Acute Myelogenous Leukemia In Complete Remission Research Articles

Influence of Conditioning Regimen Intensity on Outcomes Post-Allogeneic Transplantation for AML in Complete Morphological Remission

Introduction: Acute myelogenous leukemia (AML) is a major indication for allogeneic hematopoietic cell transplantation (alloHCT). Myeloablative (MAC) regimens are preferred for their intensity, however, reduced intensity conditioning regimens (RIC) have been increasingly used to permit older patients and patients with comorbidities to undergo transplant. The literature is conflicting regarding the comparison of outcomes between RIC and MAC patients. While MAC regimens are associated with less relapse, non-relapse mortality (NRM) is higher. RIC regimens on the other hand, demonstrate less NRM but higher relapse rates. We sought to compare RIC vs MAC regimens at our centre for alloHCT of AML in complete remission (CR). Methods: We retrospectively analyzed the outcomes of 451 patients that underwent alloHCT for AML at the Princess Margaret Cancer Centre (PMCC) with either RIC or MAC using various donors between the years 2015-2020. Primary endpoint was 2-year overall survival (OS), secondary endpoints included cumulative incidence of relapse (CIR), cumulative NRM, and GVHD free/relapse free survival (GRFS). Conditioning regimen intensity was determined as defined by Bacigalupo et al (BBMT 2009). Of the total cohort 331 patients received RIC and 121 MAC. Among MAC regimens, 59% received FLU(4)Bu(4) (Fludarabine 140mg/m2 + Busulfan 12.8mg/m2). Among RIC patients 71% received Flu(4)Bu(2)TBI(200) (Fludarabine 140mg/m2+ Busulfan 6.4 mg/m2 + TBI 200cGy). Results: Median age at transplant was 48 years (range: 19-67) for MAC recipients and 61 (range: 18-75) for RIC recipients (p<0.001). Other patient characteristics are described in Table 1. For the entire cohort at 2 years, the incidence of NRM was 19.1% for MAC (95% CI: 12.4-26.8) and 22.5% for RIC (95% CI: 18.1-27.1) (p=0.44). Two-year CIR was 19.8% (95% CI: 12.9-27.8) for MAC recipients and 24.5% (95% CI: 20.0-29.4) for RIC recipients (p=0.15). Two-year OS was 61% and 53% for MAC and RIC, respectively (p=0.02). Acute GVHD occurred in 58.3% of MAC recipients versus 46.8% of RIC recipients. Chronic GVHD occurred in 43.3% of the MAC recipients versus 38% of the RIC recipients. At two years GRFS was 40.8% (95% CI: 35.4-46.1) for MAC and 33.7% (95% CI: 25.0-42.6) for RIC, p=0.30. When examining the Disease Risk Index (DRI) for the entire cohort, OS for high risk was 43.3% (95% CI: 32.5-53.5) vs 66.6% (95% CI: 61-71) and 64% (95% CI: 38-80) for intermediate risk and low risk respectively, p<0.001. A propensity score (PS) matched analysis was done matching patients for age, HLA matching (mismatched vs full match), DRI (low, intermediate, high risk) and in vivo T cell depletion (yes vs no). Two-year OS was 67% for the MAC recipients (95% CI: 57-76) and 66% for the RIC recipients (95% CI: 56-75), p=0.95 (Figure 1a). NRM for MAC was 22% (95% CI: 14-30) versus 14% (95% CI: 8-22) for RIC, p=0.19. CIR at 2 years was 18.5% for MAC (95% CI 11-27) and 24.3% for RIC (95% CI: 16-33), p=0.22. GRFS at 2 years was 36% (95% CI: 26.4-45.7) for MAC and 48.3% (95% CI: 38-58) for RIC recipients, p=0.17. In the subgroup analysis examining matched related donor (MRD) recipients in particular, the OS at 2 years was for MAC 83.6% (95% CI: 66.8-91.3) vs 57.3% (95% CI: 45.1-67.7) for RIC, p=0.006 (Figure 1b) Two-year NRM was 10.3% for MAC vs 23.4% for the RIC group, p=0.14. CIR at 2 years was 12.2% for MAC vs 23.4% for RIC in the MRD setting, p=0.11. Conclusions: Our study shows that in the MRD setting there is a statistically significant improved survival, especially in patients with low and intermediate DRI scores. In other donor settings, there is no significant difference in outcomes between patients that undergo alloHCT with MAC vs RIC regimens. MAC conditioning regimens should continue to be the preferred choice of intensity for patients that may tolerate it. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Outcomes after Unrelated Double-Unit Cord Blood and Haploidentical Peripheral Blood Stem Cell Transplantation in Adults with Acute Myelogenous Leukemia: A Study on Behalf of Eurocord and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Unmanipulated haploidentical hematopoietic stem cell transplantation (HCT) with post-transplantation cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (haplo-PTCY) and unrelated double-unit umbilical cord blood transplantation (dUCBT) are feasible options for treating patients with high-risk acute myelogenous leukemia (AML). This study compared outcomes after dUCBT and haplo-HCT using peripheral blood stem cells (PBSCs) in adult patients with AML in complete remission (CR) who underwent transplantation in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers. In a population of adults with de novo AML in first or second CR, we compared outcomes after dUCBT (n = 165) and after haplo-PTCY PBSC (n = 544) performed between January 2013 and December 2018. Patients receiving in vivo antithymocyte globulin, Campath, or ex vivo T cell depletion were excluded. The median follow-up was 33 months for the haplo-PTCY arm and 52 months for the dUCBT arm. No statistically significant differences were observed between the 2 arms in the rates of grade II-IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 1.31; P = .18), grade III-IV acute GVHD (HR, 1.17; P = .56), chronic GVHD (HR, .86; P = .48), relapse (HR, 1.07; P = .77), nonrelapse mortality (NRM) (HR, .94; P = .77), leukemia-free survival (LFS) (HR, .99; P = .95), or overall survival (OS) (HR, .99; P = .97). Favorable cytogenetic risk was the sole factor predictive of lower relapse incidence (RI). Younger age at transplantation was associated with lower NRM and higher LFS and OS. Both dUCBT and haplo-PTCY with PBSCs can be considered valid approaches for adult AML patients in CR. New strategies should be investigated in both settings to define the most appropriate conditioning regimen and potentially decrease RI and NRM through better immune reconstitution and optimal supportive care.

Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia

Programmed death 1 (PD-1) is an integral component of acute myelogenous leukemia (AML) immune evasion, chemotherapy resistance, and disease progression. PD-1 inhibitors are being investigated as treatment for AML in combination with hypomethylating agents and cytotoxic chemotherapy with encouraging findings. Although allogeneic stem cell transplantation (alloSCT) remains the most established curative treatment for patients with relapsed and refractory AML in complete remission, there are limited data on the clinical outcomes and safety of immune checkpoint inhibitors (ICIs) prior to alloSCT in AML. In the present study, we compared clinical outcomes of 9 patients with AML receiving high-dose cytarabine followed by pembrolizumab in a phase II clinical trial (NCT02768792) prior to alloSCT versus a historical control group of 18 AML patients who underwent alloSCT without prior ICI exposure. The nonparametric Jonckheere-Terpstra test was used to test for a difference in the ordered severity categories of acute graft-versus-host disease (GVHD) within 100 days of transplantation. Time-to-event estimates for overall survival and relapse-free survival were calculated using the Kaplan-Meier method and compared using a log-rank test. One-year survival was not significantly different between the treatment groups (67% versus 78%; P=.34). 100-day mortality was 0% in the ICI group versus 17% in the control group, and there was no increase in grade III-IV acute GVHD in patients treated with pembrolizumab prior to alloSCT. No chronic GVHD was seen in patients treated with pembrolizumab prior to alloSCT and who received post-transplantation cyclophosphamide (PTCy) as part of their conditioning regimen. These findings reinforce the safety and feasibility of ICI therapy prior to alloSCT in patients with AML, and suggest that PTCy may abrogate GVHD risk and severity in patients who receive ICI prior to undergoing alloSCT for AML.

Less Is More: Superior Graft-versus-Host Disease-Free/Relapse-Free Survival with Reduced-Intensity Conditioning and Dual T Cell Depletion in Acute Myelogenous Leukemia.

In this study, we compared the outcomes of patients with acute myelogenous leukemia (AML) in complete remission treated with myeloablative conditioning (MAC) and those treated with reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HCT). In addition, we explored the efficacy of dual T cell depletion using anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) for the prevention of graft-versus-host disease (GVHD) in patients undergoing RIC allo-HCT. Our study cohort comprised 356 adults with AML in complete remission who underwent allo-HCT between 2013 and 2018. One hundred eleven patients (31.2%) received a MAC regimen, and 245 (68.8%) received an RIC regimen. One hundred seventy-one of the patients who received an RIC regimen (68.4%) received ATG, PTCy, and cyclosporine (ATG-PTCY-CsA) for GVHD prophylaxis in accordance with our institutional protocol. Data were collected retrospectively and updated in July 2019. With a median follow-up of 14.5 months (range, 0 to 76 months), 161 patients (45.2%) died, and 66 (18.5%) relapsed. Two-year overall survival (OS), relapse-free survival (RFS), and GVHD-free/RFS (GRFS) were 55%, 52.6%, and 35%, respectively. The intensity of the conditioning regimen, with or without ATG-PTCY-CsA, did not have a significant impact on OS and RFS. However, RIC in combination with ATG-PTCY-CsA was associated with a significantly lower cumulative incidence of acute GVHD and chronic GVHD. The use of RIC with ATG-PTCy-CsA was a significant predictor for higher GRFS secondary to the reduction of clinically relevant GVHD (P= .0001). In patients with AML, RIC allografts and dual T cell modulation with ATG and PTCy led to superior GRFS. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity using RIC, may result in better long-term quality of life for allo-HCT recipients.

Allogeneic Hematopoietic Cell Transplantation for Acute Myelogenous Leukemia in Remission - a Prospective Comparison of Three Different Donor Groups; Matched Sibling, Matched Unrelated, and Haploidentical Family Donors

Allogeneic hematopoietic cell transplantation (HCT) from HLA-matched sibling (MS) or unrelated donors (MU) is a well-established treatment for patients with intermediate/high-risk acute myelogenous leukemia (AML) in remission. When HLA-matched donors are not available, however, use of haploidentical family (HF) donors for HCT remains controversial.Therefore, we performed a prospective study, where patients with AML in complete remission (CR) underwent allogeneic HCT according to the donor priority of MS, MU, or HF donors. Conditioning regimen for MS-HCT was busulfan (3.2 mg/kg • 4 days)-cyclophosphamide (60 mg/kg • 2 days) or, for patients >55 years or with co-morbidity, busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (1.5 mg/kg • 3 days). Patients undergoing MU- or HF-HCT received busulfan (3.2 mg/kg • 2 days)-fludarabine (30 mg/m2 • 6 days)-Thymoglobulin (3 mg/kg • 3 days) (Lee K-H et al; Blood 2011;118:2609-2617; Am J Hematol 2011;86:399-405). Ex-vivo T cell depletion was not performed. GVHD prophylaxis included cyclosporine plus a short course of methotrexate.Between January 2010 and December 2014, 244 patients enrolled. Of those, 16 patients were excluded from the analysis (12 patients relapsed before HCT; 3 with major protocol violation; and 1 with incomplete data). Of remaining 228 patients, 81 underwent HCT from MS donors, 90 from MU donors, and 57 from HF donors. The donors for MU-HCT were younger and more male-dominant than those for MS- or HF-HCT. The characteristics of patients and their donors were summarized in Table 1.Table 1MS-HCT (n=81)UD-HCT (n=90)HF-HCT (n=57)P*Median age, yr (range)48 (19-66)43 (16-66)46 (17-69)Sex, male/female37/4444/4629/280.824CR1/CR276/582/847/100.098Chromosome risk,low**/intermediate/high/high-monosomal6/57/10/54/65/16/32/40/7/50.751Donor median age, yr (range)45 (18-63)28 (20-45)29 (15-58)Donor age, yrup to 2526-45over 454413629610193260.000Donor sex, male/female46/3576/1436/210.000Donor relation, parents/sibling/offspring7/24/26HLA allele mismatch/8 (GVH direction), 0/1/2/3/481/0/0/051/26/10/2/10/0/5/22/300.000Graft, bone marrow/peripheral blood28/530/900/570.000Median nucleated cell count, •108/kg (range)8.0 (0.9-19.0)10.8 (4.1-31.4)10.8 (5.1-19.3)Median CD34+ count, •106/kg (range)4.9 (0.8-18.0)8.0 (1.4-26.2)6.4 (2.4-25.7)*by Chi-square test; **Twelve patients with AML of low-risk chromosomal abnormality included 6 patients in CR2, 3 with c-kit mutation, and 3 with persistent aml1-eto or cbf beta-myh11 after induction chemotherapy.The median follow-up duration of 164 survivors in the study was 34.7 months (range, 3.7-63.6) after HCT. The donor-group effect on the HCT outcomes was described in Table 2. Patients who underwent MS-HCT showed slightly slower neutrophil engraftment and higher incidence of chronic GVHD. Otherwise, in terms of disease recurrence, NRM, graft failure, EFS, and OS, there was no significant difference according to the donor-type. For AML recurrence, cytogenetic risk was an independent prognostic factors (P =0.003; hazard ratio of low-risk to; intermediate-risk, 1.42; high-risk, 2.53; high-risk with monosomal karyotype, 5.47).Table 1MS-HCT (n=81)UD-HCT (n=90)HF-HCT (n=57)PCumulative incidence ( 95% confidence interval)*AML recurrence29% (19-40%)26% (17-36%)35% (20-51%)0.785Non-relapse mortality (NRM)8% (3-16%)7% (2%-16%)11% (4-21%)0.435Graft failure1% (0.1-6%)6% (2-12%)5% (1-13%)0.293ANC>500/uL median days (range)100% 13 (9-20)99%12 (10-45)98% 12 (6-22)0.049Platelet>20,000/uL median days (range)99% (86-100%) 14 (0-83)97% (88-99%) 13 (0-77)96% (83-99%) 14 (0-106)0.352Grades 2-4 acute graft-versus-host disease (GVHD)12% (6-21%)13% (7-21%)23% (13-34%)0.176Moderate to severe chronic GVHD39% (28-50%)22% (13-30%)23% (13-35%)0.04524-year survival**Event-free (EFS)63%69%54%0.381Overall (OS)62%74%64%0.077*compared by Gray's method; **compared by log-rank testOur study showed that, despite heterogeneity of baseline donor characteristics (age and sex), conditioning regimen, and graft source (bone marrow vs. peripheral blood), overall post-transplant outcomes were similar among recipients from MS-, MU-, and HF-donors. Therefore, for patients with AML in CR but without an HLA-matched donor available, HCT from a haploidentical family member may be considered. DisclosuresNo relevant conflicts of interest to declare.

Reduced Intensity Versus Myeloablative Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia

▪IntroductionReduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT) offer a potential treatment for otherwise incurable cases of acute myelogenous leukemia (AML) with less associated toxicity compared to myeloablative conditioning (MAC). Eradication of malignant cells after RIC depends largely on the graft-versus leukemia effect (GVL). These regimens are becoming increasingly popular, particularly in older patients or those with comorbidities. They may also be offered to otherwise healthy patients based on personal or physician preference, as there is growing evidence that overall survival may be equivalent for both treatments. We retrospectively reviewed the charts of Saskatoon Cancer Centre patients receiving either RIC or MAC to compare the incidence and grade of graft versus host disease (GVHD), progression free survival (PFS), and overall survival (OS).MethodsWe identified 74 patients who underwent HSCT for AML in complete remission (CR) between January 2000- December 2013. Of these patients, 55 received MAC and 19 received RIC.Median age at HSCT was 48 years (range 18-68). In the group receiving MAC, 36% of patients were >50 years, whereas 74% of patients receiving RIC were >50 yrs of age.ResultsPatients receiving RIC experienced greater incidence of chronic GVHD (63% vs 41%, p=.09) and relapse (54% vs 30%, p=.07). Incidence of acute GVHD was the same for either regimen (53%).Median overall survival was similar (39 vs 38 months), with lower early mortality in RIC later overtaking MAC at 27 months. Progression free survival demonstrated a non-statistically significant advantage for MAC (median 43 vs 49 months).ConclusionRIC has been associated with greater incidence of chronic GVHD and relapse, with no difference in overall survival. Patients receiving RIC are more likely to be >50 years of age, making comparisons challenging. The results of this review suggest that MAC is the preferred regimen for patients who can tolerate its toxic effects due to reduced incidence of chronic GVHD and relapse, however the similarity in overall survival makes the choice of either conditioning regimen reasonable. Future studies to identify the best conditioning regimen are warranted.Overall Survival [Display omitted] Progression Free Survival [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mobilized Peripheral Blood Stem Cells Compared with Bone Marrow as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced-Intensity Conditioning in Patients with Acute Myeloid Leukemia in Complete Remission: An Analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Reduced-intensity conditioning allogeneic stem cell transplant (RIC-alloSCT) is being increasingly used for patients with acute myelogenous leukemia (AML) with comorbidities. Few published data are currently available regarding for the use of peripheral blood stem cells (PBSCs) compared to bone marrow (BM) in the RIC-alloSCT using unrelated donors (URDs). This retrospective report compared the outcomes of PBSC versus BM RIC-alloSCT. Between 2000 and 2007, 602 patients with AML in complete remission (CR) underwent RIC-alloSCT from URDs with PBSC (508) or BM (94) grafts. Recipient's age was higher in the PBSC versus BM groups 57 (range, 17-77 years) and 51 (range, 17-76 years), respectively (P < .0001). Leukemia features and disease status at RIC-alloSCT were also comparable between the PBSC versus BM groups. Engraftment was achieved in 97% and 96% with BM versus peripheral blood (PB), respectively. Acute graft-versus-host disease (aGVHD) grade >II was significantly higher in the PBSC group: 27% versus 12% in the BM group (P < .002). Similarly, chronic graft-versus-host disease (cGVHD; at 2 years) was somewhat higher in the PBSC group with 43% ± 3% versus 35% ± 6% in the BM group, respectively (P = .04). The 2-year probabilities of leukemia-free survival (LFS) were 46% ± 3% for the PBSC group in comparison to 43% ± 6% for the BM transplant group (P = NS), whereas relapse incidence was significantly higher in the BM versus the PB transplant group: 46% ± 6% versus 32% ± 3%, respectively (P = .014). Non-relapse mortality (NRM) was significantly higher for the PBSC versus the BM group: 28% ± 2% versus 13% ± 4%, respectively (P = .004). In multivariate analysis, after adjustment for differences between both groups, the PBSC group was associated with a higher incidence of aGVHD (grade II-IV; hazard ratio [HR] = 2.33; P = .06), higher NRM (HR = 2.3; P = .015), and a decreased relapse incidence (HR, 0.61; P = .02) with no statistical difference of LFS between the 2 groups (P = .88). In conclusion, our results indicate significantly higher incidence of aGVHD and NRM and a lower incidence of relapse but not statistically different LFS comparing unrelated PBSC to BM grafts after RIC-alloSCT.

The prognostic value of serum lysozyme activity in acute myelogenous leukemia

Serum lysozyme activity was measured in samples from adult patients with acute leukemia, malignant tumors, and in normal adults. Twenty-eight adult patients with acute myelogenous leukemia (AML) had significantly elevated levels of lysozyme at diagnosis, and none of the adults fell within the normal range. Thirty-two patients with AML in complete remission had lysozyme levels comparable to normal adults, whereas patients with AML in relapse (eight cases) also had abnormally high levels of lysozyme activity. Ten patients with AML in remission and off therapy also had normal lysozyme levels. Three patients with acute lymphatic leukemia had normal lysozyme levels, while one child with monomyelocytic leukemia had substantially elevated lysozyme levels before treatment. It seems that in patients in remission and with normal blood values, the serum lysozyme activity is valuable for monitoring the remission.