BONE MARROW TRANSPLANTATION

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias with Hyperdiploid Karyotype

BONE MARROW TRANSPLANTATION , , ,

TL Gindina, NN Mamaev, ES Nikolaeva, SN Bondarenko, OA Slesarchuk, AS Borovkova, SV Razumova, OV Pirogova, AL Alyanskii, LS Zubarovskaya, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician IP Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel: + 7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Gindina TL, Mamaev NN, Nikolaeva ES, et al. Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias with Hyperdiploid Karyotype. Clinical oncohematology. 2016;9(4):383–90 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-383-390

ABSTRACT

Aim. To evaluate the prognostic impact of the different cytogenetic characteristics, including the modal number, the number of chromosomal aberrations in a complex karyotype, and adverse chromosomal abnormalities (ACA) (–7/7q–, –5/5q–, –17/17p–, t(6;9)(p22;q34)) on the results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hyperdiploid acute myeloid leukemia (H-AML).

Methods. Forty seven H-AML patients (21 women and 26 men, aged from 1 to 58 years, median — 23.9 years) were examined. The analysis of overall (OS) and event-free survival (EFS) predictors after allo-HSCT in patients with different clinical, transplant and cytogenetic characteristics was performed.

Results. The modal number of chromosomes (MN) of 47–48 was the most common one in the karyotype which was observed in 31 (66 %) patients. High hyperdiploidy with the modal number of 49–65 was identified in 13 (28 %) patients, near-triploid and near-tetraploid karyotypes were found in 3 (6 %) patients. Quantitative chromosomal abnormalities were nonrandom. Chromosome 8 (50 %), 21 (32 %), 13 (16 %) и 22 (16 %) trisomy was the most common one. Structural chromosomal abnormalities were detected in 22 (47 %) patients, at that, ACA were found in 7 (19 %) patients. In univariate analysis, the OS and EFS after allo-HSCT differed in patients with different clinical status (remission vs. active disease; p = 0.003 and p = 0.002, respectively), different chromosomal abnormalities in hyperdiploid karyotype (ACA– vs. ACA+; p = 0.001 and p = 0.03, respectively). An additional analysis of selected patients group with a structurally complex karyotype (n = 19) showed, that patients without ACA had a higher OS than patients with ACA (p = 0.03). In multivariate analysis, the disease status (relapse) at allo-HSCT was an independent predictor of decreased OS and EFS (p = 0.004 и p = 0.006, respectively), as well as the presence of the ACA (p = 0.002 only for OS).

Conclusion. ACA were high-risk factors in H-AML patients received allo-HSCT. Therefore, the patients with formal criteria of a complex karyotype should not be automatically included in the cytogenetic unfavorable risk group.

Keywords: hyperdiploid and complex karyotypes, acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation, prognosis.

Received: April 17, 2016

Accepted: May 5, 2016

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REFERENCES

  1. Chilton L, Hills RK, Harrison CJ, et al. Hyperdiploidy with 49-65 chromosomes represents a heterogeneous cytogenetic subgroup of acute myeloid leukemia with differential outcome. Leukemia. 2013;28(2):321–8. doi: 1038/leu.2013.198.
  2. Sandahl JD, Kjeldsen E, Abrahamsson J, et al. Ploidy and clinical characteristics of childhood acute myeloid leukemia: a NOPHO-AML study. Genes Chromos Cancer. 2014;53(8):667–75. doi: 1002/gcc.22177.
  3. Stolzel F, Mohr B, Kramer M, et al. Karyotype complexity and prognosis in acute myeloid leukemia. Blood Cancer J. 2016;6:e386. doi: 101038/bcj.2015.114.
  4. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74. doi: 1182/blood-2009-07-235358.
  5. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354–65. doi: 1182/blood-2009-11-254441.
  6. Гиндина Т.Л., Мамаев Н.Н., Бархатов И.М. и др. Сложные повреждения хромосом у больных с рецидивами острых лейкозов после аллогенной трансплантации гемопоэтических стволовых клеток. Терапевтический архив. 2012;8:61–6.
    [Gindina TL, Mamaev NN, Barkhatov IM, et al. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantations. Terapevticheskii arkhiv. 2012;8:61–6. (In Russ)]
  7. Schaffer L, McGovan-Jordan J, Schmid M. An International System for Human Cytogenetic Nomenclature. Basel: S. Karger; 2013. pp. 140. doi: 10.1002/ajmg.a.35995.
  8. Guo RJ, Atenafu EG, Craddock K, et al. Allogeneic hematopoietic cell transplantation may alleviate the negative prognostic impact of monosomal and complex karyotypes on patients with acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20(5):690–5. doi: 1016/j.bbmt.2014.01.027.

Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis

BONE MARROW TRANSPLANTATION , , ,

MV Barabanshchikova, EV Morozova, VV Baikov, IM Barkhatov, NN Mamaev, SN Bondarenko, AL Alyanskii, LS Zubarovskaya, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Lyudmila Stepanovna Zubarovskaya, DSci, Professor, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-64; e-mail: zubarovskaya_ls@mail.ru

For citation: Barabanshchikova MV, Morozova EV, Baikov VV, et al. Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis. Clinical oncohematology. 2016;9(3):279-86 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-279-286

ABSTRACT

Background & Aims. At present, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment option with curative potential in patients with myelofibrosis (MF), especially in intermediate and high risk categories. The aim of the study is to perform a retrospective analysis of allo-HSCT outcomes in MF patients.

Materials & Methods. Outcomes of allo-HSCT in 11 intermediate-2 (n = 3) and high (n = 6) risk patients (based on Dynamic International Prognostic Scoring Scale, DIPSSplus) performed in the R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation over the period from 2005 till 2015 were analyzed in the study. Two more patients underwent allo-HSCT in MF blast phase. Two patients received ruxolitinib before allo-HSCT and 1 patient before and after allo-HSCT. Reduced intensity conditioning regimen was used in all cases.

Results. Primary engraftment was documented in 8 patients. 72 % of patients achieved complete hematological remission. Molecular remission and myelofibrosis regression were confirmed in 5 patients. 5 of 11 patients were still with remission and followed-up by the date of the paper submission. The overall two-year survival was 46 %.

Conclusion. Allo-HSCT is an effective treatment option for MF patients. Further trials are required to evaluate an optimal timing for allo-HSCT in MF patients and efficacy of Janus kinase (JAK) inhibitors as pre- and posttransplant therapy in MF.

Keywords: myelofibrosis, allo-HSCT, reduced intensity conditioning regimen, ruxolitinib.

Received: January 28, 2016

Accepted: March 22, 2016

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REFERENCES

  1. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895–901. doi: 10.1182/blood-2008-07-170449.
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  3. Passamonti F, Rumi E, Arcaini L, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93(11):1645–51. doi: 10.3324/haematol.13346.
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  5. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2009;115(9):1703–8. doi: 10.1182/blood-2009-09-245837.
  6. Gangat N, Caramazza D, Vaidya R, et al. DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status. J Clin Oncol. 2011;29(4):392–7. doi: 10.1200/jco.2010.32.2446.
  7. Vannucchi AM, Guglielmelli P, Rotunno G, et al. Mutation-Enhanced International Prognostic Scoring System (MIPSS) for Primary Myelofibrosis: An AGIMM & IWG-MRT Project. ASH; 2014. Abstract 405.
  8. Verstovsek S, Mesa R, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100(4):479–88. doi: 10.3324/haematol.2014.115840.
  9. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Long-Term Effects of Ruxolitinib on Bone Marrow Morphology in Patients With Myelofibrosis and Comparison to Best Available Therapy. Haematologica. 2014;14: Abstract S155. doi:10.1016/j.clml.2014.06.098.
  10. Giorgino T, Scott BL, Ditschkowski M, et al. CME Article Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125(21):3347–51. doi: 10.1182/blood-2014-10-608315.
  11. Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(26):5264–70. doi: 10.1182/blood-2009-07-234880.
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  14. Kroger N, Zabelina T, Alchalby H, et al. Dynamic of bone marrow fibrosis regression predicts survival after allogeneic stem cell transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2014;20(6):812–5. doi: 10.1016/j.bbmt.2014.02.019.
  15. Slot S, Smits K, van de Donk NW, et al. Effect of conditioning regimens on graft failure in myelofibrosis: a retrospective analysis. Bone Marrow Transplant. 2015;11;1424–31. doi: 10.1038/bmt.2015.172.
  16. Shanavas M, Popat U, Michaelis LC, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis with Prior Exposure to Janus Kinase 1/2 Inhibitors. Biol Blood Marrow Transplant. 2016;22(3):432–40. doi: 10.1016/j.bbmt.2015.10.005.
  17. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of INCB018424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis. N Engl J Med. 2010;363(12):1117–27. doi: 10.1056/nejmoa1002028.
  18. Stubig T, Alchalby H, Ditschkowski M, et al. JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis. Leukemia. 2014;28(8):1736–8. doi: 10.1038/leu.2014.86.
  19. Jaekel N, Behre G, Behning A, et al. Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. Bone Marrow Transplant. 2014;49(2):179–84. doi: 10.1038/bmt.2013.173.

Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias: Prognostic Significance of Complex Karyotype Including del(5q), –7, del(7q) Abnormalities

BONE MARROW TRANSPLANTATION , , , ,

TL Gindina, NN Mamaev, SN Bondarenko, ES Nikolaeva, IA Petrova, OA Slesarchuk, AS Borovkova, SV Razumova, AL Alyanskii, LS Zubarovskaya, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Gindina TL, Mamaev NN, Bondarenko SN, et al. Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias: Prognostic Significance of Complex Karyotype Including del(5q), –7, del(7q) Abnormalities. Clinical oncohematology. 2016;9(3):271-78(In Russ).

DOI: 10.21320/2500-2139-2016-9-3-271-278

ABSTRACT

Aim. To evaluate the prognostic significance of the complex karyotype including del(5q), –7, del(7q) abnormalities in acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Materials & Methods. Forty-four AML patients with chromosome 5 and/or 7 abnormalities (22 women and 22 men, aged from 1.2 to 67 years, median 31.2 years) were examined. Analysis of overall (OS) and event-free survival (EFS) predictors after allo-HSCT in patients with different clinical, transplant and cytogenetic characteristics was performed.

Results. Prior to allo-HSCT, the complex karyotype (with three or more chromosomal abnormalities) was observed in 19 (43 %) patients, the monosomal karyotype was in 8 (18 %) patients. Univariate analysis demonstrated that OS and EFS differed in patients from different age groups (³ 18 vs. < 18 years; p = 0.01 and p = 0.05, respectively), with different disease status at transplantation (1 remission vs. other clinical status; p = 0.1 and p = 0.008, respectively), with and without complex karyotype (СK– vs. CK+; p = 0.05 and p = 0.002, respectively), with and without monosomal karyotype (МK– vs. MK+; p = 0.009, only for EFS), and with different stem cells source (bone marrow vs. other source; p = 0.03 only for OS). Multivariate analysis confirmed that age of 18 years and more (p = 0.02 and p = 0.01, respectively), active disease at allo-HSCT (p = 0.04 and p = 0.005, respectively), complex karyotype (p = 0.04 и p = 0.0008, respectively) and stem cell source other than bone marrow (p = 0.02 only for OS) were independent predictors of OS and EFS deterioration.

Conclusion. The study demonstrates that chromosome 5 and/or 7 abnormalities as a part of the complex karyotype is high-risk factor in AML patients undergoing allo-HSCT (unlike the monosomal karyotype), that requires the special therapeutic approach.

Keywords: acute myeloid leukemias, complex karyotype, chromosome 5 and 7 abnormalities, allogeneic hematopoietic stem cell transplantation, prognosis.

Received: March 5, 2016

Accepted: April 5, 2016

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REFERENCES

  1. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–74. doi: 10.1182/blood-2009-07-
  2. Breems DA, Van Putten WL, De Greef GE, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26(29);4791–7. doi: 10.1200/jco.2008.16.0259.
  3. Medeiros BC, Othus M, Fang M, et al. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood. 2012;116(13):2224–8. doi: 10.1182/blood-2010-02-
  4. Fang M, Storer B, Estey E, et al. Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. Blood. 2011;118(6):1490–4. doi: 10.1182/blood-2011-02-
  5. Lazarus HM, Litzow MR. AML cytogenetics: the complex just got simpler. Blood. 2012;120(12):2357–8. doi: 10.1182/blood-2012-08-
  6. Kayzer S, Zucknick M, Dohner K, et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood. 2011;119(2):551–8. doi: 10.1182/blood-2011-07-
  7. Voutiadou G, Papaioannou G, Gaitatzi M, et al. Monosomal karyotype in acute myeloid leukemia defines a distinct subgroup within the adverse cytogenetic risk category. Cancer Genet. 2013;206(1–2):32–6. doi: 10.1016/j.cancergen.2012.10.003.
  8. Guo RJ, Atenafu EG, Craddock K, et al. Allogeneic hematopoietic cell transplantation may alleviate the negative prognostic impact of monosomal and complex karyotypes on patients with acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20(5):690–5. doi: 10.1016/j.bbmt.2014.01.027.
  9. Cornelissen JJ, Breems D, Putten WLJ, et al. Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories. J Clin Oncol. 2012;30(17):2140–6. doi: 10.1200/jco.2011.39.6499.
  10. Hemmati P, Schuzle-Luckow A, Terwey T, et al. Cytogenetic risk grouping by the monosomal karyotype classification is superior in predicting the outcome of acute myeloid leukemia undergoing allogeneic stem cell transplantation in complete remission. Eur J Haematol. 2013;92(2):102–10. doi: 10.1111/ejh.12216.
  11. Гиндина Т.Л., Мамаев Н.Н., Бархатов И.М. и др. Сложные повреждения хромосом у больных с рецидивами острых лейкозов после аллогенной трансплантации гемопоэтических стволовых клеток. Терапевтический архив. 2012;84(8):61–6.
    [Gindina TL, Mamaev NN, Barhatov IM, et al. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantations. Terapevticheskii arkhiv. 2012;84(8):61–6. (In Russ)]
  12. Schaffer L, McGovan-Jordan J, Schmid M. ISCN. An international System for Human Cytogenetic Nomenclature. Basel: S. Karger; 2013. pp. 140.
  13. Wawrzyniak E, Wierzbowska A, Kotkowska A, et al. Different prognosis of acute myeloid leukemia harboring monosomal karyotype with total or partial monosomies determined by FISH: Retrospective PALG study. Leuk Res. 2013;37(3):293–9. doi: 10.1016/j.leukres.2012.10.022.
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Plerixafor in Patients with Decreased Mobilizing Ability of Autologous Hematopoietic Stem Cells

BONE MARROW TRANSPLANTATION , , ,

MA Kucher1, МS Motalkina2, ОU Klimova1, ЕV Kondakova1, ОB Kalashnikova1, SМ Alekseev2, DV Motorin3, DV Babenetskaya3, EI Podol’tseva4, NB Mikhailova1, МА Estrina1, ЕV Babenko1, AYu Zaritskii3, BV Afanas’ev1

1 R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

2 N.N. Petrov Scientific Research Institute of Oncology, 68 Leningradskaya str., settlement Pesochnyi, Saint Petersburg, Russian Federation, 197758

3 V.A. Almazov Federal North-West Medical Research Centre, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

4 Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110

For correspondence: Maksim Anatol’evich Kucher, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)338-62-60; e-mail: doctorkucher@yandex.ru

For citation: Kucher MA, Motalkina MS, Klimova OU, et al. Plerixafor in Patients with Decreased Mobilizing Ability of Autologous Hematopoietic Stem Cells. Clinical oncohematology. 2016;9(2):155–61 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-155-161

ABSTRACT

Background & Aims. Autologous hematopoietic stem cell transplantation (autoHSCT) is an effective treatment for patients with malignant lymphoproliferative disorders, multiple myelomas and solid tumors sensitive to chemotherapy. Harvesting of hematopoietic stem cells (HSC) prior autoHSCT may be ineffective in up to 40 % of cases, if aggravating factors are present. One of methods to overcome the reduced mobilization ability is to include a CXCR4-inhibitor (plerixafor) to the mobilization strategies. The aim was to evaluate the efficacy and safety of different autologous HSC mobilization regimens containing plerixafor.

Methods. 63 patients with solid and hematological malignancies were included into the study. 2 mobilization regimens were used: filgrastim + plerixafor (n = 47) and pegfilgrastim + plerixafor (n = 16). Filgrastim was prescribed at a dose 5 mg/kg twice a day subcutaneously on days 1–4; on day 4, at 12.00 am, plerixafor was prescribed at a dose of 0.24 mg/kg subcutaneously; on day 5, filgrastim 5 mg/kg was administered subcutaneously, and then a cytapheresis session was performed at 10.00 am. Pegfilgrastim was administered subcutaneously at a dose of 6 mg on day 1; on day 4, plerixafor was administered subcutaneously at a dose of 0.24 mg/kg at 06.00 am; then, 11 hours later, cytapheresis was performed. The cytapheresis was performed at a level of CD34+ cells ³ 20 ´ 106/mL.

Results. In 73.7 % of cases (n = 42), patients had an advanced stage disease and underwent more than one chemotherapy line prior to mobilization of autologous HSC. After mobilization with G-CSF (filgrastim or pegfilgrastim), the CD34+ cell count in peripheral blood was 0–17 ´ 106/mL (median 9.8 ´ 106/mL). Further injection of plerixafor increased the CD34+ cell count to 2–89 ´ 106/mL (median 31.6 ´ 106/mL) (p = 0.0001). In 85.7 % of cases (n = 54), the sufficient amount of CD34+ cells (³ 2 ´ 106/kg; median 5.1 ´ 106/kg) was harvested for transplantation. The effectiveness of mobilization in two groups was comparable 90.2 % for the filgrastim + plerixafor regimen and 68.7 % for pegfilgrastim + plerixafor (p = 0.08). The use of the filgrastim + plerixafor combination in patients with low baseline CD34+ cell counts increased the number of hematopoietic stem cells up to 6.6–63 ´ 106/mL (median 27.1 ´ 106/mL), thus allowing to harvest a good quality graft in 83.3 % of cases (p = 0.0001). When the level of CD34+ cell counts was in the «grey zone», successful graft harvesting was performed in 90 % of cases: 1.74–4.6 ´ 106/kg; median 3.1 ´ 106/kg (p = 0.0001). Complications associated with plerixafor were observed in 2 cases: diarrhea (n = 1) and hypocalcaemia (n = 1).

Conclusion. In patients who are poor mobilizers, the use of plerixafor-containing regimens increased the chance of successful graft harvesting with good tolerability.

Keywords: hematopoietic stem cell mobilization, G-CSF, pegfilgrastim, plerixafor.

Received: February 17, 2016

Accepted: February 18, 2016

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REFERENCES

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  19. Herbert KE, Demosthenous L, Wiesner G, et al. Plerixafor plus pegfilgrastim is a safe, effective mobilization regimen for poor or adequate mobilizers of hematopoietic stem and progenitor cells: a phase I clinical trial. Bone Marrow Transplant. 2014;49(8):1056–62. doi: 10.1038/bmt.2014.112.
  20. Maschan AA, Balashov DN, Kurnikova EE, et al. Efficacy of plerixafor in children with malignant tumors failing to mobilize a sufficient number of hematopoietic progenitors with G-CSF. Bone Marrow Transplant. 2015;50(8):1089–91. doi: 10.1038/bmt.2015.71.

 

Results of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia with t(8;21)(q22;q22)/RUNX1-RUNX1T1 and Additional Cytogenetic Abnormalities

BONE MARROW TRANSPLANTATION , ,

TL Gindina, NN Mamaev, SN Bondarenko, ES Nikolaeva, OA Slesarchuk, AS Borovkova, OV Paina, SV Razumova, AL Alyanskii, LS Zubarovskaya, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Gindina TL, Mamaev NN, Bondarenko SN, et al. Results of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia with t(8;21)(q22;q22)/RUNX1-RUNX1T1 and Additional Cytogenetic Abnormalities. Clinical oncohematology. 2016;9(2):148–54 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-148-154

ABSTRACT

Aim. To evaluate the impact of additional chromosomal aberrations on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) with t(8;21)(q22;q22)/RUNX1-RUNX1T1 translocation.

Methods. Twenty-five AML patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 translocation (10 women and 15 men, aged from 2 to 58 years; median 20.2) were examined. Analysis of overall (OS) and event-free survival (EFS) predictors after allo-HSCT in patients with different clinical, transplant and cytogenetic characteristics was performed.

Results. The additional cytogenetic abnormalities were found in 13 (52 %) patients before the transplantation, at that, complex karyotype with three or more chromosomal abnormalities were registered in 9 (69 %) patients. The univariate analysis showed that OS and EFS after allo-HSCT differed in patients with different characteristics such as age (p = 0.03; p = 0.0006), clinical status at transplantation (p = 0.0002; p = 0,006), donor type (p = 0.0003; p = 0.002), the interval from diagnosis of leukemia to allo-HSCT (p = 0,008, for OS only), additional cytogenetic abnormalities (p = 0.03; p = 0.009) and complex karyotype (p = 0.004; p = 0.0003), respectively. In multivariate analysis, independent predictors of OS were donor type (p = 0.01), the interval from diagnosis of leukemia to allo-HSCT (p = 0.01), and additional cytogenetic abnormalities in karyotype (p = 0.04), as well as donor type (p = 0.04) and patient’s age (p = 0.004) for EFS.

Conclusion. AML with t(8;21)(q22;q22)/RUNX1-RUNX1T1 translocation is a heterogeneous disease. The prognosis in patients with the additional cytogenetic abnormalities, especially in those with the complex karyotype, is worse both after the standard chemotherapy (i.e. before allo-HSCT), and after allo-HSCT.

Keywords: AML with t(8;21) translocation, allo-HSCT, cytogenetic abnormalities.

Received: February 6, 2016

Accepted: February 15, 2016

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REFERENCES

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  7. Shlenk RF, Benner A, Krauter J, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;22(18):3741–50. doi: 10.1200/JCO.2004.03.012.
  8. Shlenk RF, Pasquini MC, Perez WS, et al. HLA-identical sibling allogeneic transplant versus chemotherapy in acute myelogenous leukemia with t(8;21) in first complete remission: collaborative study between the German AML Intergroup and CIBMTR. Biol Blood Marrow Transplant. 2008;14(2):187–96. doi: 10.1016/j.bbmt.2007.10.006.
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    [Mamaev NN, Gorbunova AV, Gindina TL, et al. Hematopoietic stem cell transplantation in AML patients with t(8;21) (q22;q22) translocation. Klinicheskaya onkogematologiya. 2013;6(4):439–50. (In Russ)]
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  14. Mosna F, Papayannidis C, Martinelli G, et al. Complex karyotype, older age, and reduced first-line dose intensity determine poor survival in core binding factor acute myeloid leukemia patients with long-term follow-up. Am J Hematol. 2015;90(6):515–23. doi: 10.1002/ajh.24000.
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    [Gindina TL, Mamaev NN, Barhatov IM, et al. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantations. Terapevticheskii arkhiv. 2012;8:61–6. (In Russ)]
  16. Schaffer L, McGovan-Jordan J, Schmid M. ISCN. An international System for Human Cytogenetic Nomenclature. Basel: S. Karger; 2013.
  17. Gindina T, Mamaev N, Nikolaeva E, et al. Jumping translocations in a 13-year-old child with RUNX1/RUNX1T1-positive acute myeloid leukemia. 10th European Cytogenetics Conference 2015. Chromosome Res. 2015;23(Suppl 1):88. doi: 10.1007/s10577-015-9476-6.
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    [Mamaev NN, Gorbunova AV, Barkhatov IM, et al. Molecular Monitoring of WT1 Gene Expression Degree in Acute Myeloid Leukemias after Allogeneic Hematopoietic Stem Cell Transplantation. Klinicheskaya onkogematologiya. 2015;8(3):309–20. (In Russ)]
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Analysis of Karyotype Aberrations in Children and Adolescents with Post-Transplantation Relapses of Acute Leukemia

BONE MARROW TRANSPLANTATION , ,

T.L. Gindina, N.N. Mamaev, E.N. Nikolaeva, I.A. Petrova, S.N. Bondarenko, A.L. Alyanskii, N.V. Stancheva, O.A. Slesarchuk, M.Yu. Aver’yanova, L.S. Zubarovskaya, B.V. Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Gindina TL, Mamaev NN, Nikolaeva EN, et al. Analysis of Karyotype Aberrations in Children and Adolescents with Post-Transplantation Relapses of Acute Leukemia. Clinical oncohematology. 2015;8(4):420–427 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-420-427

ABSTRACT

Aim. To analyze the karyotype aberrations at the relapse after allogeneic HSCT (alloHSCT) in children and adolescents with acute leukemias, in order to evaluate their relation with disease-free survival and overall survival (OS) rates after the relapse and to identify prognostic groups of patients based on clinical and cytogenetic characteristic of a tumor.

Methods. Cytogenetic investigations were performed in 30 children and 15 adolescents (26 males and 19 females aged from 1.2 to 21 years; median age 10 years) with a post-transplant relapse (PTR) of acute myeloid leukemia (n = 29) and acute lymphoblastic leukemia (n = 16). The analysis of aberrating chromosomal abnormalities was performed by comparison of the karyotypes in relapse with those before the alloHSCT.

Results. Karyotype aberrations in PTR were observed in 29 (64 %) patients. 2 and more abnormal cytogenetic clones were observed in 10 (34 %) patients with PTR. Additional chromosomal aberrations acquired in PTR were related primarily to chromosomes 1, 11 and 19. OS after the relapse was higher in patients with alloHSCT performed during the remission and with one abnormal cytogenetic clone in PTR. Based on this, we formed three prognostic groups: the first group consisted of 8 (18 %) patients with 2 adverse factors and median 40-day OS after relapse; the second group included 20 (44 %) patients with 1 adverse factor and median OS after PTR equal to 152 days, and the 4-year survival was 16 %; the third group included 17 (38 %) patients without the above negative factors and median OS after relapse equal to 549 days, and the 4-year survival was 31 %. The multivariate analysis showed that the number of abnormal cytogenetic clones in leukemic population is an independent predictor of OS after PTR.

Conclusion. The presence of leukemic population of ³ 2 abnormal cytogenetic clones is the most important prognostic factor affecting the OS in PTR patients. Since the clonal evolution of the karyotype may be associated with the use of cytotoxic drugs in the therapy of acute leukemia in children and adolescents with indications for alloHSCT, the latter should be done as soon as possible and non-myeloablative conditioning regimen should be preferred.

Keywords: pediatric acute leukemias, post-transplantation relapses, clonal cytogenetic evolution.

Received: June 13, 2015

Accepted: November 8, 2015

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REFERENCES

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  6. Yuasa M, Uchida N, Kaji D, et al. Prognostic significance of the cytogenetic evolution after the hematopoietic stem cell transplantation in adult acute myeloid leukemia. Blood. 2013;122(21):1391.
  7. Cho Y, Chi H, Park S, et al. Comparative analysis of cytogenetic evolution patterns during relapse in the hematopoietic stem cell transplantation and chemotherapy settings of patients with acute leukemia. Blood. 2013;122(21):1320.
  8. Гиндина Т.Л., Мамаев Н.Н., Бондаренко С.Н. и др. Сложные хромосомные нарушения у больных с посттрансплантационными рецидивами острых лейкозов: клинические и теоретические аспекты. Клиническая онкогематология. 2015;8(1):69–77.
    [Gindina TL, Mamaev NN, Bondarenko SN, et al. Complex chromosomal aberrations in patients with post-tranplantation relapses of acute leukemias: clinical and theoretical aspects. Klinicheskaya onkogematologiya. 2015;8(1):69–77. (In Russ)]
  9. Гиндина Т.Л., Мамаев Н.Н., Бархатов И.М. и др. Сложные повреждения хромосом у больных с рецидивами острых лейкозов после аллогенной трансплантации гемопоэтических стволовых клеток. Терапевтический архив. 2012;8:61–6.
    [Gindina TL, Mamaev NN, Barhatov IM, et al. Complex chromosome damages in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantations. Terapevticheskii arkhiv. 2012;8:61–6 (In Russ)]
  10. Schaffer L, McGovan-Jordan J, Schmid M. An International System for Human Cytogenetic Nomenclature. Basel: S. Karger; 2013.
  11. Gindina T, Mamaev N, Bondarenko S, et al. Complex aberrant karyotype in patients with post-transplant relapses of acute myeloid and lymphoid leukemias evaluated by serial cytogenetic assays, including mFISH. Blood. 2014;124(21):5313.

Bone Marrow Transplantation in Patients with Acute Lymphoblastic Leukemia with Extremely Poor Prognosis: Literature Review and Case Report

BONE MARROW TRANSPLANTATION , , ,

NN Subbotina, AV Popa, IS Dolgopolov, VK Boyarshinov, RI Pimenov, VV Dailidite, GL Mentkevich

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Natal’ya Nikolaevna Subbotina, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-45-08; e-mail: natik-23@yandex.ru

For citation: Subbotina N.N., Popa A.V., Dolgopolov I.S., Boyarshinov V.K., Pimenov R.I., Dailidite V.V., Mentkevich G.L. Bone Marrow Transplantation in Patients with Acute Lymphoblastic Leukemia with Extremely Poor Prognosis: Literature Review and Case Report. Klin. Onkogematol. 2015; 8(3): 331-6. (In Russ.)

ABSTRACT

The difference in the survival rate between patients receiving the chemotherapy alone and those receiving the chemotherapy with hematopoietic stem cell transplantation (HSCT) becomes more significant with the increased number of acute lymphoblastic leukemia (ALL) risk factors. Myeloablative conditioning regimens remain a gold standard before HSCT in children and young adults with ALL. The traditional TBI-CPM based conditioning regimen followed by HSCT from related HLA identical donor demonstrates the highest survival rates. The survival rate of patients with ALL relapses after allogeneic HSCT remains low. The second HSCT is the only possible therapeutic option that provides a longer survival rate for not more than 10–15 % of patients. Delayed relapses after the first HSCT and patient’s age less than 10 y.o. are statistically significant factors of a better prognosis. The article describes author’s own experience in the management of an ALL high-risk group patients who have undergone chemotherapy, 3 allogeneic related HSCT with involvement of several donors, as well as an additional transfusion of peripheral blood stem cells obtained from the second HLA matching donor. The patient remains under medical supervision in the N.N. Blokhin Russian Cancer Research Center by the date of composition of this paper (23 months after a haploidentical HSCT).

Keywords: acute lymphoblastic leukemia, extremely poor prognosis, hematopoietic stem cell transplantation, conditioning regimen.

Received: March 3, 2015

Accepted: June 3, 2015

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Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug?

BONE MARROW TRANSPLANTATION , , , ,

GD Petrova1, KN Melkova1, TZ Chernyavskaya1, NV Gorbunova1, BV Afanas’ev2, EA Demina1, VN Kostrykina1, VA Doronin1

1 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022

For correspondence: Galina Dmitrievna Petrova, graduate student, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-13-59; e-mail: galina_petrova@bk.ru

For citation: Petrova GD, Melkova KN, Chernyavskaya TZ, et al. Autologous Stem Cell Transplantation in Primary Refractory Hodgkin’s Lymphoma: Supposed Zugzwang or Zwischenzug? Clinical oncohematology. 2015;8(3):321–30 (In Russ).

ABSTRACT

Background & Aims. The role of single and double autologous hematopoietic stem cell transplantations (autoSCT) in patients with primary refractory Hodgkin’s lymphoma (HL) has not been determined yet. The aim of the study is to present the results of a one-center prospective study evaluating the role of single and double autoSCT in patients with HL who have not achieved the complete remission (CR) after first line induction polychemotherapy (PCT).

Methods. 62 HL patients were enrolled in the study over the period from 2007 till 2014. High-dose chemotherapy (HDCT) with autoSCT was performed once in 53 patients, and twice in 10 patients.

Results. The study demonstrated an unfavorable prognostic impact of the large volume of previous chemotherapy on the overall survival (OS) rate after the autoSCT (p = 0.03). Results of the 1st autoSCT had an independent prognostic value for the OS rate (p = 0.004). The study identified the main indication for the 2nd autoSCT, namely, partial remission (PR) or stable disease (SD) achieved after the 1st autoSCT (when the 2nd HDCT with autoSCT should be preferred to the alternative treatment; p = 0.004). Progressive disease (PD) after the first autoSCT is a contraindication for the second one. Due to low efficacy and high toxicity, the 2nd autoSCT does not improve outcomes when compared to alternative approaches (p = 0.6). The importance of achieving CR at any stage of treatment which is associated with a long life span with no signs of disease and good quality of life has been demonstrated.

Conclusion. AutoSCT is an effective treatment option for patients without complete remission after the first line antitumor treatment. Carrying out 2nd autoSCT is advisable for patients who have reached the PR/SD after the first one. Patients with PD after the 1st autoSCT require an alternative treatment option.

Keywords: Hodgkin’s lymphoma, high-dose chemotherapy, autologous hematopoietic stem cell transplantation, primary resistance, double autoSCT.

Received: May 5, 2015

Accepted: June 2, 2015

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Molecular Monitoring of WT1 Gene Expression Degree in Acute Myeloid Leukemias after Allogeneic Hematopoietic Stem Cell Transplantation

BONE MARROW TRANSPLANTATION , , , , ,

N.N. Mamaev, A.V. Gorbunova, I.M. Barkhatov, Ya.V. Gudozhnikova, T.L. Gindina, V.A. Katerina, E.V. Volchkov, A.L. Alyanskii, E.V. Babenko, O.A. Slesarchuk, N.V. Stancheva, S.N. Bondarenko, B.V. Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Nikolai Nikolaevich Mamaev, DSci, Professor, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Gorbunova AV, Barkhatov IM, et al. Molecular Monitoring of WT1 Gene Expression Level in Acute Myeloid Leukemias after Allogeneic Hematopoietic Stem Cell Transplantation. Clinical oncohematology. 2015;8(3):309–20 (In Russ).

ABSTRACT

Objective. To evaluate the possibility of serial analysis of WT1 gene expression level for prediction and diagnosis of post-transplant acute myeloid leukemia (AML) relapses.

Methods. Serial analyses of WT1 gene expression were performed using quantitative real-time PCR during the post-transplant period of 34 patients with AML. All patients underwent allogeneic hematopoietic stem cell transplantation: unrelated (n = 22), related (n = 12), including haploidentical (n = 4). 5 of 34 patients had AML transformed from the myelodysplastic syndromes (MDS). In addition, the level of donor chimerism and the bone marrow/peripheral blood blast cells counts were evaluated. AML1/ETO (n = 4) or EVI1 (n = 4) gene expression degrees were measured in 8 patients in order to compare those with the WT1 gene expression.

Results. Based on obtained data on the WT1 gene expression, two equal subgroups of patients were formed. The first one consisted of patients with stable normal expression of the investigated molecular indicator during the post-transplant period, whereas the second group consisted of patients with impaired expression. The initial level of WT1 gene expression almost did not depend on both cytological and cytogenetic AML subtypes. During the post-transplant period, the WT1 gene expression degree correlated with that of AML1/ETO or EVI1. Increased WT1 gene expression take the lead over the decreased donor chimerism and blast cell count increase in bone marrow and blood typical for post-transplant relapses of AML.

Conclusion. The higher level of WT1 gene expression may serve not only as a marker for timely diagnosis of post-transplant relapses in AML patients, but also as a monitoring parameter for testing their treatment quality.

Keywords: acute myeloid leukemias, hematopoietic stem cell transplantation, WT1 gene expression monitoring, AML1/ETO and EVI1, diagnosis of post-transplant relapses, molecular monitoring of treatment.

Received: March 19, 2015

Accepted: June 1, 2015

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Allogeneic Hematopoietic Stem Cell Transplantation for ALL Patients with t(12;21)(p13;q22) Translocation

BONE MARROW TRANSPLANTATION , , , ,

N.N. Mamaev1, E.V. Semenova1, N.V. Stancheva1, V.A. Katerina1, I.M. Barkhatov1, A.V. Evdokimov1, E.G. Boychenko2, T.L. Gindina1, V.M. Kravtsova1, L.S. Zubarovskaya1, B.V. Afanasyev1

1 R.M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation under I.P. Pavlov State Medical University, Saint Petersburg, Russian Federation

2 1st Municipal Children’s Hospital, Saint Petersburg, Russian Federation

For citation: Mamaev N.N., Semenova E.V., Stancheva N.V., Katerina V.A., Barkhatov I.M., Evdokimov A.V., Boichenko E.G., Gindina T.L., Kravtsova V.M., Zubarovskaya L.S., Afanas’ev B.V. Allogeneic Hematopoietic Stem Cell Transplantation for ALL Patients with t(12;21)(p13;q22) Translocation. Klin. onkogematol. 2014; 7(3): 327–34 (In Russ.).

ABSTRACT

The results of allogeneic hematopoietic stem cell transplantation (alloHSCT) in 10 pediatric patients (4 boys, 6 girls at the age of 4 to 17 years, mean age is 9.8 years) with relapses of acute lymphoblastic leukemia (ALL) with TEL-AMLI fusion gene are presented. The first remission duration ranged from 20 to 70 months (mean duration 39.9 months). Transplantation was performed in 6 patients during the second (and further) remission, whereas 4 patients underwent transplantation during the relapse. Six patients received a graft from matched related (n = 3) or unrelated (n = 3) donors, haploidentical HSCT was performed in four other patients because there was no donor. Conditioning regimens were myeloablative in 8 cases and RIC (Reduced Intensity Conditioning) in 2 cases. Successful engrafting took place in 9 (90 %) of 10 patients. Additional haploidentical transplantation was performed in 1 case, when the transplant was rejected.

Monitoring of treatment was performed by means of serial testing of TEL-AMLI fusion gene expression level, of serial donor chimerism and the blast cell count in bone marrow and peripheral blood. The study demonstrated that four patients younger than 4 years had TEL-AML1 gene expression at all stages of their disease, including pre- and post-transplantation period. Due to it, even the donor chimerism and blast cell count in bone marrow and/or peripheral blood changed. On the contrary, in 3 more patients, TEL-AML1 gene expression levels were low before alloHSCT, being absent after HSCT.

In general, seven patients have been monitored for 178–2627 days (at the average of 870 days) including two patients with post-transplant relapses. At the same time, 3 patients died on days 20–263 after transplantation.

The observed difference in response to chemotherapy might be supposedly explained by involvement of not only hematopoietic, but also mesenchymal cells into the leukemic process (this fact was demonstrated for this group of patients by S. Shalapour et al., 2010). But this fact should be confirmed in further studies.

Keywords: ALL, t(12;21)(p13;q22) translocation, alloHSCT, molecular monitoring, difference in response to treatment.

Address correspondence to: nikmamaev524@gmail.com

Accepted: May 22, 2014

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