bluuebunny/crossref_metadata_2025_split huggingface dataset:
Addition of Cladribine to the Standard AML Treatment Improves Long-Term Outcome in High Tumor Burden and Older Than 40 Years Acute Myeloid Leukemia Patients. Five-Year Follow-Up of the Polish Adult Leukemia Group (PALG 1999 DAC vs. DA Study).
Authors: Holowiecki Jerzy , Grosicki Sebastian , Robak Tadeusz , Krzemien Slawomira , Giebel Sebastian , Hellmann Andrzej , Skotnicki Aleksander , Jedrzejczak Wieslaw W. , Konopka Lech , Kuliczkowski Kazimierz , Zdziarska Barbara , Dmoszynska Anna 
Published: October 2019

Abstract
The goal of the study was to evaluate long-term outcome of acute myeloid leukemia (AML) patients treated within the PALG 1999 DAC vs, DA Study.
Between 1999–2002, 445 patients, aged 18–60 years, were randomized to the induction DAC-7: daunorubicin 60 mg/m2/d iv 1–3; cytarabine 200 mg/m2/d ci 1–7; cladribine 5 mg/m2 2h inf. iv d 1–5 or standard DA-7 regimen (the same regimen without cladribine). Patients achieving CR received two courses of subsequent intensive consolidation: 1) HAM (HD AraC, mitoxantrone) 2) HD AraC with or without cladribine in the DAC-7 or DA-7 arm, respectively. In case of PR after the first induction course the same regimen was repeated, NR patients received CLAG (2-CDA, HD-AraC, G-CSF), regardless the randomization arm. Post-consolidation therapy was in both arms comparable.
As previously reported, a single course of DAC-7 induction resulted in 17% higher CR rate compared to the DA-7 treatment. The difference was particularly pronounced in a population of patients >40 years and for those with initial WBC >100x109/L. In the latter subgroup also the overall CR rate (achieved after >=1 induction course) was higher in the DAC-7 arm (71% vs. 43%). [Leukemia. 2004 May;18(5):989–97]
In the present report we analyzed long-term outcome (median follow-up 3.2 years) in the whole study group and in pre-defined subgroups taking into account initial tumor burden, age, cytogenetics, FAB subtype, and preceding myelodysplasia. At five years the overall survival (OS) rate equaled 31% for DAC-7 and 25% for DA-7 arm (p=0.42) and leukemia free survivall (LFS) 32% vs. 29% (p=0.38), respectively.
The subgroup analysis revealed higher probability of the OS in patients with initial WBC ≥100 G/l assigned to DAC-7 compared to DA-7 arm (39% vs. 11%, p=0.02). The LFS rate and the probability of relapse equaled 50% and 32% (p=NS) and 36% and 68% (p=0.0497), respectively.
In patients aged >40 years, the therapy containing cladribine was associated with improved LFS (30% for DAC-7 vs. 20% for DA-7, p=0.01), and a tendency to improved OS (28% vs. 18%, p=0.09). In this subgroup DAC-7 therapy resulted in reduced relapse incidence (60% vs. 69%, p=0.04).We conclude that addition of cladribine to induction/consolidation therapy of AML may improve long-term outcome in higher age ranges patients and in those with high tumor burden. The improvement results mainly from reduced risk of relapse, and, in patients with high initial WBC, from higher CR rate.
Effects of the FLT3 Inhibitor PKC 412 in Combination with Cytostatic Drugs In Vitro in Acute Myeloid Leukemia.
Authors: Möllgård Lars , Bengtzen Sofia , Fioretos Thoas , Andersson Anna , Paul Christer , Lehmann Sören 
Published: October 2019

Abstract
FLT3 is a member of the class III tyrosine kinase receptor family. Interaction with its ligand results in reactions that involve different signalling pathways in the cell. A majority of acute myeloid leukemias (AML) express FLT3. FLT3 is mutated and activated in about 30% of all patients with AML. The new compound PKC412 was found to specifically an potently inhibit the growth of leukemic cell lines with a FLT3 mutation.
In the first part of this study the primary objective was to evaluate the in vitro effect of the combination of PKC412 and ara-C focusing on the timing of the two drugs. Samples from 21 patients with AML have been included. IC50 curves for PKC 412 curves were obtained to find appropriate concentrations for the study. Two different in vitro models were used. In the 4+3 model the incubation time for the first drug was 4 days and the second drug was added after 1 day. In the 2+2 model the cells were incubated for 2 days with the first drug, then centrifuged and resuspended and incubated with the second drug for another 2 days. The FLT3 status was analysed with PCR and the ATP bioluminiscens method was used to determine viable cells after the incubations.
The preliminary results show that most of the possible combinations of the 2 drugs had an additive effect. In the 2+2 model 2 days with ara-C 0,5 m M followed by 2 days with PKC 0,2 m M resulted in a synergistic effect in the AML patient cells with FLT3-ITD. We also found a synergistic effect in the FLT3 mutated cells when PKC412 0,2 m M and daunorubicin 0,15 m M was combined in a 4 days incubation
Our results suggest that the timing of PKC412 in combination with cytostatic drugs can influence the effect. The timing of the drugs may be of importance in the designing of future clinical trials of PKC412 in AML patients.
Radiotherapy-Based Conditioning Is Effective Immunosuppression for Patients Undergoing Transplantation with T-Cell Depleted Stem Cell Grafts for Severe Aplasia.
Authors: Novitzky Nicolas , Thomas Valda , Stubbings Helen , Hale Geoff , Waldmann Herman 
Published: October 2019

Abstract
The combination of cyclophosphamide and ALG is highly effective in inducing engraftment in patients with aplastic anaemia undergoing allogeneic stem cell transplantation. However, the incidence of graft vs. host disease remains substantial. We studied the outcome of individuals with aplastic anaemia conditioned with a radiation containing regimen followed by the infusion of stem cell grafts that had been depleted of lymphocytes with CAMPATH-1H. The conditioning regime consisted of fractionated (f) total body irradiation 8 Gy followed by f total nodal irradiation 6 Gy. Additionally, patients received cyclophosphamide 60 mg/kg on 2 consecutive days. Cytokine mobilised peripheral blood grafts from HLA identical siblings were T-cell depleted with CAMPATH-1H “in the bag”. Cyclosporin was commenced on day -1 and continued until day +90. Seventeen heavily transfused patients with aplastic anaemia with a median age of 18 years (range 14–56) were studied. Median time from diagnosis to transplantation was 172 days (range 34–443). The median CD34+ cell number infused was 3.47 x106/kg (range 1.03–18.4). All patients engrafted. Recovery was fast and patients reached 0.5 x 109/L polymorphs by median day 11 (range 9–17) days. Toxicity from the conditioning included grade 4 haematological toxicity in all. Other major toxicity was gastrointestinal mucosal damage, which exceed grade 2 in only 2 instances. 1 patient developed thrombotic thrombocytopenic purpura which responded to substitution of cyclosporin with tacrolimus and plasmapheresis. Another, who had normal blood counts died of infection on day 241. Chimerism studies at 6 months post transplantation confirmed donor origin of haematopoiesis in all 7 patients tested. None of the patients developed acute or chronic graft vs. host disease. There was no delayed graft failure and 94% of patients survive disease free, at a median of 1303.5 days (range 216–2615) from graft infusion. In this cohort of multiply transfused patients, the radiation containing schedules described in this study led to universal engraftment with limited toxicity despite T-cell depletion. No patient developed graft vs. host disease or late graft failure. Lower doses of radiation containing conditioning should be explored further.
Fludarabine Is Superior to Cladribine When Added to Busulfan and Low Dose TBI as Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation (HCT): A Prospective Randomized Trial.
Authors: Markova M. , Barker Juliet N. , Wagner John E. , Miller Jeffrey S. , Arora Mukta , Burns Linda J. , MacMillan Margaret L. , Repka Tanya , Blazar Bruce R. , Weisdorf Daniel J. 
Published: October 2019

Abstract
Purine analogues have been combined with alkylator/irradiation as immunosuppressive and anti-tumor conditioning prior to allogeneic hematopoietic stem cell transplantation (HCT) though differing purine analogues have not been compared. We prospectively tested Fludarabine (F) 40 mg/m2/d x 5d vs. Cladribine (C) 10 mg/m2/d x 5d plus Busulfan (Bu) (2mg/kg q12h x 2d) and total body irradiation (T) 200cGy followed by cyclosporine and mycophenylate mofetil in 19 recipients of matched sibling peripheral blood stem cell and 13 unrelated donor (URD) marrow HCT. Patients in each randomly assigned cohort [FBuT vs. CbuT] were similar in age (median 52 years in both groups), diagnosis (leukemia/MDS 38 vs. 31%; lymphoid malignancy 57 vs 69%), extensive pre-HCT therapy (56 vs. 63%), high risk disease status (81 vs. 93%) and Karnofsky (median 90 in each)[all p= NS] though fewer FBuT were URD recipients 25% vs. CBuT 56%, p=0.07. Engraftment was prompt in both groups (median 11 vs. 12 days), but the cumulative incidence of neutrophil engraftment was 75% (95% C.I. 54–96%) using CBuT vs. 100% with FBuT (p<0.01) and randomization was halted. Platelet recovery was prompt (median FBuT 18 vs CBuT 24 days) and after FBuT 75% (95% C.I. 49–100) vs. CBuT 69% (43–95) recovered platelets > 50,000/μL by day +180, p=0.19. The cumulative incidence of GVHD after FBuT vs. CbuT was similar (acute grade II/IV 56 vs. 69%, p=0.26) and (chronic 50 vs. 31%, p=0.27). Transplant related mortality at day +180 was also similar [FBuT 25% (4–46) vs. CbuT 38% (14–61), p=0.47]. Survival was equivalent: at 1 year 50% in each group; at 3 years FBuT 25% vs. CBuT 38%, p=0.55. Multivariate analyses adjusted for age, donor type, diagnosis and stage as well as conditioning regimen showed lower relative risk (RR) of engraftment with CBuT (RR 0.6 (95% C.I. 0.2–1.3) p=0.16) and with URD RR 0.4 (0.2–1.0) p=0.04). RR of Platelet recovery was equivalent with FBuT (RR 0.7 (0.3–1.7) p=0.45) but inferior with URD (RR .16 (.05–.5) p<0.01). RR of GHVD II/IV similar with FBuT RR 1.1, p=0.95, but more frequent with URD RR 2.0, p=.2 and high risk status patients (RR 4.5, 1.5–13.5, =<0.01). Prevalence of remission (CR or PR) at 18 months was high and was similar in both groups (FBuT 100% vs CBuT 86%, p=NS). These data suggest that older patients with advanced hematologic malignancies can achieve satisfactory post-transplant outcomes using either of these combination/reduced intensity conditioning regimens. Fludarabine may be superior to cladribine as a component of pre-HCT conditioning with Bu/TBI due to reduced risks of graft failure. Further modifications of the regimen may confirm universal engraftment with even lower peri-transplant morbidity.
High Relapse Rate Following Alemtuzamab Use in Allogeneic Transplants for Myeloid Hematologic Malignancies.
Authors: Shea Thomas C. , Serody Jonathan , Gabriel Don , Comeau Terrance , Harvey Donald , Irons Robert , Morris David , Sharf Andrew , Krasnov Carol , Dunphy Cherie , Banderenko Nicholas , Brecher Mark 
Published: October 2019

Abstract
Chakravarti, (Blood, 2002, p1071) and others have described the use of alemtuzamab, a monoclonal antibody that binds to CD52 on T cells, B cells, monocytes and dendritic cells in vivo for control of graft vs host disease in reduced intensity or fully-ablative matched related and unrelated transplant regimens for hematologic malignancies. Control of GVHD has been good, but high relapse rates and infectious complications have been seen. We report our experience with 42 pts who underwent matched related (27) or unrelated (15) bone marrow (8), blood stem cell (33), or both (1) transplants for hematologic malignancies. There were 16 women and 26 men, median age 48, and median f/u is 9 months. All AML pts had high-risk disease defined as beyond CR1 (11), CR1 with high risk cytogenetics (5), AML with tri-lineage dysplasia (6), or failed prior autologous transplant (1) Three had >10% marrow blasts at time of transplant. All other pts had advanced and multiply recurrent disease. All pts received alemtuzamab either at 20 mg/m2/d x 5 (17), or 30 mg/m2/d x 3 (25) between days -8 through -4. The conditioning regimens also included 12.8 mg/kg IV busulfan, (27), 6.4 mg/kg IV busulfan (8), melphalan 140 mg/m2 (6), or Cy/TBI (1). All non-TBI patients received 30 mg/m2/d x 5 of fludaribine. Median recovery of ANC to >500/ul and platelets > 20,000/ul w/o transfusion were 13 and 14 days, respectively. TRM included 1 pt each with intracranial hemorrhage at day 8, multi-organ failure/sepsis at day 28, and IPS/ARDS at day 119. Two of the 3 deaths were in MRD transplants; no serious episodes of VOD were observed. Grade 2–4 GVHD was seen in 4/14 evaluable MUD pts and 1 (sex mismatched) of 26 evaluable MRD pts. CMV reactivation has been seen in nearly all CMV sero+ pts, and bk reactivation was seen in 25 pts with hemorrhagic cystitis in 10. One case of PTLD, 3 graft failures, and one severe case of disseminated adenovirus infection resulting in nephritis, cystitis and transient cardiomyopathy were also seen. Relapse/# evaluable for different diseases are as follows: AML 12/22, Gleevec-resistant CML 3/3, MDS 0/4, MM 3/3, NHL 0/3, ALL 0/3, CLL 0/2. Relapse rates in evaluable MRD pts, 15/26 (58%), were statistically higher compared to MUD pts, 3/14 (21%) (p = 0.05). RR in marrow, 2/8, vs BSC, 16/32, were comparable. Alemtuzamab use has been effective at controlling GVHD and infectious complications can be reduced with early and pre-emptive use of ganciclovir. Nevertheless, high relapse rates remain a significant problem and preclude routine use of this approach in MRD patients with advanced myeloid diseases. Current use of this agent has been individualized for donor (MRD vs MUD) and disease (myeloid vs other) status.〉
Radiation Dose Determines Degree of Donor Chimerism after Nonmyeloablative Hematopoietic Cell Transplantation.
Authors: Kahl Christoph , Mielcarek Marco , Iwata Mineo , Harkey Michael , Storer Barry , Torok-Storb Beverly 
Published: October 2019

Abstract
Efforts to replace total body irradiation (TBI) used for transplant conditioning with agents that have less acute and long-term toxicities require a better understanding of the biological effects of low dose TBI. We therefore retrospectively analyzed the role of radiation dose, stem cell source, and type of immunosuppression on both the stability and degree of donor chimerism in canine recipients of matched littermate hematopoietic cell transplants. Recipients were prepared with 200 cGy (n=26), 100 cGy (n=76) or 50 cGy (n=19) total body irradiation (TBI) at 7 cGy/min. Stem cell sources included bone marrow (BM) alone (n=58), BM plus G-CSF mobilized peripheral blood mononuclear cells (G-PBMC) (n=42), BM and CD14-depleted G-PBMC (n=13), or BM and T-cell-depleted G-PBMC (n=8). Posttransplant immunosuppression consisted of cyclosporin (CSP) only (n=53), CSP plus mycophenolate mofetil (MMF) (n=23), CSP and rapamycin (n=12), CSP, MMF and rapamycin (n=5); or CSP and MMF in combination with pretransplant immunosuppression (n=28). The percentage of donor granulocytes in the peripheral blood, as determined by PCR amplification of variable numbers of tandem repeats (VNTR), served as a marker for engraftment. TBI dose and stem cell source were both significantly associated with long-term (>26 weeks) stable engraftment in multivariate analysis (p=0.0001 and p=0.004, respectively). Among the 39 dogs with stable engraftment, however, TBI dose was the only factor examined that was associated with the degree of donor chimerism (mean % of donor granulocytes after 200 cGy, 100 cGy and 50 cGy of TBI: 65%, 52%, and 24%, respectively; p=0.008). To determine whether low-dose irradiation directly affected recipient stem/progenitor cell numbers and thereby conferred a competitive disadvantage to donor cells, CD34+ cells were isolated from two normal human donors. One preparation of CD34 cells was ex vivo irradiated (=200 cGy) and then injected into NOD/SCID beta2m-/- mice in combination with an equal number of unirradiated CD34 cells from the second donor. The contributions of each donor to human engraftment were assessed at 10 weeks by VNTR. After 200 cGy, the irradiated population contributed 74% less than expected, 24% less after 100 cGy, but only 6% less after 50 cGy. Flow analysis of Caspase-3 activation indicated that a significant percentage of cells irradiated with 200 cGy were apoptotic, and that this was associated with the loss of L-selectin and P-selectin glycoprotein ligand-1. In conclusion, our findings suggest that TBI, in addition to its well-characterized immunosuppressive effects, determines the degree of donor cell engraftment by directly compromising recipient stem cells, thereby providing a competitive advantage to donor stem cells.
Engraftment and Survival Following Non-Myeloablative Allogeneic Peripheral Blood Hematopoietic Cell Transplantation for Malignant Diseases Is Affected by CD8+ T-Cell Dose.
Authors: Cao Thai M. , Shizuru Judith A. , Wong Ruby M. , Sheehan Kevin , Laport Ginna G. , Stockerl-Goldstein Keith E. , Johnston Laura J. , Stuart Monic J. , Brown Janic M.Y. , Grumet F. C. , Negrin Robert S. , Lowsky Robert 
Published: October 2019

Abstract
The influence of graft composition on clinical outcomes after non-myeloablative allogeneic hematopoietic transplantation is not well characterized. In this report we evaluated the influence of CD34+, CD3+, CD4+, and CD8+ cell doses on donor engraftment, graft-versus-host disease (GVHD), freedom from progression (FFP), and overall survival (OS). Patients (n=63) were given total body irradiation 200 cGy (n=8) or total body irradiation 200 cGy plus fludarabine (n=55) followed by allografting with granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC). The median age was 53 years, and donors were HLA-identical siblings (n=38) or HLA-matched unrelated individuals (n=25). Almost all patient were treated for a hematologic malignancy (n=60), with 30 patients (48%) characterized as having advanced diseases. G-PBMC cell doses were prospectively enumerated by FACS analysis at the time of collection. Median donor G-PBMC cell doses were 7.4x106 CD34+/kg (range: 1.9–17.7), 3.2x108 CD3+/kg (range: 0.8–6.4), 2.1x108 CD4+/kg (range: 0.4–4.1), and 1.1x108 CD8+/kg (range: 0.2–3.4). By univariate analysis only G-PBMC CD8+ T-cell dose ≥ the 50th percentile favorably correlated with attainment of full donor blood T-cell chimerism (P = .03). The incidences of grade 2–4 acute GVHD was 16.3% (95% CI: 6.9–25.8) and extensive chronic GVHD was 42.9% (95% CI: 27.8–57.9). No G-PBMC cell dose significantly influenced grade 2–4 acute or extensive chronic GVHD. With a median follow-up of 13 months (range: 5–45), estimates for FFP was 53.7% (95% CI: 37.7–69.7) and OS was 33.4% (95% CI: 17.4–49.4). G-PBMC CD8+ T-cell dose ≥ the 50th percentile T-cell dose was favorably prognostic for both FFP (P = .001) and OS (P = .01). Survival curves for FFP and OS are shown in Figure 1. Extensive chronic GVHD also predicted better FFP (P = .02), but in multivariate analysis only G-PBMC CD8 + T-cell dose (P = .004; RR = 0.2, 95% CI = 0.1–0.6) was associated with improved FFP. Infusion of low G-PBMC CD8+ T-cell dose for non-myeloablative allografting with total body irradiation 200 cGy plus fludarabine may adversely affect donor T-cell engraftment, disease progression and survival outcomes.
Invasive Pulmonary Aspergillosis Is Not a Contraindication to Reduced-Intensity Conditioned Allogeneic Haematopoietic Stem Cell Transplantation (RIC allo-HSCT).
Authors: Ho Aloysius Y.L. , Desai Sujal R. , Stanton Ian D.P. , Copley Susan J. , Wells Athol U. , Pagliuca Antonio , Devereux Stephen , Mufti Ghulam J. 
Published: October 2019

Abstract
Ten patients with focal abnormalities on CT prior to RIC allo-ASCT, in whom follow-up CT studies were available, were studied. All 10 had received prior chemotherapy for AML/MDS and had received treatment for high probability invasive pulmonary aspergillosis (IPA). The RIC protocol comprised “FBC”- fludarabine 30 mg/m2 intravenously from Day -9 to Day -5; busulphan 4mg/kg/day orally from Day -3 to Day -2 and alemtuzumab (CAMPATH-1H) 20mg intravenously from Day -8 to Day -4. Unselected peripheral blood stem cells (PBSCs) or bone marrow (BM) was infused on Day 0. Immunosuppression was achieved with cyclosporine 1.5 mg/kg intravenously 12 hourly from Day -1. Neoralâ was substituted when a good oral intake was tolerated and tapered from Day +56 in the absence of GvHD. Filgrastim 300 mcg iv/sc was administered from Day +7 to neutrophil engraftment (neutrophils ≥ 0.5x109/l). All patients received standard nursing and supportive care protocols for neutropenic patients. In addition these patients received Ambisome 3mg/kg intravenously daily until full neutrophil regeneration had occurred, then prophylactic Ambisome (2mg/kg thrice a week) till immunosuppression was stopped. Two thoracic radiologists (blinded to the timing of examinations) independently reviewed the CT studies pre- and post-RIC allo-HSCT. The site and size of individual lesions was evaluated. The likelihood (recorded as probable, possible, indeterminate or unlikely; denoting probabilites of ≥75%, ≥50%, ≥25% and <25% [respectively]), that individual lesions represented foci of angioinvasive fungal infection was noted. Serial changes in size, the appearance of new lesions (if any), and an overall impression of change in each patient (somewhat better or worse, significantly better or worse, no change) at follow-up CT, were also recorded. There were 48 lesions (probable, n=16; possible, n=18; indeterminate, n=13 and unlikely, n=1) on CT prior to RIC allo-HSCT. At follow-up CT, 12/16 (75%) probable and 10/18 (56%) possible lesions had either regressed or were smaller than prior to RIC allo-HSCT. Only 1/18 (6%) lesions graded as possible had increased in size following RIC allo-HSCT. Five new lesions (probable, n=2; possible, n=2; indeterminate, n=1) were demonstrated in five patients. The overall impression on follow-up was that CT studies were somewhat better (n=3) or significantly better (n=6) in 9/10 (90%) patients. In patients with pre-existing lesions on CT prior to RIC allo-HSCT, there was no evidence of progression in the majority of patients, and no patient died of IPA in the follow-up period. Documented IPA may not be a contraindication to RIC allo-HSCT in patients with haematological malignancy, which can be safely performed with our conditioning and supportive care protocol.