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Leukemia Research 38 (2014) 1154–1155

Contents lists available at ScienceDirect

Leukemia Research

j ourna l h om epa ge: www.elsev ier .com/ locate / leukres

ditorial

LL—Clear sailing ahead for many, while rough waters remain for

ome

Chronic lymphocytic leukemia (CLL) is a common blood cancerhere for the ‘many’ a reasonable survival measured in years toecades with good quality of life can occur [1–3]. However, for the

few’ with poor prognosis [1] characterized by features such as sub-ptimal response to conventional therapy or presence of high-riskenetic markers such as deletion (del) 11q [4] or del 17p [5,6] byISH testing [7], the outlook is poor, with expected survival in therder of 1–5 years [8–11].

The article by Chavez and colleagues [12] in this issue illustrateshe challenges faced by such patients even following allogeneicematopoetic stem cell transplantation (allo HSCT). Prior studiesave shown that patients with these two high-risk FISH abnor-alities may be cured with allo HSCT [13–16]. Long term results

owever have varied in different series, with some showing pooresults in this patient population despite allo HSCT [17]. It is likelyhat factors including timing of transplant and co-presence of otheroor-risk features account for the fact that some of these patientsay achieve cure with transplant, while some will have higher

han average risk of mortality related to the transplant (non-relapseortality, NRM) and/or the CLL. Full analysis of outcomes for these

atients, including impact of pre and post transplant factors, ismportant so that we may modify and improve their treatmentlgorithm in the future.

In the absence of a randomized trial comparing transplantersus conventional therapy for high-risk CLL patients we mustely on good observational and analytical data, such as this currentohort study analyzing consecutive high-risk patients proceedingo allo HSCT [12], well conducted decision analyses [18], andonor/no donor comparisons [19]. The latter two studies sup-ort the conclusion that for high-risk relapsed/refractory patientsnd/or those meeting the European Society for Blood and Mar-ow Transplantation (EBMT) criteria for allo HSCT for CLL [20], lifexpectancy is superior for transplanted patients. This would sup-ort the strategy of taking such high-risk patients to transplants soon as EBMT criteria or similar are met. The current studyescribes a lower progression-free survival and a higher NRM forigh-risk patients with 11q and 17p deletions. There is a highroportion of patients (44%) who had unresponsive disease sta-us (less than partial response) at transplant, in other words stabler progressive/refractory disease, which has been linked to nega-

ive outcome in some prior series [13,14,21]. In the current paper,tatus of disease at transplant and presence of 17p del or 11qel were associated with worse overall and disease-free survival

DOI of original article: http://dx.doi.org/10.1016/j.leukres.2014.04.006.

ttp://dx.doi.org/10.1016/j.leukres.2014.07.008145-2126/© 2014 Elsevier Ltd. All rights reserved.

in multivariate analysis; lower performance status also negativelyimpacted progression-free survival.

At diagnosis of CLL, only 4–7% of patients have del 17p andapproximately 20% have del 11q [7]. However, over time, and fol-lowing therapy, clonal evolution [22,23] may occur, such that inpre-treated relapsed/refractory patients at time of allo HSCT, amuch higher percentage will have one or both of these high-riskgenomic changes, at times over 50% of patients (as in this series). Itis therefore imperative that eligible patients with high risk featuresare taken to allo HSCT as soon as recognized, ideally prior to theonset of acquisition of these high-risk genomic changes, refractorydisease status and/or loss of performance status. Data from the Ger-man CLL 3X trial [14], where patients proceeded to transplant oncethey met one of the high-risk EBMT criteria, demonstrated goodoutcomes irrespective of high-risk genetic markers. While it is dif-ficult to make cross population comparisons, this prospective studydemonstrated what may be accomplished if patients proceed totransplant at an optimal time. In the German cohort, 24% of patientshad refractory disease at HSCT, lower than in the current paper,which may account for their promising outcomes in the high-riskgroups. It has been our experience in Vancouver, as in the cur-rent article, that patients with del 17p who are heavily pre-treatedand refractory to therapy have a higher treatment-related mortal-ity (TRM) and risk of relapse with resultant lower overall survival[17]. Earlier recognition of such patients and referral for transplantis likely to produce results more in line with the German CLL3X trial.

The CLL community is poised for a paradigm shift in CLL ther-apy and outcomes once newer therapies such as pathway inhibitorsand next generation antibodies are fully tested in clinical trialsand assigned their optimal place in the CLL treatment algorithm[24]. However, even with best therapy, as previously seen withintegration of tyrosine kinase inhibitors (TKI) into chronic myeloidleukemia (CML) therapy, there will always be patients who eitherfail to have an optimal response to best treatment, possess high-risk genetic or other markers at diagnosis, or acquire these alongtheir disease course. For these patients, understanding the optimaltime at which to apply allo HSCT with curative intent, and having agood predictive model to communicate outcome expectations willremain important.

The Chavez study [12] highlights the fact that it remains chal-lenging to rescue high-risk 17p and 11q deleted patients with alloHSCT in the setting of refractory disease and points the way for-

ward to earlier recognition of such high-risk patients and earlierapplication of effective therapy. Previously, CML was a commondiagnosis for patients requiring allo HSCT. In the current TKI era,these transplants are reserved for the uncommon high-risk patients

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Editorial / Leukemia Re

ho have suboptimal response to best therapy. It is possible thatn the future, a similar paradigm shift will occur in CLL wherebyncreasing effectiveness of early therapies may lead to less riskf acquisition of high-risk genetic markers, refractory disease, andower risk of transformation, but that for select high-risk patients,roceeding to allo HSCT at the optimal time will lead to improved

ong-term outcomes.

cknowledgements

None.

eferences

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Cynthia L. Toze a,b,c,∗a Leukemia/Bone Marrow Transplant Program of

British Columbia, Canadab Division of Hematology, Vancouver General

Hospital and British Columbia Cancer Agency, Canadac University of British Columbia, Canada

Alina S. Gerrie a,b,c

a Leukemia/Bone Marrow Transplant Program ofBritish Columbia, Canada

b Lymphoma Tumour Group, Divisions of Hematologyand Medical Oncology, British Columbia Cancer

Agency, Canadac University of British Columbia, Canada

∗ Corresponding author at: Division of Hematology,10th Floor, GLDHCC, 2775 Laurel St., Vancouver,

BC, Canada V5Z 1M9.Tel.: +1 604 875 4863.

E-mail address: ctoze@bccancer.bc.ca (C.L. Toze)

11 July 2014

Available online 12 August 2014