Autologous Stem Cell Transplantation for Multiple Myeloma: Identification of Prognostic Factors

IntroductionThe purpose of this study was to evaluate the effect of prognostic factors on the outcome of patients with MM after ASCT.Patients and MethodsWe analyzed results of 170 consecutive patients (121 male and 49 female) of MM who underwent ASCT. Patients' median age was 52 years (range, 26-68 years). High dose melphalan (200 mg/m²) was used for conditioning. One hundred thirty-two patients (77.6%) had evidence of chemosensitive disease before transplant. Response was assessed using European Group for Blood and Bone Marrow Transplantation criteria.ResultsPost ASCT 44.7% of patients achieved CR, 24.7% had very good partial response (VGPR), and 21.2% had partial response (PR). Presence of pretransplant chemosensitive disease (CR, VGPR, and PR) and transplant within 12 months of diagnosis for years before 2006 were associated with higher response rates on multivariate analysis. At a median follow-up of 84 months, median overall (OS) and event-free survival (EFS) is 85.5 and 41 months, respectively. Estimated OS and EFS at 60 months is 62 ± 0.04% and 41 ± 0.04%, respectively. Patients who responded to transplant (CR, VGPR, and PR) had a longer OS (P < .001) and EFS (P < .001). Additionally, patients who achieved CR post transplant had a longer OS (P < .001) and EFS (P < .001). Patients who received novel agents for induction pretransplant had a longer OS (P < .001) and EFS (P < .002).ConclusionOutcome after ASCT is better for myeloma patients with pretransplant chemosensitive disease and those who achieve CR after transplant.     

Induction Treatment With Cyclophosphamide,Thalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma: A Phase II Study

Background:Thalidomide has alternative mechanisms of action; it can be combined with dexamethasone or alkylating agents for the treatment of multiple myeloma (MM); however, the optimal doses and appropriate intervals of thalidomide continue to be debated.Patients and Methods:We assessed the clinical efficacy and toxicity of thalidomide in patients with newly diagnosed MM; 68 patients were treated with pulsed cyclophosphamide, thalidomide, and dexamethasone (CTD) chemotherapy for induction treatment.Results:After a median of 28 months' follow-up, the overall response rate was 79.4%, with a 42.6% complete response (CR) or very good partial response (VGPR). Patients with cytogenetically high-risk disease had poor CR/VGPR rates (27.3%) at a median of 11.5 months of time to progression (TTP) compared with patients with standard-risk disease who achieved CR/VGPR rates (50%) at a median of 20.3 months of TTP. The major adverse events included peripheral sensory neuropathy (14.3%), infection (10.2%), and thromboembolic complications (5.9%). Thirty-two patients who achieved more than a PR proceeded to peripheral blood stem cell collection with a median number of 5.0 × 10⁶ CD34⁺ cells/kg collected.Conclusion:CTD resulted in a favorable response with tolerable toxicity in patients with MM and did not affect the yield of the stem cell collection.     

IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy

Background

Immunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes.

Design and methods

Seventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group.

Results

Median age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT.

Conclusions

Despite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients.     

自体造血干细胞移植可使中国高危多发性骨髓瘤患者获益更多

目的 评价自体造血干细胞移植（ASCT）对初治多发性骨髓瘤（MM）的疗效.方法 选取诱导治疗后获得部分缓解（PR）及以上疗效的42例初治MM患者进行ASCT,中位随访34.2个月后,观察患者的疗效、无进展生存（PFS）和总生存（OS）.选择同时期的49例诱导治疗后获得PR及以[上疗效的初治MM患者,进入非移植组（non-ASCT）,经巩固维持治疗后观察疗效、PFS和OS,比较两组的差异,分析ASCT在MM中的作用.结果 与non-ASCT组相比,ASCT可明显延长患者的OS（未达到/37.2个月,P=O.000）,而且对PFS也有延长趋势（33.9个月/39.8个月,P=0.133）.ASCT可明显改善DSⅢ期（P=0.009）和ISSⅢ期（P=0.049）患者PFS,但对DSⅠ /Ⅱ期和ISS Ⅰ/Ⅱ期患者的PFS改善不明显.ASCT可明显改善诱导治疗后获得CR患者的PFS（P=0.016）,对非常好的PR （VGPR） /PR患者的PFS改善不明显;不同年龄患者OS均明显改善（≤55岁,P=0.039;＞ 55岁,P=0.000）.ASCT可明显改善不同ISS分期患者的OS（Ⅰ/Ⅱ期,P=0.003;Ⅲ期,P=0.012）,对DSⅢ期患者的OS也有明显改善作用（P=0.000）,但对DSⅠ/Ⅱ期患者OS的作用不明显（P=0.446）.诱导治疗后获得CR和VGPR/PR的患者进行移植后,OS可进一步得到改善（CR,P=0.004; VGPR/PR,P=0.004）.结论 ASCT可明显改善初治MM患者的生存,使高龄和分期预后不良的MM患者获益更多.     

Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: a retrospective survey of 50 patients

BACKGROUND:

Intracranial involvement in multiple myeloma is extremely rare. The effect of new drugs (eg, thalidomide, bortezomib, lenalidomide) with respect to old drugs (eg, alkylators, steroids) has not been reported.

METHODS:

We collected clinical and biological data of patients presenting with an osteo‐dural or primary dural multiple myeloma (OD‐DMM) or a central nervous system myelomatosis (CNS‐MM) by sending a questionnaire to the centers of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA).

RESULTS:

A total of 50 patients were registered. New therapies were used in 35 patients, whereas 15 patients received old treatments. Twenty‐five out of 50 patients obtained a complete remission or a very good partial remission (CR+VGPR). Overall survival (OS) for CNS‐MM was 6 months, for OD‐DMM 25 months. OS was 25 months for patients treated with new agents versus 8 months with old agents. Improved OS and progression‐free survival were predicted by response (CR+VGPR) and by patients who underwent stem cell transplantation versus chemotherapy. β2‐Microglobulin >5 mmol/L was a poor prognostic factor. Multivariate analysis showed poor survival for patients with β2‐microglobulin >5 mmol/L and better survival for patients achieving CR+VGPR.

CONCLUSIONS:

The overall data highlight the relevance of therapy with new drugs in intracranial myeloma, providing a framework for future clinical trials. Cancer 2011;. © 2011 American Cancer Society.     

PAD及VAD样-T方案治疗多发性骨髓瘤126例效果比较

目的：探讨多发性骨髓瘤（MM）行 PAD 方案（硼替佐米、多柔比星、地塞米松）及 VAD 方案（长春新碱、多柔比星／多柔比星衍生物、地塞米松）联合沙利度胺（VAD 样-T 方案）治疗效果的差异。方法回顾性分析54例接受 VAD 样-T 方案及72例接受 PAD 方案治疗的 MM 患者的疗效,包括完全缓解（CR）率、非常好的部分缓解（VGPR）率、总有效率（ORR）、总生存（OS）、无进展生存（PFS）及不良反应发生情况。结果 PAD 组 CR 率高于 VAD 样-T 组,差异有统计学意义[31.5%（23／72）比9.3%（5／54）,χ2＝0.30,P＝0.002],但是 VGPR 率及 ORR 两组相比差异无统计学意义[16.7%（12／72）比16.6%（9／54）,P＝0.180;82.2%（65／72）比81.5%（44／54）,P＝0.190]。 PAD 组中位 PFS 时间长于 VAD 样-T 组[（38.2±2.2）个月比（28.0±7.6）个月,P＝0.017];PAD 组3年 PFS 率和5年 OS 率高于 VAD 样-T 组,但差异均无统计学意义（均 P＞0.05）。 PAD 组末梢神经损害发生率高于 VAD 样-T 组,差异有统计学意义[31.5%（23／72）比14.5%（8／54）,P＝0.03]。结论虽然 VAD 样-T 方案的 CR 率低于 PAD 方案,中位PFS 时间短于 PAD 方案,但 VGPR 率、ORR、3年 PFS 率、5年 OS 率与 PAD 方案相当,且相对安全,末梢神经损害的发生率相对较低。对于国内无法使用硼替佐米及骨髓移植的初发 MM 患者,可选择 VAD 样-T作为一线诱导化疗方案。     

Flow cytometric minimal residual disease monitoring in patients with multiple myeloma undergoing autologous stem cell transplantation: a retrospective study.

We retrospectively reviewed the flow cytometry (FCM) data from bone marrow aspirates of multiple myeloma (MM) patients before and after autologous stem cell transplantation (ASCT). Light scatter properties and CD38 expression were used to identify plasma cells, and CD19/CD45/CD56 further distinguished normal from abnormal plasma cells (NPC and APC, respectively), the latter defined as plasma cells with aberrant CD56, decreased or absent CD19 and/or CD45 expression. Forty-seven patients were screened. After ASCT, 66% (31/47) patients achieved complete remission (CR)/very good partial remission (VGPR), as compared to only 40% (19/47) prior to ASCT (P = 0.01). In 39 patients with data before and after ASCT, all 39 (100%) had a detectable APC population prior to ASCT. Twenty-six out of 39 patients (67%) also had detectable NPC. Following ASCT, the number of patients with detectable NPC increased to 35/39 (89%), while 3/39 (8%) had no detectable NPC and 1/39 (3%) had neither NPC nor APC. The proportion of APC decreased significantly after transplant from a median of 79% to 52% post-transplant (P < 0.001). The APC/total events ratio decreased significantly (P < 0.0001) after transplant. Prior to transplant, patients with less than 1.8% APC had significantly longer progression free survival (PFS) than patients with greater than 1.8% (P = 0.017, by log rank test), while the difference in overall survival did not achieve statistical significance (P = 0.081). Patients who achieved CR/VGPR after transplant had significantly longer PFS in comparison to all others (26 months vs. 11 months, P = 0.004). In conclusion, the detection of a significant population of APC by FCM prior to ASCT significantly correlates with poorer PFS in MM patients.     

Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation

BACKGROUND:

Indolent nonfollicular non‐Hodgkin B‐cell lymphomas (INFLs) are clonal mature B‐cell proliferations for which treatment has not been defined to date.

METHODS:

In this phase 2 study of patients with advanced INFL, the authors evaluated the efficacy and safety of first‐line rituximab, fludarabine, and cyclophosphamide (FCR) as induction immunochemotherapy (rituximab 375 mg/m² intravenously on day 1 of each cycle and on days 1 and 14 of cycles 4 and 5; fludarabine 25 mg/m² intravenously on days 2‐4, cyclophosphamide 250 mg/m² intravenously on Days 2‐4) every 28 days for 6 cycles followed by a maintenance phase with 4 infusions of rituximab (375 mg/m² intravenously on day 1) every 2 months for responders.

RESULTS:

Forty‐seven patients were enrolled. Among 46 evaluable patients (28 men; median age, 59 years), 19 were diagnosed with lymphoplasmacytic lymphoma, 21 were diagnosed with small lymphocytic lymphoma, and 6 were diagnosed with nodal marginal zone lymphoma. The overall response rate after maintenance was 89.1% with a 67.4% complete remission (CR) rate (CR/unconfirmed CR) and a 21.7% partial response rate. After a median follow‐up of 40.9 months, the failure‐free survival and progression‐free survival rates both were 90.1%, and the overall survival rate was 97.4%. The main toxicity was hematologic, and related grade 3 and 4 neutropenia was observed in 55.3% of patients.

CONCLUSIONS:

FCR induction therapy followed by a short maintenance phase is a highly effective regimen with acceptable toxicity. Cancer 2012. © 2011 American Cancer Society.     

Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study)

Complete response (CR) after treatment for multiple myeloma is associated with superior progression‐free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto‐HCT) between 2010 and 2012. If patients did not achieve CR after auto‐HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto‐HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto‐HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post‐HCT VGPR and in 2 of 12 patients with post‐HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto‐HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post‐HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.     

Daratumumab Improves Depth of Response and Progression-free Survival in Transplant-ineligible,High-risk,Newly Diagnosed Multiple Myeloma

BackgroundPatients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients.Materials and MethodsA pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control.ResultsAmong 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control.ConclusionThese findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients.     

Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma

BACKGROUND:

Early versus delayed autologous stem cell transplantation (SCT) results in comparable overall survival in patients with multiple myeloma (MM) who receive alkylator‐based therapies. It is not clear whether this paradigm holds true in the context of new therapies, such as immunomodulatory drugs (IMiDs).

METHODS:

The authors studied 290 patients with untreated MM who received IMiD‐based initial therapy, including 123 patients who received thalidomide‐dexamethasone (TD) and 167 patients who received lenalidomide‐dexamethasone (LD) induction before SCT. Patients who underwent a stem cell harvest attempt were considered transplantation‐eligible and were included. SCT within 12 months of diagnosis and within 2 months of harvest were considered early SCT (n = 173; 60%). SCT >12 months after diagnosis was considered delayed SCT (n = 112; 40%).

RESULTS:

In the delayed SCT group, 42 patients had undergone SCT at the time of the current report, and the median estimated time to SCT was 5.3 months and 44.5 months in the early SCT and delayed SCT groups, respectively. The 4‐year overall survival rate from diagnosis was 73% in both groups (P = .3) and was comparable in those who received TD (68% vs 64%, respectively) and those who received LD (82% vs 86%, respectively) as initial therapy. The time to progression after SCT was similar between the early and delayed SCT groups (20 months vs 16 months; P value nonsignificant).

CONCLUSIONS:

The current results indicated that, in transplantation‐eligible patients who receive IMiDs as initial therapy followed by early stem cell mobilization, delayed SCT results in similar overall survival compared with early SCT. It is noteworthy that an excellent 4‐year survival rate of >80% was observed among transplantation‐eligible patients who received initial therapy with LD regardless of the timing of transplantation. Cancer 2011;. © 2011 American Cancer Society.     

30例自体外周造血干细胞移植治疗多发性骨髓瘤的疗效及预后因素评价

目的:对30例多发性骨髓瘤（multiple myeloma,MM）患者经自体外周造血干细胞移植（autologous hematopoietic stem cell transplantation ,APBSCT）治疗后的临床疗效进行评估,并分析可能影响预后的因素。方法:30例MM患者有2 例复发行2 次APBSCT,因此共计移植32例次。移植前予常规联合化疗（11例含万珂）,化疗联合G-CSF 动员APBSC ,选择以马法兰为基础的预处理方案,d0 天回输。结果:动员后患者采集的单个核细胞（MNC）中位数为6.41× 108/kg,CD34+细胞4.75× 106/kg。APBSCT后中位中性粒细胞和血小板重建时间分别为9.5 天和11天。APBSCT后CR和VGPR 率分别为37.5% 和34.4% ,中位生存期（overallsurvival ,OS）为67.27个月,中位无进展生存期（progression-freesurvival ,PFS）为29.77个月,其中CR组、PR组中位PFS 分别为29个月、20个月,VGPR 组中位PFS 未达到,CR+VGPR组与PR组PFS 比较P=0.025。万珂组和非万珂组CR率分别为63.6% 和23.8%（P=0.034）,万珂组中位OS及PFS 均未达到,非万珂组中位PFS 为22个月（P=0.045）。 结论:硼替佐米诱导序贯APBSCT可获得更长的无病生存。APBSCT作为MM诱导缓解后的强化治疗,缓解率高,且移植后获得VGPR 以上反应的患者PFS 获益。      

Combination therapy with rituximab and intravenous or oral fludarabine in the first‐line,systemic treatment of patients with extranodal marginal zone B‐cell lymphoma of the mucosa‐associated lymphoid tissue type

BACKGROUND:

Currently, there are no consensus guidelines regarding the best therapeutic option for patients with extranodal marginal zone lymphomas of the mucosa‐associated lymphoid tissue (MALT) type.

METHODS:

Patients with systemically untreated or de novo extranodal MALT lymphoma received rituximab 375 mg/m² intravenously on Day 1 and fludarabine 25 mg/m² intravenously on Days 1 through 5 (Days 1‐3 in patients aged >70 years) every 4 weeks, for 4 to 6 cycles. After the first cycle, oral fludarabine could be given orally at 40 mg/m² on the same schedule. After 3 cycles, a workup was done. Patients who achieved a complete remission (CR) received an additional cycle, and patients who achieved a partial remission (PR) received a total of 6 cycles.

RESULTS:

Twenty‐two patients were studied, including 12 patients with gastric lymphoma and 10 patients with extragastric MALT lymphoma. Six patients (27%) had stage IV disease. In total, 101 cycles were administered (median, 4 cycles per patients). After the third cycle, 13 patients (62%) achieved a CR, and 8 patients (38%) achieved a PR. Primary extragastric disease was an adverse factor to achieve CR after 3 cycles of chemotherapy (hazard ratio, 23.3; 95% confidence interval, 2.0‐273.3). At the end of treatment, the overall response rate was 100%, and 90% of patients achieved a CR. The progression‐free survival rate at 2 years in patients with gastric and extragastric MALT lymphoma was 100% and 89%, respectively. Toxicities were mild and mainly were hematologic.

CONCLUSIONS:

Combination therapy with rituximab and fludarabine is a very active treatment with favorable safety profile as first‐line systemic treatment for patients with extranodal MALT lymphoma. Cancer 2009. © 2009 American Cancer Society.     

硼替佐米联合沙利度胺和地塞米松方案序贯造血干细胞移植治疗初治多发性骨髓瘤的临床观察

目的探讨硼替佐米联合方案序贯造血干细胞移植治疗初治多发性骨髓瘤的疗效和相关毒副作用。方法选取2006年6月至2014年4月初治多发性骨髓瘤33例为研究对象,采用硼替佐米+沙利度胺+地塞米松(BTD)方案诱导治疗(2⁷个疗程),其中14例继以马法兰预处理后行造血干细胞移植;所有患者均接受沙利度胺+地塞米松(TD)或来那度胺+地塞米松(LD)方案维持治疗。随访57个疗程),其中14例继以马法兰预处理后行造血干细胞移植;所有患者均接受沙利度胺+地塞米松(TD)或来那度胺+地塞米松(LD)方案维持治疗。随访5⁹2个月,观察疗效及不良反应。结果 BTD方案诱导治疗后获得完全缓解(CR)、很好的部分缓解(VGPR)、部分缓解(PR)的例数分别为8例(24.2%)、11例(33.3%)、12例(36.4%),总有效率(ORR)为94.0%。14例移植患者中,移植后获VGPR 9例,单用BTD组和序贯移植组的中位随访时间分别为51和32个月,中位生存时间尚未获得,预期3年无进展生存率分别为42.3%和58.7%。BTD方案的不良反应主要为血细胞减少、周围神经病变、带状疱疹病毒感染、便秘、感染和乏力等,大多数患者给予对症治疗后可耐受。结论以硼替佐米联合诱导治疗并以造血干细胞移植序贯治疗多发性骨髓瘤,毒副反应可耐受,疗效显著,生存期较长。     

A randomized study of 2 dose levels of intravenous clofarabine in the treatment of patients with higher-risk myelodysplastic syndrome

BACKGROUND:

Clofarabine is a nucleoside analog with activity in myeloid malignancies. Experience in myelodysplastic syndrome (MDS) is limited.

METHODS:

The goal of this study was to evaluate the activity and safety of 2 different doses (15 mg/m² vs 30 mg/m² daily × 5 days) of intravenous clofarabine in patients with higher‐risk MDS. Fifty‐eight patients with a median age of 68 years (range, 25‐89) including 15 patients (28%) with secondary MDS and 35 patients (60%) who received prior DNA methyltransferase (DNMT) inhibitors were adaptively randomized between the 2 dose cohorts.

RESULTS:

The overall response rate (ORR; based on a modification of International Working Group criteria) was 36% including 26% with complete remission (CR) (ORR, 41% at 15 mg/m² and 29% at 30 mg/m²). Responses were lower in patients who failed DNMT inhibitors (ORR, 17%; CR rate, 14%). The 8‐week mortality rate was 19%. Median survival was 7.4 months for all patients, 13.4 months for responders, and 21.7 months for complete responders. Some adverse events, particularly hepatic and renal, were more severe (grade >2) in patients randomized to 30 mg/m² of clofarabine. Myelosuppression and infectious complications were frequent.

CONCLUSIONS:

Both the lower and higher doses of clofarabine have comparable clinical activity, but the lower dose appeared less toxic. If these results are confirmed, lower doses of clofarabine, possibly in alternative schedules, should be pursued. Cancer 2012;. © 2011 American Cancer Society.     

A phase 2 study of tasisulam sodium (LY573636 sodium) as second-line treatment for patients with unresectable or metastatic melanoma

BACKGROUND:

Tasisulam sodium (hereafter, tasisulam) is a novel anticancer agent that induces apoptosis through the intrinsic pathway and has antiangiogenic activity in preclinical models. Tasisulam demonstrated activity across a broad range of tumors, including melanoma. The primary objective of this phase 2 study was to determine the objective response rate (ORR) in patients who had received 1 previous systemic chemotherapy for unresectable/metastatic melanoma; secondary objectives were to evaluate the clinical response rate (CRR), progression‐free survival (PFS), overall survival (OS), duration of response, safety, and pharmacokinetics.

METHODS:

Tasisulam was administered intravenously on Day 1 of 21‐day cycles according to a lean body weight‐based dosing algorithm targeting a peak plasma concentration (C_max) of 420 μg/mL.

RESULTS:

In 68 enrolled patients, the median age was 59 years (range, 26‐83 years). No patients had a complete response (CR), 8 patients had a partial response (PR), and 24 patients had stable disease (SD); the ORR (CR + PR) was 11.8%, and the CRR (CR + PR + SD) was 47.1%. The median PFS was 2.6 months, and the median OS was 9.6 months. The predominant treatment‐related grade 3/4 toxicity was thrombocytopenia (20.6% of patients). Tasisulam exhibited a biexponential disposition with a predicted distribution half‐life of 0.3 hours to 2.8 hours and a median terminal elimination half‐life of 10 days (consistent with the turnover of albumin), suggesting that tasisulam is very tightly bound to albumin.

CONCLUSIONS:

Tasisulam administered at a targeted C_max of 420 μg/mL on Day 1 of 21‐day cycles demonstrated activity and tolerable toxicity as second‐line treatment in malignant melanoma. These results led to a registration trial in metastatic melanoma. Cancer 2011;. © 2011 American Cancer Society.     

Nodular,lymphocyte‐predominant Hodgkin lymphoma

BACKGROUND:

Nodular, lymphocyte‐predominant Hodgkin lymphoma (NLPHL) represents a rare entity.

METHODS:

A clinical registry was launched from 1973 to 2003 in France. To determine the histologic transformation (HT) rate to diffuse large B‐cell lymphoma (DLBCL) and long‐term outcomes, 164 patients were selected after histologic review.

RESULTS:

The median follow‐up was 9.5 years. The high biopsy rate (85%) at each recurrence enabled the analysis of HT. The median patient age was 30 years (range, 6‐69 years), 80% of patients were men, 83% had Ann Arbor stage I/II disease, 65% had supradiaphragmatic‐disease; 27% received radiotherapy, 9% received chemotherapy, 29% received combined‐modality therapy, and 35% were followed with a watch‐and‐wait strategy. All 106 treated patients achieved complete remission and 66 patients developed disease recurrence at a median of 3.3 years (range, 0.4‐18.3 years after diagnosis). The majority of recurrences were NLPHL, but 19 patients progressed to DLBCL at a median of 4.7 years (range, 0.4‐18 years after diagnosis). The 10‐year cumulative HT rate was 12% and was found to be associated significantly with a poor prognosis. The 10‐year overall survival rate was 91%. Fourteen patients died (7 died of progressive disease, 3 died of secondary cancers, and 4 died from other causes). HT was diagnosed at a median of 4.7 years (range, 0.4‐18 years after diagnosis). The 19 patients who had HT were treated with curative intent: Nine patients received high‐dose therapy with subsequent autologous stem cell transplantation (ASCT), and 10 patients received different chemotherapy regimens. The overall survival rate after HT did not differ between patients who underwent ASCT and the others.

CONCLUSIONS:

This long‐term follow‐up study confirmed that NLPHL is a separate entity that has a favorable clinical presentation and outcome despite frequent recurrences. The current findings also emphasize the importance of biopsies at the time patients develop recurrent disease to evaluate HT. Cancer 2010. © 2009 American Cancer Society.     

High-dose cytarabine induction is well tolerated and active in patients with de novo acute myeloid leukemia older than 60 years

BACKGROUND:

High‐dose cytarabine (HiDAC) is safe and very effective in younger patients with acute myeloid leukemia (AML), but it generally is not well tolerated in the elderly.

METHODS:

The authors explored the safety and tolerability of a modified HiDAC induction regimen consisting of 6 daily doses of cytarabine at 2 g/m² in combination with 3 daily doses of daunorubicin at 45 mg/m² in 59 consecutive patients aged >60 years who had de novo AML diagnosed between July 1996 and February 2005.

RESULTS:

The median patient age was 68 years (range, 60‐86 years). The regimen was well tolerated. Infections were common and occurred in 39% of patients, but cerebellar toxicities occurred in only 7% of patients and were reversible. The day‐30 induction‐related mortality rate was 10%. Overall, 69% of patients achieved complete remissions (CR), and 80% received up to 3 consolidations with HiDAC. The median follow‐up for surviving patients was 53 months (range, 17‐114 months). The median overall survival was 15.3 months (range, 1‐114 months), and the relapse‐free survival was 13.8 months (range, 1‐113 months). Survival for patients who achieved CR was 27 months (range, 2‐114 months).

CONCLUSIONS:

The modified HiDAC regimen was well tolerated in patients aged >60 years with AML and was associated with low induction mortality and high rates of CR. Nevertheless, these high remissions still were associated with poor overall outcomes. Cancer 2011;. © 2011 American Cancer Society.     

Bendamustine is effective therapy in patients with rituximab‐refractory,indolent B‐cell non‐Hodgkin lymphoma

BACKGROUND:

Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single‐agent bendamustine in patients with rituximab‐refractory, indolent B‐cell lymphoma.

METHODS:

Eligible patients (N = 100, ages 31‐84 years) received bendamustine at a dose of 120 mg/m² by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0‐6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression‐free survival (PFS).

RESULTS:

An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).

CONCLUSIONS:

Single‐agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab‐refractory indolent B‐cell lymphoma. Cancer 2010. © 2010 American Cancer Society.     

A Clinical and Correlative Study of Elotuzumab,Carfilzomib, Lenalidomide,and Dexamethasone (Elo-KRd) for Lenalidomide Refractory Multiple Myeloma in First Relapse

IntroductionTreatment of patients with multiple myeloma (MM) in first relapse remains a challenge. This phase II study combined elotuzumab (Elo) with carfilzomib, lenalidomide, and dexamethasone (KRd) for treatment of MM in first relapse with the aim of improving efficacy.MethodsEnrolled patients received Elo-KRd induction for 4 cycles, and Elo-lenalidomide maintenance until progression. The primary endpoint was VGPR or better (≥VGPR) postinduction. Secondary endpoints were MRD by flow cytometry, OS, PFS, and safety. Correlatives included characterization of the impact of Elo-KRd on NK and T cell subsets via flow cytometry. Target accrual of 40 patients was not met due to COVID-19 pandemic.ResultsOf 15 patients enrolled, 10 (67%) had high-risk features (del17p, t[4;14], t[14;16], 1q gain/amplification, plasma cell leukemia, extramedullary MM, or functional high risk), 12 (80%) were lenalidomide-refractory, and 5 (33.3%) bortezomib-refractory. Postinduction ≥VGPR was 7/15 (46.7%) and MRD-negative (10⁻⁵) rate 20%. Overall response during study was 80%, including ≥VGPR as best response of 53.3%. At median follow-up of 28.2 (range, 3.8 to 44.2) months, the median PFS was 11.5 months (95% CI 1.9, 18), and median OS not reached (95% CI 10.1, NA). No new safety concerns were reported. Elo-KRd treatment did not augment NK cell distribution or activity in blood or bone marrow. Effector CD4+ and CD8+ T cells significantly decreased postinduction, with concomitant acquisition of T central memory phenotype, particularly at a high rate in ≥VGPR group.ConclusionA short course of Elo-KRd induction followed by Elo-lenalidomide maintenance demonstrated activity in predominantly lenalidomide-refractory and / or high-risk MM. The results with this well-tolerated combination are comparable to other contemporary approved triplet combinations.