Dexamethasone, Cytarabine and Cisplatin or Oxaliplatin Schedule (DHAP or Ox-DHA) Is Effective and Widely Applicable in Chronic Lymphocytic Leukemia and Waldenström Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3434-3434
Author(s):  
Marco Ruella ◽  
Irene Ricca ◽  
Angela Gueli ◽  
Daniela Gottardi ◽  
Daniele Caracciolo ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Hematological Toxicity ◽  
High Dose ◽  
Main Concern ◽  
Low Grade ◽  
First Line ◽  
Salvage Regimen

Abstract Abstract 3434 Poster Board III-322 Introduction Fludarabine alone or in combination is considered the standard treatment for Chronic Lymphocytic Leukemia (CLL). A high response rate is usually observed following fludarabine, particularly if delivered together with rituximab. In spite of the high therapeutic efficacy, most patients subsequently relapse. For these patients there are no defined salvage treatments. Moreover, fludarabine-containing regimens may have some restrictions due to non-negligible side effects. In particular, there are some concerns in employing fludarabine first-line in patients with autoimmune hemolytic anemia (AHA) or with renal function impairment. In addition, fludarabine has been reported to compromise the capacity of progenitor cell mobilization. Thus, novel effective treatment approaches are needed, for the management of patients failing after fludarabine-based regimens and for those unfit to receive fludarabine first-line. A very effective salvage regimen for refractory/relapsed lymphoproliferative disorders is the DHAP combination. DHAP has been widely used in the rescue of both low-grade and high-grade lymphoma. However, its efficacy in CLL has not been verified yet. The main concern with DHAP is the well known renal toxicity of cisplatin. However, the use of the less toxic analog Oxaliplatin, might circumvent this problem. Indeed, recent reports have shown that the inclusion of oxaliplatin into the original DHAP regimen (Ox-DHA) markedly improves the tolerability and widens regimen applicability. Aim: To evaluate retrospectively feasibility and efficacy of the DHAP and Ox-DHA regimens in CLL and in other non-follicular low-grade lymphomas, in particular in Waldenström Macroglobulinemia (WM). Patients and Methods Between 2002 and 2008, 84 low-grade lymphoma patients received DHAP or Ox-DHA; their median age was 60 yrs. (range: 24-84), 58 were male; 70 patients had CLL with advanced stage (65 patients with Binet stage B and C) and 14 had WM. Thirty-eight patients were treated at first relapse, 27 at second or subsequent relapse, whereas 19 received the DHAP or Ox-DHA schedule as first-line treatment, in place of Fludarabine, due to: i. AHA (3 patients), ii. concomitant second malignancy (4 cases), iii. need of initial debulking, before a high-dose program with autograft. The original DHAP schedule requires hospitalization for three to five days; it includes: Cisplatin 100 mg/sqm on day 1, Cytarabine 2 g/sqm/b.i.d. every 12 hrs. on day 2, Dexamethasone 40 mg days 1-4. Ox-DHA can be delivered in the outpatient setting, compared to DHAP, there are two main modifications: Oxaliplatin 100 mg/sqm in two-hr i.v. infusion on day 1, and Cytarabine 2 g/sqm two doses delivered in two consecutive days (day 2 and day 3). Rituximab (375 mg/sqm) was added in 12 DHAP and 28 Ox-DHA courses. Patients aged over 70 yrs had variable dose reductions (25% to 50%). Results Ox-DHA had hematological toxicity analogous to that commonly observed with the original DHAP schedule; 11 patients required short hospitalization for severe infectious complications; 7 patients developed fever of unknown origin, 4 showed reversible peripheral neurotoxicity. The program was discontinued in four patients due to disease progression (3 patients) and AHA (1 case). There were no severe liver or renal toxicities. No toxic deaths were recorded. The overall response (OR) rate was 90%; in details, complete remission (CR), or very good partial remission (VGPR), was achieved in 41% of patients receiving DHAP without rituximab and 50% of those receiving DHAP supplemented with rituximab. In the Ox-DHA group, 50% of patients treated without rituximab and 75% of those treated with rituximab reached CR or VGPR. Among patients treated at diagnosis, overall 47% reached CR or VGPR and 42% reached partial remission (PR). The OR rate was unexpectedly high at 91% in patients treated for refractory/relapsed disease, with 66% of them achieving CR/VGPR (74% and 55% for patients at 1st and ≥ 2nd relapse, respectively) and 35% PR. Among 14 WM patients, 1 obtained a CR, 5 a VGPR, 6 a PR and 2 had a stable disease. Conclusions Dexamethasone, Cytarabine and Cisplatin or Oxaliplatin schedule is a well tolerated regimen, highly effective both front-line and in the rescue for relapsed/refractory disease in CLL and WM patients. Future clinical trials will define the real efficacy of the DHAP or Ox-DHA regimen in the management of CLL and WM patients. Disclosures No relevant conflicts of interest to declare.

The Fate of Chronic Lymphocytic Leukemia Patients After Failure of Fludarabine, Cyclophosphamide, and Rituximab Regimen

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4603-4603
Author(s):  
Anna Panovska ◽  
Daniel Lysák ◽  
Lukas Smolej ◽  
Yvona Brychtova ◽  
Martin Simkovic ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Treatment Option ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Group 2 ◽  
Group 1

Abstract Abstract 4603 Background: The clinical course of patients with chronic lymphocytic leukemia (CLL) is remarkably heterogeneous. All CLL patients who require therapy are destined to relapse. The prognosis and management of these relapsed patients differs based on the nature of the first-line therapy and the quality and duration of remission to that therapy, as well as biological prognostic factors. Currently, the first treatment option for younger and fit CLL patients is FCR (fludarabine, cyclophosphamide, rituximab) chemoimmunotherapy. Although it regards a very potent treatment option, patients inevitably relapse after the treatment and even approximately 7% of the patients, during initial FCR regimen treatment would fit the standard definition of refractory CLL. So far, little is known about the efficacy of subsequent therapy of patients who relapsed after FCR or were refractory to FCR. Therefore, the goal of this study was to analyze the fate of these patients in the context of routine hematological practice. Methods: We retrospectively analyzed the data of 119 patients (85 males; 34 females) consecutively entered into the databases of three large tertiary Czech hematological centers. All patients were indicated to receive FCR regimen in standard doses (F: 25mg/m2i.v. day 1–3; C: 250mg/m2i.v. day 1–3; R: 375mg/m2i.v.day 0 cycle 1, and 500mg/m2day 1 of all subsequent cycles). Results: The median age was 57 years (range, 31–75) at the time of the CLL diagnosis, and 60 years (range, 32–78) at the start of FCR therapy. The median follow-up was 42 months (range, 3–114). Our cohort of patients consisted of two groups of patients which received the FCR regimen as first-line therapy (Group 1; n=63) and patients receiving FCR in second or subsequent line of treatment (Group 2; n=56). With respect to the basic parameters (age, clinical stage, FISH cytogenetics, molecular genetics), the statistics of these groups did not differ significantly. In Group 1, the overall response rate (ORR) was 84%, in Group 2, 78% (p=ns) after FCR. Complete remission (CR) rate was 53% in Group 1, and 38% in Group 2 (p=0.04). The median progression-free survival (PFS) was 18.6 months for Group 1 and 14.7 months for Group 2 (p=ns). With subsequent therapy (repeated FCR, alemtuzumab, R-CHOP, rituximab plus high-dose corticosteroids) for relapsed disease after FCR, ORR was 59% in Group 1 (33% CR) and 44% in Group 2 (21% CR) (p=ns). PFS after subsequent therapy after FCR was 13.3 months (Group 1) and 5.9 months (Group 2) (p=0.01). The median OS was insignificantly shorter in Group 2 (44.5 months in Group 2 vs. not reached in Group 1; p=ns). After FCR therapy, there was no statistically significant change in cytogenetic findings, however, new occurrence of 17p deletion was observed in 5 patients. Prior to FCR therapy and during relapse after FCR, the p53 function was analyzed in 37 patients. After FCR, the new mutation of p53 was newly found in 6 patients (16%). These patients received a higher cumulative dose of FCR than the patients who did not develop the mutation (F 591 mg vs. 334 mg; C 5072 mg vs. 3375mg; R 3700mg vs. 2000 mg) (p=ns). Conclusion: Subsequent treatment for patients who relapse after FCR or are FCR refractory is very heterogeneous. Regardless of the type of therapy selected, the prognosis of these patients is poor. In addition, new p53 mutations/deletions occur after FCR. Disclosures: No relevant conflicts of interest to declare.

Comparative Efficacy of First-Line Chemotherapy-Free Combinations in Chronic Lymphocytic Leukemia (CLL): A Network Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Philip A Haddad ◽  
Nowell Ganey ◽  
Kevin M. Gallagher
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
English Language ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Meta Analysis ◽  
The Elderly ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Significant Difference ◽  
Anti Cd20

Introduction: Chronic Lymphocytic Leukemia (CLL) is an incurable B-cell malignancy which disproportionately affects the elderly. Although first-line chemoimmunotherapy (CIT) improved CLL clinical outcomes, recent randomized trials revealed superior outcomes with novel chemotherapy-free combinations (CFC) incorporating anti-CD20 monoclonal antibodies and inhibitors of BTK or Bcl-2. So far, these CFC have not been compared head-to-head. We conducted this network meta-analysis to evaluate their relative efficacy to each other. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of CLL; trials that explored the efficacy of first-line CFC with Obinutuzumab (O), Rituximab (R), Ibrutinib (IB), Acalabrutinib (ACAL), Venetoclax (VEN) compared to standard CIT that included Chlorambucil (CHLOR) with either R or O, Bendamustine+Rituximab, or Fludarabine+ Cyclophosphamide+R; and phase 3 randomized studies reporting responses, progression, death, and adverse (AE) events. A frequentists network meta-analysis was conducted using netmeta package and random-effects model. Results: Five studies comprising a total of 2,272 participants were included. When O-based CFC data was analyzed, only ACAL-O had a significant lower relative risk (RR) of progression and death (P&D). There were no significant differences with respect to overall response rates (ORR), complete remission (CR), minimal residual disease (MRD), or grade >3 adverse events (Grd3+) among O-based CFC. When R-based CFC data was analyzed, IB and IB-R were not different with respect to RR of P&D, ORR, CR, MRD, or Grd3+. When the data was analyzed as CFC versus combined CIT, only ACAL-O was found to be significantly superior to other O- and R-based CFC with respect to RR of P&D. ORR and Grad3+ rates of O- and R-based CFC were not significantly different. While ACAL-O, IB-O, and VEN-O had superior CR and MRD rates compared to other CFC, there were no significant differences among each other. Conclusions: This network meta-analysis is the first to compare and rank first-line CFC therapies in CLL. It indicates that ACAL-O has a superior profile having the lowest RR of P&D without significant difference in Grd3+ among CFC. Disclosures No relevant conflicts of interest to declare.

Rituximab and High-Dose Dexamethasone (R-dex) Is Effective In The Treatment Of Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4184-4184
Author(s):  
Martin Simkovic ◽  
David Belada ◽  
Monika Motyckova ◽  
Lukas Smolej ◽  
Pavel Zak
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Antimicrobial Prophylaxis ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Published Data ◽  
High Dose ◽  
High Dose Dexamethasone ◽  
Tertiary Center

Abstract Introduction High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but serious infections are frequent. Recently published data suggest that high-dose dexamethasone might be equally effective to HDMP despite lower cumulative dose. Aims To assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in relapsed/refractory CLL. Patients and Methods A total of 60 pts (pts) with relapsed/refractory CLL treated at a single tertiary center between September 2008 and October 2012 were included in this retrospective analysis. Basic characteristics are summarized in Table 1. The schedule of R-dex consisted of rituximab 500 mg/m2 i.v. day 1 (375 mg/m2 in cycle 1) and dexamethasone 40 mg orally on days 1-4 and 10-13. Treatment was repeated every 3 weeks for a maximum of 8 cycles. All pts received antimicrobial prophylaxis with sulfamethoxazole/trimethoprim and aciclovir. Results Median number of administered R-dex cycles was 6 (range, 1-8). The overall response (ORR)/complete remissions (CR) were achieved in 75/3%. At the median follow-up of 9 months, median progression-free survival was 8 months and median overall survival 24 months. Significant predictors of short PFS in univariate analysis were bulky lymphadenopathy (p=0.023) and refractoriness to fludarabine (p=0.02). Interestingly, activity of R-dex in bulky fludarabine-refractory CLL was similar to ofatumumab (ORR 62 %, median PFS, 4 months, median OS, 12 months) (Wierda et al., 2010). R-dex was successfully used as a debulking regimen before allogeneic stem cell transplantation in 8 patients. Serious (CTCAE grade III/IV) infections occurred in 29% of patients; 19% pts developed steroid diabetes requiring temporary short-acting insulin. Conclusions Our data show that R-Dex is an active and feasible treatment for patients with relapsed/refractory CLL; however, major infections remain relatively frequent despite combined antimicrobial prophylaxis. In addition, durable responses are infrequent. Therefore, further optimization of this therapeutic approach is warranted. Updated results will be presented. Disclosures: No relevant conflicts of interest to declare.

Early Autologous Stem Cell Transplantation (SCT) in Genetically Poor-Risk Chronic Lymphocytic Leukemia Is Feasible and Effective: Results from a Prospective Multicenter Study (GCLLSG CLL3 Protocol).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 146-146 ◽  
Author(s):  
Peter Dreger ◽  
Raimonde Busch ◽  
Stephan Stilgenbauer ◽  
Hildegard Greinix ◽  
Manfred Hensel ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Single Case ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Lymphocytic Leukemia ◽  
Hematological Toxicity ◽  
High Dose ◽  
Post Transplant ◽  
Poor Risk ◽  
One Year

Abstract From July 1997 through June 2002, the German CLL Study Group conducted a prospective multicenter trial to assess the feasibility and efficacy of early SCT in patients with poor-risk chronic lymphocytic leukemia (CLL). The protocol comprised optional cytoreduction with CHOP, fludarabine, or FC; PBSC mobilization using the Dexa-BEAM regimen; and myeloablative therapy with TBI/CY followed by reinfusion of purged stem cells. Inclusion criteria were age <61 years, stage Binet B/C or poor-risk stage A as defined by short lymphocyte doubling time plus elevated STK, and one line of pretreatment or less. Endpoints were feasibility (as defined by the proportion of patients able to successfully undergo all study procedures); toxicity; efficacy; and quality of life (QOL) as defined by the Spitzer QOL Index. Results: As of July 2004, 128 of 179 eligible patients were evaluable. Median age was 51 (27–60) years. Binet stages were poor-risk A 15%; B 61%; C 24%. An unmutated VH rearrangement was present in 72%. Eighty-six percent of the patients were chemotherapy naive at study entry. Best documented response during the pretransplant phase was complete remission (CR) in 28% and partial remission (PR) in 64% of the patients, giving an overall response rate of 92%. Immunomagnetically purged grafts were obtained in 83% of the patients in whom mobilization was attempted, containing 4.6 (1.2–22.1) CD34+ cells per kg body weight. Altogether, 98 of 128 patients (77%) proceeded to SCT. Reasons for exclusion from SCT were disease progression, mobilization failure, toxicity during the mobilization phase, or patient’s refusal. At 3 months post SCT CR was reported in 78% and PR in 21%. With a follow-up time of 36 (3–77) months, median progression-free survival of all 128 patients intended to treat was 59 months (54 months for those with unmutated VH). 4-year overall survival of all 128 patients was 84% (95%CI 74–94). Grade 3/4 non-hematological toxicity was mainly due to infections, which occurred in 21% of the patients (18% pretransplant; 7% post transplant). Six complications were fatal (4 pretransplant, 2 post transplant), translating into a 5% probability of treatment-related death. A single case of treatment-related myelodysplasia / AML has been reported to date. One year after SCT, QOL index had the maximum score of 10 points in 48 of 57 evaluable patients (84%). In comparison to prestudy levels, QOL had increased in 35%, remained similar in 50%, and decreased in 15% of the patients. Conclusions: Early sequential high-dose therapy including SCT for poor-risk CLL is feasible and has promising efficacy. Whereas the transplant-related toxicity appears to be acceptable, future studies should aim at replacing Dexa-BEAM by a similarly effective but less toxic mobilization regimen.

Fludarabine, Cyclophosphamide and Rituximab (FCR) Related Prolonged Cytopenia Is Frequent and Adverse Factor Affecting Survival of Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1790-1790
Author(s):  
Petra Obrtlikova ◽  
Anna Jonasova ◽  
Magda Siskova ◽  
Eduard Cmunt ◽  
Adela Berkova ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Significant Difference

Abstract Abstract 1790 Background: The immunochemotherapy regimen composed of fludarabine, cyclophosphamide and rituximab (FCR) has emerged as highly effective frontline or second line therapy for chronic lymphocytic leukemia (CLL). This regimen may be however associated with prolonged cytopenia and the risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Aims and methods: In our retrospective single center analysis, we evaluated the efficacy and the toxicity of FC or FCR regimen in unselected population of CLL patients with treatment indication. The overall survival (OS) and progression free survival (PFS) was calculated for all patients as intent to treat analysis. The prolonged cytopenia was defined as cytopenia (grade 2–4 according to CTCAE v.4 ) developing during of after the last cycle of FC/FCR and persisting two or more months. Cytopenia was evaluated in patients with follow-up at least 6 months after this treatment. Patients were excluded from analysis of cytopenia if they underwent immediate other treatment (antibody maintenance, high dose therapy with autologous stem cell transplantation (ASCT) consolidation, or they received other therapy due to unsatisfactory response to FCR). Patients with missing laboratory data after FC(R) were also excluded. Kaplan Maier curves for PFS and OS were calculated and log rank test was used for survival comparison. Results: Altogether, 252 patients started the treatment with FC or FCR in the years 2000–2012 at our institution. There were 86 (34%) women and 166 (66%) men with a median age of 62 years (31–87) at the time of FC(R) therapy. 52 (21%) pts received FC regimen, including 40 pts treated in first line therapy and 12 pts in second line therapy. FCR therapy was administered in 200 pts (79%): 153 pts received FCR as first line therapy, 38 pts as second line therapy and 8 pts as third or fouth line therapy. The median number of FC cycles was 5 (1–8) with or without R. The estimated OS for the first line therapy was 87,5% in FCR group vs 80% at 3y in FC group (p ns) (Hallek,CLL8: 87% vs 83%) and PFS was 70% in FCR group vs 50% in FC group (p=0,004) with the median of follow-up 45 months. Altogether 184 pts fulfill the criteria for cytopenia analysis. The most frequent immediate subsequent therapy considered as exclusion for this analysis was ASCT consolidation (n 20). Out of 184 pts, 146 recieved FC(R) as 1st line treatment and 38 subsequent therapy. The prolonged cytopenia was observed in 54 pts (29%), 42 (29%) in 1st line group and 12 (32%) in subsequent line group. Median duration of cytopenia was 8 m (2–65), 29 out of 54 patients have had persistent cytopenia at the time of last follow up. The cumulative probability to develop cytopenia was 30.3% at 2y among all pts and 29.7% among first line FCR treated pts. There was no significant difference between FC and FCR treated pts. Eleven pts developed MDS/AML, 7 cases were observed in the followed group of 184 pts (with probability 6.1% at 6y), in all cases the cytopenia preceded the MDS onset, 6y probability to develop MDS was 25.2% for patients who develop prolonged cytopenia after FC(R). Moreover 2 MDS and 1 AML were observed among 20 pts treated with ASCT (6y probability 5.6%, 8y probability 22.5%). The OS probability from 1stcycle of FC(R) was significantly better for pts without cytopenia (75.5% vs 57.5% at 5y, p<0.005), nonsigificant trend was observed if only first line FCR pts were analyzed (88% vs 85%). The median survival for the MDS pts from the time of MDS dg was 6 months only. Conclusions: Although the FCR is the best available standard treatment option for CLL pts, it is associated with prolonged cytopenia in 30% of cases. These patients with prolonged cytopenia afte FC(R) have considerably high probability (25.2%) to develop MDS and they have worse OS compared to pts without cytopenia. Disclosures: No relevant conflicts of interest to declare.

Rituximab® and High Dose Methylprednisolone (HDMP) as a First Line Treatment for Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2969-2969
Author(s):  
Januario E. Castro ◽  
Jan E. Bole ◽  
Carlos E. Prada ◽  
Olivier Loria ◽  
Thomas J. Kipps
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Working Group ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Combination Regimen ◽  
Line Treatment ◽  
First Line ◽  
Female Ratio ◽  
High Dose Methylprednisolone ◽  
First Line Treatment

Abstract High-dose methylprednisolone (HDMP) and the anti-CD20 mAb Rituximab® each can effect partial responses in patients with chronic lymphocytic leukemia (CLL). Previously, we noted that these two agents used in combination were highly effective in treating CLL patients with relapse/refractory disease. We examined whether patients with CLL could respond to these agents when used in combination as a first line therapy. To mitigate the toxicity associated with HDMP, the dose of methylprednisolone was reduced to 60% of that used in salvage regimens. Sixteen patients with CLL were treated with three four-week cycles of methylprednisolone at 1 gm/m2 daily for 3 days and weekly Rituximab® at 375 mg/m2 for four weeks. All patients satisfied NCI-working group criteria for requiring treatment. The median age of the patients was 60 years, the male to female ratio was 4:1, the ECOG performance status was ? 2. Eighty-six percent of the patients had high-risk disease prior to therapy, as per the modified Rai classification. Fifty-six percent of the patients had CLL cells that expressed ZAP-70 and/or unmutated immunoglobulin variable region genes. Response assessment was performed at the end of each cycle, two months after completion of treatment, and each 3–6 months thereafter until the patient experienced disease progression and/or required further treatment. Objective responses were observed in 14 out of 16 patients (Overall response rate 93%), with 1 patient achieving a complete response (CR) without disease detectable in the marrow, 1 patient achieving a nodular PR, 12 patients obtaining an excellent PR only with minimal residual disease in the bone marrow, and 1 patient having stable disease, as per the NCI-working group criteria. We observed significant reductions in the white blood cell (WBC) counts, increases in hemoglobin, elevations in platelet counts, and dramatic reduction and resolution in lymphadenopathy and splenomegaly. The median time to progression (TTP) after 12 months of follow up has not been reached. Overall, the treatment was well tolerated and all but one patient completed 3 cycles of therapy. Most adverse events were Grade I-II (fluid retention, cough, transient hyperglycemia, fatigue). We also observed 2 transient episodes of grade III–IV toxicity secondary to infection, resulting in pneumonia or sinusitis that resolved completely after antibiotic treatment. Pharmacodynamic studies showed that leukemia cells from patients responding to this combination regimen were induced to express pro-apoptotic molecules, such as Bid, Apaf-1, Smac-Diablo, and to downregulate expression of anti-apoptotic molecules, such as XIAP and Mcl-1. These data indicate that modified-dose HDMP/Rituximab® may be an effective and well-tolerated first line treatment for patients with CLL.

MECp, a Salvage Regimen with Drugs Not Employed as Frontline Therapy, Allowed to Obtain a High CR Rate and to Bring to Unrelated Allogeneic Transplantation a High Proportion of Adult Patients with Relapsed ALL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4101-4101
Author(s):  
Erika Borlenghi ◽  
Elisa Cerqui ◽  
Chiara Cattaneo ◽  
Francesco Zuccalà ◽  
Piero Galbiati ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Adult Patients ◽  
Haematopoietic Stem Cell ◽  
High Dose ◽  
Cell Transplant ◽  
First Line ◽  
Salvage Regimen ◽  
Term Survival ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 4101 Background and aim The only curative option for adult patients with refractory or relapsed ALL is allogeneic haematopoietic stem cell transplant (allo-HSCT), which can offer a 28-34% long term survival in transplanted patients. However the actual feasibility of allo-HSCT is only 20-30% in unselected patients because of the low rate (30-50%) of complete remission (CR) achieved with salvage regimens (Tavernier, 2007- Thomas, 1999), the high rate of early relapse (Martino, 1999) and the difficulties in finding a suitable donor before progression (Davies, 1996). Hence, relapsed ALL can be actually cured in less than 10% of unselected adult patients. Using a second line treatment capable of obtaining a higher proportion of CR of longer duration may improve the dismal overall prognosis of patients. We report on the efficacy and toxicity profile of the combination of 6-metilprednisolone, mitoxantrone, etoposide and high-dose cytarabine (MECp), a salvage regimen containing cytostatic drugs to which patients had not been exposed during first line therapy, except for cytarabine at lower doses. Patients and Methods Between October 2000 and May 2009, 18 refractory/relapsed ALL patients were treated at our Institution with MECp regimen, consisting of a single course of etoposide 80mg/mq/die iv, cytarabine 1000mg/mq/die iv for 6 hours and mitoxantrone 6mg/mq/die iv 9 hours after cytarabine infusion for 6 days associated to metilprednisolone 50 mg/mq/die for 21 days, subsequently tapered to zero over one week. Three patients received an experimental sequential pulsed chemotherapy program in a multiinstitutional setting. At diagnosis, all patients had been treated according to the NILG-ALL 00/09 program (Bassan, Blood 2009). Four had been refractory to induction therapy and 14 had relapsed after a median of 12 months (range 3-43), 11 while on consolidation/maintenance, one after allo-HSCT, two after 3 and 12 months from the end of maintenance. There were 10 males and 8 females with a median age of 28 (range 17-64). ALL lineage was B in 9 cases (4 pro-B, 4 common, 1 pre B), T in 8 (5 pro-T, 3 cortical-TIII) and biphenotypic in 1. Molecular studies showed MLL/AF4 rearrangement in 3 and bcr/abl rearrangement in 3 cases, all before tyrosine-kinase inhibitors were available. Karyotypic abnormalities were present in 10 of 16 evaluable cases. Patients were treated in single/double bed rooms with reverse isolation. In 3 cases treatment duration was reduced to 4 days. Results CR was obtained in 13 of 18 patient (72,2%), independently of immunophenotype and time to relapse. CR rate was 100% in all ten patients with karyotypic abnormalities. Three patients (16%) died in aplasia during treatment, 2 of septic shock and 1 of unexplained shock. Two patients (T-ALL) were resistant. Recovery of neutrophils (>0,5×109/L) and platelets (>20×109/L) required a median of 22 days (range 17-37) and 28 days (range 21-45) from the start of therapy, respectively. Infections were documented in 9 of 18 (50%), being fatal in 2 (11%). Non-haematologic toxicity, mainly mucositis, was negligible. The median duration of CR was 5 months (range 2-5) which allowed 9 of 13 CR patients (69%) to undergo allo-HSCT (7 MUD, 1 HLA-identical sibling and 1 cord blood) after a median of 4 months (range 2-7) from CR. Reason for not being transplanted was failure of donor search in 4 patients who relapsed a median of 4 months. Causes of death included progressive disease in 7 patients, in 3 cases after HSCT, and transplant-related toxicity in 3 patients. The median survival of patients achieving CR was 13 months (range 7-33) and overall survival of the entire cohort was 8 months (range 1-33m). Conclusions With MECp, a combination of drugs not used during previous first-line therapy, a higher CR rate (72%) than commonly reported could be obtained, with acceptable toxicity. CR duration was long enough to allow 44,4% of patients to receive a non-family donor allo-HSCT, which is presently the best, yet still unsatisfactory, treatment option for adult patients with refractory/relapsed ALL. Disclosures: No relevant conflicts of interest to declare.

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