allogeneic HSCT

Acute Lymphoblastic Leukemia with t(4;11)(q21;q23)/KMT2A-AFF1 Translocation: The Results of Allogeneic Hematopoietic Stem Cells Transplantation in Children and Adults

BONE MARROW TRANSPLANTATION , ,

TL Gindina, NN Mamaev, OV Paina, AS Borovkova, PV Kozhokar’, OA Slesarchuk, YaV Gudozhnikova, EI Darskaya, AL Alyanskii, SN Bondarenko, LS Zubarovskaya, BV Afanas’ev

RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Pavlov First Saint 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, Paina OV, et al. Acute Lymphoblastic Leukemia with t(4;11)(q21;q23)/KMT2A-AFF1 Translocation: The Results of Allogeneic Hematopoietic Stem Cells Transplantation in Children and Adults. Clinical oncohematology. 2017;10(3):342–50 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-342-350

ABSTRACT

Aim. The aim was to evaluate the results of the allogeneic hematopoietic stem cells transplantation (allo-HSCT) in children and adults with the most prognostically unfavorable acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23)/KMT2A-AFF1 translocation.

Methods. We examined 21 patients (12 females, 9 males) aged from 3 months to 48 years (median 18.9 years). The analysis of prognostic factors of overall (OS) and event-free survival (EFS) after allo-HSCT in patients of different age groups with various clinical, transplantation and cytogenetic characteristics was performed. Allo-HSCT from HLA-compatible related and unrelated donors, as well as haploidentical allo-HSCT were performed in 4, 9 and 8 patients of age groups < 1 year, 1–18 years, and >18 years, respectively. In 10 (48 %) patients, allo-HSCT was performed in the first remission, in 2 (10 %) patients in the second remission, and in 9 (43 %) patients during the disease relapse.

Results. In 8 (38 %) patients, the only chromosomal disorder was the translocation t(4;11)(q21;q23). Additional changes in chromosomes were found in 11 (52 %) patients. In 8 (38 %) of them, 3 or more chromosomal abnormalities in the karyotype were found. According to the results of a univariant analysis, the OS and EFS were significantly different in patients with allo-HSCT performed in the first remission and at other stages of ALL (in the second remission and in relapse: p < 0.001 in both cases), as well as in patients with or without 3 or more cytogenetic disorders in the karyotype (p = 0.04 in both cases). The multivariant analysis showed that the only independent prognostic factor affecting the OS and EFS in ALL patients with t(4;11) was the allo-HSCT, including the haploidentical procedure, during the first complete hematological and molecular remission (p = 0.002 and p = 0.0004, respectively).

Conclusion. ALL with t(4;11)/KMT2A-AFF1 was as an absolute indication for allo-HSCT in first remission, including children of < 1 year age group. Satisfactory results can be obtained with the use of haploidentical transplantation from the parents. This approach eliminates the search in the registers completely HLA-compatible donor and facilitates the treatment procedure.

Keywords: acute lymphoblastic leukemia, t(4;11)/KMT2A-AFF1 translocation, allogeneic HSCT.

Received: January 17, 2017

Accepted: May 10, 2017

Read in PDF (RUS)pdficon

REFERENCES

  1. Marchesi F, Girardi K, Avvisati G. Pathogenetic, clinical and prognostic features of adult t(4;11)(q21;q23)/MLL-AF4 positive B-cell acute lymphoblastic leukemia. Adv Hematol. 2011;2011:1–8. doi: 10.1155/2011/621627.
  2. Marks DI, Moorman AV, Chilton L, et al. The clinical characteristics, therapy and outcome of 85 adults with acute lymphoblastic leukemia and t(4;11)(Q21;Q23)/MLL-AFF1 prospectively treated in the UKALLXII/ECOG2993 trial. Haematologica. 2013;98(6):945–52. doi: 10.3324/haematol.2012.081877.
  3. Vey N, Thomas X, Picard C, et al. Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2a-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006;20(12):2155–66. doi: 10.1038/sj.leu.2404420.
  4. Cimino G, Cenfra N, Elia L, et al. The therapeutic response and clinical outcome of adults with ALL1(MLL)/AF4 fusion positive acute lymphoblastic leukemia according to the GIMEMA experience. Haematologica. 2010;95(5):837–40. doi: 10.3324/haematol.2009.009035.
  5. Koh K, Tomizawa D, Saito MA, et al. Early use of allogeneic hematopoietic stem cell transplantation for infants with MLL gene-arrangement-positive acute lymphoblastic leukemia. Leukemia. 2015;29(2):290–6. doi: 10.1038/leu.2014.172.
  6. Parma M, Vigano C, Fumagatti M, et al. Good outcome for very high risk adult B cell acute lymphoblastic leukemia carrying genetic abnormalities t(4;11)(q21q23), if promtly submitted to allogeneic transplantation after obtaining a good molecular remission. Mediterr J Hematol Infect Dis. 2015;7(1):e2015041. doi: 10.4084/MJHID.2015.041.
  7. Kosaka Y, Koh K, Kinukawa N, et al. Infant acute lymphoblastic leukaemia with MLL gene arrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood. 2004;104(12):3527–34. doi: 10.1182/blood-2004-04-1390.
  8. Mann G, Attarbaschi A, Schrappe M, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: Results from the Interfant-99 Study. Blood. 2010;116(15):2644–50. doi: 10.1182/blood-2010-03-273532.
  9. Kato M, Hasegawa D, Kato K, et al. Allogeneic haematopoietic stem cell transplantation for infant acute lymphoblastic leukemia with KMT2A (MLL) rearrangements: a retrospective study from the paediatric acute lymphoblastic leukemia working group of the Japan Society for Haematopoietic Cell Transplantation. Br J Haematol. 2015;168(4):564–70. doi: 10.1111/bjh.13174.
  10. Wang Y, Liu QF, Liu Dh, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of patients with mixed-lineage-leukemia-rearranged acute leukemia: results from a prospective, multi-center study. Am J Hematol. 2014;89(2):130–6. doi: 10.1002/ajh.23595.
  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;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)]
  12. Schaffer L, McGovan-Jordan J, Schmid M. An International System for Human Cytogenetic Nomenclature. Basel: S. Karger; 2013. p. 140.
  13. Sanjuan-Pla A, Bueno C, Prieto C, et al. Revisiting the biology of infant t(4;11)/MLL-AF41 B-cell acute lymphoblastic leukemia. Blood. 2015;126(25):2676–85. doi: 10.1182/blood-2015-09-967378.
  14. Motllo C, Ribera J-M, Morgades M, et al. Frequency and prognostic significance of t(v;11q23)/KMT2A rearrangements in adult patients with acute lymphoblastic leukemia treated with risk-adapted protocols. Leuk Lymphoma. 2017;58(1):145–52. doi: 10.1080/10428194.2016.1177182.
  15. Dreyer ZE, Dinndorf PA, Camitta B, et al. Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children’s Oncology Group. J Clin Oncol. 2011;29(2):214–22. doi: 10.1200/jco.2009.26.8938.
  16. Tomizava D, Kato M, Takahashi H, et al. Favourable outcome in non-infant children with MLL-AF4-positive acute lymphoblastic leukemia: a report from the Tokyo Children’s Cancer Study Group. Int J Hematol. 2015;102(5):602–10. doi: 10.1007/s12185-015-1869-y.

Allogeneic Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndromes and Clinical Significance of WT1 Gene Overexpression

MYELOID TUMORS , , , , ,

N.N. Mamaev1, A.V. Gorbunova1, T.L. Gindina1, E.V. Morozova1, Ya.V. Gudozhnikova1, O.A. Slesarchuk1, V.N. Ovechkina1, A.A. Rats1, E.G. Boichenko2, E.A. Ukrainchenko3, V.M. Kravtsova1, A.V. Evdokimov1, I.M. Barkhatov1, S.N. Bondarenko1, B.V. Afanas’ev1

1 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

2 Municipal Children’s Hospital No. 1, 14 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

3 Alexandrovskaya Municipal Hospital No. 17, 4 pr-t Solidarnosti, Saint Petersburg, Russian Federation, 193312

For correspondence: N.N. Mamaev, DSci, Professor, 12 Rentgena str., Saint Petersburg, Russian Federation, 197022; Tel: +7(812)233-12-43; e-mail: nikmamaev524@gmail.com

For citation: Mamaev N.N., Gorbunova A.V., Gindina T.L., Morozova E.V., Gudozhnikova Ya.V., Slesarchuk O.A., Ovechkina V.N., Rats A.A., Boichenko E.G., Ukrainchenko E.A., Kravtsova V.M., Evdokimov A.V., Barkhatov I.M., Bondarenko S.N., Afanas’ev B.V. Allogeneic Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndromes and Clinical Significance of WT1 Gene Overexpression. Klin. Onkogematol. 2014; 7(4): 551–563 (In Russ.).

ABSTRACT

The results of allogeneic hematopoietic stem cell transplantation (HSCT) in 17 patients (pts, 11 male, 6 female) with myelodysplastic syndromes (3 RA/RARS/RCMD, 5 RAEB-1, 7 RAEB-2, 2 JMML) are presented. The median age was 26 years with a range between 1 and 55 years. Serial cytogenetic investigations were carried out in all of them. Seven pts demonstrated monosomy 7, which was associated with other chromosome abnormalities in 4 cases. In addition, deletion at 11q23 (n = 3), trisomy 8 (n = 2) and 21 (n = 2), involvement into rearrangement at 3q (n = 2), t(6;9) translocation, and others more rare abnormalities were found. Prior to aHSCT, 11 of 7 received hypomethylating agents (HA) which proved to be effective in a half of them. In order to prepare for aHSCT, ablative (busulfan, cyclophosphamide) or non-ablative (fludarabine, cyclophosphamide) conditioning regimes were applied (4 and 13 respectively). Repeated aHSCT was carried out in 6 pts because of transplant rejection or post-transplant relapses. Molecular monitoring of minimal residual disease as well as early diagnosis of these relapses was performed by means of serial tests of the WT1 gene level expression and donor chimerism. Maximum WT1 values varied between 15 and 43133 copies/104 copies of ABL gene; and molecular relapses were registered in a half of them, including 5 patients with transformation into acute leukemia (AL). HA were used for prevention and treatment of relapses in 4 (24 %) patients; and HA were combined with donor lymphocyte infusions. Standard chemotherapy was applied for these purposes relatively rarely. This study demonstrated WT1 gene overexpression to be not only an important marker for diagnosis of post-transplant MDS/AL relapses, but it also can be used for evaluation of the treatment efficacy.

Keywords: myelodysplastic syndromes, allogeneic HSCT, post-transplant relapses, minimal residual disease, molecular monitoring, serial WT1 gene expression.

Accepted: September 30, 2014

Read in PDF (RUS) pdficon

REFERENCES 

  1. Barrett A.J., Battiwala M. Relapse after allogeneic stem cell transplantation. Exp. Rev. Hematol. 2012; 3(4): 429–41.
  2. Tamura K., Kanazawa T., Suzuki M. et al. Successful rapid discontinuation of immunosuppressive therapy at molecular relapse after allogeneic bone marrow transplantation in a pediatric patient with myelodysplastic syndrome. Am. J. Hematol. 2006; 81: 139–41.
  3. Wertheim G.B., Bagg A. Minimal residual disease testing to predict relapse following transplant for AML and high-grade myelodysplastic syndromes. Exp. Rev. Mol. Diagn. 2011; 11(4): 361–6.
  4. Brieger J., Weidmann E., Fenchel K. et al. The expression of the Wilms’ tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells. Leukemia. 1994; 8: 2138–43.
  5. Inoue K., Sugiyama H., Ogawa H. et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood. 1994; 84: 3071–9.
  6. Inoue K., Ogawa H., Yamagami T. et al. Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood. 1996; 88: 2267–78.
  7. Tamaki H., Ogawa H., Inoue K. et al. Increased expression of the Wilms tumor gene (WT1) at relapse in acute leukemia. Blood. 1996; 88: 4396–8.
  8. Patmasirivat P., Fraizer G., Kantarjian H. et al. WT1 and GATA1 expression in myelodysplastic syndrome and acute leukemia. Leukemia. 1999; 13: 891–900.
  9. Ogawa H., Ikegame K., Kawakami M., Tamaki H. WT1 gene transcript assay for relapse in acute leukemia after transplantation. Leuk. Lymphoma. 2004; 45: 1747–53.
  10. Cilloni D., Gottardi E., De Micheli D. et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia. 2002; 16: 2115–21.
  11. Cilloni D., Messa F., Arruga F. et al. Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy. Haematologica. 2008; 93: 921–4.
  12. Candoni A., Tribelli M., Cilloni D. et al. Quantitative assessment of WT1 gene expression after allogeneic stem cell transplantation is a useful tool for monitoring minimal residual disease in acute myeloid leukemia. Eur. J. Haematol. 2009; 82: 61–8.
  13. Miyawaki S., Hatsumi N., Tamaki T. et al. Prognostic potential of detection of WT1 mRNA level in peripheral blood in adult acute myeloid leukemia. Leuk. Lymphoma 2010; 51: 1855–61.
  14. Zhao X.-S., Jin S., Zhu H.-H. et al. Wilms’ tumor gene 1 expression: an independent acute leukemia prognostic indicator following allogeneic hematopoietic SCT. Bone Marrow Transplant. 2012; 47: 499–507.
  15. Nomdedeu J.F., Hoyos M., Carricondo M. et al. Bone marrow WT1 levels at diagnosis, post-induction and post-intensification in adult de novo AML. Leukemia. 2013; 27: 2157–64.
  16. Pozzi S., Geroldi S., Tedone E. et al. Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression. Br. J. Haematol. 2013, 160: 503–9.
  17. Frairia Ch., Aydin S., Riera L. et al. WT1 expression in acute myeloid leukemia: a useful marker for improving therapy response evaluation. Blood. 2013; 123(21): 2588.
  18. Tamaki H., Ogawa H., Ohyashiki K. et al. The Wilm’s tumor gene is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia. 1999; 13: 393–9.
  19. Patmasiriwat P., Fraizer G., Kantarjian H. et al. WT1 and GATA1 expression in myelodysplastic syndrome and acute leukemia. Leukemia. 1999; 13: 891–900.
  20. Cilloni D., Gottardi E., Messa F. et al. Significant correlation between the degree of WT1 expression and the international prognostic scoring system score in patients with myelodysplastic syndromes. J. Clin. Oncol. 2003; 21: 1988–95.
  21. Cilloni D., Saglio G. WT1 as a universal marker for minimal residual disease detection and quantification in myeloid leukemias and in myelodysplastic syndrome. Acta Haematologica. 2004; 112: 79–84.
  22. Абдулкадыров К.М., Грицаев С.В., Капустин С.И. и др. Экспрессия гена опухоли Вилмса (WT1) в клетках крови больных миелодиcпластическим синдромом. Вопросы онкологии 2004; 50(6): 668–71. [Abdulkadyrov K.M., Gritsaev S.V., Kapustin S.I. et al. Wilms tumor gene (WT1) expression in blood cells of patients with myelodysplastic syndrome. Voprosy Onkologii. 2004; 50(6): 668–71. (In Russ.)]
  23. Bader P., Niemeyer C., Weber G. et al. WT1 gene expression: useful marker for minimal residual disease in childhood myelodysplastic syndromes and juvenile myelomonocytic leukemia? Eur. J. Haematol. 2004; 73: 25–8.
  24. Iwasaki T., Sugisaki C., Nagata K. et al. Wilms’ tumor 1 message and protein expression in bone marrow failure syndrome and acute leukemia. Pathol. Int. 2007; 57: 645–51.
  25. Qin Y.-Z., Zhu H.-H., Liu Y.-R. et al. PRAME and WT1 transcripts constitute a good molecular marker combination for monitoring minimal residual disease in myelodysplastic syndromes. Leuk. Lymphoma. 2012; DOI: 10.3109/10428194.2012.743656.
  26. Ueda Y., Mizutani C., Nannya Y. et al. Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes. Leuk. Lymphoma. 2013; 54(7): 1450–8.
  27. Lange T., Hubmann M., Burkhardt R. et al. Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning. Leukemia. 2011; 25: 498–505.
  28. Maurer U., Brieger J., Weidmann E. et al. The Wilms’ tumor gene is expressed in a subset of CD34+ progenitors and downregulated early in the course of differentiation in vitro. Exp. Hematol. 1997; 25: 945–50.
  29. Kwon M., Marti nez-Laperche C., Infante M. et al. Evaluation of minimal residual disease by real-time quantitative PCR of Wilms’ Tumor 1 expression in patients with acute myelogenous leukemia after allogeneic stem cell transplantation: correlation with flow cytometry and chimerism. Biol. Blood Marrow Transplant. 2012; 18: 1235–42.
  30. Jacobsohn D.A., Tse W.T., Chaleff S. et al. High WT1 gene expression before haematopoietic stem cell transplant in children with acute myeloid leukaemia predicts poor event-free survival. Br. J. Haematol. 2009; 146: 669–74.
  31. Мамаев Н.Н., Горбунова А.В., Гиндина Т.Л. и др. Лейкозы и миело- диспластические синдромы с высокой экспрессией гена EVI1: теоретиче- ские и клинические аспекты. Клин. онкогематол. 2012; 5(4): 361–4. [Mamaev N.N., Gorbunova A.V., Gindina T.L. et al. Leukemias and myelodysplastic syndromes with high EVI1 gene expression: theoretical and clinical aspects. Klin. Onkogematol. 2012; 5(4): 361–4. (In Russ.)]
  32. Alonso-Dominguez J.M., Tenorio M., Velasco D. et al. Correlation of WT1 expression with the burden of total and residual leukemic blasts in bone marrow samples of acute myeloid leukemia patients. Cancer Gen. 2012; 205: 190–1.
  33. Gerds A.T., Deeg H.J. Transplantation for myelodysplastic syndrome in the era of hypomethylating agents. Curr. Opin. Hematol. 2012; 19: 71–5.
  34. Nishihori T., Perkins J., Mishra A. et al. Pretransplantation 5-Azacitidine in high-risk myelodysplastic syndrome. Biol. Blood Marrow Transplant. 2014; 20: 776–80.
  35. Raza A., Gezer S., Mundle S. et al. Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood. 1995; 86(1): 268–76.