bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Efficacy of Lenalidomide {Revlimid®} in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Updated Results of a Phase II Clinical Trial.
Authors: Chanan-Khan Asher Alban , Miller Kena C. , Musial Laurie , Padmanabhan Swaminatha , Lawrence David , Bernstein Zale P. , Takeshita Kenichi , Spaner David , Byrne Catriona , Chrystal Cynthia , Czuczman Myron S. 
Published: October 2019

Abstract
Introduction: Lenalidomide (L) is an immunomodulatory agent (IMiD®), recently approved for treatment of patients (pts) with previously treated multiple myeloma and del 5q- MDS. Its antitumor effects are reported to be mediated at least in part through modulation of both the cytokine and the immune cellular tumor microenvironment. Clinical efficacy of L in pts with B-CLL has not been investigated previously. In a phase II clinical study, we examined the antileukemic effects of L in pts with relapse (rel) or refractory (ref) B-CLL.
Patients and Methods: CLL pts with rel or ref disease were eligible. L was given at 25mg PO QD from days 1–21 of 28-day cycle. Response was assessed every month using the NCI-WG 1996 criteria. Treatment with L was continued until progressive disease (PD) or molecular complete response (CR). Pts with PD received rituximab (R) (375mg/m2) with L. Target enrollment was 45 patients.
Results: Forty-five pts, median age of 64 years (range: 42–75) were enrolled. Advance stage disease was noted in 64%, elevated B2M in 24% and fludarabine refractory disease in 51% of the pts. Pts had a median of 3 prior therapies (range 1–10). All pts are evaluable for toxicity. Thrombocytopenia and neutropenia were the most common hematologic toxicity while fatigue and flare reaction (sudden, tender enlargement of lymph node, liver and/or spleen, with or without rash, low grade fever and/or increase in white blood counts) were the most common non-hematologic complications. Two patients experience reversible tumor lysis syndrome. On an intent-to-treat analysis, overall response rate was 42% with complete remission in 9% (n=4) and partial remission in 33% (n=15) of the pts. Molecular complete response (determined by PCR) was noted in 3 pts. Twelve pts were inevaluable (unable to complete 2 treatment cycles; either for toxicity or consent withdrawal) 4 are too early for response evaluation. Response rate among evaluable patients was 65.5% (19/29). To date only 2 pts have required the addition of R to L due to PD. Both have achieved a PR with combination therapy.
Correlative studies: we evaluated baseline T and NK cell repertoire, modulation of cytokines (VEGF, IL-10, IL-6, TNF-alpha) as well as modulation of gene expression profiles before and after treatment with L, this data will be presented at the meeting.
Conclusion: L is clinically active in pts with rel/ref CLL. CR’s, as well as, molecular CR determined by PCR were achieved with single agent L. Interestingly, in pts who developed resistance to L alone, addition of R resulted in a clinical response. These results are exciting and warrant further investigation of L in CLL pts. Final results of this study will be presented at the meeting.
Rapid and Wide Immunereconstitution Obtained with HSV-TK Engineered Donor Lymphocyte Add-Backs Permits Long-Term Survival after haplo-HSCT.
Authors: Bonini Chiara , Ciceri Fabio , Stanghellini Maria Teresa Lupo , Bondanza Attilio , Magnani Zulma , Perna Serena Kimi , Bernardi Massimo , Peccatori Jacopo , Servida Paolo , Crippa Fulvio , Kaneko Shin , Valtolina Veronica , Salomoni Monica , Turchetto Lucia , Toma Salvatore , Traversari Catia , Bruzzi Paolo , Castagna Luca , Santoro Armando , Apperley Jane , Slavin Shimon , Colombi Scialini , Stampino Corrado Gallo , Bregni Marco , Bordignon Claudio 
Published: October 2019

Abstract
T-cell depletion of allogeneic hematopoietic stem cell graft (HSCT) represents the most powerful approach to prevent graft-versus-host disease (GvHD), thus allowing to overcome HLA barriers in patients with high risk malignancies, lacking a conventional donor. We hypothesized that early add-back of suicide-gene transduced donor lymphocytes (TK cells) to leukemic patients undergoing haploidentical HSCT (haplo-HSCT) could provide early immune-reconstitution and selective control of GvHD. In a phase II clinical trial (protocol MMTK007), 17 of 29 enrolled pts, (median age 52), received add-backs of 10^7/kg TK cells 42 days after haplo-HSCT. TK cells engraftment, observed in 14 patients, was necessary and sufficient for a rapid and effective immunereconstitution (IR), with a median of 144 (101–336) CD3+, 59 (28–149) CD4+ and 86 (52–279) CD8+ cells/mcl at day 100 after HSCT. Accordingly, engraftment of TK cells was tightly correlated with clinical outcome: while 3/3 pts who failed TK cells engraftment died of infections, only 1/14 TK engrafted patients died from infections (last event at day +166). As shown in Table I, the immune repertoire of treated patients improved significantly at 6 months post transplant and normalized completely in 12 months.
High numbers of T cell precursors specific for CMV and EBV were detected at immune reconstitution (median of 86 and 69 gIFN specific spots/10^5 PBMC respectively) and predicted subsequent freedom from viral reactivation (p=0.002). Six pts developed acute (GvHD), (grade I to IV) that was always completely abrogated by the suicide system. Overall survival of TK cells treated patients is 50% at three years.
These results indicate that TK-DLI abolish late mortality after CD34+ haplo-SCT in adults. A phase III multicentric study will start in 2007 to validate prospectively the advantage of TK-DLI in haplo-SCT.
Sequential Heart and Autologous Stem Cell Transplantation for AL Amyloidosis.
Authors: Lacy Martha , Dispenzieri Angela , Hayman Suzanne R. , Kumar Shaji , Kyle Robert , Rajkumar S. Vincent , Edwards Brooks S. , Rodeheffer Richard J. , Robert Frantz P. , Kushwaha Sudhir S. , Clavell Alfedo L. , Dearani Joseph A. , Sundt Thoralf M. , Daly Richard C. , McGregor Christopher G. A. , Gastineau Dennis A. , Gertz Morie Abraham 
Published: October 2019

Abstract
Background: Patients with AL and congestive heart failure have a median survival of less than one year.
Methods: Between 1994 and 2005, 11 patients underwent sequential heart transplant followed by autologous peripheral blood stem cell transplant (SCT) for treatment of AL. Patients had heart dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma.
Results: Patients ranged in age from 35 to 63 years (median 54). All had biopsy proven amyloidosis and monoclonal protein detectable in serum (73%) or urine (100%). Free light chain assay was available prior to SCT in 6 and was abnormal in all. All patients presented with NYHA Class III or IV heart failure. All but two patients had no other organ involved at the time of heart transplant. One patient had his heart transplant at another facility and had renal involvement at the time of heart transplant. One patient had peripheral nerve involvement documented prior to heart transplant. Five patients had progression of amyloid to involve other organs by the time of SCT. These included: renal (6), peripheral nerve (2), macroglossia (3), gastrointestinal (2). The median time from diagnosis to heart transplant was 3 months (range 1 to 5). The median time from heart transplant to SCT was 8 months, (range 3 to 24). Conditioning chemotherapy consisted of melphalan 200 mg /m2 (6 patients) or melphalan 140 mg/m2 (5 patients). Two patients died of complications before day +100, (TRM of 18%). Hematologic remissions were seen in 8 and organ responses in 3. Five were unable to be evaluated for organ response due to the heart transplant. Three died from progressive amyloidosis at 66, 56.7, and 55 months following SCT. The median survival is 56.7 months from SCT. Six are alive with a median follow-up of 24 months, range 9 to 90 months. Among the 6 surviving patients, one patient relapsed and one patient has failed to improve, but 4 patients are in continued remission. One patient developed secondary myelodysplastic syndrome.
Conclusions: Heart transplant followed by SCT is feasible and offers durable remissions for carefully selected patients with cardiac AL.
Figure Figure
Relapse Rate and Long-Term Survival of AL Amyloidosis Patients Treated with High-Dose Melphalan and Autologous Stem Cell Transplantation (HDM/SCT).
Authors: Seldin David C. , Skinner Martha , Oran Betul , Quillen Karen , Finn Kathleen T. , Sanchorawala Vaishali 
Published: October 2019

Abstract
AL amyloidosis is a plasma cell dyscrasia in which clonal immunoglobulin light chains misfold and are deposited in tissues, leading to organ failure in untreated patients, with median survival of only ~1 year. Oral melphalan and prednisone is minimally effective for the disease, with an increase in median survival to ~1.5 years, and a low rate of hematologic complete responses (CRs). Twelve years ago, we began treating patients with AL amyloidosis with HDM/SCT. In the plasma cell malignancy multiple myeloma, this approach produces hematologic CRs and improves survival, but is not curative, as all patients eventually relapse. In AL amyloidosis, the relapse rate and long-term survival have not been studied, but early results are promising, with most centers reporting CR rates of ~40% and excellent survival in responding patients. To address the durability and long-term results of treatment with HDM/SCT, here we report on the outcome for AL amyloidosis patients treated at Boston Medical Center with HDM/SCT >10 years ago. The first autologous transplant took place on July 18, 1994 in two years, by July 18, 1996, 43 patients with AL amyloidosis without myeloma or other hematologic disease had been treated with HDM/SCT, receiving 100–200 mg/m2 melphalan depending upon age and protocol. Of the 43 patients treated in this 2 yr period, 76% of the patients were male, 81% had a lambda monoclonal disease, and their median age was 52 (range, 29–71). In these first 43 patients, the 100 day peri-transplant mortality rate was 16%. Nineteen of the 43 patients (44%) achieved a hematologic CR after treatment. In annual followup, 4 of 19 patients (21%) eventually relapsed. Fourteen of 43 patients (33%) are still alive; 12 of 19 patients who achieved a CR (63%) are still alive, while only 2 of 34 patients who did not (6%) are still alive. Although there were fewer (8) patients with kappa clonal disease, they had a better outcome, with an 87% CR rate vs. 34% for lambda (P=0.006); 75% of the kappa patients are still alive, vs. 23% of the lambda patients (P=0.005). The median survival of all 43 patients is 4.7 years. Thus, treatment of AL amyloidosis patients with HDM/SCT produces a high CR rate that is durable and is associated with excellent 10 year survival, particularly for those patients achieving a hematologic CR and for patients with kappa clonal disease. Ongoing clinical trials of HDM/SCT, along with strategies to reduce morbidity and mortality and to improve the CR rate, incorporating additional cycles of HDM/SCT or new anti-plasma cell agents, appear to be well-justified by these results.
High Proportions of CD4+CD25hi T Cells Pretransplant Correlate with Worse Overall Survival after Stem Cell Transplant.
Authors: Prieto-Hinojosa Adria , Madrigal J. Alejandro , Shaw Bronwen E. , Mayor Neema P. , Marsh Stephen G.E. , Travers Paul J. , Duarte Rafael F. 
Published: October 2019

Abstract
Regulatory cells may have a modulatory effect on alloreactive phenomena following hematopoietic stem cell transplantation (HSCT), although their role in this setting in patients remains controversial. We have analysed the effect of pre-conditioning peripheral blood levels of T-regs on the outcome of 89 adult patients undergoing HLA-identical (10/10) unrelated donor (UD)-HSCT. Allografts were T-cell depleted with Alemtuzumab, which has been described to spare T-regs from, and we found that higher proportion of CD4+CD25hi T-cells correlated with worse survival (p=0.002). This higher proportion also correlated with higher incidence of relapse (p=0.0274) and with higher incidence of chronic (c) GvHD (p=0.033) but not with the incidence of aGvHD.
Regulatory T cells (T-regs) are a naturally occurring regulatory population of CD4+CD25hi T-cells known to express the transcription repressor FoxP3 and to produce anti-inflammatory cytokines such as TGFβ and may therefore affect patient survival. We analyse the profile of the CD4+CD25hiT cells in our cohort. In our healthy donor control group (n=30), CD4+CD25hi-expression associated with both, FoxP3 mRNA-levels (r=0.649; p=0.001) and TGFβ production (r=0.912; p<0.001), as previously described for T-regs. In preconditioning patient samples however, CD4+CD25hi-expression had a strong correlation with TGFβ regulatory cytokine production (r=0.863; p<0.001) as expected. However, FoxP3 mRNA-expression correlated neither with the CD4+CD25hi T-regs phenotype (r=0.280; p=0.040), nor with the production of TGFβ (r=0.229; p=0.156), and appeared not be an accurate marker for regulatory T-cell function in this patient setting. In addition, an inverse correlation with TNFα expression (r=−0.458 p<0.001) was found that may argue that the CD4+CD25hi cells represent a true regulatory population and not activated cells. This suggests either that activated cells that are not expressing FOXP3 might be included in the CD4+CD25hi population or that CD4+CD25loFOXP3+ cells have not acquire the regulatory function (i.e. they are not expressing TGFβ).
In summary, CD4+CD25hi Regulatory T cells may have an impact suppressing allo-responses against the tumour, decreasing the overall survival by increasing the rates of relapse.
Although, in mice CD4+CD25hi population have been clearly identified by the expression of the FOXP3, which encodes a transcription repressor, in humans this remains controversial, where FOXP3 expression is not exclusive of the CD4+CD25hi population.
Relying on the expression of CD4+CD25hi and FOXP3 in patients is insufficient to determine regulatory T cell numbers and suggests that other parameters of regulatory function should be taken in to account.
Four Cases of Donor Cell-Derived Acute Myeloid Leukemia Following Unrelated Cord Blood Transplantation for Adult Patients; Tokyo Cord Blood Bank Experiences.
Authors: Nagamura-Inoue Tokiko , Kodo Hideki , Takahashi Tsuneo A. , Mugishima Hideo , Tojo Arinobu , Asano Shigetaka 
Published: October 2019

Abstract
Donor cell leukemia (DCL) is considered as a rare complication following allogeneic bone marrow transplantation (BMT), whereas the actual frequency of DCL has not yet been specified. Cord blood (CB) is now recognized as an alternative source for stem cell transplantation (SCT), with more than 6000 cord blood transplants (CBTs) performed worldwide, and a few cases of DCL following CBT have also been reported. Here we report four cases of DCL developed after unrelated CBTs using 490 shipped units from Tokyo cord blood bank (TCBB). Development of DCL was informed to TCBB by attending physicians of the recipients in CBT centers as soon as definite diagnosis was made. The feed-back from CBT centers on four DCL cases is summarized in Table 1. All the donors were well at the follow-up questionnaire 6–12 months after birth, but further information of their health conditions has not yet been obtained.
Table 1. Four cases of DCL following CBT Case 1 2 3 4 Recipient 32F 32F 56F 30M Disease AML in REL1 AML-M0 in REL1 ATL Hodgkin’s disease SCT 1st 2nd 2nd 2nd Regimen Myeloablative Myeloablative Non-myeloablative Non-myeloablative TBI 12Gy 12Gy (−) 2Gy G-CSF (+) (+) (+) (+) GVHD prophylaxis CsA+sMTX CsA+sMTX FK506+PSL CsA+sMTX aGVHD II II 0 III cGVHD (−) (−) (−) limited DCL AML AML-M2 AML AML-M5 Latent period 15 Mm after CBT 11 Mm after CBT 7 Mm after CBT 16 Mm after CBT Diagnosis FISH STR FISH STR
The etiology of DCL is unclear and a common mechanism is unlikely according to the reported literature. There exist several possibilities including occult leukemia or preleukemic state in the donor, defect in immune surveillance, therapy-related stromal abnormalities, excess of cytokine stimulation, and DNA replication and/or repair errors associated with post-transplant expansion of stem/progenitor cells. The possibility of occult leukemia in the donor raises serious problems regarding to the ethical responsibilities of the CBB to the donor.
Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults with Reduced-Intensity Conditioning and CD3/CD19-Depleted Grafts: Low Toxicity and Fast Engraftment.
Authors: Bethge Wolfgang A. , Faul Christoph , Bornhaeuser Martin , Stuhler Gernot , Lang Peter , Stelljes Matthias , Handgretinger Rupert , Kanz Lothar 
Published: October 2019

Abstract
Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device and reduced intensity conditioning may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer-, graft-facilitating- and dendritic-cells. Reduced intensity conditioning was performed with fludarabine (150–200 mg/m²), thiotepa (10 mg/kg), melphalan (120 mg/m²) and OKT-3 (5 mg/day, day −5 to +14) and no posttransplant immunosuppression. Twenty two consecutive patients (median age=43 (range, 21–59) years) have been transplanted with this regimen. Diagnosis were AML (n=12), ALL (n=5), NHL (n=2), MM (n=2) and CML (n=1). Patients were “high risk” with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6 x 106 (range, 3.4–17x106) CD34+cells/kg, 6.7x107 (range, 0.02–18.2 x107) CD56+cells/kg and 5.5x104(range, 0.006–44x104) CD3+T-cells/kg.
Donor-recipient KIR-ligand-mismatch was found in 14 of 22 patients. The regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m² fludarabine, the dose was reduced to 150 mg/m² with no further cases of neuropathy thereafter. Engraftment was rapid with median time to >500 granulocytes/μL of 12 (range, 10–21) days, >20000 platelets/μL of 11 (range, 7–28) days and full donor chimerism after 2–4 weeks in all patients. Incidence of grade II–IV GVHD was 59% with grade II=9, III=2 and IV=2. One patient, who received the highest T cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/22 (27%) with deaths due to idiopathic pneumonia syndrome (n=1), mucormycosis (n=1), pneumonia (n=3) or GVHD (n=1). Six patients died after day 100, five due to relapse and one with systemic adenoviral infection. Overall survival is 10/22 patients (45%) with a median follow-up of 185 days (range, 17–988). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.
No Impact of Adverse Karyotype on Outcome after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Lymphoblastic Leukemia.
Authors: Tamm Ingo , Massenkeil Gero , Wagner Mandy , Terwey Theis , Lutz Christoph , Neuburger Stefan , Bommert Christiane , Dörken Bernd , Arnold Renate 
Published: October 2019

Abstract
Karyotypes like Philadelphia-chromosome (Ph+) and t(4;11) adversely influence clinical outcome in adult patients with acute lymphoblastic leukemia (ALL) after chemotherapy. Here, we analyze the potential impact of karyotype on outcome after allogeneic hematopoietic stem cell therapy (HSCT) in ALL.
We present a retrospective analysis of 135 adult ALL patients treated unicentrically within the German ALL (GMALL) protocol using allogeneic HSCT. All patients were high-risk patients in CR1 according to GMALL definitions (i.e., WBC > 30.000/μl, pro-B-ALL, t(4;11), t(9;22), early T- or mature T-ALL, no CR after first induction) or were beyond CR1.
Median age of all patients was 29 years (range 16 – 55), 99 B-lineage and 36 T-lineage ALLs were transplanted. Normal karyotype was present in 57 patients, Ph+ in 36 patients, complex chromosomal anomalies in six patients, t(4;11) in five patients, other aberrations in 22 patients and no growth/no cytogenetic data were available for 9 patients. Patients were transplanted in complete remission (CR) CR1 (60), CR2 (23), CR3 (7), first relapse (30), second relapse (6), third relapse (1) and eight patients had primary induction failure. 41 patients received bone marrow and 94 patients received peripheral blood stem cell transplants. Patients received standard high-dose (n=125) or reduced intensity conditioning (RIC) (n=10) HSCT from related (n=58) or unrelated (n=77) donors.
Overall, after a median follow-up of 11 months (range 1–120), 74 (55%) patients died and 61 (45%) are alive. Median follow-up of the living is 29 months (range 1–120). Deaths were due to treatment-related mortality (TRM; n=33; 24%) or relapse (n=41; 31%). Leukemia-free survival (LFS), overall survival, and TRM were not significantly different between the karyotype subgroups studied. LFS at 6 months, 1 year, 3 years, and five years was 62%, 60%, 50%, and 41% for patients with a normal karyotype; 63%, 47%, 40%, and 28% for patients with Ph+; and 61%, 40%, 27%, and 27% for patients with other aberrations. 4/5 patients with t(4;11) and 4/6 patients with complex chromosomal abnormalities are alive in CR.
In conclusion, there is no adverse impact of classical poor risk karyotypes on outcome within this high-risk group of ALL patients after allogeneic stem cell transplantation. In contrast, there was a trend that patients with t(4;11) and complex chromosomal anomalies did better (4/5 alive, 1/5 TRM and 4/6 alive, 1/6 TRM, 1/6 relapse, respectively) than patients with other aberrations (8/22 alive, 8/22 death due to relapse, 6/22 TRM). High-risk ALL patients with poor risk cytogenetics are candidates for allogeneic stem cell transplantation which can be curative. Whether other conditioning regimens or adoptive immunotherapy can reduce relapse rate in this patient group is a matter of ongoing clinical research.