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Successful double umbilical cord blood transplantation for relapsed juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of early childhood for which allogeneic hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment.1 HSCT for JMML is burdened with a high probability of relapse (5-year cumulative incidence at 35%), despite high-intensity conditioning regimens and rapid tapering of immunosuppressants so as to maximize graft-versus-leukemia effects.1, 2 In relapsed cases, donor lymphocyte infusions fail to show consistent therapeutic efficacy, and it is generally felt that the risk-benefit ratio of this modality does not warrant universal recommendation in relapsed JMML. Data compiled by the European Working Group of Myelodysplastic Syndromes in Childhood indicate that approximately half of relapsed cases can be rescued with a second HSCT.3

Assuming inferior engraftment capability and weaker graft-versus-leukemia properties, umbilical cord blood (UCB) is not considered as the stem cell source of choice for children with JMML undergoing HSCT. However, it remains a potential alternative option for patients who lack a suitable related or unrelated donor. A total of 19 UCB transplantations for children with JMML have been reported in the literature with a failure rate of 8/19 or 42% (relapse 6/19; non-engraftment and subsequent relapse 1/19; other transplantation-related mortality 1/19).1, 4, 5, 6, 7 A large retrospective evaluation of 110 UCB transplantations for JMML was presented by Crotta et al.8 at the 2011 annual meeting of the European Group for Blood and Marrow Transplantation; the 4-year cumulative incidence of relapse was 37% and 4-year transplant-related mortality was 20%.

In general, UCB transplantations are handicapped by low stem cell numbers relative to the recipient’s body weight. Therefore, the simultaneous infusion of two UCB units (double UCB transplantation, DUCBT) has been advocated especially for adult patients as a strategy to increase cell dose and prevent graft failure.9 One may reason that the higher stem cell dose and enhanced antitumor immunity associated with DUCBT10 would also be beneficial in pediatric high-risk situations, such as relapsed JMML. However, the use of DUCBT for JMML has not yet been reported in the literature. Here we present the first case of JMML successfully treated with DUCBT.

A 6-year-old boy was presented with abnormal fatigue, leukopenia, anemia and progressive hepatosplenomegaly. Initial blood counts were: white blood cells 3.5 × 109/l (26% monocytes), platelets 234 × 109/l, hemoglobin 6.4 g/dl and reticulocytes 2/1000. Bone marrow (BM) cytology revealed increased cellularity, signs of dysplasia and 9% blasts. Molecular and cytogenetic work-up excluded a BCR-ABL1 rearrangement, and revealed the presence of monosomy 7 as well as concurrent PTPN11 c.227 A >G and NRAS c.38 G >A mutations (both somatic). Taken together, the patient fulfilled current international consensus criteria for the diagnosis of JMML.11 The patient received an interim cytoreductive phase with cytarabine and azacitidine, underwent splenectomy for hypersplenism, and HSCT preparations were initiated. In the absence of an human leukocyte antigen (HLA)-compatible related or unrelated donor, the boy was subjected to haploidentical transplantation from his mother at 3 months after diagnosis. The conditioning regimen consisted of busulfan 4 × 3.2 mg/kg, cyclophosphamide 2 × 60 mg/kg, melphalan 1 × 40 mg/m2 and muromonab 26 × 0.1 mg/kg. The graft was CD3/CD19-depleted peripheral blood (PB) containing 19.6 × 106 CD34+ cells/kg and 5.2 × 104 CD3+ cells/kg. Graft-versus-host disease (GVHD) prophylaxis included methylprednisolone and mycophenolate mofetil. Neutrophil engraftment (>0.5 g/l) occurred on day +10, and chimerism was complete on day +13. However, autologous cells re-emerged on day +20, and a BM examination on day +28 revealed hypoplastic marrow, indicating graft rejection. Seven days later, the boy was re-transplanted from his haploidentical father, after preparation with total lymphoid irradiation of 1 × 7 Gy, thiotepa 1 × 5 mg/kg, fludarabine 3 × 40 mg/m2 and anti-thymocyte globulin (ATG) rabbit (Thymoglobulin, Genzyme, Cambridge, MA, USA) 2 × 2 mg/kg. Graft composition was CD3/CD19-depleted PB with 25.4 × 106 CD34+ cells/kg and 5.0 × 104 CD3+ cells/kg. Medication for GVHD prophylaxis was the same as above. The procedure resulted in neutrophil engraftment on day +10, but ultimately failed due to leukemia recurrence on day +56, which was unresponsive to donor lymphocyte infusions 5 × 104 CD3+cells/kg. Interim control of myeloproliferation was achieved using mercaptopurine, thioguanine and cytarabine, but the boy’s clinical condition progressively worsened due to systemic adenovirus infection and cytomegalovirus reactivation. In this situation, the decision was made to go for a third transplantation using double UCB units. After a conditioning regimen of thiotepa 1 × 8 mg/kg, fludarabine 4 × 40 mg/m2, treosulfan 3 × 14 g/m2 and ATG rabbit (ATG Fresenius, Fresenius Biotech, München, Germany) 3 × 10 mg/kg, the boy received two UCB units on day +178 after the second transplant. The units were chosen according to HLA compatibility and cell dose as follows: UCB#1/patient 5/6, UCB#2/patient 4/6, UCB#1/UCB#2 4/6 (based on two-digit typing of HLA-A and -B, and high-resolution typing of HLA-DRB1). The UCB#1 graft contained 3.8 × 107 NC/kg and 1.2 × 105 CD34+ cells/kg, whereas UCB#2 contained 4.7 × 107 NC/kg and 3.0 × 105 CD34+ cells/kg. Neutrophil engraftment occurred on day +33, but platelet engraftment (>20 g/l) was delayed until day +117. Chimerism analyses indicated full UCB#1 chimerism on days +32, +52, +94, +140 and +237; chimerism was also complete in CD3+, CD56+ and CD19+ cell fractions. Analysis of immune reconstitution revealed CD3+ 1.36 g/l, CD3+CD4+ 0.17 g/l, CD3+CD8+ 1.01 g/l, CD19+ <0.01 g/l, CD56+ 0.13 g/l in PB on day +52. These numbers improved to CD3+ 5.38 g/l, CD3+CD4+ 2.41 g/l, CD3+CD8+ 2.68 g/l, CD19+ 0.90 g/l, CD56+ 0.99 g/l in PB on day +90. Cytomegalovirus viremia resolved on day +136, and antiviral treatment was discontinued. Adenovirus remained positive in blood, stool and nasopharyngeal swab until 4 months post-HSCT, positive in stool until 6 months post-HSCT, and then reverted to negative. The boy suffered from grade 3 acute GVHD of the skin, which resolved without treatment. There was no higher-grade organ toxicity. The boy remains to be disease-free and without long-term sequelae at 3.5 years after DUCBT.

The case illustrates that DUCBT is feasible in JMML, and that the use of dual cords has the potential to rescue a high-risk case of JMML after two failing haploidentical HSCTs in the absence of a suitable sibling or unrelated donor. Other investigators have pointed out that the advantage of DUCBT might go beyond securing engraftment through higher stem cell doses.10 DUCBT does not usually result in a stable ‘mixed two-donor’ chimerism, but rather leads to long-term hematopoiesis originating from only one unit.12, 13 This was also the case in the patient reported here: interestingly, UCB#1 turned out to be the dominant graft despite threefold lower number of CD34+ cells, and significantly longer storage (duration of cryopreservation, 15 years versus 7 years for UCB#2). Other investigators observed that CD3+ cell dose was the main factor associated with unit predominance in myeloablative DUCBT.13 CD3+ numbers were roughly equal in the grafts used here (UCB#1, 2.1 × 108 total; UCB#2, 1.9 × 108).

Although UCB grafts contain relatively few T cells which are mostly naive, there is experimental evidence that the presence of two competing UCB grafts elicits powerful cytotoxic reactions during early post-HSCT phase.14 It is discussed that the immunological diversity of two UCB units contributes to graft-versus-leukemia activity, even if one unit later disappears. If true, this immunological peculiarity of DUCBT appears to be particularly attractive in JMML, as the graft-versus-leukemia effect has an important role in successful HSCT for JMML.2, 15 Although the pros and cons of UCB transplantation versus BM or mobilized PB stem cells remain to be established in JMML, we suggest that DUCBT is worth considering in certain therapeutic dilemmas as exemplified above.


  1. 1

    Locatelli F, Nöllke P, Zecca M, Korthof E, Lanino E, Peters C et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 2005; 105: 410–419.

    CAS  Article  Google Scholar 

  2. 2

    Yoshimi A, Niemeyer CM, Bohmer V, Duffner U, Strahm B, Kreyenberg H et al. Chimaerism analyses and subsequent immunological intervention after stem cell transplantation in patients with juvenile myelomonocytic leukaemia. Br J Haematol 2005; 129: 542–549.

    Article  Google Scholar 

  3. 3

    Yoshimi A, Mohamed M, Bierings M, Urban C, Korthof E, Zecca M et al. Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia. Leukemia 2007; 21: 556–560.

    CAS  Article  Google Scholar 

  4. 4

    MacMillan ML, Davies SM, Orchard PJ, Ramsay NK, Wagner JE . Haemopoietic cell transplantation in children with juvenile myelomonocytic leukaemia. Br J Haematol 1998; 103: 552–558.

    CAS  Article  Google Scholar 

  5. 5

    Tanoshima R, Goto H, Yanagimachi M, Kajiwara R, Kuroki F, Yokota S . Graft versus leukemia effect against juvenile myelomonocytic leukemia after unrelated cord blood transplantation. Pediatr Blood Cancer 2008; 50: 665–667.

    Article  Google Scholar 

  6. 6

    Yabe M, Sako M, Yabe H, Osugi Y, Kurosawa H, Nara T et al. A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Transplant 2008; 12: 862–867.

    CAS  Article  Google Scholar 

  7. 7

    de Vries AC, Bredius RG, Lankester AC, Bierings M, Trebo M, Sedlacek P et al. HLA-identical umbilical cord blood transplantation from a sibling donor in juvenile myelomonocytic leukemia. Haematologica 2009; 94: 302–304.

    Article  Google Scholar 

  8. 8

    Crotta A, Rocha V, Eapen M, Wagner JE, MacMillan ML, Zecca M et al. Analysis of risk factors influencing outcomes after unrelated cord blood transplantation in children with juvenile myelomonocytic leukaemia. An Eurocord, EBMT, EWOG-MDS, CIBMTR Study. Bone Marrow Transplant 2011; 46: S15.

    Article  Google Scholar 

  9. 9

    Brunstein CG, Gutman JA, Weisdorf DJ, Woolfrey AE, DeFor TE, Gooley TA et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 2010; 116: 4693–4699.

    CAS  Article  Google Scholar 

  10. 10

    Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH et al. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood 2009; 114: 4293–4299.

    CAS  Article  Google Scholar 

  11. 11

    Baumann I, Bennett JM, Niemeyer CM, Thiele J, Shannon K . Juvenile myelomonocytic leukaemia. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. (eds). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC: Lyon, 2008, 82–84.

    Google Scholar 

  12. 12

    Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105: 1343–1347.

    CAS  Article  Google Scholar 

  13. 13

    Ramirez P, Wagner JE, DeFor TE, Blazar BR, Verneris MR, Miller JS et al. Factors predicting single-unit predominance after double umbilical cord blood transplantation. Bone Marrow Transplant 2012; 47: 799–803.

    CAS  Article  Google Scholar 

  14. 14

    Gutman JA, Turtle CJ, Manley TJ, Heimfeld S, Bernstein ID, Riddell SR et al. Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood 2010; 115: 757–765.

    CAS  Article  Google Scholar 

  15. 15

    Orchard PJ, Miller JS, McGlennen R, Davies SM, Ramsay NK . Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia. Bone Marrow Transplant 1998; 22: 201–203.

    CAS  Article  Google Scholar 

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Grant support: Deutsche Forschungsgemeinschaft FL 345/4–1 to CF and CMN.

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Flotho, C., Vraetz, T., Lang, P. et al. Successful double umbilical cord blood transplantation for relapsed juvenile myelomonocytic leukemia. Leukemia 27, 988–989 (2013).

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