Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL).

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL. PATIENTS AND METHODS: We reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016. RESULTS: One hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin < 9.3 g/dl, lactate dehydrogenase (LDH) ≥ 1668 IU/l, white blood cell ≥ 208 K/l and ß2M ≥ 8 mg/l had significantly inferior OS and patients with hemoglobin < 9.3 g/dl had inferior progression-free survival (PFS). In multivariate analysis, we identified that presence of pleural effusion [hazard ratio (HR) 2.08 (95% CI 1.11-3.9); P = 0.02], high LDH (≥ 1668 IU/l) [HR 2.5 (95% CI 1.20-4.24); P < 0.001)], and low hemoglobin (< 9.3 g/dl) [HR 0.33 (95% CI 0.14-0.75); P = 0.008] were associated with shorter OS. Fifty-five previously untreated patients received treatment with an alemtuzumab-based regimen (42 monotherapy and 13 combination with pentostatin). Overall response rate, complete remission rate (CR) for single-agent alemtuzumab and alemtuzumab combined with pentostatin were 83%, 66% and 82%, 73% respectively. In patients who achieved initial CR, stem cell transplantation was not associated with longer PFS and OS. CONCLUSION: Outcomes in T-PLL remain poor. Multicenter collaborative effort is required to conduct prospective studies.

Multi-center analysis of the effect of T-cell acute lymphoblastic leukemia subtype and minimal residual disease on allogeneic stem cell transplantation outcomes.

This study aims to provide a detailed analysis of allogeneic stem cell transplantation (allo-SCT) outcomes in a large T-cell acute lymphoblastic leukemia (T-ALL) cohort with a specific emphasis on the effects of pre-transplant minimal residual disease (MRD) and disease subtype, including the aggressive early-thymic precursor (ETP) subtype. Data from 102 allo-SCT patients with a diagnosis of T-ALL from three centers were retrospectively analyzed. Patients were grouped into four T-ALL subtypes: ETP, early, cortical and mature. At 3 years, overall survival (OS), PFS, non-relapse mortality and cumulative incidence (CI) progression were 35, 33, 11 and 55%, respectively. Patients transplanted in first complete remission (CR1) had a 3-year OS of 62% versus those transplanted in CR2 or greater (24%) (hazards ratio 1.6, P=0.2). Patients with MRD positivity at the time of transplant had significantly higher rates of progression compared with those with MRD negativity (76 vs 34%, hazards ratio 2.8, P=0.006). There was no difference in OS, PFS or cumulative incidence (CI) progression between disease subtypes, including ETP (n=16). ETP patients transplanted in CR1 (n=10) had OS of 47%, comparable to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies are necessary to improve transplant outcomes.

Romidepsin targets multiple survival signaling pathways in malignant T cells.

Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and ß-catenin pro-survival pathways were inhibited. The decreased level of ß-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies.

Allogeneic stem-cell transplantation in patients with cutaneous lymphoma: updated results from a single institution.

BACKGROUND: Cutaneous T-cell lymphomas (CTCLs) and its common variants mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are rare extranodal non-Hodgkin's lymphomas. Patients who present with advanced disease and large-cell transformation (LCT) are incurable with standard treatments. In this article, we report the largest single-center experience with allogeneic stem-cell transplantation (SCT) for advanced CTCL. PATIENTS AND METHODS: This is a prospective case series of 47 CTCL patients who underwent allogeneic SCT after failure of standard therapy between July 2001 and September 2013. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) curves. The method of Fine and Gray was used to fit regression models to the same covariates for these cumulative incidence data. RESULTS: The Kaplan-Meier estimates of OS and PFS at 4 years were 51% and 26%, respectively. There was no statistical difference in the OS in patients who had MF alone, SS, MF with LCT, or SS with LCT. PFS at 4 years was superior in patients who had SS versus those who did not (52.4% versus 9.9%; P = 0.02). The cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 40% and 28%, respectively. The cumulative nonrelapse mortality rate was 16.7% at 2 years. CONCLUSION: Allogeneic SCT may result in long-term remissions in a subset of patients with advanced CTCL. Although post-SCT relapse rates are high, many patients respond to immunomodulation and achieve durable remissions. CLINICALTRIALSGOV: NCT00506129.

Umbilical cord blood graft engineering: challenges and opportunities.

We are entering a very exciting era in umbilical cord blood transplantation (UCBT), where many of the associated formidable challenges may become treatable by ex vivo graft manipulation and/or adoptive immunotherapy utilizing specific cellular products. We envisage the use of double UCBT rather than single UCBT for most patients; this allows for greater ability to treat larger patients as well as to manipulate the graft. Ex vivo expansion and/or fucosylation of one cord will achieve more rapid engraftment, minimize the period of neutropenia and also give certainty that the other cord will provide long-term engraftment/immune reconstitution. The non-expanded (and future dominant) cord could be chosen for characteristics such as better HLA matching to minimize GvHD, or larger cell counts to enable part of the unit to be utilized for the development of specific cellular therapies such as the production of virus-specific T-cells or chimeric-antigen receptor T-cells which are reviewed in this study.

Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial.

Lenalidomide-rituximab therapy is effective in grade 1-2 follicular and mantle cell lymphoma, but its efficacy in diffuse large B-cell lymphoma (DLBCL), transformed large cell lymphoma (TL) and grade 3 follicular lymphoma (FLG3) is unknown. In this phase II trial, 45 patients with relapsed or refractory DLBCL (n=32), TL (n=9) or FLG3 (n=4) who had received 1-4 prior lines of treatment were given 20 mg oral lenalidomide on days 1-21 of each 28-day cycle, and intravenous rituximab (375 mg/m(2)) weekly during cycle 1. Grade 3/4 hematological toxicities included neutropenia (53%), lymphopenia (40%), thrombocytopenia (33%), leukopenia (27%) and anemia (18%), with a median follow-up time of 29.1 months (range 14.7-52.0 months). Overall response (OR) rate was 33%; median response duration was 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were 3.7 and 10.7 months, respectively. Nine of the 15 responding patients (three partial response (PR), six complete response (CR)) proceeded with stem cell transplantation (SCT) and were censored at the time of transplantation. When data were analyzed without censoring, median PFS remained 3.7 months and response duration increased to 30.9 months. Rituximab plus oral lenalidomide is well tolerated and effective for patients with relapsed/refractory DLBCL and TL. SCT after lenalidomide-rituximab is associated with prolonged response duration.

Adenoviral infections in adult allogeneic hematopoietic SCT recipients: a single center experience.

Disseminated adenoviral infection (AI) is associated with profound immunosuppression and poor outcome after allogeneic hematopoietic SCT (allo-HSCT). A better understanding of AI in allo-HSCT recipients can serve as a basis to develop more effective management strategies. We evaluated all adult patients who received allo-HSCT at MD Anderson Cancer Center between 1999 and 2008. Among the 2879 allo-HSCT patients, 73 (2.5%) were diagnosed with AI. Enteritis (26%) and pneumonia (24%) were the most common clinical manifestations; pneumonia was the most common cause of adenovirus-associated death. A multivariable Bayesian logistic regression showed that when the joint effects of all covariates were accounted for, cord blood transplant, absolute lymphocyte count (ALC) ≤ 200/mm(3) and male gender were associated with a higher probability of disseminated AI. The OS was significantly worse for patients with AI that was disseminated rather than localized (median of 5 months vs median of 28 months, P<0.001) and for patients with ALC ≤ 200/mm(3) (P<0.001). Disseminated AI, in patients who received allo-HSCT, is a significant cause of morbidity and mortality. Strategies for early diagnosis and intervention are essential, especially for high-risk patients.

Intravenous BU plus Mel: an effective, chemotherapy-only transplant conditioning regimen in patients with ALL.

We investigated the administration of i.v. BU combined with melphalan (Mel) in patients with ALL undergoing allogeneic hematopoietic SCT. Forty-seven patients with a median age of 33 years (range 20-61) received a matched sibling (n=27) or matched unrelated donor transplant (n=20) for ALL in first CR (n=26), second CR (n=13), or with more advanced disease (n=8). BU was infused daily for 4 days, either at a fixed dose of 130 mg/m² (5 patients) or using pharmacokinetic (PK) dose adjustment (42 patients), to target an average daily area-under-the-curve (AUC) of 5000 µmol/min, determined by a test dose of i.v. BU at 32 mg/m². This was followed by a rest day, then two daily doses of Mel at 70 mg/m². Stem cells were infused on the following day. The 2-year OS, PFS and non-relapse mortality (NRM) rates were 35% (95% confidence interval (CI), 23-51%), 31% (95% CI, 21-48%) and 37% (95% CI, 23-50%), respectively. Acute NRM at 100 days was favorable at 12% (95% CI, 5-24%); however, the 2-year NRM was significantly higher for patients older than 40 years, 58% vs 20%, mainly due to GVHD.

Outcomes of second allogeneic hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia.

For patients with ALL who relapse following allo-SCT, only a second SCT provides a realistic chance for long-term disease remission. We retrospectively analyzed the outcomes of 31 patients with relapsed ALL after a prior allo-SCT, who received a second SCT (SCT2) at our center. With a median follow-up of 3 years, 1- and 3-year PFS was 23 and 11% and 1- and 3 year OS rates were 23 and 11%. Twelve patients (39%) were transplanted with active disease, of whom 75% attained a CR. We found a significant relationship between the time to treatment failure following first allograft (SCT1) and PFS following SCT2 (P=0.02, hazard ratio=0.93/month). In summary, a second transplant remains a potential treatment option for achieving response in a highly refractory patient population. While long-term survival is limited, a significant proportion of patients remains disease-free for up to 1 year following SCT2, providing a window of time to administer preventive interventions. Notably, our four long-term survivors received novel therapies with their second transplant underscoring the need for a fundamental change in the methods for SCT2 to improve outcome.

Clofarabine combined with busulfan provides excellent disease control in adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation.

We investigated the safety and early disease control data for i.v. busulfan (Bu) in combination with clofarabine (Clo) in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation (SCT). Fifty-one patients (median age, 36 years; range, 20-64 years) received a matched sibling (n = 24), syngeneic (n = 2), or matched unrelated donor transplant (n = 25) for acute lymphoblastic leukemia in first complete remission (n = 30), second complete remission (n = 13), or active disease (n = 8). More than one-half of the patients had a high-risk cytogenetic profile, as defined by the presence of t(9;22) (n = 17), t(4;11) (n = 3), or complex cytogenetics (n = 7). Clo 40 mg/m(2) was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic SCT 2 days later. The Bu dose was based on drug clearance, as determined by the patient's response to a 32-mg/m(2) Bu test dose given 48 hours before the high-dose regimen. The target daily area under the receiver-operating characteristic curve was 5500 µM/min for patients age <60 years and 4000 µM/min for those age ≥60 years. The regimen was well tolerated, with a 100-day nonrelapse mortality rate of 6%. With a median follow-up of 14 months among surviving patients (range, 6-28 months), the 1-year overall survival, disease-free survival, and nonrelapse mortality rates were 67% (95% confidence interval [CI], 55%-83%), 54% (95% CI, 41%-71%), and 32% (95% CI, 16%-45%), respectively. For patients undergoing SCT in first remission, these respective rates were 74%, 64%, and 25%. Our data indicate that the combination of Clo and Bu provides effective disease control while maintaining a favorable safety profile.

Long-term outcome of reduced-intensity allogeneic hematopoietic SCT in patients with AML in CR.

A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores ≥3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34-103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML.

Stem-cell transplantation in T-cell non-Hodgkin's lymphomas.

BACKGROUND: T-cell lymphomas are a heterogeneous group of non-Hodgkin's lymphomas (NHLs). With the exception of anaplastic lymphoma kinase protein-positive large-cell lymphoma, standard chemotherapy provides dismal long-term outcomes when compared with NHLs with B-cell immunophenotype. DESIGN: We review the literature on the role of high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in T-cell NHLs both as up-front treatment and in the salvage setting. The role of allogeneic transplantation will also be reviewed. RESULTS: Results from five prospective, nonrandomized and six retrospective studies evaluating the role of HDT and ASCT in the up-front setting show that patients in first complete or partial remission especially those who present with advanced disease and high prognostic index of peripheral T-cell lymphoma score may benefit from this approach. In the relapsed and/or refractory setting, most series show results that are comparable with those seen in patients with B-cell lymphomas if transplanted with chemosensitive disease. There is limited evidence to suggest that an immune-mediated graft-versus-lymphoma effect may result in long-term disease remissions in some patients after allogeneic transplantation. CONCLUSIONS: Randomized studies comparing HDT and ASCT with conventional chemotherapy are needed in T-cell lymphomas.

Phase II trial of high-dose topotecan, melphalan and CY with autologous stem cell support for multiple myeloma.

In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m(2) intravenously on days -6 to -2, melphalan 70 mg/m(2) intravenously on days -3 and -2 and CY 1 g/m(2) intravenously on days -6, -5 and -4. Overall response rate (ORR) consisting of complete response and partial response (CR+PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45-72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC>0.5 × 10(9)/L) and plt engraftment (>20 × 10(9)/L) was 10 (range 7-12 days) and 9 days (range 6-79 days), respectively. A majority of the common adverse events were grade 1-3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan.

Hepatosplenic gamma-delta T-cell lymphoma: clinicopathological features and treatment.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare peripheral T-cell lymphoma; treatment with standard anthracycline-containing chemotherapy regimens has been disappointing, and an optimal treatment strategy for this patient population has not yet been determined. METHODS: We identified 15 cases of pathologically confirmed HSTCL in the institution's database. Clinical characteristics and treatment results were reviewed. RESULTS: Complete responses (CRs) were achieved in 7 of 14 patients who received chemotherapy. Achievement of CR was followed by hematopoietic stem-cell transplantation in three patients. Median duration of CR was 8 months (range 2 to 32+ months) with four patients currently alive and in CR at 5, 8, 12, and 32 months, respectively. Median overall survival (OS) was 11 months (range 2 to 36+ months). Patients who achieved a CR had a median OS of 13 months, compared with 7.5 months in patients who did not achieve a CR. Risk factors associated with worse outcome included male gender, failure to achieve a CR, history of immunocompromise, and absence of a T-cell receptor gene rearrangement in the gamma chain. CONCLUSION: A better understanding of the pathophysiology of HSTCL and new therapeutic strategies are needed.