Treatment of relapsed or refractory FLT-3 acute myelogenous leukemia with a triplet regimen of hypomethylating agent, venetoclax, and gilteritinib.

Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35-298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation.

Prognostic factors and impact of CMV reactivation on acute myeloid leukemia patients after HLA-matched myeloablative allogeneic stem cell transplantation in a high CMV prevalence country

ABSTRACT Introduction: Relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT) leads to dismal outcomes. This study aimed to identify high-risk patients and explore the effects of cytomegalovirus (CMV) reactivation in a high CMV-seropositive population. Methods: The study involved a single-center retrospective cohort in Thailand, analyzing clinical risk factors and CMV-mediated immune responses, correlated with transplant outcomes in AML patients. Results: Eighty-five patients with AML in complete remission (CR) undergoing HLA-matched myeloablative allo-SCT between 2011 and February 2021 were enrolled. The relapse rate was 27.1% with the median time of 7 months after transplantation. The 3-year relapse-free-survival (RFS) and overall-survival (OS) were 72.2% and 80.8%, respectively. The disease status (>CR1) and absence of chronic graft-versus-host disease (cGVHD) were independently significant adverse prognostic factors of RFS and OS. Ninety-two percent of recipient-donor pairs were both CMV seropositive. The CMV reactivation occurred in 54.1% of the patients. The clinically significant CMV infection rate was 49.4%. No CMV syndrome/disease or CMV-related mortality occurred. One-year cumulative incidence of relapse among CMV-reactivation and non-reactivation groups were 14.3% and 25.6%, respectively, without a statistically significant difference. Transplantation-related mortality was 11.1%. Conclusions: The transplantation beyond CR1 and absence of cGVHD are powerful prognostic factors associated with inferior RFS and OS. In a high CMV prevalence country, there appears to be no impact of CMV reactivation on relapse in AML patients undergoing an allo-SCT.

Efficacy and toxicity of CLAG combined with pegylated liposomal doxorubicin in the treatment of refractory or relapsed acute myeloid leukemia.

BACKGROUND: Refractory and relapsed acute myeloid leukemia (r/rAML) is associated with a difficult prognosis; clinical trials are typically suggested despite lack of a recognized standard of care. Combinatorial chemotherapy regimens utilized for r/rAML salvage play a crucial role in battling this invasive phase. Although it is characterized by a low response rate, CLAG is a traditional regimen used in r/rAML. We aimed to compare the efficacy and toxicity of CLAG+PLD to explore whether there was any improvement with the addition of pegylated liposomal doxorubicin (PLD) to CLAG METHODS: A total of 110 r/rAML patients were retrospectively analyzed from February 2017 to June 2020 at the Medical Center of Hematology, XinQiao Hospital, the 303rd Hospital of the Chinese People's Liberation Army, and Central Hospital of Chang Sha, Hunan Province. The response, overall survival (OS), disease-free survival (DFS), and side effects in 110 r/rAML patients were evaluated retrospectively. Of these, 55 patients were administered CLAG+PLD, while 55 patients received CLAG alone as salvage therapy. RESULTS: In the CLAG+PLD group, there were 27 (49.1%) cases of complete response (CR) with no measurable residual disease (MRD-), 12 (21.8%) cases of CR with positive MRD (MRD+), 5 (9.1%) cases of partial response (PR), 11 (20%) cases of no response (NR), and no cases of death during the cycles. The response rates in the CLAG group were lower: CR was reached in 24 (46.6%) patients with MRD-, 6 (10.9%) patients with MRD+, 10 (18.2%) patients with PR, 13 (23.6%) patients with NR, and 2 (3.6%) patients who passed away, one from infection and the other from cerebral hemorrhage. The median OS and DFS were not attained in the CLAG+PLD group during the 2-year OS and DFS follow-up, while both values were 10 months in the CLAG group (p = 0.023 and p = 0.045, respectively). The results of the Cox regression analysis for the CLAG+PLD group were strongly illustrative of the importance of hematopoietic stem cell transplantation (HSCT) following salvage therapy. No increased toxicity was observed in the CLAG+PLD group. CONCLUSION: CLAG+PLD is a potential salvage regimen for r/r AML that has a similar toxicity profile to CLAG and that improves response rates, 2-year OS, and DFS relative to CLAG.

Prognostic factors and impact of CMV reactivation on acute myeloid leukemia patients after HLA-matched myeloablative allogeneic stem cell transplantation in a high CMV prevalence country.

INTRODUCTION: Relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT) leads to dismal outcomes. This study aimed to identify high-risk patients and explore the effects of cytomegalovirus (CMV) reactivation in a high CMV-seropositive population. METHODS: The study involved a single-center retrospective cohort in Thailand, analyzing clinical risk factors and CMV-mediated immune responses, correlated with transplant outcomes in AML patients. RESULTS: Eighty-five patients with AML in complete remission (CR) undergoing HLA-matched myeloablative allo-SCT between 2011 and February 2021 were enrolled. The relapse rate was 27.1% with the median time of 7 months after transplantation. The 3-year relapse-free-survival (RFS) and overall-survival (OS) were 72.2% and 80.8%, respectively. The disease status (>CR1) and absence of chronic graft-versus-host disease (cGVHD) were independently significant adverse prognostic factors of RFS and OS. Ninety-two percent of recipient-donor pairs were both CMV seropositive. The CMV reactivation occurred in 54.1% of the patients. The clinically significant CMV infection rate was 49.4%. No CMV syndrome/disease or CMV-related mortality occurred. One-year cumulative incidence of relapse among CMV-reactivation and non-reactivation groups were 14.3% and 25.6%, respectively, without a statistically significant difference. Transplantation-related mortality was 11.1%. CONCLUSIONS: The transplantation beyond CR1 and absence of cGVHD are powerful prognostic factors associated with inferior RFS and OS. In a high CMV prevalence country, there appears to be no impact of CMV reactivation on relapse in AML patients undergoing an allo-SCT.

Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: A Single-Centre Experience.

INTRODUCTION: Patients with relapsed/refractory acute myeloid leukemia (r/r AML) are characterized as having a poor prognosis. The only viable option of treatment for these patients is allogenic stem cell transplantation (allo-HSCT). Therefore, we have attempted to analyse factors related to both the disease itself and the transplantation procedure that could have an influence on the improvement of outcomes in this group of patients. PATIENTS AND METHODS: Sixty-four patients with r/r AML underwent allo-HSCT at our center in 2012 to 2021. Fifty-two had active disease at the beginning of theallo-HSCT procedure, with amedian number of blasts in bone marrow (BM) of 18, and 12 had therapeutic aplasia after the last reinduction (blasts < 5% in BM). RESULTS: The probability of overall survival (OS) at 2 years was 25%. The median follow-up for survivors was 21.5 months. Progression-free survival (PFS) estimates were above 46%. The main cause of death was disease progression (49%). A statistically significant effect on premature death was reported for the diagnosis of secondary AML (sAML) and cytomelovirus (CMV) reactivation post allo-HSCT. On the other hand, chronic graft versus host disease (cGVHD) decreased the risk of disease progression. sAML and CMV reactivation were found to have opposite effects.

Jiyuan oridonin A induces differentiation of acute myeloid leukemia cells including leukemic stem-like cells.

Acute myeloid leukemia (AML) is an aggressive form of hematological neoplasia characterized by failure of myeloid differentiation. AML is a leading cause of death from leukemia. Cytarabine chemotherapy resistance is a major source of refractory/relapsed AML. A major obstacle to the successful treatment of AML results from residual disease maintained by leukemic stem cells (LSCs), which are mostly resistant to conventional chemotherapy. Here, we determined the effect of a natural compound, Jiyuan oridonin A (JOA), on the differentiation blockade in the M2 subtype [particularly t (8;21)] of AML cells, M3 subtype of AML cells (APL cells), and leukemic stem-like cells both in vitro and in vivo. We found that JOA induced cell differentiation and suppressed the colony formation capacity in various AML cell lines (Kasumi-1, KG-1, MUTZ-8, NB4, and HL-60) without eliciting apoptosis. The mechanism of JOA-induced cell differentiation depends on the specificity of cell type. JOA mediated the differentiation of Kasumi-1 cells by activating the hematopoietic cell lineage signaling pathway, while inhibition of c-MYC was involved in the JOA-induced differentiation of NB4 cells. Moreover, JOA was identified to target leukemic stem-like cells by induced cell differentiation in vivo. These findings demonstrated that JOA could inhibit the proliferation of M2 and M3 subtypes of AML cells and leukemic stem-like cells by overcoming the differentiation blockade, which may offer a novel therapeutic strategy for AML to overcome relapse and drug resistance in patients with AML. Our findings highlight the possibility of using compounds like JOA as a promising differentiation-induced agent for the treatment of AML.

Prognostic significance of chromosomal abnormalities at relapse in children with relapsed acute myeloid leukemia: A retrospective cohort study of the Relapsed AML 2001/01 Study.

BACKGROUND: In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. METHODS: This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. RESULTS: Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. CONCLUSION: The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.

Unmanipulated haplo-identical donor transplantation compared with identical sibling donor had better anti-leukemia effect for refractory/relapsed acute myeloid leukemia not in remission status.

Prior studies have suggested that for leukemia patients with high-risk features, haplo-identical-hematopoietic stem cell transplantation (HID-HSCT) has a stronger anti-leukemia effect compared with HSCT using an identical sibling donor (ISD-HSCT). However, it is unclear whether an HID-HSC transplant also augments the graft-versus-leukemia (GVL) effect among refractory/relapsed (R/R) acute myeloid leukemia (AML) patients who are not in remission (NR). We conducted a retrospective analysis of 124 R/R AML patients with NR status who underwent HID-HSCT between April 2012 and December 2016 and compared these to 27 R/R AML patients who underwent an ISD-HSCT within the same timeframe. Among all of the patients, 68 (45.0%) had primary induction failure (PIF) and 83 (54.9%) were relapsed and had failed to respond to at least one cycle of salvage combination chemotherapy. Myeloablative conditioning regimens were administered to all patients. Here, we present a retrospective multivariate analysis of pre-transplantation risk factors and characteristics of all 151 patients and developed a predictive scoring system to predict patient survival. The median period of follow-up was 46 months for all patients. The HID cohort had a higher 5-year overall survival (OS) compared with the ISD cohort (48.6% ± 4.6% vs 25.9% ± 8.4, respectively; P = 0.017) and higher LFS (leukemia-free survival) (41.6% ± 7.5% vs 25.9% ± 8.4%, respectively; P = 0.019). There was no difference in the 5-year cumulative incidence of non-relapse mortality (NRM) (18.0% ± 3.8% and 34.9% ± 12.6%, respectively; P = 0.212) between the two group. However, the 5-year cumulative incidence of relapse (CIRs) was lower in the HID group compared with the ISD group (55.4% ± 8.9% vs 67.3% ± 9.9%, respectively; P = 0.021). Multivariate analysis showed three risk factors associated with OS and LFS: (1) ISD-HSCT, (2) use of a standardized conditioning regimen, and (3) less than 50% proportional reduction of blast cells in the bone marrow (BM). Based on these three risk factors, we developed a predictive scoring system for R/R AML patients undergoing HSCT. Patients who had a predictive score of 0 and 1 had a 66.6% ± 4.5% and 44.1% ± 3.6% OS rate at 5 years, respectively. Patients with a score ≥ 2 had only a 4.4 ± 0.2% OS rate at 5 years. An HID-HSCT had a better anti-leukemia effect among R/R AML patients with an NR status compared with an ISD-HSCT. We also identified pre-transplantation risk factors to delineate subgroups that could derive maximal benefit from HSCT.

Long-term follow-up of Cladribine, high-dose Cytarabine, and Idarubicin as salvage treatment for relapsed acute myeloid leukemia and literature review.

PURPOSE: Outcome for relapsed acute myeloid leukemia (AML) is poor. Cladribine has activity in AML, and an enhancing effect on other cytostatic drugs thus may help overcome resistance. Here, we present the final analysis of our phase II trial evaluating safety and efficacy of cladribine, cytarabine, and idarubicin (CAI) in relapsed AML. METHODS: Patients with relapsed AML after at least 6 months remission received two courses of CAI. After 9 patients, prolonged neutropenia prompted protocol change (omission of idarubicin in 2nd course and dose-reduction of cytarabine). Primary endpoints were remission rate and safety. RESULTS: Twenty patients received treatment, fourteen one, and six two courses CAI/CA. After first course, complete remission (CR/CRi) was achieved in 60%. Most frequent toxicity was infection. Median OS was 8.8 months in all patients and 21.1 months in those with CR. Nine patients (48%) proceeded to allogeneic stem cell transplantation (allo-SCT), four of those are still alive and in CR, accounting for a 5-year survival rate of 55% of transplanted patients. CONCLUSION: Cladribine, cytarabine, and idarubicin in relapsed AML is feasible and induces good response rates. As expected, infections are the most important complication. However, combined with allo-SCT, long-term survival can be achieved in a substantial number of patients.

Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells.

Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment-Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA-KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation.

Modified cladribine, cytarabine, and G-CSF as a salvage regimen in patients with relapsed/refractory acute myeloid leukemia: a bridge to myeloablative allogeneic hematopoietic stem cell transplantation.

Patients with primary refractory or early relapsed acute myeloid leukemia (AML) have a dismal prognosis, and the treatment options for these patients are limited. The present study retrospectively examined the efficacy and toxicities of the combination of cladribine 5 mg/m2 per day and intermediate-dose cytarabine 1 g/m2 per day for 5 days and granulocyte colony-stimulating factor (G-CSF) as a salvage treatment in 36 patients with relapsed/refractory AML. Among these, 32 patients had de novo AML, and the remaining 4 patients had secondary AML. The median age for the study cohort was 45.8 years. According to the European LeukemiaNet prognostic index, 5 patients had favorable risk, 18 had intermediate risk, and 11 had poor risk. The complete remission was achieved in 58% of the patients with tolerable toxicities. Fifteen patients underwent stem cell transplantation later. Patients who underwent allogeneic hematopoietic stem cell transplantation had a significantly improved 1-year overall survival compared with those who did not (73% vs. 29%, P < 0.001). The results suggested that, as a salvage regimen, modified cladribine, cytarabine, and G-CSF were effective and well tolerated for patients with relapsed/refractory AML, especially for patients who underwent subsequent stem cell transplantation.

Advances in the drug therapies of acute myeloid leukemia (except acute wpromyelocytic leukemia).

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy, characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. The new drugs used for treating AML are facing a big challenge, and the candidates include cytotoxic drugs, targeted small-molecule inhibitors, and monoclonal antibodies. In recent years, active research has focused on several new agents for including them in the large antileukemic drug family. This review aims to introduce some of these new drugs and highlights new advances made in the old drugs, mainly in the last 5 years.

Efficacy of single-agent decitabine in relapsed and refractory acute myeloid leukemia.

Improving therapy for relapsed/refractory AML remains a challenge. We performed a retrospective analysis of outcomes following decitabine treatment in 34 patients with relapsed/refractory AML (median age, 62; median Charlson comorbidity score, 6). Decitabine, 20 mg/m2 daily, was given in 5- (25%) or 10-day (75%) cycles. Overall response rate (OR) was 30% with 21% complete remission and 9% partial remission rate. Patients with therapy-related myeloid neoplasm (t-MN) and secondary AML had a significantly higher OR compared to those with de novo AML (70 vs. 30%; p = .02). Median overall survival of all patients was 8.5 months. Median survival in patients with t-MN or secondary AML was 12.4 months compared to 8 months in those with de novo AML (p = .20). Fifteen (44%) patients proceeded to hematopoietic stem cell transplant. These data support using 10-day treatment cycles of decitabine in patients with relapsed/refractory AML, particularly for those with secondary or therapy-related AML.

Why are there so few randomized trials for patients with primary refractory acute myeloid leukemia?

Fewer patients with primary refractory AML ("PREF") are entered into phase 3 trials than are patients with relapsed AML. This is particularly noteworthy because data from phase 3 trials for newly diagnosed AML indicated PREF and relapse are equally common. Here I discuss three possible reasons for this discrepancy. First, there is disagreement whether the criterion for PREF AML should be failure of one or two courses of initial induction therapy. Second, there may be an impression that PREF AML is qualitatively worse than relapsed AML. Third, there may be a general unwillingness to randomize patients with such poor prognoses.

Evaluation of prognostic factors in patients with relapsed AML: Clonal evolution versus residual disease.

BACKGROUND: It is widely known that the prognosis of acute myeloid leukemia (AML) depends on chromosomal abnormalities. The majority of AML patients relapse and experience a dismal disease course despite initial remission. METHODS: We reviewed the medical records and laboratory findings of 55 AML patients who had relapsed between 2004 and 2013 and who had been treated at the Division of Hematology of the Pusan National University Hospital. RESULTS: The event-free survival (EFS) was related to prognostic karyotype classification at the time of diagnosis and relapse (unfavorable vs. favorable or intermediate karyotypes at diagnosis, 8.2 vs. 11.9 mo, P=0.003; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.2 vs. 11.9 mo, P=0.009). The overall survival (OS) was significantly correlated with karyotype classification only at diagnosis (unfavorable vs. favorable or intermediate vs. karyotypes at diagnosis, 8.5 vs. 21.8 mo, P=0.001; unfavorable vs. favorable or intermediate karyotypes at relapse, 8.5 vs. 21.2 mo, P=0.136). A change in karyotype between diagnosis and relapse, which is regarded as a factor of resistance against treatment, was not a significant prognostic factor for OS, EFS, and post-relapse survival (PRS). A Cox proportional hazards model showed that the combined use of fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) as a salvage regimen, was a significant prognostic factor for OS (hazard ratio=0.399, P=0.010) and the PRS (hazard ratio=0.447, P=0.031). CONCLUSION: The karyotype classification at diagnosis predicts survival including PRS in relapsed AML patients as well as in treatment-naïve patients. We suggest that presently, administration of salvage FLAG could be a better treatment option.

High-dose cytarabine as salvage therapy for relapsed or refractory acute myeloid leukemia--is more better or more of the same?

Cytarabine is the backbone of most chemotherapeutic regimens for acute myeloid leukemia (AML), yet the optimal dose for salvage therapy of refractory or relapsed AML (RR-AML) has not been established. Very high dose single-agent cytarabine at 36 g/m(2) (ARA-36) was previously shown to be effective and tolerable in RR-AML. In this retrospective analysis, we aim to describe the toxicity and efficacy of ARA-36 as salvage therapy for patients with AML who are primary refractory to intensive daunorubicin-containing induction or those relapsing after allogeneic stem cell transplant (alloSCT). Fifteen patients, median age 53 years, were included in the analysis. Six patients were treated for induction failure, one had resistant APL, and eight relapsed after alloSCT. Complete remission was achieved in 60% of patients. Surviving patients were followed for a median of 8.5 months. One-year overall survival was 54% (95% CI 30%-86%), and relapse rate from remission (n = 9) was 56%. Grade III/IV pulmonary, infectious, ocular and gastrointestinal toxicities occurred in 26%, 20%, 20% and 20% of patients respectively. Salvage therapy with ARA-36 regimen for RR-AML has considerable efficacy with manageable toxicity in patients with induction failure or post-transplant relapse. Overall survival in these high-risk patients still remains poor.

Enhancing effect of ß-elemene emulsion on chemotherapy with harringtonine, aclacinomycin, and Ara-c in treatment of refractory/relapsed acute myeloid leukemia.

Objective : This study is to determine the curative effect of ß-elemene emulsion on chemotherapy in the treatment of refractory/relapsed acute myeloid leukemia (AML). Methods : In the ß-elemene emulsion plus HAA chemotherapy (harringtonine, aclacinomycin, Ara-c group) group, 120 cases received ß-elemene emulsion (400 mg) plus the HAA treatment. A 14-day treatment was a course of treatment, followed by an 8-14 day pause, and then the next course of treatment. The HAA treatment included Ara-C, 100 mg/m2, once every 12 h from day 1 to day 7; aclacinomycin, 20 mg/m2, from day 1 to day 7; and homoharringtonine, 4 mg/m2, from day 1 to day 7. The patients in the control HAA group received HAA treatment only. For both groups, effective antibiotics were given to patients when it was necessary. Results : The total effective rate in the ß-elemene emulsion plus HAA group was 80.8%. But the total effective rate in the HAA only group was 52.9%. These results suggest that the ß-elemene emulsion plus HAA treatment has a much better curative effect in comparison with the HAA only treatment (P < 0.05). Furthermore, ß-elemene emulsion has slightly adverse response, without causing blood and bone marrow depression. Conclusion : ß-elemene emulsion has a curative effect in treatment of refractory/relapsed AML in combination with harringtonine, aclacinomycin, and Ara-c.

Phase I study of azacitidine and bortezomib in adults with relapsed or refractory acute myeloid leukemia.

We previously reported that bortezomib indirectly modulates transcription of DNA methyltransferase 1 (DNMT). We designed a phase I study of azacitidine (a direct DNMT inhibitor) plus bortezomib in acute myeloid leukemia (AML) to determine safety and tolerability. Twenty-three adults with relapsed/refractory AML received azacitidine 75 mg/m(2) daily on days 1-7. Bortezomib was dose escalated from 0.7 mg/m(2) on days 2 and 5 to 1.3 mg/m(2) on days 2, 5, 9 and 12. The target dose was reached without dose limiting toxicities. Infection and/or febrile neutropenia were frequent. Patients received a median of 2 cycles of therapy (range, 1-12+). Five of 23 patients achieved remission, including two with morphologic and cytogenetic complete response (CR) and three with CR and incomplete count recovery (CRi). Of CR/CRi responders with cytogenetic abnormalities at baseline, three of four achieved cytogenetic CR. The combination of azacitidine and bortezomib was tolerable and active in this cohort of poor-risk previously treated patients with AML.