NcXHF

TREATMENT OF PHILADELPHIA CHROMOSOME–POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA
chance of a good outcome. However, in the TKI era, the
mechanisms of resistance are reasonably well studied. At relapse
of Ph ALL, it is possible now for patients to progress
through newer generations of targeted agents in a systematic
fashion according to the results of mutational analysis of
BCR-ABL1 transcripts. Patients in whom imatinib ceases to
produce a response may respond to nilotinib 53 or dasatinib, 54
and there is even an option, ponatinib, for patients with the
T315I mutation. 55 Although TKIs are not without adverse effects,
and ponatinib in particular carries a risk of cardiovascular
events, they are nonetheless a vastly superior option to
rounds of myelosuppressive chemotherapy in preserving
performance status and being available to and tolerated by
patients in the older age range. There is no evidence of longterm
survival mediated by TKIs after relapse. Nonetheless,
the difference between EFS and OS in relapsed Ph ALL is
moving apart. Studies should continue to carefully record
both, and readers should pay attention. In addition, results
with allografts are being reported. Although allografts have
uncertain long-term benefıts, there are case reports of good
outcomes. Immunotherapy without alloHSCT also is an option
for the treatment of relapsed ALL. An international,
phase II trial of blinatumomab in patients with Ph ALL
who have experienced relapse after treatment that included a
minimum of two lines of TKI therapy has recently been completed,
and analysis is underway. Patients with Ph ALL can
respond to CD19 CART cell therapy.
PH-LIKE ALL
In the so-called Ph-like ALL, t(9;22) is absent, but the leukemia
is characterized by a range of genomic alterations that
activate a limited number of signaling pathways similar to
those activated in Ph ALL, 56 some of which may be amenable
to inhibition with approved TKIs. The precise defınition
of these targetable, kinase-activating lesions in clinical practice
using standard techniques is not yet clear, but suggested
algorithms have emerged that provide practical advice on
when and how to consider this subtype of ALL. 57 TKIs have
yet to be formally evaluated, except in case reports. 58 Nonetheless,
there will be patients in whom physicians wish to
consider a TKI as an option, and requests for insurers or
health systems to reimburse these agents will have to be taken
into account soon.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: None. Consulting or Advisory Role: Adele K.
Fielding, Amgen. Speakers’ Bureau: None. Research Funding: Adele K. Fielding, Sigma Tau. Patents, Royalties, or Other Intellectual Property: None.
Expert Testimony: None. Travel, Accommodations, Expenses: None. Other Relationships: None.
References
1. Moorman AV, Harrison CJ, Buck GA, et al. Karyotype is an independent
prognostic factor in adult acute lymphoblastic leukemia
(ALL): analysis of cytogenetic data from patients treated on the Medical
Research Council (MRC) UKALLXII/Eastern Cooperative Oncology
Group (ECOG) 2993 trial. Blood. 2007;109:3189-3197.
2. Secker-Walker LM, Craig JM, Hawkins JM, et al. Philadelphia positive
acute lymphoblastic leukemia in adults: age distribution, BCR breakpoint
and prognostic signifıcance. Leukemia. 1991;5:196-199.
3. Moorman AV, Chilton L, Wilkinson J, et al. A population-based cytogenetic
study of adults with acute lymphoblastic leukemia. Blood. 2010;
115:206-214.
4. Dombret H, Gabert J, Boiron JM, et al. Outcome of treatment in adults
with Philadelphia chromosome-positive acute lymphoblastic leukemia:
results of the prospective multicenter LALA-94 trial. Blood. 2002;100:
2357-2366.
5. Fielding A, Rowe JM, Richards SM, et al. Prospective outcome data on
267 unselected adult patients with Philadelphia chromosome-positive
acute lymphoblastic leukemia confırms superiority of allogeneic transplantation
over chemotherapy in the pre-imatinib era: results from the
international ALL trial MRC UKALLXII/ECOG2993. Blood. 2009;113:
4489-4496.
6. Müller MC, Saglio G, Lin F, et al. An international study to standardize
the detection and quantitation of BCR-ABL transcripts from stabilized
peripheral blood preparations by quantitative RT-PCR. Haematologica.
2007;92:970-973.
7. Pfeifer H, Wassmann B, Pavlova A, et al. Kinase domain mutations of
BCR-ABL frequently precede imatinib-based therapy and give rise to
relapse in patients with de novo Philadelphia-positive acute lymphoblastic
leukemia (Ph ALL). Blood. 2007;110:727-734.
8. Soverini S, De Benedittis C, Machova Polakova K, et al. Unraveling the
complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep
sequencing of the BCR-ABL kinase domain. Blood. 2013;122:1634-1648.
9. Wassmann B, Pfeifer H, Goekbuget N, et al. Alternating versus concurrent
schedules of imatinib and chemotherapy as front-line therapy for
Philadelphia-positive acute lymphoblastic leukemia (Ph ALL). Blood.
2006;108:1469-1477.
10. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia
chromosome-positive acute lymphocytic leukemia with hyper-CVAD
and imatinib mesylate. Blood. 2004;103:4396-4407.
11. Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and
promising outcome by combination of imatinib and chemotherapy for
newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a
phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol.
2006;24:460-466.
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