Comment
in this platinum-sensitive population with little
pretreatment, making further comparison of rucaparib
monotherapy with platinum-based chemotherapy less
attractive. Nevertheless, part two of the ARIEL2 trial
(NCT01891344) is including patients who have been
more heavily pretreated (at least three previous lines), for
whom these results could be more clinically meaningful.
With respect to the predictive value of the assay, the
differences detected between the LOH high and LOH low
subgroups were not particularly clinically relevant and
the biomarker does not seem to be able to efficiently
identify a subgroup of patients with wild-type BRCA
who will achieve significant progression-free survival
with rucaparib. In a planned post-hoc analysis of this
study,9 Coleman and colleagues showed that a refined
cutoff for tumour genomic LOH of 16% is able to better
discriminate a difference in progression-free survival
between the LOH high and LOH low subgroups than is
a cutoff of 14% (HR 0·51 [95% CI 0·34–0·74]; p<0·001).
This new cutoff is prospectively applied in the ARIEL 3
trial (NCT01968213), in which patients with high-grade
ovarian cancer and platinum-sensitive relapse responding
to rechallenge with platinum-based chemotherapy will
be randomly assigned to maintenance therapy with
rucaparib versus placebo. There are great expectations
on the results of this study, because another homologous
recombination deficiency assay was shown to be unable
to significantly discriminate the efficacy of niraparib in
the maintenance setting.10
Finally, this trial constitutes a valuable effort in the
challenge of identifying which patients with wild-type
Polycythaemia vera and precision medicine: a prescription
for the 21st century
Polycythaemia vera is the most common myelo-
proliferative neoplasm and the ultimate phenotypic
consequence of the Janus kinase 2 (JAK2) Val617Phe
mutation. First described in the 19th century, we
now understand the molecular pathogenesis of
polycythaemia vera, its natural history, and the basis for
its many complications. Remarkably, however, still no
consensus exists about its clinical management.
Erythrocytosis is the hallmark of polycythaemia
vera and the cause of the most common serious
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BRCA can benefit from PARP inhibition. However, an
assay that is efficient and produces clinically meaningful
results is still some way off.
Antonio González Martín
MD Anderson Cancer Center Madrid, Madrid 28033, Spain
agonzalezm@seom.org
I report fees from Clovis for serving on a local advisory board and fees from
Roche, Astra Zenenca, and Pharmamar for being a speaker and advisory board
member.
1 Nielsen FC, van Overeem Hansen T, Sørensen CS. Hereditary breast and
ovarian cancer: new genes in confined pathways. Nat Rev Cancer 2016;
16: 599–612.
2 Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous
recombination deficiency: exploiting the fundamental vulnerability of
ovarian cancer. Cancer Discov 2015; 5: 1137–54.
3 Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in
patients with platinum-sensitive relapsed serous ovarian cancer:
a preplanned retrospective analysis of outcomes by BRCA status in a
randomised phase 2 trial. Lancet Oncol 2014; 15: 852–61.
4 Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib
monotherapy in patients with advanced cancer and a germline BRCA1/2
mutation. J Clin Oncol 2015; 33: 244–50.
5 Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with
recurrent high-grade serous or poorly differentiated ovarian carcinoma or
triple-negative breast cancer: a phase 2, multicentre, open-label,
non-randomised study. Lancet Oncol 2011; 12: 852–61.
6 Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of
heterozygosity predict homologous recombination repair defects in
epithelial ovarian cancer. Br J Cancer 2012; 107: 1776–82.
7 Watkins JA, Irshad S, Grigoriadis A and Tutt AN. Genomic scars as
biomarkers of homologous recombination deficiency and drug response in
breast and ovarian cancers. Breast Cancer Res 2014, 16: 211
8 Swisher EM, Lin KK, Oza AM et al. Rucaparib in relapsed, platinum-sensitive
high-grade ovarian carcinoma (ARIEL2 Part 1): an international,
multicentre, open-label, phase 2 trial. Lancet Oncology 2016; published
online Nov 28. http://dx.doi.org/10.1016/S1470-2045(16)30559-9.
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
rucaparib in patients (pts) with high grade ovarian carcinoma.
Proc Am Soc Clin Oncol 2016; 34: abstr 5540.
10 Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in
platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; published
online Oct 7. DOI:10.1056/NEJMoa1611310.
complication associated with the disease: major Published Online
December 1, 2016
vessel thrombosis. Thrombosis prevention is the http://dx.doi.org/10.1016/
cornerstone of polycythaemia vera therapy and the S1470-2045(16)30591-5
use of phlebotomy to achieve a sex-specific normal See Articles page 88
haematocrit concentration is the most effective
means to accomplish this.1 However, phlebotomy
has been widely shunned in favour of chemotherapy,
even though in large-scale clinical trials, alkyating
agents, ³²P, or hydroxyurea therapy did not prevent
thrombosis or prolong survival relative to phlebotomy
9
 Comment
alone in polycythaemia vera but did increase leukaemic
transformation.2,3
These results notwithstanding, chemotherapy is still
recommended for so-called high-risk patients with
polycythaemia vera, defined as those aged older than
Jim West/Science Photo Library
60 years or with a history of thrombosis,4 even though
thrombosis in polycythaemia vera is provoked by
hyperviscosity, disease complications do not differ in
patients aged younger than or older than 60 years,5 and
no evidence suggests that major vessel thrombosis is a
consequence of either leukocytosis or thrombocytosis.
Furthermore, not all patients with polycythaemia vera will
develop extramedullary haematopoiesis or myelofibrosis.6
The discovery of the JAK2 Val617Phe mutation
ushered in a new framework for the treatment of
myeloproliferative neoplasms. Targeted therapy of
committed haematopoietic progenitor cells expressing
activated JAK2 fosters the proliferation of these cells
and the production of inflammatory cytokines. Targeted
therapy is now a standard of care for high-risk patients
with primary or secondary myelofibrosis, in whom a
JAK1 or JAK2 inhibitor (ruxolitinib) controlled blood
counts, reduced inflammatory cytokine production and
extramedullary haematopoiesis, and improved survival.7
Ruxolitinib has now been assessed in two clinical
trials in polycythaemia vera without myelofibrosis.
In The Lancet Oncology,8 Francesco Passamonti and
colleagues report the results of RESPONSE-2, a
randomised, open-label, phase 3b trial of ruxolitinib in
patients with polycythaemia vera without splenomegaly,
who were intolerant of or unresponsive to hydroxyurea,
versus the best available therapy (usually hydroxyurea),
making this trial—like the previous RESPONSE trial,9
in which the effect of ruxolitinib was examined in
hydroxyurea-intolerant or unresponsive patients with
polycythaemia vera with splenomegaly—a referendum
on hydroxyurea. On the basis of their age, most
RESPONSE-2 patients were defined as so-called high risk
patients, and were phlebotomy-dependent.
Unsurprisingly, for the primary endpoint of patients
achieving haematocrit control, ruxolitinib was superior
to best available therapy (46 [62%] of 74 patients in the
ruxolitinib group vs 14 [19%] of 75 in the best available
therapy group; odds ratio 7·28 [95% CI 3·43–15·45];
p<0·0001), and also for the key secondary endpoint for
patients achieving complete haematological remission
(23% vs 5%). Additionally, symptom control, including
10
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pruritus, was superior in the ruxolitinib group, and
adverse events were more common in the best available
therapy group. The authors concluded that ruxolitinib
“could be considered a standard of care for second-line
therapy in this post-hydroxyurea patient population”.
However, I challenge this conclusion. First, the
consensus that hydroxyurea is first-line therapy for
polycythaemia vera is not evidence based. Indeed, a trial
using hydroxyurea in patients with polycythaemia vera
to achieve European LeukemiaNet criteria for complete
haematological remission did not result in better
survival or less thrombosis compared with the expected
survival of patients with similar disease characteristics.10
Second, the primary endpoint of RESPONSE-2 was
phlebotomy control but the appropriate control group
(a phlebotomy-only group) was not included, nor
was phlebotomy control or haematological remission
achieved with ruxolitinib in all patients. Ruxolitinib is
an expensive drug, but phlebotomy is an inexpensive
and immediately effective procedure, and it is unlikely
that insurers would support the use of ruxolitinib in
polycythaemia vera for haematocrit control without
proof of greater efficacy than phlebotomy therapy.
Third, no study of ruxolitinib in polycythaemia vera has
capitalised on the observation, based on both clinical and
gene-expression data, that patients with polycythaemia
vera are not all alike; male and female patients differ
clinically and in gene expression, and the disease is
indolent in some patients and aggressive in others, who
also differ in gene expression.6 Thus, it should not be
presumed that all patients with polycytaemia vera will
require ruxolitinib therapy or that all patients who do
receive this treatment will respond similarly.
Finally, polycythaemia vera is an haematopoietic stem-
cell disorder and, so far, ruxolitinib does not seem to
affect haematopoietic stem cell behaviour. At present,
pegylated interferon is the only drug that targets
haematopoietic stem cells and produces haematological
and molecular remission, although not in all patients and,
like ruxolitinib, we still do not know how best to use it.
Thus, following the data recorded in the RESPONSE trials
we now have access to two non-myelotoxic therapies
(ruxolitinib and pegylated interferon) to treat a disease
whose natural history is measured in decades but whose
patients do not all have the same genetic background or
require the same level of myelosuppression—a setting
most appropriate for precision medicine.
www.thelancet.com/oncology Vol 18 January 2017

Jerry L Spivak
Traylor 924, John Hopkins University School of Medicine,
720 Rutland Avenue, Balimore, MD 21205, USA
jlspivak@jhmi.edu
I declare no competing interests.
1 Pearson TC, Weatherly-Mein G. Vascular occlusive episodes and venous
haematocrit in primary proliferative polycythaemia. Lancet 1978;
2: 1219–21.
2 Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute
leukemia in polycythemia vera associated with chlorambucil therapy.
N Engl J Med 1981; 304: 441–47.
3 Najean Y, Rain J. Treatment of polycythemia vera: the use of hydroxyurea
and pipobroman in 292 patients under the age of 65 years. Blood 1997;
90: 3370–77.
4 Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia:
2015 update on diagnosis, risk-stratification and management.
Am J Hematol 2015; 90: 162–73.
Predicting therapy-related myeloid neoplasms—and
preventing them?
Therapy-related myeloid neoplasms are an iatrogenic
tragedy. When a patient develops therapy-related
myelodysplastic syndrome or acute myeloid leukaemia
(ie, therapy-related myeloid neoplasms) several
years after receiving curative treatment for another
neoplasm, the unexpected and unwelcome return
of frequent visits to a cancer centre and unearthing
of old fears about mortality can be psychologically
devastating. Alternatively, if a therapy-related myeloid
neoplasm emerges while the patient is still receiving
active therapy for a relapsed or refractory primary
neoplasm, cytopenias associated with therapy-related
myeloid neoplasms can make treatment of the other
neoplasm with full therapeutic intensity impossible,
and the presence of a therapy-related myeloid neoplasm
usually excludes patients from innovative clinical trials
for their other cancers. In such cases, the advent of a
therapy-related myeloid neoplasm all too often signals
the beginning of the end, accelerating the transition of
the patient into hospice care. Almost no one is cured
of therapy-related myeloid neoplasms with presently
available treatment approaches; even for patients who
are young enough and fit enough to undergo allogeneic
haemopoietic stem cell transplantation, long-term
overall survival at 3–5 years is less than 25%.1
Despite this bleak outlook, therapy-related myeloid
neoplasms are mercifully uncommon, occurring in
less than 10% of even heavily pretreated patients.
Although a few clinical characteristics are known to be
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Comment
5 Stein BL, Saraf S, Sobol U, et al. Age-related differences in disease
characteristics and clinical outcomes in polycythemia vera. Leuk Lymphoma
2013; 54: 1989–95.
6 Spivak JL, Considine M, Williams DM, et al. Two clinical phenotypes in
polycythemia vera. N Engl J Med 2014; 371: 808–17.
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.
8 Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the
treatment of inadequately controlled polycythaemia vera without
splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study.
Lancet Oncol 2016; published online Dec 1. http://dx.doi.org/10.1016/
S1470-2045(16)30558-7.
9 Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus
standard therapy for the treatment of polycythemia vera. N Engl J Med
2015; 372: 426–35.
10 Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and prognostic
value of the European LeukemiaNet criteria for clinicohematologic
response, resistance, and intolerance to hydroxyurea in polycythemia vera.
Blood 2012; 119: 1363–69.
associated with an increased risk of therapy-related
myeloid neoplasms (eg, higher total chemotherapy
dose, combination chemoradiotherapy, use of myeloid
growth factors, older patient age, and longer duration
Tek Image/Science Photo Library
of cytotoxic therapy), it is not yet fully understood
how to identify those patients at highest risk or how to
prevent therapy-related myeloid neoplasms.
In The Lancet Oncology, investigators from two large
US oncology referral centres report the results of their
genomic analyses (ie, whole-exome sequencing and Published Online
December 4, 2016
targeted resequencing of relevant myeloid neoplasia- http://dx.doi.org/10.1016/
associated genes) of serial blood samples obtained from S1470-2045(16)30622-2
patients treated for non-myeloid neoplasms who either See Articles pages 100 and 112
did or did not subsequently develop therapy-related
myeloid neoplasms. Both Nancy Gillis and colleagues2
and Koichi Takahashi and colleagues3 found that
the presence of even a small myeloid clone that was
detectable after treatment for the primary neoplasm
increased the likelihood of subsequent development
of therapy-related myeloid neoplasms. Unsurprisingly,
TP53 mutations were among the most commonly
detected clonal changes in those patients who went
on to develop therapy-related myeloid neoplasms.
Loss of p53 function aids and abets genomic instability
and acquisition of other lesions, and TP53 mutations
and deletions are the most common class of genetic
abnormality in therapy-related myeloid neoplasms.4,5
Are these mutant clones present before treatment for
the primary neoplasm and selected for by their resistance
11