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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

BLOOD RESEARCH Volume 48ㆍNumber 1ㆍMarch 2013 http://dx.doi.org/10.5045/br.2013.48.1.68

Letter to the Editor

Ruxolitinib changes the natural course of myelofibrosis and its transplant outcome

THE AUTHORÊS REPLY: In his letter referring to “Will JAK1/2 inhibitors change the standard of care for myelofibrosis (MF)?”, Dr. Raut raised two important issues about rux- olitinib: (1) its mechanism of action and (2) its beneficial effect on the outcome of hematopoietic stem cell trans- plantation (HSCT) in MF patients. The first issue was about how ruxolitinib improved survival without causing any sig- nificant effect on disease biology parameters such as the peripheral blast count, marrow fibrosis, cytogenetic re- sponse, and JAK2 V617F allele burden. At the last annual meeting of the American Society of Hematology, long-term outcome data of COMFORT-I and COMFORT-II trials that either showed significantly improved survival of ruxolitinib group compared to placebo (hazard ratio (HR) 0.58, 95%

confidence interval (CI) 0.36–0.95) or best supportive care (HR 0.52, 95% CI, 0.27–1.00) were presented. Since periph- eral blast counts, marrow fibrosis, and cytogenetics were not investigated in those trials, it is difficult to explain the survival advantage on those parameters. However, with the use of ruxolitinib, the two studies showed significant sustained reduction of the JAK2 V617F allele burden. In COMFORT-I trials, ruxolitinib resulted in reduction of JAK2 mutant allele burden by a mean of 10.9% at week 24 (P

<0.0001) and -21.5% at week 48 (P<0.0002) that were independent of baseline JAK2 V617F levels [1]. COMFORT- II trials also showed significant reduction in allele burden (median reduction rate of -7.0% at 48 weeks and -8.7%

at 72 weeks), which was associated with spleen response [2]. Verstovsek et al. reported that 50% reduction in palpable spleen length was associated with prolonged survival in ruxolitinib treated patients [3]. These observations suggest that ruxolitinib could alter MF prognosis through reduction of JAK2 V617F allele burden and spleen volume. However, we should note that survival improvement was not great

and longer follow-ups are required. The relationship be- tween JAK2 V617F allele burden and the survival is also unclear.

The second issue was regarding pre-transplant ruxolitinib and the improvement of HSCT outcome by decreasing proin- flammatory cytokines. Several convergent lines of evidence suggested that inflammatory cytokines act as mediators of acute GVHD and cause debilitating symptoms in MF. Ruxol- itinib significantly decreased tumor necrosis factor-alpha and interleukin-6 levels for a prolonged time in patients with MF through anti-JAK1-mediated downregulation [1].

In a mouse allogeneic transplant model, ruxolitinib de- creased alloreactive CD4+ T cells, expression of CXCR3 in activated T cells and GVHD, leading to improved survival [4]. Poor performance status is associated with poor outcome with HSCT in MF, whereas the reduction in symptomatic burden with JAK1/2 inhibitors may have the potential of improving transplant outcome. Massive splenomegaly is re- ported to be associated with delayed neutrophil and platelet recovery, suggesting that reduction of spleen volume may induce faster marrow recovery after HSCT [5]. Although these are indirect evidences, they support the suggestion that JAK1/2 inhibitors prior to HSCT may have a beneficial effect on the transplant outcome. Whether pre-transplant JAK1/2 inhibitors decrease GVHD and improve survival in HSCT should be addressed through a prospective trial.

Chul Won Jung, M.D.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to: Chul Won Jung Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3452, E-mail: leukemia1@skku.edu AuthorsÊ Disclosures of Potential Conflicts of Interest

No potential conflicts of interest relevant to this article

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bloodresearch.or.kr Blood Res 2013;48:68-9.

Ruxolitinib changes the natural course of myelofibrosis and its transplant outcome 69

were reported.

REFERENCES

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, place- bo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366:799-807.

2. Vannucchi AM, Passamonti F, Al-Ali HK, et al. Reductions in JAK2 V617F allele burden with ruxolitinib treatment in com- fort-II, a phase 3 study comparing the safety and efficacy of rux- olitinib with best available therapy (BAT). Blood 2012;120:634 (abst 802).

3. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term out-

comes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood 2012;120:1202-9.

4. Carniti C, Gimondi S, Vaccaroli R, et al. Inhibition of JAK1/JAK2 is more effective than inhibition of JAK3 in protecting mice from acute graft-versus-host disease (aGVHD) by significantly de- creasing alloreactive CD4+ T-cells. Blood 2012;120:702(abst 2997).

5. Ciurea SO, Sadegi B, Wilbur A, et al. Effects of extensive spleno- megaly in patients with myelofibrosis undergoing a reduced in- tensity allogeneic stem cell transplantation. Br J Haematol 2008;141:80-3.

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