Prolonged Survival of Lymphoma Patients Achieving Complete Remission Following High-Dose Sequential Chemotherapy and Autograft (HDS Program): A GITIL (Gruppo Italiano Terapie Innovative Nei Linfomi) Retrospective Study on 1,266 Patients.

Abstract Introduction. The high-dose sequential (HDS) chemotherapy approach is characterized by early dose-intensification followed by autograft with peripheral blood progenitor cells (PBPC). The HDS program was introduced several years ago (Gianni & Bonadonna, 1989); subsequently, it has been increasingly used in the management of both non-Hodgkins (NHL) and Hodgkins Lymphoma (HL). The outcome of a large series of lymphoma patients treated with the HDS approach at 10 Centers associated to GITIL is reported. Patients and Methods. Data have been collected on 1,266 patients, who received either the original or slightly modified HDS regimens. There were 213 HL and 1,053 NHL patients (630 intermediate/high-grade, 423 low-grade); median age was 46 yrs, 57% were male. Overall, 671 (53%) patients received HDS as salvage treatment after one or more recurrence; 595 (47%) had HDS front-line, either for high-risk clinical presentation or unfavorable histology, i.e. mantle-cell l. Most patients were autografted with PBPC, few received BM cells (alone or with PBPC); 158 (12%) patients did not undergo autograft, due to several reasons, namely: toxicity, disease progression, poor harvests. Results. Overall, 1,013 (80%) patients reached Complete Remission (CR) following the HDS program. Up to now, 93 (7%) patients died for early/late toxicities, 328 (26%) died for lymphoma, 844 are known to be alive; at a median follow-up of 5 yrs, the 5-yr Overall Survival (OS) projection is 64% (s.e. 2%). As shown in Figure 1 A and B, a significantly higher survival was observed in patients receiving HDS at diagnosis vs. those at relapse and in those achieving CR vs. no CR patients. On multivariate Cox survival analysis, these two parameters maintained a significant impact on the 5-yr survival (relapse status at HDS: HR 1.39, c.i.: 1.12–1.72; CR achievement: HR 0.12, c.i.: 0.10–0.16). Also some histological features (low grade vs intermediate/high; B-cell vs. T-cell) had a significant impact on OS, whereas other parameters, including sex, bone marrow involvement, HL vs NHL, use of hd-Ara-C, had no relevance. Conclusions. the HDS program including PBPC collection and re-infusion is feasible in a multicenter setting and allows prolonged survival in a good proportion of lymphoma patients presenting with unfavorable prognosis; the long-term outcome is definitely good in patients achieving CR; given their poor outcome, early salvage treatment options, including allogeneic transplant, should be considered for those patients unable to reach CR following a HDS treatment approach. Figure 1. OS according to status at HDS ( A ) and response following HDS ( B ) in 1,266 high-risk lymphoma patients Figure 1. OS according to status at HDS ( A ) and response following HDS ( B ) in 1,266 high-risk lymphoma patients

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Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8123 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8123-8123

Author(s):

C. Tarella ◽

M. Zanni ◽

A. Rambaldi ◽

F. Benedetti ◽

R. Passera ◽

...

Keyword(s):

Complete Remission ◽

High Dose ◽

Low Grade ◽

High Grade ◽

Term Outcome ◽

Term Survival ◽

Long Term Outcome ◽

Long Term Survival

8123 Background: The high-dose sequential (HDS) chemotherapy approach, including early dose-intensification and autograft with peripheral blood progenitor cells (PBPC), was introduced several years ago (Gianni & Bonadonna, 1989); subsequently, it has been broadly used in the management of both non-Hodgkin s (NHL) and Hodgkin s Lymphoma (HL). The outcome of a large series of lymphoma patients treated with the HDS approach at 10 GITIL Centers is reported. Methods: Data have been collected on 1,266 patients, who received either the original or slightly modified HDS regimens. There were 213 HL and 1,053 NHL (630 intermediate/high-grade, 423 low-grade); median age was 46 yrs. Overall, 671 (53%) patients had refractory/relapsed disease, 595 (47%) were at diagnosis. Most patients were autografted with PBPC; 158 (12%) patients did not undergo autografting due to toxicity, disease progression or poor harvests. Results: Overall, 1,013 (80%) patients reached Complete Remission (CR) following HDS. As to December 2006, 93 (7%) patients died for early/late toxicities, 328 (26%) died for lymphoma, 844 are known to be alive. At a lead follow-up of 18 years, and a median follow-up of 5 yrs, the 5-yr Overall Survival (OS) projection is 64% (S.E.: 2%). The long-term survival was quite favorable in patients achieving a Complete Remission (CR), with a 5-yr OS projection of 76%. The prolonged OS in patients achieving CR was consistent in all lymphoma subtypes, i.e. both low and high-grade NHL (5-yr OS: 77% in both), and HL (5-yr OS: 72%). Patients at diagnosis had a significantly better outcome compared to patients treated for relapsed/refractory disease, again CR achievement was associated with prolonged survival in both subgroups (82% and 69%, respectively, at 5 yrs.). On multivariate Cox survival analysis, CR achievement was the most powerful predictor of long-term survival (HR 0.13, c.i.: 0.10–0.17). Lastly, achieving substantial tumor reduction before autografting had a major influence on the clinical outcome. Conclusions: 1. the HDS program is feasible in a multicenter setting; 2. the long-term outcome is well influenced by the CR status after HDS; 3. the influence of CR achievement on the long-term survival holds true in all lymphoma subtypes, including indolent lymphomas; 4. an adequate pre-autograft tumor debulking may contribute to a favorable long-term outcome. [Table: see text]

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Benefit of Rituximab Addition to High-Dose Programs with Autograft for B-Cell Lymphoma: A Multicenter GITIL Survey on 957 Patients.

Blood ◽

10.1182/blood.v108.11.207.207 ◽

2006 ◽

Vol 108 (11) ◽

pp. 207-207 ◽

Cited By ~ 3

Author(s):

Corrado Tarella ◽

Manuela Zanni ◽

Michele Magni ◽

Fabio Benedetti ◽

Tiziano Barbui ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

Low Grade ◽

High Grade ◽

Term Outcome ◽

Long Term Outcome ◽

Prognostic Features

Abstract Background: The outcome of B-cell lymphoma has definitely improved since the introduction of the anti-CD20 Rituximab, which can be effectively combined into conventional chemotherapy regimens. Rituximab can also be added to high-dose chemotherapy programs with autograft. However, the clinical benefit of combining Rituximab and autograft-based programs has not been proved yet. This issue is addressed in the present study. Patients and Methods: Data have been retrospectively collected on 957 B-cell lymphoma patients receiving a high-dose sequential (HDS) chemotherapy program, at 10 Italian Centers associated to GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Although the HDS schedule has been introduced almost 20 yrs. ago, most patients were treated in the last decade. They received most frequently either the HDS scheme adapted for follicular lymphoma (Tarella C et al. Leukemia 2000) or the hd-Ara-C-supplemented scheme developed for mantle-cell and diffuse large cell lymphoma (Magni M et al, Blood 2000; Cuttica A et al., Cancer 2003); overall, Rituximab was added to HDS (R+) in 483 (50.5%) patients, the remaining 474 (49.5%) received Rituximab-free HDS (R−). All patients entered the HDS-protocols due to high-risk prognostic features, their median age was 49 yrs. (range 17–70). The series included 403 patients (232 R+) with low-grade and 554 (251 R+) with intermediate/high grade B-cell lymphoma subtypes; HDS was delivered to 542 (259 R+) patients at diagnosis and to 415 (224 R+) at first or subsequent relapse. Results: at a median follow-up of 5 yrs, the 5-yr Overall Survival (OS) and Event-free Survival (EFS) projections were 66% and 55%, respectively, with a significantly better outcome for patients treated at diagnosis (5-yr OS: 72%, EFS: 61%) compared to patients at relapse (5-yr OS: 56%, EFS: 45%). In all instances, Rituximab addition was associated with significant improvements; in particular, the 5-yr EFS projections were:patients at diagnosis: 68% for R+ vs. 57% for R−;patients at relapse: 59% for R+ vs. 34% for R−;low-grade subtypes: 65% for R+ vs. 41% for R− (Figure 1A);intermediate/high-grade subtypes: 64% for R+ vs. 52% for R− (Figure 1B). In the Cox multivariate survival analysis, two factors had a significant impact on the EFS, i.e. relapse status at HDS (HR: 1.74, c.i.: 1.43–2.13) and Rituximab addition to HDS (HR: 0.60, c.i.: 0.49–0.75). Conclusions: the addition of Rituximab to high-dose programs with autograft may improve response and long-term outcome in high-risk B-cell lymphoma patients. Figure 1. EFS according to Rituximab [R] administration, in (A) low-grade and (B) intermediate/high-grade, B-cell lymphoma patients treated with a HDS program Figure 1. EFS according to Rituximab [R] administration, in (A) low-grade and (B) intermediate/high-grade, B-cell lymphoma patients treated with a HDS program

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Long-Term Outcome of High-Dose Sequential Chemotherapy with Autografting (i-HDS) in Follicular Lymphoma at Diagnosis: An Update of the Prospective Multicenter Consecutive Trial of the "Gruppo Italiano Trapianto Di Midollo Osseo" (Gitmo).

Blood ◽

10.1182/blood.v104.11.903.903 ◽

2004 ◽

Vol 104 (11) ◽

pp. 903-903

Author(s):

Marco Ladetto ◽

Sonia Vallet ◽

Paolo Corradini ◽

Fabio Benedetti ◽

Umberto Vitolo ◽

...

Keyword(s):

High Risk ◽

Residual Disease ◽

Elevated Serum ◽

Stage Iv ◽

Experimental Treatment ◽

High Dose ◽

Term Outcome ◽

Long Term Outcome ◽

Treatment Implementation

Abstract Introduction. i-HDS is a promising though experimental treatment for FL patients at diagnosis. We have published that i-HDS is feasible also in the context of a multicenter trial with limited toxicity and promising results (Ladetto et al, Blood, 2002). This analysis is an update at 42 months from the previous closing date. Particular attention has been devoted to late toxicities and outcome according to molecular remission (MR). Patients and methods. 92 untreated patients aged 18–60 years with stage III-IV FL requiring treatment were enrolled by 20 Italian centers between 1997 and 1999 and evaluated on an intention-to-treat basis. Inclusion criteria have been previosly described. Clinical features at diagnosis were: Ann Arbor stage IV: 84%; BM involvement: 80%; extranodal and extra-BM disease: 55%; bulky mass: 51%; elevated serum LDH: 37%; "B" symptoms: 30%; leukemic disease: 12%; aaIPI ≥ 2: 37%. The i-HDS schedule included 2APO, 2DHAP, Etoposide 2g/sqm, Methotrexate 8g/sqm and Cyclophosphamide 7g/sqm with PBPC collection. The myeloablative regimen was Mitoxantrone 60mg/sqm + Melphalan 180mg/sqm followed by 5–8x106 CD34+ cells/kg. Minimal residual disease analysis with the bcl-2/IgH rearrangement was available in 47% of patients. Results: 87% of patients completed the planned treatment. CR rate was 88%. Currently the median follow-up is 62 months. Late toxic effects included five myelodysplastic syndromes and /or secondary leukemias (MDS/2AL) all occurring within two years from the end of treatment. In 4 of 5 cases MDS/2AML occurred in subjects already re-treated for disease relapse. Two fatal solid tumors (one gastric cancer and one lung cancer) were also recorded. Long-term hematopoietic fuction was satisfactory in all patients not developing MDS/2AML. Heart failure occurred in three patients, always manageable with oral medical treatment. The projected overall survival and progression-free survival (PFS) at 7,5 years are 74% and 56%. Notably, following i-HDS, patients with aaIPI≥2 had an outcome comparable to those with aaIPI ≤ 1 (p=NS). Attainement of MR in the first year following i-HDS was highly predictive even for the long term outcome. Among patients achieving MR the relapse rate (RR) was 13% while in those failing to achieve MR was 81% (p<0001). Conclusions. This long-term analysis indicates the following: a) i-HDS allows long-term PFS in 56% of advanced FL patients regardless of the aaIPI. This result compares favorably with those achieved with Rituximab-free non-intensified therapy at least for high-risk patients; b) MR achievement is a powerful indicator for prolonged PFS; c) although severe side effects occurred in this series, relapse remains the major cause of treatment failure. Thus, treatment implementation is required. Rituximab inclusion is probably one of the most feasible approaches, suitable for multicenter trials. The new GITMO trial, comparing CHOP vs i-HDS (both supplemented with Rituximab), currently ongoing for high-risk (aaIPI≥2) FL patients, will help clarifying wheter dose-intensification has still a role in the monoclonal antibody era.

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Reduced-Intensity Conditioning (RIC) Followed by Allogeneic Stem Cell Transplantation (SCT) for Relapsed Lymphomas: Impact of Pre-Transplantation Factors on Long-Term Outcome.

Blood ◽

10.1182/blood.v106.11.1129.1129 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1129-1129 ◽

Cited By ~ 1

Author(s):

Paolo Corradini ◽

Anna Dodero ◽

Marco Bregni ◽

Fabio Ciceri ◽

Attilio Olivieri ◽

...

Keyword(s):

Stem Cell ◽

Complete Remission ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Univariate Analysis ◽

Low Grade ◽

Term Outcome ◽

Long Term Outcome ◽

The Impact

Abstract Allogeneic stem cell transplantation (SCT) represents a potentially curative treatment for recurrent lymphoid malignancies. In fact, potential advantages include the use of a tumor free graft and immune-mediated graft-versus-lymphoma effect. Here, we analyzed the impact of pre-transplantation factors on outcome in 141 lymphoma patients (pts) receiving RIC and allogeneic SCT from HLA-identical sibling donors. Histologic types included in the study were: low-grade non-Hodgkin lymphoma (LG-NHL; n=58), high-grade NHL (HG-NHL, n=55), Hodgkin disease (HD; n= 28). Median age was 50 years (range: 20–69). The three groups (HD vs LG-NHL vs HG-NHL) had similar characteristics in terms of: chemosensitive disease (57% vs 69% vs 67%, p=ns) and complete remission (CR) at transplant (18% vs 27% vs 34%, p=ns). Pts with HD had received more lines of chemotherapy (>2 vs ≤2) as compared to LG-NHL and HG-NHL (82% vs 52% vs 42%). Furthermore, the proportion of pts receving previous autologous SCT was significantly higher in HD and HG-NHL versus LG-NHL (75% vs 54% vs 27%). In addition, patients with HG-NHL and HD underwent frequently allo-SCT less than 2 years after diagnosis as compared to LG-NHL (58% vs 39% vs 24%). All patients received debulkying chemotherapy followed by the same RIC containing thiotepa (10 mg/kg), fludarabine (60 mg/ms) and cyclophosphamide (60 mg/kg). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. At a median follow-up of 30 months (8–70), the overall survival (OS) and progression-free survival (PFS) were 65% (95%CI, 56–74%) and 57% (95%CI, 47%–67%), respectively. Univariate analysis showed that age (< or > 55 years), donor sex, interval between diagnosis and SCT, number of previous treatments did not influence outcome whereas diagnosis of HD was associated with a significant inferior PFS and OS. Chemosensitive disease (CR+PR) influenced PFS in HG-NHL (p<0.0003) and HD (p<0.0036) but not in LG-NHL (p=0.69). Complete remission at transplant was associated to a significant better PFS in HD (p<0.01) but not in HG-NHL (p= 0.14) and LG-NHL (p=0.7). Previous autologous SCT was associated to inferior PFS (64% vs 50%, p<0.04) but did not affected OS and TRM. By multivariate analysis, diagnosis of HD and refractory disease were associated to an inferior PFS (p<0.0001, p<0.001) whereas diagnosis of HD and no-CR at transplant remained of prognostic value on OS (p<0.006 and p<0.007). We conclude: 1) age and previous treatments, including autologous SCT, are no longer limitations for allogeneic SCT; 2) debulking therapy before RIC allogeneic SCT is required for HD and HG-NHL; 3) new strategies for an early indentification of chemorefractory pts are necessary.

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Improved Outcome of Adult Acute Lymphoblastic Leukemia Treated with Individualized Protocol Adjusted to the Status of Minimal Residual Disease and Age. Interim Analysis of PALG ALL 5–2007 Study

Blood ◽

10.1182/blood.v116.21.2138.2138 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2138-2138

Author(s):

Sebastian Giebel ◽

Jerzy Holowiecki ◽

Malgorzata Krawczyk-Kulis ◽

Krystyna Jagoda ◽

Jaroslaw Piszcz ◽

...

Keyword(s):

High Risk ◽

Minimal Residual Disease ◽

Bone Marrow Cells ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Term Outcome ◽

Long Term Outcome ◽

Minimal Residual ◽

Improved Outcome

Abstract Abstract 2138 In a previous study by the Polish Adult Leukemia Group (PALG 4–2002) we demonstrated that status of minimal residual disease (MRD) during induction-consolidation is the most important factor predicting long-term outcome of adult ALL (Br J Haematol 2008). In a new PALG 5–2007 protocol the treatment was intensified for patients with MRD level >0.1% of bone marrow cells and adjusted to age. Induction consisted of Epirubicine(4×), Vincristine(4×), Prednisone and PEG-asparaginase. Patients with complete remission (CR) but MRD >0.1% obtained additional 2nd phase of induction: AraC+Cyclophosphamide(Ctx) + 6MP. Consolidation consisted of 2 courses of Methotrexate(Mtx) + Etoposide + Dexamethasone and subsequent 2 cycles of Ctx + high dose AraC, asparaginase, intrathecal prophylaxis and CNS irradiation. Doses of Mtx were 500 mg/m2 for patients with MRD<0.1%, aged >35y and 1500 mg/m2 for all remaining ones. For Ph+ ALL imatinib 600 mg/d was administered in parallel to chemotherapy. Patients with standard risk disease continued with 2 years maintenance while those with high-risk were referred for alloHSCT. High risk was defined as the presence of at least one of: initial WBC >30×10e9/L, age >35y, pro-B, early-T, mature-T, late CR, t(9;22), t(4;11) or MRD >0.1% at any time during induction-consolidation. Results of PALG 5–2007 protocol (N=108, median age 32y, range 16–55y) were compared to PALG 4–2002 (N=253, age 28y, range 16–55y), in which MRD status was not taken into account for treatment decisions. CR rate was 92% for PALG 5–2007 compared to 89% for PALG 4–2002. The probability of the overall survival at 36 months was 56% vs. 33% (p=0.02), while leukemia-free survival was 53% vs. 28% (p=0.04), respectively. The probability of relapse decreased from 54% in PALG 4–2002 to 16% in PALG 5–2007 (p=0.002). In a multivariate analysis adjusted to age, initial WBC and the presence of t(9;22) treatment according to PLAG 5–2007 protocol was associated with decreased risk of mortality (HR=0.57, p=0.02), relapse (HR=0.37, p=0.006) and treatment failure (HR=0.64, p=0.049). We conclude that individualized therapeutic approach with treatment intensity adjusted to MRD status and age may result in improved outcome of adults with ALL. *This multi-institutional study was supported by Polish Ministry of Sciences Grant NN-402366433 Disclosures: Off Label Use: Dasatinib as first line therapy in Ph ALL.

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