Abstract ▪662▪This icon denotes a clinically relevant abstract
In the last 10 years IM was added to chemotherapy to improve outcome of adult patients (pts.) with Ph+ ALL, with encouraging results. ...The Northern Italy Leukemia Group (NILG) designed a clinical trial with chemotherapy plus short IM pulses (Bassan et al, JCO 2010; 28:3644–52) aiming to increase the CR rate, limit incidence of early failures and increase the number of patients proceeding to SCT with subsequent improvement of survival.
To analyze the long-term results in Ph+ ALL pts. treated with chemotherapy plus IM, in comparison to a prior cohort treated without IM.
IM 600 mg/d was given orally for 7 consecutive dd. with each chemotherapy block, starting from day 15 of induction (IDR/VCR/PDN±ASP) and day –3 of consolidation courses (5x IDR/VCR/CY/DEXA; 2x HD-MTX/ARA-C). All pts. received CNS chemo-radioprophylaxis and were eligible to allogeneic SCT, or alternatively to HD therapy with autologous SCT and long-term maintenance with 6MP/MTX and intermittent IM.
Between April ’00 and November ’08, 100 out of 404 pts. enrolled into NILG trial 09/00 had Ph+ ALL (median age 46 years, range 19–66; male 54). The pts. belonged to two subsequent treatment groups: control arm (IM-, n=35) and IM+ arm (n=65), of whom 59 received IM during induction/consolidation and 6 during consolidation only (pts. included in IM- cohort for remission induction analysis and in IM+ cohort afterwards). From March 2005 ASP was omitted during induction due to increased toxicity, so that in the IM+ group 20 pts. received ASP and 39 did not.
The complete remission (CR) rate was: 33/41 (80.5%) in IM- vs. 55/59 (93%) in IM+ pts. (p=0.05). With regard to the use of ASP in IM+ group, CR rate was: 16/20 (80%) with ASP vs. 39/39 (100%) without ASP (p=0.004). With a median follow-up of 1,6 years (maximum 11.3), 24/60 (40%) IM+ pts. are alive in 1st CR compared to 5/28 (18%) IM- pts., (p=0.04). Estimated 5-year OS, DFS and early relapse rates were significantly improved and reduced (relapse risk within 6 mos.), respectively, in IM+ vs. IM- group: OS 0.38 vs. 0.23 (p=0.012), DFS 0.40 vs. 0.25 (p=0.015) and relapse risk 0.05 vs. 0.24 (p=0.003). The probability to receive a SCT (autologous or allogeneic) was increased in IM+ pts. (72% vs. 54%), a difference that was statistically significant for allogeneic SCT (63% vs. 39%, p=0.04). In a cumulative analysis, patients receiving a SCT had the best outcome regardless of prior IM use (n=58; 5-years OS 0.49 and DFS 0.50), while in pts. unable to reach SCT outcome was slightly better in those exposed to IM (Figure). Forty CR pts. (28 IM+ and 12 IM-), were evaluable for minimal residual disease (MRD) response at weeks 10–22. PCR-negativity at weeks 10 and 16 was tendentially higher in IM+ group (32% and 37,5%) rather than IM- pts. (25% and 12,5%, p=ns).
This long-term update confirms that short IM pulses in combination with chemotherapy increased the rate of CR, reduced incidence of early failures, and allowed to increase the feasibility of SCT, with a marked outcome improvement. An allogeneic SCT appears the best consolidation option for Ph+ ALL. Display omitted
No relevant conflicts of interest to declare.
Abstract 2493
MRD is a powerful prognostic tool, increasingly adopted in adult ALL for a risk-oriented application of stem cell transplantation (SCT) in MRD-positive (MRDpos) patients. This policy ...gives the opportunity to assess the therapeutic value of allogeneic (or autologous) SCT in MRDpos patients, who are very unlikely to be cured by chemotherapy. In this study we reanalyze the long-term results of a prospective Northern Italy Leukemia Group trial (Bassan et al, Blood 2009;113:4153), aiming to determine which MRD levels were predictive of a better SCT outcome in MRDpospatients after induction/consolidation therapy.
MRD was evaluated molecularly using one or two patient-specific probe(s) with sensitivity of at least 10−4. In remission patients, bone marrow MRD was assessed after chemotherapy courses no. 3 (week 10), 4 (week 16) and 6 (week 22). In the original risk model, MRDpos was defined by a level of 10−4 or greater at week 16 and/or any positivity at week 22. For this analysis, MRD results from all three time-points were pooled, and the highest value registered in individual patients was used to identify the MRD-negative group (always MRDneg) and three other subsets characterized by increasing levels of residual leukemia (less than 10−4 MRDpos1, 10−4 and greater but less than 10−3 MRDpos2, 10−3 and greater MRDpos3. Survival, disease-free survival (DFS), and relapse incidence were assessed and compared among these MRD groups, as well as outcome following SCT in MRDpossubsets, and this in accordance with protocol design i.e. in patients having SCT at end of consolidation phase after completion of the MRD study.
Three-hundred and four patients with Ph- ALL were treated between 2000–2006 (median age 35 years, range 16–68; male gender 57%), of whom 258 (85%) entered complete remission. One or more sensitive probe(s)were available for 200 responsive patients (77.5%), of whom 141 completed consolidation and 59 did not because of elective early SCT in t(4;11)+ ALL (n=13), relapse (n=41) and toxicity (n=5). Of 141 evaluable patients, 136 completed the MRD study through weeks 10–22 (standard risk: 61 B-lineage and 14 T-lineage; high-risk: 41 B and 17 T; unspecified 3). Altogether, 64 patients were reclassified MRDneg (47%), 21 MRDpos1 (15.5%), 17 MRDpos2 (12.5%) and 34 MRDpos3 (25%). With a minimum observation time of 4 years and a maximum close to 12 years, estimated 6-year survival, DFS and relapse rates were 72.5%, 64% and 36% in MRDneg, 56%, 57% and 32% in MRDpos1, 48.5%, 46% and 50% in MRDpos2 and 23.5%, 15% and 76% in MRDpos3 cohorts, respectively (all P values <0.0001). Of 72 MRDpos patients, 44 (61%) underwent SCT as per protocol design (allogeneic 26, autologous 18). Although 6-year DFS rate was improved after allogeneic SCT (42% vs 20% with autologous SCT, P=0.09), the most influential factor for posttransplantation outcome was MRD level (DFS 48% in MRDpos1–2 group n=25 vs 16% in MRDpos3 group n19, P=0.025), and the best overall result was obtained with allogeneic SCT in MRDpos1–2 group (DFS 60% n=15 vs 18% in MRDpos3 group n=11, P=0.08).
In this study different MRD levels measured at weeks 10–22 were associated with a progressively worse outcome in the four patient subsets defined by the highest individual value at three study time-points. However, about one half of MRDpos1–2 patients could be salvaged by SCT, and even more with allogeneic rather than autologous SCT. Because of the very poor SCT results in MRDpos3 group, patients with MRD levels of 10−3 and greater should receive further therapy and not proceed to SCT until the MRD signal is below the 10−3 cutoff.
No relevant conflicts of interest to declare.
Abstract 2573
In adult Ph- ALL two major risk groups are generally identified on account of patient age, presentation white blood cell (WBC) count, disease immunophenotype and genetics/cytogenetics, ...with 5-year overall and disease-free survival (OS, DFS) rates of approximately 50% in standard-risk (SR) and 30% in high-risk (HR) patients, respectively. Although the difference is significant, this classification reflects a static risk assessment and does not recognize increasingly important factors such as individual response dynamics (complete remission CR vs induction failure or early relapse; MRD course) and risk-oriented treatment decisions with or without stem-cell transplantation (SCT).
To evaluate dynamic risk factors in association with adherence to risk-oriented therapy as major determinants of outcome.
OS and DFS rates were reanalyzed according to MRD-related risk definitions and risk-oriented treatment steps in a prospective clinical trial (Bassan et al, Blood 2009;113:4153). Different risk and treatment subsets were identified according to (i) achievement of CR vs early failure due to induction death, early relapse or toxicity precluding the application of MRD/risk-oriented therapy according to trial design, and (ii) adherence to planned MRD/risk-oriented chemotherapy or SCT vs non-adherence unrelated to early failure. Outcome results were compared with those obtained using traditional SR and HR definitions.
Three-hundred and four patients with Ph- ALL were treated (age range 16–68 years, median 35 years; male 57%), of whom 258 (85%) entered CR and 18 and 28 proved refractory or died early, respectively. Among CR patients, 78 did not complete early consolidation and MRD study (50 relapse, 9 toxicity and 19 very HR to early SCT), while 144 did it and were allocated to MRD-oriented therapy and 36 without a sensitive probe for MRD analysis were allocated according to clinical risk class. Six-year OS and DFS were 44% (n=138) and 43% (n=122) in SR vs 28% (n=166) and 28% (n=136) in HR, respectively (P=0.0009). Instead, OS and DFS results according to early treatment response, completion of MRD study for risk re-stratification and adherence to MRD/risk-oriented therapy identified several distinct prognostic categories, in which survival, largely unrelated to age and clinical risk class, ranged from 0% at 2.8 mos. (early deaths) to 73% at 6–10 years (MRD-negative), as detailed in the table and figure.
In this study, long-term survival rates were about 50% in SR patients (MRD unknown), 70% in MRD-negative ones receiving chemotherapy, and 40%–50% in all those proceeding to allogeneic SCT because very HR, HR MRD unknown or MRD-positive. Therefore, using a risk/MRD-oriented strategy, the adherence to protocol design concurs to identify the patient subsets with the highest probability of cure. Display omitted
No relevant conflicts of interest to declare.
Since the landmark study of Omura et al. (Blood 1980;55:199), validating cranial irradiation as an adjunct to intrathecal (IT) methotrexate, no other randomized trial of CNS prophylaxis was performed ...in adult ALL. Although the risk of CNS relapse is now only 1-4%, irradiation contributes to cumulative CNS toxicity together with high-dose methotrexate/cytarabine (HD-M/A), or is logistically difficult, so that developing an effective radiation-free CNS prophylaxis remains an important clinical task. IT DepoCyte® (ITD) might be advantageous, the slow release of liposome-associated cytarabine allowing therapeutic concentrations in the cerebrospinal fluid for 14+ days. An open trial reported prohibitive CNS toxicity from ITD in 6/31 patients (Jabbour et al. Blood 2007;109:3214), but ITD to ITD and HD-M/A to ITD intervals were short (14 and 10 days, respectively) and no patient suffered from CNS relapse.
In a phase II randomized trial (ClinicalTrials.gov NCT-00795756) we evaluated toxicity and feasibility (as primary study endpoint) of ITD 50 mg in comparison with IT triple therapy (ITT: methotrexate 12,5 mg, cytarabine 50 mg, prednisone 40 mg). Stratification was by cell lineage and risk class. ITT was given on d1 of courses 1,2,4,6,8; d15 of courses 1,2,8; and d1 of maintenance cycles 2-5 (12x). ITD was given on d1 of courses 1,2,4,6,8; d15 of courses 1,8 (T-ALL only); and d1 of maintenance cycle 2 (6-8x). The shortest ITD to ITD interval was 14 days in T-ALL (courses 1-2 3x and 8 2x), otherwise it was 21 days between ITD and any prior/subsequent ITD and HD course. ALL therapy consisted of eight induction-consolidation courses followed by risk/minimal residual disease-oriented maintenance or stem cell transplantation (SCT). In HD courses 3,7 (M/A) and 5 (M/Asparaginase) M dosage was 2.5 g/m2 (Ph- B-ALL) and 5 g/m2 (T-ALL) up to 55 years, and A 2 g/m2. Imatinib was used with de-intensified chemotherapy in Ph+ ALL; selected high-risk subsets received early SCT.
Between 2007-12 201 total patients were enrolled and 141 randomized to ITT (n=73) or ITD (n=68). Median age was 42 years (range 18-68) and risk subsets (ITT/ITD) were SR-B 27.4%/29.4%; HR-B Ph- 26%/25%, Ph+ 23.3%/22.1%, SR-T 5.5%/5.9%, HR-T 17.8%/17.7%. Complete remission was 89% (n=65)/89.7% (n=61). Rates of actual v planned IT injections during induction-consolidation cycles 1-8, after removal of study losses (resistance, early death, SCT, toxicity and relapse), were ITT 374/415 (90.1%) v ITD 219/245 (89.3%) (P=0.76). Although toxicity/medical reasons caused 5 ITD patients to discontinue permanently the study v none in ITT arm (P=0.02), toxicity-driven omissions of IT therapy were marginally increased in ITD arm (29/415 6.9% v 24/245 9.8%; P=0.20). Neurologic toxicity occurred in 20 (27.4%) ITT v 36 (53%) ITD patients, respectively (P=0.002). According to NCI CTC grading (G), neurotoxicity episodes were GI 7 v 10 (P=0.36), GII 13 v 32 (P=0.003), GIII 4 v 12 (P=0.04), GIV 1 v 5 (P=0.12). GIII-IV neurotoxicity developed in 5/73 (6.8%) ITT patients v 10/52 (19.2%) and 5/16 (31.2%) B- and T-ALL ITD patients, respectively (P= 0.01), correlating in T-ALL with the second/third q14d ITD at courses 1,2,8 (4/5 patients, 5/6 episodes). Apart from reversible headache/radicular pain, the most serious toxicity occurred in 3 (4.1%) ITT patients (seizures 1; leukoencephalopathy 1; loss of consciousness 1) v 5 (7.3%) ITD patients (loss of consciousness 4, 1 with seizures; cerebral oedema/pseudotumor cerebri 1) (P=0.48). Four-year overall and disease-free survival were 54% and 52.2% v 58.9% and 47.7% in ITT and ITD arms, respectively, and relapse rate was 32.3% v 24.6% (all P=NS). In ITT arm there were 2 (3%) CNS and 2 (3%) combined CNS/marrow relapses. In ITD arm only one poorly compliant subject not given any HD course had an isolated CNS relapse (1.6%); no other patient had a CNS recurrence.
A radiation-free CNS prophylaxis with six spaced ITD in conjunction with HD-M/A may be feasible and at least as effective as other regimens. Excluding reversible headache/radiculitis, serious CNS toxicity was not significantly increased compared with ITT regimen, although some patients were forced to discontinue IT prophylaxis. The occasionally severe CNS toxicity prompts the investigation of a lower ITD dosage (25 mg), also to limit GI-II side effects, and the tighter schedule used in T-ALL should be abandoned because too toxic.
Bassan:Mundipharma Oncology; Sigma-Tau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Liposome-encapsulated cytarabine (DepoCyte®) used in a prospective phase II randomized trial of CNS prophylaxis in ALL. Masciulli:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo Osseo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Gallamini:Millenium: Consultancy. Marfisi:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency: Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore-Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Marchioli:Associazione Italiana Linfomi (AIL): Research Funding; Celgene: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Sigma-Tau: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Genzyme Olanda: Research Funding; AMGEN S.p.A.: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; Ospedali Riuniti di Bergamo: Research Funding; Novartis: Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Rambaldi:Italfarmaco: Honoraria; Sanofi: Honoraria; Novartis: Honoraria.
The impact of different treatment modalities and prognostic factors on the clinical course of primary thyroid diffuse large B-cell lymphoma (PTDLBCL) is still the subject of research. This study was ...conducted to clarify these clinical aspects of this disorder. The clinical parameters of 48 patients with PTDLBCL at time of diagnosis were comparable to those of previous studies. Patients underwent either radiotherapy (RT) ± surgery (SX), chemotherapy (CHT) alone or in combination with local treatments (RT or SX), or SX followed by CHT and RT. A 90% complete remission (CR) rate was observed among patients who underwent combined treatment modalities (CTM), compared to 76% among the others. The 5-year progression-free survival differed significantly between both groups (p = 0.028). Poor performance status and advanced age correlated with decreased survival. PTDLBCL is a curable disease prevalent in elderly patients. Combined treatment modalities were able to induce an elevated rate of CR, improving long-term survival in younger patients. However, the outcome in elderly patients still remains unsatisfactory.
Highlights • MRD positivity in ALL is a major risk factor for relapse and poor outcomes • We evaluated the impact of MRD levels before alloHSCT on outcomes of Ph+ ALL • Patients with measurable ...levels of MRD have a higher risk of relapse • Achieving a MRD negativity should be a prerequisite for successful alloHSCT
Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyer's ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often ...associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.
Abstract 2005
The dismal prognosis of AML patients undergoing allogeneic stem cell transplantation not in complete remission at time of conditioning poses challenging clinical decisions. In these ...patients, a recent, large retrospective analysis conducted by the CIBMTR showed that a myeloablative HCST can induce an overall 19% long term survival. Based on five adverse pretransplantation variables (first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics) this analysis allowed to set up a pre-HSCT score (from 0 to ≥3) able to identify four risk groups defining a 3-years overall survival (OS) probability ranging from 6% up to 42% (Duval M, JCO 2010). However, this CIBMTR analysis was limited to patients with the following characteristics: a) de novo AML or secondary AML to a previous MDS b) patients receiving a TBI or busulfan based myeloablative conditioning regimens (MAC) and a BM or PB derived stem cell graft. Here we report data obtained in Italy in a similar cohort of AML patients that also included those receiving a reduced-intensity conditioning (RIC) regimen and those grafted with a cord blood unit.
We retrospectively analyzed data reported to the GITMO registry by 20 Italian centers on 523 AML patients who underwent a first HSCT being not in complete remission (CR) at time of conditioning, between 1999 and 2010. The median age at HSCT was 47,6 years (18–72), the male/female ratio 50%. At diagnosis 71,5% were de novo AML, 23% were secondary to a previous MDS/CMML, while in 5,5% the AML was therapy related or secondary to a previous CMN. Before HSCT conditioning, patients were primary refractory (PIF) in 34%, in first or subsequent untreated relapse in 45% and 16%, respectively or an untreated MDS to AML evolution in 5%. Before HSCT, 79% of PIF received ≥2 chemotherapy cycles and for relapsed patients the duration of the first CR was < 6 months in 50%. An intermediate-II or adverse karyotype was detected in 43% of patients, a greater than 25% marrow blast infiltration or any level of peripheral blood (PB) blasts was found in 53% and a pre-HSCT Karnofsky score less than 90 was present in 38%. The stem cell source was the PB in 65%, the bone marrow in 28% and the cord blood in 6%. Donors were HLA identical sibling or matched unrelated donor in 69%, a family or unrelated mismatched in 25% and a cord blood unit in 6%. Anti-CMV antibodies were present in 87% of patients and in 66% of the donors, while donor-recipient pair were sex-matched in 50% of the cases. More than 60% patients received a MAC and 37% a RIC program.
After HSCT, a myeloid and platelets engraftment was achieved in 87% of patients after a median of 17 (9–63) and 18 (2–117) days, respectively. Acute GVHD (grade ≥2 60%) was registered in 46% while chronic GVHD developed in 31%. The median follow up of the whole patients cohort was 5,36 months (0.09–133) while that of survivors was 26 months (1–133) with 96 patients alive and 77 leukemia-free. A multivariate analysis identified 7 pre-HSCT adverse variables that significantly influenced survival: an AML secondary to a previous chronic myeloproliferative neoplasm or a therapy related AML (HR 1,83, 95%CI 1,14–2,96, p 0,013), a relapsed AML with a first CR duration < 6 months (HR 1,39, 95%CI 1,06–1,82, p 0,018), an AML with a PIF after ≥2 chemotherapy cycles pre-HSCT (HR 1,74, 95%CI 1,11–2,74, p 0,016), an intermediate II/adverse cytogenetics (HR1,71, 95%CI 1,11–2,62, p 0,015), BM blasts ≥25% or any level of PB at HSCT (HR 1,65, 95%CI, 1,31–2,07, p 0.000) and a mismatched related/unrelated donor (HR 1,56, 95%CI, 1,23–1,98, p 0.000). At 3-years, the OS and LFS of our patients was 16% and 21%. Interestingly, when applied to our results, the CIBMTR score was fully validated in our patients with a 3-year survival rate decreased from 40% (score 0, HR1) to 26% (score 1, HR 1,39; 95%CI 0.88–2,12, p 0,142), to 18% (score 2, HR 1,58; 95%CI 1–2,43, p 0,04) to 5% (score 3, HR 2,83; 95%CI 1,71–4,16, p 0,000) (Figure 1).
Our results confirm that a) HSCT is a potentially curative option for a significant proportion of AML patients undergoing transplant not in remission, b) these patients may benefit from either a MAC or a RIC conditioning regimens and c) the CIBMTR score applied to this poor prognosis AML cohort is a useful tool for patient counseling and for planning the HSCT activity. Display omitted
No relevant conflicts of interest to declare.
Abstract 1494▪▪This icon denotes a clinically relevant abstract
Burkitt lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL) are very aggressive malignancies with poor prognosis unless ...treated with highly specific intensive programs. The German Multicenter Study Group for Adult ALL piloted a short intensive rituximab (R)-chemotherapy program that improved outcome compared to the prior regimen (Hoelzer et al, Blood 110:abstr 518, 2007). The Northern Italy Leukemia Group adopted the same protocol to treat 105 consecutive, unselected adult patients with BL and B-ALL.
To assess long-term outcome and toxicity according to pre-therapy risk factors predominantly identified by higher age and/or performance status (PS) according to the Eastern Cooperative Oncology Group score.
Between December 2002 and June 2010, 55 BL (stage III-IV 53%, bulky 45%, extranodal involvement 64%) and 50 B-ALL patients were treated. Median age was 47 years (range 17–78), 31% were >55 years, 15% had a PS >2, and 15% were HIV+. Treatment consisted of 6 R-chemotherapy courses (4 in stage I-II disease without mediastinal/extranodal involvement), two additional R doses at completion of chemotherapy and local radiotherapy in case of mediastinal/CNS disease or residual tumor. R-chemotherapy blocks were as follows: A) prednisone-cyclophosphamide prephase (course 1 only), R plus dexamethasone, vincristine, ifosphamide, HD-methotrexate, teniposide or etoposide, Ara-C, intrathecal therapy IT; B) R plus dexamethasone, vincristine, cyclophosphamide, HD-methotrexate, adriamycin, IT; C) R plus dexamethasone, vindesine, HD-methotrexate, etoposide, HD-Ara-C. The A-C sequence was repeated once. Patients aged >55 years received only courses A and B with methotrexate 0.5 g/m2.
Eighty-three total patients (79%) achieved CR, 8 were refractory and 14 died of complications. All early deaths occurred in patients older than 40 years, correlated with stage III-IV BL or B-ALL (n=13), PS ≥1 (n=10), and were mainly caused by infections. Among CR patients, 67 (81%) received all planned therapy and 16 did not (toxicity/CR death 11, early relapse 3, other 2). The mean intercycle time (MIT) between chemotherapy courses was 29 days (range 22–52). After a median follow-up of 23.8 months (range 0.7–99), 65 patients (61%) were alive in 1st CR, 19 (18%) died of complications (7 in CR, including 2 late deaths due to secondary AML and cardiovascular accident), and 19 had refractory or recurrent disease. Ten of 67 patients treated with MIT >25 days relapsed within 6 months (15%), compared to one of 15 treated with MIT ≤25 days (7%, P=.34). Projected 3-year overall and disease-free survival and were 67% (OS) and 75% (DFS), respectively. In univariate analysis age, normal LDH, ECOG PS <2 and lack of CNS involvement were favorable prognostic factors, whereas MIT was of borderline significance. In multivariate analysis, age and PS were highly predictive for OS and DFS. In a cumulative analysis, patients aged >55 years with PS ≥1 had the worst outcome (n=24; OS 28% and DFS 36%), those with PS=0 fared as well as patients aged ≤55 years with PS=0–1 (n=55; OS 89% and DFS 89%) and the younger patients with PS >1 represented an intermediate-good risk category (n=26; OS 61% and DFS 77%) (P=.0000). The incidence of TRM and relapse varied significantly among the 3 groups, each contributing almost equally to the final outcome.
The excellent therapeutic potential of this treatment (89% cure rate) was confirmed in patients with PS=0, regardless of age, and in younger patients with PS=0–1, whereas the results were still good, though significantly inferior, with PS >1 (61% cure rate). Prompt diagnosis and referral of BL and B-ALL patients is essential for exploiting the prognostic advantage associated with a better PS, together with maximized anti-infectious measures and rapid re-cycling of chemo-immunotherapy blocks.
No relevant conflicts of interest to declare.
•This study included 441 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent hematopoietic stem cell transplantation (HSCT) in the last 10 years.•All patients ...received tyrosine kinase inhibitor-based treatment before HSCT.•The probability of overall survival (OS) at 2, 3, and 5 years from HSCT was 61%, 52%, and 50%, respectively.•Patients who were minimal residual disease-negative both at HSCT and at 3 months after HSCT had the best prognosis (5-year OS, 70%).•The nonrelapse mortality (NRM) at 5 years was 24%, and the evaluation of modified EBMT risk score can predict NRM.
We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatment
A total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph+ ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval CI, 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph+ ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph+ ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).
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