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49th Annual Meeting and Exposition of the American Society of Hematology

Atlanta, Georgia / December 8-11, 2007

Front-line Therapy in High-risk CLL Patients

Unlike other malignancies where treatment is initiated as soon as the diagnosis is made, “watchful waiting” is still the standard approach to chronic lymphocytic leukemia (CLL). This is partly because many CLL patients are asymptomatic at the time of diagnosis and the disease can often take an indolent course. With a median age of onset around 70 years, patients may well have other comorbidities and die from other causes. Moreover, no treatment has yet proven to be curative for CLL; otherwise, physicians would likely consider introducing treatment in asymptomatic patients with curative intent.

Randomized trials carried out in the 1980s reinforced the watch and wait approach, as none of the trials showed a survival benefit for early initiation of treatment. That, however, was before researchers began to identify patients with high-risk disease who are now recognized as being far less likely to have an indolent course than low-risk patients. It is for these high-risk, poor-prognosis patients that the strategy is now shifting towards earlier initiation of therapy rather than watchful waiting.

Several large randomized trials are currently evaluating whether early initiation of treatment can make a difference to long-term, progression-free and overall survival (PFS, OS). In the meantime, results from research carried out at the University of Texas M.D. Anderson Cancer Center presented by Wierda et al. showed promising activity for the combination of cyclophosphamide, fludarabine, alemtuzumab and rituximab (CFAR) as a front-line regimen in high-risk CLL patients.

In this study, 47 previously untreated CLL patients with high-risk features received the CFAR regimen. Of 26 evaluable patients, complete response (CR) was seen in 18 and a partial response (PR) in seven. The addition of alemtuzumab to the more widely tested FCR regimen did not lead to greater hematologic toxicity or to an excess of infections. Of potential importance, over 80% of the group tested negative for residual disease following the CFAR regimen.

The activity of fludarabine, cyclophosphamide and alemtuzumab in CLL patients with largely poor prognostic indicators was reaffirmed by a multicentre Italian study reported by Montillo et al. Out of 23 evaluable patients, overall response was at 74%, 31% CR, 39% PR, and 4% nodular PR. Four out of 17 responders were also minimal residual disease (MRD)-negative in bone marrow following treatment. At a median followup of 10 months, 73% of those who had responded had no sign of progressive disease and toxicities were for the most part manageable.

Another small study in which alemtuzumab was combined with rituximab in high-risk, early-stage CLL is showing similar promise as a front-line regimen. As presented by Zent et al. from the Mayo Clinic College of Medicine, Rochester, Minnesota, 27 out of 30 patients responded to the dual monoclonal antibody strategy, for an overall response rate of 90%. Grade 3/4 toxicities were observed, but there were no long-term complications. The median time to retreatment had not yet been reached at this point in time.

Because alemtuzumab works independently of the p53 pathway, it is a rational choice for patients whose disease is refractory to fludarabine, which may be dependent on p53 for its activity. In the CLL2H trial presented by Stilgenbauer et al. from the German CLL Study Group, median PFS was 7.7 months among 109 fludarabine-refractory patients receiving subcutaneous alemtuzumab three times a week for four to 12 weeks, while median OS was 19.1 months, a clear signal that alemtuzumab is active in refractory CLL.

Whether MRD eradication, especially in bone marrow, is an appropriate therapeutic end point in relapsed CLL was also addressed by several investigators. In a previously reported study by Moreton et al. (J Clin Oncol 2005;23:2971-9), the majority of a small subgroup of patients who achieved MRD-negative remission with alemtuzumab were still alive at 60 months. In an update by Sayala et al. from the UK on this MRD-negative cohort (eight out of 18 of whom had CLL that was refractory to fludarabine), median survival was again significantly longer in MRD-negative vs. MRD-positive patients at a median follow-up of 77 months. The median time to next treatment (stem cell transplantation excluded) was 114 months.

Another analysis of MRD status following treatment with alemtuzumab/fludarabine in relapsed/refractory CLL by Flowers et al. showed an overall response rate of 64% in 28 evaluable patients. Eight out of 17 evaluable patients in the same series also were MRD-negative in bone marrow. Whether MRD negativity predicts longterm survival was not confirmed in this trial but Flowers et al. did determine that MRD assessment of bone marrow and not peripheral blood by four-colour and not two-colour flow cytometry might have advantages for assessment of MRD in clinical trials.

Turning their attention to T-cell prolymphocytic leukemia (T-PLL), the German CLL Study Group under Hopfinger et al. reported results in 26 patients treated with fludarabine, mitoxantrone and cyclophosphamide (FMC) followed by alemtuzumab consolidation. Among 18 evaluable patients, the overall response rate after FMC was 66% and 86% following alemtuzumab consolidation. Median OS and PFS were 19.2 and 10.6 months, respectively. As some patients relapsed upon completion of the regimen, investigators suggested that alemtuzumab might be included in the first-line regimen, followed by antibody maintenance to produce more durable responses in this rare but aggressive leukemia.

Controversy did arise over the risk of serious infections associated with alemtuzumab consolidation, as reported in an interim analysis of CALGB 10101 by Lin et al. In this analysis, investigators found an unacceptably high rate of toxicity in patients who achieved a CR after induction chemo-immunotherapy. Others have not found the rate of serious infection to be unacceptably high with the same approach, perhaps because the interval between the induction regimen and alemtuzumab consolidation was longer in alternative trials than in CALGB 10101. It was suggested that this interval might need to be at least five to six months in order to give patients’ immune systems time to reconstitute prior to receiving alemtuzumab.

Alemtuzumab and Graft versus Host Disease

As van Besien et al. pointed out, certain conditioning regimens can cure some patients with AML and myelodysplasia but chronic graft-versus-host disease (GVHD) remains a challenge. In an effort to reduce chronic GVHD, investigators from the University of Chicago and their colleagues at the University of Texas M.D. Anderson Cancer Center compared outcomes of patients who received fludarabine, melphalan and alemtuzumab vs. those who received the same regimen minus alemtuzumab. Results showed that alemtuzumab did not increase the risk of opportunistic infections, and it decreased both chronic GVHD and treatment-related mortality. However, disease was more likely to recur with the alemtuzumab-containing regimen.

Radioimmunotherapy and Hematologic Malignancy

Considerable interest was also paid at the ASH meeting to “hot” antibodies that eradicate not only tumour cells to which they are attached but neighbouring cells as well. As presented by Hagenbeek et al., the First-line Indolent Trial (FIT) involved 414 patients with advanced-stage follicular non-Hodgkin’s lymphoma (NHL) who had responded to first-line regimens, after which they received either a single infusion of 90Y-ibritumomab or no further treatment. Results were striking: the single infusion of radioimmunotherapy (RIT) essentially prolonged PFS by two years vs. no further treatment. Consolidation of first CR/CRu (unconfirmed) with 90Y-ibritumomab also converted 90% of patients who were Bcl-2 PCR-positive after induction therapy to PCR negativity, while 77% of patients in PR following induction therapy converted to a CR following RIT consolidation. In total, 87% of patients achieved a CR/CRu following RIT consolidation, with a median PFS extending out to 54.5 months. Very high molecular remission rates were also reported in the RIT arm. Importantly, indices of health-related quality of life showed that the durable responses induced by RIT were not accompanied by deterioration in quality of life. Indeed, measures of well-being were virtually identical in the two arms and patients in the RIT arm had significantly less diarrhea than their control counterparts.

Interim results from a small series of patients with intermediate or high-risk NHL treated with fludarabine/mitoxantrone followed by 90Y-ibritumomab and maintenance rituximab showed an overall response of 100%, with a CR in 70% and a PR in 30% of 20 evaluable patients. Interestingly, CR rates increased after each level of therapy and, as suggested by Rush University Medical Center investigators, this regimen might optimize responses in higher-risk NHL patients.

Encouraging responses were also reported by the Eastern Cooperative Oncology Group with induction chemotherapy and 90Y-ibritumomab consolidation in untreated mantle cell lymphoma. Out of 53 evaluable patients, RIT increased the response rate from 70% following rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) to 88%. Median PFS was approximately 30 months, significantly longer than with R-CHOP alone.

Lastly, a conditioning regimen that included 90Y-ibritumomab (Z-BEAM) followed by autologous stem cell transplantation produced impressive response rates in relapsed or refractory follicular lymphoma, as reported by Gisselbrecht et al. from the GELA study group. Virtually all 77 patients responded to the regimen with either a CR or a PR, and Z-BEAM was not associated with excessive toxicity. Although follow-up is short, findings suggest that 90Y-ibritumomab could replace adjuvant radiotherapy or total body irradiation in conditioning regimens for B-cell lymphoma. Collectively, these intriguing new findings offer up considerable promise that deployment of both “cold” and “hot” monoclonal antibodies may provide better and more durable responses in hematological malignancies that otherwise remain a challenge today. -

[3114] Eradication of Minimal Residual Disease with Alemtuzumab in Chronic Lymphocytic Leukemia Is Associated with Prolonged Survival and Is an Appropriate Therapeutic Endpoint for Relapsed CLL. H. A. Sayala, P. Moreton, B. Kennedy, G. Lucas, M. Leach, S.M.B. Rassam, A. Haynes, J. Tighe, D.G. Oscier, C.Fegan, A.C. Rawstron, P. Hillmen

Eradication of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is emerging as a desirable therapeutic end point predicting for better outcome. The monoclonal antibody alemtuzumab (Mabcampath) is approved for patients with fludarabine refractory CLL. We previously published 91 patients with relapsed CLL (74 men and 17 women, median age 58 years [range, 32 to 75 years]; 44 fludarabine-refractory) who received a median of 9 weeks (range 1 to 16) of alemtuzumab, 30mg 3x a week after dose escalation, between 1996 and 2003. 84 patients had i.v. alemtuzumab and 7 received it subcutaneously. Responses to alemtuzumab according to NCI WG criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 (19%) and no response (NR) in 42 (46%). Detectable CLL to a level of less than one CLL cell in 10,000 leucocytes, assessed by four-color MRD flow cytometry, was eradicated from the blood and marrow in 18 patients (20%). 8 of these 18 patients were fludarabine refractory. We report here the results of long term follow up of this cohort of patients after a median follow up of 77 months (range 5 to 123 months). Median survival was significantly longer in patients achieving MRD negative responses compared with those with detectable CLL at the end of therapy. The median survival for all 18 MRD negative responders has not been reached but was 87 months for the 8 fludarabine-refractory patients achieving MRD negativity. Overall survival for the 18 patients with MRDnegative remissions was 66% at 72 months (see Figure). MRD positive CR patients had a median survival of 56 months, MRD positive PR patients a median survival of 42 months and non-responders a median survival of 14 months. The median treatment-free interval prior to alemtuzumab for the 18 MRD negative patients was 8 months (range 4 to 35). Excluding planned stem cell transplantation performed in CR, the median time to next treatment for the 18 MRD negative patients was 114 months and 72% (13/18) have required no further therapy. Therefore alemtuzumab can induce MRD negative remissions in CLL resulting in a clear survival advantage with 66% of MRD negative patients alive 6 years after alemtuzumab. The markedly increased treatment-free survival and excellent survival for MRD negative patients strongly suggests that achieving an MRD negative remission is an appropriate therapeutic end-point in relapsed CLL.

Commentary on abstract 3114

A seminal paper by Moreton et al. (J Clin Oncol 2005;23:2971-9) involving 91 previously treated CLL patients, 44 of whom were refractory to purine analogs, sought to determine whether eradication of MRD with alemtuzumab prolonged treatment-free and OS. At the time of treatment, detectable CLL was eradicated from the blood and marrow in 18 patients and median OS was significantly longer in MRD-negative patients compared with those who remained MRD-positive even if they achieved a CR. At 60 months, most of the patients with MRD-negative remissions were still alive. In an updated follow-up of these 18 patients—eight of whom were fludarabine-refractory—median OS was again significantly longer in patients achieving MRD-negative remission at a median follow-up of 77 months compared with those who were still MRD-positive. The median time to next treatment, planned stem cell transplantation excluded, in the MRD-negative subgroup was 114 months. Thus, eradication of MRD with alemtuzumab is a feasible goal in CLL, as investigators here concluded, and those who achieve it typically live longer than those who do not.

Questions and Answers with Dr. Hazem Sayala, Leeds General Hospital, UK.

Q: What was the disease status of the original 91 patients in the overall cohort?

A: The 91 patients in the original cohort were a mix of refractory and relapsed patients, but because we know that fludarabine-refractory patients are likely to fare the worst when you try to treat them next, we analyzed their responses separately from the rest of the group. When we did that, we found that there was no significant difference in response based on whether patients were refractory to fludarabine or not, so response rates in this subgroup of patients were pretty similar to the rest of the cohort.

Q: What do you think is the main message from this very long-term follow-up of CLL patients?

A: We have to recognize the limitations of this being a phase II study but we do believe it is still something worth exploring. So these observations should be very useful in helping conduct a future study to see whether MRD eradication is worth pursuing.

[3111] Analysis of Minimal Residual Disease (MRD) from the Phase II Multicenter Study of Subcutaneous (SC) Alemtuzumab Combined with Fludarabine for Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia (CLL). C. Flowers, H. Rosenthal, J. Brown, W. Stock, H. Katzen, S. Lakhanpal, D. Jaye

Introduction: In patients (pts) with relapsed/refractory CLL, responses achieved with conventional salvage chemotherapy may have limited durability, likely due to the presence of residual disease remaining in the bone marrow (BM) or peripheral blood (PB). The anti-CD52 monoclonal antibody alemtuzumab (Campath) demonstrates single-agent efficacy in relapsed/refractory CLL and has been shown to induce MRD-negative (-) responses in 20% of pts (Moreton et al. J Clin Oncol 2005;23:2971-2979). A recent phase 2 study reported that treatment with SC alemtuzumab with or without the addition of oral fludarabine in pts with relapsed/refractory CLL resulted in a 49% overall response (OR) rate and 16% complete response (CR) rate; MRD(-) CR was achieved in 10% of pts (Sayala et al. Blood 2006;108:abstract 34). We evaluated the safety and efficacy of SC alemtuzumab combined with intravenous (IV) fludarabine in pts with previously treated CLL and report the responses and results from MRD analysis.

Methods: Eligible pts had active CLL requiring therapy and had relapsed after at least 1 prior therapy. SC alemtuzumab 30 mg days 1-5 and IV fludarabine 25 mg/m2 days 1-5 were administered on a 28-day cycle for 4 cycles. Pts with <CR after 4 cycles were eligible to receive 2 additional cycles up to a total of 6 cycles. Responses were assessed based on the 1996 NCI Working Group Criteria. MRD was measured in the BM and PB at baseline, interim analysis, end of treatment, and 2 and 9 months following treatment. Four-color flow cytometry assays (CD5+/CD19+/CD38+/CD20[dim], CD5+/CD19+/CD43+/CD79b[dim], CD5+/CD19+/CD81+/CD22[dim]) were used to evaluate 200,000 to 1,000,000 events per sample, with lower limits of detection (LLD) ranging from 0.005% to 0.01% of leukocytes.

Results: The study completed enrollment with 56 pts (median age 62 years, range 37-86; 54% Rai stage III/IV; median 3 prior lines of therapy, range 1-14) receiving at least 1 dose of study treatment; 28 pts (50%) completed 4 or more cycles of therapy and were evaluable for response; of these, 17 (30%) pts completed 5 or more cycles and 11 (20%) completed 6 cycles of therapy. MRD evaluation of the BM was available in 17 pts. The ORR among 28 evaluable pts was 64%, with CR in 6 pts (21%). Four of 6 pts in CR achieved MRD(-) in both BM and PB, which was maintained at last evaluation in all 4 pts. In addition, 9 pts with PR showed no evidence of disease in PB and/or BM below LLD, with 4 of these pts having undetectable disease in BM. The correlation between MRD(-) in the PB and BM was 0.63 and between MRD(-) by 4-color flow and CD5+/CD19+ <1% in the BM was 0.67 (Pearson correlation).

Conclusion: After treatment with SC alemtuzumab and IV fludarabine, 64% of pts responded, with 8 of 17 evaluable pts achieving molecular undetectable disease in the BM, suggesting that MRD(-) remissions can be attained in a portion of heavily pretreated pts with CLL. Four-color flow cytometry of the BM is necessary to monitor MRD after an alemtuzumab regimen.

Commentary on abstract 3111

The presence of MRD in bone marrow or peripheral blood may limit the duration of response achieved with conventional salvage chemotherapy in relapsed/refractory CLL. Previous reports indicate that alemtuzumab induces MRD-negative CR in approximately 20% of patients, while chemo-immunotherapy shows promising efficacy in relapsed/refractory CLL. The primary objective of this phase II study was therefore to determine the CR rate and safety of subcutaneous (s.c.) alemtuzumab when combined with fludarabine in patients with previously treated CLL. After four cycles of initial therapy, patients who achieved an nPR, a PR or SD were given an additional two cycles of the same combination. MRD was measured in bone marrow and peripheral blood with both two-colour and four-colour flow cytometry assays at multiple time points including up to nine months’ post-treatment. Of 28 evaluable patients, there was a 64% overall response rate: 21% CRs, 43% PRs and 25% SD. Eight of 17 evaluable patients were also MRD-negative in bone marrow. Importantly, MRD in peripheral blood did not correlate strongly with MRD status in bone marrow and investigators concluded that four-colour flow cytometry may be the preferred method of MRD assessment in clinical trials.

Questions and Answers with Dr. Christopher Flowers, Emory University Hospital, Atlanta, Georgia.

Q: Why is MRD important in CLL patients?

A: Several other investigators and notably a group from the UK [abstract #3114] have shown that MRD is an effective predictor of long-term DFS in these patients. So in this trial, our goal was to look at MRD perhaps as an early predictor of deeper response to therapy and hopefully—eventually—a predictor of survival after using this fludarabine/alemtuzumab combination.

Q: And did you find it was predictive of deeper responses to therapy?

A: The data are somewhat preliminary in terms of looking at long-term predictors of outcome. But our initial approach has been to try and understand which path of MRD evaluation may be the best predictor of fludarabine/alemtuzumab-containing regimens and we did find that four-colour flow cytometry of MRD in the bone marrow may be the best predictor of long-term outcome.

[3120] Subcutaneous Alemtuzumab (MabCampath) in Fludarabine- Refractory CLL (CLL2H Trial of the GCLLSG). S. Stilgenbauer, D. Winkler, A. Bühler, T. Zenz, S. Groner, R. Busch, M. Hensel, U. Dührsen, J. Finke, P. Dreger, U. Jäger, E. Lengfelder, L. Trümper, U. Söling, R. Schlag, M. Hallek, H. Döhner

Fludarabine-refractory CLL has a poor prognosis with a median overall survival time of less than 12 months despite salvage chemotherapy and intravenous alemtuzumab (Campath-1H) is the approved treatment based on a remission rate of 33% and a median survival time of 16 months (Keating et al., Blood 2002). The CLL2H trial of the GCLLSG was initiated to evaluate the subcutaneous application of 3 x 30 mg alemtuzumab weekly in fludarabine refractory CLL. The current analysis is based on 109 consecutive patients enrolled until completion of the trial in April 2006. Median age was 63 (36-81) years, 71% were male. A median number of 3 (1-9) prior lines of therapy had been given. Subcutaneous treatment was performed on an outpatient basis in all cases and had to be temporarily interrupted in 68 patients due to neutropenia (43%), anemia (6%), thrombocytopenia (3%), infections (40%, CMV reactivations 30%), and was stopped early in 63 cases due to insufficient response (44%), hematotoxicity (16%), infection (17%), and CMV reactivation (13%). The median alemtuzumab dose given was 722 (3-2203) mg. Toxicity was mostly grade I/II apart from hematotoxicity (grade III/IV anemia: 42%, thrombocytopenia: 52%, neutropenia: 54%) and grade III/IV infections (25%). After a median follow up time of 21.4 months, 56 deaths have occurred (due to progression 52%, infections 39%, not CLL related 9%). The overall response rate was 33% (CR 4%, PR 27%), the median progression free survival time was 7.7 months, and median overall survival time was 19.1 months. Genetic high-risk factors were present in the vast majority of cases (unmutated VH 66%, 17p- 29%, 11q- 19%, TP53 mutation 39%). Responses (CR or PR) were observed in 22% of VH unmutated, 24% of 11q-, 39% of 17p-, and 33% of TP53 mutated cases. Progression free survival and overall survival were not significantly different when comparing the genetic subgroups, particularly TP53 mutated, 11q-, and 17p- (see figure). In conclusion, subcutaneous alemtuzumab is feasible in an outpatient setting in a high-risk population of fludarabine-refractory CLL and appears to be of similar efficacy as by intravenous administration. Most importantly, genetic high risk subgroups with unmutated VH, 11q-
pond to alemtuzumab.

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Commentary on abstract 3120

High-risk CLL includes disease with 17p and 11q chromosome deletions, both reflective of a dysfunctional p53 pathway. These are usually refractory to alkylating agents and the purine analogues, as both drug classes depend upon the p53 pathway for their efficacy. In contrast, alemtuzumab works independently of p53 and is emerging as one of the few known active agents in CLL with high-risk features. In the CLL2H trial, 109 fludarabine-refractory patients were treated with 30 mg s.c. alemtuzumab, given on an outpatient basis, three times a week for four to 12 weeks. Out of these 109 patients, there were 56 deaths, approximately half due to disease progression and 39% due to infection. CRs were seen in 4% of patients, PRs in 28%, and SD in 37%. Median OS was 19.1 months, while the median PFS was 7.7 months. Importantly, responses were seen in 17p deletion CLL disease, though fewer responses were achieved in those with the 11q deletion. Investigators concluded that s.c. alemtuzumab has efficacy that is similar to that of intravenous (i.v.) alemtuzumab and that it is also active in genetic, high-risk CLL. A first-line trial in 17p deletion CLL is currently planned.

Questions and Answers with Dr. Stephen Stilgenbauer, University of Ulm, Germany

Q: Why is it particularly important to identify effective therapies for genetic high-risk subgroups of patients with CLL such as those with unmutated 17p deletions?

A: It is particularly important to identify new therapies for CLL patients who have the 17p deletion because we know these patients do not respond well to the usual types of chemotherapy including fludarabine, chlorambucil or even bendamustine. Because they don’t respond to treatment, they have a very short median survival time of only about 1.5 to two years. So current treatments for these high-risk patients are very inadequate and we obviously need to identify new treatments for patients who otherwise have a very poor outcome.

Q: Does the ability to deliver alemtuzumab subcutaneously significantly alter the potential usefulness of this approach relative to having to deliver the drug intraveneously?

A: The s.c. administration of alemtuzmab is much more convenient for patients and the side effects, including infusion reactions, myalgia and fever, are much less with the s.c. route as well. As well, administration time is very short: just a single shot vs. a three-hour infusion when the drug is given intravenously.

Q: Where in general do you see alemtuzumab offering substantive benefits in the treatment of CLL and at what stage or stages of the disease?

A: I think alemtuzumab will be particularly useful for patients who do not respond to conventional chemotherapy any longer, or as first-line treatment for patients who we know will not respond to other therapies, such as those with the 17p deletion. It will also probably be useful in other types of leukemias that express the target antigen—mainly other lymphoid malignancies such as cutaneous T-cell leukemia—but wherever the target antigen is expressed.

[643] 90Y-Ibritumomab Tiuxetan (Zevalin) Consolidation of First Remission in Advanced Stage Follicular Non-Hodgkin’s Lymphoma: First Results of the International Randomized Phase III First-Line Indolent Trial (FIT) in 414 Patients. A. Hagenbeek, A. Bischof-Delaloye, J. A. Radford, A. Rohatiner, G. Salles, A. Van Hoof, B. Putz, M. Kunz, F. Morschhauser

Radioimmunotherapy is effective in patients with relapsed/refractory and newly diagnosed follicular non-Hodgkin’s lymphoma (FL). This study investigated the efficacy and safety of Zevalin consolidation in patients with advanced stage FL responding to first-line chemotherapy. The concept tested was whether a single infusion of Zevalin would prolong progression free survival (PFS) in patients with (minimal) residual disease. Major inclusion criteria were: CD20-positive grade 1 or 2 FL; stage III or IV at diagnosis; normal peripheral blood cell counts; <25% bone marrow involvement; age 18 yrs, and CR/CRu or PR after first line chemotherapy determined by physical examination, CT scans and bone marrow biopsy. From 8/2001 to 1/2005, 414 patients were enrolled at 77 study centers in 12 European countries and Canada. After completing induction therapy, patients were randomized to receive either Zevalin (250 mg/m2 rituximab on day -7 and on day 0 followed on day 0 by Zevalin 0.4 mCi/kg; maximal dose: 32 mCi; [n=208]) or no further treatment [n=206]). The primary end point was prolongation of PFS, calculated from randomization, which was approximately 2 wks before Zevalin administration. Secondary end points were change of response status, ie, PR to CR/CRu and BCL2-JH PCR status from positive to negative; safety/tolerability and quality of life. Patient demographics were similar in both groups (Zevalin/control): males 48%/50%; median age 55/53 yrs; at diagnosis, stage III 35%/31%, stage IV 64%/66%; B-symptoms 22%/20%; response status after induction, PR 49%/47%; CR: 51%/53%. Induction therapies included: CVP n=106, CHOP (-like) n=188, fludarabine combinations n=22, chlorambucil n=39 and rituximab-chemotherapy combinations n=59. With a median follow-up of 2.9 yrs, the median PFS increased from 13.5 (controls) to 37 mo (Zevalin; p<0.0001; HR 0.463). For patient subgroups in PR or CR after induction, median PFS was 6.3 vs 29.7 mo (p<0.0001; HR 0.304) and 29.9 vs 54.6 mo (p=0.01; HR 0.609), respectively. After Zevalin consolidation, 77% of patients in PR after induction therapy converted to CR; in total, 87% of patients were in CRu, 76% in CR and 11% in CRu. Subgroup analyses based on induction treatment and outcome according to FLIPI will be presented. Toxicity was primarily hematologic. Median platelet count nadir was 45x109/L; range 8-404x109/L) at wk 7 (~5 wks post Zevalin); median neutrophil nadir was 1.0x109/L (range 0.02-6.6x109/L) at wk 8 (~6 wks post Zevalin). Grade 3/4 infections occurred in 16 (8%) patients after Zevalin vs 5 (2%) in the control arm. So far, 11 patients have died, 5 in control arm (1 sepsis, 4 progressive disease); 6 in Zevalin arm (1 neutropenic sepsis after subsequent chemotherapy, 1 pancreas carcinoma, 1 AML, 3 progressive disease).

Conclusion: Zevalin consolidation of first remission in advanced stage FL is highly effective, resulting in a total CRu rate of 87% and prolongation of PFS by 2 yrs, with a favorable toxicity profile.

Commentary on abstract 643

Advanced NHL remains incurable and novel strategies are needed to improve outcomes. In the FIT trial, 414 patients with advanced-stage follicular NHL received a variety of first-line regimens, after which responders (either PR or CR) were randomized to a single infusion of 90Y-ibritumomab or no further treatment. RIT consolidation resulted in an overall CR rate of 87% and a molecular remission rate in blood of 97%. Some 77.2% of patients in the RIT arm converted from PR to CR following consolidation vs. 17.5% in the control arm on observation. Median PFS was 37 months in the RIT group vs. 13.5 months in the control group (P<0.0001). Median PFS was 29.7 months in RIT patients in PR following induction therapy vs. 6.3 months for controls, and 54.6 months vs. 29.9 months for RIT patients in CR after induction vs. controls, respectively. RIT was well tolerated with no unexpected toxicities and low infection rates despite a high incidence of grade 3-4 neutropenia. RIT also increased response rates and PFS in all FLIPI risk groups, regardless of the first-line treatment used. Results demonstrate that 90Y-ibritumomab is one of the most effective single drugs yet tested in advanced-stage follicular NHL.

Questions for Dr. Anton Hagenbeek, University Medical Centre Utrecht/HOVON, The Netherlands.

Q: How does the conversion rate achieved with RIT in FIT compare with other marrowablative strategies?

A: Results from major randomized trials show conversion rates that range from 38% to 69%, so my conclusion is that with one shot of [90Y-ibritumomab], we are not doing a bad job.

Q: How would you interpret the results of the subset of patients receiving induction therapy with rituximab-based regimens followed by RIT consolidation?

A: There was only a small group of patients who received rituximab as part of their induction therapy so I don’t think we can address this question in this small group of patients. But we do know that rituximab chemotherapy followed by RIT is active in terms of inducing a change from PR to CR, as we saw in FIT.

Q: Do you see a role for 90Y-ibritumomab in other lymphomas?

A: The drug is being explored in a variety of other lymphomas, including mantle cell and diffuse B-cell lymphoma, and it has been shown to work there as well, in terms of inducing meaningful remissions and prolonging PFS. It is also being used to further intensify conditioning regimens so application of RIT is ever increasing in certain types of lymphomas. The advantage of RIT over a “cold” antibody like rituximab is that with a cold antibody, only the cells that attach to the antibody die but with RIT, not only do cells die that the antibody attaches to, but cells in the neighbourhood will also be irradiated to death at the same time.

Commentary on abstract 628

Chemo-immunotherapy which combines chemotherapy with monoclonal antibodies represents a significant advance in the treatment of CLL. In previously untreated patients, a CR rate of over 72% has been reported with the fludarabine/cyclophosphamide/rituximab (FCR) regimen, and an estimated median duration in remission of 77 months. In this study, previously untreated CLL patients with high-risk features were treated with reduced doses of fludarabine and cyclophosphamide compared with doses typically used in the standard FCR regimen. Alemtuzumab was also given on days 1, 3 and 5 of each course, and standard-dose rituximab on day 2. Of 26 patients evaluable for response, CR was achieved in 18 (69%) and PR in seven (26%) others. These responses compare to a CR rate of 60%, a nPR of 17% and a PR of 17% in matched historic controls treated with FCR. Rates of hematologic toxicities including neutropenia, thrombocytopenia and anemia were not different in alemtuzumab/FCR vs. FCR patients, nor were rates of minor or major infections. Over 80% of evaluable patients treated with alemtuzumab/FCR so far are also negative for residual disease. In this cohort of CLL patients burdened with negative prognostic features, responses in this early analysis are promising.

[628] Combined Cyclophosphamide, Fludarabine, Alemtuzumab, and Rituximab (CFAR), an Active Frontline Regimen for High-Risk Patients with CLL. W. M. Stadler, R. A. Figlin, M. S. Ernstoff, B. Curti, K. Pendergrass, S. Srinivas, V. Canfield, C. Weissman, M. Poulin-Costello, R. M. Bukowski, on behalf of the ARCCS investigators

Patients (pts) with CLL have diverse clinical features, including time to first treatment (Rx), response to Rx, remission duration, and outcomes with salvage Rx. We identified serum beta-2 microglobulin (B2M) of 4 mg/L or greater as a high-risk feature, predicting for lower complete remission (CR) rate and shorter progression-free survival (PFS), with frontline chemoimmunotherapy. For pts <70 years old and B2M =4 treated with the fludarabine (F), cyclophosphamide (C), rituximab (R)-based combination, the CR rate and estimated median PFS were 59% and 60 mo, compared to 81% CR and 80 mo PFS for similar aged pts with B2M <4. We combined FCR with alemtuzumab (A) in the CFAR regimen that was well-tolerated and had activity in treating relapsed/refractory pts. The CFAR regimen is being evaluated in higher-risk pts with an NCI indication for frontline therapy. Frontline CFAR consists of C-200mg/m2 d3 5; F-20mg/m2 d3-5; A-30mg IV d1,3,5, and R-375 500mg/m2 d2, each 28 days for 6 intended courses. Tumor lysis prophylaxis was allopurinol 300 mg/d for 7d, course 1 only. Neulasta 6mg d6 was routine. Antibiotic prophylaxis was TMP-SMZ DS twice daily 2-3 d/wk and valacyclovir (VA) or valgancyclovir (VG) during and for at least 2 months after completion of treatment. CMV antigen in blood was monitored before each course. There currently are 40 pts registered on this trial. The median age for the 21 pts currently evaluable for response was 63 yrs (43-69), B2M was 5.1mg/L (4-9.8), ALC was 72 K/µL (6-355), HGB was 10.9gm/dL (7.9-13.5), and PLT was 158 K/µL (65-390); 13 were Rai high-risk. The median time from diagnosis to Rx was 35 (2-117) mo. The median number of cycles administered was 4 (3-6). Reasons for not completing 6 courses included delayed recovery of counts (6), pt choice (3), AIHA (2), infection (1), and Rx failure (1). CR was achieved in 71%, nPR in 5%, PR in 19%, and 1 pt of 21 did not respond. All pts in CR and nPR and 3 of 4 in PR were free of disease in the bone marrow by 3-color flow cytometry. There was no significant correlation between CR or OR and Rai stage, IgVH mutation status, FISH status, or ZAP70 or CD38 expression. Grade 3 or 4 neutropenia and thrombocytopenia were seen in 27% and 7% of courses, respectively. Major and minor infections were seen in 2% and 8% of courses and FUO in 34% of courses. These FUO included A-infusion related fevers. CMV reactivation occurred in 2/8 pts who received VA and none of 13 pts who received VG prophylaxis during treatment. Two pts developed CMV reactivation 3-6 months after they switched from VG to VA after completing CFAR. In conclusion, CFAR is an active and promising frontline regimen in higher-risk pts with CLL. Accrual and treatment continue on this clinical trial.

Commentary on abstract 2050

Standard of care in CLL is still to treat only when treatment is clearly needed. However, now that risk analysis at a molecular level is coming to the forefront, efforts are being made to introduce treatment in high-risk, early-stage disease, when antibodies work best. Because single-agent alemtuzumab is a highly effective drug for non-bulky CLL, even in patients with the 17p deletion, this phase II study was initiated in which alemtuzumab and rituximab were given to 30 patients, among whom 27 responded for an overall response rate of 90%. Based on National Cancer Institute-Working Group 1996 criteria, 11 patients achieved a CR (37%), 10 patients a nPR (33%), six patients a PR (20%), and three patients had progressive disease (10%). Grade 3 - 4 toxicity occurred in nine patients but there were no clinical complications. The median time to retreatment has not yet been reached at a median follow-up of about 18 months. These early findings suggest that the dual antibody approach delays time to retreatment by at least two to thee years. A second trial will be starting shortly in which growth factor support will be added to the antibody strategy to increase cell kill.

[2050] Alemtuzumab and Rituximab for Initial Treatment of High Risk, Early Stage Chronic Lymphocytic Leukemia (CLL). C. S. Zent, T.G. Call, T.D. Shanafelt, D.F. Jelinek, R.C. Tschumper, C.R. Secreto, D.A. Bowen, S.M. Geyer, B.F. Kabat, B.R. LaPlant, W. Wu, N.E. Kay

Background: CLL is still an incurable lymphoid malignancy. The current standard of care is to treat only patients with obvious clinical progression as defined by the National Cancer Institute Working Group in 1996 (NCI-WG 1996). High risk CLL can be identified at diagnosis by a variety of tests including fluorescence in situ hybridization (FISH), immunoglobulin heavy-chain variable region (IgVH) analysis, and expression of ZAP-70 or CD38. With this information we can identify patients with high risk, early stage disease who are candidates for novel low toxicity therapies that could alter the natural course of their disease. Our hypothesis was that combination monoclonal antibody (MoAb) therapy using alemtuzumab and rituximab would significantly reduce the high risk clone in early stage CLL.

Methods: This phase II trial was conducted with IRB approval and accrued the planned 30 patients between January 2005 and July 2007 at Mayo Clinic Rochester. The study enrolled consenting patients with Rai stage 0-II CLL without NCI-WG 1996 criteria for treatment who had high risk CLL as defined as one or more of the following 1) 17p13-, 2) 11q22-, 3) unmutated (UM) IgVH (<2%) and expression of ZAP-70 (=30%) and/or CD38 (=20%). Treatment was one 30 day cycle (alemtuzumab 3 mg, 10 mg, 30 mg days 1-3 then 30 mg 3 x week x 4 weeks with all doses subcutaneously and rituximab at 375 mg/m2/week IV x 4 doses from day 8). Patients received 7 days of allopurinol and antimicrobial prophylaxis against PCP and herpes virus infections for 7 months. CMV testing by PCR was done weekly during treatment, then monthly x 6.

Results: All 30 patients have completed therapy and 27 have been evaluated for response. The median age of these 27 patients was 62 yr (range 29-77) with 8 patients >70 years. There was a male predominance (67%) with median time from diagnosis to treatment of 0.7 yr (range 0.1-6.1). Stage (Rai) at the start of therapy was 0 in 7 (26%), I in 19 (70%), and II in 1. High risk markers were 17p13- in 9 (33%), 11q22- in 7 (26%), UM IgV and expression of either ZAP-70 or CD38 in 11 (41%). All 27 patients completed therapy without interruption. Non hematological grade 3-4 toxicity occurred in 3 patients (2 drug reactions caused by SMX/TMP, 1 CMV reactivation responsive to IV therapy). Response evaluation at 2 months after completion of therapy using NCI-WG 1996 criteria showed an ORR of 93% with 12 (44%) CR, 8 (30%) nPR, and 5 (19%) PR. Two (7%) patients had disease progression. Median duration of follow up was 14.1 months (range 1.9-27.2). Median time to disease progression in the 25 responding patients was 14.4 months (95% CI 5.9-22.4). Seven (26%) patients have received subsequent treatment for CLL (median 5.2 months, range 2.4-20.1). A minimal residual disease assay using 3-color flow cytometry on peripheral blood was negative in 6 of the 7 patients with CR who had no evidence of residual CLL on immunohistochemical examination of the bone marrow. These 6 patients all remain in sustained CR (median follow up 15 months, range 2-27.2).

Conclusions: Alemtuzumab and rituximab is an effective and tolerable therapy in patients with high risk early stage CLL. A randomized controlled trial is now required to test if this intervention is better than the standard observation approach. In addition, this combination MoAb regimen could be used as a platform to develop even more effective combination treatments for patients with CLL.

Commentary on abstract 3133

The combination of fludarabine plus cyclophosphamide (FC) is still one of the best regimens for CLL but even those who achieve a CR with FC eventually relapse. Alemtuzumab is one of the few single agents shown to eradicate MRD in CLL, and it is particularly effective at clearing disease from bone marrow—the usual site of residual disease following purine analogue-based therapy. In this phase II study, investigators recruited 25 patients, many of whom had poor prognostic indicators—including unfavourable cytogenetics and multiple prior therapies—and treated them with FC plus subcutaneous alemtuzumab every four weeks for up to six cycles. Out of 23 evaluable patients, overall response was 74% (17 patients), seven of whom achieved a CR (31%), nine a PR (39%), and one a nPR (4%). Four out of the 17 responders were MRD-negative in bone marrow. Treatmentrelated toxicity was manageable in the majority of patients, although two episodes of tuberculosis did occur. At a median follow-up of 10 months, 73% of responders had no sign of progressive disease, suggesting that the combination is feasible, safe and effective in relapsed and refractory CLL.

[3133] Combined Fludarabine, Cyclophosphamide, and Alemtuzumab (FCC), an Active Regimen for Treated Patients with Chronic Lymphocytic Leukemia (CLL). M. Montillo, S. Miqueleiz, A. Tedeschi, F. Ricci, E. Vismara, D. Ciapanna, V. Belsito Petrizzi, M. Crugnola, M. Spriano, L. Uziel, A. De Blasio, P. Spedini, E. Morra

Fludarabine (F) in combination with cyclophosphamide (C) showed a relevant advantage over single-agent F in pts with relapsed CLL. Although minimal residual disease (MRD) remains detectable in many pts achieving CR, the combination of F and C seems to reduce MRD more efficiently. Still, pts in CR eventually relapse and require treatment, demonstrating the need for improved treatments able to further reduce or eliminate MRD and induce “better quality” and thus more durable responses. Alemtuzumab (CAM), anti-CD52 monoclonal antibody, acts synergistically with F in vitro and appears to have synergistic activity in vivo. Additionally, CAM is highly effective at clearing disease from bone marrow, the usual site of residual disease following purine analogue-based treatment. Therefore, we designed a phase II study to determine feasibility and efficacy, overall response rate (ORR)-duration of response-ability at clearing MRD, of a 4-weekly combination regimen consisting of F, C, and CAM (FCC). The study population is represented by pts with B-CLL with relapsed or refractory disease after at least one line of treatment. Subcutaneous route of administration of CAM has been adopted in this trial. MRD was measured by 4-color flow cytometry in the bone marrow. The FCC regimen consisted of F 40 mg/m2/d os (d 1-3), C 250 mg/m2/d os (d 1-3) and CAM 10 mg sc (d 1-3). This combination was repeated on d 29 for up to 6 cycles. The dose of CAM was increased after the first cohort of 10 treated pts from 10 mg to 20 mg sc. Currently, 25 pts have been enrolled in this trial. Median age was 57 years (range 42-79), 15/25 (60%) were male, 23/25 (92%) were in Binet stage B or C, median number of prior treatment regimens was 2 (range 1-4). In six (24%) pts 17p deletion was detected. IgVH unmutated was observed in 17 (68%) pts. At the moment of writing 19 pts are eligible for evaluation of toxicity and response. The ORR was 79%, with 7 (37%) pts achieving CR, 7 (37%) pts a PR, 1 (5%) pt a PRn. Three pts had SD, while 1 showed progression of the disease. MRD negativity was achieved in the bone marrow of 4/15 (27%) pts. Grade IIIIV neutropenia episodes were observed in 43% of the administered courses while grade III-IV thrombocytopenia episodes were detected only in 8% of cycles. Four major infections were recorded: two sustained by Mycobacterium tuberculosis (1 cutis, 1 lung), one by Nocardia (lung) and one by E. coli (sepsis). The patient with pneumonia due to M. tuberculosis died because of respiratory failure. CMV reactivation occurred in 6 pts: no CMV disease was recorded. After a median follow up of 10 m (range 1-22) 73% of responding pts did not progressed. In conclusion, results from the interim analysis of this new, 4-weekly dosing FCC regimen suggest that combination therapy with F, C and CAM is feasible, safe, and effective in treating pts with relapsed and refractory CLL, even in those patients with inherent poor prognostic factors and who had received.

Commentary on abstract 2039

T-cell prolymphocytic leukemia (T-PLL) is an extremely rare but very aggressive disease with OS in all series being less than 12 months. To improve these odds, the German CLL study group treated 26 patients with an initial two cycles of FMC, followed by an additional two cycles for a maximum of four cycles in responders. All patients received consolidation with intravenous alemtuzumab three times a week for a maximum of 12 weeks, starting one to three months after chemotherapy. Out of 18 evaluable patients, overall response rates after FMC were 66% and 86% following alemtuzumab consolidation. Median OS was 19.2 months, while PFS was 10.6 months. Some patients did relapse following completion of the regimen, even with alemtuzumab consolidation, suggesting that intensified first-line therapy that includes alemtuzumab, followed by alemtuzumab maintenance, might be more effective in the treatment of T-PLL.

[2039] TPLL-1 Protocol of the German CLL Study Group (GCLLSG): A Prospective Phase II Trial of Fludarabine Phosphate, Mitoxantrone and Cyclophosphamide (FMC) Followed by Alemtuzumab Consolidation in T-PLL. G. Hopfinger, R. Busch, B. Eichhorst, P. Cramer, G. Kandler, G. Fingerle-Rowson, A.-M. Fink, S. Stilgenbauer, M. Hallek

Introduction: T-cell prolymphocytic leukemia (T-PLL) is an aggressive disease with a poor median overall survival of <12 months. To improve results in T-PLL, the GCLLSG initiated the T-PLL-1 protocol evaluating the efficacy of induction therapy with fludarabine, mitoxantrone and cyclophosphamide (FCM) followed by antibody therapy with alemtuzumab.

Patients (pts) and Methods: Between November 2001 and December 2006 a total of 26 pts were entered in this trial. At the time of analysis eighteen pts. are available with confirmed diagnosis of T-PLL. Twelve patients were untreated and six pretreated. All patients were planned to receive 4 cycles of fludarabine phosphate 25 mg/m2 on Days 1-3, mitoxantrone 8 mg/m2 on Day 1, and cyclophosphamide 200 mg/m2 (FMC) on Days 1-3, which was repeated on Day 29. After 4 courses of chemotherapy, all responding patients were scheduled to receive alemtuzumab 30 mg IV 3 times per week as consolidation therapy for up to 12 weeks. Patients with stable or progressive disease at interim staging, after second cycle of FMC, were treated immediately with alemtuzumab. The median age was 71 years (range 46-75yrs). Median time from diagnosis to study entry was 2 months (range 0.2-16 months). All patients showed a typical marked hyperleukocytosis with a median of 141,600/µl (range 19,900-436,700/µl).

Results: A total of 63 cycles of FMC therapy were documented and a total of 129 weeks of Alemtuzumab at 30 mg with a median of duration of 8 weeks therapy per pt (range 2-12 weeks) were administered, which corresponds to a medium Alemtuzumab dose of 720 mg (range 6 mg-1.033 mg). The overall response (OR= complete response (CR) + partial response (PR)) rates following FMC and alemtuzumab therapies were 66% and 86%, respectively. The best response to FMC therapy included 4 pts who achieved a CR, while 8 pts achieved a PR, 5 pts had SD, and 1pt had PD. Alemtuzumab was subsequently administered as consolidation therapy to 15 pts. Of responding pts. with CR 3 of 4 and with PR 7 of 8 received alemtuzumab as consolidation therapy. The pt with PD received alemtuzumab therapy as well, but the disease continued to progress. In addition, 2 pts with SD after FMC subsequently achieved a CR following alemtuzumab therapy and three pts with SD after FMC achieved a PR. One pt with PR after FMC had a progressive disease during Alemtuzumab therapy. The median overall survival (OS) of patients with T-PLL after FMC and alemtuzumab therapy was 19.2 months and progression free survival (PFS) was 10.6 months. Only one fatal adverse event presenting as myocardial infarction during alemtuzumab run-in phase was observed. FISH analysis was performed in 12 of 20 pts showing typical involvement of the chromosome 14 (t (14; 14), t (14q11)). Furthermore, in 12 pts expression of TCL-1 was tested by PCR. However, no correlation to OS or PFS was detected according to the level of expression.

Conclusions: The combination of a fludarabine phosphate-containing regimen with subsequent alemtuzumab therapy shows clinical benefit in pts with T-PLL. To increase outcome study evaluating FMC combined with alemtuzumab followed by an alemtuzumab maintenance therapy is currently under investigation.

Commentary on abstract 1076

Reduced-intensity conditioning with fludarabine and melphalan can cure some patients with AML and MDS but chronic GVHD (cGVHD) is the primary cause of treatment failure and death. In vitro T-cell depletion with alemtuzumab reduces the incidence of both acute and cGVHD but there is concern that it may predispose patients to opportunistic infections and increase the rate of disease recurrence. In a comparison of 90 patients who received conditioning with fludarabine, melphalan and alemtuzumab vs. 112 others who received fludarabine and melphalan alone, analyses showed that alemtuzumab did not lead to an increased incidence of opportunistic infections. Furthermore, T-cell depletion led to a moderate decrease in the incidence of acute GVHD vs. no T-cell depletion, and a dramatic decrease in the incidence of cGVHD. The addition of alemtuzumab to the conditioning regimen also decreased treatment-related mortality but this decrease was offset by an increased risk of disease recurrence. Nevertheless, PFS and OS were identical between the two groups. Investigators concluded that the use of alemtuzumab in this conditioning regimen may provide a modest advantage for AML/MDS patients undergoing allogeneic transplantation, since fewer survivors suffer from cGVHD.

[1076] Alemtuzumab Reduces Chronic Graft Versus Host Disease (cGVHD) and Treatment Related Mortality (TRM) after Reduced Intensity Conditioning for AML and MDS. K. van Besien, M. de Lima, A. Artz, B. Oran, W. Stock, S. Giralt

In vivo T-cell depletion with alemtuzumab has been used to reduce acute and chronic GVHD. In order to evaluate its overall effect on transplant outcomes in AML and MDS we compared 90 pts who received fludarabine/melphalan/alemtuzumab (FMA) conditioning and post-transplant tacrolimus at the University of Chicago, with 112 who received fludarabine/melphalan (FM) and post-transplant tacrolimus/methotrexate at MD Anderson Cancer Center. Pt and transplant characteristics were well balanced except for a higher proportion of MDS in the FM group. Median age, proportion unrelated donor tx and proportion high/intermediate and low risk by ASBMT criteria were balanced between the groups. With median follow up of 28 months in both groups, one year progression free survival and overall survival are identical. TRM is significantly higher after FM, but relapse is higher in FMA. 19/103 d 28 survivors after FM vs 7/84 after FMA developed gr III-IV acute GVHD (p=0.04). 46/77 d100 survivors after FM developed ext cGVHD vs 7/63 after FMA (p=0.0000). 43 patients remain alive after FM and 27 have ext cGVHD. 41 remain alive after FMA and 1 has ext cGVHD. Alemtuzumab results in a considerable reduction in acute and particularly chronic GVHD. TRM is reduced compared with standard GVHD prophylaxis. Low incidence of chronic GVHD and reduced TRM may be the major benefit of this strategy. Relapse rates are increased, because of reduced GVL effects or because of improved early survival
. Other approaches are necessary for improving long term outcomes.

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Commentary on abstract 755

Several previously published trials demonstrated that CLL patients who achieved a CR on a fludarabine-based regimen but who were still MRD-positive showed very high rates of response and low infection rates with alemtuzumab consolidation. In contrast, interim results from the first 51 patients enrolled in the CALGB 10101 study showed unacceptably high rates of toxicity in patients who achieved a CR after chemotherapy and five deaths, all due to infections. The majority of fatal infectious complications occurred after completion of alemtuzumab consolidation, suggesting a need to monitor patients for late infections. Based on these findings, investigators felt that alemtuzumab consolidation should be given only in the setting of a clinical trial and that regardless of MRD status, CR patients should not be exposed to it. The disparity between infection rates in previous trials and those in the current trial may be explained by the timing of consolidation, which was reportedly shorter in the CALGB study compared to earlier trials, and perhaps not long enough to allow patients’ immune systems to fully recover.

[755] Consolidation Therapy with Subcutaneous (SC) Alemtuzumab Results in Severe Infectious Toxicity in Previously Untreated CLL Patients Who Achieve a Complete Response (CR) after Fludarabine and Rituximab (FR) Induction Therapy: Interim Safety Analysis of the CALGB Study 10101. T. S. Lin, K. A. Donohue, M. S. Lucas, J. C. Byrd, E. M. Bengtson, B. L. Peterson, R. A. Larson, Cancer and Leukemia Group B.

Alemtuzumab (Campath-1H) is approved for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Given the increasing role of chemoimmunotherapy in the treatment of CLL, the Cancer and Leukemia Group B initiated a phase II study administering FR followed by alemtuzumab for remission consolidation to previously untreated, symptomatic CLL patients (pts). Pts received fludarabine 25 mg/m2 IV on days 1-5; rituximab 50 mg/m2 IV on day 1, 325 mg/m2 IV on day 3, and 375 mg/m2 IV on day 5 of cycle 1, and 375 mg/m2 IV on day 1 of cycles 2-6; every 28 days for up to 6 cycles. Four months after the last dose of fludarabine, pts with stable or responsive disease by NCI 96 response criteria received consolidation therapy with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, 30 mg on day 5, and 30 mg thrice weekly thereafter for 6 weeks. Pts received standard pneumocystis (PCP) and Varicella Zoster Virus prophylaxis and were monitored weekly for Cytomegalovirus (CMV) reactivation by PCR, antigen test, or hybrid capture. We report safety data on the first 51 pts who received alemtuzumab. Median age was 60 years (range, 23-82), and 75% were male. Of 34 pts who attained an NCI 96 partial response (PR) after FR induction, 9 (26%) experienced unacceptable toxicity to alemtuzumab, as defined prospectively by the study. Eight grade 3 toxicities (4 opportunistic infections, 3 CMV reactivation, 1 hemorrhagic cystitis), and 1 grade 5 EBV lymphoproliferative disorder were observed. In contrast, 17 pts had CR after FR induction and 8 (47%) had unacceptable toxicity. Complications included grade 3 infections in 3 pts (2 CMV, 1 cryptococcus) and 5 grade 5 infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia). These infections occurred both during therapy and for up to 16 months following therapy. Analysis of alemtuzumab pharmacokinetics and genomic tumor features is currently ongoing. Continuous real-time safety monitoring prompted a study amendment to prohibit further pts in CR after FR induction from receiving alemtuzumab consolidation. Accrual of new pts to the trial is complete. Only pts in PR or with stable disease after FR induction continue to receive alemtuzumab consolidation, with close monitoring for infectious and other toxicities. Detailed response and outcome data will be reported when all pts have completed therapy. We conclude that alemtuzumab cannot be safely administered as consolidation therapy to pts who achieve an NCI 96 CR following induction chemoimmunotherapy. The safety and feasibility of alemtuzumab consolidation for pts in PR after FR induction remains under study, and such therapy should not be pursued outside of a clinical trial due to concerns about serious infectious morbidity and mortality.

Commentary on abstract 3319

FIT was conducted to determine the efficacy and safety of 90Y-ibritumomab tiuxetan compared with no further treatment in patients with stage III or IV follicular lymphoma who achieved a CR or a PR after first-line treatment. Results showed that a single infusion of RIT prolonged PFS by approximately two years vs. no further treatment. In this analysis of health-related quality of life, investigators administered a battery of tests at screening, at week 14 and every six months thereafter as well as at the end of follow-up. The scores determined multiple dimensions of wellbeing including physical, emotional and social parameters. Mean scores on various assessment tools at screening and final visit were virtually identical between the RIT arm and controls. Indeed, those who received RIT had significantly less diarrhea than those on no further treatment at six-, 24-, and 36-month assessments. Investigators concluded that RIT consolidation not only prolongs PFS, but that it does so without affecting health-related quality of life, which is a meaningful outcome for patients.

[3319] Health-Related Quality of Life in Patients with Advanced-Stage Follicular Lymphoma Receiving Consolidation with 90Y-Ibritumomab Tiuxetan (Zevalin) of First Remission: Results from the Randomized Phase III First-Line Indolent Trial (FIT). K. Gondek, S. Shah, A. Bischof-Delaloye, A. Rohatiner, G. Salles, B. Putz, M. Kunz, A. Hagenbeek

A previous phase 3 study showed that in patients with relapsed/refractory low-grade, follicular or transformed non-Hodgkin’s lymphoma, radioimmunotherapy with 90Y-ibritumomab tiuxetan (Zevalin) significantly improved patient-reported quality of life (QoL) as measured by the validated Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire (Wiseman et al Blood 2000;96(11):734a, abstract 3173). The study showed significant improvements in FACT-G total score, as well as in subscores for emotional, physical, and functional well-being. In the recent international phase 3 First-line Indolent Trial (FIT), patients with stage III or IV follicular lymphoma in first remission after initial chemotherapy were randomized to receive consolidation with Zevalin (n=208) or no further treatment (control; n=206). The impact of Zevalin on health-related QoL was evaluated as one of the secondary end points of this study. Health-related QoL was assessed using EORTC QLQ-C30 (version 2) and EuroQoL-5D (EQ-5D) questionnaires. The EORTC QLQ-C30 was developed to specifically assess QoL in patients with cancer, and comprises 30 items grouped into the following dimensions: functional (physical, role, cognitive, social, emotional), symptomatic (nausea, pain, fatigue), global QoL, and other (dyspnea, difficulty sleeping, anorexia, constipation, diarrhea, perceived financial difficulties). The EQ-5D was developed as a generic instrument to assess health-related QoL and comprises 2 sections, an assessment based on 5 dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression) and a visual analogue scale (VAS). These questionnaires were administered at the screening visit, week 14, every 6 months thereafter, and at the end of the follow-up period. Descriptive statistics were used to compare scores across treatment groups. The change in scores from baseline was also assessed by gender, age, and first-line treatment. Mixed effects model was used to assess factors associated with final scores of the VAS of EQ-5D. No notable treatment differences were observed in EORTC QLQ-C30 (all domains) scores across timepoints or changes from baseline. This result was true for all subgroups. The mean scores for EQ-5D at the screening and final visits were 0.83 and 0.84, respectively, for the Zevalin arm, and 0.84 and 0.83, respectively, for the control arm. The mean VAS scores at the screening and final visits were 77.52 and 77.64, respectively, for the Zevalin arm, and 76.57 and 78.60, respectively, for the control arm. An analysis of factors associated with final VAS scores showed that only baseline VAS scores affected final VAS scores (P<0.0001) considerably. No differences were observed in health-related QoL parameters between patients receiving consolidation therapy with Zevalin and patients in the control arm as measured by EORTC QLQ C-30 and EQ-5D questionnaires. Thus, in patients with advanced-stage follicular lymphoma responsive to first-line therapy, treatment with Zevalin consolidation does not impact the health-related QoL compared with no further treatment.

Commentary on abstract 3412

Recurrence in follicular lymphoma is likely due to treatment that has failed to eradicate disease at the molecular level. In FIT, peripheral blood samples were collected at baseline to determine Bcl-2 PCR status prior to study entry and PCR analyses were repeatedly carried out throughout the study and thereafter. Overall, consolidation with RIT significantly increased PFS by nearly 2.5 years compared with controls in patients who were Bcl-2 PCR-positive at baseline. Interestingly, among patients who received RIT, median PFS was similar between those who were PCR-positive at baseline and those who were PCR-negative. Consolidation of first CR/CRu with 90Y-ibritumomab also converted 90% of patients who were Bcl-2 PCR-positive to PCR negativity. In contrast, only 36% of control patients who were Bcl-2 PCR-positive at baseline had converted to PCR-negative status at the time of evaluation. Molecular responses in FIT closely reflected clinical responses, confirming prospectively for the first time that achievement of a molecular response appears to be associated with improved outcome. Median PFS in those who converted from PCRpositive status to PCR-negative status was 40.8 months for the RIT arm vs. 24 months for controls.

[3412] Radioimmunotherapy with 90Y-Ibritumomab Tiuxetan (Zevalin) as Consolidation of First Remission in Patients with Advanced Stage Follicular Lymphoma: A ‘Real-Time’ MBR RQ-PCR Analysis. L. Goff, K. Summers, S. Iqbal, J. Kuhlmann, M. Kunz, A. Hagenbeek, A. Lister, A. Rohatiner

Introduction: The randomized phase 3 First-line Indolent Trial (FIT) was conducted in newly diagnosed patients (pts) with stage III or IV follicular lymphoma (FL) to investigate the use of 90Y-ibritumomab tiuxetan (Zevalin) given as consolidation of first complete (CR/CRu) or partial remission (PR). Bcl-2 status was evaluated using ‘real-time’ quantitative PCR (RQ-PCR) for the major breakpoint region (MBR) Bcl2-IgH rearrangement at the time of randomization and at follow up (after treatment with Zevalin or observation).

Methods: Peripheral blood samples were available for RQ-PCR analysis from 77 centers for 414 pts with grade 1 or 2 FL, in CR/CRu (n=216) or PR (n=198) following initial therapy. Pts were randomized to receive either Zevalin (n=208) or no further treatment (control; n=206). Initial therapies included CVP, CHOP/CHOP-like regimen, fludarabine combinations, chlorambucil and rituximab + chemotherapy. Zevalin treatment comprised rituximab 250 mg/m2 on day -7 and day 0, followed on day 0 by Zevalin 0.4 mCi/kg (maximum dose: 32mCi). Peripheral blood samples were analyzed using standard methodology (Summers et al J Clin Oncol 2001;19:420), a result of 1 in 105 being regarded as negative. Only pts for whom clinical data, a peripheral blood sample at the time of randomization, and at least 1 follow-up sample (post-treatment for Zevalin arm; post-randomization for control arm) were available have been included in this analysis. Because not all pts with FL have an MBR rearrangement, the analysis was limited to those showing RQ-PCR positivity at some point.

Results: Overall, 127/291 pts (44%) who fulfilled the above criteria were RQ-PCR positive at the time of randomization, ie, 68/141 (46%) and 59/150 (39%) in the Zevalin and control arms, respectively. Progression-free survival (PFS) of the control arm served as an internal control and benchmark. In the control arm, the 59 pts who were RQ-PCR positive at time of randomization had a median PFS of 8.2 months, compared with 2.4 years for the 91 pts who were RQ-PCR negative. In the Zevalin arm, the 73 pts who were RQ-PCR negative at the time of randomization had a median PFS of 3.1 years compared with 3.2 years for the 68 pts who were RQ-PCR positive. At the time of the follow-up evaluation, 61/68 pts (90%) who received Zevalin consolidation and 21/59 pts (36%) in the control arm converted from RQ-PCR positive to negative status. The 61 Zevalin-treated pts who converted had a median PFS of 3.4 years compared with 2 years for the 21 pts who converted in the control arm (p<0.005). Clinical evidence of recurrent lymphoma was observed in 24/61 (39%) and 16/21 (76%) of pts who converted to RQ-PCR negative status in the Zevalin and control arms, respectively.

Conclusions: Conversion to RQ-PCR negativity was observed in both arms but was more frequent in the Zevalin arm. Treatment with Zevalin consolidation resulted in 90% of pts converting from RQ-PCR positive to negative status; this was associated with significant prolongation of PFS compared with the control arm.

Commentary on abstract 1360

Monoclonal antibodies are highly effective when added to chemotherapy in a variety of B-cell lymphomas, especially low-grade and follicular lymphomas. RIT given as a single front-line therapy is also an effective approach, while maintenance rituximab has proven superior compared with observation in the setting of relapsed disease. The Rush University Medical Center is currently administering RIT within six to eight weeks following an abbreviated course of chemotherapy (four months), followed by maintenance rituximab, given six months after RIT. Interim results in 20 patients from this single-centre experience showed an overall response of 100%, with a CR of 70% and a PR of 30%. Interestingly, CR rates increased from about 40% after chemotherapy to approximately 50% after RIT, then to 70% during or after maintenance rituximab. Minimal side effects have been seen with RIT use, and its earlier use as consolidation therapy following chemotherapy is associated with less hematologic toxicity. This study supports findings from FIT which demonstrated that chemotherapy could be successfully followed with consolidation RIT but that additional maintenance rituximab might lead to more durable responses.

[1360] A Prospective Study Evaluating the Safety and Efficacy of Combination Therapy with Fludarabine Plus Mitoxantrone Followed by Yttrium-90 (90Y) Ibritumomab Tiuxetan (Zevalin) and Maintenance Rituximab as Front Line Therapy for Patients with Intermediate or High Risk Follicular Non-Hodgkin’s Lymphoma. S.A. Gregory, M. Kassar, H.C. Fung, P. Venugopal, T.M. O’Brien, M. Tenuto

Background: The combination of fludarabine and mitoxantrone (FM) as a front line therapy for advanced follicular lymphoma (FL) has been shown to result in higher complete response rates when compared with standard-dose CHOP. We assessed the safety and efficacy of FM followed by 90Y-ibritumomab tiuxetan (IT) and maintenance rituximab (MR) in previously untreated patients (pts) with FL.

Methods: Pts with newly diagnosed stage III-IV FL and an intermediate or high FLIPI scores were eligible. Pts were required to have an expected survival of at least 3 months, a performance status =2, and adequate bone marrow (BM) function (ANC 1500/mm3, platelets 100,000/mm3), liver, and renal function. Initial treatment consisted of 4 cycles of FM (fludarabine 25 mg/m2 on days 1-3, mitoxantrone 12 mg/m2 on day 1 of each 28-day cycle). After restaging, complete and partial responders with =25% BM involvement proceeded to the IT therapeutic regimen. Partial responders with >25% BM involvement received 2 additional cycles of FM before IT. The 90Y IT dose (0.3 or 0.4 mCi/kg) was adjusted according to the patient’s platelet count. MR (375 mg/m2 weekly ×4) was scheduled for every 6 months over 2 years.

Results: Twenty patients have been enrolled. The median age was 53 years (range: 32-79), and 12 pts were male. 14 pts had stage IV with BM involvement and 6 had stage III. The median FLIPI score was 2 (range, 1-4). Only 1 pt had 6 cycles of FM. At the time of this analysis: 13 pts underwent therapy with IT, 3 of them finished MR cycles, 1 had 3 cycles, 5 had 2 cycles, 1 had 1 cycle, and 3 are still awaiting their first cycle of MR. 7 pts finished FM therapy but still awaiting treatment with IT. Overall response was achieved in 100% of pts; CR in 14/20 pts (70%) and PR in 6/20 pts (30%). The responses to FM were converted from PR to CR in 5 pts: 1 after IT, 1 after 2 cycles of MR, and 3 after completing MR. Grades 3 or 4 hematologic toxicities were encountered in 6/20 pts (30%); with grades 3 or 4 neutropenia in 5 pts (25%) and grades 3 or 4 thrombocytopenia in 5 pts (25%). Platelets, ANC, and hemoglobin nadirs occurred at 3-7 weeks following 90Y IT, and were reversible with median duration of nadirs of 4 weeks (range: 1-5). After median follow up of 16 months (range 3.5-39), only one pt developed progressive disease 14 months from registration, and after receiving IT therapy. Repeat BM biopsy at progression showed FL with focal areas of blastoid transformation. No death event has been reported to date.

Conclusions: The initial results from this prospective study suggest: 1- FM followed by 90Yibritumomab tiuxetan and maintenance rituximab regimen is safe and highly effective front line therapy for pts with intermediate or high risk FL (advanced stage with intermediate or high FLIPI scores at diagnosis). 2- The addition of IT and MR to the overall treatment strategy improves the quality of responses; and 3- Though the response rates are encouraging, longer follow-up will be required to evaluate the impact on progression-free survival and overall survival.

Commentary on abstract 389

Very high response rates in excess of 90% are possible in mantle cell lymphoma (MCL) with R-CHOP but responses are not durable, with median PFS rates of about 1.5 years. More intensive consolidation with stem cell transplantation may not be an option for many patients and alternative consolidation strategies are needed. As MCL is highly radiosensitive, ECOG investigators evaluated the use of 90Y-ibritumomab given between four and eight weeks after completion of four cycles of R-CHOP to patients without progressive disease in bone marrow following induction chemotherapy. Fifty-seven patients were accrued to the study and 53 are evaluable. Following R-CHOP, there was a 70% response rate, with a CR rate of 13%. Following RIT, the response rate increased to 88% while the CR rate rose to 55%. Median PFS among all 57 patients was 27 months and 31 months among the 52 who received RIT. No difference in PFS was seen between older and younger patients. Findings to date suggest PFS intervals are longer with the addition of RIT than after R-CHOP alone.

[389] Phase II Study of R-CHOP Followed by 90Y-Ibritumomab Tiuxetan in Untreated Mantle Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499. M. R. Smith, L. Zhang, L. I. Gordon, J. Foran, B. Kahl, R. D. Gascoyne, R. Advani, E. Paietta, E. Weller, S. J. Horning

Background: As MCL has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate, 90Y-ibritumomab tiuxetan (90Y-RIT), following 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction.

Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) =18 yr with measurable/evaluable disease and adequate organ function were eligible. At 4-8 weeks after 4 cycles of R-CHOP, responding (CR/PR) and stable pt received 0.4 mCi/kg 90Y-RIT. The primary endpoint was failure-free survival (FFS) and secondary objectives were evaluation of response and toxicity after R-CHOP and after 90Y-RIT. The study design required 52 eligible pt to demonstrate a prolongation of FFS by 50% compared with R-CHOP alone (median FFS 16 mo, Howard et al., JCO 20:1288, 2002). Results: The characteristics of 56 eligible pt are: 73% male, median age 61 (33-83) yrs, 91% stage III/IV, 68% >1 extranodal site, 78% marrow-positive. IPI was 0-2 in 51%, 3-5 in 49%. Fifty-one (91%) pt received all treatment and best response (n=50) was 42% CR/CRu, 32% PR, 12% stable and 4% unevaluable, with an improvement in response in 16 pt after 90Y-RIT. After 90Y-RIT, 55% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 22/23 pt. Median follow-up (all pt) is 24.4 months. Median FFS for all 56 pt is 27 months with an estimated 71% FFS and 93% overall survival at 18 months. Among pt who completed all treatment and have been followed =1.5 yr (n=45), 33 remain failure-free and 12 have progressed (4 dead).

Conclusion: 90Y-RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. These data suggest prolongation of FFS over that expected with R-CHOP alone. Consolidation of remission in MCL with 90Y-RIT shows potential as a strategy to prolong remission duration and is applicable to most pt with MCL. However, longer follow-up in needed to evaluate the durability of remissions achieved.

Commentary on abstract 22

The course of low-grade B-cell lymphoma is characterized by multiple remissions and relapses. Intensive high-dose chemotherapy or chemoradiotherapy followed by autologous stem cell transplantation (ASCT) is a potentially curative strategy. In this cohort of 77 refractory patients, those who achieved a CR, a CRu or a PR on their last salvage regimen received conventional doses of 90Y-ibritumomab along with a standard BEAM regimen, after which they underwent ASCT. Prior to ASCT, there was a 77% CR rate, while following transplantation, 64% of the remaining 75 patients had a CR, 24% had a CRu and the remainder had a PR. Toxicity during the Z-BEAM component of the regimen included grade 3-4 mucositis in 48% of patients and unexplained fever in 51%. No toxic deaths occurred during ASCT and reconstitution of blood parameters occurred quickly. At a medium follow-up of one year, there was only one death and very few adverse events. GELA investigators suggested that 90Y-ibritumomab can be safely combined with high-dose chemotherapy. It has a toxicity profile that is very similar to that seen with the BEAM regimen alone, and 90Y-ibritumomab could replace adjuvant radiotherapy or total body irradiation in conditioning regimens for B-cell lymphoma.

[22] 90Yttrium Ibritumomab Tiuxetan (Zevalin) Combined with BEAM (Z-BEAM) Conditioning Regimen plus Autologous Stem Cell Transplantation in Relapsed or Refractory Follicular Lymphoma. GELA Phase II Study. C. Gisselbrecht, D. Decaudin, N. Mounier, H. Tilly, V. Ribrag, C. Sebban, N. Milpied, F. Morschhauser, B. Coiffier, S. Le Gouill, P. Lederlin, R. Delarue, G. Laurent, A. Bosly

Autologous stem cell transplantation (ASCT) is widely used in relapsed or refractory low grade lymphoma with conditioning regimen including chemotherapy with or without total body irradiation (TBI). Radiolabelled immunotherapy 90Yttrium ibritumomab tiuxetan (Zevalin) is effective in B-cell lymphoma and delivers targeted radiation without TBI toxicity. To take advantage of this antilymphoma effect, conventional dose of 90Yttrium ibritumomab tiuxetan 15 MBq/kg (maximum 1200 MBq, total dose) was given without dosimetry day -14 before ASCT and combined to standard BEAM regimen starting at day -7. The goal of this phase II study was to evaluate efficacy and toxicity of Z BEAM. Patients <65 years with CD20+ low grade B cell Lymphoma in 1st or 2nd relapses, or not achieving complete remission after first line treatment were included in the trial. They had to be chemosensitive to last salvage therapy, no more than three lines of treatment and eligible for ASCT. The primary end point was to detect a 2 yrs EFS at least 80%. Hematological reconstitution was evaluated after transplant and during the first year follow up. From 3/2005 to 8/2006, 77 patients were included. Patients characteristics at inclusion: 90% follicular lymphoma, median age 53 yr. (31-64), FLIPI <3, 74%, bone marrow involvement, 22%. Median delay between first line and ASCT was 31 months and median last salvage and ASCT 4.4 months. Response rate before ASCT were CR 36%, CRu 41%, PR 22%, stable 1%. As first line treatment, all pts received mostly CHOP associated in 29 cases with rituximab; 29 patients had relapsed and received a second line chemotherapy with rituximab in 22 cases; 48 patients who did not achieved remission after first line treatment received another line of chemotherapy before ASCT. Overall, among the 77 pts last salvage chemotherapy regimen included rituximab in 74 pts. The haematological reconstitution after Z-BEAM followed by ASCT in 75 pts was: time to neutrophils >1G/L 12 days (9-35), time to platelets >20 G/L 12 days (3-42). Median number of platelets transfusions 4; red blood cell transfusions 2. Grade 3-4 toxicities were: infection 83%, mucositis 47%, pulmonary 4%. Safety data indicated 35 serious adverse events in 24 patients that did not appear to significantly differ from those usually seen after ASCT. No toxic death was observed. At week 12 and 42 after ASCT, median haemoglobin level were 11.6 g/dl and 11.3 g/dl, median platelets counts was 111G/L and 148 G/L, leucocytes counts 3.48 G/L and 4.80 G/L respectively. Only 5 events were reported. After a minimum follow up of one year for all patients, estimated 2 years EFS is 93%. Updated results on survival will be reported.

Conclusion: Z BEAM is a safe conditioning regimen which can be used for B cell lymphoma. Longer follow up is necessary to evaluate long term toxicity and efficacy. Further randomized study are warranted.