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Recent Research Publications

Web Resources: Fludarabine (6 links)


Recent Research Publications

Tamamyan G, Kadia T, Ravandi F, et al.
Frontline treatment of acute myeloid leukemia in adults.
Crit Rev Oncol Hematol. 2017; 110:20-34 [PubMed] Related Publications
Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients' age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40-50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30 to 40% up to 80 to 90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the "7+3"regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the "7+3" regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.

Holtick U, Herling M, Pflug N, et al.
Similar outcome after allogeneic stem cell transplantation with a modified FLAMSA conditioning protocol substituting 4 Gy TBI with treosulfan in an elderly population with high-risk AML.
Ann Hematol. 2017; 96(3):479-487 [PubMed] Related Publications
The fludarabine, amsacrine, and cytarabine (FLAMSA)-reduced-intensity conditioning (RIC) protocol has been described to be effective in patients with high-risk and refractory acute myeloic leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (aSCT). To increase safety and tolerability of the conditioning, we previously reported the feasibility to substitute the TBI component by treosulfan in elderly AML patients. We now present long-term follow-up data on patients treated with FLAMSA/treosulfan compared to the original FLAMSA/4Gy TBI protocol. We retrospectively analyzed 130 consecutive patients with high-risk or relapsed AML after aSCT following FLAMSA conditioning at our center. Fifty-eight patients were treated with FLAMSA/treosulfan due to age and/or comorbidities. Seventy-two patients were treated with FLAMSA/TBI. Median age of patients treated with FLAMSA/treosulfan was 60 years compared to 46 years in those treated with FLAMSA/TBI. The cumulative incidence of a non-relapse mortality at 4 years was 28% in FLAMSA/treosulfan patients as compared to 13% in FLAMSA/TBI. Cumulative incidence of relapse was higher in patients treated with FLAMSA/TBI (46 vs. 32%). This difference was even more prominent for patients treated in blast persistence prior to transplant (relapse incidence 70% for TBI vs. 35% for treosulfan). The overall and relapse-free survival rates at 4 years were 47 and 41%, respectively, for patients treated with FLAMSA/TBI as compared to 43 and 40% in patients treated with FLAMSA/treosulfan. These data indicate an anti-leukemic activity by FLAMSA/treosulfan especially in patients with a blast persistence prior to transplant. Older age was an independent factor for a higher non-relapse mortality. Translating FLAMSA/treosulfan to younger patients, a lower non-relapse mortality, and an improved anti-leukemic activity might add up to improved overall survival. Randomized studies are required to demonstrate an improved efficacy of treosulfan- versus TBI-based FLAMSA conditioning.

Yu CL, Zheng-Dong, Qiao ZH, et al.
The long-term outcome of reduced-intensity allogeneic stem cell transplantation from a matched related or unrelated donor, or haploidentical family donor in patients with leukemia: a retrospective analysis of data from the China RIC Cooperative Group.
Ann Hematol. 2017; 96(2):279-288 [PubMed] Related Publications
This study compared 6-year follow-up data from patients undergoing reduced-intensity conditioning (RIC) transplantation with an HLA-matched related donor (MRD), an HLA-matched unrelated donor (MUD), or an HLA-haploidentical donor (HID) for leukemia. Four hundred and twenty-seven patients from the China RIC Cooperative Group were enrolled, including 301 in the MRD, 79 in the HID, and 47 in the MUD groups. The conditioning regimen involved fludarabine combined with anti-lymphocyte globulin and cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis was administered using cyclosporin A (CsA) and mycophenolate mofetil (MMF). Four hundred and nineteen patients achieved stable donor chimerism. The incidence of stage II-IV acute GVHD in the HID group was 44.3 %, significantly higher than that in the MRD (23.6 %) and MUD (19.1 %) groups. The 1-year transplantation-related mortality (TRM) rates were 44.3, 17.6, and 21.3, respectively. Event-free survival (EFS) at 6 years in the HID group was 36.7 %, significantly lower than that of the MRD and MUD groups (59.1 and 66.0 %, P < 0.001 and P = 0.001, respectively). For advanced leukemia, the relapse rate of the HID group was 18.5 %, lower than that of the MRD group (37.5 %, P = 0.05), but the EFS at 6 years was 31.7 and 30.4 % (P > 0.05), respectively. RIC transplantation with MRD and MUD had similar outcome in leukemia which is better than that with HID. RIC transplantation with HID had lower relapsed with higher TRM and GVHD rate, particularly in advanced leukemias. RIC transplantation with MRD and MUD had similar outcomes in leukemia and they were better than those with HID. RIC transplantation with HID had a lower relapse rate but higher TRM and GVHD rates, particularly in cases of advanced leukemia.

Al-Sawaf O, Fischer K, Herling CD, et al.
Alemtuzumab consolidation in chronic lymphocytic leukaemia: a phase I/II multicentre trial.
Eur J Haematol. 2017; 98(3):254-262 [PubMed] Related Publications
OBJECTIVE: Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies.
METHODS: In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab. The aim of this phase I/II trial was to determine the maximal tolerable dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in patients who responded to second-line fludarabine-based treatment. Thirteen patients in complete (CR) or partial remission (PR) received alemtuzumab dose escalation starting with 10 mg intravenously (iv) once weekly for 8 wk and increasing in 10-mg intervals per dose level.
RESULTS: The main dose-limiting toxicities (DLTs) were infectious complications, and the MTD was determined at 10 mg. After alemtuzumab consolidation, seven of 13 patients (53%) were in CR, and four of these patients (30.7%) achieved minimal residual disease (MRD) negativity (<1 × 10E-4). At a median follow-up of 71.5 months, four patients were progression-free, with a median progression-free survival (PFS) of 28.5 months after the end of second-line treatment.
CONCLUSION: The results provide a safe and efficient schedule with weekly intravenous application of 10 mg of alemtuzumab as a consolidation regime in patients with CLL.

Park H, Youk J, Kim I, et al.
Comparison of cladribine- and fludarabine-based induction chemotherapy in relapsed or refractory acute myeloid leukaemia.
Ann Hematol. 2016; 95(11):1777-86 [PubMed] Related Publications
Induction regimens integrating cladribine or fludarabine have shown promising outcomes in relapsed or refractory (R/R) acute myeloid leukaemia (AML). We compared the outcome of a cladribine- versus a fludarabine-based regimen as induction chemotherapy for R/R-AML. We included patients with R/R-AML who were treated with a cladribine- or fludarabine-based chemotherapy between 2006 and 2015. We analysed 120 patients, 65 treated with cladribine and 55 treated with fludarabine. The CR rates were 62.7 and 61.4 % for the cladribine group and fludarabine group, respectively (p = 0.890). Poor prognostic factors included older age, secondary AML, poor cytogenetic risk group, prior induction failure, and short first CR duration. No significant overall survival (OS) or relapse-free survival (RFS) differences were found between the groups (OS, p = 0.213; RFS, p = 0.143). However, in a certain subset, survival outcomes were better with cladribine than with fludarabine, including de novo AML, CR at first induction therapy, and not-poor cytogenetic risk group inclusion without overt chemotherapy-refractoriness. By contrast, secondary AML patients had improved survival outcomes when treated with the fludarabine regimen. After CR, better outcomes were observed when allogeneic stem cell transplantation (SCT) was given as consolidation. In R/R-AML, cladribine- and fludarabine-based combination induction chemotherapy had differential survival outcomes according to disease characteristics. Allogeneic SCT after CR with a purine analogue-based regimen improved long-term outcome in these patients.

Yu KK, Dasanu CA
Rapidly Fatal Dissemination of Merkel Cell Carcinoma in a Patient Treated with Alemtuzumab for Chronic Lymphocytic Leukemia.
Conn Med. 2016 Jun-Jul; 80(6):353-8 [PubMed] Related Publications
Alemtuzumab is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL). Nonetheless, its use for this indication has fallen out of favor due to serious concerns for infectious complications and increased risks of second malignancies from the profound and lasting immunosuppression. We report here in a patient with a rapidly progressive metastatic Merkel cell carcinoma (MCC) who was previously treated with alemtuzumab and fludarabine for CLL. He developed profound lymphopenia and hypogammaglobulinemia. While the risk of MCC is increased in CLL, its rapid dissemination has not been previously reported with fludarabine alone. In light of the rapidly fatal outcome in our patient due to MCC, we advise caution with the use of alemtuzumab. In patients treated with alemtuzumab for nononcologic indications, aggressive surveillance for cutaneous malignancies should be implemented until its safety profile can be further characterized.

Song S, Hao Y, Yang X, et al.
Using Gold Nanoparticles as Delivery Vehicles for Targeted Delivery of Chemotherapy Drug Fludarabine Phosphate to Treat Hematological Cancers.
J Nanosci Nanotechnol. 2016; 16(3):2582-6 [PubMed] Related Publications
Nanotechnology is an emerging paradigm for creating functional nanoscale materials for various biomedical applications. In this study, a new nanotechnology-based drug delivery method was developed using gold nanoparticles (GNPs) as a delivery vehicle to reduce adverse drug side effects. Fludarabine Phosphate is a commercial chemotherapy drug used in cancer treatment, and has ability to kill various cancer cells. KG-1 cell, a type of acute cancer leukemia cell, was selected as a proof-of-concept target in this study. Due to the small size of GNPs, they can help Fludarabine Phosphate enter cancer cells more efficiently and better interfere with DNA synthesis in the cancer cells. To enhance targeting ability, folic acid molecules were also covalently linked to GNPs, resulting in GNP-Fludarabine-folic acid (GNP-F/f). Compared to treatments with GNP-F or drugs on its own (Fludarabine Phosphate), the GNP-F/f achieves much improved cell-killing effects. The UV-Vis spectra results also revealed that the drugs had successfully bonded covalently to the GNPs. The higher cell-killing efficiency of GNP-F/f compared with GNP-Fludarabine (GNP-F) or drugs on their own further validates the effectiveness of both the vectors (GNPs) and folic acid in enhancing the drug delivery to the cancer cells. The MTT viability tests showed that the GNPs had no cytotoxicity.

Santos-Lozano A, Morales-Gonzalez A, Sanchis-Gomar F, et al.
Response rate to the treatment of Waldenström macroglobulinemia: A meta-analysis of the results of clinical trials.
Crit Rev Oncol Hematol. 2016; 105:118-26 [PubMed] Related Publications
Waldenström macroglobulinemia (WM) is a malignant lymphoproliferative disorder characterized by the presence of a high level of serum monoclonal IgM and a lymphoplasmacytic infiltrate in the bone marrow. This meta-analysis sought to assess the effectiveness of the different treatments for WM tested in published trials using the response rate (RR) as the main outcome measure. Forty-six articles (1409 patients) identified were entered in a variable effects model meta-analysis of proportions (rates and sample sizes). A greater response to treatment was produced in patients treated with a combination of 2+ drugs (RR=73%; 95%CI: 62, 83; p<0.01) than in those receiving monotherapy with rituximab (RR=44%; 95%CI: 34, 55; p<0.01) or a purine analogue [61% (95%CI: 43, 78; p<0.01) for cladribine and 53% (95%CI: 34, 72; p<0.01) for fludarabine]. The combination rituximab+cladribine emerged as particularly effective (RR=87%; 95%CI: 78, 94; p<0.01), slightly more effective than rituximab+bortezomib/dexamethasone (RR=84%; 95%CI: 79, 88; p<0.01) and rituximab+cyclophosphamide/dexamethasone [RR=81% (95%CI: 72, 88; p<0.01)]. Our results are in overall agreement with treatment recommendations from the seventh International Workshops on WM. Our findings are limited by the fact that we could not analyze progression-free survival (PFS). More phase II/III trials are needed to corroborate promising recent findings with bendamustine and carfilzomib and further research are needed to standardize recommendations based on maximum treatment efficacy combined with lowest toxicity, differentiation between first vs second line treatment, or long-term follow up after treatment.

Brown JR, Hallek MJ, Pagel JM
Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long, How Much, and in Which Combination?
Am Soc Clin Oncol Educ Book. 2016; 35:e387-98 [PubMed] Related Publications
During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features-particularly mutated immunoglobulin heavy chain variable region (IGHV) genes-derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be approved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line), duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further study and improvement. Because the field of CLL management has become much more complex, we focus here on understanding the recent data and discuss many of the questions and controversies important for how we approach patients with CLL.

Andrade-Campos MM, Liévano P, Espinosa-Lara N, et al.
Long-term complication in follicular lymphoma: assessing the risk of secondary neoplasm in 242 patients treated or not with 90-yttrium-ibritumomab-tiuxetan.
Eur J Haematol. 2016; 97(6):576-582 [PubMed] Related Publications
BACKGROUND: Non-Hodgkin lymphoma patients have a 25% increased risk of secondary primary neoplasms (SPNs). Regarding the controversy about the increased risk of SPN in patients exposed to radioimmunotherapy (RIT), we have analyzed this issue in a cohort of follicular lymphoma (FL) patients treated with/without RIT.
PATIENTS AND METHODS: A retrospective study including all consecutive FL patients diagnosed since 2001 was performed. Demographic, clinical data including the incidence of any kind of neoplasm (excluding basocellular skin carcinoma) were recorded.
RESULTS: A total of 242 patients were registered, male/female: 103/139, mean age: 59.9 yr (15-86), stage IV (57.8%), and Follicular Lymphoma Prognostic Index (FLIPI) low-risk (62.15%) predominance. Ninety-six patients (39.7%) were treated with 90Y-IT. The median follow-up for patients treated or not with 90Y-IT was 61 (8-273) and 38 (1-171) months. With respect to SPN incidence, 38 (15.6%) patients have at least two cancers, in 17 (44.7%), FL was the SPN; for the rest (226), the global incidence of SPNs was 9.3% (21), but there were no differences related to the exposition or not to 90Y-IT (P = 0.26). In seven patients, more than two (2-6) different therapies were registered; four were exposed to fludarabine-based therapy, three to radiotherapy and two to autologous stem-cell transplantation, and in the RIT cohort, two patients developed myelodysplastic syndrome.
CONCLUSION: This is one of the largest single institution reports assessing the risk of SPN in FL patients treated (96) or not (146) with 90Y-IT. It seems that 90Y-IT does not increase significantly the risk of SPN but avoiding its use after fludarabine and other intense cytotoxic schemes is recommended.

Kurnaz F, Sahin C, Kaynar L, et al.
Factors affecting survival in acute leukemia with donor lymphocyte infusion in the first relapse after allogeneic stem cell transplantation.
J BUON. 2016 Jan-Feb; 21(1):227-34 [PubMed] Related Publications
PURPOSE: Relapse of leukemia relapsing after allogeneic (allo) stem cell transplantation (SCT) remains an important problem. Cytoreductive chemotherapy followed by donor leukocyte infusion (DLI) is one of the treatment modalities in relapsed patients. The current study evaluated the factors affecting overall survival (OS) in allo-SCT patients who received DLI after the first relapse.
METHODS: In this retrospective study 54 patients (26 with acute myeloid leukemia [AML] and 28 with acute lymphoblastic leukemia [ALL]) in their first relapse after allo-SCT who received fludarabine-based chemotherapy followed by DLI were evaluated.
RESULTS: The relative risk for mortality was significantly higher in patients with acute leukemia (AL) within the high-risk group who went through transplantation (risk ratio: 4.866; 95% CI: 2.029-11.670;p<0.001) and in transplants performed in the remission phases following the first complete remission (risk ratio: 2.371; 95% CI: 1.154 - 4.872; p=0.019). Additionally, the relative mortality risk of transplantation in patients with acute leukemia (AL) with a number of DLIs applied (risk ratio: 0.456; 95% CI: 0.29 - 0.717; p=0.001) nd non-myeloablative regimen (risk ratio: 0.229; 95% CI: 0.053-0.992; p=0.049) was significantly lower.
CONCLUSION: Efforts to enhance the number of DLIs, thus the number of infused cells, may result in better OS in cases with AL with relapse.

Eichhorst B, Cramer P, Hallek M
Initial therapy of chronic lymphocytic leukemia.
Semin Oncol. 2016; 43(2):241-50 [PubMed] Related Publications
Only chronic lymphocytic leukemia (CLL) patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. Prognostic risk factor profile and comorbidity burden are most relevant for the choice of treatment. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus milder chemotherapy (chlorambucil) may be applied. Patients with a del(17p) or TP53 mutation should be treated with the kinase inhibitors ibrutinib or a combination of idelalisib and rituximab. Clinical trials over the next several years will determine, whether kinase inhibitors, other small molecules, immunotherapeutics, or combinations thereof will further improve outcomes for patients with CLL.

Saini L, Brandwein J, Turner R, et al.
The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease.
Eur J Haematol. 2016; 97(5):471-478 [PubMed] Related Publications
We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.

Zoellner AK, Höhler T, Fries S, et al.
Altered treatment of chronic lymphocytic leukemia in Germany during the last decade.
Ann Hematol. 2016; 95(6):853-61 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66 %, 2009: 71 %, 2011: 77 %) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32 %, 2009: 14 %, fludarabine 2006: 23 %, 2009: 37 %). In 2011, the combination of rituximab with bendamustine (31 %) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide (22 %) regime. Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15 %, 2011: 73 %). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.

Casadei B, Pellegrini C, Pulsoni A, et al.
90-yttrium-ibritumomab tiuxetan consolidation of fludarabine, mitoxantrone, rituximab in intermediate/high-risk follicular lymphoma: updated long-term results after a median follow-up of 7 years.
Cancer Med. 2016; 5(6):1093-7 [PubMed] Free Access to Full Article Related Publications
Radioimmunotherapy (RIT) after an induction phase with conventional chemoimmunotherapy became an attractive strategy of consolidation for patients with advanced follicular lymphoma: in particular, in many studies RIT was represented by yttrium-90-ibritumomab tiuxetan ((90) Y-IT). Independently by the different front-line treatment, updates on the long-term follow-up of these studies are needed because the disease course of follicular lymphoma is characterised by multiple relapses and progressively shorter durations of response. We report updated long-term efficacy and toxicity results of a multicenter phase II study on sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by (90) Y-IT as front-line therapy for untreated patients with intermediate/high-risk follicular lymphoma. With a median follow-up of 84 months, only 19/49 (38.8%) complete response patients relapsed, yielding an estimated long-term disease-free survival of 62.6%. The 7-year overall survival was 72.7%. Four (7.3%) second acute myeloid leukemia occurred, with a median time following RIT of 42 months. A relevant patients' responsiveness to subsequent therapies occurred: approximately 65% of relapsed patients obtained a good clinical response after the second-line treatment. These data represented the first evidence of a real role even in the long period of 90Y-IT after a fludarabine-containing regimen plus rituximab in the treatment of high-risk follicular lymphoma.

Shin DY, Kim SJ, Yoon DH, et al.
Results of a phase II study of vorinostat in combination with intravenous fludarabine, mitoxantrone, and dexamethasone in patients with relapsed or refractory mantle cell lymphoma: an interim analysis.
Cancer Chemother Pharmacol. 2016; 77(4):865-73 [PubMed] Related Publications
PURPOSE: Mantle cell lymphoma (MCL) is a disease that frequently relapses and primarily affects elderly people. We performed an open-label, multi-center, phase II study to investigate the effect and quality of life (QoL) of treatment with vorinostat in combination with fludarabine, mitoxantrone and dexamethasone (V-FND) for relapsed or refractory MCL.
METHODS: The treatment schedule was composed of four cycles of induction treatment with V-FND and subsequent consolidation therapy involving autologous hematopoietic stem cell transplantation or six cycles of vorinostat maintenance. QoL was assessed using EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) every 2 cycles.
RESULTS: Data from a total of 20 patients were collected for an interim analysis. The median age was 67 years (range 49-75), and 14 or the patients (70 %) were male. The full course of V-FND induction treatment was completed in 11 patients, but only three completed all six cycles of maintenance therapy. Response to V-FND was not available in two patients. Among the other 18 patients, the objective response rate was 77.8 % (complete response in five patients + partial response in nine patients). Median progression-free survival was 9.3 months [95 % confidence interval (CI) 4.0-12.3]. Fifteen patients (75 %) experienced grade 3/4 toxicities. Analysis of QoL demonstrated significant deterioration of social functioning (p = 0.01), and significant aggravation of fatigue and nausea/vomiting (p = 0.04 and 0.01, respectively) after two cycles of V-FND induction.
CONCLUSIONS: V-FND is effective in patients with relapsed or refractory MCL. However, significant toxicities were hurdles to sustained V-FND therapy.

Soini E, Hautala A, Poikonen E, et al.
Cost-effectiveness of First-line Chronic Lymphocytic Leukemia Treatments When Full-dose Fludarabine Is Unsuitable.
Clin Ther. 2016; 38(4):889-904.e14 [PubMed] Related Publications
PURPOSE: The cost-effectiveness of first-line chronic lymphocytic leukemia treatments was assessed among patients unsuitable for full doses of fludarabine.
METHODS: The study's key outcome was the life-time incremental cost-effectiveness ratio (ICER) (euro/quality-adjusted life-year [QALY] gained) with an annual 3% discounting. A probabilistic Markov model with 3 health states (progression-free, progression, and death) was developed. Survival time was modeled based on age-matched clinical data by using appropriate survival distributions. Each health state was assigned an EuroQoL-5D-3L quality-of-life estimate and Finnish payer costs according to treatment received, and Binet stage of disease; severe adverse events and treatment inconvenience were also included. Six approaches considered the risk and value of key outcomes: cost-effectiveness efficiency frontiers; Bayesian treatment ranking (BTR) rated the lowest ICERs and best QALY gains; the cost-effectiveness acceptability frontier demonstrated optimal treatment; expected value of perfect information; and the cost-benefit assessment (CBA), a type of clinical value analysis, increased the clinical interpretation and appeal of modeled outcomes by including both relative and absolute (impact investment [benefit obtained with a fixed limited budget]) benefit assessments.
FINDINGS: The ICERs compared with chlorambucil varied from €29,334 with obinutuzumab + chlorambucil to €82,159 with ofatumumab + chlorambucil. Based on the BTR of ICERs versus chlorambucil, obinutuzumab + chlorambucil was the most cost-effective with 93% probability; rituximab + chlorambucil was the second most cost-effective (73%); and rituximab + bendamustine was the third most cost-effective (65%). The ICERs of obinutuzumab + chlorambucil were €20,038, €11,556, and €15,586 compared with rituximab + chlorambucil, rituximab + bendamustine, and ofatumumab + chlorambucil. Obinutuzumab + chlorambucil was the most cost-effective treatment, with 54% and 99% probability at €30,000 and €50,000/QALY gained, respectively. The corresponding expected values of perfect information were €1438 and €44 per patient. Based on the BTR of QALYs gained, obinutuzumab + chlorambucil was the most effective, with 100% probability; rituximab + chlorambucil was the second most effective (56%); and rituximab + bendamustine was the third most effective treatment (81%). Results were robust in sensitivity analyses. For obinutuzumab + chlorambucil, the CBA demonstrated the best clinical value-to-cost-effectiveness relation and the longest time progression-free with a limited budget.
IMPLICATIONS: The mean results were sensitive to large changes in time horizon, indirect comparison hazard ratios, survival distributions, and discounting; however, obinutuzumab + chlorambucil provided considerable effectiveness and best value for money among chronic lymphocytic leukemia patients unsuitable to receive full doses of fludarabine. In this case, CBA concurred with the key outcome of the study. However, the CBA cannot fully substitute the key outcome, and further cost-effectiveness studies with different cancer types are needed to assess the validity of a limited CBA.

Reda G, Orofino N, Cassin R, et al.
Treating chronic lymphocytic leukemia with obinutuzumab: safety and efficacy considerations.
Expert Opin Drug Saf. 2016; 15(6):865-73 [PubMed] Related Publications
INTRODUCTION: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody (MoAb) with a higher affinity for CD20 epitope. It was approved by the United States Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL).
AREAS COVERED: This article evaluates the safety of obinutuzumab in CLL patients, also addressing pharmacokinetics/pharmacodynamics (PK/PD), clinical use and efficacy. Moreover, a comparison with other anti-CD20 MoAb is performed. The principal available studies on obinutuzumab are reviewed, focusing on CLL. A PubMed literature search (August 2002 to September 2015) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL.
EXPERT OPINION: Obinutuzumab, a third-generation anti-CD20 MoAb, is a safe and effective treatment for elderly patients who are un-fit for fludarabine-based regimen. Its use, proven in the CLL11 study and the results of many ongoing trials evaluating other obinutuzumab-based regimen can lead obinutuzumab to be a candidate to replace rituximab as the first-line treatment option.

Bachow SH, Lamanna N
Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting.
Curr Hematol Malig Rep. 2016; 11(1):61-70 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a disease of marked clinical heterogeneity, and while some patients have a normal life expectancy, others develop rapidly progressive disease shortly after diagnosis. The current standard for upfront treatment of CLL is chemoimmunotherapy for younger fit patients, FCR (fludarabine, cyclophosphamide, and rituximab) being the prototype. For older patients, BR (bendamustine and rituximab) exhibits excellent activity with decreased toxicity. For the frailest patients, CD20 monoclonal antibodies with or without chlorambucil have proven to be efficacious. The novel oral kinase inhibitors ibrutinib and idelalisib are FDA-approved in the relapsed/refractory setting, and ibrutinib is approved upfront for those with del(17p). These drugs have produced long-term durable responses in the relapsed/refractory setting, and studies are underway using these as single agent upfront or in combination with both chemotherapy and monoclonal antibodies. Here, we review standard upfront therapies and new agents and combinations that are on the horizon for CLL.

Trněný M, Lamy T, Walewski J, et al.
Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial.
Lancet Oncol. 2016; 17(3):319-31 [PubMed] Related Publications
BACKGROUND: Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma.
METHODS: The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0-2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1-21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667.
FINDINGS: Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6-31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5-12·1] vs 5·2 months [95% CI 3·7-6·9]) with a hazard ratio of 0·61 (95% CI 0·44-0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3-4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]).
INTERPRETATION: Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options.
FUNDING: Celgene Corporation.

Cramer P, Hallek M, Eichhorst B
State-of-the-Art Treatment and Novel Agents in Chronic Lymphocytic Leukemia.
Oncol Res Treat. 2016; 39(1-2):25-32 [PubMed] Related Publications
Chemoimmunotherapy is the established first-line treatment of patients with chronic lymphocytic leukemia (CLL) who do not display the high-risk genetic features del(17p) and/or TP53 mutation: Physically fit patients without or with only mild comorbidities should receive fludarabine, cyclophosphamide and rituximab, while bendamustine and rituximab can be considered in fit elderly patients of over 65 years and in patients with a higher risk of infections. Patients with relevant coexisting conditions should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Patients with a del(17p) and/or TP53 mutation respond poorly to conventional chemo(immuno)therapies. However, the recently approved BTK and PI3K inhibitors ibrutinib and idelalisib have the best efficacy ever documented in patients with these high-risk genomic alterations and/or refractory CLL. The choice between ibrutinib and idelalisib should be based on the patients' comorbidities and concomitant medications since both agents have a distinct toxicity profile, although they are generally well tolerated in the majority of patients. For treatment of patients with a late relapse, chemoimmunotherapy instead of kinase inhibitors is still a reasonable approach, but has to be determined for every patient individually. Further targeted drugs and their combinations are currently being evaluated in clinical trials and have the potential to eradicate all residual CLL cells and thus lead to a cure of CLL.

Goto S, Goto H, Yokosuka T
The combination effects of bendamustine with antimetabolites against childhood acute lymphoblastic leukemia cells.
Int J Hematol. 2016; 103(5):572-83 [PubMed] Related Publications
Bendamustine combined with other drugs is clinically efficacious for some adult lymphoid malignancies, but to date there are no reports of the use of such combinatorial approaches in pediatric patients. We investigated the in vitro activity of bendamustine combined with other antimetabolite drugs on B cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines established from pediatric patients with refractory or relapsed ALL. We also developed a mathematically drown improved isobologram method to assess the data objectively. Three BCP-ALL cell lines; YCUB-2, YCUB-5, and YCUB-6, were simultaneously exposed to various concentrations of bendamustine and cladribine, cytarabine, fludarabine, or clofarabine. Cell growth inhibition was determined using the WST-8 assay. Combinatorial effects were estimated using our improved isobologram method with IC80 (drug concentration corresponding to 80 % of maximum inhibition). Bendamustine alone inhibited ALL cell growth with mean IC80 values of 11.30-18.90 μg/ml. Combinations of bendamustine with other drugs produced the following effects: (1) cladribine; synergistic-to-additive on all cell lines; (2) cytarabine; synergistic-to-additive on YCUB-5 and YCUB-6, and synergistic-to-antagonistic on YCUB-2; (3) fludarabine; additive-to-antagonistic on YCUB-5, and synergistic-to-antagonistic on YCUB-2 and YCUB-6; (4) clofarabine; additive-to-antagonistic on all cell lines. Flow cytometric analysis also showed the combination effects of bendamustine and cladribine. Bendamustine/cladribine or bendamustine/cytarabine may thus represent a promising combination for salvage treatment in childhood ALL.

Clark E, Boffa M, Magri C, Muscat V
Chlorambucil-Induced Radiation Recall Dermatitis.
Skinmed. 2015 Jul-Aug; 13(4):317-9 [PubMed] Related Publications
A 65-year-old woman was diagnosed with low-grade non-Hodgkin lymphoma (Figure 1). She was treated with six cycles of cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and prednisolone (CHOP) and three cycles of fludarabine and mitoxantrone. Ten months later she received radiotherapy to the left groin (total dose of 50 Gy in 25 fractions over 5 weeks) without complications.

Wang L, Hu J, Sun Y, et al.
Does High-Dose Cytarabine Cause More Fungal Infection in Patients With Acute Myeloid Leukemia Undergoing Consolidation Therapy: A Multicenter, Prospective, Observational Study in China.
Medicine (Baltimore). 2016; 95(4):e2560 [PubMed] Free Access to Full Article Related Publications
Invasive fungal infection (IFI) remains as a significant cause of morbidity and mortality in patients with acute myelogenous leukemia (AML). Here, we report the subgroup analysis of China Assessment of Antifungal Therapy in Haematological Disease (CAESAR) study to evaluate the risk of IFI in patients with AML in 1st remission receiving high-dose cytarabine (HiDAC) as consolidation. A total of 638 patients with AML in 1st complete remission were selected from the database. Among them, 130 patients received HiDAC alone with total dose of 2-3 g/m(2) × 6 while 508 patients received multiple-agent combination chemotherapy (multiagent chemo group). The patients' characteristics were generally not different but more patients in HiDAC group had peripherally inserted central catheter (61.5% vs 44.5%, P = 0.002). The median duration of neutropenia was 8.0 days in both HiDAC (2-20) and multiagent chemo group (2-28). Number of patients with prolonged neutropenia (>14 days) tended to be more in multiagent chemo group but not significant different (16.3% vs 8.8%, respectively). There was no significant difference between 2 groups in persistent neutropenic fever (40.8% vs 33.1%), antifungal treatment (11.5% vs 11.4%), and incidence of proven/probable IFI (4 probable in HiDAC vs 1 proven/4 probable in multiagent chemo, P = 0.35) or possible IFI. As to the clinical outcome in terms of duration of hospitalization and death in remission, there was a trend of shorter duration of hospitalization in HiDAC (19 days, 3-70) compare to multiagent chemo group (21 days, 1-367, P = 0.057) while no death documented in HiDAC group and only 2 patients died in the multiagent chemo group (0.4%). As to risk factors associated with IFI in all 638 patients, there was a trend of more IFI in patients with severe neutropenia (3.0%, P = 0.089) and previous history of IFI (3.85%, P = 0.086) while the antifungal prophylaxis was not associated significantly reduced IFI. Overall, our data support the perception that HiDAC alone as consolidation in first remission AML patients was well tolerated and not associated with increased hematological toxicity and IFI than conventional combination chemotherapy. Antifungal prophylaxis may not necessary except for patients with previous history of IFI.

Filanovsky K, Miller EB, Sigler E, et al.
Incidence of Profound Hypogammaglobulinemia and Infection Rate in Lymphoma Patients Following the Combination of Chemotherapy and Rituximab.
Recent Pat Anticancer Drug Discov. 2016; 11(2):228-35 [PubMed] Related Publications
BACKGROUND: The Anti-CD20 monoclonal antibody Rituximab suppresses B-lymphocytes and may induce hypogammaglobulinemia in treated patients. The incidence and clinical significance of rituximab induced hypogammaglobulinemia in lymphoma patients is underestimated.
METHODS: We retrospectively analyzed the rates of hypogammaglobulinemia, infection and infection-related mortality in 136 lymphoma patients who were treated with a combination of chemotherapy and rituximab.
RESULTS: Rituximab given in more than 8 doses (OR 6.05, 95% CI: 1.24-29.5), relative hypogammaglobulinemia at time of lymphoma diagnosis (OR 4.2, 95% CI: 1.26-14.1) and the combination of fludarabine with rituximab (OR 3.4, 95% CI: 1.24-9.47) were factors significantly associated with prolonged (more than 6 months) hypogammaglobulinemia. The combination of fludarabine and rituximab (OR 6.4, 95% CI: 1.49-27.0) and secondarily prolonged hypogammaglobulinemia (OR 4.5, 95% CI: 1.19-18.5) were found to be predictive factors for severe infections and infection-related mortality.
CONCLUSION: These data suggest the importance of following serum immunoglobulin levels before and after combination immuno-chemotherapy, particularly in patients with recurrent infections or relapsed/refractory disease.

Yamamoto W, Fujii E, Matsumoto K, et al.
Prognostic value of pretransplant serum C-reactive protein in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation.
Int J Hematol. 2016; 103(4):444-52 [PubMed] Related Publications
The impact of pre-transplant serum C-reactive protein (CRP) level on the outcome of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-SCT) is unclear. This study retrospectively investigated 78 patients who underwent RIC allo-SCT between 2005 and 2013. The conditioning regimen consisted of fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of high CRP (43.6 % of all patients) patients was significantly worse than that of normal CRP patients in whom CRP was ≤0.3 mg/dl (26.7 vs. 74.1 %, P < 0.001). Both the CRP level before transplantation and disease risk status were independent prognostic factors for overall survival by multivariate analysis. CRP was not a significant predictor of NRM by multivariate analysis (hazard ratio 3.2, 95 % confidence interval 0.8-13.1, P = 0.100). These results suggest that measuring the CRP level before transplantation can be useful to predicting the outcome of RIC allo-SCT.

Curti A, Ruggeri L, Parisi S, et al.
Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients.
Clin Cancer Res. 2016; 22(8):1914-21 [PubMed] Related Publications
PURPOSE: In acute myeloid leukemia (AML), alloreactive natural killer (NK) cells are crucial mediators of immune responses after haploidentical stem cell transplantation. Allogeneic NK cell infusions have been adoptively transferred with promising clinical results. We aimed at determining whether the composition of NK graft in terms of frequency of alloreactive NK cells influence the clinical response in a group of elderly AML patients undergoing NK immunotherapy.
EXPERIMENTAL DESIGN: Seventeen AML patients, in first complete remission (CR; median age 64 years, range 53-73) received NK cells from haploidentical KIR-ligand-mismatched donors after fludarabine/cyclophosphamide chemotherapy, followed by IL2. To correlate donor NK cell activity with clinical response, donor NK cells were assessed before and after infusion.
RESULTS: Toxicity was moderate, although 1 patient died due to bacterial pneumonia and was censored for clinical follow-up. With a median follow-up of 22.5 months (range, 6-68 months), 9 of 16 evaluable patients (0.56) are alive disease-free, whereas 7 of 16 (0.44) relapsed with a median time to relapse of 9 months (range, 3-51 months). All patients treated with molecular disease achieved molecular CR. A significantly higher number of donor alloreactive NK cell clones was observed in responders over nonresponders. The infusion of higher number of alloreactive NK cells was associated with prolonged disease-free survival (0.81 vs. 0.14, respectively;P= 0.03).
CONCLUSIONS: Infusion of purified NK cells is feasible in elderly AML patients as post-CR consolidation strategy. The clinical efficacy of adoptively transferred haploidentical NK cells may be improved by infusing high numbers of alloreactive NK cells.

Zahler S, Bhatia M, Ricci A, et al.
A Phase I Study of Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation Followed by Dose Escalation of Targeted Consolidation Immunotherapy with Gemtuzumab Ozogamicin in Children and Adolescents with CD33+ Acute Myeloid Leukemia.
Biol Blood Marrow Transplant. 2016; 22(4):698-704 [PubMed] Related Publications
Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33+ relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33+ AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m2 × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m2). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m2 per dose), 5 at dose level 2 (6 mg/m2 per dose), 3 at dose level 3 (7.5 mg/m2 per dose), and 3 at dose level 4 (9 mg/m2 per dose). Three of 14 patients received only 1 dose of GO after alloHSCT. One patient experienced grade III transaminitis, which resolved; no grade IV transaminitis, no grade III/IV hyperbilirubinemia, or sinusoidal obstructive syndrome were observed. The second dose of GO was given at median of 143 days (range, 120 to 209) after alloHSCT. Probability of grades II to IV acute and chronic graft-versus-host disease were 21% and 33.5%, respectively. Probability of overall survival after RIC alloHSCT and GO consolidation at 1 and 5 years was 78% and 61%, respectively. Probability of 5-year event-free survival after RIC alloHSCT and GO consolidation in patients in CR1 was 78%. No dose-limiting toxicities probably or directly related to GO were observed in this cohort. This preliminary data demonstrate that RIC followed by alloHSCT and consolidation with GO appears to be safe in children and adolescents with CD33+ AML in CR1/CR2. A phase II trial is currently underway investigating this approach with a GO dose of 9 mg/m2 per dose.

Shaffer BC, Le Luduec JB, Forlenza C, et al.
Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation.
Biol Blood Marrow Transplant. 2016; 22(4):705-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m2/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day -1. The median number of NK cells infused was 10.6 × 10(6)/kg (range, 4.3 to 22.4 × 10(6)/kg), and the median number of CD3 cells infused was 2.1 × 10(3)/kg (range, 1.9 to 40 × 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell infusion after allogeneic HCT.

Ikeda S, Okamoto T, Okano S, et al.
PD-L1 Is Upregulated by Simultaneous Amplification of the PD-L1 and JAK2 Genes in Non-Small Cell Lung Cancer.
J Thorac Oncol. 2016; 11(1):62-71 [PubMed] Related Publications
OBJECTIVES: The programmed death ligand 1(PD-L1)/programmed cell death protein 1 (PD-1) pathway is one of the most important checkpoint pathways for mediating tumor-induced immune suppression through T-cell exhaustion. Recently, targeted therapies using monoclonal antibodies against components of this pathway have been shown to reduce tumor burden in patients with non-small cell lung cancer (NSCLC). However, the prognostic significance of PD-L1 expression is controversial and the precise mechanisms of PD-L1 gene activation in lung cancer have yet to be clarified.
METHODS: We investigated copy number alterations (CNAs) in the PD-L1 gene by real-time PCR in 94 surgically resected lung cancer samples to find possible associations between PD-L1 CNA and lung cancer biology. Janus kinase 2 gene (JAK2) CNA and its influence on the PD-L1/PD-1 pathway were also assessed.
RESULTS: Five samples were shown to have PD-L1 gene amplification, whereas 89 samples did not. The patients with PD-L1 amplification had worse prognoses than did those without PD-L1 amplification. Genetic amplification of the PD-L1 gene was correlated with JAK2 gene amplification. The lung cancer cell line HCC4006 was found to harbor both JAK2 and PD-L1 amplification. Flow cytometry analyses revealed the level of PD-L1 protein expression to be higher in HCC4006 cells than in other NSCLC cell lines. Expression of the PD-L1 protein was significantly reduced by the JAK2 inhibitor TG-101348 and the signal transducer and activator of transcription 3 (STAT-3) inhibitor BP-1-102, but not by the STAT1 inhibitor fludarabine.
CONCLUSIONS: Our data suggest that expression of PD-L1 protein is upregulated by the simultaneous amplification of the PD-L1 and JAK2 genes through JAK-STAT signaling in NCSLC.

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