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Partially T-Cell–Depleted Allogeneic Stem-Cell Transplantation for First-Line Treatment of Multiple Myeloma: A Prospective Evaluation of Patients Treated in the Phase III Study HOVON 24 MM

Henk M. Lokhorst, Christine M. Segeren, Leo F. Verdonck, Bronno van der Holt, Reinier Raymakers, Marinus H.J. van Oers, Renee M.Y. Barge, Harry C. Schouten, Petra H.M. Westveer, Monique M.C. Steijaert, Jan J. Cornelissen, Pieter Sonneveld for the Dutch-Belgian Hemato-Oncology Cooperative Group

From the Department of Hematology, University Medical Center Utrecht, Utrecht; Department of Hematology and HOVON Data Center, Erasmus Medical Center, Rotterdam; Department of Hematology, University Medical Center Nijmegen, Nijmegen; Department of Hematology, Academic Medical Center, Amsterdam; Department of Hematology, Leiden University Medical Center, Leiden; and Department of Hematology, Academic Medical Center, Maastricht, the Netherlands.

Address reprint requests to H.M. Lokhorst, MD, PhD, Department of Hematology, University Medical Center Utrecht, HP G03.647, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; email: H.Lokhorst{at}azu.nl.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine in a prospective study the efficacy, toxicity, and long-term outcome of up-front allogeneic stem-cell transplantation (allo-SCT) in multiple myeloma (MM).

Patients and Methods: In the prospective phase III study by the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON), HOVON 24 MM, 53 patients with an HLA-identical sibling (median age at transplantation, 48 years; range, 31 to 56 years) were allocated to a partial T-cell–depleted allo-SCT after induction therapy.

Results: The overall response rate after allo-SCT was 89% (47 of 53 patients), including the 19% of patients (10 of 53 patients) with a complete remission (CR). Five patients achieved a CR only after allo-SCT. Five (71%) of seven primary refractory patients obtained a response to allo-SCT, all of whom had a partial remission. With a median follow-up of 38 months (range, 25 to 61 months), 20 patients are alive since allo-SCT and 33 patients have died (14 from progressive disease, 18 from treatment-related mortality [TRM], and one from another cause). Occurrence of acute graft-versus-host disease grades 2 to 4 predicted for higher TRM in a time-dependent analysis. The median progression-free survival time after allo-SCT was 17 months. Median overall survival time after allo-SCT was 25 months, or 29 months from the start of therapy. Only three patients are in continuing CR, indicating that the potential cure rate of this approach is, at best, 6%.

Conclusion: This first prospective evaluation of up-front allo-SCT of MM in a multicenter setting does not support the use of T-cell–depleted myeloablative allo-SCT as part of first-line therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HIGH-DOSE CHEMORADIOTHERAPY has improved response rates dramatically in multiple myeloma (MM). Especially when applied early in the course of the disease, myeloablative treatment followed by autologous stem-cell rescue may induce responses in more than 80% of the patients, including a considerable number of patients with a complete response.^1–4 To date, only one phase III trial has been published indicating that intensive treatment may also improve overall survival (OS) compared with conventional chemotherapy.⁵ A better survival also was observed by the Nordic Myeloma Study Group, which compared patients treated with melphalan 200 mg/m² with historical controls.⁶ However, it remains questionable whether chemoradiotherapy alone can eradicate the clonogenic myeloma cell. There is no plateau in the progression-free survival (PFS) and OS curves after autologous stem-cell transplantation (auto-SCT), and even patients in so-called complete remission (CR) continue to relapse. This is in accordance with the observation that after myeloablative therapy followed by auto-SCT, molecular remissions are rare.⁷

Recently, the existence of a graft-versus-myeloma (GVM) effect was proven by the induction of remissions with donor lymphocyte infusions (DLI) in patients with relapsed MM after allogeneic stem-cell transplantation (allo-SCT).^8,9 In a recent update of 27 patients, response to DLI was 52%, and 30% of patients attained a CR. In three patients a molecular remission after DLI has been sustained for more than 48 months, indicating a curative potential of adoptive T-cell therapy in MM.¹⁰

However, the necessity of performing allo-SCT in MM is still disputed. Median OS time in different reports varies from 18 to 28 months from transplantation.^11–16 A survival advantage for patients receiving an allo-SCT, compared with patients with matched characteristics who were treated with auto-SCT and no SCT at all, has not been shown. In a retrospective case-matched analysis performed by the European Bone Marrow Transplantation (EBMT) registry, the OS of patients receiving auto-SCT was significantly better than that of patients receiving allo-SCT. Only for patients alive at 1 year after transplantation were OS and event-free survival prolonged after allo-SCT.¹⁷ A major reason for the poorer outcome of patients receiving allo-SCT is the high rate (± 40%) of treatment-related mortality (TRM), which is not compensated for by a higher CR rate or a lower relapse rate. Important factors responsible for the excessive toxicity of allo-SCT in MM may be the high percentage of pretreated and refractory disease, the immunosuppressive state, and the relatively high age of patients included in published studies.

Since 1991, two intensive-treatment protocols for MM were performed in the Netherlands and Belgium under the auspices of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). In the recently closed phase III HOVON 24 MM trial with 453 patients, interferon alfa-2a (IFN-2a) maintenance was compared with auto-SCT and IFN-2a maintenance after intensive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD)¹⁸ and intermediate-dose melphalan 70 mg/m².¹⁹ Patients younger than 56 years of age with an HLA-identical sibling could be allocated to allo-SCT after induction therapy. This approach was chosen to evaluate the efficacy of early allo-SCT on TRM and the possible favorable effect of allo-SCT on long-term outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients and Study Design
Four hundred fifty-three patients were included in the HOVON 24 MM study between November 1, 1995, and April 1, 2000. Criteria for inclusion were previously untreated MM stage II and III, World Health Organization (WHO) performance status of 0 to 3, and absence of severe cardiac, pulmonary, neurologic, or metabolic disease. All patients gave written informed consent. The study was performed according to the Helsinki agreement. The outline of the HOVON 24 MM study is shown in Fig 1. After VAD, patients with a WHO performance status of 3 or 4, severe cardiac/pulmonary disease, or inadequate liver function were taken off protocol treatment. HLA typing of patients up to 55 years old was performed in the first 3 months of treatment. Patients who had an HLA-identical donor were allocated to undergo allo-SCT. Eligibility criteria for allo-SCT included a WHO performance status of 0 to 2, absence of severe cardiac or pulmonary disease, and serum creatinine 177 µmol/L. Patients with refractory disease were also allowed to proceed. In November 2001, the data of the first 379 eligible patients were analyzed to present preliminary results to the Dutch National Health Council. Among them were 56 patients who had undergone an allo-SCT. One patient with an identical twin and two patients without any T-cell depletion were excluded from the analysis. The results of the remaining 53 patients presented here are based on the data available in January 2003. Patient characteristics at diagnosis are shown in Table 1.

View larger version (24K): [in this window] [in a new window]   Fig 1. Flow sheet of the HOVON 24 MM study. VAD, vincristine, doxorubicin, dexamethasone; IDM, intermediate-dose melphalan; Cyclo, cyclophosphamide; TBI, total-body irradiation; Ida, idarubicin; IFN, interferon alfa-2a; allo-SCT, allogeneic stem-cell transplantation; auto-PBSCT, autologous peripheral-blood stem-cell transplantation; G-CSF, granulocyte colony-stimulating factor.

Graft-Versus-Host Disease (GVHD) Prophylaxis and Evaluation
Different methods of T-cell depletion were performed. The soybean agglutinin/sheep RBC method was used in three patients.²⁰ Because this technique has the risk of transmitting prions or viruses, it was no longer applied after 1997. The other methods included immunorosette T-cell depletion using CD2/CD3 tetrameric complexes (n = 19), CD34⁺ selection (n = 18), and counterflow elutriation (n = 6).^21–23 The T-cell number in the grafts varied between 1 and 7 x 10⁵ T cells/kg. Prophylactic immunosuppression consisted of cyclosporine only. In seven patients, in vitro T-cell depletion was performed with alemtuzumab (Campath-1, Cambridge, United Kingdom).²⁴ Acute and chronic GVHD were evaluated according to standard criteria.²⁵

Cytomegalovirus (CMV) Monitoring and Treatment
CMV seropositive patients were monitored by the immediate early antigen assay once a week, as described previously.²⁶ Pre-emptive ganciclovir therapy was initiated (5 mg/kg intravenously twice daily) if four or more positive leukocytes were identified or if the patient had GVHD grade 2 to 4 for which high-dose corticosteroids were prescribed. CMV disease was diagnosed as described previously.²⁶

Response Criteria
CR was defined as the complete disappearance of myeloma proteins from blood and/or urine as determined by immunofixation and normalization of the bone marrow. In addition to the CR criteria of the Autologous Blood and Marrow Transplant Registry/International Bone Marrow Transplant Registry criteria, monoclonal plasma cells, as determined by cytoplasmic staining with monoclonal antibodies against light and heavy chains, had to be absent in cytocentrifuged bone marrow cells. Monoclonality was defined as a kappa-to-lambda ratio of more than 85:15 (or vice versa) within the relevant (tumor) heavy chain. Partial remission (PR) was defined as a decrease of more than 50% of monoclonal proteins in the peripheral blood and a decrease in urinary light-chain excretion to less than 0.2 g/24 h, combined with improvement of myeloma-related symptoms such as bone pain, anemia, and hypercalcemia. Relapse from CR was defined as reappearance of monoclonal proteins in serum and/or urine and/or recurrence of bone marrow infiltration. Progression from PR was defined as doubling of measurable myeloma proteins in two samples at least 4 weeks apart, doubling of bone marrow infiltration, or progression of myeloma-related symptoms.

End Points and Statistical Analysis
The data were first analyzed as of November 15, 2001, and the results presented are based on the data as of January 6, 2003. End points included response rate, time to acute GVHD grades 2 to 4, PFS, time to progression (TTP), OS, and TRM.

Time to acute GVHD grades 2 to 4 was calculated from the date of transplantation until occurrence of acute GVHD of at least grade 2. Patients who died before 100 days after transplantation (n = 2) without having suffered from acute GVHD grade 2 to 4 were censored at the date of death.

PFS was determined from transplantation until progression, relapse, or death, whichever came first. TTP was measured from transplantation until progression or relapse; patients who died of MM with no date of progression specified were considered to have progression at the date of death. Patients who died from other causes were censored at the date of death.

OS was calculated from transplantation until death. Patients still alive at the date of last contact were censored. Patients who died were scored as death caused by TRM, death caused by progression, or death as a result of another cause. Actuarial failure probabilities were calculated considering these three possible causes of death as competing risks.

Time to acute GVHD grades 2 to 4, PFS, TTP, OS, and TRM were estimated by the Kaplan-Meier method, Kaplan-Meier curves were generated to illustrate survival, and the log-rank test was used to compare survival curves between subgroups. Univariate survival analysis was performed using Cox regression. The following variables were included in the analysis of prognostic factors: sex, age, CMV serostatus of the patient and donor (both negative v at least one positive), stem-cell source (bone marrow v peripheral blood; one patient who received a combined graft was included in the peripheral-blood group), CD3⁺ count ( 1.0 x 10⁵/kg v > 1.0 x 10⁵/kg; patients with alemtuzumab T-cell depletion were considered to have received 1.0 x 10⁵/kg CD3⁺ cells),²⁷ beta₂-microglobulin ( 3 mg/L v > 3 mg/L), and disease status at 3 months after transplantation (CR v PR or no response; restricted to the 48 patients who were still alive at 3 months after transplantation). Moreover, a Cox regression analysis, with occurrence of acute GVHD grades 2 to 4 included as a time-dependent covariate, was performed to examine whether acute GVHD grades 2 to 4 predicted for higher TRM, worse OS, and/or worse PFS.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Toxicity of Allo-SCT
GVHD. Acute GVHD grade 1 was present in 20 patients (38%), GVHD grade 2 was present in 18 patients (34%), and six patients (11%) had GVHD grades 3 to 4 (Fig 2). Chronic GVHD could be evaluated in 45 patients. Chronic GVHD was limited in six of these 45 patients (13%) and extensive in 14 patients (30%).

View larger version (8K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve of time to acute graft-versus-host disease (GVMD) grades 2 to 4 from transplantation. The two patients who died before 100 days after transplantation were censored at the date of death. , number of patients with acute GVMD grades 2 to 4.

Outcome of Allo-SCT
Response rate. Forty-six patients (87%) were in remission before allo-SCT, including six patients with a CR and 40 patients with a PR. Seven patients were refractory at the time of transplantation. In 48 patients, the response could be evaluated at 3 months after transplantation. The overall response rate (calculated on all 53 patients) after allo-SCT was 89% (47 of 53 patients), including 19% of patients (10 of 53 patients) with a CR. One patient in CR before allo-SCT progressed immediately after transplantation. Five patients achieved a CR only after allo-SCT. In three patients, the CR is ongoing. Five of seven primary refractory patients obtained a response to allo-SCT; all five had a PR.

Survival. The median follow-up time of the 20 patients who are still alive is 38 months (range, 25 to 61 months); 33 patients have died. Fourteen patients (26%) died from progressive MM, 18 patients (34%) died from TRM (Table 2), and one patient died from another cause. Median OS time was 25 months from transplantation (Fig 3) and 29 months from start of initial therapy. The median PFS after transplantation was 18 months (Fig 4). Patients who were in CR 3 months after transplantation had no significantly longer OS or PFS compared with patients who were in PR or who had no response (Figs 5 and 6).

View larger version (11K): [in this window] [in a new window]   Fig 3. Kaplan-Meier curve of overall survival from transplantation, with treatment-related mortality and death caused by progression/other cause as competing risks. Abbreviations: OS, overall survival; TRM, treatment-related mortality; prog/oth, progression or other cause.

View larger version (12K): [in this window] [in a new window]   Fig 4. Kaplan-Meier curve of progression-free survival from transplantation. Abbreviations: PR, partial remission; NR, no response; CR, complete remission.

View larger version (8K): [in this window] [in a new window]   Fig 5. Kaplan-Meier curve of overall survival by response at 3 months after transplantation. Only the 48 patients who were alive at 3 months are included.

View larger version (11K): [in this window] [in a new window]   Fig 6. Kaplan-Meier curve of progression-free survival by response at 3 months after transplantation. Only the 48 patients who were alive at 3 months are included. Abbreviations: PR, partial remission; NR, no response; CR, complete remission.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This is the first prospective multicenter study of allo-SCT as part of first-line treatment for MM. Patients up to 55 years of age participating in the HOVON 24 MM study with an HLA-identical family donor were allowed to receive allo-SCT. Allo-SCT was performed after induction therapy with VAD alone or after VAD and intermediate-dose melphalan. The OS after allo-SCT is disappointing. Median survival after allo-SCT is 25 months, which is inferior to that observed after standard chemotherapy.²⁸ Only a minority of the patients are in continuing CR, indicating that the potential cure rate of this approach is, at best, 6%. Patients up to 55 years old who had no HLA-identical donor and also were included in the HOVON 24 MM study survived a median of 47 months after auto-SCT or start of IFN-2a maintenance.²⁹ This indicates that either there is no important GVM effect induced after allo-SCT as part of front-line therapy or it does not affect the relapse rate sufficiently enough to detect a therapeutic benefit in this group of patients. As in the retrospective EBMT study, a GVM effect may become detectable only after long follow-up.¹⁷ The lack of GVM may be a result of the fact that a partial T-cell–depleted graft was used in this study, and the outcome may be different for patients receiving a full allograft. In the previous EBMT analysis (with the drawback that it is a retrospective registry-based comparison), however, the outcome of patients receiving full or T-cell–depleted allografts was identical.¹³ In addition, in patients with low-grade lymphomas and acute leukemias, PFS and OS after partial T-cell–depleted allo-SCT or non–T-cell–depleted allo-SCT were not different.³⁰ Only in patients with chronic myeloid leukemia was the relapse rate significantly higher after T-cell depletion.³⁰

Not unexpectedly, an important reason for the inferior outcome after allo-SCT compared with auto-SCT is the significant TRM (34%). In this study, TRM is somewhat lower than usually reported for allo-SCT performed with full allografts in myeloma, but is higher than the TRM of T-cell–depleted allo-SCT in other hematologic malignancies.^{11,13,17,31–33} One of the goals of T-cell depletion is to prevent acute GVHD. In our group, however, 45% of patients suffered from acute GVHD grades 2 to 4. The occurrence of GVHD had a significant impact on TRM. Excessive toxicity continues to be a major problem in MM, even when allo-SCT is applied in patients with a good performance status who receive transplantation early after diagnosis (median interval, 7 months). Our study underscores the inferior outcome of allo-SCT in myeloma. In a controlled setting, there proved to be a high relapse rate and continuing relapses. From these data, it may be concluded that T-cell depletion does not seem to influence the TRM in myeloma. A potential GVM effect may, however, be partially deleted by this procedure. A recent update of the EBMT registry showed a remarkable improvement in outcome after allo-SCT for myeloma during the last decade mainly because of the reduction of TRM.³⁴ However, a plateau in the survival curve was not observed, although the majority of these patients received full allografts.

In a recent study³⁵ of 351 patients undergoing transplantation with CD34⁺-selected cells from HLA-identical siblings, the occurrence of acute GVHD critically depended on the number of CD3⁺ T cells infused. Recipients receiving more than 1.0 x 10⁵ CD3⁺ cells had significantly more acute GVHD grades 1 to 4 than patients receiving a lower number of T cells. In another prospective randomized study,²² the inferior outcome of patients receiving an allogeneic T-cell–depleted peripheral-blood SCT, compared with an allogeneic T-cell–depleted bone marrow transplantation, was mainly because of increased acute GVHD grades 2 to 4, which was related to a higher number of CD3⁺ cells. In our patients, we also found an association between occurrence of acute GVHD grades 2 to 4 and increased risk of TRM. However, and perhaps because of the small number of patients, we could not show that this was a result of a higher number of CD3⁺ T cells infused. In addition (probably also because of the small number of patients), other well-known prognostic factors for myeloma and for outcome after allo-SCT, such as stem-cell source, CMV serostatus of patient and donor, and acute GVHD, had no impact on PFS and OS (results not shown).^26,36

Our results indicate that there is no indication for the use of myeloablative, partially T-cell–depleted, allo-SCT as up-front therapy because of the lack of a significant GVM effect, despite considerable GVHD. One way to avoid excessive toxicity might be the recently published strategy of CD6 depletion as a method of GVHD prophylaxis followed by DLI of CD4⁺ cells to induce a GVM effect.³⁷ However, in this study with 24 patients, although TRM was only 21%, OS was disappointing, with 2-year estimated OS and PFS rates after transplantation of 55% and 42%, respectively. Alternative approaches such as nonmyeloablative SCT are now being explored that include patients with a deletion 13 or with refractory and relapsed disease.^38–40 An important approach may be the use of prophylactic DLIs because this strategy has been shown to be highly effective in relapsed patients after allo-SCT, especially in patients with a low tumor burden after response to reinduction therapy.¹⁰

	NOTES

 
Supported by grant no. Ontwikkelingsgeneeskunde OG 96-020 from the Dutch Ministry of Health.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted April 3, 2002; accepted February 10, 2003.

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