Damned if you do, damned if you don’t

 Despite advances in our understanding of the pathogenesis of MPNs, processes for risk stratification and therefore indications for cytoreduction lack better refinement…debate continues over the role of venesection versus cytoreduction as a first-line therapy in PV, and whether hydroxyurea, which is associated with better thrombotic prophylaxis, may be linked to a higher rate of leukemic transformation.
Dr. Claire Harrison
Guy’s and St. Thomas’ National Health Service Foundation Trust

There is a cruel dilemma at the heart of treatment for polycythemia vera.

The management of the disease often requires reduction of hematocrit (HCT), the red blood cell proportion of blood, to avoid the worst of complications: hemorrhage, thrombosis, cardiovascular events.  Yet the means and level of reduction can itself be a complicating factor in maintaining a patient’s overall health and quality of life.

There are physical  and chemical means to reduce red blood mass. For practical purposes, venesection and, usually, hydroxyurea dominate in current practice. Leaving aside the virtue of each of these methods for a moment, two questions remain:

To what target level should HCT be lowered?

Are there unforeseen consequences of maintaining HCT at this target level?

Does this reduction actually reduce the incidence of thrombosis?

Evidence from the European Collaboration on Lowdose Aspirin in Polycythaemia Vera (ECLAP) and the PV Study Group, PVSG-01, the two largest prospective studies of this disease – suggested there’s no difference in the rate of thrombosis in patients maintained at different HCT values below 50-52%.

So when an Italian group began its large scale, multi-site clinical study, CYTO-PV, in 2008 seeking to determine the optimum hematocrit level for PV patients, its work was followed with some interest.  (Related questions about the efficacy of reducing platelet and leukocyte counts — a concomitant of cytoreduction —  in lowering risk of thrombosis were not considered.)

This year, Roberto Marchioli, Alessandro Vannucchi , Tiziano Barbui, et. al. presented the group’s findings in the New England Journal of Medicine,  “Cardiovascular Events and Intensity of Treatment in Polycythemia Vera.” This is an important milestone in the process of understanding the effects of reducing hematocrit in managing PV.  In the response and serious public debate that followed this publication, the dimensions of the associated challenges have become clearer.

What follows is a brief and partial summary of the CYTO-PV report and ensuing reactions in the journals and in papers presented at the European Hematology Association meeting earlier this month. Links to full texts are provided at the conclusion of this summary.

1.  Description, May 2011: A large scale clinical study to test the effectiveness of cytoreductive therapy in reducing cardiovascular risk among PV patients  was undertaken by an Italian group (Marchioli et al.) .   The means of cytoreduction were limited to either phlebotomy or hydroxyurea. (As reported in Thrombosis. )

Roberto Marchioli, et. al. Thrombosis Volume 2011 (2011),  doi:10.1155/2011

Roberto Marchioli, et. al. Thrombosis
Volume 2011 (2011),
doi:10.1155/2011

2. Jan, 2013: Publication of first results in the NEJM  “We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group)….In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%.

Letter from Jerry Spivak endorsing the results and use of the hematocrit measurement accompanied the article

3.  April, 2013 Series of NEJM letters:  McMullin, Harrison et al.  “Since HU also lowers leukocyte count as well as hematocrit  “it is impossible to discern the relative merits of more stringent hematocrit control  from the merits of a lower leukocyte count.”

Guiseppe Leone: Study did not take into account differences between male and female normal hematocrit levels.

Josef Prchal and Victor Gordeuk:  Need more sophisticated analysis of data to avoid false generalizations For example, “Smoking is associated with elevated hematocrit level  and multivariate analysis showed a correlation between the risk of stroke and increased blood pressure and smoking.  However, without the factor of smoking, the association between an elevated hematocrit level and stroke was no longer significant. (Emphasis added.)

Robert Marchioli, et al. response:   CYTO-PV study was powered to compare the benefit-risk of intensive vs. less intensive hematocrit reduction. “…the results of subgroup analysis …indicate a similar benefit in patients treated with phlebotomy alone, drug therapy, or both.” nejm pv harrison Re Leone: “…we found no hint as to the need for more intensive treatment in women since no thrombotic event was observed in the 66 women whose hematocrit was kept below 45% as compared with the nine events reported in the 72 women (12%) who were assigned to the group with a hematocrit target of 45 to 50%.” Re Prchal and Gordeuk:  “Our study confirms and extends previous data pointing to an association between an increased hematocrit level and vascular complications in patients with polycythemia vera…”

Jerry Spivak:   It is possible to separate the effects of phlebotomy from those of the leukocyte count (since)..”.the on-study leukocyte counts overlapped completel between the study groups.”  Cytoreduction with hydroxyurea “has not been shown to prevent major vessel thrombosis or even prolong survival in patients with polycythemia vera. However these agents. including hydroxyurea, have been shown by evidence-based studies to cause acute leukemia in some patients.”

4. The EHA meeting, June, 2013:  Robyn Emanuel, Roberto Marchioli, Ruben Mesa et al., Abstract: “Impact of Hematocrit on Symptom Burden among Polycythemia Vera Patients.”  (EHA18ABSSUB-4343)  Analysis of patient data from two studies, the CYTO PV trial and the MPN-SAF study (JCO 2012) indicates symptom burden HCT impact PV Chartis more severe in those with HCT greater than 45%.  Conversely, strict adherence to the lower HCT leve [emphasis added] was associated with loss of concentration, insomnia, weight loss, night sweats and pruritus. “Patients with lower HCT had significantly higher rate of fatigue…” “Iron deficiency likely contributes to cognitive and fatigue complaints seen among patients with strict HCT control.”

5. The EHA meeting, June 2013, Roberto Marchioli et al: Abstract “White Blood Cells Count Influence the Prognosis of Polycythemia Vera Patients; A sub-analysis of the CYTO-PV Study.” (EHA18aBSSUB=-4631)  “Keeping HCT levels >45% and leukocyte count >12×109/L, the risk of fatal and nonfatal cardiovascular events is significantly increased….Future clinical studies are needed to evaluate the benefit-risk profile of more aggressive therapy to target the WBC counts.”

Sources: 

Leader quote:  Claire Harrison,  Rethinking Disease Definitions, http://www.ncbi.nlm.nih.gov/pubmed/21239782

1. Large-scale study, Marchioli et al., As reported in Thrombosis http://www.hindawi.com/journals/thromb/2011/794240/

 2. Marchioli et al., publication of first results in the NEJM, (abstract:  http://www.ncbi.nlm.nih.gov/pubmed/23216616

3. April, 2013, Series of NEJM letters:  http://www.nejm.org/doi/full/10.1056/NEJMc1301262

4,  EHA Meeting, Robyn Emanuel, et al.,  (EHA18ABSSUB-4343)   http://www.postersessiononline.eu/pr/aula_poster.asp?congreso=602733790

5. EHA Meeting, Marchioli, (EHA 18ABSSUB-4631)  http://www.postersessiononline.eu/pr/aula_poster.asp?congreso=602733790.

© MPN Quarterly Journal, 2013. This work is licensed under a Creative Commons Attribution-NonCommercial No-Derivs 3.0 Unported License.

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