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in this platinum-sensitive population with little BRCA can benefit from PARP inhibition. However, an
pretreatment, making further comparison of rucaparib assay that is efficient and produces clinically meaningful
monotherapy with platinum-based chemotherapy less results is still some way off.
attractive. Nevertheless, part two of the ARIEL2 trial
(NCT01891344) is including patients who have been Antonio González Martín
more heavily pretreated (at least three previous lines), for MD Anderson Cancer Center Madrid, Madrid 28033, Spain
agonzalezm@seom.org
whom these results could be more clinically meaningful.
I report fees from Clovis for serving on a local advisory board and fees from
With respect to the predictive value of the assay, the Roche, Astra Zenenca, and Pharmamar for being a speaker and advisory board
differences detected between the LOH high and LOH low member.
subgroups were not particularly clinically relevant and 1 Nielsen FC, van Overeem Hansen T, Sørensen CS. Hereditary breast and
ovarian cancer: new genes in confined pathways. Nat Rev Cancer 2016;
the biomarker does not seem to be able to efficiently 16: 599–612.
identify a subgroup of patients with wild-type BRCA 2 Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous
recombination deficiency: exploiting the fundamental vulnerability of
who will achieve significant progression-free survival ovarian cancer. Cancer Discov 2015; 5: 1137–54.
3 Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in
with rucaparib. In a planned post-hoc analysis of this patients with platinum-sensitive relapsed serous ovarian cancer:
study,9 Coleman and colleagues showed that a refined a preplanned retrospective analysis of outcomes by BRCA status in a
randomised phase 2 trial. Lancet Oncol 2014; 15: 852–61.
cutoff for tumour genomic LOH of 16% is able to better 4 Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib
discriminate a difference in progression-free survival monotherapy in patients with advanced cancer and a germline BRCA1/2
mutation. J Clin Oncol 2015; 33: 244–50.
between the LOH high and LOH low subgroups than is 5 Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with
a cutoff of 14% (HR 0·51 [95% CI 0·34–0·74]; p<0·001). recurrent high-grade serous or poorly differentiated ovarian carcinoma or
triple-negative breast cancer: a phase 2, multicentre, open-label,
This new cutoff is prospectively applied in the ARIEL 3 non-randomised study. Lancet Oncol 2011; 12: 852–61.
6 Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of
trial (NCT01968213), in which patients with high-grade heterozygosity predict homologous recombination repair defects in
ovarian cancer and platinum-sensitive relapse responding epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82.
7 Watkins JA, Irshad S, Grigoriadis A and Tutt AN. Genomic scars as
to rechallenge with platinum-based chemotherapy will biomarkers of homologous recombination deficiency and drug response in
be randomly assigned to maintenance therapy with breast and ovarian cancers. Breast Cancer Res 2014, 16: 211
8 Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive
rucaparib versus placebo. There are great expectations high-grade ovarian carcinoma (ARIEL2 Part 1): an international,
multicentre, open-label, phase 2 trial. Lancet Oncology 2016; published
on the results of this study, because another homologous online Nov 28. http://dx.doi.org/10.1016/S1470-2045(16)30559-9.
recombination deficiency assay was shown to be unable 9 Coleman RL, Swisher EM, Oza AM. Refinement of prespecified cutoff for
genomic loss of heterozygosity in ARIEL2 part 1: a phase II study of
to significantly discriminate the efficacy of niraparib in rucaparib in patients (pts) with high grade ovarian carcinoma.
the maintenance setting.10 Proc Am Soc Clin Oncol 2016; 34: abstr 5540.
10 Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in
Finally, this trial constitutes a valuable effort in the platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; published
challenge of identifying which patients with wild-type online Oct 7. DOI:10.1056/NEJMoa1611310.

Polycythaemia vera and precision medicine: a prescription


for the 21st century
Polycythaemia vera is the most common myelo- complication associated with the disease: major Published Online
December 1, 2016
proliferative neoplasm and the ultimate phenotypic vessel thrombosis. Thrombosis prevention is the http://dx.doi.org/10.1016/
consequence of the Janus kinase 2 (JAK2) Val617Phe cornerstone of polycythaemia vera therapy and the S1470-2045(16)30591-5

mutation. First described in the 19th century, we use of phlebotomy to achieve a sex-specific normal See Articles page 88

now understand the molecular pathogenesis of haematocrit concentration is the most effective
polycythaemia vera, its natural history, and the basis for means to accomplish this.1 However, phlebotomy
its many complications. Remarkably, however, still no has been widely shunned in favour of chemotherapy,
consensus exists about its clinical management. even though in large-scale clinical trials, alkyating
Erythrocytosis is the hallmark of polycythaemia agents, ³²P, or hydroxyurea therapy did not prevent
vera and the cause of the most common serious thrombosis or prolong survival relative to phlebotomy

www.thelancet.com/oncology Vol 18 January 2017 9


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Comment

alone in polycythaemia vera but did increase leukaemic pruritus, was superior in the ruxolitinib group, and
transformation.2,3 adverse events were more common in the best available
These results notwithstanding, chemotherapy is still therapy group. The authors concluded that ruxolitinib
recommended for so-called high-risk patients with “could be considered a standard of care for second-line
polycythaemia vera, defined as those aged older than therapy in this post-hydroxyurea patient population”.
Jim West/Science Photo Library

60 years or with a history of thrombosis,4 even though However, I challenge this conclusion. First, the
thrombosis in polycythaemia vera is provoked by consensus that hydroxyurea is first-line therapy for
hyperviscosity, disease complications do not differ in polycythaemia vera is not evidence based. Indeed, a trial
patients aged younger than or older than 60 years,5 and using hydroxyurea in patients with polycythaemia vera
no evidence suggests that major vessel thrombosis is a to achieve European LeukemiaNet criteria for complete
consequence of either leukocytosis or thrombocytosis. haematological remission did not result in better
Furthermore, not all patients with polycythaemia vera will survival or less thrombosis compared with the expected
develop extramedullary haematopoiesis or myelofibrosis.6 survival of patients with similar disease characteristics.10
The discovery of the JAK2 Val617Phe mutation Second, the primary endpoint of RESPONSE-2 was
ushered in a new framework for the treatment of phlebotomy control but the appropriate control group
myeloproliferative neoplasms. Targeted therapy of (a phlebotomy-only group) was not included, nor
committed haematopoietic progenitor cells expressing was phlebotomy control or haematological remission
activated JAK2 fosters the proliferation of these cells achieved with ruxolitinib in all patients. Ruxolitinib is
and the production of inflammatory cytokines. Targeted an expensive drug, but phlebotomy is an inexpensive
therapy is now a standard of care for high-risk patients and immediately effective procedure, and it is unlikely
with primary or secondary myelofibrosis, in whom a that insurers would support the use of ruxolitinib in
JAK1 or JAK2 inhibitor (ruxolitinib) controlled blood polycythaemia vera for haematocrit control without
counts, reduced inflammatory cytokine production and proof of greater efficacy than phlebotomy therapy.
extramedullary haematopoiesis, and improved survival.7 Third, no study of ruxolitinib in polycythaemia vera has
Ruxolitinib has now been assessed in two clinical capitalised on the observation, based on both clinical and
trials in polycythaemia vera without myelofibrosis. gene-expression data, that patients with polycythaemia
In The Lancet Oncology,8 Francesco Passamonti and vera are not all alike; male and female patients differ
colleagues report the results of RESPONSE-2, a clinically and in gene expression, and the disease is
randomised, open-label, phase 3b trial of ruxolitinib in indolent in some patients and aggressive in others, who
patients with polycythaemia vera without splenomegaly, also differ in gene expression.6 Thus, it should not be
who were intolerant of or unresponsive to hydroxyurea, presumed that all patients with polycytaemia vera will
versus the best available therapy (usually hydroxyurea), require ruxolitinib therapy or that all patients who do
making this trial—like the previous RESPONSE trial,9 receive this treatment will respond similarly.
in which the effect of ruxolitinib was examined in Finally, polycythaemia vera is an haematopoietic stem-
hydroxyurea-intolerant or unresponsive patients with cell disorder and, so far, ruxolitinib does not seem to
polycythaemia vera with splenomegaly—a referendum affect haematopoietic stem cell behaviour. At present,
on hydroxyurea. On the basis of their age, most pegylated interferon is the only drug that targets
RESPONSE-2 patients were defined as so-called high risk haematopoietic stem cells and produces haematological
patients, and were phlebotomy-dependent. and molecular remission, although not in all patients and,
Unsurprisingly, for the primary endpoint of patients like ruxolitinib, we still do not know how best to use it.
achieving haematocrit control, ruxolitinib was superior Thus, following the data recorded in the RESPONSE trials
to best available therapy (46 [62%] of 74 patients in the we now have access to two non-myelotoxic therapies
ruxolitinib group vs 14 [19%] of 75 in the best available (ruxolitinib and pegylated interferon) to treat a disease
therapy group; odds ratio 7·28 [95% CI 3·43–15·45]; whose natural history is measured in decades but whose
p<0·0001), and also for the key secondary endpoint for patients do not all have the same genetic background or
patients achieving complete haematological remission require the same level of myelosuppression—a setting
(23% vs 5%). Additionally, symptom control, including most appropriate for precision medicine.

10 www.thelancet.com/oncology Vol 18 January 2017


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Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
Comment

Jerry L Spivak 5 Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease
Traylor 924, John Hopkins University School of Medicine, characteristics and clinical outcomes in polycythemia vera. Leuk Lymphoma
2013; 54: 1989–95.
720 Rutland Avenue, Balimore, MD 21205, USA 6 Spivak JL, Considine M, Williams DM, et al. Two clinical phenotypes in
jlspivak@jhmi.edu polycythemia vera. N Engl J Med 2014; 371: 808–17.
I declare no competing interests. 7 Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled
trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799–807.
1 Pearson TC, Weatherly-Mein G. Vascular occlusive episodes and venous 8 Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the
haematocrit in primary proliferative polycythaemia. Lancet 1978; treatment of inadequately controlled polycythaemia vera without
2: 1219–21. splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study.
2 Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute Lancet Oncol 2016; published online Dec 1. http://dx.doi.org/10.1016/
leukemia in polycythemia vera associated with chlorambucil therapy. S1470-2045(16)30558-7.
N Engl J Med 1981; 304: 441–47. 9 Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus
3 Najean Y, Rain J. Treatment of polycythemia vera: the use of hydroxyurea standard therapy for the treatment of polycythemia vera. N Engl J Med
and pipobroman in 292 patients under the age of 65 years. Blood 1997; 2015; 372: 426–35.
90: 3370–77. 10 Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic
4 Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: value of the European LeukemiaNet criteria for clinicohematologic
2015 update on diagnosis, risk-stratification and management. response, resistance, and intolerance to hydroxyurea in polycythemia vera.
Am J Hematol 2015; 90: 162–73. Blood 2012; 119: 1363–69.

Predicting therapy-related myeloid neoplasms—and


preventing them?
Therapy-related myeloid neoplasms are an iatrogenic associated with an increased risk of therapy-related
tragedy. When a patient develops therapy-related myeloid neoplasms (eg, higher total chemotherapy
myelodysplastic syndrome or acute myeloid leukaemia dose, combination chemoradiotherapy, use of myeloid
(ie, therapy-related myeloid neoplasms) several growth factors, older patient age, and longer duration

Tek Image/Science Photo Library


years after receiving curative treatment for another of cytotoxic therapy), it is not yet fully understood
neoplasm, the unexpected and unwelcome return how to identify those patients at highest risk or how to
of frequent visits to a cancer centre and unearthing prevent therapy-related myeloid neoplasms.
of old fears about mortality can be psychologically In The Lancet Oncology, investigators from two large
devastating. Alternatively, if a therapy-related myeloid US oncology referral centres report the results of their
neoplasm emerges while the patient is still receiving genomic analyses (ie, whole-exome sequencing and Published Online
December 4, 2016
active therapy for a relapsed or refractory primary targeted resequencing of relevant myeloid neoplasia- http://dx.doi.org/10.1016/
neoplasm, cytopenias associated with therapy-related associated genes) of serial blood samples obtained from S1470-2045(16)30622-2

myeloid neoplasms can make treatment of the other patients treated for non-myeloid neoplasms who either See Articles pages 100 and 112

neoplasm with full therapeutic intensity impossible, did or did not subsequently develop therapy-related
and the presence of a therapy-related myeloid neoplasm myeloid neoplasms. Both Nancy Gillis and colleagues2
usually excludes patients from innovative clinical trials and Koichi Takahashi and colleagues3 found that
for their other cancers. In such cases, the advent of a the presence of even a small myeloid clone that was
therapy-related myeloid neoplasm all too often signals detectable after treatment for the primary neoplasm
the beginning of the end, accelerating the transition of increased the likelihood of subsequent development
the patient into hospice care. Almost no one is cured of therapy-related myeloid neoplasms. Unsurprisingly,
of therapy-related myeloid neoplasms with presently TP53 mutations were among the most commonly
available treatment approaches; even for patients who detected clonal changes in those patients who went
are young enough and fit enough to undergo allogeneic on to develop therapy-related myeloid neoplasms.
haemopoietic stem cell transplantation, long-term Loss of p53 function aids and abets genomic instability
overall survival at 3–5 years is less than 25%.1 and acquisition of other lesions, and TP53 mutations
Despite this bleak outlook, therapy-related myeloid and deletions are the most common class of genetic
neoplasms are mercifully uncommon, occurring in abnormality in therapy-related myeloid neoplasms.4,5
less than 10% of even heavily pretreated patients. Are these mutant clones present before treatment for
Although a few clinical characteristics are known to be the primary neoplasm and selected for by their resistance

www.thelancet.com/oncology Vol 18 January 2017 11


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Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.