COMMENTS

An unselected population of 635 consecutive extragonadal GCT patients (EGCT) treated between 1975 through 1996 at 11 cancer centers was retrospectively evaluated for clinical prognosis and biological features of this disease. Five hundred twenty-four patients (83%) had a nonseminomatous GCT, and 104 patients (16%) a seminomatous histology; 341 (54%) patients had a primary mediastinal EGCT, and 283 patients (45%) a retroperitoneal EGCT. Following platinum based induction chemotherapy+/-secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow up period: 19 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow up period: 29 months) are alive [p=0.0006]. In contrast, the overall survival rate for patients with seminomatous EGCT is 88% with no difference between patients with mediastinal or retroperitoneal tumor location (median follow up period: 49 months). Multivariate analysis revealed nonseminomatous histology, the presence of non-pulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-HCG as independent prognostic factors for shorter survival. Sixteen patients (4.1%) developed a metachronous testicular cancer despite the use of platinum based chemotherapy. The cumulative risk of developing a MTC 10-years after a diagnosis of EGCT was 10.3% (95% CI=4.9 to 15.6%), but higher among patients with nonseminomatous EGCT (14.3%; 95% CI=6.7 to 21.9%) or retroperitoneal EGCT location (14.2%; 95% CI=5.6 to 22.8%) than among patients with seminomatous EGCT (1.4%; 95% CI=0.0 to 4.2) or mediastinal EGCT location (6.2%; 95% CI=0.1 to 12.2). After a median follow-up of 51 months (range=1 to 154 months), all 16 MTC patients were alive without disease. Patients with pure seminomatous EGCT histology have a long term chance of cure of almost 90% irrespective of the primary tumor site. Patients with mediastinal nonseminomas have a five-years survival rate of 45%. This outcome is clearly inferior compared to patients with nonseminomatous retroperitoneal primaries who have a five-year survival rate of 62%.     

Electron microscopy of fine-needle aspiration biopsy from extragonadal germ cell tumors.

We describe five cases of extragonadal germ cell tumor (EGCT) diagnosed by the electron microscope (EM) on cytological material. The clinical diagnosis was incorrect in all cases and EGCT was suspected in two cases; cytological diagnosis by light microscopy confirmed the presence of malignant tumor cells, but did not identify the cytotype/s correctly except in one case. Ultrasonography, laparoscopy, and autopsy (in case 3) excluded a primitive germ cell tumor (GCT). Histology confirmed the EM diagnosis in all cases. EM, even of scanty or necrotic cytological material, is particularly useful for mediastinal and retroperitoneal masses. In case of EGCT, EM can identify the different cytotypes and the different ultrastructural subcellular cytotypes and demonstrates a close relation between seminomatous and nonseminomatous GCT, which could influence their classification and prognosis.     

Autologous Hematopoietic Stem Cell Transplantation for Male Germ Cell Tumors: Improved Outcomes Over 3 Decades

The curative potential of autologous hematopoietic cell transplantation (autoHCT) for male germ cell tumors (GCTs) is well established. The optimal timing and number (single transplant [ST] versus tandem transplants [TT] versus triple transplants) of autoHCT are controversial, with wide practice variations. We examined survival trends among 2395 recipients of autoHCT for male GCTs between 1990 and 2015 reported to the Center for International Blood and Marrow Transplant Research. Trends and outcomes were analyzed by year of transplantation for intervals 1990 to 1994 (N = 288), 1995 to 1999 (N = 351), 2000 to 2004 (N = 376), 2005 to 2009 (N = 509), and 2010 to 2015 (N = 871). Multivariate analysis was restricted to the subset from 2000 to 2015 with research-level data (n = 267). The median duration of follow-up was 51 months. The median age at autoHCT was 31 years; 633 patients (26%) had primary extragonadal GCT, and 1167 (49%) underwent TT. The 3-year progression-free (PFS) and overall survival (OS) improved from 24% (95% confidence interval [CI], 18% to 31%) and 35% (95% CI, 29% to 40%), respectively, in 1990 to 1994 to 47% (95% CI, 43% to 50%) and 54% (95% CI, 50% to 57%), respectively, in 2010 to 2015 (P < .0001). TT recipients were more likely than ST recipients to undergo autoHCT as first salvage treatment. The proportion of TTs increased from 38% of all autoHCTs in 2000 to 2004 to 77% in 2010 to 2015. Nonseminoma histology, residual disease at autoHCT, >1 line of pretransplantation chemotherapy, and ST versus TT were associated with inferior PFS and OS. Post-transplantation survival has improved significantly over time for relapsed/refractory male GCT and is associated with the increased use of TTs (compared with STs) and performance of autoHCT earlier in the disease course.     

子宫内膜癌淋巴结转移的危险因素及预后分析

目的探讨子宫内膜癌腹膜后淋巴结转移的高危因素及淋巴结转移对于预后的影响。方法回顾性分析2005年1月至2010年12月期间在北京协和医院妇产科进行诊治的289例行腹膜后淋巴结切除的子宫内膜癌患者的临床病理资料,对影响子宫内膜癌腹膜后淋巴结转移的高危因素和影响子宫内膜癌患者预后的因素进行统计分析。结果 1)289例患者中位发病年龄55岁,Ⅰ期224例(77.5%),Ⅱ期13例(4.5%),Ⅲ期45例(15.6%),Ⅳ期7例(2.4%)。289例行盆腔淋巴结切除,30例(10.4%)有盆腔淋巴结转移;96例行腹主动脉旁淋巴结切除,11例(11.5%)有腹主动脉旁淋巴结转移。复发21例(7.3%),死亡11例(3.8%),中位随访时间37个月,中位无瘤生存时间34个月。2)单因素分析显示术前CA125≥35 U/m L、非子宫内膜样癌、组织学分级为G3、深肌层浸润、肿瘤≥2 cm、宫颈间质受累、腹腔冲洗液细胞学阳性及阴道或宫旁受累是淋巴结转移率的高危因素(P0.05)。多因素分析显示术前CA125值≥35 U/m L、低分化、肌层浸润深度≥1/2是淋巴结转移的独立危险因素(P0.05)。3)Kaplan-Meier单因素分析显示,腹腔冲洗液细胞学阳性、阴道或宫旁受累、附件受累及淋巴结转移缩短无瘤生存时间(P0.05);非子宫内膜样癌、低分化、肌层浸润深度≥1/2、腹腔冲洗液细胞学阳性、附件受累及淋巴结转移缩短总生存时间(P0.05)。COX回归多因素分析显示,腹膜后淋巴结转移是5年无瘤生存率的独立预后因素(未转移者92.1%vs转移者65.3%,P=0.002,95%CI 0.078~0.552);虽不是5年总生存率的独立预后因素,但无淋巴结转移者的5年总生存率有高于淋巴结转移者的趋势(未转移者96.1%vs转移者70.0%,P=0.086,95%CI 0.039~1.238)。结论本研究发现:1)肿瘤分化程度和肌层浸润深度对淋巴结转移有预测意义,能够指导子宫内膜癌患者是否进行淋巴结切除术,为个体化治疗奠定理论基础。2)淋巴结转移患者仍然有较无淋巴结转移者预后更差的趋势,因此对于淋巴结转移的患者需要进行辅助治疗,减少复发风险。     

SALL4 is a useful marker in the diagnostic work-up of germ cell tumors in extra-testicular locations

We evaluated the impact of SALL4 immunostaining on the diagnosis of non-testicular germ cell tumors in clinical practice. We retrieved cases of six mediastinal, five retroperitoneal, and eight central nervous system tumors that were diagnosed as extra-testicular germ cell tumors (GCT) as well as 20 location-matched non-GCT. Each tumor we stained immunohistochemically for PLAP, OCT3–4, CD117, CD30, FP, -HCG, glycipan-3, SALL 4, AE1–AE3, EMA, CK7, CK20, CD45, TTF1, vimentin, and GFA. The results were assessed independently by two experienced pathologists. In 18 of 19 cases (95 %), SALL4 was strongly expressed, either homogenously (16 cases) or focally (two cases). All other GCT markers (PLAP, OCT3–4, CD117, CD30, FP, -HCG, and glycipan-3) were expressed with a lower frequency (21–69 %). The specificity of SALL4 was 100 % in our series. SALL4 should be part of the first panel of antibodies for the diagnosis of a midline tumor (mediastinal, retroperitoneal, or pineal) in patients under the age of 40 years. We also recommend that SALL4 be used in the diagnostic work-up of undifferentiated tumors in any location and in patients of any age. When a tumor is SALL4 positive, in case of need the diagnosis of germ cell tumor can be further confirmed using additional conventional markers.     

Distant metastasis in retroperitoneal dedifferentiated liposarcoma is rare and rapidly fatal: a clinicopathological study with emphasis on the low-grade myxofibrosarcoma-like pattern as an early sign of dedifferentiation.

The metastatic incidence of retroperitoneal dedifferentiated liposarcoma is comparatively lower than other pleomorphic sarcomas, varying widely from 1 to 18%. Low-grade dedifferentiation resembling low-grade fibrosarcoma has been recently accepted as part of the morphologic spectrum of dedifferentiated liposarcoma and was reported to have similar metastatic and survival rates to its high-grade counterpart. We sought to determine the metastatic incidence of retroperitoneal dedifferentiated liposarcoma, the clinicopathological features related to metastasis, and their postmetastatic behavior. Of all 354 retroperitoneal liposarcoma cases diagnosed at Memorial Sloan-Kettering Cancer Center during 1982-2003, we identified seven patients developing distant metastases, occurring in four females and three males, ranging from 35 to 73 years in age at presentation. They were all de novo dedifferentiated, while none of the well-differentiated liposarcoma or secondary dedifferentiated liposarcoma developed distant metastasis. Primary tumor sizes varied from 7.5 to 25 cm. All seven patients developing metastases contained >or=50% dedifferentiated elements in the primary tumor, with a predominant morphology resembling myxofibrosarcoma in five cases. The metastatic sites included the lung in four patients, somatic soft tissue in two, and liver in one. The median metastasis-free survival was 48 months, with only two patients experiencing local recurrences before developing metastasis. Six patients died of disease at median follow-up of 53 months after diagnosis and only 5 months after their first metastases. In conclusion, retroperitoneal dedifferentiated liposarcoma have a low metastatic rate, which is strongly related to de novo dedifferentiated histology that usually constitutes a prominent component of the primary tumor. Irrespective of the grade dedifferentiated liposarcoma with myxofibrosarcoma-like features should be closely monitored. Once metastases occur, they tend to follow a rapidly fatal course.     

Somatic isoform of angiotensin I–converting enzyme in the pathology of testicular germ cell tumors

Retained fetal expression of angiotensin I–converting enzyme (ACE, CD143) has recently been shown in intratubular germ cell neoplasms (IGCN) and invasive germ cell tumors (GCT), suggesting the somatic isoform (sACE) as a characteristic component of neoplastic germ cells. We analyzed the distribution of sACE in 159 testicular GCT, including 87 IGCN. sACE protein was determined by immunohistochemistry (MAb CG2) on routinely formalin-fixed and paraffin-embedded tissue sections, supplemented by mRNA expression analysis using in situ hybridization. These data were compared with those obtained by germ cell/placental alkaline phosphatases (PIAP; MAbs PL8-F6 and 8A9) employing an uniform score system for the evaluation of immunoreactivity (IRS; possible values from 0 to 12). Expression of sACE and PIAP was found in all 87 analyzed IGCN (IRS > 4, median IRS of 12). Heterogeneous staining patterns were not related to the type of adjacent GCT but correlated with low expression in adjacent seminomas (P = .032 for sACE; P = .005 for PIAP). Both sACE and PIAP often showed a decreased and more heterogeneous but still moderate expression in 91 classic seminomas (median IRS of 8) and were completely absent in tumor cells of spermatocytic seminomas. Despite all similarities, we found sACE and PIAP differently regulated during GCT progression. This was documented by a well-preserved expression of either sACE or PIAP or both in all classic seminomas, low PIAP immunoreactivity in metastasis of seminomas, and completely diverging expression patterns in nonseminomatous GCT. Our findings underline the close molecular relationship between IGCN and seminoma, and suggest sACE as an appropriate marker for seminomatous differentiated tumors. H P 31:1466-1476.     

Early Lymphocyte Recovery Predicts Superior Survival after Autologous Stem Cell Transplantation in Non-Hodgkin Lymphoma: A Prospective Study

Day 15 absolute lymphocyte count (ALC-15) after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) has been reported to be a significant predictor for survival in multiple hematologic malignancies. Limitations of previous reports included their retrospective nature and the lack of ALC-15 lymphocyte subset analyses. To address these limitations, from February 2002 until February 2007, 50 non-Hodgkin lymphoma (NHL) patients were enrolled in a prospective study. The primary endpoint of the study was to confirm prospectively the ALC-15 survival role after APHSCT in NHL. The secondary endpoint was to identify the ALC-15 lymphocyte subset affecting survival after APHSCT. With a median follow-up of 22.2 months (range: 6-63.7 months), patients with an ALC-15 ≥500 cells/μL (n = 35) experienced superior overall survival (OS) and progression-free survival (PFS) compared with those who did not; median OS: not reached versus 5.4 months, 3-year OS rates of 80% (95% confidence interval [CI]: 55%-95%) versus 37% (95% CI: 15%-65%), P < .0001; and median PFS: not reached versus 3.3 months, 3-year PFS rates of 63% (95% CI: 40%-85%) versus 13% (95% CI: 4%-40%), P < .0001, respectively. Univariately, CD16⁺/56⁺/CD3⁻ natural killer (NK) cells were the only ALC-15 lymphocyte subset identified as a predictor for survival. Patients with an NK cell count ≥80 cells/μL (n = 38) experienced superior OS and PFS compared with those who did not (median OS: not reached versus 5 months, 3-year OS rates of 76% [95% CI: 57%-92%] versus 36% [95% CI: 11%-62%], P < .0001; and median PFS: not reached versus 3 months, 3-year PFS rates of 57% [95% CI: 38%-85%] versus 9% [95% CI: 1%-41%], P < .0001, respectively). Multivariate analysis showed that NK cells are an independent predictor for survival. This is the first study confirming the ALC-15 survival role prospectively and identifying NK cells as the key ALC-15 lymphocyte subset affecting survival after APHSCT.     

Teratoma with somatic-type malignant components in germ cell tumors of the testis: a clinicopathologic analysis of 40 cases with outcome correlation

Teratoma with a malignant somatic component (MSC) is a rare phenomenon recognized when a somatic type malignancy occurs in the context of a germ cell tumor (GCT). The authors present their 29-year experience with 40 patients treated from 1981 to 2009 in their institution. The average age was 31 years. All patients underwent radical orchiectomy, which demonstrated a GCT in 19 with an MSC. The MSC was observed in the other 21 cases in metastatic sites, including lung (13), liver (3), pleura (1), mediastinum (7), supraclavicular lymph nodes (1), and retroperitoneal lymph nodes (9). The most common histologic types were rhabdomyosarcoma (n = 11) and primitive neuroectodermal tumors (n = 10), followed by adenocarcinoma (n = 9), sarcoma, not otherwise specified (n = 5), well-differentiated liposarcoma (n = 2), leiomyosarcoma (n = 2), chondrosarcoma (n = 2), nephroblastoma (Wilms's tumor), carcinoid, malignant peripheral nerve sheath tumor, and a gemistiocytic astrocytoma with choroid plexus tumor (each n = 1). Clinical data were collected through a dedicated database and are available for all 40 cases. After a median follow-up of 37 months, 29/40 (72.5%) were alive and disease-free. Stage-specific survival was 100% for stage I, 87.5% for stage II, and 53% for stage III patients suggesting that patients with MSC confined to the testis have a good prognosis. A lower sensitivity to chemotherapy for a MSC when compared with typical GCT is reported. Surgical excision of the MSC is therefore an essential part of the management.     

Combination chemotherapy with 5-fluorouracil and heptaplatin as first-line treatment in patients with advanced gastric cancer

Heptaplatin is a recently developed platinum derivative. This agent has been reported to have a response rate of 17% as a single agent, and tolerable toxicity in the treatment of advanced gastric cancer. The aim of this study was to evaluate the efficacy and toxicity of a combination of 5-fluorouracil (5-FU) and heptaplatin in patients with advanced gastric cancer. Forty-seven chemotherapy-naive patients with advanced or recurred gastric cancer were recruited. 5-FU was administered over 120 hr by continuous intravenous infusion from day 1 to 5, at a daily dose of 1,000 mg/m2 and heptaplatin was administered over 1 hr by intravenous infusion on day 1 at 400 mg/m2, and this cycle was repeated every 4 weeks. The response rate was 21%, median progression-free survival was 1.9 months (95% CI, 1.6 to 2.2 months). Median overall survival was 6.2 months (95% CI, 4 to 8.4 months) and the 1-yr survival rate was 29% for all patients. The most frequent toxicity was proteinuria. Toxicities were generally mild and reversible. This study demonstrates that the combination of 5-FU/heptaplatin combination is less active but tolerated in patients with advance gastric cancer.     

The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin's lymphoma in second complete or partial remission.

Autologous hematopoietic stem cell transplantation (auto HSCT) has become the standard treatment for patients with relapsed diffuse large-cell non-Hodgkin's lymphoma (NHL) responding to conventional salvage chemotherapy. Nevertheless, more than half of these patients will relapse following auto HSCT and die. This study was undertaken to determine whether the International Prognostic Index (IPI) assessed at time of relapse (IPI-R) could be used to identify patients with greater probability for long-term survival following auto HSCT. Eighty patients, median age 47 years (range 19-68 years), with diffuse large cell lymphoma in either second complete remission (CR 2, n = 27) or partial remission (PR 2, n = 53) were treated between 1984 and 2002 with auto HSCT. Clinical features predictive of overall survival (OS) and progression-free survival (PFS) were analyzed. Post-auto HSCT, CR was achieved in 73 patients (91%). With a median follow-up of 5 years (range 1.0-14.2 years), OS and PFS at 5 years were 38% (95% confidence interval [CI] 27%-50%) and 32% (95% CI 22%-42%), respectively. Two risk groups with significantly different OS and PFS were identified by the IPI-R. The high-risk group (3, 4, or 5 IPI factors) had 2.0 times (95% CI 1.1-4.0, P = .03) the risk of death and 2.2 times (95% CI 1.2-4.0, P = .01) the risk of relapse as the low-risk group (0, 1, or 2 IPI factors). The median OS was 5 months versus 27 months and the median PFS was 2 months versus 8 months for the high- and low-risk IPI-R groups, respectively. In Cox regression analysis, high-risk IPI-R status (relative risk [RR] 2.4, 95% CI 1.2-4.8, P = .02) and bone marrow (BM) involvement at diagnosis (RR 2.9, 95% CI 1.3-6.4, P = .01) were independent predictors for poor OS. Similarly, high-risk IPI-R status (RR 2.5, 95% CI 1.3-4.7, P = .01) and BM involvement at diagnosis (RR 3.9, 95% CI 1.7-8.7, P = .001) were independent predictors for poor PFS. These results suggest that the IPI-R predicts OS and PFS following auto HSCT for patients with aggressive NHL in CR 2 or PR 2. Patients with high-risk IPI-R should be considered for novel therapeutic approaches.     

Megadose CD34+ Cell Grafts Improve Recovery of T Cell Engraftment but not B Cell Immunity in Patients with Severe Combined Immunodeficiency Disease Undergoing Haplocompatible Nonmyeloablative Transplantation

To determine whether T cell engraftment and recovery of B cell immunity could be improved, we prospectively treated 15 children with severe combined immunodeficiency disease (SCID) with megadoses of haplocompatible CD34⁺ cells and a fixed number of CD3⁺ cells without previous myeloablative chemotherapy. Evidence of T cell engraftment was seen in 73% of patients (95% confidence interval [CI] = 48%-90%). Engraftment was more likely in patients with X-linked SCID and in those with evidence of maternal engraftment at the time of diagnosis. In patients with T cell engraftment, the median time to development of a CD4 count > 200 cells/mm³ and a phytohemagglutinin response > 50% of control was 1.2 and 4.9 months, respectively. Clearance of preexisting infections occurred after a median of 2.8 months. B cell function developed in 33% of engrafted patients (95% CI = 14%-61%). The 1-year event-free survival (EFS) rate was 60% (95% CI = 36%-80%), and the overall survival (OS) rate was 87% (95% CI = 61%-98%), with a median follow-up of 39 months. The use of megadoses of CD34⁺ cells with a fixed number of CD3⁺ cells in nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with SCID is associated with excellent engraftment, T cell recovery, and OS; however, B cell function does not recover in most patients.     

Successful allogeneic stem cell transplantation with nonmyeloablative conditioning in patients with relapsed hematologic malignancy following autologous stem cell transplantation.

The use of myeloablative preparative therapy and allogeneic stem cell transplantation (alloSCT) as salvage therapy for adult patients with relapsed hematologic malignancy after autologous stem cell transplantation (autoSCT) is generally unsuccessful due to very high treatment-related mortality rates. We evaluated the outcome of HLA-matched related donor alloSCT following nonmyeloablative preparative therapy in 13 patients (median age, 38 years) with relapsed hematologic malignancies (Hodgkin's disease, n = 4; Hodgkin's disease and advanced myelodysplastic syndrome, n = 1; non-Hodgkin's lymphoma, n = 6; multiple myeloma, n = 2) after initial autoSCT. Median time from autoSCT to alloSCT was 12 months (range, 3-24 months); 6 patients had chemotherapy-refractory disease following autoSCT, 6 were in untreated relapse, and 1 had a partial response from salvage chemotherapy. Preparative therapy consisted of cyclophosphamide, 150-200 mg/kg; peritransplantation anti-thymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal irradiation); and a very short course of cyclosporine as GVHD prophylaxis. All patients achieved initial mixed chimerism as defined by greater than 1% donor peripheral white blood cells. Seven patients, who had no evidence of GVHD, received prophylactic DLI beginning 5 to 6 weeks after transplantation for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-tumor effect. Six patients showed conversion to full donor chimerism and 1 lost the graft. Grade II or greater acute GVHD occurred in 9 patients. Seven patients achieved a complete response; 6 had no response. The median survival time of the 13 patients is currently 10 months (range, 3-39 months), with an overall survival probability at 2 years of 45% (95% confidence interval [CI], 19%-73%) and a disease-free survival probability at 2 years of 37.5% (95% CI, 12%-65%). Thus, this novel nonmyeloablative alloSCT strategy followed by prophylactic DLI was well tolerated and can result in durable disease-free survival among patients with advanced hematologic malignancies after a failed autoSCT. Further follow-up and evaluation of additional patients are required to conclusively establish the role of this strategy in the treatment of hematologic malignancies after an autologous transplantation.     

Outcomes of Allogeneic Stem Cell Transplantation after Inotuzumab Ozogamicin Treatment for Relapsed or Refractory Acute Lymphoblastic Leukemia

Attaining complete remission of acute lymphoblastic leukemia (ALL) before hematopoietic stem cell transplantation (HSCT) correlates with better post-transplant outcomes. Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, has shown significantly higher rates of remission, minimal residual disease negativity, and HSCT versus standard chemotherapy in treating relapsed/refractory (R/R) ALL. We investigated the role of previous transplant and proceeding directly to HSCT after remission as factors in determining post-transplant survival in the setting of InO treatment for R/R ALL. The analyzed population comprised InO-treated patients who proceeded to allogeneic HSCT in 2 clinical trials (phase 1/2: NCT01363297 and phase 3: NCT01564784). Overall survival (OS) was defined as time from HSCT to death (any cause). Of 236 InO-treated patients, 101 (43%) proceeded to allogeneic HSCT and were included in this analysis. Most received InO as first salvage (62%); 85% had no previous HSCT. Median (95% confidence interval [CI]) post-transplant OS was 9.2 months (5.1, not evaluable) with 2-year survival probability (95% CI) of 41% (32% to 51%). In first-HSCT patients (n = 86), median (95% CI) post-transplant OS was 11.8 months (5.9, not evaluable) with 2-year survival probability (95% CI) of 46% (35% to 56%); some patients relapsed and needed additional treatment before HSCT (n = 28). Those who went directly to first HSCT upon remission with no additional salvage/induction treatment (n = 73) fared best: median post-transplant OS was not reached with a 2-year survival probability (95% CI) of 51% (39% to 62%). In patients with R/R ALL, InO followed by allogeneic HSCT provided an optimal long-term survival benefit among those with no previous HSCT who went directly to transplant after remission.     

Unrelated Cord Blood Transplantation for Severe Aplastic Anemia

In the present study we evaluated the feasibility of unrelated cord blood transplantation (UCBT) in patients with severe aplastic anemia (SAA). The outcome of 31 SAA patients (median age 28; range: 0.9-72.3 years old) who received UCBT was analyzed. The cumulative incidences of the neutrophil and platelet recovery after UCBT were 54.8 and 72.2%, respectively (95% confidence interval [CI] = 36.0%-70.3% and 51.3%-85.3%, respectively). The cumulative incidences of grade ≥II acute and chronic graft-versus-host disease (aGVHD, cGVHD) were 17.1% (95% CI = 6.2%-32.8%) and 19.7% (95% CI = 6.2%-38.8%), respectively. Currently, 13 patients are alive, having survived for 33.7 months (median; range: 6-77 months) after UCBT. The probability of overall survival (OS) at 2 years was 41.1% (95% CI = 23.8%-57.7%). A conditioning regimen that included low-dose total body irradiation (TBI) (2-5 Gy), fludarabine, and cyclophosphamide resulted in a favorable OS (80%; 95% CI = 20.4%-96.9%). This result suggests that UCBT using the optimal conditioning regimen can be a salvage treatment for patients without a suitable bone marrow donor and warrants evaluation in further prospective studies.     

Comparison of double and triple high-dose chemotherapy with autologous blood stem cell transplantation in patients with metastatic breast cancer

In patients with metastatic breast cancer (MBC), early dose intensification with multiple cycles of peripheral blood stem cell-supported high-dose chemotherapy (HDCT) seems superior to a late dose-intensification strategy. We compared the progression-free survival (PFS) and overall survival (OS) of 20 patients treated with a double (D)-HDCT regimen to 20 patients who received a triple (T)-HDCT, matched by age, estrogen receptor (ER) status, adjuvant chemotherapy, initial disease-free interval, predominant metastatic site, and number of metastatic sites. At a median follow-up of 41.5 months (range, 14-88 months) an intent-to-treat analysis showed no difference in PFS (p = 0.72) and OS (p = 0.93) between the matched patients. For all 76 patients treated within the D- or T-HDCT trial, median PFS and OS was 13 months (range, 2-78 months) and 24.5 months (range, 7-78 months), respectively. In multivariate analysis independent predictors of shorter OS included negative ER (relative risk [RR] = 3.0 [95% confidence interval (CI) 1.5-5.9]; p = 0.002), more than two metastatic sites (RR = 2.4 [95% CI 1.0-5.7]; p = 0.049) and failure to achieve complete remission/no evidence of disease (CR/NED) after HDCT (RR = 4.5 [95% CI 2.0-10.1]; p < 0.0001). These data show that early dose intensification with T-HDCT is not superior to a D-HDCT regimen in patients with MBC. ER-negative tumors, more than two metastatic sites and no CR/NED after HDCT, are associated with inferior outcome.     

Second Autologous Stem Cell Transplantation for Relapsed Lymphoma after a Prior Autologous Transplant

We determined treatment-related mortality, progression-free survival (PFS), and overall survival (OS) after a second autologous HCT (HCT2) for patients with lymphoma relapse after a prior HCT (HCT1). Outcomes for patients with either Hodgkin lymphoma (HL, n = 21) or non-Hodgkin lymphoma (NHL, n = 19) receiving HCT2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were analyzed. The median age at HCT2 was 38 years (range: 16-61) and 22 (58%) patients had a Karnofsky performance score <90. HCT2 was performed >1 year after HCT1 in 82%. The probability of treatment-related mortality at day 100 was 11% (95% confidence interval [CI], 3%-22%). The 1-, 3-, and 5-year probabilities of PFS were 50% (95% CI, 34%-66%), 36% (95% CI, 21%-52%), and 30% (95% CI, 16%-46%), respectively. Corresponding probabilities of survival were 65% (95% CI, 50%-79%), 36% (95% CI, 22%-52%), and 30% (95% CI, 17%-46%), respectively. At a median follow-up of 72 months (range: 12-124 months) after HCT2, 29 patients (73%) have died, 18 (62%) secondary to relapsed lymphoma. The outcomes of patients with HL and NHL were similar. In summary, this series represents the largest reported group of patients with relapsed lymphomas undergoing SCT2 following failed SCT1, and with long-term follow-up. Our series suggests that SCT2 is feasible in patients relapsing after prior HCT1, with a lower treatment-related mortality than that reported for allogeneic transplant in this setting. HCT2 should be considered for patients with relapsed HL or NHL after HCT1 without alternative allogeneic stem cell transplant options.     

Chronic graft-versus-host disease: a prospective cohort study.

Chronic graft-versus-host disease (CGVHD) is a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). We studied 159 patients with CGVHD longitudinally to characterize the natural history of CGVHD and identify reliable predictors of response and long-term mortality. Rates of response to treatment were 61%, 53%, and 50% at 6 months, 1 year, and 2 years, respectively. A high incidence of infections (7 of 1,000 patient-days at 0 to 6 months, 2.5 of 1,000 patient-days at 6 months to 1 year, and 0.6 of 1,000 patient-days at 1 to 2 years) was observed. After a median follow-up of 8.4 years, an overall survival rate of 40% was observed. The overall survival rate was 63% (95% confidence interval [CI], 56%-71%) at 1 year, 51% (95% CI, 43%-59%) at 2 years, and 39% (95% CI, 31%-47%) at 10 years. In multivariate analysis, age older than 20 years (RR = 1.5; 95% CI, 0.9%-2.5%; P =.09), progressive onset of CGVHD (RR = 1.6; 95% CI, 1.0%-2.4%; P =.04), platelet count of <100,000/ microL (RR = 2.1; 95% CI, 1.3%-3.4%; P =.001), and GI involvement (RR = 1.5; 95% CI, 1.0%-2.4%; P =.05) were associated with increased mortality. Among patients surviving more than 6 months, no response (RR = 4.5; 95% CI, 1.9%-10.5%; P =.0006) and partial response (RR = 2.5; 95% CI, 1.1%-6.1%; P =.04) to treatment at 6 months also were significant predictors of mortality. The prevalence of active CGVHD was 33% at 2 years. However, the cumulative incidence of successful discontinuation of therapy was only 13% at 2 years. Among patients with clinical resolution of CGVHD, only 18% were off immunosuppressive therapy by 2 years, and 89% by 4 years. Despite high initial response rates, a large majority of patients had active disease requiring prolonged immunosuppression. This requires improved infection prevention for a longer time. Recognition of a high-risk group should facilitate assignment of more intensified regimens. Better treatment regimens need to be identified to improve survival and limit toxicity of prolonged immunosuppression.