Treatment and outcomes of UK and German patients with relapsed intracranial germ cell tumors following uniform first‐line therapy

We aimed to retrospectively assess treatments/outcomes, including the value of high‐dose‐chemotherapy and autologous‐stem‐cell‐rescue (HDC + AuSCR) and re‐irradiation, in a large, European patient‐cohort with relapsed intracranial germ‐cell‐tumors (GCTs) receiving uniform first‐line therapy, including radiotherapy as standard‐of‐care. Fifty‐eight UK/German patients (48 male/10 female) with relapsed intracranial‐GCTs [13 germinoma/45 non‐germinomatous GCT (NGGCT)] treated 1996–2010 as per the SIOP‐CNS‐GCT‐96 protocol were evaluated. For germinoma, six patients relapsed with germinoma and five with NGGCT (one palliative, one teratoma patient excluded). Five‐year overall‐survival (OS) for the whole‐group (n = 11) was 55%. Four of six germinoma relapses and two of five relapsing with NGGCT were salvaged; patients were salvaged with either standard‐dose‐chemotherapy (SDC) and re‐irradiation or HDC + AuSCR with/without re‐irradiation. Of 45 relapsed NGGCT patients, 13 were excluded (three non‐protocol adherence, five teratoma, five palliation). Five‐year OS for the remaining 32 relapsed malignant NGGCT patients treated with curative intent was 9% (95%CI: 2–26%). By treatment received, 5‐year OS for the 10 patients receiving SDC and 22 patients treated with intention for HDC + AuSCR was 0% (0–0%) and 14% (3–36%), respectively. The three relapsed NGGCT survivors had raised HCG markers alone; two received additional irradiation. Patients with relapsed germinoma had better 5‐year OS than those with relapsed NGGCT (55 vs. 9%; p = 0.007). Patients with relapsed germinoma were salvaged both with SDC and re‐irradiation or HDC + AuSCR with/without re‐irradiation; both represent valid treatment options. Outcomes for malignant relapse following initial diagnosis of NGGCT were exceptionally poor; the few survivors received thiotepa‐based HDC + AuSCR, which is a treatment option at first malignant relapse for such patients, with further surgery/irradiation where feasible.     

A phase II trial of bendamustine in combination with ofatumumab in patients with relapsed or refractory marginal zone B‐cell lymphomas

Marginal zone lymphomas (MZLs) are indolent yet incurable lymphomas with frequent relapses following therapy. For patients with relapsed/refractory disease, no standard therapies exist. Here we report results of an exploratory phase II study aimed at assessing the efficacy and safety of the alkylator agent bendamustine in combination with the second‐generation anti‐CD20 monoclonal antibody, ofatumumab, in patients with relapsed or refractory MZL. Patients with MZL and previously treated with at least one line of systemic therapy were eligible. Treatment consisted in bendamustine (90 mg/m² on days 1 and 2) and ofatumumab (1000 mg on day 1) in 28‐day cycles for up to six cycles. Sixteen patients were included in the trial. In one patient, the diagnosis was revised after two cycles of treatment and was excluded from the efficacy analysis. Among 15 patients with MZL, 14 were evaluable for response: the overall and complete response rates were 92.9% and 57.1%, respectively. The median duration of response was 30.4 months (95% confidence interval [CI], 15.5 –not estimable) and 2‐years progression‐free survival 77% (95% CI, 43%–92%). Fifteen patients (94%) experienced grade 3–4 adverse events. Toxicity was mostly hematological. Neutropenia grade ≥3 was recorded in 27% of patients, lymphocytopenia in 93%, and infections and febrile neutropenia each in 13%. One patient discontinued treatment due to myocardial infarction; no treatment‐related deaths occurred. The combination of bendamustine with ofatumumab was active with an acceptable toxicity profile in this small phase II trial and can be considered for further investigation in relapsed/refractory MZL patients.     

HIA与IA方案治疗初治急性髓系白血病的临床对比观察

目的分别用去甲氧柔红霉素（IDA）与HA方案[高三尖杉酯碱（HH）+阿糖胞苷（Ara-C）]组成的双诱导HIA方案与传统IA方案治疗初治急性髓系白血病,比较两组化疗方案的疗效及不良反应。方法HIA方案为：IDA 7 mg/（m²·d）,静脉滴注第1~3天;HH 2.5 mg/（m²·d）,静脉滴注,第1~5天;Ara-C 100 mg/（m²·d）,静脉滴注,第1~5天。IA方案为：IDA 10 mg/（m²·d）,静脉滴注,第1~3天; Ara-C 100 mg/（m²·d）,静脉滴注,第1~5天。结果HIA方案组第一疗程 74.4%（32/43）获CR,其中9例复发（早期复发1例,晚期复发8例）。IA方案组第一疗程73.3%(26/30）达CR,其中8例复发（早期复发5例,晚期复发3例）。两组在CR率和生存分析比较上差异均无明显统计学意义。但HIA方案组患者心脏不良反应发生率（2.3%）显著低于IA组（16.7%）。HIA方案化疗的不良反应主要为骨髓抑制和粒细胞缺乏所致感染,未见严重的非造血系统不良反应,尤其未加重心脏毒性,治疗过程中未发生早期死亡。结论HIA方案可以减少蒽环类药物的剂量,不加重心脏毒性,增加了患者的耐受能力,且不影响疗效。     

Evolution of FLT3-ITD and D835 activating point mutations in relapsing acute myeloid leukemia and response to salvage therapy

Internal tandem duplications (ITDs) of the juxtamembrane region of the FLT3 tyrosine kinase receptor are the most frequent genetic alterations in acute myeloid leukemia (AML). The presence of this mutation has been recognized as an independent poor prognostic factor. In this study, we compared the FLT3 mutational status between diagnosis and subsequent relapses in 31 patients with AML. At diagnosis, seven patients were identified to contain FLT3-ITD mutations and one patient to harbor the D835 mutation. Five patients remained FLT3-ITD positive throughout the disease course (+/+). Three patients lost the FLT3 gene mutation at first (one FLT3-ITD, one D835 mutation), or second relapse (one FLT3-ITD) (+/-). One additional patient lost a small FLT3-ITD positive clone at relapse and at the same time gained an apparently unrelated FLT3-ITD positive clone. One patient without FLT3 mutation at diagnosis relapsed with an FLT3-ITD mutation (-/+). A shorter median duration of first remission (6 months versus 11.5 months) and a higher relapse rate after salvage therapy (e.g. allogeneic peripheral blood stem cell transplantation) resulted in a lower leukemia-free survival in the FLT3 mutated group (11% versus 31%). The loss of a clone with a mutation in the FLT3 gene at relapse did not improve the prognosis.     

Surveillance imaging during remission identifies a group of patients with more favorable aggressive NHL at time of relapse: a retrospective analysis of a uniformly-treated patient population.

BACKGROUND: Approximately one-third of the patients with relapsed aggressive non-Hodgkin's lymphoma (NHL) are cured by second-line chemotherapy followed by high-dose consolidation. The age-adjusted international prognostic index determined at the time of relapse (sAAIPI) predicts outcome in relapsed diffuse large B-cell lymphoma, suggesting that the success of salvage therapy could be enhanced by early relapse detection. This study evaluated the role of surveillance imaging in detection of relapsed disease and its impact on outcome of salvage treatment. PATIENTS AND METHODS: One hundred and eight patients with relapsed aggressive NHL were treated with ICE-based second-line chemotherapy. Relapses were categorized as detected by imaging, examination, or patient-reported symptoms. RESULTS: Twenty per cent of relapses were detected by routine imaging while 80% were identified by reported symptoms or abnormalities on exam. Patients were 4.1 times (95% CI: 1.7-10.2) more likely to have low risk disease if relapse was diagnosed by routine imaging (group 1) compared with those diagnosed by reported symptoms or physical findings (group 2). Median overall 5-year survival for group 1 versus group 2 was 54% and 43% respectively (P = 0.13). CONCLUSION: These results suggest that routine surveillance imaging can identify a population of patients with a more favorable outcome based on the sAAIPI.     

Management of malignant colonic polyps: a population-based analysis of colonoscopic polypectomy versus surgery

BACKGROUND:

The management of colon polyps containing invasive carcinoma includes surgical resection or colonoscopic polypectomy. To date, there are very limited population‐based data comparing outcomes with the 2 management approaches.

METHODS:

Using the linked Surveillance Epidemiology and End Results–Medicare database, we identified 2077 patients aged ≥66 years with an initial diagnosis of stage T1N0M0 malignant polyp from 1992‐2005. Patients were categorized as surgical or polypectomy depending on the most invasive treatment. To adjust for potential selection bias in treatment assignment, using multivariate analysis, patients were divided into quintiles of likelihood of polypectomy (propensity scores), and outcomes were compared in each quintile.

RESULTS:

Surgical resection was performed in 1340 (64.5%) patients and polypectomy was performed in 737 (35.5%) patients. Predictors for undergoing polypectomy (P<.001) included older age, greater comorbidity, no history of polyps, diagnosis in 2002 or later, left colon site of cancer, well‐differentiated tumors, and colonoscopy performed in an outpatient setting. Both 1‐year and 5‐year survival were higher in the surgical group (92% and 75%, respectively) than in the polypectomy group (88% and 62%, respectively). The unadjusted hazard ratio was 1.51 (95% confidence interval [CI], 1.31‐1.74). After adjusting for propensity quintile, the hazard ratio was 1.15 (95% CI, 0.98‐1.33). Within each propensity quintile, the risk of death was similar between the 2 groups (interaction test P = .96).

CONCLUSIONS:

In this large, population‐based sample, more than one‐third of patients with malignant polyps were treated with colonoscopic polypectomy. Outcomes were similar to surgical patients with comparable clinical characteristics and could be offered to patients who meet appropriate clinical criteria. Cancer 2012;. © 2011 American Cancer Society.     

Second central nervous system prophylaxis in children with acute lymphoblastic leukemia who relapse after elective cessation of therapy

A treatment plan to achieve better disease control in patients with acute lymphoblastic leukemia (ALL) who relapse after elective cessation of therapy was assessed. The principal modifications were (1) a second preventive treatment of the central nervous system (CNS) at relapse and every six weeks throughout therapy, using intrathecal methotrexate with cytosine arabinoside, and (2) a four-week course of systemic chemotherapy given immediately before therapy was stopped a second time. Twenty-four patients were studied. There have been no meningeal relapses, in contrast to seven among 16 similar patients who were retreated without CNS prophylaxis. Although the median length of second hematologic remission was not significantly different from the outcome in the comparison group, a much higher proportion of patients (eight of 24 versus zero of 17) remain in prolonged reinduced complete remission (48-79 months). Children whose first relapse occurred later than six months after cessation of therapy had significantly longer subsequent remissions. These end results establish the value of intrathecal CNS prophylaxis in relapsed ALL and suggest that a late intensive phase of therapy will extend remissions in a substantial proportion of patients.     

Relapsed Childhood Acute Myeloid Leukemia: Experience from a Single Tertiary Center in Thailand

Background: Few studies have examined survival outcomes in relapsed childhood acute myeloid leukemia (AML) in resource-limited countries. This study aimed to evaluate the prognostic factors and survival outcomes of relapsed childhood AML in Thailand. Methods: The medical records of AML patients aged 0-15 years treated in a major tertiary center in Southern Thailand between December 1979 and December 2019 were reviewed retrospectively. The overall survival (OS) was calculated using the Kaplan-Meier method. Results: A total of 316 AML patients were included and relapse occurred in 98 (31%) patients. Of these, 57 (58.2%) and 41 (41.8%) patients had early [≤1 year from first complete remission (CR1)] and late (>1 year from CR1) relapses, respectively. Only 54 (55.1%) patients received chemotherapy after relapse. The 3-year OS of all relapsed patients was 3.5%. The 3-year OS of patients with early and late relapse were 0% and 8.5%, respectively (p=0.002). The 3-year OS of patients who received chemotherapy and those who did not were 6.5% and 0%, respectively (p <0.0001). The median survival time of patients who did not receive chemotherapy was 1.7 months. The 3-year OS of patients who achieved second complete remission (CR2) and those who did not were 12.6% and 0%, respectively (p <0.001). Conclusion: The relapsed AML rate was 31% and the survival outcome was poor with a 3-year OS of 3.5%. The adverse prognostic factors were early relapse, failure to achieve CR2 and those who did not receive chemotherapy after relapse.     

Relapse in stage I(E) diffuse large B‐cell lymphoma

Despite a general favourable outcome in limited stage diffuse large B‐cell lymphoma (DLBCL), relapses occur in about 10 to 20% of patients. Prognostic models only partially identify patients at risk for relapse. Moreover, it is not known whether the outcome after such a relapse is similar to the outcome after relapse in advanced stages. From January 2004 through December 2012, all newly diagnosed patients with stage I(E) DLBCL were retrospectively analysed from 2 clinical databases to investigate the relapse pattern and outcome in relation to initial treatment and clinical characteristics. In 126 patients (median age 64 years), histologically confirmed stage I(E) DLBCL was diagnosed. With a median follow‐up of 53 months (range 5‐132 months), 1 progressive disease and 18 relapses occurred. The 5‐year time to tumour progression and disease‐specific survival were 85% (95% CI 79‐91%) and 92% (95% CI 87%‐97%), respectively. We observed no significant difference in relapse localization, time to tumour progression, and disease‐specific survival between patients treated with abbreviated R‐CHOP plus involved field radiotherapy or with 6 to 8 cycles of R‐CHOP. Analysis of relapses showed relapse >5 years after initial treatment (late relapse) in 5 of 19 patients (26%). Six of 19 patients (32%) had central nervous system relapse. Three of 11 relapsed cases available for analysis (28%) showed an MYC translocation, suggesting an overrepresentation in the relapse group. Outcome of patients with a relapse was poor with a median survival after relapse of 8 months. Only 1 patient (5%) underwent successful autologous stem cell transplantation. To improve outcome in these patients, early identification of new biological factors such as a MYC translocation or a high risk for CNS dissemination might be helpful. Moreover, treatment of any relapse after stage I disease should be taken seriously. Salvage treatment should be similar to relapses after advanced DLBCL.     

Therapy and survival after recurrence of Ewing's tumors: the Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997.

BACKGROUND: Many papers have reported the results achieved with combined therapy for Ewing's tumors, but little is known about the treatment and outcome of those 30-40% of patients who relapse. PATIENTS AND METHODS: In a retrospective study, we evaluated 195 patients with Ewing's tumors treated at our institution from 1979 to 1997 with chemotherapy, radiotherapy, surgery or combined therapies after recurrence. RESULTS: A second complete remission was achieved in only 26 patients (13.3%); 12 relapsed again and died of the tumor. The 5-year post-relapse event-free survival and overall survival were 9.7% and 13.8%, respectively; both of which were significantly better for patients who had relapsed >/=2 years after the beginning of the first treatment (14.3% versus 2.5%; P <0.001) and for patients who relapsed with only lung metastases (14.5% versus 0.9%; P <0.0005). In terms of treatment, patients treated with surgery or radiotherapy, alone or in combination with chemotherapy, had better survival rates than patients treated with chemotherapy alone (15.4% versus 0.9%; P <0.0001). CONCLUSIONS: The outcome of Ewing's tumor patients who relapse after combined treatment is very poor. However, these patients may be divided into two groups: those that can be cured with traditional treatments (late relapse and/or only lung metastases), and a second group of patients (early relapses with metastases in lungs and/or other sites) who gain no benefit from traditional therapies. For the latter group, multicenter studies are needed to evaluate new strategies of treatment.     

Relapse in Hodgkin lymphoma

The retrospective study revealed the 15% relapse rate in patients with stage II-IV unfavorable prognosis Hodgkin lymphoma, 5-year OS in relapsed patients was 84%. Karnofsky score less than 80 (p=0,0001), more than 1 extranodal lesion (p=0,0004), extensive (equal to stage III-IV) involvement on relapse (p=0,001), b-symptoms on relapse (p=0,023), more than 5 lymph nodal lesions (p=0,027), albumin level less than 40 g per liter (p=0,037), detection of new nodal lesions (p=0,041) were shown by discriminative analysis as the therapy effect predictors in patients with Hodgkin lymphoma relapse. In patients with second-line therapy failure the actuarial survival rate was lower by 55% in comparison to patients with chemosensitive relapses (40% and 95%). The secondary therapy resistance was shown to be an unfavorable prognosis predictive factor (p=0,0001). The multifactorial overall survival analysis revealed the following adverse prognostic factors: failure of second-line treatment (p=0,0001), first early relapse (p=0,01), albumin level on relapse less than 40 g per liter (p=0,02), use of standard chemotherapy instead of irradiation (p=0,02). The relapse patients with 1 or less risk factors had 95% 5-year OS, the patients with 3 or more adverse risk factors had 70% OS (p=0,0002). The lowest 10-year OS was observed in patients with 2 or more adverse risk factors, 48% and 28% accordingly. Adverse risk factors must be considered while choosing the optimal treatment strategy aimed at better survival rate.     

Assessment of Aspergillus‐specific PCR as a screening method for invasive aspergillosis in paediatric cancer patients and allogeneic haematopoietic stem cell recipients with suspected infections

Invasive aspergillosis (IA) remains difficult to diagnose in immunocompromised patients, because diagnostic EORTC/MSG criteria are often not met. As biomarkers might elucidate the pathogen, we analysed the performance of an Aspergillus PCR assay in blood for diagnosis of IA in immunocompromised paediatric patients with suspected infections. Ninety‐five haemato‐oncological paediatric patients were included over a period of 3 years, the underlying diseases consisting of acute leukaemia, solid tumours, non‐malignant immunocompromising disorders and haematopoietic stem cell transplantation recipients. We retrospectively analysed 253 consecutive episodes of suspected infections. Thirty‐eight patients had possible IA, none of the patients fulfilled EORTC/MSG criteria of probable/proven IA. PCR positivity was observed in 97/967 analyses. Sensitivity, specificity, positive and negative predictive value of the PCR per episode were 34%, 78%, 31% and 81% using possible IA as endpoint. Taken together, an undirected blood screening by Aspergillus‐specific PCR is of little diagnostic value in a heterogenous paediatric patient cohort. Harnessing PCR for diagnosis of IA should thus be focused on blood analyses of more homogenous high‐risk patients and/or analyses of bronchoalveolar lavage, tissue or cerebrospinal fluid specimens.     

Late recurrences of germ cell malignancies: a population-based experience over three decades

The purpose of this study was to explore the incidence of late relapse in patients with malignant germ cell tumour (MGCT) in a population-based series, with emphasis on the mode of detection, survival, and the relevance of histological findings. The clinical records from a population-based cohort of patients with seminoma (n=1123) or non-seminoma (n=826) were evaluated for late relapses. Twenty-five patients developed a late relapse. The cumulative 10-year incidence rate was 1.3%. All 10 seminoma patients, but only eight of 15 non-seminoma patients relapsed with vital malignant tumour (P=0.02). Teratoma or necrosis was found in seven of nine primarily chemotherapy-treated non-seminoma patients with normal tumour markers at late relapse. Six of nine patients operated with limited retroperitoneal lymph node dissection as part of the primary treatment had relapsed retroperitoneally outside the original operation field. The 10-year cause-specific survival was 68% in all patients, 50% in patients relapsing with vital malignant tumour and 100% in those with teratoma/ necrosis before or after salvage chemotherapy. The 10-year incidence rate of late relapses of 1.3% might reflect the true incidence rate in a population-based cohort of MGCT patients, with cure in at least half of them.     

Allogeneic stem cell transplantation using lymphoablative rather than myeloablative conditioning regimen for relapsed or refractory lymphomas

In relapsed or refractory non‐Hodgkin lymphoma (NHL), allogeneic hematopoietic stem cell transplantation (allo‐HSCT) provides graft‐versus‐lymphoma activity resulting in fewer incidences of relapse. However, therapy‐related mortality (TRM) remains an important challenge. We attempted to introduce our reduced‐intensity conditioning (RIC) regimen. From 2007 to 2013, we treated 28 relapsed or refractory NHLs with allo‐HSCT. All were pre‐conditioned with fludarabine [FLU, 180 mg/body surface area (BSA)/6 days] and melphalan (MEL, 70 mg/BSA/1 day); 25 (all but 3) were additionally treated with total body irradiation (TBI, 800 cGy/4Fx/2 days). Peripheral blood stem cells were collected from matched siblings (n = 10) or suitably matched unrelated (n = 18) donors. There were eight diffuse large B‐cell lymphomas, seven peripheral T‐cell lymphoma not otherwise specified, give lymphoblastic lymphomas, two mantle cell lymphomas, and six various other lymphomas. Of these patients, 10 relapsed after auto‐HSCT, 5 relapsed after chemotherapy, and 13 were refractory lymphomas. After allo‐HSCT, complete remission was achieved in 22 (78.5%) patients. After a median follow‐up of 24.8 months, 3‐year overall survival and disease‐free survival were 62.4 and 59.2% and the 3‐year TRM and relapse incidence were 14.9 and 28.6% respectively. Acute and chronic graft‐versus‐host diseases (GVHDs) were identified in 17 (≥Grade II in 12 patients) and 18 patients respectively, and the group with chronic GVHD showed favourable survival outcomes. In relapsed or refractory NHL, RIC‐allo‐HSCT using FLU + MEL + 800 cGy TBI showed favourable survival outcomes with acceptable TRM and relapse incidence. Copyright © 2015 John Wiley & Sons, Ltd.     

侵袭性肺部真菌感染在实体恶性肿瘤与血液肿瘤中发病及抗菌治疗疗效的临床对比分析

目的:对比分析侵袭性肺部真菌感染（IPFI）在实体恶性肿瘤与血液肿瘤患者中的发病率、危险因素、临床特征及抗真菌治疗结果,从而提高对侵袭性肺部真菌感染诊治的认识。方法:回顾性分析2017年6月至2019年6月中国医学科学院肿瘤医院深圳医院实体恶性肿瘤或血液肿瘤合并侵袭性肺部真菌感染并进行抗真菌治疗的患者临床资料,对比两组间的危险因素、临床特征、抗真菌治疗缓解率、用药中位时间差异。结果:实体恶性肿瘤患者合并IPFI 30例,发病率0.42%;血液肿瘤患者合并IPFI 228例,发病率10.6%,差异有统计学意义（P<0.05）。实体恶性肿瘤组和血液肿瘤组男性比例分别为33.3%（10/30）和61.4%（140/228）,多因素分析粒缺状态、有类固醇激素治疗、糖尿病史、慢性肺部疾病史、有咳嗽咳痰症状、G/GM试验阳性率、微生物培养阳性率差异有统计学意义,两组在年龄≥65岁、发热、呼吸困难、肺部特征性影像学表现方面无明显差异。血液肿瘤组中联合抗真菌治疗比例为35.1%（80/228）,实体恶性肿瘤组无,两组患者治疗中位时间为(17.89±7.738)天和(13.55±5.176)天,总有效率为61.5%（91/148）和75%（60/80）,差异有统计学意义(P<0.05)。结论:侵袭性肺部真菌感染在血液肿瘤患者中发病率更高,血液肿瘤联合抗真菌治疗疗效确切且安全,值得在实体恶性肿瘤临床进一步应用。     

复发难治性弥漫大B细胞淋巴瘤靶向药物治疗进展

淋巴瘤为一组起源于淋巴结或其他淋巴组织的异质性血液系统恶性肿瘤，包括霍奇金淋巴瘤（Hodgkin's lymphoma，HL）和非霍奇金淋巴瘤（non-Hodgkin's lymphoma，NHL），其中弥漫性大B细胞淋巴瘤（diffuse large B-cell lymphoma，DLBCL）为一类异质性明显的淋巴系统恶性肿瘤，也是最常见的NHL亚型。标准R-CHOP方案（利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和泼尼松）治疗可显著提高60%以上患者的生存期，然而仍有约30%~40%患者出现疾病复发或难治，预后较差，如何延长复发难治性DLBCL患者的生存期并改善其预后已成为目前国内外研究的热点。随着疾病基因表达谱、耐药分子机制等的不断深入研究，化疗新方案及新药不断探索，为个体化精准治疗复发难治性DLBCL带来新希望。本文拟对新近的靶向药物在复发难治性DLBCL中的治疗进展进行综述。      

Treatment of pelvic sarcomas in adolescents and young adults with intensive combined modality therapy

Adolescent and young adult patients with pelvic sarcomas continue to have a poor prognosis with standard combination chemotherapy and local irradiation. In addition to a significant risk of local failure, these patients are at high risk for systemic relapse. Twenty-three consecutive patients with Ewing's sarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or malignant peripheral neuroepithelioma originating in the pelvis were treated with short, intensive combined modality therapy. This approach integrates 5 cycles of VADRIAC chemotherapy (Vincristine, Adriamycin, Cyclophosphamide) with high dose irradiation to the primary lesion (55-60 Gy) and sites of gross metastatic disease (45-50 Gy). Following achievement of a complete response, intensification therapy consisting of total body irradiation (TBI) (8.0 Gy), high dose VADRIAC chemotherapy, and autologous bone marow transplantation is given. All therapy is completed within 6-7 months. No maintenance chemotherapy is given; no surgery is intended. Of the twenty-three patients with pelvic sarcomas treated on this combined modality protocol, 22 achieved a complete remission. Local control was achieved and maintained in all twenty-three patients. With a median follow-up of 21 months since initiation of treatment, there have been nine relapses (all systemic). Seven relapses occurred among the thirteen patients who presented with overt metastatic disease and the other two relapses were among the ten patients with localized disease at presentation. All seven metastatic patients who relapsed have died, whereas both of the relapsed localized patients remain alive. Acute and late toxicities have been acceptable using this aggressive combined modality approach. Induction chemotherapy had a significant impact on reduction of the typically large (greater than 10 cm diameter) soft tissue mass associated with these pelvic tumors, thus facilitating achievement of local control by high dose irradiation. Of 18 patients with measureable soft tissue tumor, all experienced a partial response (greater than 50% reduction in size) following the initial two cycles of chemotherapy given prior to local irradiation. In conclusion, this short, intensive chemoradiotherapeutic regimen is highly effective in controlling the primary lesion (100% local control) and inducing a complete response in a high proportion (96%) of these high risk pediatric and young adult patients with pelvic sarcomas. The role of TBI as "systemic" adjuvant therapy to control micrometastatic disease is discussed as still under investigation.     

Prevention of chemotherapy-induced leukemia and of leukemia relapses.

Fifty percent of patients with the myelodysplastic syndrome, frequently following treatment by radiation or chemotherapy, have prognostically unfavorable deletions of the long arms of chromosomes 5 and 7, or trisomy 8, as have the 25% of patients with acute myeloblastic leukemia where remissions last 6-12 months, and where relapse cannot be prevented. In contrast, patients with prognostically favorable cytogenetics (translocation 15; 17 or 8; 21 or inversion 16) maintenance chemotherapy may prevent relapses. Of chronic myelocytic leukemia patients, 85% can achieve hematological remission with interferon alpha, and 40% a partial cytogenetic remission, which probably delays relapse.     

The European Medicines Agency Review of Pomalidomide in Combination With Low‐Dose Dexamethasone for the Treatment of Adult Patients With Multiple Myeloma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

On August 5, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pomalidomide in combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Pomalidomide is an immunomodulating agent. The recommended starting dose of pomalidomide is 4 mg once daily taken on days 1–21 of repeated 28‐day cycles. The main evidence of efficacy for pomalidomide in MM was based on a phase III multicenter, randomized, open‐label study (CC‐4047‐MM‐003) in which pomalidomide plus low‐dose dexamethasone therapy (POM+LoDEX) was compared with high‐dose dexamethasone alone (HiDEX) in previously treated adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including both lenalidomide and bortezomib, and had demonstrated disease progression on the last therapy. For the intent‐to‐treat population, median progression‐free survival based on International Myeloma Working Group criteria was 15.7 weeks (95% confidence interval [CI]: 13.0–20.1) in the POM+LoDEX group versus 8.0 weeks (95% CI: 7.0–9.0) in the HiDEX group (log‐rank p value <.001). Overall survival (secondary endpoint) was also different in the two treatment groups (hazard ratio 0.53 [95% CI: 0.37–0.74]). The most commonly reported adverse reactions to pomalidomide in clinical studies were anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%), fatigue (28.3%), pyrexia (21%), peripheral edema (13%), and infections including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients, and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. Pomalidomide is expected to be teratogenic. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website ( http://www.ema.europa.eu ).     

Prevention of chemotherapy-induced leukemia and of leukemia relapses

Fifty percent of patients with the myelodysplastic syndrome, frequently following treatment by radiation or chemotherapy, have prognostically unfavorable deletions of the long arms of chromosomes 5 and 7, or trisomy 8, as have the 25% of patients with acute myeloblastic leukemia where remissions last 6–12 months, and where relapse cannot be prevented. In contrast, patients with prognostically favorable cytogenetics (translocation 15; 17 or 8; 21 or inversion 16) maintenance chemotherapy may prevent relapses. Of chronic myelocytic leukemia patients, 85% can achieve hematological remission with interferon α, and 40% a partial cytogenetic remission, which probably delays relapse.