1) PHASE II MULTICENTRIC EXPLORATIVE STUDY OF INTERMITTENT IMATINIB (IM)
TREATMENT (INTERIM) IN ELDERLY PATIENTS WITH PH CHRONIC MYELOID LEUKEMIA
(CML) WHO ACHIEVED A STABLE COMPLETE CYTOGENETIC RESPONSE (CCGR) WITH
STANDARD IM THERAPY
Author
Russo, Domenico, Chair of Haematology, Brescia, Brescia, Italy(P)
Co-author(s)
Rosti, Gianantonio, "Insitute of Hematology "Seragnoli", Bologna, Italy
Martinelli, Giovanni, Institute of Haematology "Seràgnoli", Bologna, Italy
Malagola, Michele, Chair of Haematology, Brescia, Italy
Mirto, Salvatore, Division of Haematology, Palermo, Italy
Turri, Diamante, Division of Haematology, Palermo, Italy
Vitolo, Umberto, Chair of Haematology, Torino, Italy
Pregno, Patrizia, Chair of Haematology, Torino, Italy
Gobbi, Marco, Chair of Haematology, Genova, Italy
Pierri, Ivana, Chair of Haematology, Genova, Italy
Di Raimondo, Francesco, Chair of Haematology, Catania, Italy
Stagno, Fabio, Chair of Haematology, Catania, Italy
Foà, Robin, Chair of Haematology - La Sapienza, Roma, Italy
Alimena, Giuliana, Chair of Haematology - La Sapienza, Roma, Italy
Breccia, Marco, Chair of Haematology - La Sapienza, Roma, Italy
Saglio, Giuseppe, University of Torino, Orbassano, Italy
Rege Cambrin, Giovanna, University of Torino, Orbassano, Italy
De Fabritiis, Paolo, Chair of Haematology - Sant'Eugenio Hospital, Roma, Italy
Abruzzese, Elisabetta, Chair of Haematology - Sant'Eugenio Hospital, Roma, Italy
Fanin, Renato, Chair of Haematology, Udine, Italy
Tiribelli, Mario, Chair of Haematology, Udine, Italy
Galieni, Piero, Division of Haematology, Ascoli Piceno, Italy
Bigazzi, Catia, Division of Haematology, Ascoli Piceno, Italy
Liso, Vincenzo, Chair of Haematology, Bari, Italy
Specchia, Giorgina, Chair of Haematology, Bari, Italy
Rambaldi, Alessandro, Division of Haematology, Bergamo, Italy
Intermesoli, Tamara, Division of Haematology, Bergamo, Italy
Lauria, Francesco, Chair of Haematology, Siena, Italy
Bocchia, Monica, Chair of Haematology, Siena, Italy
Quarta, Giovanni, Division of Haematology, Brindisi, Italy
Girasoli, Mariella, Division of Haematology, Brindisi, Italy
Angelucci, Emanuele, Division of Haematology, Cagliari, Italy
Usala, Emilio, Division of Haematology, Cagliari, Italy
Bosi, Alberto, Chair of Haematology, Firenze, Italy
Santini, Valeria, Chair of Haematology, Firenze, Italy
Colombi, Chiara, Chair of Haematology, Brescia, Italy
Amabile, Marilina, Institute of Haematology "Seràgnoli", Bologna, Italy
Fogli, Miriam, Institute of Haematology "Seràgnoli", Bologna, Italy
De Vivo, Antonio, Institute of Haematology "Seràgnoli", Bologna, Italy
Baccarani, Michele, Institute of Haematology "Seràgnoli", Bologna, Italy
Background: Standard therapy with Imatinib (IM) significantly prolongs the survival of Ph+ CML patients who obtain
a complete cytogenetic response (CCgR). Elderly patients (i.e. > 65 yrs) have similar cytogenetic responses and
survival, but they usually show a low compliance.
Aims: The aim of the study is to investigate if CCgR that has been achieved with standard (daily administration) IM
therapy can be maintained with the same dose of IM given intermittently (INTERIM). The study population is
represented by elderly patients (at least 65 years) with Ph+ CML and with stable CCgR after at least 2 years of
standard IM therapy (daily administration).
Methods: IM is given at the same dose that was given at the time of enrollment by the following intermittent
schedule: 1 week on / 1 week off for the 1st month; 2 weeks on / 2 weeks off for the 2nd and 3rd month; 1 month
on / 1 month off from the 4th month thereafter. The CgR status will be evaluated at baseline (by conventional
cytogenetics on bone marrow and FISH on peripheral-blood) and every 3 months during the study (only by FISH
on peripheral-blood). Quantitative molecular assessment of BCR-ABL transcript by RQ-PCR on peripheral blood
is due at baseline and every 3 months during the study and mutational analysis of ABL will be performed in case
of loss of CCgR. If FISH documents a variation of the baseline value of more than 1% in two consecutive
examinations, evaluation of marrow cells metaphases will be performed to confirm the loss of CCgR and to check
for additional cytogenetic abnormalities. In case of loss of CCgR INTERIM will be stopped and standard therapy
(daily administration) will be resumed. After 12 months, the patients who are in continuous CCgR are advised to
continue the intermittent study schedule and to be followed indefinitely.
Results: One-hundred and nine patients have been considered eligible, but 17 (16%) refused to enter into the
protocol. Out of 92 enrolled patients, 61 started INTERIM, 4 patients (4%) went off the study for major protocol
violation before the 3rd month and, at present, 57 patients are ongoing. Of these 57 patients, 25 and 10
completed the 3rd and 6th month, respectively. At the 3rd month, all the 25 evaluable patients maintained the
CCgR. As detected by RQ-PCR, 19/25 (76%) maintained a major molecular response (MMR) and 6/25 (24%)
showed at least 1 log increase of BCR-ABL ratio. At the 6th month, all the patients maintained the CCgR; 9/10
(90%) maintained a MMR and 1/10 (10%) showed a 1 log increase of BCR-ABL ratio.
Conclusions: These preliminary data suggest that IM given intermittently can be sufficient to maintain the CCgR in
those patients who have a stable CCgR, previously achieved with standard IM therapy.
2) SOKAL SCORE AND RESPONSE TO IMATINIB IN EARLY CHRONIC PHASE CML: THE
GIMEMA CML WORKING PARTY EXPERIENCE ON 559 PATIENTS
Author
Baccarani, Michele, Dept. of Hematology and Oncological Sciences, Bologna, Italy(P)
Co-author(s)
Rosti, Gianantonio, Dept. of Hematology and Oncological Sciences, Bologna, Italy
Castagnetti, Fausto, Dept. of Hematology and Oncological Sciences, Bologna, Italy
Palandri, Francesca, Dept. of Hematology and Oncological Sciences, Bologna, Italy
Gugliotta, Gabriele, University of Bologna, Bologna, Italy
Ferrara, Felicetto, Division of Hematology, Ospedale "Cardarelli", Napoli, Italy
Gozzini, Antonella, Chair of Hematology, University of Firenze, Firenze, Italy
Pulini, Stefano, Division of Hematology, Ospedale Civile, Pescara, Italy
Montefusco, Enrico, Division of Hematology, Ospedale Sant'Andrea, Roma, Italy
Sica, Simona, Chair of Hematology, University Cattolica, Roma, Italy
Turri, Diamante, Division of Hematology, Ospedale " Vincenzo Cervello", Palermo, Italy
Ferrero, Dario, Chair of Hematology, University of Torino, Torino, Italy
Musolino, Caterina, Chair of Hematology, University of Messina, Messina, Italy
Bocchia, Monica, Chair of Hematology, University of Siena, Siena, Italy
Radaelli, Franca, Chair of Hematology, University of Milano, Milano, Italy
Martinelli, Giovanni, Dept. of Hematology and Oncological Sciences, Bologna, Italy
Breccia, Massimo, Chair of Hematology, University "La Sapienza", Roma, Italy
Pane, Fabrizio, Dept. of Biochemistry and Medical Biotechnology, University Federico II, Napoli, Italy
Saglio, Giuseppe, Division of Hematology, Ospedale Luigi Gonzaga, Orbassano, Italy
BACKGROUND: Imatinib (IM) 400 mg daily is the standard treatment for chronic myeloid leukemia in early chronic
phase (ECP): the results of the IRIS trial have shown for the IM 400 mg arm a 12-months probability of complete
cytogenetic response (CCgR) of 69% but CCgR rates were different according to Sokal risk, being 76%, 67% and
49% in low, intermediate and high Sokal risk categories, respectively (Hughes et al, NEJM 2003). At 84 months,
overall survival was 86%, EFS and PFS (no ABP) 81% and 93%, respectively. The outcome was significantly
influenced by the Sokal score: at 5 years, the estimated probability of progression to ABP was 17%, 8% and 3%
for low, intermediate and high risk Sokal. However, the risk of progression to ABP was not significantly influenced
by the Sokal risk in pts who obtained a CCgR (Druker et al, NEJM 2006). AIMS To evaluate the long-term
outcome, overall and by Sokal risk, of 559 IM treated, early chronic phase patients, treated according to 3
investigator sponsored trials of the GIMEMA CML Working Party. METHODS The 559 patients were enrolled in 3
simultaneously running trials of the GIMEMA CML WP: CML/022 (Clin Trials Gov. NCT00510926), phase III, IM 400
vs 800 mg in high Sokal risk; CML/021 (Clin Trials Gov. NCT00514488), phase II, IM 800 mg in intermediate Sokal
risk; CML/023, observational, IM 400 mg. Response monitoring was based on conventional cytogenetic
examination of bone marrow cells every 6 months and quantitative molecular (Q-PCR) evaluations (PB) after 3, 6
and 12 months on IM (every 6 months thereafter). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL
ratio < 0,1%IS. Failures (ELN criteria): no CHR at 6 months, no CgR at 6 months, no PCgR at 1 year, no CCgR at
18 months, loss CHR, loss CCgR, progression to accelerated/blastic phase and death. Events: failures, off-
treatment for toxicity, refusal and lost to follow-up. RESULTS (Table): 559 patients were treated with IM 400mg
daily (76%) or 800 mg daily (24%). Currently the median follow-up is 42 (1-64) months. Responses and outcome
are significantly different by Sokal group; the overall CCgR rate was not different but comparing low and
intermediate risk vs high the P resulted significant. The PFS of CCgR patients only, stratified by Sokal risk, is not
significantly different but high risk CCgR patients have a significantly greater probability to fail treatment (ELN
criteria) vs low and intermediate CCgR ones. CONCLUSIONS These data confirms that the Sokal risk influences
significantly responses and outcome. Moreover, high risk patients achieving a CCgR still has a significantly
greater probability of failing IM with respect to non high risk ones. Acknowledgements: Work supported by
European LeukemiaNet, COFIN, University of Bologna and BolognAIL.
3) FINAL SAFETY ANALYSIS OF 1,793 CML PATIENTS FROM ENACT (EXPANDING NILOTINIB
ACCESS IN CLINICAL TRIALS) STUDY IN ADULT PATIENTS WITH IMATINIB-RESISTANT OR –
INTOLERANT CHRONIC MYELOID LEUKEMIA (CML)
Nicolini, Franck, Alimena, Giuliana, Al-Ali, Haifa-Kathrin, Turkina, Anna, Shen, Zhixiang, Jootar, Saengsuree,
Smith, Graeme, De Souza, Carmino, Wang, Jim, Berton, Myriam, Szczudlo, Tomek, Rizzieri , David (Lyon, France)
Co-author(s)
Alimena, Giuliana, University La Sapienza, Rome, Italy
Al-Ali, Haifa-Kathrin, Universitat Leipzig, Leipzig, Germany
Turkina, Anna, Hematological Scientific Center, Moscow, Russian Federation
Shen, Zhixiang, Hematological Scientific Center, Moscow, Russian Federation
Jootar, Saengsuree, Mahidol University, Salaya, Thailand
Smith, Graeme, Leeds Teaching Hospital, Leeds, United Kingdom
De Souza, Carmino, University of Campinas, São Paulo, Brazil
Wang, Jim, Novartis Pharmaceutical Corportation, East Hanover, United States of America
Berton, Myriam, Novartis Pharma AG, Basel, Switzerland
Szczudlo, Tomek, Novartis Pharmaceutical Corportation, East Hanover, United States of America
Rizzieri , David, Duke University Medical Center, Durham, United States of America
Background: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of Ph+
CML patients (pts) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior
therapy, including imatinib.
Aims: The ENACT study, which is a Phase IIIb, open label, multicenter study, was initiated to obtain additional
safety information in pts with imatinib-resistant or -intolerant CML in chronic, accelerated, or blast crisis (BC)
phase in a clinical practice setting outside of a registration study.
Methods: Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Pts who required
dose reduction to 400 mg once daily due to toxicity were allowed to have a dose re-escalation to 400 mg BID after
resolution of the adverse events (AEs), lack of response, or persistent disease at the investigator’s discretion.
Efficacy was provided by investigator assessment. Patients who failed dasatinib were also eligible.
Results: A total of 1,793 pts enrolled in the ENACT study between Jan. 2006 and Oct. 2008, including 1,422 CP
pts (79%), 181 AP pts (10%) and 190 BC pts (11%), from 293 study sites worldwide. The median age of all pts
was 52 years and 69.2% of patients received prior imatinib ≥600mg/d. At study completion, 941 (53%) pts were
continuing on nilotinib. Median (range) duration of nilotinib exposure was 266 (1-807) days for CP pts, 160 (6-
736) days for AP pts, and 78 (1-642) days for BC pts; median average dose intensity was 783, 779 and 773
mg/day, respectively. The main reasons for treatment discontinuation were inadequate responses (22%) and AEs
(14%). The majority of grade 3/4 AEs were hematologic and the most common hematologic toxicities were
thrombocytopenia (24%) and neutropenia (17%). Non-hematologic AEs were mostly grade 1/2. Grade 3/4 non-
hematologic AE’s were infrequent and included headache, rash and nausea. Death on study was reported for 54
(3%) pts and occurred most frequently among those with BC (n = 27; 14%). A low incidence of QT prolongation
(defined as absolute QTcF > 500 msec; n = 6, 0.3%) was observed overall. Grade 3/4 lipase elevation was
observed in 115 patients (6.4%), but only 5 patients (0.3%) had lipase elevation associated with treatment
discontinuation. Pancreatitis, including acute, occurred in 27 patients (1.5%) and was associated with
discontinuation in 4 patients (0.2%). Only one patient (0.1%) had hyperglycemia associated with treatment
discontinuation. Overall major cytogenetic response (MCyR) rates were consistent with those observed in earlier
phase II trial at 45.1% in CP (34.2% CCyR,) 19.3% in AP and 19.5% in BC pts. Likewise, complete hematologic
response (CHR) rates were 43% in CP, 22.1% in AP and 8.4% in BC pts.
Conclusion: This final safety analysis of a large expanded access study further demonstrates that nilotinib is
generally well tolerated in heavily pretreated pts in all phases of CML with safety profile reported in ENACT being
similar to that observed in the pivotal phase II registration study.
4) A SHORT (12M) IFNA/IMATINIB COMBINED THERAPY CAN SECURE LONG TERM
MAINTENANCE OF IMATINIB INDUCED CYTOGENETIC REMISSION AFTER
DISCONTINUATION OF IMATINIB IN CML PATIENTS WITHOUT MOLECULAR REMISSION
Hardan, Izhar, Stemmer, SM, Amariglio, N, Koren-Michowitz , M, Levi , I, Shimoni, A, Binenbaum, Y, Ben-Yehuda ,
D, Bennett, M, Rechavi, G, Nagler, A (Tel-Hashomer, Israel)
Co-author(s)
Stemmer, SM, Davidof Cancer Center, Petach Tikva, Israel
Amariglio, N, Sheba Medical Center, Tel-Hashomer, Israel
Koren-Michowitz , M, Sheba Medical Center, Tel-Hashomer, Israel
Levi , I, Soroka Medical Center , Beer Sheva, Israel
Shimoni, A, Sheba Medical Center, Tel-Hashomer, Israel
Binenbaum, Y, Sheba Medical Center, Tel-Hashomer, Israel
Ben-Yehuda , D, Hadassah Medical Center, Jerusalem, Israel
Bennett, M, Haemek Medical Center, Afula, Israel
Rechavi, G, Sheba Medical Center, Tel-Hashomer, Israel
Nagler, A, Sheba Medical Center, Tel-Hashomer, Israel
Background. Imatinib Mesylate (IMA) is a gold standard of therapy in CML, however it is a crucial question whether
this therapy can cure CML, as its discontinuation usually results in an early disease progression. Cessation of IMA
therapy is feasible in about half of the patients that achieve complete molecular remission (CMR, the minority of
CML patients), mainly those that were also previously exposed to IFN . IFN is active in CML. Responding patients
can maintain long term complete cytogenetic remission (CCyR) off therapy, probably due to the effect of IFN on
the early/dormant leukemic progenitor stem cells. Recently it was shown that IFN activates dormant
haematopoietic stem cells to be exposed to therapy.
Aims. To facilitate discontinuation of IMA therapy in patients with CML and complete cytogenetic, but not
molecular, remission, by the addition of a short course of IFN to the therapy.
Methods. CML patients with IMA induced CCyR (without molecular remission) of more than 12 month duration
were randomized to either continue with IMA therapy and no cessation of therapy, or to add a weekly injection of
IFN to the IMA therapy followed by cessation of therapy (study group). The study group patients received Peg- IFN
(Pegasys, Roche pharmaceutics) for 52 weeks and stopped IMA therapy after 39 weeks of IFN therapy.
Results 12 eligible patients (9M,3F, median age 49y) were enrolled in the study group since January 2006. One
patient stopped therapy after two weeks dew to intolerability, and 11 patients completed 52 weeks of Peg-IFN
therapy (median dose/w/pt 135ug), stopped IMA therapy after 39 weeks of IFN therapy and are eligible for
evaluation > 12 month off all therapy. The median time from diagnosis to enrolment for the 11 patients was 55
month (range 18-84 month). Five of the eleven patients were exposed to IFN at diagnosis, one had a previous
allogeneic and one an autologous BMT. After a median follow up of 18 month (range 12-25) from discontinuation
of IFN therapy (21 month from cessation of IMA therapy), six of the 11 patients ("responders") are in a maintained
CCyR of a median duration of 24 month (four patients > 24 month, one patient 18 month and one patient 12
month). Five patients ("non responders") progressed (at 6-7 month after cessation of therapy in the five pt's) and
regain complete remission following reintroduction of IMA therapy. The Sokal score of the responders is higher
than in the non responders.The degree of molecular response was similar or responders and non responders.
Five of the six patients that were exposed to IFN at diagnosis responded compared with two of five patients that
were not exposed.
Summary. The addition of a short (12 month) course of IFN to Imatinib can facilitate discontinuation of Imatinib
therapy and secure a long term maintenance of Imatinib induced cytogenetic remission off all therapy in patients
with CML and complete cytogenetic, without a molecular, remission. Exposure to IFN at diagnosis may be a
positive predictor of success by this strategy.
5) PREGNANCY AMONG THE PATIENTS WITH CHRONIC MYELOID LEUKEMIA ON IMATINIB
THERAPY
0644
Chelysheva, Ekaterina, Turkina, A.G., Gusarova, G.A., Kolosheinova, T.I., Sokolova, M.A., Khoroshko, N.D.,
Pepelyaeva, V.M., Gavrilova, L.V. (Moscow, Russian Federation)
Co-author(s)
Turkina, A.G., Hematology Research Center, Moscow, Russia, Moscow, Russian Federation
Gusarova, G.A., Hematology Research Center, Moscow, Russia, Moscow, Russian Federation
Kolosheinova, T.I., Hematology Research Center, Moscow, Russia, Moscow, Russian Federation
Sokolova, M.A., Hematology Research Center, Moscow, Russia, Moscow, Russian Federation
Khoroshko, N.D., Hematology Research Center, Moscow, Russia, Moscow, Russian Federation
Pepelyaeva, V.M., Regional Clinical Hospital, Perm, Russian Federation
Gavrilova, L.V., Hematology Department of Clinical Hospital ?4, Saransk, Russian Federation
Topic
21. Chronic myeloid leukemia - Clinical
Keywords
Chronic myeloid leukemia, Imatinib, Pregnancy
Background
The imatinib therapy has improved a survival rate and a quality of life for the majority of CML patients. Therefore
the ability to become parents is one of the crucial issues for the patients of childbearing potential. Current view is
to avoid pregnancy because of a possible fetus injury. Furthermore, imatinib discontinuation at pregnancy period
can be critical for possible disease relapse. Clinicians are forced to find individual decisions for the patients
wishing to maintain pregnancy despite of all the risks. We report about the 6 cases of successful pregnancy of the
females and the 6 cases of pregnancy in the partners of the males on imatinib therapy.
Results
We observed 6 females with CML, 5 in chronic phase (CP), 1 in accelerated phase (AP) at diagnosis, age 27-36
years (median 31.8), disease duration 30-112 months (median 86.6), imatinib treatment period 25.7-84.2 months
(median 44.4). Imatinib dose was 400 mg for 3 of 6, 600 mg for 2 of 6 and 1 of 6 had a temporal 3 weeks
treatment interruption at the impregnation. 5 of 6 females had been exposed to imatinib for the first 4-8 weeks of
pregnancy (except 1 of 6 mentioned above). After pregnancy identifying the patients expressed their strong wish
to keep the pregnancy and the imatinib treatment was stopped. At that moment their CML status was the following:
complete molecular response (CMR) –3 of 6, major molecular response (MMR)– 1 of 6, only partial cytogenetic
response (PCyR) – 2 of 6. During the pregnancy period 2 patients remained in CMR but after the delivery both of
them had only MMR. 1 patient lost CMR and kept the complete hematologic remission (CHR), cytogenetic
examination wasn’t done during the pregnancy. 1 patient lost MMR and had a cytogenetic relapse (CyR) (Ph+
cells 59%). 2 patients lost PyCR and 1 of them had a partial hematologic response (PHR). For those 3 patients
with CyR and PHR a maintenance treatment by interferon alpha 3 ME daily was applied during pregnancy.
All 6 females delivered healthy infants at term, restarted imatinib immediately after delivery and didn’t breastfeed.
At present time the infants are from 3 months to 2.7 years old with no abnormalities in their development.
There were also 6 pregnancy cases in the partners of the CML CP males receiving imatinib therapy. The patients
age was 26-36 years (median 31.5), disease duration 21-93 months (median 42.8), imatinib treatment period 13-
78 months (median 26.2). Imatinib dose was 400 mg for 4 of 6 patients, 600 mg for 2 of 6 at impregnation
moment. In all 6 cases the healthy infants were born at term, now the children are from 6 months to 5.5 years old
with no abnormalities in their development.
Summary
We demonstrated that despite of all risks the successful outcomes of pregnancy in CML patients are possible.
Pregnancy management is still an individual decision for every patient. An experience exchange and careful study
of every case is significant for developing the further strategy for this actual issue.
6) CHRONIC MYELOID LEUKEMIA AS SECOND MALIGNANCY; A RETROSPECTIVE
MULTICENTRIC STUDY
0861
Iannitto, Emilio, Minardi, V, Barone, R, Cascavilla, N, Caracciolo, C, Di Raimondo, F, Ferrara, F, Franco, G,
Liardo, E, Mancuso, S, Martino, B, Mazza, P, Musolino, C, Musso, M, Musto, P, Pagnucco, G, Palmieri, F, Russo-
Rossi, A, Specchia, G, Turri, D, Abbadessa, V (Palermo, Italy)
Author
Iannitto, Emilio, Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy(P)
Co-author(s)
Minardi, V, Ospedale A. Perrino, Brindisi, Italy
Barone, R, Ematologia Università di Palermo, Palermo, Italy
Cascavilla, N, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Caracciolo, C, Ematologia, A.O.U. Policlinico P.Giaccone, Palermo, Italy
Di Raimondo, F, Ematologia Università di Catania, Catania, Italy
Ferrara, F, Ospedale Caldarelli, Napoli, Italy
Franco, G, Ematologia, A.O.U. Policlinico P.Giaccone, Palermo, Italy
Liardo, E, Ematologia, A.O.U. Policlinico P.Giaccone, Palermo, Italy
Mancuso, S, Ematologia Università di Palermo, Palermo, Italy
Martino, B, Ospedale Melacrino-Morelli, Reggio Calabria, Italy
Mazza, P, Ospedale di Taranto, Taranto, Italy
Musolino, C, University of Messina, Messina, Italy
Musso, M, CDC La Maddalena, Palermo, Italy
Musto, P, IRCCS, Centro di Riferimento Oncologico di Basilicata, Rionero in Vulture, Italy
Pagnucco, G, ARNAS Civico, Palermo, Italy
Palmieri, F, Divisione di Ematologia, Ospedale Moscati , Avellino, Italy
Russo-Rossi, A, Ematologia Università di Bari, Bari, Italy
Specchia, G, Ematologia Università di Bari, Bari, Italy
Turri, D, Ospedale V. Cervello, Palermo, Italy
Abbadessa, V, Ematologia Università di Palermo, Palermo, Italy
Background
Neither studies on the effects of alkylating agents and topoisomerase inhibitors nor epidemiological studies on
secondary leukaemias following cytotoxic therapy have so far indicated a relationship between chemical exposure
and increased risk of BCR-ABL-positive CML. Although cases of treatment-related CML are increasingly reported
in the literature, few are the studies focusing on the survival of patients with CML occurring after a prior
malignancy. Moreover, it is not clear if the previous exposure to an antiblastic treatment can modify the clinical
course of a “secondary-CML” and its response to tyrosine-kinase inhibitors.
Aim
To examine the incidence, the presenting clinical and biological features and the outcome of CML diagnosed after
a prior malignancy.
Methods:
All incident cases of CML diagnosed during the last 10 years by 12 hematological centres of Southern Italy were
reviewed and those occurring after a prior malignancy were included in the present analysis.
Results:
Among the 569 patients with CML, 47 (8.2%) were diagnosed following a previous malignancy. Of them, nineteen
(40.5%) were male with a median age at the time of diagnosis of the primary malignancy and of CML of 52 yrs
(range 22-84) and 60 yrs (range 29-86) respectively. The most common preceding malignancy was breast cancer
(23.4% of all preceding cancers), followed by colon/rectum (21.3%), prostate (8.5%), lymphoma (8.5%) and
hypophysis (6.4%). The median time from primary malignancy to CML was 54 months (range 2-328) with the
following distribution according to Sokal’s score: 36% low, 45% intermediate, and 18% high. Only two patients
showed additional cytogenetic abnormalities besides Ph chromosome. Thirty-one patients received treatment with
Imatinib and all attained at least an haematological response at 3 months (48.4% Major or Complete Cytogenetic
response and 6.4% molecular response); at 12 months 54% achieved a molecular response (complete 9.1%) and
31.8% a Cytogenetic Response (Complete 27.3%) and at 18 months the percentage of complete molecular
responses raised up to 31.8% with only two patients (9%) losing response or progressing.
With a median observation time of 28 months (range 1- 166) only one out of 37 patients treated with Imatinib and
3 out of 10 who received alternative therapies died of CML (overall survival at 5 yrs 94% vs 60% p= 0.017).
Looking at the series according to the treatment received for the primary neoplasm, 19 patients had received
chemotherapy and/or radiotherapy while 28 surgery with or without hormonal therapy. The median age at primary
tumor diagnosis was similar in the two groups (52 vs 57 yrs) while in the former group the median age at CML
diagnosis was significantly lower (57 vs 65 p=0.04) and a trend toward a shorter interval between first neoplasm
and CML diagnosis was detected (62 vs 103 months; p=0.06).
Conclusion
CML secondary to other neoplasms emerges from this study as a well-defined entity with biological, clinical and
prognostic features paralleling those of primary CML and in which the role of a prior chemotherapeutic treatment
seems to be related to the progression of the leukaemic clone more than to its rise.
7) ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN THE ERA OF
TARGETED THERAPY: COMPARABLE SURVIVAL RATES FOLLOWING ALLOGENEIC HSCT
AFTER IMATINIB AND IMATINIB THERAPY IN FIRST CHRONIC PHASE; RESULTS OF THE
GERMAN CML STUDY IV
Author
Saussele, Susanne, Universitätsmedizin Mannheim, Mannheim, Germany(P)
Co-author(s)
Lauseker, M., IBE, Universität, München, Germany
Gratwohl, A., University Hospital, Basel, Switzerland
Beelen, D.W., BMT Unit, University, Essen, Germany
Bunjes, D., Universität Ulm, Ulm, Germany
Schwerdtfeger, R., German Diagnostic Clinic, Wiesbaden, Germany
Kolb, H.J., Department of Medicin, university, München, Germany
Ho, A.D., Medical Faculty, University, Heidelberg, Germany
Falge, C., Klinikum Nord, Nürnberg, Germany
Holler, E., Innere Medizin I, Regensburg, Germany
Schlimok, G., Zentralklinikum, Augsburg, Germany
Zander, A., Univ.-Krankenhaus Eppendorf, Hamburg, Germany
Arnold, R., Campus Virchow-Klinikum, Berlin, Germany
Kanz, L., Universitätsklinikum, Tübingen, Germany
Dengler, R., Hämatologische Onkologische Praxis, Regensburg, Germany
Haferlach, C., MLL Leukemia Laboratory, München, Germany
Schlegelberger, B., Institut für Zell- und Molekularpathologie, MHH, Hannover, Germany
Pfirrmann, M., IBE, Universität, München, Germany
Müller, M.C., Universitätsmedizin Mannheim, Mannheim, Germany
Schnittger, S., MLL Leukemia Laboratory, München, Germany
Leitner, A., Universitätsmedizin Mannheim, Mannheim, Germany
Pletsch, N., Universitätsmedizin Mannheim, Mannheim, Germany
Hochhaus, A., Universitätsmedizin Mannheim, Mannheim, Germany
Hasford, J., IBE, Universität, München, Germany
Hehlmann, R., Universitätsmedizin Mannheim, Mannheim, Germany
For, The Germa, Universitätsmedizin Mannheim, Mannheim, Germany
Topic
21. Chronic myeloid leukemia - Clinical
Keywords
Chronic myeloid leukemia, Imatinib, Survival prediction, Transplant
Background: HSCT remains an important option for patients with chronic myeloid leukemia (CML) who failed
imatinib. Studies published so far have focused on a potential unfavourable effect of imatinib on the outcome after
HSCT. Further, there are hints that pre-transplantation imatinib therapy might even improve outcome in line with
observations that reduction of leukemia load prior to transplantation is associated with better transplantation
outcome.
Aim and methods: The German CML-Study IV (five-arm randomized controlled trial to optimize imatinib therapy by
combination, dose-escalation and transplantation) is designed to determine the role of transplantation in the
imatinib era.
Results: By November 2008, 1242 pts were randomized, 84 (6.8 %) pts transplanted. 55 pts were male (65%),
median age at diagnosis was 37 years (yrs, range 16-62), median time to HSCT was 12.9 months (mo, range 3.5-
55). Based on the indications for HSCT three groups were defined: i) elective HSCT (n= 20, 24%); ii) HSCT after
imatinib failure or intolerance in first CP (n=36, 43%) and iii) HSCT in advanced disease (n=28, 33%) including 25
in blast crisis. All randomized therapies were evenly represented as treatments prior to HSCT. Median follow-up in
the 56 CP patients was 30 mo. 3-year survival probability after HSCT in first CP was 91%. Incidence of transplant-
related mortality was 7%. Median follow-up in 28 advanced disease pts was 24 mo (0-50). Survival probability at 2
years was 59%. To compare survival of transplanted with that of non-transplanted pts on imatinib therapy in first
CP, a matched pair analysis was performed. For 53 transplanted pts two non-transplanted pts in first CP at the
time of transplantation of the partner were identified. Survival estimates at five years (92% vs 93%) did not show
any significant difference. After HSCT, molecular data for 59 of 70 living patients demonstrated major molecular
remission (MMR) in 55 pts (93%) being complete (CMR) in 52 pts (88%) at most recent follow-up analysis.
Conclusions: We conclude that reduction of tumor load by initial imatinib therapy and improvements in
transplantation procedures translate into improved outcome of pts after HSCT. In view of the curative potential of
transplantation and the survival results that are equally good as with drug treatment, we propose HSCT as
preferred second line option after failure or intolerability of first line TKI-therapy for eligible pts.