Comment
[95% CI 15·8–30·9] for busulfan plus cyclophosphamide
vs 25·2% [18·6–34·1] for busulfan plus fludarabine).
However, this study also shows that much more
progress is needed, since only half of all patients achieved
long-term disease control. In future, research should be
focused on strategies that prevent disease recurrence
without increasing non-relapse mortality. Fortunately,
many such strategies are potentially available today. For
example, dose-targeted intravenous busulfan aiming
to obtain an area under the curve (AUC) of 5000 μmol/L
per min was shown in a randomised trial8 to improve
disease-free survival for patients with acute myeloid
leukaemia and myelodysplastic syndrome. Similarly, in a
disease in which the risk of relapse following allogeneic
haemopoietic stem-cell transplantation can be greater
than 50% for some cytogenetic subtypes or for patients
receiving transplants for active disease, exploration of
some form of maintenance therapy seems to be essential.
However, only now are trials of targeted therapies
(eg, FLT3 inhibitors) or non-targeted therapies (eg,
hypomethylating agents) being explored.
So what’s next? The GITMO group should be
commended for having completed a large randomised
trial that allows health-care providers treating acute
myeloid leukaemia to comfortably switch to busulfan
plus fludarabine in the knowledge that the regimen is
less toxic and does not compromise leukaemic control
significantly (although relapse deaths were increased in
the busulfan plus fludarabine group). However, treatment
needs to move away from a casual approach and towards
careful risk assessment of each patient with acute myeloid
leukaemia. Rational decisions must be made about
whether haemopoietic stem-cell transplantation can
significantly reduce the risk of relapse compared with
conventional treatments (with transplantation left as
first-line salvage therapy) and if so, how it should best be
done. Specifically, what donor or cell source should be used
Early rectal cancer: opening the door to change
In The Lancet Oncology, Julio Garcia-Aguilar and
colleagues1 report the results of an important, multi-
institutional phase 2 trial for patients with clinically
staged T2N0 rectal cancer. Patients received an intensive
regimen of neoadjuvant radiotherapy combined with
capecitabine and oxaliplatin followed by local excision.
www.thelancet.com/oncology Vol 16 November 2015
(ie, KIR-advantaged donor vs a matched sibling donor) and
what is the optimum regimen intensity? Furthermore, are
there are protocol or non-protocol strategies that can be
explored to reduce the risk of relapse without significantly
increasing transplant-related morbidity and mortality?
In the meantime, I believe that, whenever possible,
busulfan plus fludarabine should be the conditioning
regimen of choice for patients with acute myeloid
leukaemia undergoing matched sibling or unrelated
donor haemopoietic stem-cell transplantation.
Sergio Giralt
Weill Cornell Medical College, New York, NY, USA; and Memorial
Sloan Kettering Cancer Center, New York, NY, USA
giralts@mskcc.org
I declare no competing interests.
1 Tutschka PJ, Copelan EA, Klein JP. Bone marrow transplantation for
leukemia following a new busulfan and cyclophosphamide regimen. Blood
1987; 70: 1382–88.
2 Giralt S, Estey E, Albitar M, et al. Engraftment of allogeneic hematopoietic
progenitor cells with purine analog-containing chemotherapy: harnessing
graft-versus-leukemia without myeloablative therapy. Blood 1997;
89: 4531–36.
3 de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and
fludarabine: clinical and pharmacokinetic results of a myeloablative,
reduced-toxicity conditioning regimen for allogeneic stem cell
transplantation in AML and MDS. Blood 2004; 104: 857–64.
4 Andersson BS, de Lima M, Thall PF, et al. Once daily i.v. busulfan and
fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and
cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in
AML/MDS. Biol Blood Marrow Transplant 2008; 14: 672–84.
5 Lee JH, Joo YD, Kim H, et al. Randomized trial of myeloablative conditioning
regimens: busulfan plus cyclophosphamide versus busulfan plus
fludarabine. J Clin Oncol 2012; 31: 701–9.
6 Liu H, Zhai X, Song Z, et al. Busulfan plus fludarabine as a myeloablative
conditioning regimen compared with busulfan plus cyclophosphamide for
acute myeloid leukemia in first complete remission undergoing allogeneic
hematopoietic stem cell transplantation: a prospective and multicenter
study. J Hematol Oncol 2013; 6: 15.
7 Rambaldi A, Grassi A, Masciulli A. Busulfan plus cyclophosphamide versus
busulfan plus fludarabine as a preparative regimen for allogeneic
haemopoietic stem-cell transplantation in patients with acute myeloid
leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet
Oncol 2015; published online Sept 29. http://dx.doi.org/10.1016/S1470-
2045(15)00200-4.
8 Andersson BS, de Lima MJ, Saliba RM, et al. Pharmacokinetic dose guidance
of IV busulfan with fludarabine with allogeneic stem cell
transplantation improves progression free survival in patients with AML and
MDS; results of a randomized phase III study. Blood 2011; 118: abstract 892.
This combination seems highly active in small early Published Online
October 14, 2015
cancers in terms of tumour response but might not be http://dx.doi.org/10.1016/
widely embraced because of the generally disappointing S1470-2045(15)00304-6
results of other phase 3 studies integrating oxaliplatin See Articles page 1537
into chemoradiation in more locally advanced rectal
cancer.2–7 This trial was carefully controlled with a long-
1449
 Comment
term follow-up of 56 months (IQR 46–63); 3-year
disease-free survival for the intention-to-treat group
was 88·2% (95% CI 81·3–95·8) and only three (4%) of
Steve Gschmeissner/Science Photo Library
79 patients had local recurrence. Rectal preservation was
achieved in 72 (91%) of 79 patients. The idea that major
surgery can be avoided in a large proportion of patients
with early tumours is encouraging; however, only
short-term effects on anorectal function and quality of
life at 12 months were measured in this study. The key
message is that the strategy is feasible but might need
refining because acute toxic effects were significant,
although we cannot yet avoid major surgery for all
patients with early (cT1–T2) rectal cancers.
Local excision and major resection with total
mesorectal excision or abdomino-perineal excision
of the rectum are the two extreme ends of the
surgical spectrum. Historically, retrospective studies
of local excision alone have been dogged by a high
proportion of patients having local recurrence,8
although local excision is an imprecise term that covers
different procedures ranging from a mucosectomy
to a partial mesorectal excision, where the specimen
usually includes four of five lymph nodes. This study
uses neoadjuvant chemoradiotherapy. Additionally,
selection by ultrasound and MRI has become more
accurate during the past decade. Selection criteria for
local excision alone has usually included small, mobile,
well-to-moderately differentiated tumours without
high-risk pathological features, and less than a third
of the circumference of the lumen, which need to be
excised with a margin of more than 2 mm. However,
the accuracy of nodal staging remains less than ideal. A
European consensus statement affirms that endoscopic
transrectal ultrasound is the method of choice for
staging superficial tumours (T1), and MRI for staging T2
or large tumours.9
Unfavourable histopathological features after local
excision have led to the presumption of lymph node
involvement and led to recommendation to treat
with postoperative chemoradiotherapy if a patient
refuses major salvage surgery. Yet, in studies where
organ preservation is intended, 24% of patients do
not proceed to have major surgery when local excision
shows a residual tumour with unfavourable features
after chemoradiotherapy.10 Whether this reluctance
to operate is patient driven, surgeon driven, or both,
remains unclear.
1450
A previous pooled retrospective analysis11 showed
that neoadjuvant chemoradiotherapy followed by local
excision achieved excellent local control. Only 17 (7%)
of 237 cT2–3 tumours recurred locally. By contrast,
tumours that did not respond to therapy (ypT3) showed
local recurrence rates of 42%. An excellent response to
neoadjuvant chemoradiotherapy in the specimen is the
key to the success of this strategy of chemoradiotherapy
followed by local excision, and has been proposed as a
discriminating marker predicting favourable outcomes
in terms of low incidence of local recurrence or
metastatic disease.
Preliminary results of the French GRECCAR 2
phase 3 trial9 supports this strategy. Patients with
cT2–T3 low rectal carcinomas of at least 4 cm had
neoadjuvant chemoradiotherapy. The proportion of
patients achieving a pathological complete response
for T2–T3 stage tumours was much higher than
for more advanced cT3–T4 tumours (40% vs 15%).
So selection might be crucial. A good pathological
response (ypT0–1) seemed to be associated with an
absence of positive mesorectal nodes.
It is clear that the strategy of chemoradiotherapy
and local excision requires meticulous postoperative
endoscopic and radiographic surveillance and long-
term follow-up if regrowth or recurrence is to be
identified at a stage where surgical salvage is feasible.
Surgeons and teams might need sufficient experience
in assessing initial scans, planning target volumes
for radiotherapy, performing transanal endoscopic
microsurgery, assessing the pathological specimen,
and following up the patients, among other tasks.
Hence, some would argue that management of these
patients should be concentrated in centres, where
adequate numbers, familiarity with the techniques,
and expertise in imaging, allow optimum outcomes.
However, several issues are yet to be resolved. Some
of the ypT0, ypTis, or ypT1 tumours in this trial might
have been initially overstaged as cT2 by the reliance
on endoscopic transrectal ultrasound. Equally,
even after chemoradiotherapy, three patients had
ypT3 tumours. Future studies will need to mandate
both endoscopic transrectal ultrasoundand MRI to
accurately image T-stage and improve definition of
nodal staging. We need an internationally accepted
validated endpoint to capture late function and
late toxic effects in a meaningful way. We need to
www.thelancet.com/oncology Vol 16 November 2015

define the optimum chemoradiation regimen and
establish whether or not this includes oxaliplatin.
We also need to determine what the optimum dose
of radiotherapy is now that intensity-modulated
radiation therapy, image-guided radiation therapy,
brachytherapy, and contact therapy are widely
available. And we need to establish whether patients
(even though they are initially staged as cT1–T2) need
to receive additional chemotherapy after completion
of chemoradiotherapy treatment as an adjuvant to
maximise local control.
In summary, we need a common language where
procedures and methods are clearly defined and
consistently used. The outlook for patients with early
rectal cancer is excellent. We need to know the real
impact of chemoradiotherapy and local excision on
long-term anorectal function and quality of life. Further
trials are the best method to achieve these goals.
Robert Glynne-Jones
Mount Vernon Cancer Centre, Northwood HA6 2RN, UK
rob.glynnejones@nhs.net
I declare no competing interests.
1 Garcia-Aguilar J, Renfro LA, Chow OS, et al. Organ preservation for clinical
T2N0 distal rectal cancer using neoadjuvant chemoradiotherapy and local
excision (ACOSOG Z6041): results of an open-label, single-arm,
multi-institutional phase 2 trial. Lancet Oncol 2015; published online
Oct 14. http://dx.doi.org/10.1016/S1470-2045(15)00304-6.
Chemotherapy plus ponatinib: a new standard for
Ph-positive ALL?
Adults with high-risk acute lymphoblastic leukaemia are
recommended for intensive treatment with contemporary
protocols. Patients with Philadelphia chromosome-
positive or BCR-ABL1-positive Philadelphia chromosome-
positive acute lymphoblastic leukaemia, who constitute
about 25% of patients with B-lineage acute lymphoblastic
leukaemia, traditionally have a very poor outcome with
chemotherapy, particularly if they did not undergo
allogeneic stem-cell transplantation in first remission.
Progress has been made with targeted therapy,
extending the existing backbones of chemotherapy and
allogeneic stem-cell transplantation. The incorporation
of first-generation and second-generation BCR-ABL1
tyrosine-kinase inhibitors with chemotherapy has
revolutionised the treatment of patients with Philadelphia
www.thelancet.com/oncology Vol 16 November 2015
Comment
2 Gerard JP, Azria D, Gourgou-Bourgade S, et al. Comparison of two
neoadjuvant chemoradiotherapy regimens for locally advanced rectal
cancer: results of the phase III trial accord 12/0405-Prodige 2. J Clin Oncol
2010; 28: 1638–44.
3 Aschele C, Cionini L, Lonardi S, et al. Primary tumor response to
preoperative chemoradiation with or without oxaliplatin in locally
advanced rectal cancer: pathologic results of the STAR-01 randomized
phase III trial. J Clin Oncol 2011; 29: 2773–80.
4 Roh MS, Yothers GA, O’Connell MJ, et al. The impact of capecitabine and
oxaliplatin in the preoperative multimodality treatment in patients with
carcinoma of the rectum: NSABP R-04. Proc Am Soc Clin Oncol 2011;
29 (suppl): abstr 3503.
5 Rödel C, Liersch T, Becker H, et al, for the German Rectal Cancer Study Group.
Preoperative chemoradiotherapy and postoperative chemotherapy with
fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced
rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised
phase 3 trial. Lancet Oncol 2012; 13: 679–87.
6 Schmoll H-J, Haustermans K, Price TJ, et al. Preoperative
chemoradiotherapy and postoperative chemotherapy with capecitabine
and oxaliplatin versus capecitabine alone in locally advanced rectal cancer:
First results of the PETACC-6 randomized trial (abstract).
Proc Am Soc Clin Oncol 2013; 31 (suppl): abstr 3531.
7 Rödel C, Graeven U, Fietkau R, et al, for the German Rectal Cancer Study
Group. Oxaliplatin added to fluorouracil-based preoperative
chemoradiotherapy and postoperative chemotherapy of locally advanced
rectal cancer (the German CAO/ARO/AIO-04 study): final results of the
multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2015;
16: 979–89.
8 Mellgren A, Sirivongs P, Rothenberger DA, Madoff RD, García-Aguilar J.
Is local excision adequate therapy for early rectal cancer? Dis Colon Rectum
2000; 43: 1064–71.
9 Morino M, Risio M, Bach S, et al. Early rectal cancer: the European
Association for Endoscopic Surgery (EAES) clinical consensus conference.
Surg Endosc 2015; 29: 755–73.
10 Rullier E, Rouanet P, Michot F et al. Local versus rectal excision in
downstaged low rectal cancer after radiochemotherapy: preliminary results
of the randomized GRECCAR 2 trial. Colorectal Dis 2013; 15 (suppl 3): 7.
11 Borschitz T, Wachtlin D, Möhler M, Schmidberger H, Junginger T.
Neoadjuvant chemoradiation and local excision for T2–3 rectal cancer.
Ann Surg Oncol 2008; 15: 712–20.
chromosome-positive acute lymphoblastic leukaemia,
and represents the standard of care for these patients.
Dept Of Clinical Cytogenetics,
However, the 3-year event-free survival is only 40% and
Addenbrookes Hospital/SPL
3-year overall survival 60%.1 The advent of resistance to
tyrosine-kinase inhibitors therapy is a clinically significant
issue, and overcoming the development of resistance
represents a therapeutic challenge. About half of losses in
response are characterised by point mutation within the Published Online
September 30, 2015
ABL kinase domain. The so-called T315I mutation involves http://dx.doi.org/10.1016/
the replacement of a threonine with an isoleucine at ABL S1470-2045(15)00247-8
residue 315, which is present in up to 70% of patients See Articles page 1547
who relapse after being treated with second-generation
tyrosine-kinase inhibitors.2 The high mutation frequency
and the fact that T315I-mutant clones are not amenable
to treatment with tyrosine-kinase inhibitors suggests an
1451