Scholarly article on topic 'CMV and Relapse: What Has Conditioning to Do with It?'

CMV and Relapse: What Has Conditioning to Do with It? Academic research paper on "Clinical medicine"

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Academic research paper on topic "CMV and Relapse: What Has Conditioning to Do with It?"

Biol Blood Marrow Transplant 20 (2014) 1-3

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CMV and Relapse: What Has Conditioning to Do with It?

Ahmet H. Elmaagacli*

Asklepios Klinik Altona, Hamburg, Germany

American Society for Blood and Marrow Transplantation

Article history:

Received 4 November 2013

Accepted 4 November 2013

Manjappa and colleagues confirmed in the present study reports by us and others that a cytomegalovirus (CMV) reactivation is associated with a significant relapse risk reduction in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (SCT) with mye-loablative conditioning (MA) [1-3]. This finding challenged fundamentally our established perceptions toward CMV reactivation after SCT. This knowledge evokes, besides amazement, the insight that we know little about the sophisticated immunological processes interacting between leukemia and a donor-derived immune system that is challenged by a CMV infection. However, it is of great interest to understand the mechanism by which CMV reactivation increases such an observed antileukemic effect in AML.

Green and colleagues [2] showed in a large cohort study that a decreased relapse risk after CMV reactivation was detectable only in AML at day 100 after transplant, but not in other diseases such as chronic myeloid leukemia, acute lymphoblastic leukemia, or lymphoma. These results differed from those published by Ito and colleagues [4], who observed that CMV reactivation was associated with a decreased relapse in a cohort of 110 patients with chronic myeloid leukemia. Green and colleagues argued that the great majority of patients in the Ito study received ex vivo T- cell—depleted grafts, which typically results in a robust natural killer (NK) cell reconstitution after transplant.

In contrast to these results, Thomson et al. [5] found no association between CMV reactivation and relapse risk in 100 patients with AML who received alemtuzumab, which depletes a variety of immune cells, including NK cells, and persists in vivo for prolonged periods. Their results are in line with our results of a retrospective study showing that patients with AML (n = 64) after myeloablative T cell—depleted transplantation using alemtuzumab did not benefit from a CMV reactivation. Although alemtuzumab completely abolished the CMV induced antileukemic effect in our study, antithymocyte globulin (ATG) may have only a moderate influence on it according to our observations in a different cohort of 100 AML patients transplanted from HLA-mismatched unrelated and sibling donors after using a myeloablative conditioning regimen (unpublished

Financial disclosure: See Acknowledgments on page 2.

* Correspondence and reprint requests: Ahmet H. Elmaagacli, MD, Asklepios Klinik Altona, Paul-Ehrlichstr. 1, 22763 Hamburg, Germany.

E-mail address: 1083-8791/$ - see front matter © 2014 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.

observation). The reason for that might be that ATG worsens only the reconstitution of CD4 T cells but not of NK and CD8 T cells, which might play a role in the CMV-mediated anti-leukemic effect [6]. Thus, Scheper and colleagues [7] reported that gamma/delta T cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia. They supposed that this T cell population contributed to the CMV-induced antileukemic effect. Foley et al. [8] demonstrated increased populations of interferon-g producing NKG2C1 and NKG2A2 NK cells in SCT recipients as soon as 2 weeks after CMV viremia was detected. In addition to T cells, NK cells possess remarkable antileukemic affects against AML in the transplant setting [9].

But what is the role of a conditioning regimen in this context? Manjappa and colleagues [1] reported that the antileukemic effect of a CMV reactivation was only found in patients receiving MA conditioning (n = 206) but not in patients who received reduced-intensity conditioning (RIC; n = 58). What is different about RIC compared with MA conditioning for the CMV-induced antileukemic effect? In their smaller RIC cohort, 44 of 58 patients received ATG as part of their conditioning regimen and a higher proportion of patients were in first complete remission (60%) than in the MA cohort (44%). Manjappa and colleagues argued that in vivo T cell depletion by ATG in the RIC cohort may result in mitigating the enhanced graft-versus-leukemic effect induced by CMV reactivation, which underlines the importance of graft-derived T cells in mediating this effect. Furthermore, they argued that host-derived memory T cells can persist for up to 6 months in RIC patients and contribute toward immunity against CMV [1].

Persisting host T cells could contribute to clearing of CMV upon its reactivation, thereby possibly preventing optimal donor T cell and NK cell activation that cross-reacts toward AML. It is unclear, however, whether these differences explain the distinct mechanism or simply reflect other variables, including a small sample size with insufficient statistical power. On the other hand, it is true that most patients in the study by Green et al. [2] and in our study [3] received MA conditioning, which supports this thesis of Manjappa and colleagues.

Besides the great interest to learn the mechanism of the protective effect of CMV reactivation, it is finally of importance if and how we can clinically use this finding. Because it is not justified to change our CMV treatment strategy due to the higher therapy-associated mortality of a CMV reactivation after SCT, CMV vaccination might be an option to induce similar effects without increasing the rate of therapy-associated mortality. First results from a phase II study of a CMV vaccine showed a stimulation of specific immune responses to CMV [10]. Therefore, it remains to be seen if CMV vaccination might not only prevent CMV infections but also reduce the relapse risk of patients with AML. This might be possible if the CMV vaccine induced

O. Fasan / Biol Blood Marrow Transplant 20 (2014) 1-3

stimulation of specific immune responses to CMV in patients with AML after SCT is potent enough. However, this effect cannot be expected from new antiviral drugs towards CMV discussed elsewhere.


Conflict of interest statement: There are no conflicts of interest to report.

Financial disclosure: The authors have nothing to disclose.


1. Manjappa S, Bhamidipati PK, Stokerl-Goldstein KE, et al. Protective effect of CMV reactivation on relapse after allogeneic hematopoietic cell transplantation in AML patients is influenced by their conditioning regimen. Biol Blood Marrow Transplant. 2014;20:46-52.

2. Green ML, Leisenring WM, Xie H, et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood. 2013;122:1316-1324.

3. Elmaagacli AH, Steckel NK, Koldehoff M, et al. Early human cyto-megalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus leukemia

effect in acute myeloid leukemia patients. Blood. 2011;118: 1402-1412.

4. Ito S, Pophali P, Co W, et al. CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML. Bone Marrow Transplant. 2013;48:1313-1316.

5. Thomson KJ, Mackinnon S, Peggs KS. CMV-specific cellular therapy for acute myeloid leukemia? Blood. 2012;119:1088-1090. author reply, 1090-1091.

6. Bosch M, Dhadda M, Hoegh-Petersen M, et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy. 2012;14:1258-1275.

7. Scheper W, van Dorp S, Kersting S, et al. gdT cells elicited by CMV reactivation after allo-SCT cross-recognize CMV and leukemia. Leukemia. 2013;27:1328-1338.

8. Foley B, Cooley S, Verneris MR, et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood. 2012;119: 2665-2674.

9. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097-2100.

10. Kharfan-Dabaja MA, Boeckh M, Wilck MB, et al. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Diss. 2012;12:290-299.

Optimal Autologous Peripheral Blood Progenitor Cell Mobilization Involves More Than the CD34+Yield

Omotayo Fasan*

Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina

Article history:

Received 7 November 2013

Accepted 7 November 2013

Peripheral blood progenitor cell (PBPC) mobilization is the first step in the autologous stem cell transplant (ASCT) procedure. The regimen used for PBPC mobilization affects not just the cost of ASCT but also the patient's total transplant experience. We often focus on the absolute numeric progenitor cell yield as measured by the CD34+ cell dose in the mobilized graft; however, the optimal mobilization strategy should be judged on more than this metric alone. The PBSC graft quantity and quality affects engraftment kinetics and, although controversial, may influence relapse-free survival, overall survival, and the development of post-transplant complications such as therapy-related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML) [1-3]. The choice of whether to mobilize patients using either gran-ulocyte colony-stimulating factor (G-CSF) alone, G-CSF plus plerixafor, or chemotherapy plus G-CSF is usually based on the patient's disease status, prior therapy, predicted poor mobilizer status, transplant center protocol, cost considerations, and the individual patient situation. Chemotherapy plus G-CSF is generally viewed as an attractive strategy to achieve needed anti-tumor effect and to ensure at least an adequate (2 x 106/kg CD34+ cells) or a successful (>5 x 106/ kg CD34+ cells) apheresis yield at a reasonable cost.

Financial disclosure: See Acknowledgments on page 3.

* Correspondence and reprint requests: Omotayo Fasan, Suite 5300 Levine Cancer Institute, Carolinas Healthcare System, 1021 Morehead Medical Drive, Charlotte, NC 28204.

E-mail address: 1083-8791/$ - see front matter © 2014 American Society for Blood and Marrow Transplantation.

In this issue, Shin Young Hyun et al. [4] reports on the outcomes of mobilizing with high dose etoposide plus GCSF as compared to cyclophosphamide plus GCSF and platinum based salvage regimens plus GCSF. Etoposide plus GCSF is not a new mobilization regimen, however its utilization declined following concerns regarding the reported higher incidence of tMDS/AML following etoposide based mobilization and ASCT [3]. This is probably not so and there are reports indicating that the incidence of t(MDS/AML) after etoposide is not significantly increased [5-7]. The dose of etoposide utilized in this retrospective study by Shin Young Hyun et al. was 1.5g/m2. This dose is lower than the more conventional 2g/m2. It however appears to have led to an overall greater number of successful (> 5 x 106/kg CD34+ cells) mobilizations at 86% compared to cyclophosphamide 4g/m2 plus GCSF and the platinum based regimens (ICE, DHAP and ESHAP) plus GCSF at 45% and 61% respectively (p=0.004). The success of this lower dose is in keeping with the observation by Kanfer et al., that reducing the dose of etoposide to 1.6g/m2 or 1.8g/m2 resulted in adequate and successful mobilizations compared to higher doses. An even lower dose of etoposide (0.75g/m2) was utilized with success in patients with multiple myeloma, some of whom were predicted poor mobilizers [8]. Consistent across all reports of high and intermediate dose etoposide based mobilization is the high incidence of neutropenic fever compared to growth factor based strategies where the incidence is zero. The incidence of 67% in this report is higher than previously reported rates that range from of 17 — 27%. This complication unfortunately increases the cost and inconvenience to patients due to the need for readmission for intravenous antibiotics. There is more myelo-suppression and utilization of blood products with all chemo-mobilization based strategies; however in this report etoposide plus GCSF induced a significantly lower