Chemotherapy with Idarubicin, Ara-C,VP-16, Amsacrine, Followed by G-CSF and Maintenance Immunotherapy with Interleukin-2 for Patients with High-Risk Acute Myeloid leukemia: a 3-Years Follow-Up

Background/Aims: The aim of this work was to investigate the efficacy and predictive factors of CLAG treatment in refractory or relapsed (R/R) acute myeloid leukemia (AML) patients. Methods: Sixty-seven R/R AML patients were enrolled in this prospective cohort study and treated by a CLAG regimen: 5 mg/m2/day cladribine (days 1–5), 2 g/m2/day cytarabine (days 1–5), and 300 μg/day filgrastim (days 0–5). The median follow-up duration was 10 months. Results: A total of 57 out of 67 patients were evaluable for remission after CLAG therapy, of whom 57.9% achieved a complete remission (CR) and the overall remission rate was 77.2%. The median overall survival (OS) was 10.0 months, with a 1-year OS of 40.3 ± 6.0% and 3-year OS of 16.7 ± 5.7%. CR at first induction after the initial diagnosis was associated with a favorable CR. Age above 60 years, high risk stratification, second or higher salvage therapy, and bone marrow (BM) blasts ≥42.1% were correlated with an unfavorable CR. Secondary disease, age ≥60 years, high risk stratification, and second or higher salvage therapy were associated with worse OS. Patients developed thrombocytopenia (41, 61%), febrile neutropenia (37, 55%), leukopenia (33, 49%), neutropenia (18, 27%), and anemia (9, 13%). Conclusion: CLAG was effective and well tolerated for R/R AML. BM blasts ≥42.1%, age ≥60 years, high risk stratification, and second or higher salvage therapy were independent factors for a poor prognosis.

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Early Allogeneic Hematopoietic Cell Transplantation during Induction Chemotherapy in High-Risk Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v104.11.2299.2299 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2299-2299 ◽

Cited By ~ 1

Author(s):

Gerhard Ehninger ◽

Uwe Platzbecker ◽

Christian Thiede ◽

Thomas Illmer ◽

Ulrich S. Schuler ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Complete Remission ◽

Cell Transplantation ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Minor Response ◽

Cytogenetic Aberrations ◽

Acute Myeloid

Objectives: In patients with acute myeloid leukemia and high-risk cytogenetic aberrations or minor response to the first cycle of induction chemotherapy (IC) the probability of achieving a sustained complete remission is low. Thus early treatment intensification may be warranted in order to achieve long-term disease control. We performed a prospective trial to evaluate whether reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors can be performed during the aplastic phase of IC in patients with poor-risk AML. Methods: Seventeen patients (n=17) aged between 17 and 63 years (median 45) with acute myeloid leukemia and high-risk cytogenetic aberrations (n=14, complex, inv3 or t(3;3), t(3;5), −7 or del 7q, +8) or more than 10 % marrow blasts on day 15 after the first cycle of IC (n=3) were included so far. During aplasia a median of thirteen days (range 7–35) after the first (n=8) or second (n=9) cycle of IC patients received 5 x 30 mg/m2 fludarabine i.v. combined with either 8 mg/kg busulfan p.o. (n=4) or 150 mg/m2 melphalan iv. (n=13) followed by allogeneic G-CSF mobilized peripheral blood stem cells (PBSC, n=16) or bone marrow (n=1) from related (n=7) or unrelated (n=10) donors. Nine out of seventeen patients were not in complete remission before conditioning therapy was started. Patients with unrelated grafts received antithymocyte globulin (4 x 10 mg/kg ATG Fresenius). GvHD prophylaxis was performed with cyclosporine A (CSP). Results: All patients engrafted (ANC > 0.5 Gpt/l on day 11, range 8–19, platelets > 50 Gpt/l day 15, range 11–32) and went into remission. Acute GvHD grade II-IV occurred in 8 patients and extensive chronic GvHD was documented in 5 patients with a follow-up of > 100 days. Two patients died while being in remission from infectious complications associated with acute (n=1) or chronic (n=1) GvHD and two patients died during relapse eight and twelve months after PBSC. With a median follow-up of 15 months (range 1–65) thirteen out of seventeen patients (76 %) are alive and in remission. Conclusion: Early allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in AML patients with either poor risk karyotype or minor response to the first induction cycle.

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Sequential Chemotherapy Followed By Reduced Intensity Conditioning and Allogeneic Hematopoietic Transplantation For High Risk Acute Myeloid Leukemia Patients In First Complete Remission: A Prospective Pilot Study

Blood ◽

10.1182/blood.v122.21.2162.2162 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2162-2162

Author(s):

Mauricette Michallet ◽

Mohamad Sobh ◽

Marie Y. Detrait ◽

Helene Labussiere ◽

Sandrine Hayette ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Reduced Intensity Conditioning ◽

Secondary Aml ◽

Prospective Pilot Study ◽

First Complete Remission ◽

Reduced Intensity ◽

Acute Myeloid

Abstract Advances in chemotherapy have improved the prognosis of patients with acute myeloid leukemia (AML), however, high-risk patients still have a poor outcome. In this category of patients, the only therapeutic strategy with curative potential remains allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the aim to improve the effect of allo-HSCT by sequential use of chemotherapy followed by reduced intensity conditioning (RIC), we conducted a prospective pilot study in high-risk AML patients in first complete remission (CR1). The high-risk population included intermediate II [t(9;11)(p22;q23); MLLT3-MLL, cytogenetic abnormalities not classified as favorable or adverse] and unfavourable patients [inv(3)(q21q26.2) or t(3;3)(q21;q26.2); t(6;9)(p23;q34); t(v;11)(v;q23); MLL rearranged, -5 or del(5q); -7; abnl(17p); complex karyotype] (Dohner et al. Blood 2010), secondary AML, and patients requiring 2 induction courses to obtain CR. The chemotherapy sequential regimen consisted in fludarabine 30 mg/m2, high-dose cytarabine 2 g/m2, and amsacrine 100 mg/m2 from days -12 to -9 (FLAMSA). After 3 days of rest, RIC consisted of 4 Gy total-body irradiation (TBI) on day -5, cyclophosphamide (40 mg/kg with HLA-identical sibling, 60 mg/kg for unrelated or mismatched donors) on days -4 and -3, and rabbit antithymocyte globulin (ATG, Genzyme) (5 mg/kg total dose) from day -3 to day -1. As a new experimental approach, we replaced TBI by iv. busulfan (BU) (Busilvex, Pierre Fabre) 3.2 mg/kg/d during either 4 or 2 days according to patient age (>55 years) (from day -7 to -4 or from day -5 to -4). Peripheral-blood stem cells (PBSC) were preferred; bone marrow (BM) and cord blood (CB) were also accepted. Graft-versus-host disease (GvHD) prophylaxis consisted in ciclosporine from day -1, and mycophenolate mofetil (15 mg/kg bid), starting from day 0. In the absence of GvHD, MMF was discontinued by day+50 and ciclosporine was tapered from day +60 to +90. Except for cord blood transplantation, patients received 3 prophylactic increased doses of donor lymphocyte infusions (DLI) if they were in CR and GvHD-free at day +120 or 30 days after discontinuation of immunosuppressive agents starting at 1x106 CD3+ cells/kg. Between August 2010 and March 2013, 26 consecutive AML patients in CR1 were included; 11 males and 15 females with a median age at allo-HSCT of 55 years (range: 24-67), 19 (73%) were de novo AML and 7 (27%) secondary AML. According to cytogenetics and molecular markers, 22 (85%) were unfavourable and 4 (15%) were in intermediate II category. Before allo-HSCT, to reach CR1, 20 (77%) patients received one induction chemotherapy and 6 (23%) needed 2 inductions. Cell source was PBSC for 23 (88%) patients, CB for 2 and BM for 1 patient. Donors were 10/10 HLA matched siblings in 9 (35%) patients, 10/10 HLA matched unrelated in 8 (31%) patients and HLA mismatched for the rest of patients [unrelated 9/10 (n=7), CB 4/6 (n=2)]. For ABO compatibility, 13 (50%) were compatible, 5 (19%) had minor incompatibility and 8 (31%) had major incompatibility. For conditioning, 6 (23%) patients received TBI, 13 (50%) received 4 days BU and 7 (27%) received 2 days BU. After transplantation, 23 (88%) patients engrafted, 3 patients died early (1 at day 1 and 1 at day 2 both from septic shock; 1 at day 8 from pneumonia and pericardial effusion). At day 90 post-allo-HSCT, 18 (78%) showed total donor chimerism and 5 (22%) had mixed chimerism and all patients were in CR. There were 6/23 (26%) patients with acute GvHD [2 gr I, 2 gr II and 2 gr III] and 5/23 (22%) chronic GvHD [4 limited and 1 extensive], all before DLI. After a median follow-up of 9 months (range: 0.03-35), the 2-years probability of overall survival (OS) for the whole population was 58% (confidence interval: 47-69) (Figure 1a) and the 2 years cumulative incidence of relapse was 18% (confidence interval: 17-19). At the latest follow-up, 16/23 (70%) engrafted patients were alive, 4/23 (17%) patients relapsed and died later and 3/23 (13%) patients died from transplant related infectious complications. No statistical difference in terms of OS and relapse incidence was found between the 3 types of conditioning, (Figure 1b). FLAMSA-RIC regimen followed by allo-HSCT showed promising results in high-risk CR1 AML patients. Because of some early severe infections, an efficient prophylactic anti-infectious strategy is recommended. The use of BU instead of TBI does not impact on transplant outcomes. Disclosures: No relevant conflicts of interest to declare.

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Azacitidine Maintenance after Allogeneic Stem Cell Transplantation Is Feasible in Patients with Acute Myeloid Leukemia and Myelodysplasia

Blood ◽

10.1182/blood.v124.21.5884.5884 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5884-5884 ◽

Cited By ~ 6

Author(s):

Ahmad Antar ◽

Mohamed A Kharfan-Dabaja ◽

Hussein Abou Ghaddara ◽

Rami Mahfouz ◽

Ali Bazarbachi

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

High Risk ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Maintenance Therapy ◽

Myeloid Leukemia ◽

Abnormal Karyotype ◽

Acute Myeloid

Abstract Background: 5-Azacidine (5-AZA) is a DNA hypomethylating agent with proven clinical activity in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A recent non-randomized study reported promising results with the use of lower doses of 5-AZA as maintenance therapy after hematopoietic stem cell transplantation (HSCT). It is important to note that 5-AZA has an immunomodulatory effect and might enhance the graft-versus-leukemia (GVL) effect. Here, we report the successful use of 5-AZA maintenance following allogeneic HSCT in patients with high risk AML and MDS. Patients and methods: Nine patients (M=6, F=3; median age=49 (36-65) years ) with high-risk AML (n=6 including 2 abnormal karyotypes) or MDS (n=3 including 1 abnormal karyotype) received 5-AZA as post-transplant maintenance at a dose of 32mg/m2 daily for 5 days every 4 weeks starting at a median time of 100 (30-210) days post-transplant. All patients were in complete remission at initiation of 5-AZA. A median of 12 cycles (1-18) were delivered. Patients’ characteristics, treatment details, response and side effects are summarized in Table I. Results: After a median follow-up of 19 months post HSCT and 15 months after starting 5-AZA treatment, five patients with normal karyotype are still in CR. Conversely, all three patients with abnormal karyotype rapidly developed disease recurrence while they were receiving 5-AZA after a median of 3 months. Overall, the actuarial 1-year progression free and overall survival rates were 65% and 90%, respectively. 5-AZA was generally well tolerated with only mild thrombocytopenia observed in 2 patients. No clinically evident graft-versus-host disease exacerbation was observed. Conclusion: These results suggest that Low-dose 5-AZA is an effective maintenance therapy post- allogeneic SCT in high-risk AML and MDS particularly when a normal diploid karyotype is present. The relative lack of efficacy in the presence of an abnormal karyotype is intriguing and questions whether these subjects might benefit from higher doses of 5-AZA or other novel therapies within the context of a well-designed clinical trial. Prospective clinical trials and longer follow-up are needed to confirm these observations. Abstract 5884 TABLE I.Patients characteristics and Outcomes After Azacitidine maintenanceSubject #123456789Age at transplant655848433649495851genderMMFMFMFMMDiseaseAMLAMLAMLAMLSecondary AMLSecondary AMLMPD/MDSMDS (RAEB-2)MDS (RAEB-2)cytogeneticnormalnormalT(6,9)normalDel 5normalnormalnormalHypoploidy(43-45)Molecular abnormalityNoneNoneNoneFLT3 ITDNoneNoneNoneNoneNoneDisease status at HSCTCR2CR3CR1CR1RefractoryCR1PRPRCR1Donor typeMRDMRDMRDMRDMUDMRDMRDMRDMRDConditioningFB2+ATGFB3+ATGFB3+ATGFB4+ATGFB3+ATG+ TBI (4Gy)FB4+ATGFB4+ATGFB3+ATGFB2+ATGGVHD prophylaxisCSACSACSACSACSACSACSACSACSA, mycophenolate mofetilTime from HSCT to 5-AZA (days)37701001503021010055104Disease status at 5-AZACRCRCRCRCRCRCRCRCRnb of cycles12131241218129ToxicityNoneNoneNoneNoneGrade II thrombocytopeniaGrade II thrombocytopeniaNoneNoneNoneGVHD after 5-AZANoNoYesYesYesNoYesNoNoDisease recurrencenonoyesnoyesnononoyesSalvage therapy if recurrenceN/AN/AChemotherapy followed by DLIN/ANoneN/AN/AN/AChemotherapy followed by DLIProgression free survival, months13+24+124+319+21+18+10Status at last follow upCRCRCRCRdiedCRCRCRCRSurvival, months13+24+18+24+519+21+18+34+ Stem cell source for all patients: peripheral blood; CR: complete remission; PR: partial remission; CSA: cyclosporine A; MRD: matched related donor; MUD: matched unrelated donor; PBSC: peripheral blood stem cell; CCR: continuous complete remission; FB4: 5 days fludarabine plus 4 days busulfan (130 mg/m2/day); FB3: 5 days fludarabine plus 3 days busulfan (130 mg/m2/day); FB2: 5 days fludarabine plus 2 days busulfan (130 mg/m2/day) ATG: anti-thymoglobuline; DLI: donor lymphocyte infusion. Disclosures Off Label Use: Azacitidine maitenance post HSCT.

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A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.99.99 ◽

2016 ◽

Vol 128 (22) ◽

pp. 99-99 ◽

Cited By ~ 26

Author(s):

Jorge E. Cortes ◽

Florian H. Heidel ◽

Michael Heuser ◽

Walter Fiedler ◽

B. Douglas Smith ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

P Value ◽

Employment Equity ◽

Equity Ownership ◽

Acute Myeloid

Abstract Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML). Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events. Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm. Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004). Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS. Disclosures Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heuser:Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Fiedler:Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Teva: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; GSO: Other: Travel. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Robak:Pfizer: Research Funding. Montesinos Fernandez:Gamida Cell: Consultancy. Ma:Pfizer: Employment, Equity Ownership. Shaik:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.

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Adoptive Immunotherapy with Haploidentical Kir Ligand-Mismatched Natural Killer Cells In Elderly High Risk Acute Myeloid Leukemia Patients: Biological and Clinical Results of A Pilot Study

Blood ◽

10.1182/blood.v116.21.4287.4287 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4287-4287

Author(s):

Antonio Curti ◽

Loredana Ruggeri ◽

Alessandra D'Addio ◽

Andrea Bontadini ◽

Valeria Giudice ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Nk Cells ◽

Natural Killer ◽

Myeloid Leukemia ◽

Nk Cell ◽

Conflicts Of Interest ◽

Interleukin 2 ◽

Active Disease ◽

Acute Myeloid

Abstract Abstract 4287 Purpose: To evaluate safety, feasibility and anti-leukemia potential of haploidentical KIR-L mismatched natural killer (NK) cell infusion in elderly high risk acute myeloid leukemia (AML) patients. Patients and Methods: Thirteen patients (5 active disease, 2 molecular relapse and 6 complete remissions) with median age 62 years (range 53–73) received NK cell infusion after immunosuppressive chemotherapy (fludarabine/cyclophosphamide), followed by interleukin-2. Highly purified CD56+CD3- NK cells from haploidentical KIR-L mismatched donors were used. The median number of infused NK cells was 2.74 × 106/Kg. T cells were less than 105/Kg. NK cell chimerism, phenotyping, and functional assays were performed. Results: No significant toxicity, including graft versus host disease, related to NK cell infusion was observed. Among patients with active disease, 1/5 obtained transient complete remission (CR), whereas 4/5 patients had no clinical benefit. Both patients in molecular relapse obtained CR, which lasted 9 and 4 months. Three/6 patients in morphologic CR are disease-free after 34, 32 and 18 months. Donor NK cells were demonstrated in the peripheral blood (PB) of all evaluable patients with a peak at day 10 after infusion and, in some cases, also in the bone marrow (BM). NK alloreactivity was demonstrated in vivo by the detection of donor-derived postinfusion NK clones capable of killing recipient targets. Conclusion: Infusion of purified CD56+CD3- NK cells is feasible and safe in elderly high risk AML patients. Adoptively transferred NK cells, which can be detected in PB and BM after infusion, are alloreactive against recipient cells and may induce an anti-leukemic activity. Disclosures: No relevant conflicts of interest to declare.

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Prospective Evaluation of Azacitidine Maintenance Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v126.23.5476.5476 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5476-5476 ◽

Cited By ~ 1

Author(s):

Harinder Gill ◽

Albert Kwok Wai Lie ◽

Yok Lam Kwong ◽

Anskar Y.H. Leung

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

High Risk ◽

Myeloid Leukemia ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Poor Risk ◽

Acute Myeloid

Abstract Introduction and aim. Relapse following allogeneic hematopoietic stem cell transplantation (HSCT) is a major cause of treatment failure and is associated with a poor prognosis. Overall survivals are around 50% at 5 years following allogeneic HSCT in intermediate and high risk AML. Survivals remain less than 20% in poor-risk and very poor-risk patients based on the cytogenetic profile. Thus, prevention of relapse following allogeneic HSCT remains an unmet clinical need. Low-dose azacitidine maintenance post-HSCT has been shown to augment graft-versus-leukemia effect and may prolong survivals. We aim to prospectively evaluate the effect of azacitidine maintenance following allogeneic HSCT in high risk AML and MDS. Method. Consecutive patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in remission following first allogeneic HSCT or second allogeneic HSCT (from the original donor) were recruited. High risk AML in this study comprised patients with poor risk karyotype, secondary AML transformed from underlying MDS, presence of fms-like tyrosine kinase 3-internal tandem duplication (FLT3 -ITD) and non-remission before HSCT. Azacitidine was administered at 100mg daily for 3 days per cycle every 28 days until progression or a maximum of 8 cycles. The clinicopathologic and treatment characteristics were determined. The occurrence of graft-versus-host disease (GVHD) was determined. DNA chimerism was determined in the bone marrow before the initiation of azacitidine, after 4th and 8th cycles of azacitidine and at 1 year. DNA chimerism was determined by quantification of polymorphic short tandem repeat sequences. The progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier analysis. Results. Thirty-four patients with high-risk AML (N=31) and MDS (N=3) were recruited. The median duration of follow-up was 14 months (range: 2 - 44 months). Twenty-two patients received azacitidine maintenance after first allogeneic HSCT, whereas 12 patients received azacitidine maintenance after a second allogeneic HSCT from the same donor following relapse from a first allogeneic HSCT For patients receiving azacitidine after first HSCT, at a median follow-up of 18.5 months (range: 5- 36 months), the median PFS was not reached, and the median OS was 32 months (95% confidence interval [C.I.]: 24.85-39.15). The 24-month PFS and OS were 66.1% and 73.2% respectively. Acute and chronic GVHD occurred in 7 (31.8%) and 17 patients (77%). For patients receiving azacitidine after second HSCT, at a median follow-up of 14 months (range: 9 - 46 months), the median PFS and OS were 9 months (95% C.I.:6.94-11.04) and 14 months (range: 11.77 - 16.23 months). The 24-month PFS and OS were 25% and 14% respectively. Acute and chronic GVHD occurred in 1 (8.3%) and 5 (41.7%) patients respectively. In both groups, 100% donor chimerism was achieved during azacitidine maintenance. Conclusion. Azacitidine maintenance following first allogeneic HSCT resulted in favorable 2-year survivals in selected patients with high-risk AML and MDS. Nevertheless, survivals were poor despite azacitidine maintenance after second allogeneic HSCT from the same donor. Full donor chimerism was maintained during azacitidine maintenance. Disclosures No relevant conflicts of interest to declare.

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Azacitidine Alone Or The Combination With Valproic Acid As a Bridge Therapy For Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes Before Transplantation

Blood ◽

10.1182/blood.v122.21.2812.2812 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2812-2812

Author(s):

Cristina Calderón Cabrera ◽

Jose F Falantes ◽

Marina Gómez ◽

Rocío Parody ◽

Francisco J Márquez Malaver ◽

...

Keyword(s):

Bone Marrow ◽

Valproic Acid ◽

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Refractory Anemia ◽

Intensive Chemotherapy ◽

Bone Marrow Blast ◽

Acute Myeloid

Abstract Introduction Intensive chemotherapy (IC) followed by allogeneic stem cell transplantation (AlloSCT) is standard of care for intermediate and high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). However, morbidity and lack of response are common with IC. Retrospective data have shown similar outcomes with azacitidine (AZA) when compared to IC. Moreover, the combination of AZA with other epigenetic modifiers such as HDAC inhibitors seems to improve quality of responses. Aim Evaluate response, toxicity and feasibility of AlloSCT after AZA alone or the combination with valproic acid (VPA) as a bridge strategy in MDS and AML. Patients Nineteen consecutive patients (pts) receiving azacitidine alone (n=11) or in combination with valproic acid (VPA) (n=8) were analyzed. Median age of the cohort was 57 years (18-67). Diagnosis by WHO classification included: RAEB-2 (n=10/19; 52.6%), RAEB-1 (n=2; 10.5%), RCMD (n=2; 10.5%) and AML (n=5; 26.3%). Four out of 5 AML pts had bone marrow blast count >30% at diagnosis. In MDS patients, according to International Prognostic Scoring System (IPSS): 1 intermediate-1 (7%), 3 intermediate-2 (21.5%) and 10 high-risk (71.5%) and by IPSS-revised (IPSS-R): 1 intermediate (7%), 4 high (29%) and 9 very high (64%). Regarding karyotype, in MDS: 5 good (35.7%), 2 intermediate (14.3%), 6 poor (43%) and 1 insufficient metaphases (7%) whereas in AML Patients 1 intermediate (20%) and 4 adverse (80%). Eleven out of 19 pts (58%) received AZA as frontline therapy. The remaining 8 pts experienced disease relapse after intensive chemotherapy (IC) or had primary refractory AML, and subsequently received AZA plus VPA as salvage therapy. Median courses of previous IC were 2 (1-4). For pts receiving AZA/VPA, median bone marrow blast % and leukocyte were 31% (2-60) and 1.9x10e9/L (0.3-4.2) when therapy started. Most of these pts had refractory or relapsed disease (n=6/8; 75%) with 4 pts displaying poor karyotype. Treatment schema was AZA (75 mg/m2, 7d/4w) and VPA (20-25 mg/kg/d, 10 days). Results At analysis, 17/19 pts are evaluable for response. Median courses of AZA: 5 (2-53). Overall response (ORR) at 4 courses: 59% (CR=4/17; 23.5%, CRm=5/17; 29.5% and PR=1/17; 6%). For pts receiving AZA/VPA (Table 1, n=8), ORR: 83% (CR=1/6; 17% and CRm=4/6, 66%) in 6 evaluable pts. Median courses to response were 2. Among pts achieving CR/CRm/PR/SD at 4 courses (n=12), 2 pts lost response prior to AlloSCT. Most frequent toxicity was hematological (58% grade 3-4) with no treatment related mortality attributable to AZA/VPA. Eleven out of 19 pts (58%) received AlloSCT (matched related=5, matched unrelated=5, haploidentical=1). Causes for not proceeding to AlloSCT: Disease progression (n=4; 50%), infection (n=1; 12.5%), pending evaluation after 2 courses (n=2; 25%) and 1 pt (12.5%) scheduled for matched unrelated AlloSCT. Conditioning regimen: Reduced intensity (9/11) and myeloablative (2/11). Tacrolimus/sirolimus (50%) and cyclosporine/MMF (40%) as GVHD prophylaxis. With a median follow-up of 4 months after AlloSCT (1-26), only 1 pt developed acute GVHD, 1 had early relapse postransplant and 9 patients continue in CR at last follow up. Conclusions AZA alone and particularly the combination AZA/VPA prior to AlloSCT is a well-tolerated and highly effective schema even in pts with poor prognostic features and refractory to prior IC. Adequate selection of pts (leukocyte <10x10e9/L) and larger prospective studies are needed to assess the role of this strategy. AML; Acute myeloid leukemia, RAEB-2; Refractory anemia with excess blasts type 2, RAEB-1; Refractory anemia with excess blasts type 1, IM; Insufficient metaphases, IC; Intensive chemotherapy, CR; Complete response, CRm; marrow CR, NA; Not assessable (pending bone marrow evaluation). 1Refractory to IC. 2Relapsed after IC. aBone marrow evaluation after 2 and 4 courses of therapy Disclosures: No relevant conflicts of interest to declare.

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Prognostic Prediction of Novel Risk Scores (AML-DRG and AML-HCT-CR) in Acute Myeloid Leukemia Patients with Allogeneic Hematopoietic Stem Cell Transplantation

10.21203/rs.3.rs-1045274/v1 ◽

2021 ◽

Author(s):

Weijie Cao ◽

Xiaoning Li ◽

Ran Zhang ◽

Zhilei Bian ◽

Suping Zhang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

High Risk ◽

Myeloid Leukemia ◽

Predictive Accuracy ◽

Risk Groups ◽

Hematopoietic Stem ◽

Post Transplant ◽

Acute Myeloid

Abstract Purpose We aimed to validate and prove the novel risk score models of acute myeloid leukemia (AML)-specific disease risk group (AML-DRG) and AML-Hematopoietic Cell Transplant-composite risk (AML-HCT-CR) in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (AHCT). Methods One hundred twenty-three AML (non-APL) patients underwent AHCT was enrolled in this study. Patients were stratified into 3 AML-DRG and 4 AML-HCT-CR risk groups. Of the 123 patients, 57 (46.3%) were females, and the median age was 31 years (range 12 to 62 years). All patients received myeloablative conditioning. Median follow-up was 46 months (range 1 to 94 months). AML-DRG and AML-HCT-CR score models were applied with the overall survival (OS) and progression-free survival (PFS) analysis after the clinical follow-up. Results For the AML-DRG model, the 3-year OS in the low, intermediate and high-risk groups were 65.4%, 34.9% and 8.3%, respectively (p<0.001). The corresponding 3-year PFS were 64.0%, 34.9% and 8.3% (p<0.001). The OS predictive accuracy measured by C-index was 0.680. In the AML-HCT-CR model, the 3-year OS in the low, intermediate, high and very high-risk groups were 65.4%, 52.0%, 11.1% and 8.3%, respectively (p<0.001). The corresponding 3-year PFS were 64.0%, 52.0%, 11.1% and 8.3% (p<0.001). The OS predictive accuracy measured by C-index was 0.705. The AML-DRG and AML-HCT-CR models significantly predicted cumulative incidence of relapse (p=0.002; p=0.005). But both scores were not associated with NRM (p=0.314; p=0.095). Univariate analysis showed that the AML-DRG model could better stratify AML patients into different risk groups compared to the AML-HCT-CR model. Multivariate analysis confirmed that prognostic impact of AML-DRG and AML-HCT-CR models on post-transplant OS was independent to age, sex, conditioning type, transplant modality, and stem cell source (p<0.001; p<0.001). Conclusions The AML-DRG and AML-HCT-CR models can be used to effectively predict post-transplant survival in patients with AML receiving AHCT in our center. Compared to AML-HCT-CR score, the AML-DRG score allows better stratification and improved survival prediction of AML patients post-transplant.

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Allogeneic Stem Cell Transplantation in Patients with Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndromes: Effect of Patient Characteristics and Treatment History.

Blood ◽

10.1182/blood.v116.21.4577.4577 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4577-4577

Author(s):

Francesco Spina ◽

Emilio Paolo Alessandrino ◽

Lucia Farina ◽

Raffaella Milani ◽

Francesca Bonifazi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Treatment History ◽

Acute Myeloid

Abstract Abstract 4577 Patients with therapy-related acute myeloid leukemia (tAML) and myelodysplastic syndromes (tMDS) have a bad prognosis. Allogeneic stem cell transplantation (alloSCT) is potentially curative, but the majority of these patients die because of the high incidence of relapse (RI) and non relapse mortality (NRM). Since it is critical to understand which patients should receive alloSCT, we designed this retrospective study to assess which patients’ characteristics may predict the alloSCT outcome in tAML/tMDS. All the patients affected by tAML or tMDS and allografted in 4 Italian hematology units between 1998 and 2009 were included. Total patients were 28: 24 (86%) had tAML, 4 (14%) had tMDS. Patients had a median age of 49 years (range 21–65) at transplant; 15 patients were female (54%). Previous neoplasia was lymphoma in 23 patients (82%, 15 Hodgkin and 8 non-Hodgkin), or non-hematologic cancer (5, 18%) like breast carcinoma (2), seminoma (1), testicular embryonal carcinoma (1), and osteosarcoma (1). Previous cancer had been treated with chemotherapy (CT, 7 patients, 25%), radiotherapy (RT, 4 patients, 14%), or both (17, 61%). Fourteen patients (50%) had received >=2 therapy lines, 6 (21%) had received autologous stem cell transplant. tAML/tMDS occurred after a median time of 86 months (range 13–253) after the previous cancer treatment. Cytogenetic analysis was performed in 24 patients (86%): 8 patients (33%) had intermediate risk and 16 (57%) high risk cytogenetics according to Medical Research Council AML10 Trial definitions. Twenty-three patients (82%) received induction CT for tAML/tMDS, 19 (68%) received consolidation; 5 patients (18%) received upfront alloSCT. Induction consisted of idarubicin+cytarabine+/−etoposide (12 patients, 43%) or fludarabine+cytarabine+/−idarubicin (11 patients, 39%); 15 patients (54%) had an infection after induction. Median time from tAML/tMDS diagnosis to alloSCT was 5.7 months (range 0–25). At transplant, 10 patients (36%) had a Karnofsky Performance Status (KPS)<=80% and 13 (46%) a Sorror comorbidity score >1. Donor was identical sibling for 9 patients (32%), and alternative for 19 patients (68%): mismatched related (1, 3%), matched unrelated (15, 54%) or haploidentical (3, 11%). Disease status of patients at transplant was as following: 12 patients (43%) were in CR (11 in CR1), 4 (14%) in PR and 7 (25%) in PD; 5 patients (18%) received alloSCT at diagnosis. Patients underwent reduced intensity (11 RIC, 39%) or myeloablative (17, 61%) alloSCT. Myeloablative conditioning was mainly busulfan-based (15 patients, 54%); the majority of RIC patients received thiotepa+cyclophosphamide-based conditioning (9, 32%). Twelve patients (43%) are alive at last follow-up, 7 patients (25%) died of disease, 9 (32%) died of NRM. The main reason of death by NRM was infection (8 patients, 29%). Median follow-up of surviving patients was 528 days (55-1704). One- and 2-years overall survival (OS) was 50% and 36%, progression free survival (PFS) was 42% and 38%. RI was 28% at both 1 and 2 years, NRM was 18% at 100 days, 30% at 1 year and 35% at 2 years. Nine (32%) patients had acute GVHD of grade >=2, 8 patients had chronic GVHD (cGVHD, 29%), 3 patients (11%) had extensive cGVHD. OS and PFS were reduced in patients with high-risk cytogenetics (p=0.03 and p=0.01, respectively) and KPS<=80% (p=0.008 and p<0.001). RI was higher in patients with KPS<=80% (p=0.02); high-risk cytogenetics increased RI (trend, p=0.08). Patients treated for previous neoplasia with >2 CT lines had a worse NRM (p=0.005) and a reduced OS (p=0.05); treatment type (CT vs RT vs CT+RT) did not have a significant impact on OS, PFS nor NRM. NRM was higher in patients who had infections after induction (p=0.009), or received consolidation (p=0.03). AlloSCT after >180 days from tAML/tMDS diagnosis increased NRM (p=0.05). Conditioning (RIC vs myeloablative), donor type (identical sibling vs alternative) and type of previous neoplasia (hematologic vs non-hematologic) did not affect survival (OS and PFS), NRM and RI. In conclusion, alloSCT is effective in a minority of patients with tAML/tMDS. Survival is reduced by high risk cytogenetics and poor KPS. Number of previous treatments, infections after induction, and consolidation CT increase NRM. Thus, patients’ selection for alloSCT in tAML/tMDS setting should be based on cytogenetics, KPS, and treatment history. Prospective trials are awaited in order to confirm these results. Disclosures: Corradini: Novartis Pharmaceuticals, Inc: Consultancy; Genezyme: Consultancy; Roche: Speakers Bureau; Celegene: Speakers Bureau.

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