Thirty six APML patients achieving hematological remission with As2O3 were serially monitored using RT-PCR. Though only 5.5% achieved molecular remission at induction remission, 94.5% became negative during consolidation. At 20 months follow-up, 85% remain in remission but longer follow up studies are needed to monitor late relapses

Balasubramanian, P.

Chandy, M.

George, B.

Mathews, L.

Shaji, R. V.

Srivastava, A.

English

Publications of the IAS Fellows

Letters to the Editor
haematologica 2004; 89(10):October 20041266
References
1. Temerinac S, Klippel S, Strunck E, Roder S, Lubbert M, Lange W,
et al. Cloning of PRV-1, a novel member of the uPAR receptor
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ination of polycythemias and thrombocytoses by novel, simple,
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F, et al. Hydroxyurea for patients with essential thrombocythemia
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yurea exerts bi-modal dose-dependent effects on erythropoiesis
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Haematol 2002; 119:1098-105.
Acute Promyelocytic Leukemia
Molecular remission with arsenic trioxide in patients with
newly diagnosed acute promyelocytic leukemia
Thirty six APML patients achieving hematologic remis-
sion with As2O3 were serially monitored using RT-PCR.
Though only 5.5% achieved molecular remission at induc-
tion remission, 94.5% became negative during consoli-
dation. At 20 months follow-up, 85% remain in remis-
sion but longer follow up studies are needed to monitor
late relapses. haematologica 2003; 89:1266-1267
(http://www.haematologica.org/2004/10/1266)
Arsenic trioxide (As2O3) achieves induction remission in
70-90% of patients with newly diagnosed acute promyelo-
cytic leukemia (APL) with 65-70% long term remission
rates1,2 but there is limited data on molecular remission in
these patients. We evaluated this aspect in 40 patients and
describe our findings here. The study population was formed
of 40 patients with t(15;17) APL treated with As2O3 between
January 2000 and February 2004. As2O3 was administered in
teh context of an institutional study protocol after obtain-
ing ethical clearance in the first 5 patients, but since 2001,
As2O3 has become standard therapy for patients who can-
not afford treatment with ATRA. Intravenous As2O3, pre-
pared in the hospital pharmacy at the cost of $0.5 per vial,
was administered at a daily dose of 10 mg (adults) and 0.15
mg/kg/day (children) as per protocol (Figure 1). Full blood
counts, coagulation parameters, as well as renal and hepat-
ic function were closely monitored. Electrocardiograms were
done if patient was symptomatic. Platelet and fresh frozen
plasma transfusions were given to maintain platelet counts
>20,000/mm3 or if the patients had a coagulopathy. Bone
marrow examination was done to assess remission on nor-
malization of blood counts. The molecular monitoring was
carried out by reverse transciption polymerase chain reac-
tion (RT-PCR) to detect PML-RARα transcripts, as described
by van Dongen et al.,3 and was done at diagnosis, at hema-
tologic remission, prior to consolidation therapy, twice dur-
ing maintenance therapy (3 months apart) and subsequently
every 6 months. This method, with nested amplification, has
a sensitivity of 10-3 to 10-4. There were 23 males and 17
females, including 31 adults and 9 children (mean age 27.8
years; range: 6-60) with hypergranular APL. The median
white cell count at diagnosis was 2.5×109/L (range: 0.6 to
58.9). Thirty-six patients (90%) achieved hematologic
remission (HCR) at a median time of 42.6 days (range: 26-
60) with 4 early deaths due to intracranial hemorrhage.
Molecular remission was achieved in all at a median time
of 83.9 days (range: 51-136). Though only 2 (5.5%) patients
became PML-RARα transcript negative at HCR, another 25
(69.5%) had became negative at the start of consolidation
without further treatment. Seven patients (19.5%) became
negative at the end of consolidation while 2 (5.5%) became
negative during maintenance therapy. Thirty-four patients
(94.5%) were in molecular remission by the end of consol-
idation. As far as concerns toxicity, 20 patients (50%) had
leukocytosis requiring addition of hydroxyurea with tempo-
rary discontinuation of As2O3 in 5 patients and prolonged
neutropenia in 1 patient. Asymptomatic elevation of liver
enzymes was noted in 7 (17.5%) patients. There were no
cases of clinical cardiac toxicity. Isoform analysis showed
that 29 patients (72.5%) were bcr-1-positive, 2 (5%) were
bcr-2-positive and 9 (22.5%) were bcr-3 positive. The rate
Figure 1. Protocol for tretament of patients with  APML
with As2O3.
As2O3 was administered at a fixed dose of 10 mg/day for adults
and 0.15 mg/kg/day for children
Maintenance therapy 
As2O3 administered once daily for 10 days 
every month for 6 months 
4 week   interval
4 week   interval
Consolidation therapy 
As2O3 administered once daily for 28 days 
Induction therapy
As2O3 administered once daily until 
hematologic CR or for a maximum of 60 days  
  
Letters to the Editor
haematologica 2004; 89(10):October 2004 1267
of HCR was similar in patients with all isoforms though the
median time to HCR was significantly shorter in those with
bcr-3 than in those with the bcr-1 isoform [31 vs 46.5 days]
(p<0.001) with no significant difference was seen in the
median time to molecular remission [67.5 days bcr-3, 84.8
days bcr-1] (p = 0.2). Two patients relapsed 6 and 7 months
after treatment: one patient achieved a second complete
remission on repeat treatment with a combination of As2O3
and ATRA while the second died of intracranial hemorrhage.
At a median follow-up of 20.3 months (range: 4-53), thir-
ty-four patients (85%) remain in remission with a leukemia-
free survival of 94.5%. As2O3 achieves induction remission
rates similar to those produced by treatment with ATRA or
a combination of ATRA and As2O3 with similar numbers of
patients achieving molecular remission by the end of con-
solidation therapy.4,5,6 Trials in patients with relapsed APL
have also shown 80-90% PCR negativity by the end of con-
solidation.7,8 Interestingly As2O3 may show anti-leukemic
efficacy for many days after the drug has been stopped, as
suggested by the 70% of patients who became RT-PCR neg-
ative prior to starting consolidation despite being positive
at the time of hematologic remission. There does not seem
to be a major difference between patients with the bcr-1 or
bcr-3 isoform but larger numbers need to be studied. There
are, however, no data available on the significance of iso-
forms in APL patients primarily treated with As2O3. The medi-
an follow-up in our patients in our study is too short (20
months) to evaluate late relapses and the long-term signif-
icance of the various isoforms. These preliminary data show
that all patients achieving hematologic remission on pri-
mary treatment with As2O3 also achieve molecular remission.
Ninety-five percent of patients are in molecular remission
by the end of consolidation with 85% achieving long-term
remission. However, follow-up studies are needed to assess
the durability of remissions in these patients.
Biju George, Likram Mathews, Poonkuzhali Balasubramanian,
Ramachandran V. Shaji, Alok Srivastava, Mammen Chandy  
Dept of Hematology, Christian Medical College,
Vellore, Tamil Nadu, India
Key words: APML, As2O3, molecular remission.
Correspondence: Dr. Biju George, Department of Hematology,
Christian Medical College, Vellore 632004, Tamil Nadu, India.
Phone: international +91.416.2222102/2352. Fax: international
+91.416.2232035/2232054. E-mail: biju@cmcvellore.ac.in
References
1. Mathews V, Balasubramanian P, Shaji RV, George B, Chandy M,
Srivastava A. Arsenic trioxide in the treatment of newly diagnosed
acute promyelocytic leukemia: a single center experience. Am J
Hematol 2002;70:292-9.
2. Lu DP, Qiu JY, Jiang B, Wang Q, Liu KY, Liu YR, et al. Tetra-arsenic
tetra-sulfide for the treatment of acute promyelocytic leukemia: a
pilot trial. Blood 2002;99:3136-43.
3. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio
G, et al. Standardized RT-PCR analysis of fusion gene transcripts
from chromosome aberrations in acute leukemia for detection of
minimal residual disease: report of the BIOMED-1 Concerted
Action: investigation of minimal residual disease in acute leukemia.
Leukemia 1999;13:1901-28.
4. Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C,
Link H, et al. Effect of all transretinoic acid in newly diagnosed
acute promyelocytic leukemia. Results of a multicenter randomized
trial. European APL 91 Group. Blood 1993;82:3241-9.
5. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH,
Ogden A, et al. All-trans retinoic acid in acute promyelocytic
leukemia. N Eng J Med 1997;337:1201-8.
6. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, et al. All-trans
retinoic acid /As2O3 combination yields a high quality remission
and survival in newly diagnosed acute promyelocytic leukemia. P
Natl Acad Sci USA 2004;101:5328-35.
7. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calle-
ja E, Et al. United States multicenter study of arsenic trioxide in
relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19:
3852-60.
8. Shen ZX, Chen CQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of
arsenic trioxide (As2O3) in the treatment of acute promyelocytic
leukemia(APL). II. Clinical efficacy and pharmacokinetics in relapsed
patients. Blood 1997;89:3354-60.
9. Gallagher RE, Willman CL, Slack JL, Andersen JW, Li YP, Viswanatha
D, et al. Association of PML-RARα fusion mRNA type with pre-
treatment hematologic characteristics but not treatment outcome
in acute promyelocytic leukemia: an intergroup molecular study.
Blood 1997;90:1656-63.
10. Gonzalez M, Barragan E, Bolufer P, Chillon C, Colomer D, Borstein
R, et al. Pretreatment characteristics and clinical outcome of acute
promyelocytic leukemia patients according to the PML-RARα iso-
forms: a study of the PETHEMA group. Spanish Programme for the
Study and Treatment of Haematological Malignancies (PETHEMA)
Group. Br J Haematol 2001;114:99-103.
Acute Myeloid Leukemia
Quantification of DEK-CAN fusion transcript by real-time
reverse transcription polymerase reaction in patients with
t(6;9) acute myeloid leukemia 
Real-time reverse transcription polymerase reaction
(RT-PCR) was used to examine DEK-CAN transcript lev-
els in serial samples from three patients with t(6;9) acute
myeloid leukemia treated with intensive chemotherapy.
All three patients achieved short first clinical remission,
but without achieving RT-PCR negativity. DEK-CAN lev-
el significantly increased in two patients before relapse,
while in the third a level of 2×10-3 in remission bone mar-
row preceded relapse by 2 months. haematologica 2004; 89:1267-1269
(http://www.haematologica.org/2004/10/1267)
The t(6;9)(p23;q34) translocation which produces the
DEK-CAN fusion gene is detected predominantly (90%) in
acute myeloid leukemia (AML) with FAB type M2 or M4
and associated with basophilia.1-3 t(6;9) is associated with
a poor prognosis.2 There have been few studies to date
using this aberration as a marker for monitoring minimal
residual disease (MRD).4-6 We have developed a highly sen-
Table 1. Hematologic and molecular remission on treat-
ment with As2O3.
Hematologic remission 90%
bcr-1 isoform (n=29) 89.6%
bcr-3 isoform (n=9) 88.8%
bcr-2 isoform (n=2) 100%
Time to hematologic remission 42.6
(days) (25-60)
bcr-1 isoform 46.5 (30-60)
bcr-3 isoform 31 (25-37)* 
bcr-2 isoform 38.5 (33-44)
Time to molecular remission 83.9
(days) (51-136)
bcr-1 isoform 84.5 (51-119)
bcr-3 isoform 67.5 (60-136)°
bcr-2 isoform 84 (74-94)
*p < 0.001; °p=0.25.
                              


Molecular remission with arsenic trioxide in patients with newly diagnosed acute promyelocytic leukemia

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Molecular remission with arsenic trioxide in patients with newly diagnosed acute promyelocytic leukemia

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