Original Paper Received: April 24, 2013 Accepted after revision: December 2, 2013 Published online: April 8, 2014

Acta Haematol 2014;132:226–232 DOI: 10.1159/000357659

Thalidomide, Cyclophosphamide and Dexamethasone Induction Therapy: Feasibility for Myeloma Patients Destined for Autologous Stem Cell Transplantation Won Jin Chang a Eun-Suk Kang b Seung-Tae Lee b Sun-Hee Kim b Dae Won Kim b Seok Jin Kim a Kihyun Kim a   

 

a

 

 

 

 

 

Division of Hematology-Oncology, Department of Medicine and b Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea  

 

Key Words Myeloma · Autologous stem cell transplantation · Induction therapy

Abstract This study explored the effect of thalidomide and cyclophosphamide on stem cell collection, in addition to assessing their efficacy as induction therapy for myeloma patients destined for autologous stem cell transplantation (ASCT). We analyzed newly diagnosed myeloma patients who received TCD (thalidomide 100 mg/day for 28 days, oral cyclophosphamide 150 mg/m2/day and dexamethasone 40 mg/day on days 1–4) as induction therapy prior to ASCT. Peripheral stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide. Thirty-six patients (median age 54 years) received TCD chemotherapy (median 4 cycles). The overall response rate to TCD was 77.8% (28/36). The median number of CD34+ cells was 6.5 × 106/kg, and 2 patients failed to achieve the optimal number of CD34+ cells, i.e. 4.0 × 106/kg, although they were able to attain >2.0 × 106/kg. The overall response rate increased up to 94.4% (34/36) after ASCT; this included 9 patients with a stringent complete response without transplantation-related mortality. Four patients died due to disease progression and 17 were found to have progressed after ASCT (the median progression-free

© 2014 S. Karger AG, Basel 0001–5792/14/1322–0226$39.50/0 E-Mail [email protected] www.karger.com/aha

survival after ASCT was 19.6 months). TCD chemotherapy can be an effective and feasible induction regimen prior to ASCT for myeloma patients. © 2014 S. Karger AG, Basel

Introduction

Autologous stem cell transplantation (ASCT) has been an integral part of the treatment of newly diagnosed myeloma patients since it was found to improve response and survival outcomes in comparison to standard-dose conventional chemotherapy [1–3]. As a result, induction treatment followed by ASCT is now regarded as routine clinical practice for patients eligible for ASCT. As novel agents have been developed, various induction regimens have been tried prior to ASCT. The ideal induction treatment should be effective in reducing tumor burden, while having minimal negative effects on stem cell mobilization. A combination of thalidomide, cyclophosphamide and dexamethasone (TCD) has been widely used in the upfront or salvage setting for treating patients both eligible and ineligible for ASCT [4–8]. The antimyeloma effect of these drugs is mainly based on their activity as immune modulators. It has been postulated that low-dose cyclophosphamide has a similar immune-modulating effect to that of thalidomide Kihyun Kim, MD, PhD and Seok Jin Kim, MD, PhD Division of Hematology-Oncology, Department of Medicine Samsung Medical Center, Sungkyunkwan University School of Medicine 50 Irwon-dong, Gangnam-gu, Seoul 135-710 (Korea) E-Mail kihyunkimk @ gmail.com and kstwoh @ skku.edu

[9, 10]. However, there has been concern regarding the negative influence of both these drugs on stem cell mobilization. This concern is based on observations that melphalan (an alkylating agent like cyclophosphamide) and lenalidomide (an immune-modulating agent like thalidomide) negatively affect stem cell mobilization [11, 12]. While previous studies combining cyclophosphamide and drugs such as bortezomib and dexamethasone provide evidence of a negative effect on stem cell mobilization [13–15], there have been few data on the impact of cyclophosphamide and thalidomide in combination on stem cell mobilization in patients destined for ASCT. One recent study did report a higher rate of failure of stem cell mobilization in patients receiving TCD than in those receiving VAD (vincristine, doxorubicin and dexamethasone) [16]. In that particular study, which focused on a Western patient population, 25.4% of patients failed to achieve a minimum target number of CD34+ cells (2 × 106), suggesting that the combination of thalidomide and oral cyclophosphamide might have additive negative effects on the bone marrow microenvironment with resulting mobilization failure. In a study involving Asian patients, a substantial number of the patients (11.1%) failed to mobilize ≥2 × 106 CD34+ cells/kg [17]. Stem cell mobilization can be influenced by multiple factors with no clear evidence of an additive effect between thalidomide and cyclophosphamide, making it debatable whether, in combination, they have a negative effect on stem cell mobilization. We performed this study to explore the effects of this combination on stem cell mobilization.

Materials and Methods Patients We retrospectively analyzed patients who had received thalidomide, low-dose cyclophosphamide and high-dose dexamethasone (TCD) chemotherapy as induction treatment at the Samsung Medical Center between April 2010 and April 2012. All patients had newly diagnosed myeloma based on the International Myeloma Working Group diagnostic criteria [18], without any history of previous treatment for myeloma. ASCT was planned in all patients after the completion of induction treatment. Clinical data for 41 patients who were initially treated with TCD chemotherapy were obtained. Five patients with evidence of amyloid light-chain amyloidosis were excluded from the study population. Out of 36 patients, 31 underwent ASCT after planned induction treatment with TCD. Five underwent ASCT after their chemotherapy regimens were switched to bortezomib/dexamethasone due to a poor response to TCD chemotherapy. Treatment and Stem Cell Transplantation Patients received 28-day cycles of TCD chemotherapy (thalidomide 100 mg/day, oral cyclophosphamide 150 mg/m2/day on days 1–4 and high-dose dexamethasone 40 mg/day on days 1–4).

TCD and ASCT for Myeloma

Four cycles of TCD induction treatment were planned for patients destined for ASCT. Treatment was given for up to 6 cycles, however, if patients wanted to delay ASCT for personal reasons. All patients received aspirin as prophylaxis for deep-vein thrombosis (DVT) and trimethoprim/sulfamethoxazole for preventing Pneumocystis jirovecii pneumonia. Peripheral stem cells were mobilized by granulocyte colony-stimulating factor (G-CSF) and cyclophosphamide. Cyclophosphamide (2,500 mg/m2) was administered intravenously on day 1. The G-CSF injection (10 μg/kg/day) was started on approximately day 5 after cyclophosphamide chemotherapy, and was repeated daily until the collection of stem cells was completed. This collection was done via a central venous catheter using the COBE Spectra apheresis system. Apheresis was started if the peripheral white blood cell count exceeded 3,000/ml and continued to climb towards the ideal target number of 4 × 106 CD34+ cells per kilogram according to previous studies reporting the optimal number for a single ASCT to be 4–6 × 106 CD34+/kg [19, 20]. If patients failed to achieve the target stem cell collection number, a minimum requirement for ASCT was designated as 2 × 106 CD34+/kg. The cell counts were assessed using a singleplatform method [21]. After stem cell mobilization was completed,  patients received conditioning with high-dose melphalan (200 mg/m2) and underwent ASCT. Response and Toxicity Assessment The response evaluation was repeated after every cycle of TCD chemotherapy with serum and 24-hour urine electrophoresis and immunofixation, and a serum-free light-chain assay. The final response to TCD induction treatment was based on the values for the last evaluation prior to ASCT. The post-ASCT response evaluation was done within 3 months of ASCT and included bone marrow aspiration and biopsy. The international uniform response criteria for multiple myeloma were used for the response assessment [22]. Complete response (CR) was defined as negative immunofixation in the serum and urine, ≤5% plasma cells in the bone marrow and the disappearance of any soft-tissue plasmacytoma. When there was normalization of the free light-chain ratio and an absence of clonal cells in the bone marrow, this was judged as a stringent CR (sCR). Partial response (PR) was defined as a 50% decrease in serum M-protein or a 90% decrease (25% with an absolute increase of ≥200 mg in 24 h. Toxicity of TCD chemotherapy was graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 3.0, and the maximum toxicity grade per patient was recorded. The transplantation-related mortality was defined as the occurrence of any mortality within 100 days of ASCT. Statistical Analysis The Fisher exact test for categorical data and the Mann-Whitney U test for continuous data were used. Post-ASCT survival outcomes were calculated with a Kaplan-Meier curve and were compared using the log-rank test. Post-ASCT overall survival (OS) was calculated from the date of ASCT to the date of any cause-related deaths or the last follow-up date. Progression-free survival (PFS)

Acta Haematol 2014;132:226–232 DOI: 10.1159/000357659

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was calculated from the date of ASCT to the date of disease progression or any cause of death. p < 0.05 was considered statistically significant and the statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS v.12.0).

Results

Characteristics of Patients We analyzed 36 patients who had received the TCD regimen as an induction therapy and who subsequently received high-dose melphalan and ASCT. All patients were 50% plasma cells in the bone marrow (table 1). Cytogenetic information based on conventional cytogenetics and fluorescence in situ hybridization was available for 31 patients. The most common translocation was t(11:14) (n = 9), so 63.9% of the patients (23/36) had ‘standard risk’ cytogenetics as previously reported [23]. Eight of 36 patients (22.2%) were considered to be high-risk, including 5 with t(4:14), 2 with t(14:16) and 1 with cytogenetic deletion 13. One patient was diagnosed with asymptomatic myeloma; in this case, induction treatment was delayed until 3 years after the initial diagnosis. Response to TCD Chemotherapy and Toxicity The median number of TCD chemotherapy cycles was 4 (range 2–6). Twenty-seven patients (75.0%) completed the planned number of 4 cycles. Two received 5 cycles of TCD and 1 received 6 cycles, delaying ASCT for personal reasons. Due to a poor response to TCD, some of the patients stopped earlier than expected: 3 after the 2nd cycle and another 3 after the 3rd cycle. As a result, the confirmed overall response rate to TCD chemotherapy, including CR, VGPR and PR, was 77.8% (28/36; fig. 1). One patient with nonsecretory myeloma could not be evaluated during the treatment period, but their clinical manifestations improved (even though an objective response could not be evaluated). The most common side effects were cytopenia, sensory neuropathy and constipation (47.2, 33.3 and 33.3%, respectively; table 2). However, most adverse events were reversible and did not result in serious harm. Two patients (5.6%) developed grade 3 cytopenia and 3 (8.3%) experienced grade 4 infections, including 2 with pneumonia and 1 with Herpes zoster. Although all patients re228

Acta Haematol 2014;132:226–232 DOI: 10.1159/000357659

Table 1. Patient characteristics

Characteristics

Age, years >60 ≤60 Sex Male Female Hemoglobin, g/dl >10 ≤10 Immunophenotype IgG/κ IgG/λ IgA/κ IgA/λ IgD/λ κ λ Nonsecretory ISS stage I II III DS stage I II III BM PC ≥50% 0.99

Figures in parentheses are percentages. BM PC = Bone marrow plasma cell; DS = Durie-Salmon; ISS = International Staging System; LDH = lactate dehydrogenase.

ceived aspirin for DVT prophylaxis, 1 still developed DVT. This did not result in serious morbidity and was controlled by anticoagulation therapy. Among 7 patients who failed to achieve PR, including 1 case of PD, 5 received bortezomib plus dexamethasone as salvage therapy. The final responses prior to ASCT for these 5 patients was as follows: 2 VGPR, 1 PR and 2 with stable disease (SD). Thus, all Chang/Kang/Lee/Kim/Kim/Kim/Kim

100%

NE (n = 1, 2.8%)

90%

SD (n = 6, 16.7%)

80%

PD (n = 1, 2.8%)

PR (n = 4, 11.1%)

SD (n = 2, 5.6%)

70% PR (n = 11, 30.6%)

60%

VGPR (n = 19, 52.8%)

50% 40%

20% 10%

CR (n = 4, 11.1%)

0%

TCD

Fig. 1. The comparison of response between TCD chemotherapy and post-ASCT.

Table 2. Toxicity profiles following TCD induction chemotherapy

Cytopenia Thromboembolic events Sensory neuropathy Motor neuropathy Constipation Infection Rash

All grades, n (%)

Grade 3 + 4, n (%)

17 (47.2) 1 (2.8) 12 (33.3) 0 (0) 12 (33.3) 8 (22.2) 4 (11.1)

2 (5.6) 1 (3.7) 0 (0) 0 (0) 0 (0) 3 (8.3) 0 (0)

patients could undergo stem cell mobilization with cyclophosphamide plus G-CSF for ASCT. The baseline characteristics for patients were not significantly different according to the response to TCD chemotherapy (table 1). Peripheral Blood Stem Cell Mobilization In order to explore the effect of TCD chemotherapy on peripheral stem cell mobilization, we analyzed the results of the 31 patients who received only TCD induction chemotherapy. The median number of collected CD34+ cells was 6.5 × 106/kg (range 2.6–23.0 × 106/kg). The median number of CD34+ cells on the first day of apheresis was 3.4 × 106/kg (range 0.4–10.4 × 106/kg); 10 patients achieved the target number of cells within 1 day. However, the other 21 (67.7%) needed ≥2 days to reach this target number; 12 TCD and ASCT for Myeloma

CR (n = 1, 2.8%)

VGPR (n = 13, 36.1%)

30%

sCR (n = 10, 27.8%)

Post-ASCT

achieving >4.0 × 106/kg CD34+ cells within 2 days and 9 requiring up to 10 days of apheresis. The median age of patients who required more than 3 or 4 days of apheresis was 56 years (range 51–63). Their immunotypes were IgG/κ (n = 1, 11.1%), IgG/λ (n = 2, 22.2%), IgA/κ (n = 2, 22.2%), IgD/λ (n = 1, 11.1%), the λ type of light-chain disease (n  = 2, 22.2%) and nonsecretory myeloma (n  = 1, 11.1%). They received the median number of 4 cycles of TCD chemotherapy and the overall response rate was 88.9% (PR: n = 3 and VGPR: n = 5). All-grade cytopenia and grade 3 cytopenia developed in 3 (33.3%) and 1 (11.1%) patients, respectively. Apheresis was performed a median number of 4 times and the median number of collected CD34+ cells was 6.5 × 106/kg. In spite of the prolonged apheresis process in these patients, 2 failed to collect the target number of CD34+ cells, i.e. 4.0 × 106/kg. One of them was a 53-year-old female with the λ type of lightchain disease, who completed the planned number of 4 TCD chemotherapy cycles and had a VGPR to TCD. Grade 3 cytopenia developed during chemotherapy. Apheresis was performed and the total number of CD34+ cells collected was 3.99 × 106/kg. The other patient was a 62-yearold man with an immunophenotype of IgA/κ. He also completed the 4 cycles of TCD chemotherapy and had a CR to TCD, with no cytopenia developing. A total of 2.65 × 106/kg CD34+ cells were collected over the 4 days of apheresis. Although the target number of CD34+ cells was not achieved, a cell count of 3.99 or 2.65 × 106/kg is higher than Acta Haematol 2014;132:226–232 DOI: 10.1159/000357659

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1.0

1.0

0.8

OS

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0.6 OS

Survival

0.8

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PFS

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p = 0.0003

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Fig. 2. a The comparison of OS and PFS of patients. b The OS of patients with standard cytogenetic risk was better than that of those with a high cytogenetic risk.

the minimal target number of 2.0 × 106/kg. Thus, there was no mobilization failure in our study. Of the 5 patients who switched to bortezomib and dexamethasone due to their poor response after the 2nd or 3rd cycle of TCD, 4 achieved >4.0 × 106/kg CD34+ cells within 2 days of apheresis. Only 1 required 4 days of apheresis (data not shown). Response and Survival Outcomes for ASCT The majority of patients improved after ASCT, except for the 2 aforementioned patients who showed SD after the salvage therapy with bortezomib and dexamethasone failed to achieve PR. Nine patients, i.e. 3 with a CR, 4 with a VGPR and 2 with a PR after TCD chemotherapy achieved sCR. One with nonsecretory myeloma who could not be evaluated also achieved sCR after ASCT. Thus, the percentage of patients achieving sCR or CR after ASCT was 30.6% (11/36; fig. 1). The other 23 achieved VGPR (n = 19) or PR (n = 4), yielding an overall response rate of 94.4% (34/36) after ASCT. There was no engraftment failure. The median time to engraftment (absolute neutrophil count >0.5 × 109/l and platelet count >20 × 109/l) was day (D)+10 (range D+8–D+14) and D+11 (range D+8–D+21). There were no transplantation-related deaths but 4 patients died due to disease progression, so the median OS after ASCT was not reached (fig. 2a). Seventeen patients showed PD after ASCT, with a median PFS after ASCT of 19.6 months (95% CI 13.1–26.0). The 230

Acta Haematol 2014;132:226–232 DOI: 10.1159/000357659

OS and PFS of 5 patients who switched to salvage chemotherapy were not significantly different from those of patients who received TCD and ASCT (p > 0.05, data not shown). However, the cytogenetic high-risk group showed a significantly worse OS and PFS after ASCT than the patients with a standard risk (fig. 2b; p < 0.05).

Discussion

Multiple myeloma is the second-most common hematologic malignancy, accounting for 10% of blood cancers in Western countries [24]. Its incidence is also increasing in Asia, making myeloma the third-most common hematologic malignancy after lymphoma and myeloid leukemia in Korea [25]. With advances in treatment, including the development of novel agents and the accumulation of experience with these agents, outcomes for myeloma have improved [26]. Newer agents such as bortezomib and lenalidomide have diminished thalidomide’s role in induction treatment, but, owing to the expense of the novel agents, it is still used in many countries. Thalidomide has been widely used in combination with highdose dexamethasone (TD); with other drugs also being incorporated into the TD regimen. Among them, cyclophosphamide is one of the most common to be combined with TD, because it has been reported to increase the efChang/Kang/Lee/Kim/Kim/Kim/Kim

ficacy of thalidomide [27, 28]. In this study, a combination of thalidomide, low-dose oral cyclophosphamide and high-dose dexamethasone yielded an overall response rate of 77.8% (28/36) acceptable hematologic and nonhematologic toxicities (table 2). Furthermore, all patients who received TCD induction treatment achieved a high enough CD34+ cell count (>2.0 × 106/kg) to be able to undergo single ASCT. These results suggest the feasibility of TCD induction treatment of patients for whom ASCT is planned, both in terms of their response and their stem cell mobilization yield. Our study results for stem cell mobilization were different from those of a previous study performed in a Western population [16]. The failure rate for stem cell mobilization was significantly lower in our study; this is likely related to several factors. The total dose of cyclophosphamide per cycle was higher in the Western study (1,500–2,000 mg) than in ours (600 mg/m2) and the total number of cycles was also higher (6 and 4 cycles, respectively). The median age of the study population was younger in our study (54 years, range 35–63) than in the Western study (60 years, range 30–72). Considering the impact of age on the stem cell collection yield, this might have contributed to the better stem cell mobilization results [29]. The fact that there was no failure to collect the minimum number of CD34+ cells was also better than in a recent Asian study that reported an 11.1% of stem cell mobilization failure [17]. However, the overall response rate in our study was lower than that of previous studies that reported it as >95% [16, 17]. Although difficult to compare between studies, these differences in response might be related to differences in unfavorable characteristics such as genetic mutations and serum lactate dehydrogenase [30]. Furthermore, several differences in the treatment protocol such as the dose of cyclophosphamide

and the administration schedule for high-dose dexamethasone might also have affected our response rate. After ASCT, responses improved to the point that 27.8% of patients achieved sCR and all but 2 patients showed at least a PR (fig. 1). This improved response rate after ASCT supports the rationale for upfront ASCT for newly diagnosed myeloma patients. Furthermore, the absence of engraftment failure and transplantation-related mortality implies an advancement of post-ASCT supportive care and an improvement in the quality of collected CD34+ cells. TCD induction treatment may be feasible for myeloma patients who are scheduled for immediate ASCT, particularly in the light of its safety in terms of stem cell mobilization. Unfortunately, a substantial number of patients progressed during follow-up, resulting in a median PFS of 25.6 months (95% CI 17.0–34.2) after ASCT (fig. 2a). So, even though the median OS was not reached, the frequent progression after ASCT observed in our study remains a challenge. Risk stratification by cytogenetics was significantly associated with worse OS in our study (fig. 2b). Our high-risk patients included 5 with t(4:14). Considering that the risk associated with translocation (4:14) is reported to be overcome by treatment with bortezomib [31], this poor outcome in patients with high-risk cytogenetics might reflect the lower efficacy of TCD treatment. In conclusion, our results demonstrate that combination chemotherapy with thalidomide, low-dose cyclophosphamide and high-dose dexamethasone can be a feasible induction regimen for patients planning ASCT.

Acknowledgements This study was supported by a Samsung Biomedical Research Institute grant (CRS1100331).

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Acta Haematol 2014;132:226–232 DOI: 10.1159/000357659

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Chang/Kang/Lee/Kim/Kim/Kim/Kim

Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.

Thalidomide, cyclophosphamide and dexamethasone induction therapy: feasibility for myeloma patients destined for autologous stem cell transplantation.

This study explored the effect of thalidomide and cyclophosphamide on stem cell collection, in addition to assessing their efficacy as induction thera...
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