acute leukemia. To the best of our knowledge, this is the first report permitting high-dose of cytarabine, considered a cornerstone of leukemia therapy, to be given to a population of patients that heretofore did not have this option. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 and 6 g/m2/day. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. [Display omitted] DisclosuresZuckerman:BioSight Ltd: Consultancy, Research Funding. Gengrinovitch:BioSight Ltd: Employment, Equity Ownership, Patents & Royalties: Inventor all of the patents. Ben-Yakar:BioSight Ltd: Consultancy, Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties: Inventor of all patents.

The Role of Conditioning in Hematopoietic Stem-Cell Gene Therapy

Gene therapy (GT) approaches based on autologous hematopoietic stem cells (HSC) corrected ex vivo have shown therapeutic benefit in a number of inherited disorders. GT bares the advantage of allowing each patient to be her/his own donor while reducing the risks of immune-mediated complications as compared with allogeneic hematopoietic stem-cell transplantation (HSCT). In order to achieve stable engraftment of HSC, patients undergoing transplantation of allogeneic or autologous HSC receive a chemotherapy- and/or radiotherapy-based preparation. With regard to HSC-GT for inherited genetic disorders, the ideal conditioning regimen should aim to contain toxicity by reducing the dosage and/or the number of chemotherapeutic agents administered, in comparison to fully myeloablative preparations employed in conventional allogeneic HSCT. To meet this aim, a profound knowledge of the disease-specific biological background and of the therapeutic transgene levels, as well as of the key principles of transplantation, are required. While low-dose conditioning is sufficient to create a mixed chimerism when gene-corrected cells are endowed with a natural selective advantage, such as in the case of immune deficiencies, myeloablative doses are necessary when high levels of engraftment are required in disease such as lysosomal storage disorders and beta thalassemia. Therefore, the intensity and type of conditioning regimen administered to patients undergoing HSC-GT should be tailored to reach a minimal efficacious therapeutic target level while sparing toxicity. Novel strategies based on monoclonal antibodies selectively depleting blood cells and associated with limited extramedullary toxicity might be successfully employed in the context of HSC-GT in the near future. This review focuses on the role of the conditioning regimen in HSC-GT, and in particular, it highlights the importance of modulating the preparative chemotherapy based on disease biology and transgene expression in order to optimize outcome.

The combination therapy of imatinib and dasatinib achieves longterm molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia.

For patients with chronic myeloid leukemia (CML) failing imatinib therapy, second-generation tyrosine kinase inhibitors (TKIs) are recommended. Here, we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib, but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullary toxicity. Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.

Momelotinib Treatment-Associated Neuropathy: Prevalence, Risk Factors and Outcome in 100 Patients with Myelofibrosis

Background: Momelotinib (a JAK1 and JAK2 inhibitor) induces both anemia and spleen response in patients with myelofibrosis (MF) (Leukemia 2013;27:1322). The favorable effect on anemia was a distinguishing feature for momelotinib, compared to other JAK inhibitors, but the drug was also associated with treatment-emergent peripheral neuropathy (TE-PN). We examined the natural history and risk factors of momelotinib-associated peripheral neuropathy.Methods: The study patients constitute part of a larger phase-1/2 clinical trial (CCL09101; NCT00935987) using momelotinib for the treatment MF. Toxicity grading was according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.03. Momelotinib capsules (as opposed to the newer tablet formulation used in the currently ongoing phase-3 study) were used in the current study, which represents a sponsor-independent analysis.Results: 100 patients with MF (median age 66 years; 58% males) were treated at the Mayo Clinic between 11/20/09 and 11/10/10. DIPSS-plus (JCO. 2011;29:392) risk distribution was 63% high, 36% intermediate-2 and 1% intermediate-1. 75% of the patients harbored JAK2V617F and 50% abnormal karyotype. Previous treatment included other JAK inhibitors in 21 patients, thalidomide/lenalidomide/pomalidomide in 31 and hydroxyurea or other cytoreductive agents in 55. History of diabetes was documented in 7% of the patients at baseline and 14 (14%) of the patients had symptoms of PN before starting treatment with momelotinib, all of which were grade-1.Momelotinib was initiated at 100 mg/day in 3 patients, 150 mg/day in 21, 150 mg twice-daily in 20, 200 mg/day in 3, 300 mg/day in 47 and 400 mg/day in 6. The maximum momelotinib dose was 150 mg/day in 6 patients, 150 mg twice-daily in 20, 300 mg/day in 68 and 400 mg/day in 6. Treatment duration was <6 months in 12 patients, 6-12 months in 22, 12-24 months in 19 and >24 months in 47.Median follow-up after the institution of protocol drug therapy was 35 months (range 1-49). During this period, TE-PN was documented in 44 (44%) patients; of these, 42 were in patients without baseline neuropathy. TE-PN involved the feet only in 28 patients, hands only in one patient and both feet and hands in 15 patients. Median (range) for the time of onset of TE-PN was 32 weeks (1-132) and duration of TE-PN 11 months (0-40). All 42 newly-emergent PN were grade-1 sensory while the two patients with grade-1 baseline PN progressed to grade-2. Formal neurological evaluation, which was performed in 9 patients, mostly showed length-dependent sensory-motor large and small fiber neuropathy with axonal features.TE-PN resulted in drug discontinuation in 7 patients and reduction in drug dose in 28 patients. Improvement after drug dose reduction was documented in only one patient and in none of those with drug discontinuation. Progression to grade-2 PN was documented in 3 patients.TE- PN was significantly associated with clinical improvement (CI) with 54% incidence in responders vs 30% in non-responders (p=0.02); however, longer treatment duration was also associated with higher prevalence of TE-PN (p=0.03). In univariate analysis, patients with TE-PN lived longer than those without TE-PN (p=0.048); however, significance was lost during multivariable analysis that included either achievement of CI or treatment duration.Neither the initial (p=0.53) nor maximum (p=0.37) momelotinib dose was correlated with TE-PN, which was also not influenced by JAK2V617F (p>0.99), karyotype (p=0.26), history of diabetes (p=0.39) or previous treatment with JAK inhibitor therapy (p=0.7), thalidomide (p=0.24), lenalidomide (p=0.59), pomalidomide (p=0.63) or hydroxyurea (p=0.56). There were no correlations between TE-PN and age (p=0.37), sex (p=0.37), type of MF (p=0.98), DIPSS-plus score (p=0.07), baseline transfusion dependency (p=0.15), constitutional symptoms (p=0.83) or spleen size (p=0.53). TE-PN did not correlate with hematologic (p=0.14) or extramedullary toxicity other than PN (p=0.41) or lipase/amylase abnormalities (p=0.35).Conclusions: Momelotinib-associated neuropathy in MF might not be reversible in the majority of cases but also does not appear to be progressive. We were not able to identify risk factors for TE-PN, other than duration of treatment, which also explains its apparent association with response/survival. We are currently looking into possible correlations with serum thiamine levels. DisclosuresNo relevant conflicts of interest to declare.

High Risk Older AML Patients May be Benefited from the Treatment of Decitabine Combined Wih CAG Regimens

Patients over age 60 maked up more than 50% of newly diagnosed patients with acute myeloid leukemia (AML). Futhermore, with an aging population, more and more older AML patients were diagnosed in China. But the treatment approaches of this disease were variable, with many uncertainties and controversies. Treatment options for older patients with adverse prognostic features, such as poor performance status, unfavorable cytogenetics or an antecedent hematologic disorder were limited, and outcomes were poor. Aggres­sive induction chemotherapy had a high mortality and relatively low efficacy in this population. There were several new therapeutic schemes for older patients with AML. CAG regimens consisting of low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor for the treatment of older patients with AML showed higher rates of CR (42-68%). Decitabine, a DNA-hypomethylating agent induces differentiation and apoptosis of leukemic cells. The current National Comprehensive Cancer Care guidelines suggested decitabine as alterative options for older patients with AML. Previous studies have shown that decitabine demonstrated efficacy in a phase II multicenter study of older patients with AML, with a CR rate of 25%, 30-day mortality of 7%, median overall survival 7.7 months and little extramedullary toxicity. In our study, decitabine(15 mg/m2/d, d1-5) combined with CAG regimens (aclarubicin 20 mg/d, d3-6, Ara-C 10 mg/m2, q12h, d3-9, G-CSF 300ug, qd, d1-9) treated 27 older patients with AML, repeated every 4 weeks. Effectiveness and safety were assessed.27 older patients with newly diagnosed AML who were in Tianjin First Central Hospital of China from January 2011 to December 2013 were enrolled in our study. They were all treated with decitabine combined with CAG regimens. The characteristics of the 27 patients were described in Table I. The study population included 15 males and 12 females, with a median age of 68 years (range 60-79 years). All patients had Eastern Cooperative Oncology Group (ECOG) performance status of <3. Cytogenetics were classified according to criteria of the Cancer and Leukemia Group B(CALGB), and were adverse in 11 patients (40.7%) and intermediate in 16 patients (59.3%). No patient had favorable cytogenetics. 12 patients (44.4%) had secondary AML or an antecedent MDS or myeloproliferative disorder. Molecular diagnostics with mutations of FLT3-ITD in 6 patients (22.2%), NPM1 in 7 patients (25.9%) patients and JAK-2 in 4 patients (14.8%). Clinical responses, survival and adverse events of all 27 patients were analyzed. The median treatment cycle was 4 cycles. Rate of complete remission, overall response rate and a 30-day mortality rate were 40.1%, 66.7%, 7.4%, respectively. The median overall survival and median recurrence-free survival were 13.0months (95%CI, 7.0-18.0 months ) and 7.0 months (95%CI, 3.0-11.0 months), respectively. Adverse events in the regimens were mainly included myelosuppression, infection, nausea, vomiting and liver dysfunction. The adverse events could be well tolerated after managements.In conclusion, the treatment of decitabine combined with CAG regimens was found to be feasible and useful in high-risk older patients with AML. This regimen was a well-tolerated therapeutic alternative, was effective in producing remissions lasting several months or disease stabilization in high-risk older patients with AML.Table 1The characteristics of newly diagnosed patients with AMLTotal number of patients n=27median age(range)68 years(60-79 years)Male/female15/12 (1.25/1)ECOG performance status, n (%)05 (18.5%)110 (37.0%)212 (44.4%)Cytogenetics, n (%)Adverse 11 (40.7%)Intermediate16 (59.3%)secondary AML, n (%)MDS6 (22.2%)myeloproliferative5 (18.5%)Other tumors1 (3.7%)Molecular mutations, n (%)FLT3-ITD6 (22.2%)NPM17 (25.9%)JAK-24 (14.8%) DisclosuresNo relevant conflicts of interest to declare.

The combination therapy of imatinib and dasatinib achieves long-term molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia

For patients with chronic myeloid leukemia (CML) failing imatinib therapy, second-generation tyrosine kinase inhibitors (TKIs) are recommended. Here, we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib, but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullary toxicity. Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.

Decitabine in patients with newly diagnosed and relapsed acute myeloid leukemia

Treatment options for older patients with acute myeloid leukemia (AML) and for patients with relapsed/refractory AML are limited, and outcomes are poor. Decitabine, a hypomethylating agent, is active in patients with myelodysplastic syndrome (MDS) and AML, but its optimal dose and schedule are unknown. We report the efficacy and safety of repeated 10-day cycles of decitabine 20 mg/m2 administered intravenously over 1 h in 52 newly diagnosed and 102 relapsed/refractory patients. Repeated 10-day cycles of decitabine produced a complete response (CR) in 40% of newly diagnosed older patients with AML, many of whom had adverse prognostic features. The median overall survival (OS) was 318 days but there was prolonged survival in responders of 481 days. Relapsed/refractory patients had a CR rate of 15.7% with a median OS of 177 days. Extramedullary toxicity was mild and the regimen was well tolerated for ongoing post-remission, outpatient maintenance cycles. Responses were durable for over 1 year.

Safety and Efficacy of Bendamustine and Idarubicin in Combination Therapy for Patients Age ≥50 with Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome – Results From a Phase I/II Adaptive Design Study.

AbstractAbstract 2622 Background:Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal (<30%) grade 3–4 extramedullary toxicity in untreated AML or high-risk MDS patients age > 50. Methods:Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status <3 and creatinine and bilirubin each less <2.0. Patients received 1 of 3 doses of Bendamustine (45, 60 or 75 mg/m2 daily days 1–5) together with Idarubicin (12 mg/m2 days 1–2). Response was assessed according to the International Working Group (IWG) criteria (Cheson et. al., JCO, 2003) and non-hematologic toxicities according to the NCI CTCAE v.3. After each cohort of 3 patients at a given dose had been evaluated for toxicity and response, Bayesian posterior probabilities based on the data and non-informative prior probabilities were computed. If no Bendamustine dose was associated with a >95% posterior probability of both grade 3–4 extramedullary toxicity <30% (between the 1/6 and 2/6 of the conventional 3+3) and CR rate >40%, the study stopped. Otherwise, the study would continue at the highest dose that met the above criteria until 45 patients had been treated. Treatments were administered in the outpatient setting and patients were admitted to the hospital only if medically indicated. Results:Between October 2010 and May 2012, 39 patients were treated per protocol. The median age was 73 (range, 56–82). Patients had ECOG performance status of 1 (92%), or 2 (7%). AML patients comprised majority of the cases (34/39; 87%). Among AML patients, 35% (12/34) had primary AML, 47% (16/34) had AHD (antecedent hematologic disorders) and 18% (6/34) had secondary AML with a prior history of chemotherapy or radiation. None of the patients had favorable-risk cytogenetic (CG) and 19 (49%) had poor-risk CG including 9 patients (23%) with monosomal karyotype. None of the patients with normal CG had favorable molecular markers. Treatment was given in 1, 2, and 3 cycles in 25 (64%), 7 (18%) and 7(18%) patients, respectively. The number of patients in each cohort and the treatment efficacy and toxicity is reported in the table below. The MTD (maximum tolerated dose) was established at 60 mg/m2 of Bendamustine as two grade 3 toxicities were seen at the dose of 75 mg/m2 (congestive heart failure and mucositis in one patient each). Patients were treated as outpatients but hospitalization was required in 90% of the patients (35/39; 90%). The leading cause of admission was febrile neutropenia (26/35; 74%) followed by fungal infections (4/35; 11%). Conclusion:The combination of Bendamustine (60 mg/m2 (for 5 days) with Idarubicin (12 mg/m2 for 2 days) can be delivered in the outpatient setting and had a <95% posterior probability of >30% toxicity. However, the posterior probability of a CR rate >40% was also <95%, suggesting that continued exploration of new therapeutic combinations is warranted in elderly patients with AML or high-grade MDS.Table-1:Toxicity and Efficacy in each dose groupDose level for Bendamustine# Patients TreatedToxicityEfficacyCRCRiCR + CRi45 mg/m230/3 (0%)000/3 (0%)60 mg/m2330/33 (0%)6410/33 (30%)75 mg/m232/3 (66%)011/3 (33%) Disclosures:Off Label Use: Bendamustine is indicated for the treatment of CLL and indolent non-Hodgkin's lymphoma. In our study we are using Bendamustine to treat AML.

Salvage Therapy with the Combination of ARA-C and Gemtuzumab Ozogamicin in Post-Allo-SCT High Risk AML Patients Is Feasible and Results in Modest Responses.

AbstractAbstract 2629Acute myeloid leukemia (AML) relapse is often associated with a poor outcome, in particular in the post allogneic stem cell transplantation ( Allo-SCT) setting. Therapeutic options in patients relapsing early after SCT are further limited partially due to the risk of increased toxicity. In patients who did not develop graft versus host disease ( GVHD), reduction or cessation of immunosuppression therapy may result in the achievement of a graft versus leukemia (GvL) effect. However, this is usually only beneficial in patients with a low disease burden. Gemtuzumab Ozogamicin (GO) was introduced into therapy of CD33 positive AML patients as a targeted therapy with a relatively safe extra-medullary toxicity profile. Although withdrawn from the USA market by the FDA, recent studies have shown efficacy of combining GO with chemotherapy in newly diagnosed AML patients. We hypothesized that in patients with AML relapsing early after an Allo-SCT, combination of GO with single agent chemotherapy will result in disease control for a sufficient amount of time to allow a trial of GvL induction. Therapy consisted of high dose ARA-C (1 gr/m2) for 4 days followed by one dose of GO, 9 mg/m2 on day 5. To decrease hematopoietic toxicity, therapy was supported by donor stem cells, when available. Responding patients which did not develop GVHD, where eligible for cell mediasted immunotherapy with a donor lymphocyte infusion(DLI) or a second Allo-SCT. 16 patients (F=10, M=6), median age 52 years (range 26–63) are included in this analysis. The majority (14/16) of patients were previously transplanted for a high risk AML (secondary AML-6, unfavorable cytogenetics-5, FLT3-ITD-3); disease status at SCT were CR1 (n=8), CR2 (n=4), untreated 1st relapse (n=1) and at diagnosis (n=1, MDS with excess of blasts). AML relapse occurred at a median of 104 days (range 15–403) after SCT. ARA-C/GO therapy was supported with donor stem cells in 8/16 patients and was relatively well tolerated. One patient died in aplasia in day +2 due to sepsis resulting in overall 6% induction mortality. Five patients developed veno occlusive disease of the liver ( VOD )(36% of evaluable patients); all were mild and resolved with symptomatic care. Responses were achieved in 8/15 (53%) evaluable patients, all CR/CRp. Four patients in CR/CRp received further therapy with DLI (n=3) or Allo SCT from a different donor (n=1), and 2 non-responding patients received a second Allo-SCT after second line salvage chemotherapy. At long follow up, 1 patient (6%) is alive in and continuous remission (1040 days after therapy). In patients surviving induction, death occurred due to relapse (n=10) or severe GVHD (n=5). Median EFS and OS were 55 and 133 days, respectively in the entire cohort. Median EFS was longer in responding patients (156 vs. 16 days, p<0.0001), while median OS was not significantly different in these 2 patients cohorts (204 vs. 33 days, p=0.2).ARA-C/GO combination is a valid option for salvage therapy in AML patients relapsing after an Allo-SCT and is well tolerated. Although responses are usually of a short duration, they may allow immunogenic manipulation in the absence of an already established significant GVHD, and may result in a long term disease control in a minority of patients. Disclosures:No relevant conflicts of interest to declare.