Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India

Purpose There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML). Patients and Methods We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%). The 5-year overall survival (OS) and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1), second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively ( P < .001). From 2007, reduced intensity conditioning (RIC) with fludarabine and melphalan (Flu/Mel) was used in a majority of patients in CR1 (n = 67). Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38). Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% ( P = .003) and 63.8 ± 6.4% versus 32.3 ± 7.9% ( P = .002), respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients.

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Acute Myeloid Leukemia Treatment Outcomes: First Report from Single Center Retrospective Study in Kazakhstan

10.21203/rs.3.rs-757253/v1 ◽

2021 ◽

Author(s):

Jamilya Saparbay ◽

Gulnara Kulkayeva ◽

Vadim Kemaykin ◽

Aset Kuttymuratov ◽

Zhanna Burlaka ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Good Prognosis ◽

Event Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common hematological malignancy in adults. In the last decade, internationally approved AML treatment guidelines, including hematopoietic stem cell transplantation are widely used in Kazakhstan. The categorization of acute myeloid leukemia was done according to the French-American British classification. The prognosis of patients at the time of diagnosis was determined by cytogenetic tests following the guidelines of the European LeukemiaNet. The overall survival and event-free survival were analyzed using the Kaplan-Meier method, and hazard ratios were defined with Cox regression. Totally 398 patients with AML were treated in the National Research Oncology Center between 2010 and 2020. The mean age was 38.3 years. We have found the correlation between ethnicity, cytogenetic group, white blood cell count, and treatment approaches with overall and event-free survival. There was a significantly longer OS in a cytogenetic group with a good prognosis compared with intermediate and poor prognosis. The median survival time in the group with a good prognosis was 43 months, 23 months in the intermediate group (p=0.7), and 12 months in the poor prognosis group (p=0.016). There was a significantly longer OS for the group of patients who received hematopoietic stem cell transplantation (HSCT), 52 months versus 10 months in the group who received chemotherapy only, p-value < 0.0001. Prognostic factors, such as cytogenetic group, initial WBC count, and treatment approaches are significantly associated with patient survival. Our study data were consistent with previous reports.

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Clinical Relevance of IDH1 and IDH2 Mutations and Single Nucleotide Polymorphism (SNP) rs11554137 in Patients with Acute Myeloid Leukemia Treated with Stem Cell Transplant in First Complete Remission

Blood ◽

10.1182/blood.v118.21.4643.4643 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4643-4643

Author(s):

Hala Abalkhail ◽

Naeem A. Chaudhri ◽

Claudia Ulrike Walter ◽

Hazzaa Al Zahrani ◽

Randa Nounou ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Complete Remission ◽

Myeloid Leukemia ◽

Intensive Chemotherapy ◽

Event Free Survival ◽

Free Survival ◽

Snp Polymorphism ◽

First Complete Remission ◽

Acute Myeloid

Abstract Abstract 4643 Background: Mutations in the genes encoding for the cytosolic isocitrate dehydrogenase 1 (IDH1) and the mitochondrial version of this enzyme (IDH2) have been reported in acute myeloid leukemia (AML) and other types of cancer. Presence of these mutations in AML correlated with more aggressive disease in some studies, but other studies did not find significant correlation with outcome when patients were treated with intensive chemotherapy. The polymorphism at rs11554137 in IDH1 was reported to correlate with inferior outcome in cytogenetically normal AML patients. Most of the studies evaluating the prognostic relevance of IDH1, IDH2 and the rs11554137 polymorphism were reported in patients treated with standard chemotherapy. The prognostic significance of these markers is not fully studied when AML patients are treated with intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the prognostic value of the IDH1, IDH2, and rs11554137 polymorphism in patients with AML treated with HSCT in first complete remission (CR1). Methods: Samples from 69 patients with AML were analyzed for mutations in IDH1, IDH2, and the SNP rs11554137 by direct sequencing. All patients were diagnosed with AML, treated with chemotherapy followed by HSCT in CR1. They included intermediate (N=42) and adverse (N=27) cytogenetic risk groups. Results: The R132H and the SNP C to T change at rs11554137 (silent G105) in IDH1 were detected in 5 (7%) and 6 (9%) of 69 AML patients. The IDH2 mutations (N=5; 7%) included R140Q, 172K, and T169A. Patients with IDH1 or IDH2 mutations did not differ significantly in their overall survival, event free survival, or time to relapse from those without mutation. In addition, the rs11554137 SNP polymorphism did not correlate with outcome in this group of AML patients. We also looked at the combination of mutations as compared with cytogenetic risk and found no difference in survival or event free survival based on IDH1 or IDH2 mutations or rs11554137 polymorphism in the intermediate cytogenetic risk group. Conclusion: The data suggests that HSCT after intensive chemotherapy in CR1 may neutralize the negative prognostic impact of IDH1 and IDH2 or the rs11554137 SNP polymorphism. However, the number of cases is relatively small and further studies with larger number of cases are needed. Disclosures: No relevant conflicts of interest to declare.

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First report from a single center retrospective study in Kazakhstan on acute myeloid leukemia treatment outcomes

Scientific Reports ◽

10.1038/s41598-021-03559-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

G. U. Kulkayeva ◽

V. M. Kemaykin ◽

A. M. Kuttymuratov ◽

Z. I. Burlaka ◽

J. Z. Saparbay ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Good Prognosis ◽

Event Free Survival ◽

Hematopoietic Stem ◽

Free Survival ◽

Acute Myeloid

AbstractAcute myeloid leukemia (AML) is the most common hematological malignancy in adults. In the last decade, internationally approved AML treatment guidelines, including hematopoietic stem cell transplantation are widely used in Kazakhstan. The categorization of acute myeloid leukemia was done according to the French-American British classification. The prognosis of patients at the time of diagnosis was determined by cytogenetic tests following the guidelines of the European LeukemiaNet. The overall survival and event-free survival were analyzed using the Kaplan–Meier method, and hazard ratios were defined with Cox regression. In total, 398 patients with AML were treated in the National Research Oncology Center between 2010 and 2020. The mean age was 38.3 years. We found a correlation between ethnicity, cytogenetic group, white blood cell count, and treatment approaches with overall and event-free survival. There was a significantly longer OS in a cytogenetic group with a good prognosis compared with intermediate and poor prognosis. The median survival time in the group with a good prognosis was 43 months, 23 months in the intermediate group (p = 0.7), and 12 months in the poor prognosis group (p = 0.016). There was a significantly longer OS for the group of patients who received hematopoietic stem cell transplantation (HSCT), 52 months versus 10 months in the group who received chemotherapy only, p-value < 0.0001. Prognostic factors, such as cytogenetic group, initial WBC count, and treatment approaches are significantly associated with patient survival. Our study data were consistent with the most recent studies, available in the literature adjusted for the population in question.

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Individualized prediction of leukemia‐free survival after autologous stem cell transplantation in acute myeloid leukemia

Cancer ◽

10.1002/cncr.32344 ◽

2019 ◽

Vol 125 (20) ◽

pp. 3566-3573 ◽

Cited By ~ 6

Author(s):

Roni Shouval ◽

Myriam Labopin ◽

Norbert C. Gorin ◽

David Bomze ◽

Mohamed Houhou ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Autologous Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Free Survival ◽

Individualized Prediction ◽

Acute Myeloid

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Effect of Diagnosis (Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, or Acute Myeloid Leukemia [AML]) on Outcome of AML-Type Chemotherapy

Blood ◽

10.1182/blood.v90.8.2969 ◽

1997 ◽

Vol 90 (8) ◽

pp. 2969-2977 ◽

Cited By ~ 171

Author(s):

Elihu Estey ◽

Peter Thall ◽

Miloslav Beran ◽

Hagop Kantarjian ◽

Sherry Pierce ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Multivariate Analyses ◽

Patient Characteristics ◽

Refractory Anemia ◽

Event Free Survival ◽

Free Survival ◽

Current Medical Practice ◽

Acute Myeloid

Abstract In current medical practice, patients with refractory anemia with excess blasts in transformation (RAEB-t), and especially patients with RAEB, receive chemotherapy regimens (AML Rx) administered to patients with acute myeloid leukemia (AML) less often than do patients with AML. These entities are distinguished primarily by marrow blast percentage (5% to 19% RAEB, 20% to 29% RAEB-t, and ≥30% AML). The poor prognosis of many RAEB or RAEB-t patients, if untreated, led us to give them AML Rx using the same plan as for AML. The purpose of this analysis was to see if diagnosis (RAEB, RAEB-t, or AML) affected outcome. We treated 372 patients with AML (acute promyelocytic leukemia [APL] excluded), 106 with RAEB-t, and 52 with RAEB. AML Rx produced a 62% complete remission (CR) rate in RAEB, essentially identical to the rates in RAEB-t and AML, but event-free survival (EFS) from CR and from start of treatment (start of Rx), as well as overall survival, were poorer in RAEB than in AML or RAEB-t, with AML and RAEB-t being identical. However, patients with RAEB or RAEB-t were more likely to have poor prognostic characteristics, in particular complex abnormalities involving chromosomes 5 and/or 7. Multivariate analyses indicated that, when considered together with cytogenetics and other patient characteristics, a diagnosis of RAEB rather than AML or RAEB-t had no effect on EFS from start of Rx, EFS from CR, survival, or achievement of CR. These analyses suggested a trend for patients with RAEB-t to have better EFS from start of Rx than patients with AML or RAEB (P = .08; relative risk, 0.80; 95% confidence interval, 0.62 to 1.03), but there were no differences with respect to the other outcomes. Our data suggest that the propriety of administering AML Rx to patients with RAEB or RAEB-t who have poor prognosis without treatment is identical to the propriety of treating AML in this fashion. Deterrents to standard AML Rx in these patients could justifiably include cytogenetics, age, etc, but not a diagnosis of RAEB or RAEB-t per se.

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MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.7451 ◽

2017 ◽

Vol 35 (35) ◽

pp. 3964-3977 ◽

Cited By ~ 20

Author(s):

Emilia L. Lim ◽

Diane L. Trinh ◽

Rhonda E. Ries ◽

Jim Wang ◽

Robert B. Gerbing ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Oxidative Phosphorylation ◽

Treatment Failure ◽

Myeloid Leukemia ◽

Outcome Prediction ◽

Classification Scheme ◽

Event Free Survival ◽

Free Survival ◽

Pediatric Aml ◽

Acute Myeloid

Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

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Autologous Bone Marrow Transplantation as an Intensive Consolidation Therapy for Adult Patients in Remission from Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v110.11.5121.5121 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5121-5121

Author(s):

Andre S. Jung ◽

Asad Bashey ◽

Peter R. Holman ◽

Eva Carrier ◽

Januario Castro ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myeloid Leukemia ◽

Disease Free Survival ◽

Consolidation Therapy ◽

Free Survival ◽

Risk Patients ◽

Disease Free ◽

Acute Myeloid

Abstract Introduction: Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myeloid leukemia. The optimal consolidation therapy for adults in remission without a histo-compatible donor has yet to be clearly established. Patients and Methods: This was a retrospective analysis of forty patients (23 females and 17 males) diagnosed with de novo acute myeloid leukemia, who were without a histo-compatible donor, that underwent APBSCT between the year 2000 and 2006 at a single institution. The patients’ age ranged from 18 to 73 with a median age of 50. Cytogenetic analysis was available on 37 of the patients. Complete remission (CR) was confirmed by bone marrow morphology and immunophenotype analysis by flow cytometry. Patients in remission were further consolidated with variable cycles of chemotherapy prior to stem cell transplantation. For stem cell mobilization, patients received high-dose cytarabine (2000mg/m2) and etoposide (5mg/kg) for three days followed by G-CSF at 10μg/kg, starting 10 days after the chemotherapy, before the peripheral stem cell collection. The preparative regimen prior to transplantation with unpurged stem/progenitor cells consisted of a combination of intravenous busulfan (0.8 mg/kg for 16 doses) and cyclophosphamide (60 mg/kg for two doses) (37 patients) or busulfan and melphalan (3 patients). Patients were then followed for treatment-related mortality, disease free survival, and overall survival. The analysis was stratified according to age, cytogenetic risk, and remission state. Results: There was no treatment-related mortality. Nineteen out of forty patients had relapse of their disease. The relapse rate was lowest in the low risk cytogenetic group who were under the age of 60 and highest in the high risk cytogenetic group who were over the age of 60. The overall 5 year survival for all patients was 47%. When stratified for cytogenetic risk and age, the overall survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 67%, 59%, and 75% respectively. The overall survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0% respectively. The projected rate of disease free survival at 5 years was 40%. When stratified for cytogenetic risk and age, the disease free survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 33%, 52%, and 50% respectively. Disease free survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0%. Comparing patients in CR1 versus patients in CR2, the overall survival was 47% in CR1 and 50% in CR2. The disease free survival, when grouped as above, were 41% for those in CR1 and 33% for those in CR2. Conclusion: APBSCT is a reasonable and safe intensive consolidation therapy for those patients without a compatible HLA matched donor in first or second complete remissions, notably for those under the age of 60 regardless of their cytogenetic risk. The number of standard consolidations prior to APBSCT may be an important variable predicting outcome.

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Allogeneic Stem Cell Transplantation for Refractory Acute Myeloid Leukemia in Pediatric Patients: The UK Experience

Blood ◽

10.1182/blood.v126.23.4404.4404 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4404-4404

Author(s):

Patricia M O'Hare ◽

Giovanna Lucchini ◽

Michelle Cummins ◽

Paul Veys ◽

Mike Potter ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Allogeneic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Pediatric Patients ◽

Refractory Disease ◽

Free Survival ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid ◽

Refractory Aml

Abstract INTRODUCTION The prognosis for children with refractory acute myeloid leukemia (AML) treated with chemotherapy is dismal and data on the outcome after allogeneic haematopoietic stem cell transplant (SCT) are scanty with reported leukemia free survival (LFS) rates of 10-20%. Thus there is significant controversy about whether SCT is appropriate in such patients (pts). We performed a retrospective, national study to analyse outcomes and prognostic factors for children undergoing SCT for refractory AML in the UK. METHODS A retrospective analysis of all pts <18 years of age reported to the BSBMT registry who received their first allogeneic SCT between 2000-2012 for refractory AML (ie >5% blasts in the bone marrow (BM) or proven extramedullary disease (EM) was performed. Source data verification (SDV) was performed to ensure pts were indeed refractory. The primary end-point was 5 year LFS. Secondary end-points were Relapse Rate (RR), Treatment Related Mortality (TRM), Graft Versus Host Disease (GVHD) and Overall Survival (OS). The Kaplan Meyer method was used to estimate survival data and Fisher's exact and Mantel-Cox Log Rank tests were used to compare disease- transplant- and survival-related variables. RESULTS Following SDV, a total of 44 pts from 13 centres were included in the study. The median age at SCT was 11.5 yrs and the median number of prior lines of chemotherapy was 3. The median time from diagnosis to SCT was 197 days. 23 pts had primary refractory AML and 21 had relapsed refractory AML. 12 pts showed adverse risk cytogenetics, 26 standard risk and 6 favourable. EM disease was documented in 5 pts. 42 children had >5% myeloid blasts in the BM immediately prior to conditioning and refractory disease was confirmed by cytogenetics/molecular genetics in 23. 2 pts were in BM remission but had frank EM disease. 38 pts (86%) received myeloablative conditioning (14 TBI based) and 6 (14%) had reduced intensity conditioning (RIC). In vivo T cell depletion was used in 25 pts. 15 pts (35%) were transplanted from an HLA identical family donor, 15 from a matched unrelated donor and 14 (32%) a mismatched donor. BM was used as the stem cell source in 18 (41%), peripheral blood in 20 (46%) and cord blood in 6 cases (14%). Median follow up was 4 years 10 months. 5 pts never achieved engraftment and had disease progression. The remaining 39 pts engrafted at a median of 15 days post-SCT. 30 pts (68%) achieved a complete remission (CR) following SCT. TRM at 1 year was 18% (5 infections, 1 cardiac failure, 1 GVHD-related). Acute GVHD occurred in 23 pts and was severe (grade ≥III) in 8 (19%). The incidence of chronic GvHD was low (1 limited, 2 extensive). Relapse was the major cause of treatment failure and occurred in 17 pts (39%) at a median 2.3 months post SCT. At last follow-up, 18 pts remain alive and in continuous complete remission (CCR). In this cohort, the 5 year OS and LFS were both 43% (95%CI 31-61%) (Figure1). Outcomes in pts with primary refractory disease (9/23, 39% in CCR) and those with relapsed refractory AML (9/21, 43% in CCR) were equivalent. Outcome for pts with cytogenetic confirmation of refractory disease was not statistically different (7/23, 30% in CCR) from the overall group. Pts transplanted with ≤30% blasts in the BM had improved outcomes (5-year LFS 52% vs 27%, p= 0.05). Likewise, the development of aGVHD of any grade was associated with a significantly better LFS (5-year LFS 56% vs 30%, p= 0.05). Cytogenetics including monosomy 7 (n=7) and molecular risk classification did not translate into a significant prognostic factor for relapse. Since RIC was used in only 6 pts, the impact of the intensity of conditioning cannot be determined. CONCLUSIONS This is the largest series of outcomes for SCT for refractory paediatric AML reported to date. Our data indicate that for selected pts, particularly those with a lower disease burden, SCT offers a realistic chance of salvage in both primary refractory and relapsed refractory AML (5 year LFS 43%) with acceptable toxicity. The association of aGVHD with improved LFS suggest a possible role in engineering a graft-versus-leukemia effect in this patient group. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

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