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ASH 2014 – Primi risultati del protocollo GIMEMA LAL 1509

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Al 56°congresso dell’American Society of Hematology (ASH) tenutosi a San Francisco dal 5 al 9 dicembre 2014, la Dott.ssa Sabina Chiaretti dell’Ematologia dell’Università ‘Sapienza’ di Roma ha presentato in sessione orale i primi risultati del protocollo GIMEMA LAL 1509total therapy’ per pazienti adulti con leucemia acuta linfoblastica (LAL) Ph+*.

Questo studio basato su una induzione con dasatinib più steroidi e senza chemioterapia sistemica, seguito da un programma uniforme di terapia post-remissionale, rappresenta la naturale conseguenza dello studio GIMEMA LAL 1205 – ‘Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia’ – pubblicato su BLOOD nel 2011 (118: 6521-6528). Questa prima analisi dello studio, che ha confermato e ulteriormente migliorato i precedenti risultati riportati dal gruppo cooperatore italiano, ha destato molto interesse e discussione.

Le principali conclusioni di questa prima analisi sono qui di seguito riassunte:

  • A total therapy strategy is feasible for adult Ph+ ALL.
  • All patients (100%) achieved a complete hematologic response within day +57 with dasatinib plus steroids.
  • Two patients lost the hematologic remision at day +85 (both p210+).
  • No deaths in induction.
  • 18% of patients achieved a complete molecular response at the end of induction.
  • A complete molecular response at day +85 was predictive of a better DFS.
  • Patients with the p210 fusion protein responded less to TKI.
  • At the first analysis, OS and DFS look promising.

Oltre alla presentazione orale, lo studio è stato altresì selezionato per la sessione speciale e conclusiva del congresso, ‘Best of ASH’, dove in 90 minuti sono state riassunte da Benjamin Ebert e Steven Lentz, 2014 Annual Meeting Scientific Program Co-Chairs, le più importanti novità emerse a San Francisco e selezionate tra gli oltre 4000 abstracts. Una ulteriore soddisfazione a sottolineare la bontà dal lavoro svolto dal gruppo cooperatore GIMEMA nell’ambito delle LAL Ph+.

Robin Foà

Ecco di seguito il testo completo dell’abstract.

* First Results of the Multicenter Total Therapy Gimema LAL 1509 Protocol for De Novo Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients

Sabina Chiaretti, MD, PhD1*, Antonella Vitale, MD1*, Loredana Elia, PhD1*, Silvana Albino, Bsc1*, Alfonso Piciocchi, PhD2*, Paola Fazi, MD2*, Francesco Di Raimondo, MD3, Antonella Fornaro, MD4*, Francesco Fabbiano, MD5, Alfonso Maria D’Arco, MD6*, Giovanni Martinelli, MD7, Francesca Ronco, MD8*, Lidia Edwige Santoro, MD9*, Nicola Cascavilla, MD10*, Piero Galieni, MD11*, Alessandra Tedeschi, MD12*, Simona Sica, MD13*, Nicola Di Renzo, MD14, Angela Melpignano, MD15*, Angelo Michele Carella16, Felicetto Ferrara17, Marco Vignetti, MD2* and Robin Foa, MD1

1Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Roma, Italy; 2GIMEMA Data Center, GIMEMA Foundation, Roma, Italy;  3Catania University, Hematology, “Ospedale Ferrarotto”, Catania, Italy;  4Clinical Hematology – Azienda USL di Pescara, Pescara, Italy;  5Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy;  6Onco-hematology of Nocera Inferiore-plesso ospedaliero – Pagani (SA), Nocera Inferiore, Italy;  7Institute of Hematology and Medical Oncology “L. e A. Seràgnoli”, Bologna, Italy;
8Hemato-oncology, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy; 9Azienda Ospedaliera S.G.Moscati, Avellino, Italy;  10Hematology – IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy;  11Hematology and Cellular Therapy, Ospedale”C. e G. Mazzoni”, Ascoli Piceno, Italy;  12Niguarda Hospital, Division of Hematology, Milano, Italy;  13Hematology, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Roma, Italy;  14Hematology, ASL Le/1 P.O. Vito Fazzi, Lecce, Italy
15Ospedale “A. Perrino”, Brindisi, Italy;  16Division of Hematology 1, IRCCS A.O.U. San Martino IST, Genova, Italy;  17Azienda Ospedaliera di Rilievo Nazionale, Napoli, Italy.

Introduction: Ph+ ALL management has changed since the introduction of tyrosine kinase inhibitors (TKI). In the GIMEMA LAL 1509 protocol for adult Ph+ ALL, Dasatinib was administered in combination with steroids as induction treatment, and chemotherapy and/or allogeneic transplantation (HSCT) was given if patients did not reach a sustained complete molecular response (CMR) after induction.

Methods: Steroids were administered from day -6 to day 31. Dasatinib (140 mg/day) was given between days 1 and 84. Patients reaching a confirmed CMR (i.e. BCR/ABL to ABL ratio=0) at the end of induction (day +85), continued Dasatinib for 6 additional months. Patients in complete hematologic remission (CHR), but not in CMR, were stratified according to HSCT eligibility: those with a promptly available donor underwent directly a HSCT; if the donor was not readily available, a consolidation cycle with clofarabine and cyclophosphamide was administered. HSCT non-eligible patients received two cycles of clofarabine and cyclophosphamide of 5 and 3 days, respectively. Dasatinib was administered until disease progression. Molecular testing was used to identify the presence of a BCR/ABL transcript, define the fusion protein and quantify BCR/ABL levels at baseline and at follow-up. Mutational screening was performed in relapsed cases.

Results: Sixty of the 64 enrolled patients were eligible. Median age was 41.9 years (range: 18.7-59.1), 34 were males and 26 females; the median WBC count was 12.5 x 109/l (range 1.4-178.0); the p190 fusion product was detected in 33 patients, p210 in 18 and p190/p210 in 9. Median follow-up is 17.6 months (range 4.1-31.6). After the steroid pre-phase, 38 patients (63%) had a blast reduction ≥75%. At day 85, 58 patients achieved a CHR (97%) and 2 were non-responders (1 hematologic relapse and 1 disease progression): notably, both had a p210 fusion transcript. A CMR was obtained in 11 patients (18.6%): of these, 72% had a p190 fusion transcript. Overall, 24% of p190+ patients and 11% of p210+ or p190/210+ cases obtained a CMR. As previously reported in other GIMEMA trials, no deaths in induction occurred. Among the CMR patients, only 1 experienced a hematologic relapse and harbored a T315I mutation. Among the 46 non-CMR cases, 17/27 eligible patients underwent a HSCT, while 9 did not; 5 relapses occurred in the non-transplanted group, while 1 was observed in the HSCT group. Of the 19 HSCT non-eligible patients, 14 received the planned therapy: in this group, 2 relapses occurred. At 24 months, the overall survival (OS) is 69.1% (95%CI: 55.3-86.3), with a disease-free survival (DFS) at 18 months of 61.6% (95%CI: 47.6.0-79.8). A better DFS was observed in patients who obtained a CMR at day +85. Dasatinib exerted a rapid blast clearance, that was highly significant (p<0.0001) between the onset and day +22, and between day +22 and +45; a significantly more rapid clearance (p=0.0005, p=0.0013 and p=0.001 at days +22, +45 and +57, respectively) was observed in patients who achieved a CMR at day +85, underlining the heterogeneous sensitivity of Ph+ ALL blasts to TKI. Importantly, a significantly greater clearance was observed in p190 (n=33) vs p190/210 and p210 (n=27) cases (p=0.0008, p=0.0032, p=0.0031, p=0.0016, p=0.007 at diagnosis, days +22, +45, +57, and +85, respectively). Mutational screening was performed in 6/12 patients who relapsed and mutations were detected in 5: 3 T315I and 2 V299L, of which 1 with a concomitant F317L. Overall, 12 relapses (5 in the p190 and 7 in the p210 subgroup) and 7 deaths in CR occurred, 5 of which in allografted patients. The median time to relapse was 6.7 months (range 0.3-22.5).

Conclusions: We confirm that a chemo-free induction approach for adult Ph+ ALL patients results in a very high CHR rate (97%), with no deaths in induction. In this Dasatinib-based protocol, a sustained CMR is achieved after induction in >18% of cases, suggesting that a subset of patients may be spared further intensive treatment. We witnessed an increase in p190/p210-p210+ cases compared to earlier studies; these patients showed a worse prognosis as underlined by a lower susceptibility to TKI, lower blast clearance and greater incidence of relapses (58%). At this first analysis, OS and DFS are at least comparable to those obtained in previous GIMEMA studies, despite the higher incidence of p210+ patients – which accounted for 45% of cases in this cohort – and which may require an intensified approach.

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