The relevance of high-dose chemotherapy followed by auto-SCT in CLL remains to be defined. The aim of the prospective, randomized, GOELAMS LLC 98 trial was to compare two strategies in previously untreated CLL patients aged <60 years. Conventional chemotherapy (Arm A) consisted of six monthly courses of CHOP followed by six CHOP courses in every 3 months in those achieving a complete or PR. Arm A was compared with high-dose therapy with auto-SCT (Arm B), used as consolidation after three CHOP courses in case of CR or very good PR. A total of 86 patients were enrolled, of which 39 and 43 patients were evaluable in arm A and arm B, respectively. The primary endpoint was PFS. On an intent-to-treat basis and with a median follow-up time of 77.1 (range 1–135.5) months, the median PFS was 22 months in Arm A and 53 months in Arm B (P<0.0001). Median survival time was 104.7 months in arm A and 107.4 months in arm B. This trial demonstrates that frontline high-dose therapy with auto-SCT prolongs PFS but does not translate into a survival advantage in advanced CLL patients in the pre-rituximab era.
B cell CLL is the most common form of leukemia in western countries. It follows an extremely variable course, with survival ranging from months to decades. CLL mostly affects elderly individuals, yet up to 40% of patients with CLL are under the age of 65 at presentation. These patients almost invariably die of their disease or its complications.1 Recently, there has been considerable progress in the identification of molecular and cellular markers that may predict disease progression in CLL patients. Particularly, IgVH mutational status (MS) and cytogenetic abnormalities have strong prognostic value.2, 3, 4 Classically, treatment of CLL was based on alkylating agents, resulting in a modest CR rate without improvement in survival. During the past two decades, the combined use of purine analogs and other cytotoxic agents or monoclonal antibodies like anti-CD20 or anti-CD52 showed promising results, leading to higher CR rates and increased PFS.5, 6, 7 Recently, a German group reported an advantage in terms of PFS as well as OS with a regimen of fludarabine and CY (FC) and rituximab compared with FC alone.8 As demonstrated in other lymphoproliferative disorders, these recent data suggest a correlation between response rate and survival. In the 1990s and in the absence of CLL-effective drug regimens, auto-SCT appeared to be the most promising modality for achieving prolonged disease control in CLL. auto-SCT is based on the observation that for some chemotherapeutic agents, efficacy is linearly related to the dose administered, such that increasing the dose of a given drug may result in higher anti-tumor efficacy. Hence, auto-SCT is a logical approach in CLL, given previous evidence that dose intensification results in increased response rates in patients with CLL. Encouraging clinical and molecular remissions have been reported after auto-SCT, even in patients with poor prognostic features.9, 10 A German risk-matched retrospective comparison of auto-SCT vs conventional chemotherapy showed a survival benefit in auto-SCT patients, even in patients with unmutated IgVH.9 Michallet et al.11 recently reported the EBMT experience in the first randomized trial of autografting vs observation for responding patients: inclusion criterion was patients after first- or second-line treatment; these treatments were left to the discretion of investigators and the trial population was restricted to those who had already achieved a CR, VGPR (very good PR) or nPR.
In 1998, we designed a multicenter, prospective, randomized study to evaluate, on an intent-to-treat basis, the potential benefit of auto-SCT in young high-risk CLL patients.
Patients and methods
CLL was diagnosed according to the criteria established by the National Cancer Institute-Sponsored Working Group in 1996.12 Treatment-naïve patients in Binet stage B or C (with no limitation regarding time from diagnosis),13 aged between 18 and 60 years old, were eligible for the trial. Additional inclusion criteria were: no previous chemotherapy for CLL and no contraindication to intensive therapy and fludarabine treatment. All patients underwent initial staging, including clinical examination, computed tomographic scans of the chest, abdomen, and pelvis; BM aspiration and biopsy for biological diagnosis and staging; assessment of serum-creatinine level to ensure proper renal function; and direct antiglobulin test. Lymphocytes were harvested at diagnosis and cryopreserved for further assessment of MS. No cytogenetic analysis was performed. Peripheral blood and BM aspirate smears, immunophenotypes and biopsy slides were centrally reviewed. All patients provided informed consent before inclusion. The Ethics Committee of Besançon University Hospital approved the study in December 1998. There were 16 participating centers, and patients were randomized through a centralized assignment procedure in Besançon University Hospital. The main end point was PFS from the date of randomization on an intent-to-treat basis. Secondary end points were OS, adverse events and incidence of second neoplasms.
Assessment of response
Response evaluation was assessed according to the National Cancer Institute revised sponsored working group guidelines.12 In addition, VGPR was defined by an infiltration of <30%, as reported by Dreger,14 in BM aspirate associated with a reduction of at least 50% of all measurable lymph nodes and normal blood cell counts.
Conventional treatment (Arm A) consisted of six monthly courses of the CHOP regimen (vincristine 1 mg/m2 i.v., doxorubicin i.v. 25 mg/m2 on day 1, plus CY 300 mg/m2 and oral prednisone 40 mg/m2 from day 1 to day 5) followed by six additional CHOP courses administered every 3 months in patients achieving PR or CR. Patients with stable disease received a consolidation regimen of three to six courses of fludarabine 25 mg/m2 i.v. or 40 mg/m2 orally each day for 5 days. This reference regimen was identical to that published by Leporrier et al.15 The doxorubicin dose in this CHOP regimen is 50% of the traditional dose used for lymphoma. Intensive treatment (Arm B) consisted of three monthly CHOP courses; in patients with VGPR or CR, PBPC mobilization was achieved with CY 3 g/m2 i.v. followed by the sub-cutaneous injection of 10 μg/kg/day G-CSF until harvest could be performed. Patients with PR or stable disease received one to three courses of fludarabine until VGPR or CR was reached then conditioned for PBPC mobilization. The time of PBPC collection was adjusted to obtain at least 2 × 106/kg CD34+ immunoselected cells. CD34+ cell selection was performed using one of the available devices (CliniMACS-Baxter Immunotherapy Division, Munich, Germany or CellPro, Bothell, WA, USA). A backup BM harvest was performed when <2 × 106/kg CD34+ cells were collected. The auto-SCT conditioning regimen consisted of CY 60 mg/kg/day i.v. on 2 successive days, and TBI using 1200 cGy in six fractions over 3 days. G-CSF was recommended after PBPC infusion. Supportive care consisted of valacyclovir or acyclovir plus cotrimoxazole prophylaxis and irradiated blood products for patients receiving fludarabine therapy.
IgVH MS analysis
Genomic DNA was isolated from PBL and subjected to amplification of the VDJ (variable/diversity/joining) gene rearrangements of framework region I using variable VH primers and JH consensus primers of the Ig heavy-chain (IgH) gene according the Biomed-2 protocol.16 PCR clonal products, identified by either Genescan analysis or heteroduplex acrylamide electrophoresis, were spin-column purified (Qiagen, Courtaboeuf, France) then cloned in the TA cloning pGEMT-easy vector (Promega, Charbonnières, France). Plasmid DNA extracted from at least three recombinant bacterial colonies were sequenced in two directions using M13 universal primers with the Big Dye terminator Cycle V3.1 sequencing kit (Applied Biosystems, Courtaboeuf, France). Sequences were aligned with published germline sequences using VBase2 (http://www.vbase2.org/) and/or the International ImmunoGenetics databases (http://imgt.cines.fr/). MS was calculated as the percent deviation from the closest matching germline VH segment. Sequences showing 98% or more homology to the nearest germline gene were considered unmutated.
Each arm was initially designed with a target sample size of 65 included patients to achieve adequate power (β=0.1 and α=0.05) to detect 25% improvement in PFS when comparing the two arms. Because of the development of new therapeutic options, it became progressively difficult to ethically keep proposing arm A to eligible patients, and the study was deliberately closed in 2004. Data used for this analysis were updated as of 20 October, 2010. The χ2-test was used to compare progression rates. All time-to-event distributions were calculated with the Kaplan–Meier method and compared with the log-rank test. Statistical analysis was performed using the SPSS 14.0 software (SPSS inc. Chicago, IL, USA).
From March 1999 to December 2004, 86 patients were randomized. Four patients were excluded because of misdiagnosis (one marginal zone lymphoma, two high grade lymphomas), or patient's refusal (n=1). A total of 82 patients were thus evaluable, 39 in arm A and 43 in arm B. Matutes score17 was ⩾3 in 73 of the 75 evaluable patients. The main characteristics of the 82 patients are reported in Table 1. There were no significant differences between groups in terms of sex ratio, mean age or Binet stage. In 46 of 59 cases (21 in arm A, and 25 in arm B) tested (78%), the VH genes were unmutated (P=not significant).
A total of 30 patients received induction treatment in arm A, 26 with six CHOP courses and 4 with three CHOP courses followed by three to six courses of fludarabine. Other patients progressed before the end of treatment (n=7) or received fludarabine and CY in addition (n=1), or did not receive the planned number of CHOP courses (n=1). In arm B, 29 of 43 patients underwent auto-SCT resulting in 67.44% feasibility. Overall response rates in evaluable patients were 83% (44% VGPR+CR, 39% PR) in arm A before maintenance therapy and 90% (64% VGPR+CR, 26% PR) in arm B before auto-SCT or after three CHOP plus three to six courses of fludarabine in patients with insufficient response before transplantation. After intensification, 28 of 29 auto-SCT recipients were in CR or VGPR (Table 2).
Among the 43 patients in arm B, 30 grafts were harvested. In all 29 patients underwent auto-SCT, with a CD34+ cell selected graft in 14 cases. Mean CD34+ cell count was 3.8 × 106/kg (range, 2.0–5.8 × 106/kg) for selected grafts. Mean CD34+ cell count was 4.7 × 106/kg (2.1–11.0) for non-selected grafts. Because of poor peripheral stem cell collection, BM graft alone was used in two cases (with CD34+ cell selection in one case) or in addition to PB cells in two cases. A total of 14 patients were not intensified because of bacterial contamination of the graft (1 case), death (1 case), poor response (10 cases) or failure to harvest (2 cases). All but one patient showed stable persistent hematopoietic recovery. In the latter patient, who had received a mix of BM and PBPC grafts, platelet counts remained below 50 × 109/L until progression 18 months later. Neutrophil counts reached 0.5 × 109/L after a median of 12 days (range 0–24 days).
On an intent-to-treat basis, the median PFS was 22.0 (95% CI, 12.6–31.3) months in arm A and 53.1 (95% CI, 40.3–65.9) months in arm B (P<0.0001; Figure 1). The median PFS of the 29 autografted patients was 61.3 months (95% CI, 53.3–69.2). Among the 13 patients with mutated CLL, 10 (76.9%) progressed compared with 41 of 46 (89.1%) patients with an unmutated status (not significant). In this subgroup of patients, progression occurred in 21 of 21 in arm A vs 20 of 25 in arm B (P=0.05).
The cumulative number of deaths was 19 in arm A and 16 in arm B. Median survival time was 104.7 (95% CI, 99.9–109.5) months in arm A and 107.4 (95% CI, 58.2–156.6) in arm B. Mean survival time was 101.0 (95% CI, 88.6–113.4) months in arm A and 91.4 (95% CI, 76.8–106.1) months in arm B (Figure 2). In arm A, 16 deaths were related to CLL, including 2 deaths caused by the development of AML and multiple myeloma in progressive patients, and 1 death caused by allogeneic SCT. In arm B, 15 deaths were related to CLL, including 1 toxic death that occurred during the first course of CHOP; one patient with CR died in a car crash 57 months after autologous SCT.
Relapse and second-line therapy
By October 2010, 70 patients had progressed; most of them received fludarabine and/or alemtuzumab and/or rituximab-containing regimens. In arm A, five patients received auto-SCT, four received allogeneic SCT and one received auto-SCT followed by allogeneic SCT. In arm B, two patients received auto-SCT, three received allogeneic SCT, and one received auto-SCT then allogeneic SCT.
Adverse events and secondary cancers
A total of 16 secondary malignancies were observed in 14 patients, eight in arm A including AML associated with a non-melanogenous skin cancer (n=1), three other non-melanogenous skin cancers (one developed after intensification of second-line therapy), one prostate cancer, one breast cancer and one multiple myeloma. The eight secondary cancers in arm B included two non-melanogenous skin cancers, one breast cancer, one bladder cancer, one myelodysplastic syndrome (MDS) and one MDS associated with lung cancer. The first case of MDS with complex karyotype was reported 88 months after intensification in a patient autografted after three CHOP courses. The second case of MDS was reported 78 months after autologous SCT in a patient treated with 2CDA-CY-rituximab 68 months after auto-SCT for relapse. Karyotype was normal. Both patients received a conditioning regimen including CY and TBI, and one graft including CD34+-selected cells and in addition, non-selected backup marrow in one case. Altogether, the rate of secondary cancers was 15% in Arm A and 13% in Arm B.
In Arm A, grade 3 and 4 adverse events consisted of three infectious diseases requiring hospitalization, one rash and one phlebitis. In Arm B, before auto-SCT, grade 3 and 4 adverse events included one lethal septic shock during the first course of CHOP, four bacterial infectious diseases, one pneumocystosis, one aspergillosis, one herpes zona infection, three CMV disease, one phlebitis and one non-specific mild cholestasis, and one case of unexplained neurological disorder leading to interruption of fludarabine.
This study reports on a prospective, randomized trial comparing conventional chemotherapy to a high-dose therapy strategy followed by auto-SCT. On an intent-to-treat basis, this strategy yielded a benefit in terms of PFS in the auto-SCT arm without transplantation-related mortality. PFS benefit was observed irrespective of the MS of the patients. The impact of graft purging could not be assessed in our study because only a small number of patients in specific centers benefited from such preparations. The CHOP regimen reference arm was the standard regimen in France at the start of the study in 1998, before fludarabine was authorized as first-line treatment for CLL. The median survival time (104.7 months) observed in this conventional arm was superior to that of a previous prospective study using the same regimen (67 months).16 Median PFS in the CHOP arm (22 months) was comparable to results reported with fludarabine, bendamustine or alemtuzumab monotherapy in prospective randomized trials (23, 21 and 19 months, respectively)18, 19, 20 Moreover, median PFS in auto-SCT arm (53.1 months) was superior to that reported with the association of fludarabine and CY in four recent prospective trials (48, 31.6, 43 and 32.8 months, respectively).8, 18, 21, 22 It was also similar to the median PFS reported in the FCR (FC plus rituximab) arm of the CLL8 trial (51.8 months).8 It can be argued that in our trial, patients with non-evolutive B Binet stages were included. However, many unmutated patients were included in this trial, suggesting an aggressive disease behavior. We did not observe any OS difference between the two arms, probably because relapses in the observation arm could be successfully treated with salvage therapies.
Only three prospective trials evaluating the role of auto-SCT in first-line CLL patients are reported. In 2005, Gribben10 published on a series of 137 CLL patients transplanted after achieving a good response to previous chemotherapy. The conditioning regimen used by these authors included CY and TBI, and the stem cell source was BM purged in vivo with a cocktail of monoclonal antibodies (B5, anti- CD10 and anti-CD20). TRM was 10% with a 4-year disease-free survival of 63% and an OS of 85%. The majority of patients achieved a complete clinical response after auto-SCT, and over 50% were MRD-free using IgH-PCR with sequence-specific oligonucleotide probes.23 The MRC study enrolled 115 previously untreated patients and followed them prospectively to assess the feasibility of performing auto-SCT.24 On an intent-to-treat basis, 65 of 115 patients proceeded to auto-SCT. Only one patient died of early transplant-related complications and the CR rate after transplantation was 74%. The predicted 5-year OS and disease-free survival were 77.5 and 51.5%, respectively. In all 16 of 20 evaluable patients achieved a molecular CR in the first 6 months following transplantation. Molecular disease detected by PCR was highly predictive of disease recurrence. Finally, Michallet et al.11 recently reported the EBMT experience in the first randomized trial of autografting vs observation for responding patients after first- or second-line treatment. First- and second-line induction treatments were left to the discretion of investigators and were heterogeneous. Moreover, the trial population was restricted to those who had already achieved a CR, VGPR or nPR. They showed that auto-SCT prolonged EFS from 2 years to more than 4 years (median EFS 24.4 months vs 51.2 months), similar to what we observed in the auto-SCT arm.
The feasibility of auto-SCT was quite high (67.44%) and collection of PBSC was possible after fludarabine regimens. However, different reports suggest that previous therapy with purine analogues may impair the ability to mobilize PBSC in sufficient numbers for transplants.25 We did not observe these difficulties, probably because other factors such as the number of previous therapeutic regimens and the time of mobilization may affect the ability to mobilize stem cells. In the future, new mobilization agents like plerixafor can overcome these difficulties. A risk of secondary MDS/AML was also reported after auto-SCT, particularly after TBI.26, 27, 28 Friedberg et al.27 previously observed a high risk of MDS in patients with follicular non-Hodgkin's lymphoma after TBI, but the same authors did not report a higher incidence of MDS in autografted CLL patients. In Gribben's series,10 and with a median follow-up of 78 months, secondary malignancies occurred in 19% of patients at a median of 35 (range 1–138) months, with secondary MDS occurring in 9% at a median of 36 (range 11–87) months after auto-SCT. Of concern, 5 of 65 (8%) patients developed post transplant MDS/AML in the MRC trial.
With a median follow-up of 77 months in this trial, the incidence of secondary cancers was high (15% in Arm A and 13% in Arm B), without any difference between the two arms. This high incidence was mainly due to development of solid tumors; this could be explained by the high usage of alkylating agents (induction treatment, auto-SCT conditioning), as well as the continuing cytotoxic treatment used in repeated relapses. Less cytotoxic and more effective first-line treatment should reduce the risk of secondary malignancies. With a longer follow-up (6.5 vs 5 years) Incidence of secondary MDS/AML was similar to that reported in the EBMT trial (2.7% in the auto-SCT arm)24 yet such adverse events may develop at later stages of follow-up.
Since this trial was started, much progress has been made in CLL treatment; CHOP or fludarabine are not the first treatment choices and FCR has became the gold standard in fit patients without deletion 17. As a result, not only does larger proportion of patients achieve CR, but also in some of these responders there is no evidence of persistent leukemic cells. This is important because achieving MRD-negative status is correlated with longer survival.8, 29, 30, 31, 32, 33, 34 In 2010, the goals of CLL treatment in fit patient should be CR with MRD-negative status. Consequently, new treatment approaches for patients with an initial response to first-line chemotherapy are designed to eliminate MRD or maintain MRD-negative CR. Issues to discuss in this context include the number of FCR courses, necessity of maintenance or consolidation treatment with lymphocyte-depleting monoclonal antibodies and immunomodulatory therapy. In this context, it might be attractive to explore strategies combining fludarabine and rituximab regimens with consolidating autografting to maximize disease control for those patients who have predefined high-risk features.
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The authors declare no conflict of interest.
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Brion, A., Mahé, B., Kolb, B. et al. Autologous transplantation in CLL patients with B and C Binet stages: final results of the prospective randomized GOELAMS LLC 98 trial. Bone Marrow Transplant 47, 542–548 (2012) doi:10.1038/bmt.2011.117
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