Six-month freedom from treatment failure is an important end point for acute GVHD clinical trials.

We studied the American Society for Blood and Marrow Transplantation (ASBMT) 6-month (m) freedom from treatment failure (FFTF) as a predictor of survival for patients with acute GVHD (aGVHD) requiring treatment. Adult patients undergoing allogeneic hematopoietic cell transplant (HCT) from February 2007 to March 2009 who were enrolled in a prospective biomarker clinical trial and developed aGVHD requiring systemic corticosteroids by day +100 were included (N=44). Six-month FFTF was defined as per the ASBMT guidelines (absence of death, malignancy relapse/progression or systemic immunosuppression change within 6 months of starting steroids and before chronic GVHD development). aGVHD was treated with systemic corticosteroids in 44 patients. Day 28 response after steroid initiation (complete response+very good partial response+partial response) occurred in 38 (87%) patients, but only 28 (64%) HCT recipients met the 6-m FFTF end point. Day 28 response predicted 6-m FFTF. Achieving 6-m FFTF was associated with improved 2-year (y) OS (81% vs 48%; P=0.03) and decreased 2-y non-relapse mortality (8% vs 49%; P=0.01). In multivariate analysis, 6-m FFTF continued to predict improved OS (hazard ratio, 0.27; P=0.03). The 6-m FFTF end point measures fixed outcomes, predicts long-term therapeutic success and could be less prone to measurement error than aGVHD clinical response at day 28.

Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers.

Seventy-nine patients with AML in CR1 received allo-SCT between May 2006 and May 2011, and the prognostic impact of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutation was evaluated in the context of other clinical prognostic factors. Patients with FLT3/ITD + AML had significantly inferior DFS (2-year DFS: 19% vs 64%, P = 0.0027), increased risk of relapse (1-year: 59% vs 19%, P = 0.01), and a trend towards decreased OS (P = 0.08) compared with patients without FLT3/ITD. Multivariate analysis confirmed FLT3/ITD + independently predicted a shorter DFS (HR, 3.0; 95% CI), 1.4-6.5; P = 0.01) and increased risk of relapse (HR, 4.9; 95% CI, 2.0-12.3, P = 0.01). Time to relapse in patients with FLT3/ITD + was short with 100-day cumulative risk of 45% (95% CI, 33-57). Our data suggest that the poor prognostic implication of FLT3/ITD positivity remains even after early allo-SCT in patients with FLT3/ITD + AML, and patients remain at high risk of early relapse. FLT3/ITD positivity also outweighs other conventional prognostic markers in predicting relapse.

Prevalence and risk factors associated with development of ocular GVHD defined by NIH consensus criteria.

We studied 172 patients for development of ocular graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT) from 2002 to 2009. Ocular GVHD was diagnosed in 60 patients (38%), with 27 (16%) being diagnosed at days 100 and 33 (23%) beyond day 100 for a 2-year cumulative incidence of 35% (95% confidence interval (CI), 28-43). The positive and negative predictive values of a Schirmer I test score (using 5 mm as a cutoff) in predicting ocular GVHD (day 100) were 41 and 82%, respectively. In patients with ocular GVHD beyond day 100, extraocular manifestations of GVHD preceded the development of ocular GVHD in most patients (27 of 33, 81%). Prior acute skin GVHD (odds ratio 2.57, 95% CI 1.17-5.64, P=0.019) and male recipients of female donors (odds ratio 2.57, 95% CI 1.09-6.06, P=0.03) were independent risk factors for ocular GVHD. We recommend comprehensive ocular evaluation rather than a screening Schirmer's test to establish the diagnosis of ocular GVHD. Early diagnosis and preventive strategies in high-risk populations need to be studied in clinical trials to prevent devastating impact on quality of life in patients with prolonged ocular GVHD.

Long-term outcome after autologous or allogeneic stem cell transplantation in patients with recurrent follicular lymphoma.

Thirty-five consecutive patients with follicular lymphoma (FL) receiving SCT at our institution between January 2000 and December 2010 were included in this study. At the time of presentation, 30 (86%) had advanced stage disease and 25 (71%) received three or more chemotherapy regimens prior to transplantation. In all, 12 (34%) patients were in complete response pre-SCT following salvage therapy. At the time of analysis (median follow-up 6 years from diagnosis and 4 years from transplantation), 24 patients were alive with an estimated 5-year OS and PFS of 66.5 and 53%, respectively. OS and PFS in patients receiving auto-SCT (91.7%, 73.3%) were superior compared with patients receiving allo-SCT (53.9%, 43%). Our data support early use of auto-SCT in patients with FL and suggest the need to improve allo-SCT outcome. Integrating novel agents in a combined modality approach may improve long-term outcome in FL.

Regulatory T cell expression of CLA or α(4)ß(7) and skin or gut acute GVHD outcomes.

Regulatory T cells (Tregs) are a suppressive subset of CD4(+) T lymphocytes implicated in the prevention of acute GVHD (aGVHD) after allo-SCT (ASCT). To determine whether increased frequency of Tregs with a skin-homing (cutaneous lymphocyte Ag, CLA(+)) or a gut-homing (α(4)ß(7)(+)) phenotype is associated with reduced risk of skin or gut aGVHD, respectively, we quantified circulating CLA(+) or α(4)ß(7)(+) on Tregs at the time of neutrophil engraftment in 43 patients undergoing ASCT. Increased CLA(+) Tregs at engraftment was associated with the prevention of skin aGVHD (2.6 vs 1.7%; P=0.038 (no skin aGVHD vs skin aGVHD)), and increased frequencies of CLA(+) and α(4)ß(7)(+) Tregs were negatively correlated with severity of skin aGVHD (odds ratio (OR), 0.67; 95% confidence interval (CI), 0.46-0.98; P=0.041) or gut aGVHD (OR, 0.93; 95% CI, 0.88-0.99; P=0.031), respectively. This initial report suggests that Treg tissue-homing subsets help to regulate organ-specific risk and severity of aGVHD after human ASCT. These results need to be validated in a larger, multicenter cohort.

Pegfilgrastim after high-dose chemotherapy and autologous peripheral blood stem cell transplant: phase II study.

Pegfilgrastim is equivalent to daily filgrastim after standard dose chemotherapy in decreasing the duration of neutropenia. Daily filgrastim started within 1-4 days after autologous stem cell transplant (ASCT) leads to significant decrease in time to neutrophil engraftment. We undertook a study of pegfilgrastim after high-dose chemotherapy (HDC) and ASCT. In all, 38 patients with multiple myeloma or lymphoma, eligible to undergo HDC and ASCT, were enrolled. Patients received a single dose of 6 mg pegfilgrastim subcutaneously 24 h after ASCT. There were no adverse events secondary to pegfilgrastim. All patients engrafted neutrophils and platelets with a median of 10 and 18 days, respectively. The incidence of febrile neutropenia was 49% (18/37). Neutrophil engraftment results were compared to a historical cohort of patients who received no growth factors or prophylactic filgrastim after ASCT. Time to neutrophil engraftment using pegfilgrastim was comparable to daily filgrastim and was shorter than in a historical group receiving no filgrastim (10 vs 13.7 days, P<0.001). Pegfilgrastim given as a single fixed dose of 6 mg appears to be safe after HDC and ASCT. It accelerates neutrophil engraftment comparable to daily filgrastim after ASCT. Pegfilgrastim may be convenient to use in outpatient transplant units.

T cell and NK cell lymphoproliferative disorders.

This review covers the diagnosis and management of natural killer and peripheral T-cell lymphomas (PTCL). Problems with PTCL include their rarity, representing usually 10-15% of non-Hodgkin's lymphomas in the Western Hemisphere, morphologic heterogeneity, and lack of immunophenotypic markers for clonality. Additionally, their clinical behavior is variable and may not correlate with morphology. Dr. Kinney gives a general overview of the diagnosis of PTCL and NK cell neoplasms. Emphasis will be placed on extranodal T cell and natural killer (NK) cell lymphomas such as hepatosplenic lymphoma, subcutaneous panniculitis-like lymphoma and nasal/nasal type T/NK-cell lymphoma. The use of ALK gene regulation in the classification of anaplastic large cell lymphoma is also reviewed. Dr. Loughran describes current understanding of the pathogenesis of large granular lymphocyte (LGL) leukemia. The discussion focuses on LGL leukemia as an instructive model of dysregulated apoptosis causing both malignant and autoimmune disease. Current management options and mechanisms of therapeutic response are also described. Dr. Greer addresses whether PTCL should be treated differently from the more common diffuse large B cell lymphomas. He discusses the therapeutic options for anaplastic large cell lymphoma (ALCL), from a conservative approach for primary cutaneous ALCL to combination chemotherapy for the highly chemosensitive ALCL expressing anaplastic lymphoma kinase. He reviews therapy options for the extranodal subtypes of PTCL by drawing from series in adults, pediatrics, dermatology, and the Far East.

Age and cytogenetics as predictors of event free survival in patients with acute non-lymphocytic leukemia receiving high dose cytosine arabinoside and daunorubicin as consolidation chemotherapy.

Between 1991 and 1999, 67 patients with acute non-lymphocytic leukemia (ANLL) in complete remission received high dose cytarabine (HiDAC) 3 gm/m2 q12h x 12 doses followed by daunorubicin 45 mg/m2/day x 3 days as consolidation therapy. Five year actuarial event free survival (EFS) was 34% +/- 6%. Age was significantly associated with EFS. EFS was 60% +/- 15% in patients age 20 to 29, 48% +/- 16% in patients age 30 to 39, 23% +/- 10% in patients age 40 to 49, 31% +/- 11% in patients age 50 to 59, and 0% in patients age > or = 60. Contrary to other reports which have used different HiDAC regimens, we found no relationship between cytogenetics and EFS. Cytogenetics were defined as favorable risk: t(8;21), inv (16), and del (16); neutral risk: normal or t(15;17); and unfavorable risk: any abnormality not included in favorable risk or neutral risk. EFS was 29% +/- 17% in patients with favorable cytogenetics, 37% +/- 14% in patients with neutral cytogenetics, and 31% +/- 12% in patients with unfavorable cytogenetics. These differences were not statistically significant. Because of the successful use of allogeneic transplantation at relapse in patients with matched related donors, five year actuarial survival (S) in this series was 40% +/- 6%. Five year actuarial survival was 57% +/- 9% for patients age < or = 44 and 25% +/- 8% for patients age > or = 45. This difference is statistically significant, p < .025. Clinicians should be cautious about making clinical decisions regarding consolidation therapy of ANLL on the basis of the presence or absence of cytogenetic abnormalities as the importance of cytogenetics may depend on the specific therapy which is employed.

Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis.

A retrospective single center study was performed to evaluate the safety and efficacy of valacyclovir for prevention of cytomegalovirus (CMV) infection (reactivation) after allogeneic stem cell transplantation (SCT). We compared a group of 31 patients at risk for CMV reactivation (donor, recipient or both seropositive for CMV) who received valacyclovir at an oral dose of 1 g three times a day for CMV prophylaxis with a matched cohort of 31 patients who did not receive the drug or any other form of CMV prophylaxis. Valacyclovir was used as primary prophylaxis in 12 patients and as secondary prophylaxis (after a prior CMV reactivation was effectively treated with either ganciclovir or foscarnet and without CMV antigenemia at the start of valacyclovir) in the remaining 19 patients. The two treatment groups were well matched for the donor-recipient CMV serological status and other pre-transplant characteristics. CMV reactivation was detected by blood antigenemia testing using a commercially available immunofluorescence assay for CMV lower matrix protein pp65 in circulating leukocytes. For primary prophylaxis, 3/12 patients who received valacyclovir reactivated CMV compared to 24/31 patients in the control group (P < 0.001). For secondary prophylaxis, 5/19 valacyclovir patients reactivated compared to 16/24 control patients (P < 0.05). Valacyclovir was well tolerated except for infrequent and mild gastrointestinal side-effects. There was no difference in the incidence of CMV disease in the two groups. Prophylaxis with valacyclovir appears to be safe and efficacious in preventing both primary and secondary CMV reactivation in at-risk patients after allogeneic SCT. Larger prospective randomized studies will be required to confirm these observations.

Limited efficacy of intensified preparative regimens and autologous transplantation as salvage therapy in high grade non-Hodgkin's lymphoma.

Between 9/86 and 6/98, 22 patients with relapsed or refractory high grade lymphoma received intensified preparative therapy and underwent autologous transplantation at a single institution. Two intensified preparative regimens were used--cyclophosphamide, etoposide, total body irradiation (CY-VP-TBI) (N=17) and cyclophosphamide, BCNU, etoposide (CBV) (N=5). For all patients undergoing autologous transplantation, 5 year actuarial survival (S) and 5 year event free survival (EFS) were only 18% +/- 8%. Treatment related mortality was 14% overall but only 8% in patients receiving G-CSF or GM-CSF. Survival was significantly inferior to the survival observed in a concurrent series of patients with intermediate grade lymphoma, 34% +/- 6%, p < .05. Using high dose therapy in conjunction with autologous transplantation at the time of relapse may not be as valuable a strategy in high-grade lymphoma as in intermediate grade lymphoma although most studies combine the two disorders. Alternative strategies for the use of transplantation in high grade lymphoma, such as the use of transplantation as consolidation therapy, need to be investigated.

Is total body irradiation a necessary component of preparative therapy for autologous transplantation in non-Hodgkin's lymphoma.

Between September 1986 and June 1998, 157 patients with low grade, intermediate grade, or high grade lymphoma underwent autologous transplantation at a single institution. Two preparative regimens were used: cyclophosphamide, etoposide, total body irradiation (CY-VP-TBI) (N=110) and cyclophosphamide, BCNU, etoposide (CBV) (N=47). The two groups were not significantly different with respect to source of stem cells, gender, stage at presentation, incidence of prior bone marrow involvement, sensitivity to salvage therapy, or histologic grade of lymphoma. The CBV group was significantly older, 49% of patients over age 50, as compared to 26% of patients over age 50 for the CY-VP-TBI group. Response rates and the incidence of fatal toxicity were similar for the two groups. Five year actuarial survival was 31% +/- 9% for CBV and 38% +/- 5% for CY-VP-TBI, p =.85. In a multivariate analysis, in which preparative regimen, age, histologic grade of lymphoma, and sensitivity to salvage therapy were the independent variables, TBI was not significantly associated with survival, and the direction of the trend was for TBI to be less effective than CBV. TBI does not appear to be an essential component of preparative therapy for autologous transplantation in patients with lymphoma.

Intensified preparative regimens and allogeneic transplantation in refractory or relapsed intermediate and high grade non-Hodgkin's lymphoma.

Between September 1986 and June 1998, 32 patients with relapsed or refractory intermediate or high grade lymphoma received intensified preparative therapy and underwent allogeneic transplantation at a single institution. Patients were considered for allogeneic transplantation if they failed to respond to initial therapy, failed to respond to salvage therapy, relapsed after autologous transplantation, had bone marrow involvement, or failed attempts to harvest autologous stem cells. Patients had a median age of 39 years and had generally received at least two chemotherapy regimens. Five year actuarial survival (S) was 16% +/- 6%; median survival was 4 months. Survival was significantly worse in patients who had received high intensity brief duration chemotherapy prior to transplantation and was also significantly worse in patients who did not receive total body irradiation (TBI). This likely reflects the fact that the patients with the most resistant disease had required local radiotherapy and could not receive TBI. While treatment related mortality played a major role in limiting the effectiveness of allogeneic transplantation, in this heavily pre-treated population of patients with resistant disease, only 39% of patients achieved a complete response following allogeneic transplantation, and in only 40% of that group was long term disease free survival achieved.

Recombinant human thrombopoietin (rhTPO) after autologous bone marrow transplantation: a phase I pharmacokinetic and pharmacodynamic study.

Thrombocytopenia following myelotoxic therapy is a common problem and when severe (<20,000/microl) can lead to severe morbidity and mortality. Thrombopoietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenitor cells, induces the expression of megakaryocyte differentiation markers, promotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. This open label phase I study was designed to determine the safety, tolerance and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administered to patients after undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. rhTPO was administered intravenously by bolus injection at doses ranging from 0.3 to 4.8 microg/kg/day every 3 days to 30 patients and 0.6 microg/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to >20,000/microl. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41). Neither the dose nor the schedule of rhTPO appeared to have any impact upon the time course of platelet recovery. In this phase I study, rhTPO was found to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was similar for all doses studied warranting further evaluation in phase II and III trials designed to test for platelet recovery efficacy.

Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia.

The objective of this study was to describe the outcome of allogeneic stem cell transplantation (alloSCT) in a series of patients with B cell chronic lymphocytic leukemia (B-CLL). Twenty-three B-CLL patients were transplanted between 1988 and 1997 using stem cells from a related (n = 20) or an unrelated donor (n = 3). The median age of the patients was 46 years, and the median number of prior chemotherapy regimens received was two. At transplantation, 14 patients had chemorefractory disease and 12 of these were refractory to fludarabine. The preparative regimens included total body irradiation (TBI) in 22 of the 23 cases. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporine and methotrexate. Twenty patients (87%) achieved a complete remission (CR). The incidence of grade II-IV acute GVHD was 54%. Fourteen (61%) patients are alive and disease-free, including two with unrelated donors, at a median of 26 months (range, 9-115 months). Nine patients (39%) have died, one of whom had progressive B-CLL. The only favorable prognostic factor for failure-free survival (FFS) and overall survival (OS) after alloSCT was the use of a cyclophosphamide/TBI rather than an etoposide/cyclophosphamide/TBI regimen (P = 0.03). The projected 5-year FFS, OS, and relapse rates after alloSCT were 65% (95% CI, 48-88%), 62% (95% CI, 43-88%), and 5% (95%, CI 0-13%), respectively. These findings demonstrate the potential of high-dose therapy and alloSCT for inducing and maintaining a remission in patients with advanced or chemorefractory B-CLL. The low relapse rate may be due to an allogeneic graft-versus-leukemia effect.

Intensified preparative regimens and autologous transplantation in refractory or relapsed intermediate grade non-Hodgkin's lymphoma.

Between September 1986 and June 1998, 99 patients with relapsed or refractory IGL received intensified preparative therapy and underwent autologous transplantation at a single institution. Two intensified preparative regimens were used: cyclophosphamide, etoposide, total body irradiation (CY-VP-TBI) (n = 66) and cyclophosphamide, BCNU, etoposide (CBV) (n = 33). As clinical features and results were not different for the two preparative regimens, results were combined. For all patients undergoing autologous transplantation, 5-year actuarial overall survival (OS) was 34% +/- 6%; 5-year event-free survival (EFS) was 26% +/- 5%. For patients who responded to primary therapy, salvage therapy, or both, OS was 42% +/- 7%; for non-responders to prior therapy, OS was 14% +/- 7%, P < 0.025. OS was better among patients responding to salvage therapy (50% +/- 9%), than among patients who had a complete response to initial therapy, but failed to respond or were untested/unevaluable with respect to salvage therapy (26% +/- 10%; P < 0.025). On multivariate analysis, response to salvage therapy was associated with survival following autologous transplantation (P < 0. 005). Treatment related mortality was 9% overall and only 6% after G-CSF and GM-CSF were introduced into routine clinical practice. High-intensity preparative therapy is highly effective, with acceptable treatment-related mortality, in patients with IGL who have responded to induction therapy, salvage therapy, or both. The best responses are observed in patients responding to salvage therapy. Randomized prospective studies will be needed to further define the role of intensified preparative regimens. Bone Marrow Transplantation (2000) 25, 257-262.

Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: a phase II study from the North American Marrow Transplant Group.

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hodgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkin's disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (300-600 mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related toxicity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkin's disease, producing long-term, durable remissions.

High-dose therapy with autologous or allogeneic transplantation as salvage therapy for small cleaved cell lymphoma of follicular center cell origin.

Between 1985 and 1996, 51 patients with relapsed or refractory small cleaved cell lymphoma (SCCL) received high-dose chemotherapy +/- TBI in conjunction with autologous (ABMT) (36 patients) or allogeneic transplantation (15 patients). Patients were eligible for ABMT if the bone marrow biopsy done prior to the planned transplant did not reveal microscopic involvement with SCCL. Patients receiving ABMT had a median age of 48 years, had received a median of 2.5 chemotherapy regimens prior to transplantation, and were transplanted a median of 35.5 months from diagnosis. Among patients receiving ABMT, 5 year actuarial survival was 56+/-11%. Median survival was 126+ months, and median survival from diagnosis was 191 months. Univariate and multivariate analysis identified sensitive disease as the best predictor of a favorable response. Five-year actuarial survival was 66+/-12% for patients with sensitive disease at the time of transplant as compared to 29+/-17% for patients with resistant disease, P = 0.015. Median survival in patients with sensitive disease at the time of ABMT was 126+ months. By univariate analysis, survival was significantly better for patients receiving ABMT as compared to patients receiving allogeneic transplants. Median survival following allogeneic transplantation was 5 months; 5 year actuarial survival was 15+/-13%. In a multivariate analysis, which considered autologous vs allogeneic transplantation, sensitive vs resistant disease, <3 vs > or = 3 prior treatments, and prior bone marrow involvement, allogeneic transplantation was significantly associated with poor survival. Treatment-related mortality occurred in eight of 15 patients receiving allogeneic transplantation and limited the effectiveness of this therapy. High-dose therapy in conjunction with ABMT is effective therapy for patients with SCCL whose disease is sensitive to chemotherapy and whose marrows are microscopically free of disease. Because of possible selection bias, it has not been proven that this approach increases survival in these patients. Treatment-related mortality limits the effectiveness of allogeneic transplantation in SCCL.

Transformation of the small cell variant Ki-1+ lymphoma to anaplastic large cell lymphoma: pathologic and clinical features.

The disease spectrum of anaplastic large cell lymphoma (ALCL) includes a biologically aggressive small cell variant (SCV). The SCV may progress to ALCL, but little is known about the transformation process and its significance. The goals of this study were (1) to identify the clinical and pathologic features that characterize ALCL arising in SCV and (2) to determine whether some cases with ALCL histologic appearance at the outset arose from an SCV. Seventeen SCV were reviewed, and four cases (24%) transformed to ALCL as shown by subsequent biopsy. The ALCLs were predominantly monomorphic (3 cases) rather than pleomorphic (1 case). Residual SCV was detected at transformation in 3 of 4 cases. Twenty-one de novo T-cell ALCLs were reviewed for an SCV component; such a component was identified in two ALCLs with monomorphic features, suggesting a preceding SCV phase. There was no change in the immunophenotype between the SCV and ALCL, all marking as EMA+ T cells. Expression of p80 was detected in 3 of 4 (75%) SCV with transformation and 10 of 12 (77%) SCV without transformation. Chromosomal abnormalities involving the sex chromosomes and 6, 7, 9, and 15, in addition to the characteristic t(2;5)(p23;q35), were present in 2 cases at transformation. Times to transformation ranged from 1 to 146 months (mean: 63 months) after diagnosis. Transformation to ALCL signaled a rapid clinical course, with 75% of patients dying in less than a year; one patient remains alive at 15 months. In summary, some ALCLs, particularly those with monomorphic features, arise from an SCV. Transformation to ALCL signals a rapid course, with death occurring in less than a year in most cases. Necrosis in the SCV may be predictive of transformation. Chromosomal abnormalities in addition to the t(2;5)(p23;q35) are present at transformation, suggesting that multiple genetic alterations are involved in disease progression.